Badyal - Practical Manual of Pharmacology

Practical Manual of Pharmacology

Practical Manual of Pharmacology

Dinesh Badyal

MBBS, MD (PGI)

Associate Professor Department of Pharmacology Christian Medical College Ludhiana, Punjab India

®

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD New Delhi • Ahmedabad • Bengaluru • Chennai • Hyderabad • Kochi Kolkata • Lucknow • Mumbai • Nagpur

Published by Jitendar P Vij Jaypee Brothers Medical Publishers (P) Ltd Corporate Office 4838/24 Ansari Road, Daryaganj, New Delhi - 110002, India, Phone: +91-11-43574357 Registered Office B-3 EMCA House, 23/23B Ansari Road, Daryaganj, New Delhi - 110 002, India Phones: +91-11-23272143, +91-11-23272703, +91-11-23282021 +91-11-23245672, Rel: +91-11-32558559, Fax: +91-11-23276490, +91-11-23245683 e-mail: [email protected], Visit our website: www.jaypeebrothers.com Branches  2/B, Akruti Society, Jodhpur Gam Road Satellite Ahmedabad 380 015, Phones: +91-79-26926233, Rel: +91-79-32988717 Fax: +91-79-26927094, e-mail: [email protected]  202 Batavia Chambers, 8 Kumara Krupa Road, Kumara Park East Bengaluru 560 001, Phones: +91-80-22285971, +91-80-22382956 91-80-22372664, Rel: +91-80-32714073, Fax: +91-80-22281761 e-mail: [email protected]  282 IIIrd Floor, Khaleel Shirazi Estate, Fountain Plaza, Pantheon Road Chennai 600 008, Phones: +91-44-28193265, +91-44-28194897 Rel: +91-44-32972089, Fax: +91-44-28193231, e-mail: [email protected]  4-2-1067/1-3, 1st Floor, Balaji Building, Ramkote Cross Road, Hyderabad 500 095, Phones: +91-40-66610020, +91-40-24758498 Rel:+91-40-32940929Fax:+91-40-24758499 e-mail: [email protected]  No. 41/3098, B & B1, Kuruvi Building, St. Vincent Road Kochi 682 018, Kerala, Phones: +91-484-4036109, +91-484-2395739 +91-484-2395740 e-mail: [email protected]  1-A Indian Mirror Street, Wellington Square Kolkata 700 013, Phones: +91-33-22651926, +91-33-22276404 +91-33-22276415, Rel: +91-33-32901926, Fax: +91-33-22656075 e-mail: [email protected]  Lekhraj Market III, B-2, Sector-4, Faizabad Road, Indira Nagar Lucknow 226 016 Phones: +91-522-3040553, +91-522-3040554 e-mail: [email protected]  106 Amit Industrial Estate, 61 Dr SS Rao Road, Near MGM Hospital, Parel Mumbai 400 012, Phones: +91-22-24124863, +91-22-24104532, Rel: +91-22-32926896, Fax: +91-22-24160828 e-mail: [email protected]  “KAMALPUSHPA” 38, Reshimbag, Opp. Mohota Science College, Umred Road Nagpur 440 009 (MS), Phone: Rel: +91-712-3245220, Fax: +91-712-2704275 e-mail: [email protected] Practical Manual of Pharmacology © 2008, Jaypee Brothers Medical Publishers All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the author and the publisher. This book has been published in good faith that the material provided by author is original. Every effort is made to ensure accuracy of material, but the publisher, printer and author will not be held responsible for any inadvertent error(s). In case of any dispute, all legal matters are to be settled under Delhi jurisdiction only. First Edition: 2008 ISBN 978-81-8448-362-8 Typeset at JPBMP typesetting unit Printed at Ajanta Offset & Packagins Ltd., New Delhi

To My beloved students (who have been my teachers too) and My daughter Anvi

Preface

We are what we repeatedly do, excellence then is not an act, but becomes a habit. —Aristotle To impart skills to budding doctors practical pharmacology is an essential area of teaching. This practical manual describes what you do with your own hands which will help you throughout the life. This manual has been written keeping in view the desired shift in the pharmacology practical teaching from pharmacy based redundant experiments to more meaningful, clinically relevant problem based exercises. The topics covered in the manual have been carefully selected based on the most recent (2007) improvised problem based curriculum design for pharmacology (Appendix I). The book covers all essential components to impart the necessary required skills to students in the subject of pharmacology as per prevailing regulations in the country. The manual highlights the important skills to be imbibed by budding doctors which will aid in rational therapeutics. The manual covers all feasible exercises in pharmacology. The manual is flexible enough to suggest various modifications for various medical colleges as per availability of material for practicals. A time schedule is also included (Appendix II), which can be modified as per requirements. The exercises vary from simple demonstrations to computer simulation models. Special care is taken to keep the cost of material needed for practicals as low as possible. There are sufficient examples for students to apply the concepts learned in practicals. There are also new topics like ethics, which has become very important now after implementation of consumer protection Act to doctors. I am thankful to all my students for sharing their concern about existing pharmacology practicals and for their views on modifications in pharmacology practical training. That in a way, encouraged me to write this manual. I am thankful to Mr Tarun Duneja of M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi for expediting the publication. I hope that students and teachers would benefit from this manual. Suggestions for improvements from teachers and students are most welcome. Dinesh Badyal [email protected]

Contents

Section 1: Clinical Pharmacy 1. 2. 3. 4. 5. 6. 7.

Introduction to Clinical Pharmacy ........................................................................ 3 Weights, Measures and Abbreviations ............................................................... 7 Labeling of Drugs ....................................................................................................13 Pharmacy Preparations ..........................................................................................21 Common Dosage Forms and Routes of Administration-I .............................30 Common Dosage Forms and Routes of Administration-II ............................39 Common Dosage Forms and Routes of Administration-III ..........................54

Section 2: Experimental Pharmacology 8. 9. 10. 11. 12. 13. 14.

Introduction to Experimental Pharmacology ....................................................73 Effects of Drugs on Rabbit Eye ............................................................................75 Effect of Drugs on Frog Heart ...............................................................................80 Effect of Drugs on Rabbit Intestine ....................................................................86 Effect of Drugs on Dog Blood Pressure .............................................................90 Short Experiments for Efficacy and Safety .......................................................94 Ethics and Animals ................................................................................................. 98

Section 3: Clinical Pharmacology 15. Introduction to Clinical Pharmacology ........................................................... 103 16. Pharmacokinetic Parameters and Calculations ............................................ 104

x  Practical Manual of Pharmacology 17. Prescription Writing Through Problem Based Learning (Rational Prescribing) .......................................................................................... 112 18. Critical Evaluation of Prescription (Audit of Prescriptions) ..................... 157 19. Problem Based Drug Interactions .................................................................... 162 20. Adverse Drug Reaction (ADR) Monitoring ................................................... 178 21. Therapeutic Drug Monitoring (TDM) ............................................................. 187 22. Drug Use in Special Population/Diseases/Physiological Conditions ...... 194 23. Critical Appraisal of Drug Promotional Literature ..................................... 207 24. Therapeutic Follow-up Cases/Problems ......................................................... 215 25. New Drug Development ..................................................................................... 219 26. Calculation of Drug Doses and Dilutions ...................................................... 223 27. Evaluation of Drug Formulations ..................................................................... 232 28. Ethics and Humans .............................................................................................. 238 29. Management of Some Common Poisonings .................................................. 243 30. Objective Structured Practical Examination (OSPE) ................................... 253 Appendix I ............................................................................................................... 257 Appendix II ............................................................................................................. 259 Appendix III ............................................................................................................ 261 Appendix IV ............................................................................................................ 262 Terminologies Used in Pharmacology ............................................................... 283 Index ......................................................................................................................... 287

Section 1 Clinical Pharmacy

CHAPTER

1

Introduction to Clinical Pharmacy

Earlier, pharmacy used to be typically related to preparing and dispensing of drugs only. In those days, a doctor would himself prepare or formulate the drug in his dispensary and dispense it to his patients. This practice is now almost obsolete. These days doctor gets all the drugs in ready-made form. The pharmaceutical industry (Ranbaxy, Cipla, etc.) are now manufacturing these drugs on mass scale. The doctor’s job is to rationally prescribe and use these drugs. With this, there is now shift in pharmacy practicals. The redundant practicals comprising of preparing and dispensing can be replaced by more clinically relevant clinical pharmacy practicals. That’s why this chapter focusses on clinical pharmacy and not just pharmacy. I feel that a budding doctor needs to be trained better in recognizing various dosage forms available to be used for patients, correct way of administration of these drugs and interpretation of information on drug labels. A number of medical colleges have reduced/ deleted pharmacy preparation practicals from the course. The MCI also insists on replacing unnecessary pharmacy practicals with more relevant clinical pharmacy practicals. Some people are still continuing with pharmacy preparation practicals as they find no alternative available. However, we can generate alternatives with the available resources in the department. These alternatives can be easily arranged with no cost involved. To achieve this, total number of pharmacy practicals can be divided into 12 practical sessions assuming that there is one practical session per week, so this comes out to be initial three months of pharmacology practical course (Appendix 2). Conventional pharmacy is art of preparation, compounding and dispensing of drugs. It also includes interpretation and evaluation of prescriptions. Some hospitals have their own pharmacies. Usually it is managed by a qualified pharmacist. There can be main pharmacy and satellite pharmacies throughout the hospital. These hospitals usually follow a computerised coded system for drugs. The common source to get drugs is usually chemist shops which can be labeled as retail pharmacies. There is a difference between functioning of pharmacies in hospitals and chemist shops. The pharmacies in hospitals, these days do not manufacture/ prepare a large number of drugs. Only few preparations related with dermatological sciences are prepared. In chemist shops only ready-made drugs are available. The common functions of both is to advise proper use of drugs and other precautions to patients. At some places they also provide information to doctors, nurses and other health care providers.

4  Practical Manual of Pharmacology Instruments which are used in pharmacy are:

DISPENSING BALANCE It is meant for weighing of more than 100 mg of a substance, i.e. sensitivity is 100 mg. Left pan is made up of metal (for putting weights). Right pan is made up of glass/metal for putting substances to be weighed. Advantages of glass pan is that it is inert, non-reactive, can be easily washed and anything sticking to it can be seen. A butter paper can be used to weigh salts, salts do not stick to butter paper. This balance is sensitive for most of pharmacy work for common preparations (Fig. 1.1). It can be dismantled and packed in a small wooden box. These days electronic balances (Fig. 1.2) are available which can be conveniently used to measure even a very small quantity of drugs. The information about balance will help a doctor in clinics when you need to give a small dose to a child or when you want to divide one dose into multiple doses. Usually pharmacist/pharmacologist is approached by pediatric department to divide the dose into small multiple fractions.

WEIGHTS Students are provided with a box containing weights ranging from 1 to 100 gm. There is one additional small box containing very small weights ranging from 1 to 500 mg.

MEASURING CYLINDERS AND FLASK (FIG. 1.3) The capacity can vary from 5 to 1000 ml. They are used for measuring liquid or solution, but they are less accurate as compared to pipettes. They are safer as compared to pipettes. With pipettes there are chances of contact of liquid with oral cavity, hence manual pipettes are not recommended.

MORTAR AND PESTLE It is made up of porcelain. It is used to grind the drug to powder form and also used to mix ingredients of powders, liquid or semiliquid, ointments, mixtures, suspensions, etc. These days glass mortar and pestle are available (Fig. 1.4). An advantage is that less drug sticks to glass and they are easy to clean.

Fig. 1.1: Dispensing balance and weights

Introduction to Clinical Pharmacy  5

Fig. 1.2: Electronic Balance

Fig. 1.3: Measuring cylinder and flask

Fig. 1.4: Mortar and Pestle

CONTAINERS (FIG. 1.5) Prescription bottle is used for liquids of low viscosity like mixtures, suspensions and solutions. It is made up of glass or plastic. Wide mouth bottle is used for solutions of high viscosity like ointment, etc. Amber coloured bottle prevents degradation of solution inside by absorption of UV rays, e.g. calamine lotion.

SPATULAS They are used to mix various chemicals, e.g. powders or ointments. They are formed of plastic or metal (Fig. 1.6).

PILL TILE It is used to mix the powders or ointments.

WASH BOTTLE It contains tap or demineralised water.

Fig. 1.5: Dispensing bottle

Fig. 1.6: Spatula

6  Practical Manual of Pharmacology PHARMACEUTICAL CONTAINERS The basic requirement for a container is that it should not interact with the formulation. Glass, plastics are commonly used components of containers. Glass containers have some disadvantages, e.g. leaching of alkali and insoluble flakes into the formulation. These can be offset by the choice of an appropriate glass material, e.g. phenytoin has the ability to (in dilute solution) to react with glass. When added to glass infusion bottles much of the drug remains stuck to the glass and does not reach the patient. Plastic containers are convenient to handle but the major disadvantage is the two-way permeation or ‘breathing’ through the container walls. Volatile oils, perfumes and flavouring agents can permeate through plastics to some extent. Components of emulsions and creams have been reported to migrate through the walls of some plastics causing either a deleterious change in the formulation or collapse of the container. Loss of moisture from a formulation is also common, e.g. paraldehyde (a hypnotic) is one example. This liquid dissolves plastic so it must be injected parenterally using glass syringe. Closure must form an effective seal for the container. It must not react chemically or physically with the formulation. Rubber is a common component of stoppers, cap liners, and parts of dropper assemblies. Absorption of the active ingredients, preservatives into the rubber and the extraction of one or more components of rubber into the formulation is a common problem. The application of an epoxy lining to the rubber closure reduces the amount of leached extractives but has no effect on the absorption of the preservative from the solution. Tefloncoated rubber stoppers may prevent most of the leaching and absorption.

OBJECTIVES At the end of this session a student shall be able to: 1. Identify various instruments used in pharmacy. 2. Describe uses of instruments used in pharmacy.

CHAPTER

2

Weights, Measures and Abbreviations

These are important to know dose and other details about administration of drugs. The drugs and solutions can be measured by using various units. Metric or decimal system of measure is usually used to measure due to two advantages: i. Its tables are simple as they are based on decimal system of notation ii. Its tables of length, volume and weight are conveniently correlated.

METRIC SYSTEM In metric system: • Base for weight is kilogram (kg) • Base for volume is litre (l) Measures of weight (mass) in metric system 1 1 1 1 1 1

kilogram (kg) gram milligram (10-3 g) microgram (10-6 g) nanogram (10-9 g) picogram (10-12 g)

= = = = = =

1000 grams (G or g) 1000 milligrams (mg) 1000 micrograms (μg or mcg) 1000 nanograms (ng) 1000 picograms (pg) 1000 femtograms (fg)

Measures of capacity (volume) in metric system 1 liter (L) 1 ml

= =

1000 milliliters (ml) 1000 μl

Another less commonly used system is imperial system. It can be: a. Avoirdupois system Standard for weight = pounds (lb) 1 lb = 7000 grains 1 lb = 16 ounce (oz)

8  Practical Manual of Pharmacology b. Apothecary system (UK)/Troy system Standard for weight is grains 1 oz = 480 grains 1 lb = 12 oz Measure for volume in both these system is Gallon 1 gallon (C. or gal.) = 4 quarts = 8 pints 1 quart (qt.) = 2 pints = 32 fluid ounces 1 pint (pt.) = 16 fluid ounces (fl. oz. or )

CONVERSION BETWEEN SYSTEMS Weight

2.2 pounds = 1 kilogram (kg.) 1 grain (gr.) = 60 milligrams (mg.) Fluid Measure 1 fluid ounce (fl. oz.) = 30 milliliters 1 pint = 473 milliliters There are also domestic measures to measure: Domestic weights and measures Domestic measures 1 drop 1 teaspoonful 1 dessertspoonful 1 tablespoonful 1 glassful 1 tumblerful

= = = = = =

Metric equivalent 1/20 ml, 1 ml = 20 drops (approx.) 5 ml 10 ml 15 ml 150 ml 240 ml

PHARMACEUTICAL CALCULATIONS 1. Percent Calculation The word percentage can have different meanings under different circumstances. In solution, we are dealing with solids that are weighed and liquids that can be weighed or measured. There are three different percentage solutions. a. Percentage weight in weight (w/w)—expresses the number of grams of solute in 100 ml of solution. b. Percentage weight in volume (w/v)—expresses the number of grams of solute in 100 ml of solution, regardless of whether water or another liquid is used as the solvent. c. Percentage volume in volume (v/v)—expresses the number of milliliters of solute in 100 ml of solution. a. Percent weight in volume (%w/v) It is a solution of solid in liquid and represents number of solutes per 100 ml of solution.

Weights, Measures and Abbreviations  9 1% w/v is 1 g of solute in a total of 100 ml of solution. 1% w/v means 1 part by weight, whereas the solvent is added upto 100 parts. 1% = 10 mg/ml e.g. To calculate the quantity of CaCl2 required for 200 ml preparation of 1% solution in distilled water 1% means 1 g/100 ml for 100 ml volume, CaCl2 = 1 g For 200 ml CaCl2 = 1/100 × 200 = 2 g b. Percent by weight (%w/w) It represents number of grams of solute per 100 gm of solution. 1% w/w is 1 g of solute in 100 g solution. Add solid 1 part by wt and then add upto 100 parts, ensuring uniform mixing (Highly viscous substances like glycerin are considered solids and are measured in grams) e.g. To prepare 25 g of 10% of a drug 10% means 10 g/100 g of the preparation if 100 g has drug = 10 g 25 g of preparation will have drug = 10/100 × 25 = 2.5 g c. Percent by volume (%v/v) It is a preparation of a liquid in liquid and represents number of millilitres of solute per 100 ml of solution. 1% v/v is 1 ml of a liquid constituent in 100 ml of solution, e.g. To make 2% v/v, to 2 part of volume of the constituent add upto 100 parts by volume. 2. Proportion Calculation Involves mixing of 2 similar preparations of different strength to produce a preparation of intermediate strength. Proportions are equations containing ratios of equal value. For example 3:4 = 6:8. This may also be written as fractions, 3/4 = 6/8. (see chapter 27 for more). 3. Others i. Units Potency of certain drugs like heparin, insulin either cannot be determined by chemical or physical methods or these methods are very costly. The measurement of these drugs is expressed in units. The unit is based on the effect/ amount of effect produced by a particular amount of drug in biological systems, i.e. isolated tissues of animals or whole animals, e.g. 40 units of insulin. ii. Molality: It is the number of moles of solute in 1000 grams of solvent. iii. Normality: It is the number of gram equivalents of solute dissolved in 1000 ml of solution.

10  Practical Manual of Pharmacology ABBREVIATIONS USED IN PRESCRIPTIONS A prescription should be written in simple and/or in regional language without using abbreviations, however, certain abbreviations are still in use as under: A. Time of Drug Administration Phrase Abbreviation ante cibum ac post cibum pc hora somni hs opus in die od bis bis bis in die bid ter in die tid ter die sumendum tds quarter in die qid quaque q quarta quake qqh omni mane om omni nocte on si opus sit sos statim stat ad libitum Ad lib omni die od repetatur Rep

Meaning before meals after meals at bedtime once a day twice twice daily three times a day three times a day four times a day every 6 hour every 4 hour every morning every night when required immediately freely, use as much as one desires every day let it be repeated

B. Formulations Phrase capsula tabella liquor mistula injectio ampoule syrupus gutta nebula

Meaning capsule tablet solution mixture an injection an ampoule syrup drops spray

Abbreviation cap tab liq mist inj amp syr gtt nebul

Weights, Measures and Abbreviations  11 C. Routes of Drug Administration Phrase Abbreviation intramuscular IM intravenous IV subcutaneous sc per os po per vaginam PV bolus bol

Meaning by Intramuscular injection by Intravenous injection by subcutaneous injection by mouth by vaginal route as a large single dose (usually IV)

D. Others Phrase Ad aqua receipe signa aurio dextra aurio laeve auris utrae oculus dexter oculus sinister oculus uterque ex modo prescripto misce dispensa signa tablespoon teaspoon

Meaning to, up to water (you) take you write right ear left ear both ears right eye left eye both eyes as directed mix Dispense you write tablespoon teaspoon

Abbreviation Ad aq R sig ad al au od os ou emp M Disp. sig tbsp tsp

OBJECTIVES At 1. 2. 3.

the end of this session a student shall be able to: Understand meaning of all abbreviations used in Pharmacology. Convert various measurements given. Understand percent and proportion calculations.

12  Practical Manual of Pharmacology Exercise in examination based on these practical can be: 1. Expand the following: a. Cap. Rifampicin 600 mg od ac

b. Tab. diazepam 5 mg hs

c. Syr. Amoxycillin 5 ml tid po

d. Tab. FeSO4 200 mg 2 bd pc

e. Tab. PCM 500 mg sos

f. Inj. Ampicillin 0.5 g IM qid

2. What do you understand by: a. 1% NaCl solution

b. 15% tannic acid glycerin

c. 5% lignocaine ointment

C H A P T E R

3

Labeling of Drugs

If you pick up a strip of any medicine, you will find a lot of information on it, regarding drug name, manufacturer, expiry date, etc. as shown below in Figure 3.1.

Fig. 3.1: Labels on premanufactured medicines

Let us discuss in detail what various components of these labels are.

COMMERCIAL PREPARATIONS Label of the given dosage form consists of Name and quantity of the drug Pharmacopeias used for preparation

14  Practical Manual of Pharmacology Batch No Manufacturing and expiry date Manufacturing license number Maximum retail price (MRP) Schedule of the drugs, i.e. H, L, P, X, etc. Instructions about use of drugs Address of the pharmaceutical company To explain these terms let us discuss some general points:

A. DRUGS ARE CLASSIFIED INTO VARIOUS CATEGORIES 1. Prescription-only Drugs: These drugs are dispensed by pharmacist only when you have a prescription from a registered medical practitioner (RMP), e.g. diazepam, morphine and antimicrobials. Prescription is a written order from physician for pharmacist. Registered medical practitioner is a doctor registered with regional or central medical council. An allopathic RMP can not prescribe drugs from homeopathic stream and vice versa, e.g. an allopathic doctor can not prescribe Liv 52. These drugs are covered under Schedule 'H' in India (Fig. 3.2). These drugs are considered to be unsafe for general use, except under medical supervision. They are dispensed only on physician's prescriptions. 2. Over-the counter (OTC) drugs: These are non prescription drugs, i.e. these can be purchased from pharmacies or chemist shops without a Fig. 3.2: Schedule H warning prescription. These drugs are considered safe and medical supervision is not required; e.g. Paracetamol. The drugs which are mainly used as OTC drugs are: • H2-antihistamines • NSAIDs • Oral contraceptives • Hydrocortisone cream • Nicotine-cessation of smoking OTC drugs may lead to adverse drug reactions (ADRs) because of: • Incorrect self-diagnosis and choice of incorrect therapy • Incorrect route of administration • Excessively prolonged use • Risk of dependence and abuse • Food and drug interactions • Storage in incorrect conditions

Labeling of Drugs  15 • Failure to recognise o Contraindications o Interactions o Warnings o Precautions So to avoid these, whenever you use an over-the-counter (OTC) medicine, reading the drug label is important for taking care of yourself and your family. This is especially true because you probably take OTC medicines without first seeing a doctor. The label tells you what a medicine is supposed to do, who should or shouldn't take it, and how to use it. The OTC medicine labels have always contained usage and safety information for consumers, but now the information will be more uniform and easier to read and understand (Fig. 3.3). All nonprescription, over-the-counter (OTC) medicine labels have detailed usage and warning information so consumers can properly choose and use the products. You'll find this information: • Active Ingredient: Therapeutic substance in product; amount of active ingredient per unit. • Uses: Symptoms or diseases the product will treat or prevent. • Warnings: When not to use the product; conditions that may require advice from a doctor before taking the product; possible interactions or side effects; when to stop taking the product and when to contact a doctor; if you are pregnant or breastfeeding, seek guidance from a health care professional; keep product out of children's reach. Fig. 3.3: Labeling of OTC medicine • Inactive Ingredients: Substances such as colors or flavors. • Purpose: Product action or category such as antihistamine, antacid, or cough suppressant.

16  Practical Manual of Pharmacology • Directions: Specific age categories, how to take, how much, how often, and how long. • Other Information. How to store the product properly, and required information about certain ingredients such as the amount of calcium, potassium, or sodium the product contains. • The expiry date, when applicable (date after which you should not use the product). • Lot or batch code (manufacturer information to help identify the product). • Name and address of manufacturer, packer or distributor. • Net quantity of contents (how much of the product is in each package). • What to do if an overdose occurs.

B. DRUG NOMENCLATURE You will frequently find existence of multiple names for a single drug. These names are: 1. Chemical name: It indicates full name according to chemical constituents. It is lengthy, complicated and not commonly used, e.g. 4-[2-Hydroxy-3-[(1-methyl ethyl) amino] propoxy] benzene acetamide for atenolol. 2. Non proprietary name/Generic name/Approved name: Name in official books which is accepted worldwide, e.g. aspirin. It allows identification of different products with the same ingredient to be identified, although there are few exceptions, e.g. adrenaline in India is known and epinephrine in United States of America. Drugs if prescribed by generic name are cheaper as promotional expenditure is avoided, but quality control is difficult for generic drugs. 3. Proprietary name/Trade name/Brand name: Names given by innovative manufacturing company, e.g. Crocin for paracetamol. Patent protection enables innovative pharmaceuticals to market the drug exclusively till the patent expires. After that the same drug is available under various brand names, e.g. paracetamol brand names are crocin, acemol, bepamol, calpol and dolopar. Brand names are popular names of the drug and are easy to remember, but so many brand names for a single drug can create confusion in prescribing. Brand names are expensive also as advertisement cost is added. The drugs can have strikingly similar names leading to prescription errors or medication errors. To overcome these WHO has initiated a programme on selection of International non-proprietary names (INN) for assigning a unique, globally accepted and recognized name.

C. PHARMACOPOEIA Name is usually followed by the reference according to which drug was prepared, e.g. IP means Indian pharmacopoeia. Pharmacopoeia is a class of DRUG COMPENDIA (official books of summarized information sources). The term pharmacopoeia is derived from two Greek words—Pharmakon (means drug) and poiein (means make). Pharmacopoeia contains formula or other standards required for preparation and testing of drugs to ensure uniform purity and potency. The description of preparation given in pharmacopoeia is known as

Labeling of Drugs  17 monograph. These monographs describes drug, characteristics for identification, standards of purity and strength limits of impurities, assay method of drugs, storage and instructions. Drug and the information mentioned in pharmacopoeia are official. It also includes official range of dosage for drugs, system of weights, measures and the formulations and the methods used for sterilization of pharmaceutical products. Most of the countries have their own pharmacopoeia. Other source for this type of information is National Formulary. These are the books of standards for drugs and devises. These are compilations of those drugs, which have been recognized as legal standards of purity, quality and strength by government agency of that country. Official reference books of India: Indian Pharmacopoeia (IP) National Formulary of India (NFI) Chemical and Medical Formulary of India Drug Bulletins International official books: British Pharmacopoeia (BP) British Pharmaceutical Codex (BPC) United States Pharmacopoeia (USP) International Pharmacopoeia (By WHO for those countries who do not have their own pharmacopoeia) Others: British National Formulary Martin Dale's Extra Pharmacopoeia Physician's Desk Reference

D. THESE DAYS YOU MAY FIND A DRUG NAME CARRYING A POST SUFFIX. These are: D-dispersible, e.g. Doxycycline-D CR-controlled release, e.g. Indomethacin-CR SR-sustained release, e.g. Diclofenac-SR

E. DRUGS SCHEDULES AND ACTS Sometimes you will find drug names followed by a boxed warning, e.g. Schedule H drug. These are based on drugs schedules and acts. There are various drug schedules and acts in India. The important ones are as per Drugs and Cosmetics Act (1940) as amended in 2001 are:

18  Practical Manual of Pharmacology DRUG SCHEDULES Schedule A: gives specimen of prescribed form. Schedule B: gives fees for test and analysis of drugs. Schedule C: gives details with biological and other special products. Schedule D: is concerned with exemption regarding drug import. Schedule FF: gives details of standard ophthalmic solutions. Schedule G: deals with details of drugs to be labeled 'CAUTION-it is dangerous to take this medicine except under medical supervision'. Schedule H: deals with drugs and medicine to be sold on prescription-only. Schedule I: lists all ailments for which no cure can be claimed, e.g. AIDS. Schedule Q: deals with cosmetics. Schedule R: deals with standards for contraceptives. Schedule W: gives details of drugs which should be marketed under generic name only. Schedule X: deals with psychotropic drugs which require special license for manufacturing and sale. Schedule Y (new addition): specifies the requirements and guidelines on conduct of clinical trials, import and manufacturing of new drugs.

FDA (USA) SCHEDULES ARE: Schedule I (C-I) • High abuse potential • No accepted medical use in the United States • Examples: heroin, marijuana, LSD (lysergic acid diethylamide), peyote Schedule II (C-II) • Potential for high abuse with severe physical or psychological • dependence • Examples: narcotics such as meperidine, methadone, morphine, oxycodone, amphetamines and barbiturates Schedule III (C-III) • Less abuse potential than schedule II drugs • Potential for moderate physical or psychological dependence • Examples: nonbarbiturate sedatives, nonamphetamine stimulants, limited amounts of certain narcotics Schedule IV (C-IV) • Less abuse potential than schedule III drugs • Limited dependence potential • Examples: some sedatives and anxiety agents, nonnarcotic analgesics

Labeling of Drugs  19 Schedule V (C-V)* • Limited abuse potential Examples: small amounts Drugs which are prepared and dispensed by pharmacist usually have different label than the ones prepared by pharmaceutical industry. The label is divided into two: 1. Primary Label 2. Secondary Label

PRIMARY LABEL It is the main label used on pharmacy preparations. It should be proportional to the size of container and it usually should occupy middle 1/3rd of the container. It should cover less. This label should have following information: Title of preparation, e.g. The Powder Name : Age/Sex : Reg. No. : Directions : Date/Signature Registration no. Directions/instructions to patients for proper use of drug. Name of the pharmacy laboratory from which the drugs have been dispensed.

SECONDARY LABEL As obvious from the name, it is the other label than the primary label. It is smaller in size and is usually put above the primary label with a small gap in between. This label usually contains some important precautions about the use of drug in capital letters, for example: Shake Bottle Well Before Use The number of secondary labels may be more than one.

OBJECTIVES At 1. 2. 3.

the end of this session a student shall be able to: Understand all information written on label of drugs. Understand primary and secondary labels. Knows drug nomenclature.

20  Practical Manual of Pharmacology Exercise in examination bases on these practical can be: 1. Enumerate all the information written on the label of drugs: A strip of tablets A container of liquid An ampoule A vial 2. What do you understand by the following terms? Mention the clinical importance of each of them. a. Manufacturing Date

b. Expiry Date

c. Batch Number

d. MRP

e. Schedule H

CHAPTER

4

Pharmacy Preparations

To give an idea to students about how drugs are prepared in pharmacy, a few pharmacy preparations practicals can be demonstrated in two session. Exercise 1: To prepare and dispense 50 ml of Calamine lotion Formula: Calamine Zinc oxide Bentonite Liquefied phenol Sodium citrate Glycerine Purified water ad

For 100 ml 15 gm 5 gm 63 gm 0.5 ml 5 gm 5 ml 100 ml

PROCEDURE • Weigh out the calculated quantities of calamine, zinc oxide and bentonite. Mix them thoroughly in a mortar. • Take 20 ml of purified water in graduated flask and add the required quantity of sodium citrate. • Pour a little of water from flask into mortar containing calamine, bentonite and zinc oxide. Triturate to make homogenous paste. Add required amount of glycerin and phenol to this mortar and triturate. • Transfer the mixture to the flask. Rinse the mortar with a little quantity of purified water and transfer this rinsing into the flask. Add sufficient quantity of water to make up the final volume 50 ml. Transfer it to an amber coloured bottle, label and dispense.

HOW TO APPLY • Wash and completely dry the affected area before applying the lotion. Shake lotion well before use.

22  Practical Manual of Pharmacology • Apply this medication to the affected area of skin, generally three to four times daily or as directed by your physician. • Do not dilute or mix with other lotions.

LABELING FOR EXTERNAL USE ONLY SHAKE WELL BEFORE USE Name Rajesh Singh Age/Sex 35 M Address 145, BRS Nagar, Ludhiana Directions: Apply on the affected part with cotton swab. Do not rub. Sign and Regd No. of 24-05-2007 Pharmacist Pharmacy, ABC Delhi

Secondary Labels

←

Primary Label

←

PHARMACOLOGICAL ACTIONS Calamine: Calamine is a mixture of zinc oxide (ZnO) with about 0.5% iron (III) oxide (Fe2O3). It is the main ingredient in calamine lotion and is used as an antipruritic to treat sunburn, eczema, rashes, poison ivy, chickenpox, insect bites and stings. It is used as a mild antiseptic to prevent infections that can be caused by scratching the affected area. It is also used to dry weeping or oozing blisters and acne abscesses. It is also used as colouring agent in various cosmetics. Zinc oxide: It is insoluble in water, used as dusting powder, ointment, lotion and paste. It has soothing and protective action in eczema. It is also used as mild astringent for skin. Bentonite: It is colloidal aluminum silicate insoluble in water but swells into a homogenous mass. It is used as suspending agent because it increases the viscosity of the vehicle. It is also used as a bulk laxative. It should be sterilised before using on open wounds. Sodium citrate: It helps in the dispersion of solids in this preparation and reduces the viscosity of this preparation. Liquefied phenol: It has an antiseptic and mild local anesthetic effect. However, in the amount used, it acts as a preservative in this preparation. It is particularly required as glycerin promotes the growth of microorganisms. Glycerine: When applied locally it acts as an emollient and helps in penetration of ingredients by making the skin moist and soft. Due to its viscous nature, the lotion stays for a longer time at the site of application. It is hygroscopic in nature, so prevents drying up and cracking of skin and the lesions.

Pharmacy Preparations  23 THERAPEUTIC USES 1. 2. 3. 4. 5.

In pruritis: used as soothing and protective lotion. To allay pain and swelling of sun burns. For prickly heat Any other irritating skin condition It is also used in herpes zoster and chickenpox.

PRECAUTIONS • Avoid contact with the eyes, on the inside of your nose, mouth or genital area • Contraindicated if known sensitivity or allergy to any ingredient • Ask a doctor before using calamine lotion on children younger than 6 months of age. Exercise 2: To prepare and dispense 25 ml of Mandle's throat paint Formula for 100 ml: Iodine Potassium iodide Mentha oil Water Alcohol 90% Glycerine upto

For 100 ml 1.24 gm 2.48 gm 0.40 ml 2.48 ml 3.76 ml 100 ml

PROCEDURE • Weigh out the required amount of iodine and potassium iodide and transfer to a glass jar. 10 drops of water and 5 ml of glycerin. Stir the contents. When contents are completely dissolved, add required amount of Mentha oil and dissolve it. • Transfer the contents into a measuring cylinder and add glycerin to make volume upto 25 ml. Transfer contents into amber colored bottle, label and dispense.

LABELING FOR EXTERNAL USE ONLY Name Rajesh Singh Age/Sex 35 M Address 145, BRS Nagar, Ludhiana Directions: Apply on the affected part with cotton swab. 3 times a day. Sign and Regd No. of 24-05-2008 Pharmacist Pharmacy, ABC Delhi

←

Secondary Label

←Primary Label

24  Practical Manual of Pharmacology PHARMACOLOGICAL ACTIONS Iodine: It is nonmetallic component. It acts locally and has antiseptic properties. It is an oxidising agent and acts as bactericidal. Potassium iodide: It is used to dissolve iodine as iodine is highly soluble in aqueous solution. Water acts as solvent for potassium iodide. Mentha oil acts as flavouring agent and is volatile. Alcohol is used to dissolve mentha oil and glycerin. It also acts as preservative, antiseptic and astringent. Glycerine helps iodine to stick to affected area for longer period. It also has antiseptic action and reduces edema.

THERAPEUTIC USES 1. Tonsillitis 2. Pharyngitis

PRECAUTIONS Do not take food/water half an hour before and after the application of the paint. Exercise 3: To prepare and dispense 1:5000 solution of Potassium Permanganate with directions to dilute it to 1:15000 before use.

Calculations Prepare 1% stock solution 1% stock solution is 1 gm in 100 ml or 1000 mg in 100 ml or 100 mg in 10 ml or 100 mg in 1 ml For 1:5000 solution of KMnO4 we need: 1g in 5000 thousand ml or 1000 mg in 5000 ml or 10 mg in 50 ml Procedure 1. Measure accurately 100 mg of KMnO4 crystals. Dissolve it in 10 ml of distilled water (1% stock solution). Stir with a glass rod to mix potassium permanganate solution. 2. Take 1 ml of solution and add 49 ml of water to make volume 50 ml. This is 1:5000 solution. 3. Label and dispense it in an amber coloured bottle to privet oxidation.

Pharmacy Preparations  25 LABELING FOR EXTERNAL USE ONLY Name Rajesh Singh Age/Sex 35 M Address 145, BRS Nagar, Ludhiana Directions: Dilute the solution before use by mixing 1 part of solution with 2 parts of water. Use it for gargles and mouth washes 3-4 times in a day. Sign and Regd No. of 24-05-2009 Pharmacist Pharmacy, ABC Delhi

← Secondary Label

←Primary Label

STORAGE CONDITIONS It should be stored in a tightly corked container in a cool dark place away from the sunlight.

PHARMACOLOGICAL ACTIONS Potassium permanganate has bactericidal and fungicidal activity. Potassium permanganate, on contact with organic matter, liberates nascent oxygen that oxidizes enzymes essential for living microorganisms and their metabolism, thus producing antiseptic effects. It also acts as astringent. It is readily soluble in water.

THERAPEUTIC USES The 1. 2. 3.

major uses of this preparation are: As disinfectant for water and utensils-1 in 100 solution. As a cleansing application to ulcers and abscesses-1 in 1,000 solution. As mouthwash (in gingivitis and steatites), gargles (Condyl's gargles), for washing wounds and for vaginal irrigation-1 in 4,000 solution. 4. Sitz's baths given in hemorrhoids, piles and fissures. 5. As gastric lavage in the treatment of morphine, opium, strychnine, aconitine and other alkaloid poisonings (but not for cocaine and atropine because they are not easily oxidised by potassium permanganate)-1 in 5,000 solution is employed as applications for weeping skin lesions and for urethral irrigation-1 in 5,000 and 1 in 10,000 solutions. 6. Treatment of snake bite (effective only if the venom is on the skin). It oxidize venom (within 1-2 minutes of bite).

26  Practical Manual of Pharmacology ADVERSE EFFECTS • The crystals and concentrated solutions of KMnO4 are caustic and can cause corrosive burns. • Higher concentration can cause skin irritation, edema and mucous membrane turns brown. • There can be staining of clothes • Do not disinfect surgical instruments, rusting can happen. Exercise 4: To prepare and dispense one dose of oral rehydration powder for 1000 ml of oral rehydration solution (ORS) ORS is a simple, cheap and effective treatment for diarrhea-related dehydration, e.g. cholera or rotavirus. It consists of a solution of salts and other substances such as glucose, sucrose, citrates or molasses, which is administered orally. It is used around the world, but is most important in the Third World, where it saves millions of children from diarrhea, still their leading cause of death.

WHO FORMULA (FOR 1 LITRE ORS) Sodium chloride Sodium citrate Potassium chloride Glucose anhydrous

3.5 2.9 1.5 20.0

gm gm gm gm

OBJECTIVE OF ORS • To prevent dehydration • To reduce mortality.

PROCEDURE • Weigh the required quantities of sodium chloride, sodium citrate, potassium chloride and glucose. • Mix them on a paper placed over pill tile by using powder spatula. • Put the powder in a packet (Fig. 4.1). • Label the packet and dispense.

Fig. 4.1: Folding of packet for powder

Pharmacy Preparations  27

Name Akash Age/Sex 20 M Address 132, BRS Nagar, Ludhiana Directions: Dissolve the contents of powder in 1000 ml of freshy boiled and cooled water and take frequent sips. Sign and Regd No. of 24-05-2007 Pharmacist Pharmacy, ABC Ludhiana The frequency of sips will depend on level of dehydration.

PHARMACOLOGICAL ACTIONS In diarrhea loss of water and electrolytes leads to dehydration. Hence, both water and electrolytes are given for treatment of dehydration. If water alone is given it will dilute the salts present in body and aggravates the condition. WHO ORS (for 1 litre) provides following salts as mEq/L: Na+ 90.0 K+ 20.0 HCO3– 30.0 Glucose 111.0 Cl-80.0 Osmolarity of 311 mOsm/l 215 calories

PHARMACOLOGICAL ACTION OF SALTS Sodium chloride As you know, sodium is the main ion involved in various processes in the body, e.g. action potential generation. It helps to maintain muscle tone. Symptoms associated with hyponatremia are fatigue, muscle weakness, abdominal cramps, confusion, hypotension, weak pulse, cyanosis, oliguria, tachycardia, loss of skin elasticity and dryness of mucous membranes. Glucose Glucose is the source of energy. Apart from that it helps in absorption of sodium. Molar ratio of glucose is more than sodium in ORS. Sodium is absorbed through facilitated diffusion or cotransport with the help of glucose. Other contents provide sufficient amount of potassium, chloride and bicarbonate lost in diarrhea. Sodium citrate is the source of HCO3– and also provides stability to the solution. Potassium chloride influences the muscle action and ameliorates the cramps. Chloride helps to maintain the fluid balance and production of gastric acid.

28  Practical Manual of Pharmacology THERAPEUTIC USES 1. Diarrhoea Oral rehydration therapy is widely considered to be the best method for combating the dehydration caused by diarrhea and/or vomiting. Rehydration does not stop diarrhea, but keeps the body hydrated and healthy until the diarrhea passes. ORS is recommended in mild to moderate cases of diarrhea. Intravenous fluids are required in severe cases of dehydration. The amount of rehydration that is needed depends on the size of the individual and the degree of dehydration. Rehydration is generally adequate when the person no longer feels thirsty and has a normal urine output. A rough guide to the amount of ORS solution needed in the first 4-6 hours of treatment for a mildly dehydrated person is: • Up to 5 kg (11 lb): 200-400 ml • 5-10 kg (11-22 lb): 400-600 ml • 10-15 kg (22-33 lb): 600-800 ml • 15-20 kg (33-44 lb): 800-1000 ml • 20-30 kg (44-66 lb): 1000-1500 ml • 30-40 kg (66-88 lb): 1500-2000 ml • 40 plus kg (88 lb): 2000-4000 ml The degree of dehydration can be assessed by following parameters: — Pulse in dehydration has low volume and is thready. — No tears, dry mouth in case of moderate to severe dehydration. — Urine output is decreased in dehydration. 2. Heat stroke. 3. In patients of burns/surgery to maintain hydration. 4. Change from parenetral to enteral therapy. 5. High grade fever.

HOME MADE ORS In a glassful of water, add I teaspoonful of sugar and a pinch of salt. You can also add half a lemon. Rice water and dal water can also be used. or An inexpensive home-made solution consists of 8 level teaspoons of sugar and 1 level teaspoon of table salt mixed in 1 liter of water. A half cup of orange juice or half of a mashed banana can be added to each liter both to add potassium and to improve taste.

SUPER-ORS In this amino acids are added, e.g. alanine and glycine.

Pharmacy Preparations  29 NEW WHO ORS Because of the improved effectiveness of reduced osmolarity ORS solution, especially for children with acute, non-cholera diarrhoea, WHO and UNICEF now recommend that countries use and manufacture the following formulation in place of the previously recommended ORS solution.

REDUCED OSMOLARITY ORS Ingredient (grams/litre) ion (mmol/litre) Sodium chloride (2.6) Sodium (75) Glucose, anhydrous (13.5) Glucose, anhydrous (75) Potassium chloride (1.5) Chloride (65)/Potassium (20) Trisodium citrate, dihydrate (2.9) Citrate (10) Total Osmolarity = 245. In the human body, the plasma osmolality is about 285 mOsm/l.

PRECAUTIONS • Hot water should not be used as it may lead to breakdown of bicarbonate and alteration in flavor • Do not use if the solution is coloured. • Always use freshly prepared solution. • The solution made should not be used 24 hours after its preparation. • Use clean utensils to make solution. Today, the total production is around 500 million ORS sachets per year, with the children's rights agency UNICEF distributing them to children in around 60 developing countries. ORS represents a cheap and effective way of reducing the millions of deaths caused each year by diarrhea.

OBJECTIVES At the end of this session a student shall be able to: 1. Understand how preparations are made in hospital pharmacy. 2. Various parts of a label on hospital pharmacy preparations.

CHAPTER

5

Common Dosage Forms and Routes of Administration-I

Various dosage forms of drugs are used in therapy. Before discussing dosage forms let's see what are the various sources of drugs.

SOURCES OF DRUGS Plants: One third of allopathic drugs are still derived from plants. Problem associated with a plant drug are: identification of plant, conditions of storage, standardization of active principle, purity and maintenance of supply line, e.g. morphine, codeine Animals: Some drugs are still obtained from animals due to expensive and cumbersome synthesis, e.g. gonadotropins, heparin Microorganisms: Antimicrobials are obtained, e.g. penicillin, erythromycin Minerals: Some minerals are important for body and given prophylactically or for treatment of deficiency, e.g. Zinc Synthetic: Most of the drugs in use today are synthetic in origin. These drugs are chemically pour and it is easy to maintain their supply, e.g. oral antidiabetics Semisynthetic: Changes are made after synthesis, e.g. insulin Biosynthetic: Recombinant technology is used to produce drugs, e.g. recombinant insulin Drugs need to be presented in a form that can be administered to an organism. Formulation is a recipe by which a drug is prepared. Drug formulation can allow specific tissue sites to be selectively targeted or systemic absorption of the drug to be avoided. Formulation is not only about a small amount of a drug that needs to be encapsulated or bottled for easy delivery but it is also about how to present a drug for administration so that it is guaranteed to reach the target area. The administration of drugs is one of the most important and exacting duties performed in caring for sick and injured patients. The appropriate drug given in the correct dosage will very often hasten a patient's recovery. On the other hand, an inappropriate drug or dosage may worsen a patient's condition or even result in his death.

Common Dosage Forms and Routes of Administration-I  31 To discuss formulation we will discuss route of administration of drugs, dosage forms used and their advantages and disadvantages. Various routes of drug administration are: A. For systemic effects 1. Enterable-oral, sublingual, etc. 2. Parenteral (which bypasses GIT)-i.v, i.m. etc. B. For local effects 3. Local, e.g. topical application C. Special preparations, e.g. controlled release Remember that there are six "rights" in the administration of drugs: 1. Right patient 2. Right drug 3. Right dose 4. Right route 5. Right time 6. Right documentation

ORAL The drug is given through mouth. It is the commonest and most acceptable method of drug administration.

ADVANTAGES 1. 2. 3. 4.

Most convenient and cheapest Non-invasive, painless and no assistance is required. Aseptic precautions are not required. Both, solid and liquid dosage forms can be given • Solid preparations are: tablets, capsules, moulded tablets, powders, spansules, etc. • Liquid preparations are: syrups, mixtures, elixirs, emulsions, etc.

ORAL-TABLETS A tablet is a disc, containing one or more medications, prepared by compressing a granulated powder (Fig. 5.1). As most drugs are presented in small quantities (sometimes less than a milligram), other materials (excipients) must be added to make them easy to handle, to be seen and to compress. Tablets must have property to disintegrate in the gastrointestinal tract.

Fig. 5.1: Tablets

32  Practical Manual of Pharmacology Capsules and tablets should be swallowed with a glass of water with the patient in upright posture either sitting or standing, as this enhances the passage into the stomach and permits rapid dissolution. Giving drugs orally to a recumbent patient should be avoided if possible, especially in the case of drugs which can damage the esophageal mucosa, e.g. doxycyline, iron salts, etc. Oesophagitis induced by these drugs is very difficult to treat. Tablets may be scored i.e. a line demarcation is there to divide tablet into two equal parts (Fig. 5.2).

DISADVANTAGES 1. 2. 3. 4. 5. 6.

Action is slow so it is not suitable for emergency Unpalatable drugs (e.g. paraldehyde) are difficult to administer It may cause gastrointestinal adverse effects e.g. nausea and vomiting (e.g. emetine) It can not be used for non cooperative/unconscious/vomiting patients Certain drugs are not absorbed if given by this route (e.g. streptomycin) Certain drugs are destroyed by gastric juices (penicillin G, insulin) or extensively metabolized during first pass in the liver or GIT (e.g. nitroglycerine, testosterone, lidocaine).

ORAL-CAPSULES They can be of two types: 1. Hard gelatin type: It contains the drug as solid. It can be opened. Capsules can come in many colors for easy identification. Hard capsule consists of 2 cylinders which fit into one another (Fig. 5.3), e.g. amoxycillin capsules. 2. Soft gelatine type: It contains the drug in liquid or semi-liquid form. They are completely sealed (Fig. 5.4). They are useful for liquid drugs and for drugs which are water insoluble, e.g. nifedipine Gelatin is heterogenous mixture of water soluble proteins of high molecular weight. Pearls are transparent or translucent capsules that contain liquid or semisolid drugs, e.g. vitamin A capsules.

Fig. 5.2: Tablets

Fig. 5.3: Capsules

Fig. 5.4: Soft Capsules

Common Dosage Forms and Routes of Administration-I  33 ADVANTAGES 1. Masks the bad smell and taste of drugs. 2. Avoids destruction by gastric juice and avoids gastric irritation.

DISADVANTAGE More expensive than tablets. ORAL-Pills means round or ovoid body, usual coated with sugar or even silver or gold paint, e.g. oral contraceptives. Tablets, capsules and pills are packed in the plastic coated paper or aluminum strips or in blister packing (Fig. 5.5). ORAL-powder: Powder is a solid form of drugs, which is finely divided and intimately mixed (Fig. 5.6). They are mainly of three types. (i) Simple powders: contain one ingredient only, e.g. glucose powder. (ii) Compound powders: contain more than one ingredients, e.g. ORS powder. Simple powder - ORS and (iii) Effervescent powder, e.g. Antacid effervescent powder, Seidlitz. Powders are packed in sachets.

ADVANTAGES 1. They are flexible in compounding. 2. Powders have a good chemical stability.

DISADVANTAGES 1. Needs proper instruction for preparing. 2. Time consuming to prepare. 3. It is not suitable for dispensing bitter drugs. For effective use of this dosage form, required amount of powder to be dissolved in required amount of water prior to administration and then to be taken orally.

Fig. 5.5: Packed tablets, capsules

Fig. 5.6: Powder

34  Practical Manual of Pharmacology ORAL-LIQUIDS Liquid oral formulations include syrups, mixtures, solutions, reconstituted oral solutions, elixirs and gels (Fig. 5.7). These two preparations (suspension and emulsion) have tendency to separate and requires a thorough mixing before administration. Liquids for oral use are usually dispensed in plastic or glass bottles.

ADVANTAGES OF LIQUID PREPARATIONS 1. They are more quickly acting than pills or tablets, which require previous disintegration before absorption. 2. Certain substances can only be given in the liquid form, e.g. liquid paraffin. 3. Certain chemical substances, e.g. potassium chloride can cause gastric irritation if taken in the form of powder or tablet. 4. Patients are sometimes prone to doubt the efficacy of the treatment they are receiving unless it includes something in the bottle (e.g. placebo effect). 5. Usefulness of some substances are largely dependent upon administration of diffusible form, e.g. magnesium sulphate in the form of suspension. Syrups: They are liquid oral preparations in which the vehicle is concentrated aqueous solution of sucrose or other sugar.

ADVANTAGES 1. They are sweet in taste so masking the bad taste of drugs, especially suitable for children. 2. Quicker effect than tablets which require previous disintegration.

DISADVANTAGES 1. Maintenance not easy. 2. They are costlier than tablets.

PRECAUTION Close the bottle properly after use. Elixir: Some drugs are insoluble in water, they are dissolved in alcohol. These preparations are termed elixirs. They are clear liquid oral preparations containing hydroalcoholic vehicle, e.g. bromhexine, promethazine.

ADVANTAGE Potent or nauseous drugs are pleasantly flavored and usually attractively coloured so patient compliance is better.

Fig. 5.7: Syrup

Common Dosage Forms and Routes of Administration-I  35 DISADVANTAGES 1. Maintenance not easy. 2. They are costlier than tablets.

PRECAUTION Close the bottle properly after use. Suspension: A liquid preparation that is made from a drug in solid form but not dissolved in alcohol is refers to as a suspension. It is a liquid medicament containing insoluble (diffusible or indiffusible) solid substances which are homogeneously distributed throughout the vehicle with or without the help of a suspending agent (Fig. 5.8).

ADVANTAGES 1. They are chemically more stable than the syrup. 2. Mask the unpleasant taste and odor of the drugs. 3. Insoluble solids can be given in liquid form.

DISADVANTAGES 1. A suitable preservative is required to avoid microbial contamination. 2. For effective use of this dosage form, shake the bottle well before use. Emulsions: They are liquid medicaments containing two immiscible liquids, one of which is broken into minute globules, each globule being surrounded by a thin film of emulsifying agent and then dispersed throughout the other liquid, e.g. liquid paraffin emulsion.

ADVANTAGES 1. Oily drugs can be given in this form 2. Oil in finely dispersed state is quickly absorbed. 3. Emulsifying agents mask the unpleasant taste and smell of the drugs.

DISADVANTAGES 1. A suitable preservative is required to avoid microbial contamination. 2. For effective use of this dosage form, shake the bottle well before use. Factors affecting oral route of administration: 1. Drug characteristics 2. Luminal pH along the GI tract 3. Destruction in GIT 4. Surface area per luminal volume 5. Blood perfusion 6. The presence of bile and mucus

Fig. 5.8: Suspension

36  Practical Manual of Pharmacology 7. 8. 9. 10.

The nature of epithelial membranes Presence of food Gut motility First pass metabolism

DRUG CHARACTERISTICS 1. Unionised drugs are lipid soluble, hence absorption is better. 2. Most of the drugs are absorbed from small intestine due to large surface area, longer contact time and rich vascular supply. 3. Presence of food usually delays absorption. 4. Some drugs are destroyed by gastric juices e.g. insulin, so these can not be given by oral route. 5. First pass metabolism decreases bioavailability of drugs by oral route e.g. propranolol. 6. Gut motility and gastric emptying time also affect absorption of orally administered drugs.

ORAL- SPECIAL PREPARATIONS Coated preparations Sometimes a drug needs to be disintegrated not in the stomach but in the intestine. The tablets are coated with material which does not disintegrate in the acidic conditions of the stomach but only in the alkaline conditions of the intestine, e.g. enteric coated aspirin to avoid local toxicity in stomach. • Coated tablets: Tablets may be sugar-coated or film-coated to disguise bad-tasting drugs, e.g. Chloroquine tablet. • Dispersible tablets: Tablets may be dispersible to avoid loss of disintegration in stomach or to avoid local toxicity in oesophagus, e.g. doxycyline. These dispersible tablets are to be dissolved in water prior to administration • Chewable tablets: When chewed it disintegrates due to its creamy base, e.g. antacid tablets, antihelminthic tablets and vitamin C tablets. It is useful to children who have difficulty in swallowing and to the adults who dislike swallowing, but tablet is expensive. • Effervescent tablets: Prepared by compressing granular effervescent salts. It disintegrates fast when added to water and acts by releasing carbon dioxide (Fig. 5.9). Effervescence masks the bad taste of drug. It may give psychological effect to patient, e.g. alkaline tablet, antacid tablet, aspirin tablet. The tablet is very sensitive to moisture and expensive also. The tablet to be dissolved in a glass of water and the same to be taken orally while effervescence is present. Fig. 5.9: Effervescent Take in upright posture either standing or sitting. tablets

Common Dosage Forms and Routes of Administration-I  37 • Lozenges: These are disc shaped solid dosage forms, e.g. menthol, dextromethorphan. They have local action in oral cavity. There is slow and continuous effect of the drug on the mucous membrane of the throat.

SUSTAINED RELEASE (SR) PREPARATIONS Drug is enclosed within device in such a way that the rate of drug release is controlled by its permeation through a membrane wall (Fig. 5.10). These preparations release drug slowly providing longer duration of action, e.g. diclofenac sodium SR. These are also known as retard or controlled release preparations, e.g. pilocarpine-releasing ocular insert for 4-day continuous glaucoma treatment.

Fig. 5.10: SR

ADVANTAGES 1. It modifies the rate of release of drug into the gastrointestinal tract. 2. It prolongs the effect of drug and also reduces the frequency of administration. 3. Patient compliance is better.

DISADVANTAGES 1. It is expensive as compared to uncoated tablets. 2. Dose dumping at one site producing local toxicity/systemic and loss of control release mechanism. Sustained release preparations can be formed by various techniques as follows: 1. Membrane system—drug enclosed in polymers from where it is released slowly. 2. Matrix system—drug is incorporated in a porous matrix. 3. Coated granules—drug molecules are coated, which release drug at different rates (Fig. 5.11).

RECTAL Drugs in the form of suppositories are inserted into the anal canal, e.g. diazepam in children suffering from status epilepticus. Rectum has rich vascular supply, so absorption is quick.

ADVANTAGES 1. 2. 3. 4. 5.

Unconscious, vomiting patient Swallowing problems In case of a difficulty to find the vein for intravenous injection Uncooperative children Unpleasant drugs

38  Practical Manual of Pharmacology

Fig. 5.11: Delivery systems and drug release

DISADVANTAGES 1. 2. 3. 4.

Anal or rectal irritation. Inconvenient, aesthetic considerations. Absorption slow, irregular and unpredictable. They are made to melt at body temperature, so needs to be kept refrigerated. They can even melt on the hand before insertion. The patients need to be educated about the best position for insertion and also to remove the plastic cover.

OBJECTIVES At • • • •

the end of this session a student shall be able to: Write down the name dosage form of the drug displayed at the various stations. Give instructions to patients on the proper usage of each dosage form. Write two important advantages of the dosage form. Write two important disadvantages of the dosage form. Exercises for this session can be arranged in stations. Each station has various dosage forms. The stations can have the above mentioned dosage forms like: Tablets–dispersible, sustained release, controlled release, enteric coated, sublingual tablets, pills Capsules–soft/hard gelatine capsules, pearls, spansules Liquid oral formulations (mixtures)–syrups, mixtures, solutions, reconstituted oral solutions, elixirs, suspensions, etc.

C H A P T E R

6

Common Dosage Forms and Routes of Administration-II

Any method of drug administration that avoids the gastrointestinal tract is termed parenteral administration. Parenteral is derived from combination of 2 words: Par = beyond Enteral = intestinal Transdermal, intranasal, rectal are, therefore, parenteral methods. However, the usual term parenteral is reserved for drug injections.

ADVANTAGES 1. They can be employed in an unconscious or an uncooperative patient. 2. They can be employed in cases of vomiting and diarrhoea and in the patients unable to swallow. 3. Drugs which might irritate the stomach or which are not absorbed orally can be administered, e.g. aminoglycosides. 4. They avoid drug modification by the alimentary juices and liver enzymes e.g. Insulin, nitroglycerine. 5. Rapid action and accuracy of dose are ensured.

DISADVANTAGES 1. 2. 3. 4. 5.

Less safe, once given the action of given drug will become irreversible More expensive Inconvenient for use, self-medication being difficult Liable to cause infection if proper care is not exercised Likely to injure important structures such as nerves and arteries if not given properly. Strict aseptic precaution should be taken while giving injection in order to prevent infections due to HIV and Hepatitis B virus. Disposable syringe and needle should be used and should be purchased from an authentic source. Needle should be broken down and syringe should be discarded after use. Injections: An injection is a method of putting liquid into the body with a hollow needle and a syringe which is pierced through the skin long enough for the material to be forced into the body. Preparations meant for parenteral administration must be sterile. Depending

40  Practical Manual of Pharmacology upon the volume, they are supplied in sealed glass ampoules, e.g. streptomycin or rubber capped multi-dose vials, e.g. multivitamins or large infusion bottles, e.g. 5% dextrose or in polypropylene pouches, e.g. metronidazole.

DOSAGE FORMS FOR INJECTIONS i. Aqueous or clear solution for subcutaneous/intramuscular/intravenous use. ii. Suspension for intramuscular/intravenous use. iii. Emulsion for intravenous use. Oily solution for intramuscular use long-acting forms of subcutaneous/intramuscular injections are available for various drugs; these are called depot injections. iv. Powder to be reconstituted for intramuscular/intravenous use. Powder has to be dissolved or suspended in colloidal form before injecting by adding an adequate quantity of a suitable solvent (e.g. streptomycin) because reconstitution of drug reduces the shelf life and stability.

PARENTERAL Intravenous injections (IV) An intravenous infusion is a liquid administered directly into the bloodstream via a vein. Drug is given in one of the superficial veins. Drug is either given as: 1. Bolus IV injection, e.g. adenosine in PSVT (immediate action is required), furosemide in acute pulmonary edema. 2. Slow IV injections over 5-10 minutes, e.g. calcium gluconate in arrhythmias (to avoid toxicity of calcium on heart). 3. Slow IV infusion, e.g. oxytocin in induction of labour (slow and sustained action is required) (Fig. 6.1). This is done by dissolving drug in 50-100 ml of isotonic glucose or saline. 4. Rapid IV infusion is sometimes used, e.g. fluids in shock. Drug is usually in aqueous form (Fig. 6.2). It should be nonirritant to vascular endothelium.

Fig. 6.2: IV infusion

Fig. 6.2: IV fluid

Common Dosage Forms and Routes of Administration-II  41 ADVANTAGES 1. 2. 3. 4. 5. 6.

100% bioavailability Immediate onset of action, so it can be used in emergencies Titration of dose can be done First pass metabolism bypassed GIT adverse effects not present Can be used in unconscious, uncooperative and vomiting patients.

DISADVANTAGES 1. 2. 3. 4. 5. 6. 7. 8.

Aseptic precautions are mandatory Vital organs are exposed to high concentration of drug Thrombophlebitis Expensive Invasive Painful Trained person is required If the drug extravasates there may be necrosis and sloughing, e.g. with pentothal sodium, quinine. Before learning technique of IV injection it is important to learn to fill the syringe with drug. Drug can be available as liquid or powder form. It can be present in single dose ampoule or multidose vial. Exercise: How to aspirate drug from ampoule into syringe?

REQUIREMENTS Syringe of appropriate size, ampoule with required drug or solution, needle of right size, disinfectant, gauze (Fig. 6.3).

TECHNIQUE 1. Wash your hands properly with soap and water. 2. Take out syringe and needle from disposable pack taking care not to touch naked end of syringe. 3. Put the needle on the syringe. 4. Remove the liquid from the neck of the ampoule by flicking or tapping it or swinging it fast in a downward spiralling movement. 5. File around the neck of the ampoule. 6. Carefully break off the top of the ampoule. Protect your fingers with gauze if ampoule is made of glass. 7. For a plastic ampoule twist the top. 8. Remove cover from needle.

42  Practical Manual of Pharmacology 9. Aspirate the fluid from the ampoule. 10. Remove any air from the syringe. 11. Clean up, dispose of working needle safely and wash your hands. Exercise: How to aspirate drug from vial into syringe?

REQUIREMENTS Vial, syringe of the appropriate size, needle of right size, disinfectant, gauze.

TECHNIQUE 1. Wash your hands properly with soap and water. 2. Take out syringe and needle from disposable pack taking care not to touch naked end of syringe. Use a syringe with a volume of twice the required amount of drug or solution. 3. Put the needle on the syringe. 4. Remove protective covering from vial cap. Disinfect the top of the vial with a cotton swab soaked in disinfectant (Fig. 6.3). 5. Remove cover from needle. 6. Suck up as much air as the amount of solution needed to aspirate. 7. Insert needle into vial through rubber cap and push down and then mix. 8. Pump air into vial (creating pressure). 9. Aspirate the required amount of solution and 0.1 ml extra. Make sure the tip of the needle is below the fluid surface (Fig. 6.4). 10. Pull the needle out of the vial. 11. Remove the air from the syringe. 12. Clean up, dispose of waste safely and wash your hands.

Fig. 6.3: Ampoule

Fig. 6.4: Aspiration

Common Dosage Forms and Routes of Administration-II  43 Exercise: How to dissolve dry medicine in vial and aspirate drug solution into syringe? Antibiotic drugs such as penicillins, streptomycin and the tetracyclines often are manufactured and supplied to you in the form of a sterile powder in a vial which must be reconstituted with sterile water for injection, normal saline solution, or other suitable diluent (solvent)

REQUIREMENTS Vial with dry medicine to be dissolved, syringe of the appropriate size, needle of right size, disinfectant, gauze.

TECHNIQUE 1. Wash your hands properly with soap and water. 2. Take out syringe and needle from disposable pack taking care not to touch naked end of syringe. 3. Put the needle on the syringe. 4. Aspirate solvent into syringe from the ampoule. 5. Remove protective covering from cap of vial. Disinfect the rubber cap (top) of the vial containing the dry/powdered medicine. 6. Insert the needle into the vial, hold the whole unit upright. 7. Suck up as much air as the amount of solvent already in the syringe. 8. Inject only the fluid into the vial, not the air. 9. Shake well. 10. Turn the vial upside-down. 11. Inject the air into the vial (creating the pressure). 12. Aspirate the total amount of solution. 13. Remove any air from the syringe. 14. Clean up, dispose of waste safely and wash hands. It is recommended that all antibiotics that are reconstituted and are to be used later, should be labeled in the following way (see example): 1. Hour and date reconstituted. 1400 hrs 9 Mar 07 2. Strength of reconstituted antibiotic. 50,000 units/ml 3. Initials of the preparer. Exercise: How to inject by Intravenous route?

REQUIREMENTS Syringe, drug, needle 20G, liquid disinfectant, cotton wool, adhesive tape and tourniquet.

PROCEDURE 1. Wash your hands properly with soap and water 2. Reassure the patient and explain the procedure 3. Uncover arm completely

44  Practical Manual of Pharmacology 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Have the patient relax and support his arm below the vein to be used Apply tourniquet, tell patient to clinch fist and look for a suitable vein Wait for the vein to swell. Disinfect skin Stabilize the vein by pulling the skin taut in the longitudinal direction of the vein. Do this with the hand you are not going to use for inserting the needle. Insert the needle at an angle of around 35° (Fig. 6.5) Puncture the skin and move the needle slightly into the vein (3-5 mm) Hold the syringe and needle steady If blood appears hold the syringe steady, you are in the vein. If it does not come, try again Loosen tourniquet. Withdraw needle swiftly. Check for pain, hematoma Press sterile cotton wool onto the opening. Secure with adhesive tape Check the patient's reactions and give additional reassurance, if necessary Clean up, dispose of waste safely and wash your hands.

Exercise: Model for IV injections for students in laboratory

REQUIREMENTS A simple model for IV administration can be used to teach the students about the process of IV injection. Model of hand with vein (made of latex glove stuffed with mattress foam and a rubber tube filled with red ink placed under the latex glove on top of the cotton), IV infusion sets, butterfly needles, IV fluid bottles. Follow same procedure as described forIV injection.

GENERAL PRINCIPLES Apart from the specific technique of injecting, there are a few general rules that you should be kept in mind. 1. Expiry dates: Check the expiry dates of each item including the drug. If you make housecalls and keep stock of injections, check the drugs in your medical bag regularly to make sure that they have not passed the expiry date. 2. Drug: Make sure that the vial or ampoule contains the right drug in the right strength. 3. Sterility: During the whole preparation procedure, material should be kept sterile. Wash your hands before starting to prepare the injection. Disinfect the skin over the injection site. 4. Prudence: Once the protective cover of the needle is removed extra care is needed. Do not touch anything with the unprotected needle. Once the injection has been given take care not to prick yourself or somebody else. 6. Waste: Make sure that contaminated waste is disposed of safely. Fig. 6.5: IV injection

Common Dosage Forms and Routes of Administration-II  45 7. Do not use plastic tubing for glyceryl trinitrate, paraldehyde. 8. Protect nitroprusside from light by covering infusion set with brown paper.

PARENTERAL-IM Intramuscular injections Drug is injected in one of the large skeletal muscles of the body, i.e. deltoid, gluteus and in infants in anterolateral region of the thigh in middle third region. Skeletal muscle is highly vascular and its capillaries contain small pores which enable substances of small molecular weight to pass through into the bloodstream. Several muscles of the body have considerable mass and can be injected with quantities of up to several millilitres of fluid without inducing discomfort to the patient. Generally, intramuscular injections are not self-administered, but rather by a trained medical professional, e.g. many vaccines, antibiotics, and long-term psychoactive agents. Aqueous solutions better absorbed than oily solutions. Depot preparations in oil can be given to prolong duration of action. The degree of tissue perfusion and condition of the injection site will influence the rate of drug absorption.

ADVANTAGES 1. 2. 3. 4. 5.

Rate of absorption is reasonably uniform. Less painful. Onset of action-fairly rapid. Depot preparations can be given. In addition to soluble substances, mild irritants, suspensions and colloids can be injected by this route.

DISADVANTAGES 1. 2. 3. 4. 5.

Aseptic precautions are mandatory. Danger of injecting into blood stream. Intramuscular absorption is not always faster than oral absorption. The volume of injection should not be more than 10 ml. Pain at the site of injection, irritation, abscess formation or tissue and nerve damage may occur. Rapid absorption may cause even death.

PRECAUTIONS 1. Do not inject in gluteal region in a child until child starts walking. Inject into lateral part of thigh. 2. Heparin should not be given IM (hematoma). 3. Injury to nerves leading to paresis of muscles can occur. Never give IM injection to child with suspected poliomyelitis.

Fig. 6.6: Sites for IM injection in adults

46  Practical Manual of Pharmacology 4. A healthy well developed person can tolerate 3.0 ml in large muscles, this does NOT include the deltoid. For elderly, thin clients or children the total amount should not exceed 2.0 ml. No more than 1.0 ml should be given to young children and older infants. Exercise: How to inject drug by intramuscular route?

REQUIREMENTS Syringe filled with the drug to be administered (without air), needle 22G, liquid disinfectant, cotton wool, adhesive tape.

PROCEDURE 1. Wash your hands properly with soap and water 2. Reassure the patient and explain the procedure 3. Uncover the area to be injected (lateral upper quadrant major muscle lateral side of upper leg, deltoid muscle Fig. 6.6) 4. Disinfect the skin and tell the patient to relax the muscle 5. Insert needle swiftly at the angle of 90° (watch depth) 6. Aspirate briefly, if blood appears withdraw needle. Replace it. 7. Inject slowly (less painful) 8. Withdraw needle swiftly 9. Press sterile cotton wool onto the opening. Fix with adhesive tape Check the patient's reaction and give additional reassurance, if necessary 10. Clean up, dispose of waste safely and wash your hands. Exercise: How to inject drug by intramuscular route in an orange model?

REQUIREMENTS Syringe filled with the drug to be administered (without air), needle 22G, liquid disinfectant, cotton wool, adhesive tape, Orange. Orange peel gives resistance and feeling of injecting through skin. When needle enters inside orange it gives feeling of injecting in muscle.

PROCEDURE Same as above.

PARENTERAL-SC A subcutaneous injection is administered into the subcutis, the layer of skin directly below the dermis and epidermis, collectively referred to as the cutis. Subcutaneous injections are highly effective in administering such medications as insulin, morphine, diacetylmorphine or goserelin (Fig. 6.7). Drug is injected into loose subcutaneous tissue. Hyaluronidase can increase absorption, which breaks down intracellular matrix. A person Fig. 6.7: SC injection

Common Dosage Forms and Routes of Administration-II  47 with type I diabetes mellitus typically injects insulin subcutaneously. Places on the body where people can inject insulin most easily are: • The outer area of the upper arm • Just above and below the waist, except the area right around the navel (a 2-inch circle) • The upper area of the buttock, just behind the hip bone • The front of the thigh, midway to the outer side, 4 inches below the top of the thigh to 4 inches above the knee. Subcutaneous—the volume to be administer is 1.0 ml or less.

ADVANTAGES 1. Self-administration possible. 2. Drugs in oil or implants can be given. 3. Action of the drug is sustained and uniform (Fig. 6.8).

Fig. 6.8: ROA and concentration time curve

DISADVANTAGES 1. Painful 2. Onset of action-slower 3. Only non-irritant substances can be injected by this route. Subcutaneous drug implants can act as depot therapy, e.g. Medroxyprogesterone. Exercise: How to inject drugs subcutaneously?

48  Practical Manual of Pharmacology REQUIREMENTS Syringe with the drug to be administered (without air), needle 25G, liquid disinfectant, cotton wool, adhesive tape.

PROCEDURE 1. 2. 3. 4. 5. 6. 7.

Wash hands with soap and water. Reassure the patient and explain the procedure. Uncover the area to be injected (upper arm, upper thigh, abdomen). Disinfect skin, "Pinch" fold of the skin. Insert needle in the base of the skin-fold at an angle of 20 to 30°. Release skin. Aspirate briefly, if blood appears: withdraw needle, replace it with a new one, if possible, and start again from point 4. 8. Inject slowly (0.5-2 minutes). 9. Withdraw needle quickly. 10. Press sterile cotton wool onto the opening. Fix with adhesive tape. 11. Check the patient's reaction and give additional reassurance, if necessary. 12. Clean up, dispose of waste safely and wash hands. Insulin is administered only using an insulin syringe. Most insulin vials contain 100 units/ ml. Insulin may be administered subcutaneously, intramuscularly (rarely used) and intravenously. Regular insulin is the only type that may be given IV since it does not contain any additives to prolong the action. Regular insulin is clear. If the vial is cloudy, it has been contaminated and should be discarded. Longer acting insulin is cloudy and may have a precipitate on the bottom of the vial. Be sure to mix the vial well by rotating it between the hands.

PARENTERAL-INTRADERMAL INJECTION Drug or substance is injected into the dermis using a fine needle. The absorption is very slow and only small quantities of the drug can be given by this route. This route is used for specific purpose only. Intradermal—the volume to be administered is 0.1 ml or less, e.g. BCG vaccine. Other less commonly used injectable routes are: Intra-thecal injectons are made into the cerebrospinal fluid. This drug are given to get drugs directly into the central nervous system by avoiding the blood brain barrier commonly used for spinal anesthesia and chemotherapy. Epidural injections is just like intrathecal but the drug is deposited above the dura and not in the cerebrospinal fluid. Local anesthetics are often given this way during surgical procedures, specially for procedures involving the pelvic and inferior regions, to block. Intra-arterial injections: To deliver high concentration of anticancer drugs in malignancy, e.g. vasodilator drugs in the treatment of vasospasm and thrombolytic drugs for treatment of embolism.

Common Dosage Forms and Routes of Administration-II  49 Intra-articular injections: are used to inject drugs directly into joint. But strict aseptic precautions are a must (Fig. 6.9).

PARENTERAL- SUBLINGUAL Highly lipid soluble drugs can be absorbed from sublingual and buccal mucosa, e.g. Nitroglycerin, a potent vasodilator, used in angina.

ADVANTAGES • This form of administration avoids the mixing of drug with food and/or gastric juices which may impede absorption. • Immediate action, can be used in emergency. • Action can be terminated by spitting the remaining drug. • Bypasses hepatic first pass metabolism (Fig. 6.10).

Fig. 6.9: Intraarticular injection

Fig. 6.10: Circulation

DISADVANTAGES 1. Drug taste must be pleasant. 2. Irritant drugs cannot be given. Can produce ulcers in mouth.

PARENTERAL-TRANSDERMAL The skin is relatively more impermeable to drugs than other stratified epithelia. The skin is useful to administer drugs which are very lipophilic and active in very small amounts. Drug is present in patches (Fig. 6.11) which release drug at constant and predictable rate. No peaks or troughs of drug concentration are seen. Site used are-chest, abdomen, upper arm, buttocks. Transdermal drug delivery avoids problems such as gastrointestinal irritation,

Fig. 6.11: Patch

50  Practical Manual of Pharmacology metabolism, variations in delivery rates and interference due to the presence of food. It is also suitable for unconscious patients. The technique is generally non-invasive and aesthetically acceptable and can be used to provide local delivery over several days. Examples are: • Nicotine patches-help stop smoking. • Oestradiol-prevent menopausal symptoms. • Fentanyl cytrate-prevent severe pain. • Nitrate patches-for angina. Transdermal delivery system (patches) can be of various types (Fig. 6.12) as follows: 1. Membrane controlled The drug in solution or bound to polymer is held in a reservoir between an occlusive backing film and a rate controlling micropore membrane. The drug is absorbed into systemic circulation by diffusion. 2. Matrix controlled The drug is homogeneously mixed with rate controlling polymer and rate of release is controlled by its diffusion through polymer matrix. 3. Sandwich type Combination of membrane and matrix type. Matrix is coated with a rate controlling polymer membrane. Rate of absorption depends on:

Fig. 6.12: Transdermal delivery

Common Dosage Forms and Routes of Administration-II  51 • Degree of hydration. • Keratinisation. • Rate of blood flow through skin.

ADVANTAGES 1. 2. 3. 4. 5. 6.

Bypasses first pass metabolism. Maintains constant plasma levels for a longer period. Less side effects. Easy to discontinue if toxicity appears. No GIT side effects. Convenient to use, compliance improves.

DISADVANTAGES 1. 2. 3. 4. 5. 6.

Local irritation, erythema. Onset of action-slower. Can not achieve high concentration in plasma. Can not deliver drugs in a pulsatile manner. Development of tolerance. Expensive.

Methods to increase permeation • Physical, e.g. iontophoresis. • Chemical, e.g. sorption promoters. • Biological, e.g. skin metabolism inhibitors. Instructions for correct use of this dosage form: 1. 2. 3. 4. 5. 6. 7.

Do not apply over bruised or damaged skin. Do not wear over skin folds or under tight clothing and change spots regularly. Apply with clean, dry hands. Clean and dry the area of application completely. Remove patch from package, do not touch 'drug' side. Place on skin and press firmly. Rub the edges to seal. Remove and replace according to instructions.

OBJECTIVES At the end of this session a student shall be able to: • Write down the dosage form of the drug displayed at the various stations. • Administer the drug properly by required method.

52  Practical Manual of Pharmacology • Understand and describe precautions required during use of each dosage form. • Write two important advantages of the given dosage form. • Write two important disadvantages of the given dosage form. Exercises for this session can be arranged in stations. Each station has various dosage forms. The stations can have the above mentioned dosage forms like: Ampoules, vials, IV set, syringes, needles, patches.

DEMONSTRATE 1. How you will aspirate drug from an ampoule/vial? 2. How you will make solution of dry drug for injection? 3. How you will inject drug through IV route/ IM route? Exercise 1: Inject 0.1 ml of saline intravenously into the model provided. Check-list 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Wipes area with spirit from centre to periphery. Waits for the spirit to dry. Positions needle with bevel facing upwards. Holds syringe in correct manner (without touching needle). Inserts needle into skin first. Withdraws to check whether in vein. Pushes plunger smoothly and completely. Withdraws and wipes area with cotton. Disposes needle (without recapping) and syringe correctly. Completes procedure smoothly without disruption.

Exercise 2: Give clear instructions on the proper use of a transdermal nitroglycerine patch to this patient. Check-list 1. 2. 3. 4. 5. 6. 7. 8.

Greets the patient. Offers a seat. Opens pack. Right side has to be on skin. Over the lateral chest wall. Change every day. Do not place on exactly same site. If irritation or redness - come to doctor.

Common Dosage Forms and Routes of Administration-II  53 9. Not more than two patches in a day. 10. Check whether it is there after bath. Exercise 3: You have decided to put this 24 years female going to get married, on oral contraceptives after having taken a history and done a physical examination. Give instructions on the use of this packet of contraceptive pills which contain low dose combination pills. Check-list 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Explains that she will be on a contraceptive. To start on fifth day of menstrual cycle. To start a new packet at end of this without gap. If pill is missed to take it next day. If more than 2 pills are missed additional contraceptive cover. Additional methods for first cycle. Explains withdrawal bleeding. Explains breakthrough bleeding. To take at same time each night. When to return - next visit.

C H A P T E R

7

Common Dosage Forms and Routes of Administration-III

LOCAL This refers to the application of a drug to an area of the body for direct treatment. Usually there is inefficient absorption (1-15%). High local tissue levels nevertheless achievable, often higher than by systemic route. Toxicity usually not a problem.

DROPS Eye and nose drops are made isotonic to avoid pain or discomfort. Ear drops are formulated as oily solutions to coat and adhere to the aural cavity.

EYE DROPS They are aqueous or oily solutions for instilling into conjunctival sac (Fig. 7.1). They are used as anesthetics, anti infective or anti inflammatory agents, miotics, mydriatics and artificial tears. For example atropine sulphate (mydriatic), pilocarpine nitrate (miotic), timolol maleate.

ADVANTAGES 1. Local effect at required place. 2. Easy to apply. 3. Drug interactions can be avoided.

DISADVANTAGES 1. 2. 3. 4.

It requires repeated application. Systemic effects can occur following absorption. May cause irritation. Once seal is broken, should be used within 1 month.

PROCEDURE 1. Wash your hands. 2. Do not touch the dropper opening. 3. Look upward.

Fig. 7.1: Eye drops

Common Dosage Forms and Routes of Administration-III  55 4. 5. 6. 7. 8. 9.

Pull the lower eyelid down to make a 'gutter' or pouch. Bring the dropper as close to the 'gutter' as possible without touching it or the eye. Instill the prescribed number of drops (usually 1 or 2) in the 'gutter'. Close the eye for about two minutes. Do not shut the eye too tight. Excess fluid can be removed with a tissue. Do not rub. If more than one kind of eye drop is used wait at least five minutes before instilling the next drops. Eye-drops may cause a burning feeling but this should not last for more than a few minutes. If it does last longer, consult a doctor or pharmacist.

EYE OINTMENT They are semisolid preparations with a greasy base, to be applied in the eye, e.g. neomycin eye ointment, chloramphenicol eye ointment, tetracycline eye ointment.

ADVANTAGE They have longer duration of action.

DISADVANTAGE Due to greasy base eyes may become sticky.

PROCEDURE 1. 2. 3. 4. 5. 6. 7. 8. 9.

Wash your hands. Do not touch anything with the tip of the tube. Tilt the head backwards a little. Take the tube in one hand and pull down the lower eyelid with the other hand, to make a 'gutter'. Bring the tip of the tube as close to the "gutter" as possible. Apply the amount (usually 1 cm length) of ointment. Close the eye for two minutes. Remove excess ointment with a tissue. Clean the tip of the tube with other tissue.

EAR DROPS They are aqueous or oily solutions instilled in the ear, e.g. wax softeners, sodium bicarbonate.

ADVANTAGE Avoid systemic side effect due to its local action.

DISADVANTAGE Local irritation can occur.

56  Practical Manual of Pharmacology PROCEDURE 1. 2. 3. 4. 5.

Lie on one side with the ear upward. Gently pull the lobe to expose the ear canal. Instill the amount (usually 4-5) of drops. Wait for five minutes before turning to the other ear. Use cotton wool to close the ear canal after applying the drops only if the manufacturer explicitly recommends this. 6. Ear drops should not burn or sting longer than a few minutes (Fig. 7.2).

NASAL DROPS They are aqueous solutions of drugs instilled into the nose with a dropper, e.g. Xylometazoline, ephedrine, etc.

ADVANTAGE Local and quick action.

DISADVANTAGES 1. Absorption can occur producing systemic effect. 2. May cause local irritation.

PROCEDURE 1. Blow the nose. 2. Sit down and tilt head backward strongly or lie down with a pillow under the shoulders; keep head straight. 3. Insert the dropper one centimeter into the nostril. 4. Instill the number of drops prescribed (usually 3-4 drops). 5. Sit up after a few seconds, the drops will then drip into the pharynx. 6. Repeat the producer for the other nostril, if necessary. 7. Rinse the dropper with boiled water.

NASAL SPRAYS These are drugs or combinations of drugs (Fig. 7.3) which by virtue of their high vapor pressure, can be carried by an air current into nasal passage and exert their effect, e.g. Beclomethasone, calcitonin, vasopressin, etc.

ADVANTAGES 1. Easy to use. 2. It covers large surface area so quick absorption.

DISADVANTAGE Explosion may occur in hot environment as the contents are under pressure.

Common Dosage Forms and Routes of Administration-III  57 PROCEDURE 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Blow the nose. Sit with the head slightly tilted forward. Shake the spray. Insert the tip in one nostril. Close the other nostril and mouth. Spray by squeezing the vial (flask, container) and sniff slowly. Remove the tip form the nose and bend the head forward strongly (head between the knees). Sit up after a few seconds; the spray will drip down the pharynx. Breath through the mouth. Repeat the procedure for the other nostril, if necessary. Rinse the tip with boiled water.

SUPPOSITORIES A suppository (Fig. 7.4) is a drug delivery system that is inserted either into the rectum (rectal suppository), vagina (vaginal suppository) or urethra (urethral suppository) where it dissolves. They are used to deliver both systemically acting and locally acting medications. They are solid, uniformly medicated masses of medicaments, e.g. glycerin, bisacodyl.

ADVANTAGES 1. Local application for systemic as well as local effect 2. Especially helpful for unconscious or in a patient who can not take orally.

DISADVANTAGES 1. Inconvenient and some times irritant 2. Aesthetic concerns 3. Local irritation.

Fig. 7.2: Ear drops

Fig. 7.3: Nasal spray

Fig. 7.4: Suppository

58  Practical Manual of Pharmacology PROCEDURE 1. Wash your hands. 2. Remove the covering (unless too soft). 3. If the suppository is too soft let it harden first by cooling it (fridge or hold under cold running water, still packed) then remove covering. 4. Remove possible sharp rims by warming in the hand. 5. Moisten the suppository with cold water. 6. Lie on your side and pull up your knees. 7. Hold the suppository by the non pointed end and insert the tip into the anal opening. 8. Now just gradually push, keep pushing (it may be further than you imagine) and at some point the suppository will be pulled into the rectum by the anal sphincter. Remain lying down for several minutes. 9. Try not to have a bowel movement during the first hour.

VAGINAL PESSARIES It is the term applied to suppository shaped medications for vaginal administration. This is a topical treatment and it is important that the drug coats all the vagina mucosa. Vaginal medications whether in pessaries or cream come with applicators which are designed to reach the upper parts of the vaginal canal. Vaginal preparations which are left in situ are best used at night because the vagina has no means of retention like sphincters and the medication can run out. Vaginal tablet (Pessary) with applicator They are vaginal suppositories intended for introduction into vagina, e.g. nystatin, metronidazole.

ADVANTAGES 1. Local application 2. Avoid systemic effect.

DISADVANTAGES It may cause staining and irritation.

PROCEDURE 1. 2. 3. 4. 5.

Wash your hands. Remove the wrapper from the tablet. Place the tablet into the open end of the applicator. Lie on your back, draw your knees up a little and spread them apart. Gently insert the applicator with the tablet in front into the vagina as far as possible, do not use force.

Common Dosage Forms and Routes of Administration-III  59 6. 7. 8. 9.

Depress the plunger so that the tablet is released. Withdraw the applicator. Discard the applicator (if disposable). Clean both parts of the applicator thoroughly with soap and boiled lukewarm water (if not disposable).

Without applicator 1. 2. 3. 4. 5.

Wash your hands. Remove the wrapper from the tablet. Dip the tablet in lukewarm water just to moisten it. Lie on your back, draw your knees up and spread them apart. Gently insert the tablet into the vagina as high as possible, do not use force.

OINTMENTS These are lipid-based. They have a greasy appearance and feel. The drug is trapped under the dressing and, the layer of the skin is soften from sweating, enabling the drug to penetrate deeply into the tissues. Eye ointments are formulated to melt quickly so that vision is not impaired.

PASTES They have a very high powder content. They are useful in protecting areas of skin from moisture, being water repellent.

GEL AND LOTIONS They are used on the hairy areas of the body. Alcoholic gels or lotion are less messy than ointments or creams, but the evaporation of carrier is rapid, therefore, there is little penetration of the drug (Fig. 7.5).

JELLIES For urethral application.

DUSTING POWDER They are free flowing very fine powders having particle size < 150 µm for external use. They are used to treat superficial skin conditions. They are sterilized by dry heat and supplied in airtight glass or plastic jars with reclosable perforated lid or sprinkler holes at top. Commonly used dusting powders are purified talc, magnesium sulphide powder, neomycin powder, sulphacetamide sodium, sulphadiazine Fig. 7.5: Gel powder.

60  Practical Manual of Pharmacology ADVANTAGES 1. Systemic side effects of drugs are avoided because of local application. 2. It provides greater stability.

DISADVANTAGE It requires repeated application.

LOTIONS They are liquid preparations meant for local application to the skin or mucous membrane without rubbing for providing soothing or antiseptic effects. These medications are preferably supplied in amber or blue coloured bottles to protect them from sunlight, e.g. potassium permanganate lotion (0.1%), cetrimide lotion (1%), calamine lotion.

ADVANTAGE Systemic side effects of drugs are avoided because of local application.

DISADVANTAGE Patient may experience a gritty feeling.

PROCEDURE 1. Shake the bottle well before use 2. Apply without rubbing, on the affected part with the help of cotton swab.

LINIMENTS They are liquid or semiliquid preparations intended for external application by rubbing and may contain substances possessing analgesic, rubefacient, soothing or stimulating properties. They may be either emulsions or solutions, e.g. liniment turpentine.

ADVANTAGE Systemic side effects of drugs are avoided because of local application.

DISADVANTAGE Patient may experience a burning sensation.

PROCEDURE Apply with rubbing on the affected part.

OINTMENTS They are semisolid preparations in a greasy base used for external application by inunction. They are of such consistency that they soften but not necessarily melt when applied to the skin, e.g. Whitfield's, salicylic acid, calamine ointment.

Common Dosage Forms and Routes of Administration-III  61 ADVANTAGES 1. They increase the hydration of the skin. 2. The duration of action is prolonged due to occlusive dressing.

DISADVANTAGES 1. They stain the clothes. 2. Inconvenient to the patient due to greasy base.

PROCEDURE To be applied on the affected part with inunction.

CREAMS They are semi solid preparations consisting of opaque emulsions for external use (Fig. 7.6). The term cream is most frequently applied to a soft cosmetic type of preparation. Creams are used in treatment of skin conditions like eczema, pruritis as astringent, emollient, and antiseptics. They are dispensed in collapsible metal or plastic tubes, glass or plastic pots.

ADVANTAGE They are cosmetically more acceptable due to their less greasy nature.

DISADVANTAGE They are easily washed out so requires repetitive application.

SPRAYS They are preparations of drugs in aqueous, alcoholic or glycerin containing media, e.g. adhesive sprays.

ADVANTAGE Easy to use and cover a larger surface area.

DISADVANTAGE Explosion may occur in hot environment as the contents are under pressure.

PAINTS They are simple solutions containing medicaments in semisolid solvents like liquid paraffin or glycerin, e.g. povidone iodine.

Fig. 7.6: Cream

62  Practical Manual of Pharmacology ADVANTAGE Retain the medicament in situ for longer period.

DISADVANTAGE May cause staining and irritation. LOCAL-inhalation Drug administered by nasal or oral respiratory route. Action is either on bronchial tree or systemic due to absorption through lungs, e.g. salbutamol and beclomethasone in bronchial asthma. Drugs are delivered to bronchial musculature in asthma. Aerosols are formed as drug solution or microionised drug powder is converted into mist/dust respectively. Particle size which is absorbed in between 3 to 5 µm. If size < 3 µm-particles are not retained, they come out with expiration. If size > 5 µm particles are not absorbed. Preparations used for inhalation route are: 1. Dry powder inhalers. 2. Metered dose aerosol-drug is delivered through pressurized canister equipped with a valve through which only metered dose is discharged. Medication is most commonly stored in solution in a pressurized canister. The canister is attached to a plastic, handoperated pump. The standard metered dose inhaler (MDI) on activating releases a fixed dose of medicine in aerosol form (Fig. 7.7). 3. Nebuliser—In children and other patients who can not inspire forcefully while coordinating with inhaler opening, nebulisers are used (Fig. 7.8). The air pressure required for aerosol formation is generated by an electric pump. A nebuliser, or "breathing machine," is another way to take inhaled medicines. A nebuliser treatment is given with an air compressor machine. Pressurized room air is used to create a mist of the medicine solution, which is inhaled for approximately 5-10 minutes. 4. Rotahalers—The device is loaded with rotacapsules and then drug is inhales with forceful inspiration. Only capsules specifically made for rotahalers are used with rotahalers (Fig. 7.9).

Fig. 7.7: MDI

Fig. 7.8: Nebuliser

Fig. 7.9: Rotahaler

Common Dosage Forms and Routes of Administration-III  63 Only a small portion of drug (10%) reaches respiratory tract a small fraction of this amount penetrates mucosa.

ADVANTAGES 1. 2. 3. 4. 5.

Systemic effects including toxicity is less, e.g. steroids in asthma Targeted delivery of drug Easy to use Less amount of drug is needed Onset of action is fast.

DISADVANTAGES 1. Reflex bronchospasm 2. Candida growth in oral cavity 3. Patient has to learn the technique.

PROCEDURE FOR CORRECT USE (FOR MDI) (FIGS 7.10 AND 7.11) 1. Cough up as much sputum as possible. 2. Shake the inhaler before use. 3. Hold the inhaler as indicated in the manufacturer's instructions (this is held usually upside down). 4. Fully exhale. 5. Place the lips tightly around the mouthpiece. 6. Tilt the head backward slightly. 7. Breathe in deeply and activate the inhaler (press the metallic bottle), keeping the tongue down. The co-ordination between activating the inhaler and breathing in is critical for effective delivery of the drug into the lungs. 8. The aerosolized medicine is drawn into the lungs by continuing to inhale deeply before holding the breath for 10 seconds to allow absorption into the bronchial walls.

Fig. 7.10: Absorption through lungs

Fig. 7.11: Use of Inhaler (MDI)

64  Practical Manual of Pharmacology 9. Hold the breath for ten to fifteen seconds. 10. Breathe out through the nose. 11. Rinse the mouth with warm water.

PROCEDURE (FOR ROTAHALER) 1. Check the mouthpiece for foreign objects. 2. Twist the barrel in either direction until it stops. 3. Take a capsule (designed for rotahaler) and insert the clear (thinner/white) end into the raised hole of rotahaler. Push the new capsule in until it is level with the top of the hole (Fig. 7.12). 4. Hold the Rotahaler vertically, turn the lower end as far as it will go in the opposite direction. This will open the capsule. 5. Cough up as much sputum as possible and gently breathe out. 6. Place the lips tightly around the mouthpiece. 7. Tilt the head backward slightly. 8. Breathe in through your mouth as quickly and deeply as possible. Continue to take a full, deep breath. 9. Hold your breath for upto ten seconds. This allows the medication time to deposit in the airway. 10. Resume normal breathing. 11. After each use, pull the two halves of the rotahaler apart and throw away the loose capsule shell. 12. Reassemble the rotahaler. Repeat steps 1-7 when more than one rotacap is prescribed.

CARE OF FOR THE ROTAHALER Clean the rotahaler once every two weeks or sooner if needed. Regular cleaning will prevent powder accumulation inside the rotahaler. 1. Remove the empty capsule shell before washing the rotahaler. 2. Rinse the two halves of your rotahaler in warm water. 3. Shake off any excess water.

LOCAL-ORAL Gargles and Mouthwashes They are aqueous solutions used for throat infections and hygienic purpose, e.g. saline gargles, potassium permanganate solution, povidone iodine, betahexidine.

Fig. 7.12: Parts of rotahaler

Common Dosage Forms and Routes of Administration-III  65 ADVANTAGE Local soothing and antiseptic action.

DISADVANTAGE May cause staining and irritation.

PROCEDURE 1. Use with proper instruction that is written on the label. Swish mouthwash around in the mouth for at least 30 seconds and then spit it out. Do not swallow it. 2. Keep away from children.

NEW TECHNIQUES FOR DRUG DELIVERY Conventional Drug Delivery Systems Tablets, capsules, pills, suppositories, creams, ointments, liquids, aerosols, and injectables. New drug delivery systems (NDDS) Most of the marketed drugs these days are new delivery systems of older drugs only, hence, you will find a lot of OD, CR, SR and patches in the market. The reason is that an old drug can be given a new life by putting it into new delivery system, it is less expensive and time consuming as compared to discovering a new molecule. The profits are almost similar. There is now a growing realisation that innovative delivery of drugs would not only increase safety and efficacy levels but also improve the overall performance of the drug.

WHY NDDS? • These days a consumer (patient) demands more efficacious, safe, convenient and low cost drugs, e.g. cipro-OD, intranasal insulin. • The provider spends less money in new drug delivery system as compared to new drug. New drug development takes approximately $800 million and 12 years. NDDS development takes only 20% cost of new drug and only 6-8 years. Advances in drug delivery systems are also expected to offer a host of additional advantages such as ease of administration, increased patient compliance, decreased side effects and cost reduction. Multiple injections required per week or day could be replaced by once a month dosages or even longer intervals, which would stabilise blood levels of the medication, thereby enhancing treatment outcomes and patient compliance. New delivery systems are usually offer following advantages 1. 2. 3. 4.

Targeted drug delivery. Maximum efficacy/minimum adverse effects. Maintain steady state plasma conc. Longer duration and patient compliance.

66  Practical Manual of Pharmacology NDDS-ORAL • Programmed drug delivery • Sustained release and controlled release (SR/CR), e.g. theophylline SR, Indomethacin CR • Prodrugs • Cyclodextrins.

PRODRUGS Also known as "Smart Drugs", these compounds are designed to work only when activated by certain components in the body. For example, a smart drug designed to be activated by a certain enzyme will be activated only in tissues that produces that specific enzyme. These are drugs which are inactive outside body and get activated through metabolism in the body, e.g. Enalapril. So these drugs have. • Inactive precursors • Have active metabolites.

ADVANTAGES 1. Better bioavailability 2. Increased stability 3. Less side effects 4. Targeted delivery, e.g. Cyclophosphamide, Levodopa, Zidovudine.

SUSTAINED VS. CONTROLLED RELEASE Sustained release, a pharmaceutical dosage form formulated to retard the release of a therapeutic agent such that its appearance in the systemic circulation is delayed or prolonged and its plasma profile is sustained in duration. These forms also limit fluctuation in plasma drug concentration, providing a more uniform therapeutic effect. Absorption rate is slowed by coating drug particles with wax or other water-insoluble material, by embedding the drug in a matrix that releases it slowly during transit through the GI tract, or by complexing the drug with ion-exchange resins. Most absorption of these forms occurs in the large bowel. Crushing or otherwise disturbing a controlled-release pill can often be dangerous. Alcohol can also disturb this delivery system, leading to dose dumping at one point only. Controlled release, goes beyond the scope of sustained drug action. Implies a predictability and reproducibility in drug release kinetics.

NDDS-OTHERS • • • •

Transdermal therapeutic systems Inhalation route Coated implantable devices Antibody tagging

Common Dosage Forms and Routes of Administration-III  67 • Non viral vectors for gene therapy • Special forms of subcutaneous route Demoted Pellet implantation Sialistic and biodegradable implants • Tissue specific drug delivery systems Bone specific Colon specific Lung and liver specific • Biomolecular engineering, protein drugs • Gene gun, gene pills • Nanotechnology • Microfabrication • Oral vaccines ( in banana) • Liposomal delivery.

OBJECTIVES At the end of this session a student shall be able to: • Write down the dosage form of the drug displayed at the various stations. • Administer the drug properly by required method • Understand and describe precautions required during use of each dosage form • Write two important advantages of the given dosage form • Write two important disadvantages of the given dosage form Exercises for this session can be arranged in stations. Each station has various dosage forms. The stations can have the above mentioned dosage forms (Flow Chart 7.1) like: Eye drops, ear drops, eye ointments, vaginal pessaries, inhalers, nasal sprays, suppositories, prodrugs.

DEMONSTRATE Explain the use of inhaler to a patient.

CHECK-LIST 1. 2. 3. 4. 5.

Greets the patient. Offers a seat. Open the mouthpiece. Breath normally thrice. Start inhaling mid inspiration.

68  Practical Manual of Pharmacology Flow Chart 7.1: Depicting various dosage forms

6. Hold breath for 20 secs. 7. Wipe mouthpiece. • What precautions you will give to patients to take drug through nebulisers • What precautions you will give to patients to take drug using rotahalers • What precautions you will give to patients to take drug vaginaly/rectally

PRECAUTIONS FOR STORAGE OF DOSAGE FORMS (FIG. 7.13) • Most of the commercial preparations are labeled with expiry dates. • The longevity of a medicament is governed by its shelf-life. Shelf-life of a drug is the duration from the time the product is manufactured till the potency of the drug has been reduced by 10%. • This limit is usually considered acceptable in practice; more stringent standard is required if the degradation products are more toxic or irritative than the parent drugs. This can happen with tetracycline antibiotics. • Products with a shelf-life of more than 3 years are considered to be stable as these are expected to sold and used within his period. • Products with a shorter half-life should be labeled with Fig. 7.13: Storage of drugs expiration date.

Common Dosage Forms and Routes of Administration-III  69 • As a guide to good pharmaceutical practice it is suggested that mixtures recommended to be 'freshly prepared' should be prepared not more than 24 hours before issue to the patient. • Mixtures recommended to be 'recently prepared' should be stored in unopened bottles in the dispensary for not more than 3 months. • Should there be any doubt, the pharmacist should be consulted.

ENVIRONMENTAL FACTORS AFFECTING DOSAGE FORM • pH: Affect rate of chemical reaction and hence, longevity of a drug. • Temperature: An increase in temperature usually increases the rate of chemical reaction. Storage of a medicine in a cool place (below 15°C) will prolong the shelf-life. Refrigeration may prolong shelf-life of a medicament that is unstable in room temperature but solid particles may grow and precipitate in a suspension. The temperatures suitable for storage of topical drugs lies in the range of 15-25°C. • Environmental factors affecting dosage form. • Oxygen: Many drugs show slow oxidation in the presence of atmospheric oxygen, e.g. adrenaline, glyceryl nitrate is so prone to oxidation, the shelf-life is only about 3 months after the bottle has been opened. • Light: Can induce photochemical degradation. This can be reduced by the use of lightresistant containers or more effectively, by storage in the dark. Sodium nitroprusside very light sensitive, must be kept in darkened glass ampoules, wrapped in black plastic. • Humidity: Low humidity may be responsible for the powdering of granular solids containing effervescent salts and for the 'drying out' of creams. High humidity brings about the deterioration of effervescent tablets and solid preparations that contain hygroscopic materials. The adverse effects of humidity can be avoided by the use of moisture-proof containers. Aspirin hydrolyses readily to acetic acid and salicylic acid in the presence of moisture (most people store medicine and their aspirin tablet in bathrooms).

Section 2 Experimental Pharmacology

CHAPTER

8

Introduction to Experimental Pharmacology

Today's pharmacology teaching is much different from yesterday's teaching of Materia Medica. For better healthcare and to provide more effective, safe and affordable medications research is continuously being carried on new chemicals. This continuous search for new and better drugs starts from animal experimentation, i.e. preclinical testing before clinical testing in human subjects. There is enormous change in research methodology due to new high-tech instruments and methods available to us. Just as medicine cannot be taught or learnt without going towards and clinics, similarly pharmacology cannot be taught without experimentation. But animals should not be sacrificed just to gain skills about exact methodology and the techniques of animal experiments. Animals are not easily available nowadays due to animal welfare regulations and ethics. Animal experiments are expensive, time consuming and tedious. Thus with the changing scenario alternative methods of teaching pharmacology experiments have been developed along with the advances in computer technology. Animal experiments can be substituted by demonstrations using computer simulated learning programs. Students can be taught to use these programs. Give them exercises to analyse the results obtained from experiments, interpret them and apply them in different clinical situations. To analyse the results of any experiment or drug trial and draw conclusions is good learning experience for developing clinical judgement skills. A number of animal experiments can be demonstrated to students, but important ones are: 1. Effects of various drugs on the Rabbit Eye 2. Effects of various drugs on the Frog Heart 3. Effect of various drugs on Rabbit Intestine 4. Effects of various drugs on the Dog Blood Pressure. These experiments can be carried out on animals (Fig. 8.1) or these can be demonstrated with computer simulation models. Wherever animals are sacrificed, those experiments can be demonstrated with computer simulation models. In those experiments where animals are not sacrificed or tortured and if animals are available in Fig. 8.1: Albino rat the institute, then animals can be used in experiments.

74  Practical Manual of Pharmacology Various softwares are available for computer simulation demonstrations. Exercises in the form of graphs, tables obtained from various animal experiments can be used to teach students. They will analyse and interpret them applying different methods, formulae and statistics whenever necessary. After the discussions they will draw conclusions, correlate them clinically and answer the various questions given with graphs, tables and other exercises. Exact simulation of real animal experiments on a computer is not easy because the biological responses are very complex. Many factors come control an organ or a system. Hence, the results obtained with these simulated models may not be very accurate. But remember that the aim of the software is to teach the students about major facts that have practical utility in their future life. The purpose of demonstration of these models by a teacher would be of great help to students to understand the experimental procedure and the theory behind it. These programs may be used for self-learning later on. Understanding of autonomic nervous system pharmacology is essential for planning rational drug therapy of diseases like asthma, hypertension, parkinsonism, glaucoma, etc. Theoretical discussion alone may not suffice for the same, while discussion of experimental exercises may provide a sound background for enhancing the understanding. This will give to the students a general idea about how experiments are conducted, how results are interpreted and applied clinically.

CHAPTER

9

Effects of Drugs on Rabbit Eye

INTRODUCTION The Iris is composed of two types of muscle fibres, the circular and the radial muscles. The circular fibres are supplied by parasympathetic nerve fibres (cholinergic) and the radial ones are innervated by sympathetic nerve fibres (adrenergic). The stimulation of sympathetic and parasympathetic nerves produces mydriasis and miosis respectively and their paralysis produces opposite effects. Drugs which simulate the effects of autonomic nervous system can produce the above mentioned effects. This experiment uses a few such drugs on the rabbit eye (Figs 9.1 and 9.2). Sphincter Pupillae (Circular Muscle Fibers) Muscarinic (cholinergic receptors-M3)

Fig. 9.1: Structure of eye

Dilator Pupillae (Radial Muscle Fibres) Sympathetic (adrenergic receptors-α1)

Fig. 9.2: Muscle fibres of eye

76  Practical Manual of Pharmacology

REQUIREMENTS 1. 2. 3. 4. 5. 6.

Rabbit Scissors Measuring scale Droppers Torch Cotton wool.

DRUGS AND SOLUTIONS A. Normal saline B. Mydriatic drugs: Active Phenylephrine C. Miotic drugs: Active Pilocarpine D. Local anaesthetic: Lignocaine hydrochloride

20%

Passive Atropine sulphate

4.0%

Passive Phentolamine (not used)

1.0%

1-2%

PROCEDURE • Handle rabbit with care. • Clip off eyelashes of both the eyes • Use pouch method to instill drugs into eye. Pinch lower eyelid to make a small pouch. Instill 1-2 drops of saline/drug in it using dropper. Pull the lower eyelid upwards and keep it in contact with conjunctiva for 1-2 minutes • You can also press medial canthus for 5 seconds after instillation of drug • Keep one eye (either right or left eye) as control and the other as test • Apply saline in the control eye and a drug in the test eye. Following parameters are measured at 5-15 minutes after instillation of drug (Fig. 9.3): 1. Size of pupil 2. Light reflex 3. Touch reflex (Corneal reflex) 1. Size of Pupil Measure the diameter of both the pupils. This can be measured with a pupilometer made up of cardboard or hard paper. Take a hard paper, cut it approximately equal to a 6 inch ruler. Then cut holes in it having increasing order of diameter in millimeters. You can start with 1mm then mark upto 10 mm. You can also measure with the help of a simple scale. It will Fig. 9.3: Instillation look like this:

Effects of Drugs on Rabbit Eye  77 It is difficult to force open eyes of rabbit. Hence, with pupilometer it becomes easy to measure diameter. Keep pupilometer close to eye through which you can see pupil, match the hole in pupiolometer with size of pupil and note down the size in mm written on the matched hole. 2. Light Reflex Light reflex is checked with a torch. A pencil torch is best suited for this purpose. Always put the light from side (back) and bring it to the front. Do not put the light from the front side of the rabbit. Observe the changes in the diameter of pupil when light is put into eye. Note any decrease or increase in pupillary diameter. Take 3 readings. 3. Corneal Reflex It is tested with a fine cotton wool wick. Wick is made in such a manner that there is no protruding part of cotton. Touch peripheral part of cornea with tip of cotton wick. Always bring forward the cotton wool from the side (back). Rabbit should not be able to see cotton wool or your hand. Blinking represents presence of corneal reflex. Do not forget to note down the 3 readings. Precaution: Do not touch central part of cornea it can cause corneal ulcers/opacities. This can lead to blindness as central part of cornea is the main part of cornea used for visibility. Computer Simulation Model (CSM) Procedure: The teacher will show the students the various instruments used for this experiment. Then he/she will describe the procedure and steps in setting up the experiment. Then the whole batch for a particular day is shown the experiment using LCD projector. Students are told about the various options available and how to operate the software. Then the batch is divided into groups and each group is provided with a computer which has been pre-loaded with software. Then demonstrator/ instructor will then guide students to operate the software and students are allowed to work on their own. An instructor/demonstartor is always there to help the students. Students are expected to write down the procedure and effect of drugs and tabulate findings giving reasons for the changes in heart rate, respiration or increase or decrease in BP. They have to draw the graph obtained and find out the nature of the unknown drug given in the program (Table 9.1).

78  Practical Manual of Pharmacology Table 9.1. Effect of drugs on rabbit eye DRUGS

LIGHT REFLEX Right Left +++ +++ +++ --+++ + +++ + +++ +++

Phenylephrine Atropine Pilocarpine Physostigmine Lignocaine

CORNEAL REFLEX Right Left +++ +++ +++ +++ +++ +++ +++ +++ +++ ---

PUPIL SIZE mm Right Left 4 8 4 8 4 1.4 4 1 4 4

ADDITIONAL INFORMATION Active and passive miotics and mydriasis (Table 9.2) When miosis occurs as a result of active contraction of the sphincter pupillae (circular muscle of the iris), it is known as active miosis. This usually occurs as a result of action of cholinomimetics. When miosis occurs as a result of (passive) relaxation of the dilator pupillae (radial muscle of the iris), it is known as passive miosis. It usually results from action of adrenergic blockers. Similarly with mydriatics also, there is active and passive mydriasis due to active contraction of the dilator pupillae or relaxation of sphincter pupillae. Table 9.2. Classification of miotics and mydriatics Drugs Miotics

Mydriatics

Centrally acting

Active Cholinomimetics: Pilocarpine Carbachol Anticholinesterases Physostigmine Neostigmine Sympathomimtics 1Phenylephrine

Morphine

Indications of Miotics 1. 2. 3. 4.

Cataract Anterior chamber surgery Wide angle glaucoma To break adhesions between lens and iris

Passive Adrenergic blockers Phentolamine

Anticholinergics Atropine Homatropine Cyclopentolate Tropicamide

Effects of Drugs on Rabbit Eye  79 5. Reversal of mydriatic effects of anticholinergics 6. Xerostomia. Indications of mydriatics 1. Fundoscopy for visualisation of the periphery of retina. 2. Retinoscopy in those who are unable to relax their eyes, e.g. children, very old patients. 3. To break and prevent adhesions between iris and lens in iridocyclitis (alternate miotics and mydriatics) 4. Chronic simple glaucoma 5. Corneal ulcer/uveitis 6. Preoperative: Cataract surgery/Vitrectomy/Retinal surgery 7. Fluorescent fundus or Indocyamine green angiography.

LOCAL ANAESTHETICS (LAs) LAs reversibly block impulse conduction along nerve axons and other excitable membranes that utilises the Na+ Channels as primary means of action potential generation. Procaine is not a surface anaesthetic (Poor penetration). Cocaine is not used because of corneal sloughing (protoplasmic poison). LAs block corneal reflex in the rabbit eye.

OBJECTIVES At the end of the practical class the student shall be able to: 1. Explain effect of drug A on rabbit eye. 2. Identify the nature of unknown drug B instilled into rabbit eye. 3. Name three miotics/mydriatics used clinically and their important uses and contraindications. 4. Explain difference between active and passive miosis/mydriasis. Demonstrate on animals 1. Instill drugs carefully into the rabbit's eye by making pouch without injuring the cornea. 2. Study the effect of given drug on the rabbit's eye. 3. Record, analyze and interpret the observations obtained during this experiment. Exercise in examination These days LCD projectors are available in which you can project only a part of computer screen. This type of projector it is very easy to use these softwares for examination purpose. On your projector screen everything is visible including name of drugs, but you can project only eye in which drug is instilled.

C H A P T E R

10

Effect of Drugs on Frog Heart

Many drugs act on the heart. Adrenergic and cholinergic drugs produce opposite effects on it. These drugs act through their respective receptors. Some drugs act directly on the heart. This experiment demonstrates the effects of drugs and ions (agonists, antagonists, calcium and potassium) on the frog heart.

Requirements 1. A medium sized frog, frog board and frog tray. 2. Starling's heart lever (Fig. 10.1). 3. Venous cannula attached through drip set to a reservoir containing ringer perfusion fluid. 4. A kymograph with drum and smoked paper or physiograph with chart recorder. 5. A pithing needle, 2 pairs of scissors, 2 pairs of forceps, 1cc syringe with a needle, scale and pencil.

Fig. 10.1: Starling heart lever

Procedure A frog is pithed and dissected to expose the heart (Fig. 10.2). Pericardium is removed. Heart is lifted up. Sinus venosus is cannulated using a glass cannula (Syme's cannula) and secured with thread. Then the heart is perfused with Ringer solution through the sinus venosus. Perfusion rate is adjusted at 30-40 drops/minute. A curved needle is inserted in the apex and attached to a heart lever for recording contractions on the

Fig. 10.2: Dissected frog

smoked paper pasted over the drum of a kymograph. Starling heart lever is used. It has a spring to record fast contractions.

Effect of Drugs on Frog Heart  81 Lever should be horizontal. Normal contractions are recorded followed by effect of drugs (Table 10.1). Students are demonstrated this experiment in batches of 5-6 students and then they are supposed to conduct the same experiment themselves in batches of 5-6 students. [Instead of heart lever, drum and kymograph, a physiograph can be used (Fig. 10.3). Transducer replaces the heart lever and is connected to the heart. Chart paper and pens are used for recording]. CSM Procedure: The teacher will show the students the apparatus and other instruments used for this experiment. Then he/she will describe the procedure and steps in setting up the experiment. Then the whole batch for a particular day is shown the experiment using LCD projector. Students are told about the various options available and how to operate the software. Then the batch is divided into groups and each group is provided with a computer which has been pre-loaded with software. Then demonstrator/instructor will guide students to operate the software and students are allowed to work on their own. An instructor/demonstartor is always there to help the students. Students are expected to write down the procedure and effect of drugs and tabulate findings giving reasons for the changes in heart rate, respiration or increase or decrease in BP. On screen is seen graph recording contractions. You can choose drugs from a drop down menu. You can also select dose of the drug. Then press inject button and observe changes in graph. There is also provision of use of blockers to find out nature of action of drug, i.e. whether it is direct acting or indirect acting. The students have to draw the graph obtained and find out the nature of the unknown drug given in the program. • There is NO CORONARY CIRCULATION Facts About Frog Heart! to the heart. Heart derives its energy • Heart is three chambered—there are two from atmospheric oxygen and directly atria, but only one ventricle. from the blood contained in it. • Ventricle contains mixed blood. • Heart rate is 20-80 beats /minute. • Superior and inferior venae cava open into sinus venosus. Venous blood flows from sinus venosus to right atrium and from right atrium to ventricle. Arterial blood comes from left atrium into the ventricle. Ventricle pumps mixed blood to bulbous aorta. Bulbous aorta have spiral valve that directs arterial blood to body and venous blood to lungs through pulmonary arteries. • There is no specialised conducting tissue in the heart. There is muscular continuity in all the chambers of the heart and Fig. 10.3: Physiograph there is NO VALVES in the heart.

82  Practical Manual of Pharmacology Table 10.1: Drugs and solutions used in frog heart experiment Drugs

Dose (µg) 2

Concentration (µg/ml) 10

2. Norepinephrine (Noradrenaline)

2

10

3. Isoprenaline

2

10

4. Propranolol

200

1 mg/ml

5. Acetylcholine

2

10

6. Atropine sulphate

20

100

7. Calcium Chloride

2000

10 mg/ml

8. Potassium Chloride µg = micrograms

2000

10 mg/ml

1. Epinephrine (Adrenaline)

9. Frog Ringer solution Volume of above solutions to be injected = start with 0.1 ml, if sufficient response is not there increase dose to 0.2 ml and so on.

Procedure Inject drugs one by one. Observe the following parameters before and after drug administration: a. Force of contraction–amplitude (normal, increased or decreased) b. Tone (normal, increased or decreased) c. Heart rate (beats per minute). Parameter (a) and (b) are assessed by observing the recording (Figs 10.4 and 10.5). Tables 10.2 and 10.3 shows the effect of various drugs on frog’s heart (recording 1 and recording 2 respectively). The amplitude of contractions reflect the force. Shift in the mid point of systolic and diastolic contractions indicate the change in tone. Heart rate is assessed by counting movements of lever or directly by observing the heart.

Fig. 10.4: Effect of various agonists of frog heart contractions (Recording 1)

Effect of Drugs on Frog Heart  83

Fig. 10.5: Effect of various agonists in presence of antagonists on frog heart contractions (Recording 2)

The above parameters must be recorded in a sheet or record book. Tabulate the data. Interpret the data and record your conclusions.

Precautions a. Give sufficient time for the heart to recover between drug administrations. b. Always note the parameter readings before and after giving drugs. c. Record heart rate when there is maximum effect of drug. Table 10.2. Effect of drugs on frog heart (Recording 1) S.NO. 1 2 3 4 5 6 7

DRUG Control Epinephrine Norepinephrine Isoprenaline CaCl2 Acetylcholine KCl2

HEART RATE 87 92 83 115 1 67 1

AMPLITUDE Normal Increased Increased Increased Decreased Decreased Decreased

TONE Normal Increased No change Increased Increased No change Decreased

Procedure to Inject Drugs Inject 0.2 ml of drugs 1-4 in succession (cardiac stimulants) in the tube through which the heart is being perfused and record the responses. A control reading (without addition of any drug) should be taken before and after each drug response. All the parameters mentioned above should be recorded during the control and drug responses respectively. The heart rate, drug name and the dose should be mentioned in the recording during the control and drug responses. The next drug response should be recorded only after the heart rate has returned to the approximate original value. Inject stimulants and depressants. In case the heart stops because of systolic or diastolic arrest restart only when the heart is contracting. In case adequate response is not observed use a higher dose. Inject 0.2 ml of propranolol (depressant) and note its response. Stop the drum for 3 minutes. After 3 minutes inject adrenaline (same dose as injected previously) and note whether

84  Practical Manual of Pharmacology Table 10.3. Effect of drugs on frog heart (Recording 2) S. NO. DRUG 1 2 3 4 5 6 7 8

Control Propranolol followed by Epinephrine Propranolol followed by Norepinephrine Propranolol followed by Isoprenaline Propranolol followed by CaCl2 Control Atropine followed by Acetylcholine Atropine followed by KCl

HEART RATE

AMPLITUDE

TONE

86 76

Normal Decreased

Normal Decreased

76 72

No change Decreased

No change Decreased

72 69

No change Decreased

No change Decreased

69 72

No change Decreased

No change Decreased

1 85 89

Decreased Normal No change

Increased Normal No change

89 85

No change No change

No change No change

1

Decreased

Decreased

its effect is adequately blocked. In case sufficient blockade is not obtained repeat the procedure with 0.4 ml propranolol. Inject calcium chloride immediately after adrenaline effect has been blocked and note whether its effect has been blocked or not. In case the typical increase in rate and/or systolic arrest is not observed use higher dose. Inject 0.2 ml of cardiac depressants, i.e. acetylcholine and potassium chloride after taking control readings in between drug responses. Note also the condition of the heart during diastolic arrest. Diastolic arrest is due to hyperpolarisation. Inject 0.2 ml of atropine and note its response. Normally no response is seen because it is an in vitro preparation and moreover atropine has no intrinsic activity of its own. Stop the drum and wait for 3 minutes, inject acetylcholine (same dose as given earlier) and note whether effect is completely blocked. In case sufficient blockade is not obtained, repeat the same procedure with 0.4 ml of atropine.

Effect of Drugs on Frog Heart  85 Finally inject potassium chloride after the effect of acetylcholine has been blocked by atropine and note whether the effect is blocked. There should be no blockade of KCl effect.

OBJECTIVES At the end of the practical class the student shall be able to:

CSM 1. Interpret effect of various drugs on heart rate, amplitude and tone 2. Describe mechanism of action of various drugs 3. Comment on nature of unknown drugs given.

Exercise in Examination These days LCD projectors are available in which you can project only a part of computer screen. With this type of projector it is very easy to use these softwares for examination purpose. On your computer screen everything is visible including name of drugs, but you can project only recording showing effect.

CHAPTER

11

Effect of Drugs on Rabbit Intestine

Many drugs act on the intestine. Adrenergic and cholinergic drugs produce opposite effects on it. These drugs act through their respective receptors. Some drugs act directly on the intestine. This experiment demonstrates the effects of various drugs on the rabbit intestine. Requirements 1. A medium sized rabbit. 2. Frontal writing lever. It does not stick to writing paper on drum and gives straight lineas compared to simple lever (Figs 11.1 and 11.2). 3. A water bath having temperature control unit, organ bath with aeration tube. 4. A kymograph with drum and smoked paper or Physiograph with chart recorder. 5. 2 pairs of scissors, 2 pairs of forceps, 1cc syringe with a needle, scale and pencil. Procedure A rabbit is sacrificed and dissected to expose the intestines. A part of ileum is taken 10 cm away from ileocaecal valve. An optimal length of tissue (5-6 cm) is cut and a thread is tied to antimesenteric border on both sides. Then one end is tied to a fixed point inside organ bath and other point is attached to the lever for recording contractions on the smoked paper pasted over the drum of a kymograph (Fig. 11.3). Lever should be horizontal. Normal contractions are recorded followed by effect of drugs. Students are demonstrated this experiment in batches of 5-6 students and then they are supposed to conduct the same experiment themselves in batches of 5-6 students.

Fig. 11.1: Frontal writing lever

Fig. 11.2: Simple lever

Effect of Drugs on Rabbit Intestine  87 [Instead of heart lever, drum and kymograph, a physiograph can be used. Force transducer replaces the heart lever and is connected to the heart. Chart paper and pens are used for recording]. CSM Procedure: The teacher will show the students the apparatus and other instruments used for this experiment. Then he/she will describe the procedure and steps in setting up the experiment. Then the whole batch for a particular day is shown the experiment using LCD projector. Students are Fig. 11.3: Organ bath with intestine attached to lever told about the various options available and how to operate the software. Then the batch is divided into groups and each group is provided with a computer which has been preloaded with software. Then demonstrator/instructor will guide students to operate the software and students are allowed to work on their own. An instructor/demonstartor is always there to help the students. Students are expected to write down the procedure and effect of drugs and tabulate findings giving reasons for the changes amplitude, tone and frequency of intestinal movements. You can choose drugs from a drop down menu. You can also select dose of the drug. Then press inject button and observe changes in graph. There is also provision of use of blockers to find out nature of action of drug, i.e. whether it is direct acting or indirect acting. The students have to draw the graph obtained and find out the nature of the unknown drug given in the program. Table 11.1. Drugs and solutions used in rabbit intestine experiment Drugs

Dose (µg) 2

Concentration (µg/ml) 10

2. Propranolol

200

1 mg/ml

3. Acetylcholine

2

10

4. Atropine sulphate

20

100

5. Barium chloride

2000

10 mg/ml

1. Epinephrine (Adrenaline)

6. Kreb’s solution Volume of above solutions to be injected into organ bath = start with 0.1 ml, if sufficient response is not there increase dose to 0.2 ml and so on.

88  Practical Manual of Pharmacology Procedure Inject drugs one by one (Table 11.1). Observe the following parameters before and after drug administration: a. Force of contraction—amplitude (normal, increased or decreased) b. Tone (normal, increased or decreased) c. Frequency of contractions (per minute). Parameters (a) and (b) are assessed by observing the recording. The amplitude of contractions reflect the force. Shift in the mid point of contractions indicate the change in tone. Rate is assessed by counting movements of lever. The above parameters must be recorded in a sheet or record book. Tabulate the data (Table 11.2). Interpret the data and record your conclusions. Precautions a. Give sufficient time for the intestine to recover between drug administrations. b. Always note the parameter readings before and after giving drugs. c. Record frequency of contraction when there is maximum effect of drug. Table 11.2. Effect of drugs on rabbit intestine S. NO. 1 2 3 4 5 6

Drug Control Epinephrine Acetylcholine Atropine BaCl2 Ephedrine

Frequency Normal Decreased Increased Decreased Increased Decreased

Amplitude Normal Decreased Increased Decreased Increased Decreased

Tone Normal Decreased Increased Decreased Increased Decreased

Procedure to Inject Drugs Inject 0.1 ml of drugs 1-4 in succession (spasmogenic) in the organ bath and record the responses. A control reading (without addition of any drug) should be taken before and after each drug response. All the parameters mentioned above should be recorded during the control and drug responses respectively. The drug name and the dose should be mentioned in the recording during the control and drug responses. The next drug response should be recorded only after the rate and amplitude have returned to the approximate original value. Inject spasmogenics and spasmolytics. In case adequate response is not observed use a higher dose. Inject 0.2 ml of propranolol (depressant) and note its response. Stop the drum for 3 minutes. After 3 minutes inject adrenaline (same dose as injected previously) and note whether its effect is adequately blocked. In case sufficient blockade is not obtained repeat the procedure with 0.4 ml propranolol.

Effect of Drugs on Rabbit Intestine  89 Inject barium chloride immediately after adrenaline effect has been blocked, and note whether its effect has been blocked or not. Inject 0.1 ml of atropine and note its response. Atropine produces relaxation. Stop the drum and wait for 3 minutes, inject acetylcholine (same dose as given earlier) and note whether effect is completely blocked. In case sufficient blockade is not obtained, repeat the same procedure with 0.4 ml of atropine. Finally inject ephedrine after the effect of acetylcholine has been blocked by atropine and note whether the effect is blocked. There should be no blockade of ephedrine effect.

OBJECTIVES At the end of the practical class the student shall be able to:

CSM 1. Interpret effect of various drugs on rabbit intestine. 2. Describe mechanism of action of various drugs. 3. Comment on nature of unknown drugs given.

CHAPTER

12

Effect of Drugs on Dog Blood Pressure

This experiment should be demonstrated using computer simulation model only. Experiments on large animals require permission from subcommittee of CPCSEA. Procedure A dog is anesthetized with pentobarbital 3% intravenously (30 mg/kg). Trachea and carotid arteries are exposed. A ‘Y’ shaped tracheal cannula is put in cut trachea. Through one limb artificial respiration can be given with a respiratory pump if required or secretions can be cleaned. Other limb can be attached to a tube to record respiratory movements. Carotid artery on one side is cannulated. The cannula prefilled with sodium citrate solution is attached to a mercury manometer to record blood pressure. A butterfly cannula is inserted into leg vein to inject drugs. Drugs (Table 12.1) are injected and there effect is recorded on a smoking drum. The arterial cannula may be connected to a mercury manometer or to a pressure transducer, which is connected to a polyrite or physiograph (Fig. 12.1). Heart rate is recorded by observing movements of lever.

Fig. 12.1: Dog BP and respiration recording

Effect of Drugs on Dog Blood Pressure  91 Table 12.1. Drugs and solutions used in dog BP experiment Drugs

Dose (µg/kg)

Concentration (µg/ml)

1.

Epinephrine (Adrenaline)

1-8

10

2.

Norepinephrine (Noradrenaline)

1-8

10

3.

Isoprenaline

2

10

4.

Propranolol

1mg

1 mg/ml

5.

Acetylcholine

1-5

10

6.

Atropine sulphate

0.5 mg

1 mg/ml

7.

Dopamine

1-5

10

8.

Histamine

0.2-5

1-10

9.

CaCl2

0.1

1%

KCl µg = micrograms

0.1

1%

10.

Volume of above solutions to be injected = start with 0.1 ml, if sufficient response is not there increase dose to 0.2 ml and so on.

CSM The model usually have an on screen recording. You can choose drugs and record their effect (Table 12.2). The recordings will look like as: Actual dog experiment (Fig. 12.2).

Fig. 12.2: Dog BP recording with agonists

92  Practical Manual of Pharmacology CSM (FIG. 12.3)

Fig. 12.3: Dog BP recording

Table 12.2. Effect of drugs on dog BP S. NO. 1. 2. 3. 4. 5. 6. 7. 8. 9.

DRUG Control Epinephrine Norepinephrine Isoprenaline CaCl2 Acetylcholine KCl2 Dopamine Histamine

HEART RATE 62 71 57 91 1 37 1 35 40

BP Normal Increased Increased Increased Decreased Decreased Decreased Decreased Decreased

Epinephrine (Fig. 12.4): Produces biphasic response because of its actions on all adrenergic receptors. Initially there is α1 stimulation leading to increase in BP, this followed by β2 action leading to decrease in BP. It is followed by β1 action leading to increaser in BP, after this there is compensatory decrease in BP.

Fig. 12.4: Biphasic response with adrenaline

Norephinephrine: Produces greater rise in BP as compared to equivalent dose of adrenaline. This is because there is no vasodilatory component (β2). Isoprenaline: Decreases BP, as it has predominant β2 action.

Effect of Drugs on Dog Blood Pressure  93 Dopamine: There is decrease in BP with 1-5 µg dose, but BP increase with 5-20 µg dose. Histamine (Fig. 12.5): Produces fall in BP. Acetylcholine (Fig. 12.5): Produces fall in BP.

Fig. 12.5: Effect of depressors on Dog BP

Blockers can also be used to identify nature of unknown.

OBJECTIVES At the end of the practical class the student shall be able to:

CSM 1. Interpret effect of various drugs on dog BP and heart rate 2. Describe mechanism of action of various drugs. 3. Comment on nature of unknown drugs given. Exercise in examination These days LCD projectors are available in which you can project only a part of computer screen. With this type of projector it is very easy to use these softwares for examination purpose. On your computer screen everything is visible including name of drugs, but you can project only recording showing effect.

CHAPTER

13

Short Experiments for Efficacy and Safety

These experiments are demonstrated to students so that they get an idea of how efficacy and safety of drugs is tested in animals. The following experiments can be shown to students 1. Evaluate analgesic effect of drugs on rats 2. Evaluate antidepressant effect of drugs on mice 3. Evaluate adverse effects of drugs on mice 4. Evaluate Antianxiety effect of drugs.

DEMONSTRATION I Evaluate analgesic effect of drugs on rats using Tail flick method Pain is an unpleasant sensation localized to a part of the body. Tail flick method is used to evaluate analgesic activity of narcotic analgesics. Tail flick method evaluates sharply localized pain and measures the threshold for an escape response. Procedure In this method radiant heat is used. A wire heated upto 55°C is used for radiant heat. The apparatus used is analgesiometer (Fig. 13.1). The animal is put in rat restrainer. The tail is cleaned. The tail is placed on a level surface, a radiant heat is applied to the tail and the latency of the mouse to remove its tail from the heat is recorded. To avoid the heating of surrounding metallic parts due to radiant heat, cold water is circulated through hollow metallic portion of the apparatus surrounding the hot wire. Animal are screened on the apparatus and cut off time is 5 seconds. If an animal does not flick tail after > 5 seconds, the animal is excluded from the experiment.

Wistar rats can be used for this experiment. After screening 8 animals are selected for this experiment. There are divided into 2 groups. Four animals are given normal saline (group A) by intraperitoneal

Fig. 13.1: Analgesiometer

Short Experiments for Efficacy and Safety  95 route (i.p.) other 4 are given test drug (e.g. morphine 2 mg/kg i.p.-group B). Tail flick is done at 30 minutes, 1 hour and 2 hours after the drug administration. Everytime 3 readings are taken. Mean of group is taken for calculations (Table 13.1). Calculations % antinociception =

Test latency – control latency × 100 Cut off time – control latency

or The maximum possible analgesia (MPA) can be calculated as: MPA = Exercise What is the % antinociception or MPA of the given drug using analgesiometer? Table 13.1. To record your findings

30 minutes Group A Group B P value

Mean tail flick time Test reaction time – Saline reaction time 1 hour 2 hours 15 – Saline reaction time

DEMONSTRATION II Evaluate antidepressant effect of drugs on mice using despair behaviour test Depression involves decreased self-esteem of the person. It is usually caused by reaction to some exogenous stimuli or may be due to an endogenous emotional cause. Procedure In this method mice are put in a glass jar containing water. The dimensions of glass jar can be 40 cm height and 18 cm diameter. Water can be upto 15 cm. This is an inexpensive methods, you need not buy any expensive instrument. Animals are trained for swimming for 15 minutes. Mice when left in water start swimming (Fig. 13.2). When depression sets in, they stop swimming. This is counted as immobility period. In this period mouse does effort only to keep the head above the water. There is no active swimming. Test is conducted 24 hours after training.

Fig. 13.2: Mouse swimming

96  Practical Manual of Pharmacology After training 8 animals are selected for this experiment. There are divided into 2 groups. Four animals are given normal saline (group A) by intraperitoneal route (i.p.) route 4 are given test drug (e.g. imipramine 10mg/kg i.p.-group B). Total immobility period is noted for each mice. Mean of group is taken for calculations (Table 13.2). Statistical test can be applied to see any difference in score. Exercise: Evaluate the effect of the given drug on despair behaviour test. Table 13.2. For your recordings Total immobility period (mean) Group A Group B P value

DEMONSTRATION III Evaluate adverse effects of drugs on mice using Rota Rod apparatus (Fig. 13.3) This experiment is a measure of strength and coordinated movements of the animal. The apparatus is known as rota rod treadmill. It consists of a rotating rod (diameter 3 cm). Rod is suitably machined to provide grip for animals. Five flanges divide the rod into 4 partitions and 4 animals can be placed simultaneously. The rod is rotated by a electric motor at 6-10 rpm. There is digital display at bottom of each partition. It shows time the animals spends on the rod. It is run by solid state clock running at one second interval. When a animal falls off the rod on to the plate below, it trips the corresponding circuit for that partition. The clock stops and you can note the reading of endurance time of animal on rod. Procedure Wistar rats or albino mice can be used for this experiment. Animal are trained on rota rod. The animals are placed on rod and made to walk. Each time animals falls down, keep it again on the rod. Training for an animal ended when an animal remained on rod continuously for 180 seconds or completed 20 trials, whichever is earlier. If the animal failed, it was excluded. Test is conducted 24 hours after training. After training 8 animals are selected for this experiment. There are divided into 2 groups. Four animals are given normal saline (group A) by intraperitoneal route (i.p.) route 4

are given test drug (e.g. diazepam 3mg/ kg i.p.-group B). The time spent on rod (endurance time) by each animal is noted.

Fig. 13.3: Rota rod

Short Experiments for Efficacy and Safety  97 Mean of group is taken for calculations (Table 13.3). Statistical test can be applied to see any difference in score. Exercise: Evaluate the effect of given drug on motor functions using rota rod. Table 13.3. For your recording Mean endurance time Group A Group B P value

DEMONSTRATION IV Evaluate antianxiety effect of drugs on rats using hole board test (Fig. 13.4) This experiment is a measure of anxiolytic activity of a drug. The apparatus is an inexpensive wooden platform. Its dimensions are 0.5 × 0.5 m and it has 16 holes of 3 cm diameter each. Holes are large enough for animal to dip their head into holes. Head dip is calculated as one if it dips till eyes. Head dips are counted by a counter for 30 minutes. Procedure Wistar rats can be used for this experiment. Eight animals are selected for this experiment. There are divided into 2 groups. Four animals are given normal saline (group A) by ip route 4 are given test drug (e.g. diazepam 3mg/kg ip-group B). The head dip count was noted for each animal after 30 minutes of drug administration. Mean of group is taken for calculations (Table 13.4). Statistical test can be applied to see any difference in score. Exercise Evaluate the effect of given drug using hole board test. Table 13.4. For your recordings Mean head dip count Group A Group B P value

Fig. 13.4: Hole board test

CHAPTER

14

Ethics and Animals

Ethics is whatever you do when no one is observing you. These days it is very important to understand ethical issues when we are dealing with research on animals and humans. The four principles of ethics are: • Autonomy: Right to decide • Beneficence: One must remember that whatever we do should be done for benefit of patients. • Do no harm. • Justice: Best treatment and justice to all as far as possible. The guidelines for performing experiments on animals are given by CPCSEA ( committee for purpose of control and supervision on experiments on animals). The guidelines regarding maintenance of animal house are also given by CPCSEA (http://medind.nic.in/ibi/t03/i4/ ibit03i4p257.pdf). Animals are used in pharmacology in: 1. Undergraduate teaching to show effects of various drugs. 2. Postgraduate teaching to show effects of various drugs, to find out the nature of unknown drug and for bioassay. 3. Research to conduct screening for drugs, bioassay and for preclinical testing. For all new drugs, it is mandatory to do toxicity studies in animals.

ANIMAL TOXICITY STUDIES These are done before drug can be tested in human beings. The toxicity studies are divided into three stages: 1. Acute toxicity studies (single dose studies): Acute toxicity studies should be carried out in at least two species, usually mice and rats using 2 routes of administration. One of the routes should be same as intended for humans. The effect of drug is observed for 24 hours.

Fig. 14.1: Rat in cage, ethical!

Ethics and Animals  99 2. Subacute toxicity studies (repeated dose studies): These studies last for 3 weeks-3 months. Three doses and 2 species are used. 3. Chronic toxicity studies (long term studies): Long-term toxicity studies should be carried out in at least two mammalian species, of which one should be a non-rodent. These studies can continue upto the life time of animal (1-2 years). Effects of drugs are studies even in next generation.

SPECIAL TOXICITY STUDIES 1. Fertility studies 2. Teratogenicity studies 3. Carcinogenicity studies. Rodents (rats, mice) and non-rodents (rabbits) are used in these studies. There is a lot of unnecessary pain and trauma to animals during these experiments, hence to reduce this the following principle of 3Rs is recommended: 1. Refinement: Refine experimental methods to decrease unnecessary pain and trauma to animals. 2. Reduction: Reduce the number of animals used in these experiments. 3. Replacement: Replace the animal experiments with appropriate alternative methods, e.g. computer simulation models, in-vitro methods, cell culture techniques. Whenever you think of animal experiments, critically analyse following: 1. Is the animal, the best experimental system for the problem (Fig. 14.1)? 2. Can the pain and discomfort be lessened? 3. Is the problem under review is worth solving? Debate on use of animals in teaching and research: Full class is divided in two batches. (If you get class in batches for practical, you can use one theory lecture for this activity) One batch speaks for the use of animals and other against the use of animals in teaching and research. Each batch is given fifteen minutes to discuss the issue in their respective batch and then choose a group leader to speak on behalf of group. The speaker gets 10 minutes time to speak. Ten minutes are allowed for questioning and comments. This if followed by concluding remarks by a faculty member. Visit to animal house: central animal house as well as departmental animal house: This can be done on day of practical by dividing students into small batches. This is done after debate to avoid any enthusiastic, biased reaction of students to use of animals. This is done because first time they are exposed to animal experiments as well as animal house, most of them might feel too concerned about animals by looking at cute looking animals (especially guinea pigs, rabbits).

100  Practical Manual of Pharmacology Depending upon facilities available in animal house, the following points can be discussed during the to animal house: 1. Maintenance of stock, types of animals kept 2. Why they are required (name of experiments) 3. Breeding of animals 4. Separation of pregnant, just delivered pups 5. Maintaining room temperature, humidity, air flow, light-dark cycle 6. Feeding practice (pellets, greens, etc.) 7. Care of sick animals 8. Disposal of animal waste.

OBJECTIVES At the end of the session the student shall be able to: 1. Understand principles of ethics. 2. Realize the importance of ethics when using animals for experiments. 3. Justify the need for adhering to proper standards of maintenance and care in the use of animals for research and teaching.

Section 3 Clinical Pharmacology

CHAPTER

15

Introduction to Clinical Pharmacology

Clinical pharmacology is study of drugs in clinical material, i.e. human beings. Clinical pharmacology is also the science of prescribing the correct drug at the correct dose at the right price to the right patient, i.e. rational drug utilisation. It includes clinical trials of drugs, postmarketing surveillance, pharmacokinetics, pharmacodynamics, toxicity, drug interactions, etc. The focus of pharmacology teaching has shifted more to clinical pharmacology. In clinical pharmacology, a student is expected to know the appropriate indication, dose, route of administration, frequency adverse effects, contraindications, potential drug interactions, how to reported adverse effects and above all explain these salient features to patient. Prescribing and therapeutics are important areas of clinical pharmacology. It is proposed that teaching of clinical pharmacology should be extensive for undergraduates. They should be taught more about clinical pharmacology of drugs. There should be a problem based approach to teach clinical pharmacology. Learning through curiosity, the exploitation of knowledge and critical evaluation of evidence should be encouraged. To learn this aspect of pharmacology, it is essential to learn some basic principles of pharmacology. A sound knowledge of basic principles of clinical pharmacology allows students to take a logical approach to learning about any of the drugs they are likely to encounter during the course. This section deals with the above mentioned issues. This branch of pharmacology is most demanding these days. With the shift of a number of clinical trials of new drugs to India, the training and demand has increased tremendously in this area. Most of the aims of clinical pharmacology are general requirements for the safe and effective use of dugs in most areas of clinical practice. Inculcate the attitude and behaviour required by a professional competent doctor. Prescription load can be decreased by using essential drug list. A student who is able to effectively learn these aspects of clinical pharmacology, should be able to cope safely and effectively with most of the prescribing challenges that he/she is likely to face in early postgraduation or practice. Clinical Pharmacology learning should produce graduates who are competent to prescribe safely and effectively. They should learn to assimilate information about new drug developments that will occur throughout a professional carrier.

CHAPTER

16

Pharmacokinetic Parameters and Calculations

Pharmacokinetics is what the body does to the drug. The knowledge of kinetics is very important for budding doctors to understand how dosage schedules are formed for various patients and diseases. Basically the process of pharmacokinetics involves 4 steps, i.e. ADME as follows: Step 1: Absorption of drugs from various route of administration Step 2: Distribution of drugs into body Step 3: Metabolism of drugs into body Step 4: Elimination of drugs or their products from body. The ADME process can be depicted as (Fig 16.1): Various body fluids and organs involved in ADME are (Fig. 16.2): The knowledge about pharmacokinetic principles and their clinical significance is very important for doctors to generate dosage schedules, to monitor therapy, to modify schedules in case of diseases, etc. Clinical pharmacokinetics is the name assigned to science discipline dealing with the application of pharmacokinetics to the safe and effective therapeutic management of the individual. Let us discuss important pharmacokinetic parameters.

BIOAVAILABILITY Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action. It is denoted as "f". Bioavailability is the amount of the administered drug that is available to have an effect. Bioavailability of a drug is largely determined by the properties of the dosage form (which depend partly on its design and manufacture), rather than by the drug's physicochemical properties.

Fig. 16.1: Plasma concentration time curve

Pharmacokinetic Parameters and Calculations  105

Fig. 16.2: Various organs, tissues involved in pharmacokinetics

SALIENT FEATURES 1. Drugs given intravenously may be considered to be 100% bioavailable as they are administered directly into the circulation. 2. Administration of highly lipid soluble drugs by oral route means that some of the drug molecules will be lost due to first pass metabolism and thus bioavailability is reduced. For calculating bioavailability (f) drug is give by IV route and by intended route of administration. Plasma concentration curves are plotted and area under plasma concentration curve (AUC) is measured for each mode of administration (Fig. 16.3). f=

AUC oral × 100 AUC IV

For new preparations of the same drug, bioavailability can be compared to see their bioequivalence. Bioequivalence is whether both preparations give same bioavailability in the body or not. Clinical significance: 1. Oral dose is more as compared to IV Dose. 2. Marked interindividual variation in first pass metabolism, hence dose required. 3. Hepatic diseases affect first pass metabolism, hence concentration achieved will be high.

Fig. 16.3: AUC

106  Practical Manual of Pharmacology 4. Drug interactions can occur when 2 drugs compete for same pathway of first pass metabolism.

AUC It is area under plasma concentration-time curve. It tells about total amount of drug present in the body. The most commonly method used to calculate AUC is trapezoidal rule. AUC is a measure of quantity of drugs in the body. From AUC one can determine bioavailability (f) of a drug and the relative bioavailability. AUC can be calculated by the following methods: 1. 2. 3. 4.

Square counting method Cutting and weighing method Planimetery Trapezoidal rule: This is considered to be the best method. A blood concentration, time curve can be described by a series of trapezoids that are determined by each concentration time point. In Figure 16.4, A is triangle and B-F are trapezoids. Calculate area of all and add up. This will give you AUC0-6. AUCt-α = Kel Last observed concentration AUC0-α = AUC0-6 + AUCt-α Relative bioavailability (Bioequivalence) = Other formulae for AUC: AUC = AUC = AUC =

CL = Clearance, Vd = Volume of distribution Kel = Elimination rate constant.

VOLUME OF DISTRIBUTION (VD) It is defined as "apparent or hypothetical volume of body fluids that can accommodate the total amount of drug administered so that the concentration achieved is equal to concentration in the plasma.

Fig. 16.4: Trapezoids

Pharmacokinetic Parameters and Calculations  107 If total amount of administered drug = 1000 mg And plasma conc. achieved = 50 mg/l Then Vd will be calculated as given in Figure 16.5.

Fig. 16.5: Vd calculation

Vd gives an idea about distribution of drug as given in Tables 16.1 and 16.2. Table 16.1. Vd as related to drug present in body If vd is 10-20 L 20-40 L

Drug is present in Plasma and extracellular fluid Intracellular fluid

> 40 L

Concentrated in tissues

Example Streptomycin Lipid insoluble Phenytoin Lipid soluble Chloroquine Highly lipid soluble

Table 16.2. Vd of common drugs Drug WARFARIN LIGNOCAINE DIGOXIN NORTRIPTYLINE

Vd (L/Kg) 0.1 1.5 7 20

Vd depends on the following factors: • Blood flow rate in different tissue • Lipid solubility of drug • Partition coefficient of drug and different types of tissues • pH • Binding to biological material. Vd is often proportional to body weight. In obesity Vd is lower than expected from the body weight. In edema, Vd is larger than expected for the body weight.

108  Practical Manual of Pharmacology Other formulae for Vd Vd = CL = Vd = Vd = Clinical significance 1. Hemodialysis in drug poisoning: Drugs with low Vd can be easily removed by hemodialysis, e.g. Salicylates 2. Calculation of loading dose (LD) LD = Vd × CL (IV Route) CL = clearance LD =

f = bioavailability.

HALF-LIFE The half-life (t½) is the time taken for the circulating plasma concentration of a drug to fall to 50% of original/peak concentration. Kel = elimination rate constant

t½ = Kel =

so t½ =

For example: Aspirin 15 minutes Phenobarbital 2-6 days. Salient features 1. Half-life is a derived parameter that changes as a function of both clearance and volume of distribution. Half-life is constant in first order kinetics. Half-life increase with increase in concentration in zero order kinetics 2. Plasma protein binding increase half-life 3. Drug widely distributed and sequestrated in tissues got longer half-life, e.g. amiodarone 4. Approximately 4-5 half-lives are required for complete elimination of drug from the body:

Pharmacokinetic Parameters and Calculations  109 one two three four

t½ t½ t½ t½

= = = =

50% drug is eliminated 75% (50 + 25) drug is eliminated 87.5% (75 + 12.5) drug is eliminated 93.75% (87.5 + 6.25) drug is eliminated.

Clinical significance 1. Half-life determines frequency of administration or dosing interval of drug, e.g. If t½ is 12 hours, then drug is given twice a day. 2. When rate of absorption equals rate of elimination steady state is said to be achieved. 3. The clinician usually wants to maintain steady-state concentrations of a drug within a known therapeutic range (gl), assuming complete bioavailability. 4. Approximately 4-5 half-lives are required to reach steady state (Fig. 16.6). 5. In most clinical situations, drugs are administered in a series of repetitive doses or as a continuous infusion in order to maintain a steady-state concentration of drug in plasma within a given therapeutic range. At steady state the rate of drug administration is equal to drug elimination and the mean concentration remains constant.

CLEARANCE Clearance is the most important concept to be considered when a rational regimen for longterm drug administration is to be designed. Clearance is defined as the volume of the plasma cleared of the drug in a unit time. It is expresses as ml/minute. If given clearance is 5 ml/minute, it means that 5 ml of plasma is cleared of the drug. Most of the drugs follow first order kinetics for clearance. Total body clearance is: CL = CLrenal + CLhepatic + CLother Other formulae for clearance CL = Vd * Kel CL =

CL =

Cp = Plasma concentration

Salient features 1. If a drug is only excreted by glomerular filtration, CLrenal can not exceed GFR (120 ml/min), e.g. Aminoglycoside antimicrobials.

Fig. 16.6: Steady state

110  Practical Manual of Pharmacology 2. If a drug is completely removed by tubular secretion, CLrenal can not exceed renal plasma flow (700 ml/min), e.g. Penicillin. 3. Reabsorption can decrease CLrenal to as low as 1ml/min. 4. Clearances is constant in zero order kinetics. Zero order kinetics are saturable kinetics, e.g. Phenytoin. It is also known as non-saturable kinetics. Most of the drugs follow first order kinetics. 5. Clearance increase with increase in concentration in first order kinetics. Clinical significance 1. Most of the drugs got unsaturable enzyme system for their hepatic biotransformation, hence most of the drugs are metabolised in liver. In this instance, the concentration of drug in the blood leaving the liver will be low (Cv = 0). Extraction ratio (ER) will approach unity

2. The rate limiting step will become hepatic blood flow. These drugs are known as high extraction ratio (HER) drugs, e.g. Lidocaine imipramine (Fig. 16.7). 3. In contrast, changes in intrinsic clearance and protein binding will affect. 4. The clearance of drugs with low extraction ratios, but changes in blood flow should have little effect. 5. Maintenance dose is calculated with the help of CL MD = CL × Cp.

LOADING DOSE The "loading dose" is one or a series of quickly repeated doses that may be given at the onset of therapy with the aim of achieving the target concentration rapidly (Fig. 16.8). The appropriate magnitude for the loading dose is: LD =

, e.g. 20L*20 mg/L = 200 mg, Cp = plasma concentration required

• Loading dose depends on extent of distribution. If a drug is widely distributed in the body a large loading dose is required to fill the distribution sites. • A loading dose may be desirable if the time required to attain steady state by the administration of drug at a constant rate (four elimination half-lives) is long relative to the temporal demands of the condition being treated.

Example: The half-life of lidocaine, an antiarrhythmic, is usually more than 1 hour. One cannot wait for 4 to 6 hours to achieve a

Fig. 16.7: Hepatic extraction

Pharmacokinetic Parameters and Calculations  111 therapeutic concentration, arrhythmias encountered may be life threatening, hence, a loading dose of lidocaine is used. Maintenance dose To maintain steady state a maintenance dose is required. MD = Maintenance dose depends on clearance. Whatever dose is lost in clearance is replaced by maintenance dose.

Fig. 16.8: Loading dose

OBJECTIVES At 1. 2. 3.

the end of this session a student shall be able to: Define the various pharmacokinetic parameters Calculate various pharmacokinetic parameters from given data Explain clinical significance of these parameters.

C H A P T E R

17

C H A P T E R

Prescription Writing Through Problem Based Learning (Rational Prescribing)

A prescription is a written order by a physician to a pharmacist to dispense a therapeutic agent to a patient. This therapeutic transaction is the sum of the physician's evaluation of the problem (the history, physical examination, diagnostic tests, decision on treatment, and prognosis). On this single sheet of paper are the final results of the physician's education, experience, and diagnostic acumen. Prescriptions are typically handwritten on preprinted prescription forms that are assembled into pads, or alternatively printed onto similar forms using a computer printer. Preprinted on the form is text that identifies the document as a prescription, the name and address of the prescribing provider and any other legal requirement such as a registration number. The word "prescription" can be decomposed into "pre" and "script" and literally means, "to write before" a drug can be prepared. It is estimated that 3 billion prescriptions were written in the United States in 2002. This number has grown from 1.5 billion in 1989 and is expected to continue to grow. Drugs should be prescribed only when they are necessary for treatments following clear diagnosis/ indication. Not all patients or conditions need prescriptions for drug. In certain conditions simple advice and non-drug treatment may be more suitable. All written prescriptions should contain • • • • • • •

Patient's full name and address Prescriber's full name, address, telephone number and registration number Date of issuance Signature of prescriber Drug name, dose, dosage form, amount Directions for use Refill instructions. A prescription has various parts. Predating modern legal definitions of a prescription, a prescription traditionally is composed of four parts: a "superscription", "inscription", "subscription" and "signature".

Prescription Writing Through Problem Based Learning (Rational Prescribing)  113 Superscription: it has • Name and address of doctor. • Name, age, sex and address of patient (age is desirable for safety purposes) and date. • The symbol "L" separates the superscription from the inscriptions sections. L is a traditional esoteric symbol, for the word recipe 'take thou' (Latin "recipe") the imperative form of "recipere", "to take". It should not be interpreted as instructions to the patient to "take thou" as patient instructions are in a later section. Some the literal exhortation to the pharmacist is "take thou this recipe". Significance of superscription is to expedite the handling of the prescription and to avoid confusion with the medications intended for some one else. It is also the duty of pharmacist to verify the patient's name and age to monitor the prescribed dose. Inscription: The inscription section defines what the medication is. It has name of drug, its dose, frequency, duration, route of administration • Choice of drug name: best is to use generic names or non-proprietary or official names rather than using brand names. This eliminates necessity for memorising multiple drug names. • The name, strength of drug and its inert additives should be mentioned, both for the single ingredient drug and fixed dose drug combinations (FDCs). This helps in rapid identification of drug and a quick estimate of the amount consumed and can help in the initiation of appropriate therapy in case of adverse drug reactions (ADRs) or accidental or deliberate over dosage. • Frequency and duration of administration. • One should avoid using abbreviations since it frequently leads to errors. • For decimals a zero should precede the decimal point where there is no other value, e.g. 0.5 ml not .5 ml. • Do not abbreviate microgram, nanogram • Prescription orders should always be written in metric system. Home/domestic measures or convenient kitchen utensils should not be used to measure as they are not uniform and accurate to indicate the metric unit of weight or volume desired for liquid drugs. Instead a calibrated dropper, moulded plastic cylinders, measuring oral syringe, and graduated caps have been designed for administering liquid medications. Subscription: It has dispensing directions to the pharmacist, e.g. send such number of capsules/send such number of tablets. Importance of subscription is to reduce the communication gap between patient and physician and direct the pharmacist to detect any overdose of potent drugs for safety of patient and educate the patient about compliance and how to take medication. Transcription or signature: The "signature" section contains directions to the patient and is often abbreviated "Sig." or "Signa". It also obviously contains the signature of the prescribing doctor though the word "signature" has two distinct meanings here and the abbreviations are sometimes used to avoid confusion. It has instruction or direction to the patient regarding

114  Practical Manual of Pharmacology the use of medications prescribed. Here brevity, clarity and accuracy are especially important. This is required to improve patient's compliance and to explain the patient about his or her illness and how the prescribed medication will alter the disease process. Only the registered medical practitioner can prescribe the drug. Prescribe drug therapy for a male patient age 55 years, suffering from myasthenia gravis

An example of prescription:

Superscription

Inscription

Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987

Name: Amit Sharma Age/Sex: 55 Male Address: H.No 445, Model town, Ludhiana Tel: 5058677 Unit No. C-238567 Date. 27-6-2007 L Tab. Pyridostigmine 30 mg Tab. Prednisone 60 mg Dispense 45 tablets of Pyridostigmine Dispense 15 tablets of Prednisone

Subscription

Take 1 tab. of pyridostigmine 3 times a day for 15 days Take 1 tab. of prednisone once a day for 15 days

Transcription

Revisit after 15 days

Regd.No 24456 (Punjab Medical Council)

Signature Name Dr Ankur Sharma, MD

In conventional curriculum, practice of prescription writing becomes mechanical. Most of the times the students copy the prescribing behavior of their seniors or teachers on existing standard treatment guidelines, without explanation as to why certain treatments are chosen and prescribed. The need of improvement with supplementing sufficient background information and proper orientation is felt. Prescription writing through problem-based pharmacotherapy teaching is one such way, which can help the students appreciate the relevance of acquired information for appropriate or rational prescribing in a better way. It provides step by step guidance to the process of rational prescribing.

Prescription Writing Through Problem Based Learning (Rational Prescribing)  115 To develop self-learning and thinking process in the medical students early in their career while learning pharmacology is the best way to inculcate these habit of rational prescribing. The students will be learning how to prescribe effectively and judiciously for any given situation and also the skill of choosing and prescribing drugs logically and rationally. For this we can use the WHO concept of "P" drug. WHO has introduced the concept of "P" drugs. As a doctor you may see 50 patients per day or more, many of whom need treatment with a drug. How do you manage to choose the right drug for each patient in a relatively short time? This can be achieved by using "P"drug concept. "P"drugs or personal drugs are the drugs you have chosen to prescribe regularly and with which you have become familiar. They are your priority choice for given indications. They will differ from country to country and between doctors. In general, the list of drugs registered for use in the country and the national list of essential drugs contain many more drugs than you are likely to use regularly. Most doctors use only 40-60 drugs routinely. It is, therefore, useful to make your own selection from these lists and to make this selection in a rational way. In fact, in doing so you are preparing your own essential drugs list. The Pdrug concept is more than just the name of a pharmacological substance, it also includes the dosage form, dosage schedule and duration of treatment. Students will be taught to make an inventory of possible treatments of any common disorder resulting in a set of first choice drugs called P (personal) drugs on the basis of their efficacy, safety, suitability and cost. Steps in choosing a P-drug: Step Step Step Step Step (i)

i: Define the diagnosis ii: Specify the therapeutic objective iii: Make an inventory of effective groups of drugs iv: Choose an effective group according to criteria v: Choose a P-drug Define diagnosis: When selecting a P-drug, it is important to remember that you are choosing a drug of first choice for a common disorder. Knowledge about pathophysiology of the disease will help you to choose drug of first choice. Treating symptoms without really treating the underlying disease/pathology is known as symptomatic treatment. (ii) Specify the therapeutic objective: It is very useful to define exactly what you want to achieve with a drug. For example, to control the blood pressure to a certain level, to cure an infectious disease or prevent occurrence of hepatitis. If you are sure about therapeutic objective, it becomes easier to select P drug. (iii) Make an inventory of effective drugs: In this step you link the therapeutic objective to various available drugs. Efficacy is the first criterion for selection of drugs. Initially, you should look at groups of drugs rather than individual drugs. There are tens of thousands of different drugs, but only about 70 pharmacological groups.

116  Practical Manual of Pharmacology (iv) Choose an effective group: There are two ways to identify effective groups of drugs. The first is to look at formularies or guidelines or standard treatment guidelines that exist in your institution/state/ country, or at international guidelines, such as the WHO treatment guidelines for certain common disease groups, or the WHO model list of essential drugs. You can also take help from the index of a good pharmacology reference book and determine which groups are listed for your diagnosis or therapeutic objective. In most cases you will find only 2-5 groups of drugs which are effective. (v) Choose a P-drug: Out of these shortlisted drugs choose a P-drug for a common condition. After choosing a P drug this concept can be extended to rationally treat patients. There are 6 steps: (i) Define patient's problem: Make right diagnosis based on clinical history, sign symptoms as well as investigations Patient's complaints are mostly linked to his/her symptoms. A symptom is not a diagnosis in itself, although it will usually lead to it, e.g. all patients with symptoms of sore throat will not need the same treatment even when they have same diagnosis. (ii) Define therapeutic objective: Before choosing a treatment it is essential to specify your therapeutic objective. What do you want to achieve with the treatment? (iii) Verify the suitability of your P-drugs: You have chosen a P drug as first drug of choice for common condition. You cannot assume that 'first-choice' treatment will always be suitable for everyone. You must verify whether your P-drug is suitable for this individual patient or not. It is to be remembered here that P drug for a condition may not always be the most appropriate drug for every patient. A number of patient specific factors like extremes of age, pregnancy and lactation, concurrent medications, existing diseases (hepatic or renal disease) may require a different P drug for a particular patient. The process of "personal drug" selection is centered around the drug and indication. But for patient treatment, even if the disease is same, the patient related factors become important and need to be considered. There might be some factors or characteristics peculiar to the patient that renders the personal drug unsuitable for him/her. (iv) Write a prescription: Write legibly and completely as described in various parts of prescription. (v) Give information, instructions and warnings: It has been seen that, 50% of patients do not take prescribed drugs correctly, take them irregularly or not at all. The most common reasons cited are that symptoms have ceased, side effects have occurred, the drug is not perceived as effective or the dosage schedule is complicated for patients, particularly the elderly. Hence, it is very important to talk to your patients. Explain them about treatment, specific instructions and warnings about medications.

Prescription Writing Through Problem Based Learning (Rational Prescribing)  117 (vi) Monitor and/or stop the treatment: After rational treatment of your patient, you would be interested to know what happened to patient's condition. For that you can monitor of follow up the patient. You can decide whether treatment is effective or not.

P-DRUGS AND P-TREATMENT There is a difference between P-drugs and P-treatment. The key point is that not all diseases need to be treated with a drug. Not every P-treatment includes a P-drug! Electronic prescriptions Softwares are available to write prescriptions. But more and more, doctors are writing prescriptions electronically in developed countries, but it is not so popular in our country due to various reasons.

OBJECTIVES At the end of this practical, a student shall be able to: 1. Acquire cognitive, motor and communication skills that are necessary throughout a clinical career for rational therapeutics. 2. Choose an appropriate drug from P-drug list, deciding what information or instruction is (or not) to be given and to monitor the result of treatment. 3. Write appropriate prescription for a given case. Exercises in class Anil Verma, 42 years old male is found to be diabetic during routine medical examination. He does not experience any symptoms related to increased blood glucose (PPBS 160 mg/dl). Physical examination reveals- his BP 160/130 mm of Hg, weight 76 kg, height 5 ft. 10 inches. No other abnormality is found. Exercise: Q1. What is the patient's problem? Q2. What is the goal of treatment in this patient? Q3. Prepare a list of effective groups of drugs for the given condition/s. Q4. Choose the effective group/groups of your choice for the given condition/s giving justification. Q5. Choose the most appropriate drug/drugs from your chosen group/s of drugs based on efficacy, safety, suitability and cost, for this patient. Q6. Write the prescription with suitable instructions and follow up plan for this patient.

118  Practical Manual of Pharmacology Examples of prescriptions for common diseases: 1. Anemia (microcytic hypochromic)

Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name:

Amit Sharma

Age/Sex: 55 Male

Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567

Date 07-07-2007

L •

Tab. Ferrous sulphate (60 mg elemental iron) 1od × 1 month

•

Tab. Albendazole 400 mg stat

Direction: Dispense 30 such tablets of ferrous sulphate and 1 tablet of albendazole Sig: Take one tablet of ferrous sulphate every day before food for 1 month. Take one tablet of albendazole. Revisit after 1 month for hemoglobin estimation.

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council)

Prescription Writing Through Problem Based Learning (Rational Prescribing)  119 2. Angina pectoris Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Isosorbide dinitrate 5 mg sublingually as and when required • Tab. Isosorbide mononitrate 50 mgSR 1od × 15 days • Tab. Atenolol 50 mg 1 od × 15 days • Tab. Aspirin 100 mg 1 od × 15 days Direction: Dispense 10 tablets of isosorbide dinitrate, 15 tablets of isosorbide mononitrate, atenolol and aspirin. Sig: Take these tablets after breakfast

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Other measures: • • • • • •

Life style change is recommended, e.g. work stress, smoking, etc. Stop working and sit down at the earliest indication of pain in chest Avoid tea, coffee, nasal decongestant drops Atenolol contraindicated in asthmatics Do not take aspirin empty stomach Revisit after 2 weeks or earlier in case of any distress or breathlessness, fainting or palpitations.

120  Practical Manual of Pharmacology 3. Acute asthma Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Salbutamol MDI 2 puffs (100 µg/puff) SOS Direction: Dispense one MDI of Salbutamol Sig: Use inhaler whenever needed as described in attached pictorial diagram.

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council)

Prescription Writing Through Problem Based Learning (Rational Prescribing)  121 4. Acute severe asthma Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Oxygen inhalation • Inj. Hydrocortisone hemisuccinate 100 mg iv stat, repeat 100 mg every 6 hourly • Nebuliser salbutamol 2 ml diluted to 5 ml with normal saline over 30 minutes • Inj. Terbutaline - 5mg/ml 1 ampoule SC immediately • Review the patient every 2 hourly Direction: Dispense 10 vials of hydrocortisone, nebuliser salbutamol and 5 ampoules of terbutaline.

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Other measures: • Hospitalise the patient • If patient is not in hospital, give salbutamol inhaler (100 ug/puff) 2 puffs every 10 minutes till patient reaches hospital • Admit and keep the patient in propped up position.

122  Practical Manual of Pharmacology 5. Hypertension (Essential hypertension with no associated disease) Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Salt restriction • Exercise/meditation to relief stress • Tab. Atenolol 50 mg 1 od × 15 days • Revisit after 15 days. Direction: Dispense 15 such tablets Sig: Take one tablet every day, regularly do aerobic exercises, restrict salt intake.

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Other measures/additional information: • Dose of atenolol may be increased upto 100 mg/day • The choice of drug may vary depending on age and associated diseases. Alternative drugs are: enalapril (hypertension with CHF or diabetes), thiazide diuretics, amlodipine (hypertension with asthma). • Combination therapy with more than one agent can be used if the patient does not respond to single drug therapy. • Advice to reduce/eliminate smoking/alcohol intake.

Prescription Writing Through Problem Based Learning (Rational Prescribing)  123 6. Status epilepticus Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Inj Lorazepam 0.1 mg/kg at rate of 2 mg/ml iv Can be repeated after 10 min (max 3 doses) If seizures persist then give • Inj Phenytoin 15-20 mg/kg slow iv infusion • Review the situation every 15 minutes

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Additional measures: • • • •

Admit the patient in casualty Maintain patent airway, breathing, circulation Phenytoin can be repeated at 5-10 mg/kg (max 30 mg/kg) If seizure still persist then give Inj. Phenobarbitone 20 mg/kg iv at 50-100 mg/min. It can be repeated. If seizures are not controlled then give midazolam or propofol.

124  Practical Manual of Pharmacology 7. Peptic ulcer Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Omeprazole 20 mg I od

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Additional measures: • Test for H pylori, if positive then prescribe for H pylori eradication. • Avoid alcohol, smoking, stress, caffeinated drinks, chillies and drugs like steroids, NSAIDs.

Prescription Writing Through Problem Based Learning (Rational Prescribing)  125 8. NIDDM Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Glibenclamide 5 mg ½ tablet every day before breakfast

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Additional measures: • Dose can be titrated up based on blood glucose levels. • Advice diet modification and exercise.

126  Practical Manual of Pharmacology 9. Acute abdomen Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Inj. Dicyclomine HCl 10 mg IM stat • Tab. Dicyclomine HCl 10 mg 1 sos Direction: Dispense 1 ampoule of dicyclomine and 4 tablets of dicyclomine Sig: Take one tablet whenever needed

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Additional measures: • Narcotics may be given in severe pain • If pain due to soft tissue trauma give NSAIDs • Advise semisolid diet.

Prescription Writing Through Problem Based Learning (Rational Prescribing)  127 10. Dysmenorrhoea Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Ritu Sharma Age/Sex: 35 Female Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Mefenamic acid 250 mg tds × 3 days • Tab. Dicyclomine HCl 10 mg tds × 3 days Direction: Dispense 9 tablets of mefenamic acid and dicyclomine

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council)

128  Practical Manual of Pharmacology 11. Acute attack of migraine Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Aspirin 650 mg stat, repeat after 4 hours if needed • Tab. Ergotamine (1mg) + caffeine (100 mg) 2 tab stat Then 1 tablet half hourly (max 6 in a day) If nausea/vomiting • Tab. Metoclopramide 10 mg stat and sos Direction: Dispense 4 tablets of aspirin, 6 tablets of ergotamine + caffeine and 6 tablets of metoclopramide Sig: Take tablet of aspirin immediately. Take ergotamine + caffeine 2 tab, then take 1 tablet half hourly. Take metoclopramide immediately and then whenever required.

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Additional measures: • Alternative to tablet aspirin are paracetamol and ibuprofen.

Prescription Writing Through Problem Based Learning (Rational Prescribing)  129 12. Allergic Conjunctivitis Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Betamethasone eye drops (0.1%) • Ketorolac eye drops (0.5%) q6h till symptoms subside Direction: Dispense 1 vial of betamethasone and 1 vial of ketorolac

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council)

130  Practical Manual of Pharmacology 13. Herpes zoster Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Acyclovir 800 mg 5 times a day × 7 days • Tab. Ibuprofen 400 mg tds till symptoms subside Direction to pharmacist: Please dispense 35 tabs of tablets of acyclovir and 10 tablets of ibuprofen.

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council)

Prescription Writing Through Problem Based Learning (Rational Prescribing)  131 14. Oral candidiasis (Thrush) Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Fluconazole 100 mg 1 od × 14 days or • Clotrimazole mouth paint 1% 2-3 times/day × 7 days Direction: Dispense 14 tabs of fluconazole

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council)

132  Practical Manual of Pharmacology 15. Vaginal candidiasis (Vulvovaginitis) Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Ritu Sharma Age/Sex: 35 Female Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Fluconazole 150 mg stat Direction: Dispense 1 tab of fluconazole

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council)

Prescription Writing Through Problem Based Learning (Rational Prescribing)  133 16. Hepatic amoebiasis Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Tinidazole 300 mg 2 bd × 7 days • Tab. Chloroquine 250 mg 2 bd × 1day then 1 bd × 19 days Direction: Dispense 14 tabs of tinidazole and 42 tabs of chloroquine. Sig: Take 2 tablets of tinidazole two times in a day. Take 2 tablets of chloroquine two times in the day on day 1 then 1 tablet two times in a day.

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Additional measures: • Metronidazole can be given in place of tinidazole • If severe, give metronidazole IV

134  Practical Manual of Pharmacology 17. Intestinal amoebiasis Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Tinidazole 500 mg bd × 3 days • Tab. Diloxanide furate 500 mg tds × 10 days Direction: Dispense 6 tabs of tinidazole and 30 tabs of diloxanide furate

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Additional measures: • Tinidazole can be taken as 2 g single dose • In place of tinidazole secnidazole 2 g single dose can also be taken.

Prescription Writing Through Problem Based Learning (Rational Prescribing)  135 18. Primary syphilis Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Inj. Benzathine penicillin G.2.4 M Units IM stat AST (1.2 M Units in each buttock) Direction: Dispense 1 vial of inj. benzathine penicillin

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Additional measures: • AST-after sensitivity test • If patient allergic to penicillin give tab. Doxycycline 100 mg bd × 10 days.

136  Practical Manual of Pharmacology 19. Typhoid Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Ciprofloxacin 500 mg 1 bd × 14 days • Tab. Paracetamol 500 mg tds × 5 days Direction: Dispense 28 tabs of ciprofloxacin and 15 tablets of paracetamol

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Additional information: • Dose of ciprofloxacin is 750 mg if weight of patient > 50 kg • Paracetamol is for headache and fever, but if there is any bleeding episode stop paracetamol • If patient is hospitalized start with inj. ciprofloxacin 200 mg IV bd • If no response within 5 days or condition worsens earlier shift to following therapy: Inj. Ceftriaxone or Inj. Ofloxacin or combination of both.

Prescription Writing Through Problem Based Learning (Rational Prescribing)  137 20. Acute gouty arthritis Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Aspirin 300 mg 2 q4h • Tab. Colchicine 0.6 mg 1 q4h till pain is there After that • Tab Allopurinol 100 mg tds × 7 days • Low purine diet Direction: Dispense 24 tabs aspirin, 12 tablets of colchicines and 21 tablets of allopurinol Sig: Take 2 tablets of aspirin 4 hourly and 1 tablet of colchicines 4 hourly till pain subsides. After that take 1 tablet of allopurinol three times in a day for 7 days.

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council)

138  Practical Manual of Pharmacology 21. Multibacillary leprosy Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L Day 1- Tab. Clofazimine 300 mg once in month supervised Tab. Rifampicin 600 mg once a month supervised Tab. Dapsone 100 mg 1od × 1 month Then 2-28 days Tab. Clofazimine 50 mg 1od × 1 month Tab. Dapsone 100 mg 1od × 1 month Direction: Dispense 1 tab of rifampicin, 30 tabs of dapsone and 36 tab of clofazimine (50 mg). Sig. Tablets on day 1 to be taken under supervision of doctor. Special instruction: Regular follow up every month. Repeat the same treatment every month and continue the treatment for 2 years. To report immediately in case of skin reaction. There might be red hypopigmented patches on skin due to clofazimine. There may be orange discolouration of body secretions due to rifampicin.

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council)

Prescription Writing Through Problem Based Learning (Rational Prescribing)  139 22. Paucibacillary leprosy Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L Day 1-Tab. Rifampicin 600 mg once a month supervised Tab. Dapsone 100 mg 1od × 1 month Then 2-28 days Tab. Dapsone 100 mg 1od × 1 month Direction: Dispense 1 tab of rifampicin, 30 tabs of dapsone. Special instruction: Regular follow up every month. Repeat the same treatment every month and continue the treatment for 6 months. To report immediately in case of skin reaction. There may be orange discolouration of body secretions due to rifampicin.

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council)

140  Practical Manual of Pharmacology 23. Tuberculosis Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Isoniazid (300 mg) 1 od × 30 days • Tab. Rifampicin (600 mg) 1 od × 30 days • Tab. Pyrazinamide (750 mg) 1bd × 30 days • Tab. Pyridoxine (10 mg) 1 od × 30 days • Tab. Ethambutol (1000 mg) 1 od × 30 days Direction: Please dispense 30 tablets of isoniazid, rifampicin, ethambutol, pyridoxine and 60 tabs of pyrazinamide Sig: Take tab. Rifampicin once daily empty stomach for 30 days. Take tab. Pyrazinamide two tab. once daily for 30 days. Take tab. Ethambutol and pyridoxine once daily for 30 days Special instruction: Regular follow up every month on the same day. To undergo sputum smear examination at the end of 2 months of treatment. To undergo ophthalmic examination prior to starting tab ethambutol. The colour of body secretions may turn orange with intake of tab. rifampicin.

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Additional information: • If sputum is negative after 2 months, start continuation phase Tab. Isoniazid 300 mg Tab. Rifampicin 600 mg Tab. Pyridoxine 10 mg all 1 od × 4 months • The drugs can be given 3 times in a week, but dose is more.

Prescription Writing Through Problem Based Learning (Rational Prescribing)  141 24. Chloroquine sensitive malaria Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Chloroquine (250 mg) 4 stat then 2 after 8, 24 and 48 hours • Tab. Primaquine 45 mg stat* Direction to pharmacist: Please dispense 10 tablets of chloroquine phosphate and 1 tablet of primaquine. Sig. Take 4 tablets at once, then 2 tablets after 8, 24 and 48 hours. Take single table of primaquine.

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Additional information: • Dose of chloroquine is 10 mg/kg followed by 5mg/kg • 1 tablet of 250 mg chloroquine phosphate contains chloroquine base 150 mg, hence above dose of chloroquine is 600 mg stat followed by 300 mg after 8, 24 and 48 hours • Each 5 ml of suspension contains 50 mg base • *For Falciparum malaria • For vivax/mixed malaria tab primaquine 15 mg 1 od for 5 days is given.

142  Practical Manual of Pharmacology 25. Chloroquine resistant malaria Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Mefloquine (250 mg) 3 tab stat then 2 tab after 8 hours • Tab. Pyrimetahamine + suladoxine (25 + 500 mg) 3 stat Direction: Dispense 5 tab. of tab. of mefloquine and 7 tab. primaquine Direction to patient: Take 3 tabs of mefloquine 250 mg at once followed by 2 tabs after 8 hrs. Take 3 tab of pyri + sufa together.

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Other measure: • To conduct test to assess the G-6 PD status before starting tab. primaquine. • Other alternative drugs are: Tab. Quinine sulfate (600 mg) tds × 7days plus Tab. Doxycycline (100 mg) 1od × 7days or Tab. Pyrimetahamine + suladoxine (25 + 500 mg) 3 stat or Tab Mefloquine + Tab. Artesunate 80 mg 2 tab-day1, 1 tab od × 5 days.

Prescription Writing Through Problem Based Learning (Rational Prescribing)  143 26. Cerebral malaria Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Inj. Quinine sulphate (600 mg in 1 ml) 10 mg/kg iv q8h • Inj. 5% Dextrose (100 ml) Direction to pharmacist: Please dispense such 24 ampoules of Inj. quinine and 24 Infusions of 5% dextrose. Sig. Inj. Quinine (20 mg/kg) loading dose to be mixed in 5% dextrose (20 ml) and given slowly over 20 minutes. Then inj. Quinine (10 mg/kg) mixed in 5% dextrose every 8 hours.

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Additional information • Infusion should continue for 4 hours • Once the patient attains consciousness start tab. quinine (10 mg/kg) to make total duration of therapy 7 days.

144  Practical Manual of Pharmacology 27. Upper respiratory tract infection Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Paracetamol 500 mg 1 tds × 3 days • Tab. Cetrizine 10 mg 1 od hs × 3 days Direction: Please dispense such 15 tablets of paracetamol and 3 tablets of cetrizine Sig. Take cetrizine at bedtime, avoid driving and operating heavy machinery.

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council)

Prescription Writing Through Problem Based Learning (Rational Prescribing)  145 28. CHF Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Enalapril 2.5 mg 1od × 7 days • Tab. Chlorthiazide 250 mg 1 od om × 7 days • Salt restriction Direction: Please dispense such 7 tablets of enalapril and chlorthiazide Sig. Take chlorthiazide in the morning.

Name: Dr Ankur Sharma, MD Regd.No 24456 (Punjab Medical Council) Additional measures: • In severe cases add Inj. furosemide 40 mg iv stat and repeat if required after 2-3 hours • Digoxin can be given if associated with atrial fibrillation.

146  Practical Manual of Pharmacology 29. Generalised tonic clonic and partial seizures Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date. 27-6-2007 L • Tab. Carbamazepine 200 mg tablets 1tds × 1 month Dispense 90 tablets Revisit after 30 days

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Additional measures: • Dose of carbamazepine to be increased to 800-1200 mg/day gradually • Alternative to carbamazepine are phenytoin and sodium valproate.

Prescription Writing Through Problem Based Learning (Rational Prescribing)  147 30. Depression Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Cap. Fluoxetine 10 mg bd × 1 month Direction: Dispense 30 capsule Revisit after 30 days

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council)

148  Practical Manual of Pharmacology 31. Bipolar disorder Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Lithium carbonate 300 mg 1tds x15 days Direction: Dispense such 45 tablets Revisit after 15 days

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council)

Prescription Writing Through Problem Based Learning (Rational Prescribing)  149 32. Parkinsonism Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 65 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Levodopa (100 mg) + Carbidopa (10 mg) 1tds × 15 days Dispense 45 tablets Sig: Take tablets after meals Revisit after 15 days

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Additional measures: • Dose of L-dopa to be increased gradually to 2-3 g/day.

150  Practical Manual of Pharmacology 33. Myasthenia gravis Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Pyridostigmine 60 mg 1tds × 15 days • Tab. Prednisone 30 mg 1 od × 15 day Direction: Dispense 45 tablets of pyridostigmine and 15 tablets of prednisone Sig: Take prednisolone early in the morning Revisit after 15 days

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council)

Prescription Writing Through Problem Based Learning (Rational Prescribing)  151 34. Insomnia Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Zolpidem 10 mg tablets 1od hs Direction: Dispense such 15 tablets Revisit after 15 days Sig: Do not take more dose than recommended

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Additional measures: • Advise nonpharmacological methods for sleep • Do not take medication in more than recommended doses and beyond the prescribed duration • Alternative drugs are-Tab. diazepam or alprazolam.

152  Practical Manual of Pharmacology 35. Erectile dysfunction Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Sildenafil 25 mg 1 tablet I hour before intercourse Direction: Dispense such 10 tablets

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Additional measures: • Check CVS status of patient • Check which other drugs are being taken.

Prescription Writing Through Problem Based Learning (Rational Prescribing)  153 36. Chronic simple glaucoma Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Pilocarpine (2%) eye drops tds × 1month • Timolol (0.5%) eye drops bd × 1month • Tab. Acetazolamide 250 mg bd × 1month Revisit after 1 month Direction: Dispense 1 eye drops of timolol and pilocarpine and 30 tablets of acetazolamide.

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council) Additional measures: • Revisit earlier if any deterioration in vision or persistent headache is there.

154  Practical Manual of Pharmacology 37. Aphthous ulcer Dr Rakesh Kumar MBBS, MD 115, Civil Lines, Ludhiana Phone: 0161-5030987 Name: Amit Sharma Age/Sex: 55 Male Address: H. No 445, Model Town, Ludhiana Tel: 5058677 Unit No. C-238567 Date 07-07-2007 L • Tab. Vitamin B-complex 1 bd × 1 month • Tab Ferrous sulphate (60 mg elemental iron) 1 tds × 1 month • Tab Albendazole 400 mg single dose • Metronidazole cream for local application × 7days • Lignocaine (2%) viscous for local application × 7days Direction to Pharmacist: Please dispense 60 tab. Vit B-complex, 90 tablets of ferrous sulphate, 1 tab of albendazole 250 mg, one metronidazole cream and 1 lignocaine.

Name: Dr Ankur Sharma, MD Regd. No 24456 (Punjab Medical Council)

Prescription Writing Through Problem Based Learning (Rational Prescribing)  155 Exercises in class: After going through solved examples of prescription for common diseases, students are advised to solve the following: Choose a P drug and write appropriate prescription in the following conditions: 1. A 55-year-old farmer (Kulwant Singh), was admitted in emergency department with irritation and watering of eyes, increased salivation, sweating, blurring of vision and abdominal pain. History revealed accidental exposure to heavy amount of an insecticide. 2. Tonometric examination of a 48-year-old Ram Singh patient showed raised intraocular pressure (55 mm of Hg). He was complaining of severe pain, redness in eye and nausea/ vomiting and headache. 3. A female aged 38 years (Kamlesh Kaur) came with complains of easy fatigability, weakness, dizziness and soreness of the tongue. Investigations reported reduced hemoglobin level (6.5 gm/dl) and blood film reported megaloblastic cells. 4. A 26 years pregnant female (Nisha Agarwal) patient complained of headache and visual disturbances in 2nd trimester. On examination edema of feet was present. Her BP was 160/130 mm of Hg. Urine examination reported albuminuria. 5. A 55 years Arun Kumar was brought to ICU with persistent severe chest pain for last one hours. The pain persists at rest and was radiating to left shoulder. Pain is associated with vomiting and profuse sweating. 6. Ashok Kumar, 48-year-old male, complained of dyspnoea, cough, easy fatigability and swelling over lower limbs. His BP was 170/130 mm of Hg. 7. A 22-year-old, Anushka a medical student reported loss of sleep due to examination stress for last two days. 8. Buta Singh, 55-year-old male, developed tremor, rigidity and disturbed gait following haloperidol therapy for last 1 month. 9. Anita Rani, 56-year-old female, complained of joint pain (small joints of fingers and toes) and joint stiffness. He reported that stiffness was more in the early morning. Pain increases on movement of affected joint. 10. Kanta, a 45 years, fair, fatty female complained of sudden onset of pain in epigastric region lasting for about 3 hours and some times upto 6 hours. A plain abdominal ultrasonograph reported presence of gall stones. 11. A 35-year-old Rajesh Singh complained of purulent urethral discharge, dysuria and meatal erythema. His blood smear showed leukocytosis and urethral swab culture reported neisseria gonococci. 12. A 28-year-old Kanta Kumari, complained of fever with chills, burning micturition, increased and frequency of urination. Microscopic examination of urine reported plenty of pus cells and epithelial cells. 13. A 20-year-old Sharad Gupta, complained of malaise, decreased appetite, itching all over body, abdominal discomfort and diarrhoea with mucus and blood for the last one week. Investigations revelaed high eosinophil count and stool examination reported, occult blood positive and presence of ova of both roundworm and hookworm.

156  Practical Manual of Pharmacology 14. A 20-year-old female (Sunayna), is known to vomit during journey. She approached you for help. She wants to travel for about 4 hours in bus from Chandigarh to Shimla. 15. A 35-year-old Amar Kaur, presented with history of palpitation, weight loss, increased appetite and swelling of the thyroid region for past 2 months. On clinical examination there were tremors in hands and investigations revealed raised serum T3 and T4 levels. 16. A 23-year-old female Charu, is recently getting married. She has come to you to take advice for contraception.

CHAPTER

18

Critical Evaluation of Prescription (Audit of Prescriptions)

Irrational prescribing is seen every where (developing and developed countries), at all levels (senior consultants and junior students) and in all categories (specialists, superspecialists). As drug treatment is the essence of therapeutics, it become extremely important to audit prescriptions. Wrong prescriptions can be fatal. With consumer protection Act (CPA) in force, you need to be careful when writing prescriptions. Common errors in prescription writing • Dosage form: Tab, cap, inj missing, hence difficult to dispense. Sometimes pharmacist/ patient decides on their own what can be the dosage form. Suppose patient is prescribed an injection for an spreading infection, but he takes only tablets or a patient is prescribed tablet to decrease his BP, but he takes injection. • Quantity: This is very common. You reach a pharmacist/chemist, give him prescription, but he asks which one you want 250 mg or 500 mg. Missing quantity can play havoc with lives of patients. Similarly error in dose when prescribing to children can lead to serious adverse effects. Sometimes you will find a prescription for an amount that doesn't exist. Do not assume anything, always write on prescription. • Length of therapy: This is a common error with most of the prescriptions. The result is that most of patients decide on their own when to stop or when to restart. This leads to irrational use especially with antimicrobials. With antimicrobials you need to be very specific about duration. • Patient allergies: Usually a missing part on prescriptions. • Date: Very important to track back when medication was started, how much time has passed and to refill prescription. • Signature: Missing on prescriptions. This mistake is now increasing, may be because of CPA. • Registration number: Again a serious omission. • Directions: A busy physician will not explain or explain in such a hurry that the patient does not understand or understand in incorrect way, e.g. a lady took methotrexate daily which was to be taken weekly. She died because of severe bone marrow suppression.

158  Practical Manual of Pharmacology • An error in reading the prescription by the pharmacist so that the wrong drug or dose is dispensed, e.g. cotrimoxazole-cotrimazole. • Substitution: Usually physician does not write substitution in case drug is not available. It is only when you go back ant tell them that a particular drug is not available then he/ she will write substitution. • Bad handwriting leading to confusion of drug name, e.g. similar names, e.g. Acetazolamide and acetohexamide • Drugs may be administered incorrectly, especially in institutions. A drug may be given to the wrong patient, at the wrong time or by the wrong route. Certain drugs must be given slowly when given IV, and some drugs cannot be given simultaneously. • Use of expired/outdated drugs is common. For some drugs (e.g. aspirin, tetracycline) risk of harm is great when outdated drug is used. • Most commonly, drug error results from a patient's confusion about how to take drugs. Tips for avoiding prescribing errors a) b) c) d) e) f) g) h)

Keep all blank prescription pads in a safe place Minimizing the number of prescription pads in use Write in ink Write out the amount prescribed in addition to the numerical number Avoid large quantities Only use prescription pads for prescriptions Don't sign prescriptions in advance Put only one prescription on a blank prescription form.

Precautions for controlled or unscheduled medications, e.g. morphine a) b) c) d) e) f) g) h) i)

Put the patient's diagnosis or the purpose of therapy on the prescription Print Include the patient's age and weight if relevant on the prescription Use the metric system unless dealing with units Avoid uncommon abbreviations Be consistent Sign your own prescriptions Inform patient about medications Never leave a decimal point naked. Prescription audit is part of medical audit. Medical audit is an objective and systematic way of evaluating the quality of care provided by physicians. It is conducted mainly in the hospitals, assesses only the technical aspects of medical care, and often falls short in its objectives.

Critical Evaluation of Prescription (Audit of Prescriptions)  159 Parameters of Prescription Audit : 1. Format of the prescription: Superscription, Inscription, Subscription, Transcriptioncomplete/incomplete. 2. Whether the diagnosis is recorded? Final or provisional. 3. Number of drugs prescribed. 4. Whether drugs prescribed are by official/pharmacological or brand names. 5. Choice of drugs for the given condition. First choice/Second choice/Third choice/Placebo. 6. Unnecessary/Irrational/Hazardous drugs. Unnecessary drug or injection: means a category of drugs or formulations not recommended for that particular condition in the standard text books. However, rational alternatives should not be considered unnecessary. Irrational drug or drug combinations, i.e. a drug or drug combination not recommended in the standard text books of pharmacology or other reputed scientific medical literature. Hazardous drugs: Drugs listed under the heading 'Banned and bannable drugs'. 7. Dose regime: Dosage form, dose, frequency and duration of treatment. 8. Prescription cost is calculated using the prevailing prices of drugs given in the latest volumes of Indian Drug Review, MIMS, CIMS or Drug Index. 9. Status of the prescription: Rational/Semirational/Irrational. 10. Date. 11. Signature of doctor, registration number. 12. Patient's particulars are right. Tips for writing a good prescription 1. Write or print the prescription legibly. If the physician has poor writing, preprinted or typed prescriptions may help. 2. Spell the name(s) of the drug(s) correctly, especially in view of the number of "lookalikes" and "sound-alikes." Get in the habit of writing both the trade and generic names. 3. Write the prescription in proper English grammar. Latin abbreviations such as qid may be interpreted as qd or od and are no longer recommended. Avoid phrases such as "as directed" or "as needed." Specify exact times to be taken: daytime hours, around the clock and relationship to meals. 4. Careful use of decimal points to avoid ambiguity: a. Avoid unnecessary decimal points: 5 ml instead of 5.0 ml to avoid possible misinterpretation of 5.0 = 50 b. Always zero prefix decimals: For example 0.5 instead of .5 to avoid misinterpretation with .5 = 5

160  Practical Manual of Pharmacology

5. 6. 7. 8.

9. 10. 11. 12. 13.

c. Never have trailing zeros on decimals: For example use 0.5 instead of .50 to avoid misinterpretation with .50 = 50 d. Avoid decimals altogether by changing the units: 0.5 g = 500 mg. Directions should be written out in full in English. Quantities can be given directly or implied by the frequency and duration of the directions. Where the directions are "as needed" the quantity should always be specified Where possible, usage directions should specify times (7 am, 3 pm, 11 pm) rather than simply frequency (3 times a day) and especially relationship to meals for orally consumed medication Avoid unspecified or "as needed" instructions-limits and indicators should be provided, e.g. "every 3 hours pain" For refills, minimum duration between repeats and number of repeats should be specified Provide the indication for all prescriptions even when obvious to the prescriber so that the pharmacist may identify possible errors Avoid non-standardized units such as "teaspoons" or "tablespoons" Write out numbers as words and numerals ("dispense #30 (thirty)") as in a bank draft or cheque.

Exercises: Critically analyse following prescription and rewrite the correct prescription. Example 1: L • Injection L-Dopa l0 mg IV Stat • Tab B complex 1 tab twice daily • Tab Benzhexol hydrochloride 2-5 mg. initially and then dose increased to 300 mg daily in divided doses. Dr ABC Reg No. 456 Comments: 1. Format of prescription is not proper, i.e. superscription is not given. Further the duration of drugs is not specified. 2. In the Inscription : Route and dose of L-Dopa mentioned is wrong. 3. Pyridoxine which is present in B complex tablet is dopa decarboxylase enzyme stimulator, so that very little amount of dopamine will reach the brain, further deteriorating the clinical condition.

Critical Evaluation of Prescription (Audit of Prescriptions)  161 4. Tab Benzhexol is increased to only 10-50 mg/day and also in divided doses. Such high doses can lead to toxic anticholinergic side effects. Example 2: Comment on the following prescription: Date 12/9/88

L

Name: Mr Kulwant Singh Age: 47 Sex: M Occupation: Business executive, Address: Mahim (Bombay) Diagnosis: Status asthmaticus Tab Cetrizine 10 mg stat Injection pethidine 10 mg LM. 6 hourly Tab salbutamol 20 mg tds. Injection adrenaline hydrochloride 1:1000 IV, sos

Comments: (write your comments)

C H A P T E R

19

Problem Based Drug Interactions

Drug interactions deserve a special mention because interactions are one of the leading causes of the adverse drug effects. It is estimated that drug-drug interactions represent from 3 to 5% of all in hospital medication errors. Drug interactions are also an important cause of patient visits to emergency department of hospitals. Drug interactions are often recognized only when serious toxicity occurs. Sufficient knowledge regarding effective and safe use of drugs is possible only if there is adequate knowledge understanding of pharmacokinetic and pharmacodynamic of drugs. This will enable physicians to select proper drug combinations. A number of drugs have been withdrawn from market because of drug interactions. Few important ones are: • Terfenadine February 1998 • Mibefradil June 1998 • Astemizole July 1999 • Cisapride January 2000. Hence, drug interactions between drugs represent a major concern for the pharmaceutical industry, for drug regulatory agencies and clinically for health care professionals and their patients. Drug interactions may be synergistic or antagonistic, desired or undesired, beneficial or harmful. Drug interaction can occur at 3 levels (Table 19.1): A. Pharmaceutical: These are interactions before administration of drugs. These interactions can occur in vitro (IV fluid, syringe, vial-outside the body) due to chemical interaction. Example: Heparin should not be mixed with tetracyclines, penicillins and hydrocortisone in the same syringe. Inactivation of these drugs may occur. When phenytoin is added to solutions of dextrose, a precipitate can and the phenytoin falls to the bottom of the IV bag as an insoluble salt. When this happens, it is no longer available to control convulsions. Amphotericin is still used widely as a urinary bladder perfusion to treat aggressive fungal infections. If it is administered in saline, the drug precipitates and can erode through the bladder wall if not removed. The clinical presentation of such cases is an acute abdomen due to perforation of the bladder. Lastly, it is recommended

Problem Based Drug Interactions  163 that aminoglycosides should not be mixed in IV fluids with betalactam antibiotics (penicillins, cephalosporins). This can markedly reduce antibiotic activity. Table 19.1. Sites of adverse drug interaction Site In vitro Oral Intestine Plasma Liver Kidney Receptor

Mechanism Chemical interaction Altered bioavailability Altered absorption Protein binding displacement reactions Enzyme induction/inhibition Reabsorption, secretion, altered pH Competition/antagonism

B. Pharmacokinetic: Usually the cause of drug interactions is an alteration in pharmacokinetic properties of one drug by another drug. Pharmacokinetic properties can be altered during absorption, distribution, metabolism or excretion of drugs. 1. Absorption Drug interactions can occur during absorption of drugs in the gastrointestinal Tract. Examples: a) Aluminum-containing medicines such as sucralfate and antacids to reduce the absorption of expensive and potentially life-saving antibiotics like ciprofloxacin and azithromycin. b) Women taking iron supplements often do not consider them as medicines and should be specifically questioned about whether they are taking iron if they are to be prescribed a quinolone or azithromycin. c) Drugs such as ketoconazole and delavirdine require an acidic environment to be in the unionised form that is preferentially absorbed. Solubility is drastically reduced in neutral or basic medications such as omeprazole, lansoprazole or H2antagonists that raise the stomach pH. The following drugs/food products, i.e. • Sucralfate, some milk products, antacids and oral iron preparations • Omeprazole, lansoprazole and H2-antagonists • Didanosine (given as a buffered tablet) • Cholestyramine. CAN • • • •

Block absorption of quinolones, tetracycline and azithromycin Reduce absorption of ketoconazole, delavirdine Reduces ketoconazole absorption Binds raloxifene, thyroid hormone and digoxin respectively.

164  Practical Manual of Pharmacology Distribution Displacement of highly protein bound drug (warfarin) by another drug (e.g. NSAIDs) could lead to an increase in the free plasma concentration of first drug and an adverse effect (bleeding tendency). But most of the drug interactions due to plasma protein displacement reactions are not clinically significant, because the displaced drug (free drug) is eliminated faster, i.e. more free drug is now available to kidneys for excretion. Metabolism Drug interactions involving metabolism are the most important drug interactions clinically. Some important preventable drug interactions are due to their effects on drug metabolizing enzymes, resulting in either inhibition (reduced activity) of the enzyme or induction (increased activity) of the enzyme. There are many potential consequences of changes in drug metabolism for a given drug. It is made more complex by the fact that there are multiple pathways of metabolism for many drugs. The major group of enzymes in the liver that metabolize drugs can be isolated in a subcellular fraction termed the microsomes. The largest and most important of these enzymes are the cytochrome P450(CYP450) family of enzymes, which mediate phase I reactions. Since Phase II reactions generally result in conjugation of a drug to a water-soluble group like a sugar, peptide (glutathione) or sulfur group, and because there is a large excess of these groups in well nourished cells, these reactions are rarely rate-limiting. Thus, they are rarely involved in drug interactions. In contrast, the Phase I reactions carried out by cytochrome P450 enzymes, flavin monooxygenases and reductases are more frequently rate limiting. These are the target of clinically significant drug interactions, such as the inhibition of cyclosporine metabolism by erythromycin. Although there are other enzyme systems that perform similar functions, the cytochrome P450 system is important because it is involved in most clinically relevant metabolic drug interactions. Six CYP450 isoforms are clinically important. These days drug interactions can be predicted if we know by which isoenzyme it is metabolized. The following Table 19.2 can help to predict mechanism of interaction of few important drugs.

Problem Based Drug Interactions  165 Table 19.2: Cytochrome P450 isoenzymes, their substrates, inhibitors and inducers Isoenzyme

Substrates

Inhibitors

Inducers

3A

Most calcium channel blockers Most benzodiazepines Most HIV protease inhibitors Statins Cyclosporine

Ketoconazole Fluconazole Cimetidine Erythromycin Troleandomycin

Carbamazepine Rifampicin Rifabutin Ritonavir St. John's wort

2D6

Codeine Many tricyclic antidepressants

SSRIs Haloperidol Amiodarone

Dexamethasone Rifampicin

2C9

Most NSAIDs (including COX-2) S-warfarin (the active form) Phenytoin

Fluconazole Fluvastatin Isoniazid Sulfamethoxazole

Rifampicin Secobarbital

2C19

Diazepam Phenytoin Omeprazole

Omeprazole Isoniazid Ketoconazole

Carbamazepine pentobarbital Rifampicin

1A2

Theophylline Imipramine Propranolol Clozapine

Many fluoroquinolone antibiotics Fluvoxamine

Brussel sprouts Char-grilled meat Omeprazole Tobacco

INHIBITION (FIG. 19.1)

Fig. 19.1: Drug interaction by inhibition of metabolism

Warfarin is anticoagulant and cimetidine is used in treatment of peptic ulcers.

166  Practical Manual of Pharmacology

Fig. 19.2: Drug interaction by induction of metabolism

INDUCTION (FIG. 19.2) Rifampicin is an antitubercular drug. Excretion Drugs can compete for excretion, hence, there can be inhibition of excretion of one of the drugs. This leads to increased concentration, prolonged action or toxicity. Examples: • Sulfinpyrazone inhibits excretion of tolbutamide and increases its toxicity. • Probenecid inhibits excretion of penicillins and increases their duration of action. C. Pharmacodynamic: Pharmacodynamic interaction occurs at site of action. Examples: a) The combined inhibitory effects of propranolol and verapamil or diltiazem on atrioventricular node represent potential site of an adverse interaction. b) Alteration of compensatory mechanisms could also lead to such interactions. Beta blockers prolong the recovery from hypoglycemic effects of antidiabetics. c) Drugs with sedative potential can aggravate sedation when given together especially in the elderly, e.g. tricyclic antidepressants and antiepileptics. Effects of drug interactions 1. 2. 3. 4. 5. 6. 7. 8. 9.

Diminished therapeutic response Enhanced side effects Relative overdosage toxicity Intensified allergic reactions Increased secondary effects Severe idiosyncratic reactions Greater teratogenicity Additive addiction potential Miscellaneous.

Problem Based Drug Interactions  167 Food-drug interactions Several drugs are known to interact with foods. a) Reduced absorption of tetracycline when taken with milk products. The chelation of tetracycline by calcium prevents it from being absorbed from the intestines. b) Dietary sources of vitamin K, such as spinach or broccoli, may increase the dosage requirement for warfarin by a pharmacodynamic antagonism of its effect. Patients should be counseled to maintain a consistent diet during warfarin therapy. c) Grapefruit juice contains a bioflavonoid that inhibits CYP3A and blocks the metabolism of many drugs. This was first described for felodipine but has now been observed with several drugs. This interaction can lead to reduced clearance and higher blood levels when the drugs are taken simultaneously with grapefruit juice. Grapefruit juice (GFJ) is often taken at breakfast in the western countries when drugs are also often taken. GFJ contains bioflavonoids mainly naringin and furacoumarin which cause mechanism based inhibition of presystemic elimination of a number of drugs and increase their bioavailability and toxicity. d) Cheese reaction (hyperadrenergic crisis) can occur when a patient on MAO inhibitors consumes cheese or cheese containing preparations, e.g. cheese tomato. This is because of tyramine present in cheese that leads to release of catecholamines in the body. Since the patient is on MAO inhibitors there is already decreased metabolism of catecholamines in the body, hence, there is exaggerated response. It is impossible to remember all of the drug interactions that can occur. It is, therefore, important to develop a stepwise approach to prevent drug interactions. First, taking a good medication history is essential. The following stepwise approach can help health care practitioners to develop good habits when performing this task. 1. Take a medication history 2. Remember high risk patients a. Any patient taking 2 medications b. Anticonvulsants, antibiotics, digoxin, warfarin, amiodarone, etc. 3. Check pocket reference 4. Consult pharmacists/drug info specialists 5. Check up-to-date computer program.

OBJECTIVES At the end of this session, a student shall be able to: 1. Identify type of drug interaction in a given problem 2. Explain mechanism of drug interaction 3. Provide preventive and curative treatment for the interaction.

168  Practical Manual of Pharmacology Exercises in class: Problem based exercises can be designed for this activity. These are given in the form of a statement of a case for class exercises. Students are divided into batches. Each batch has 5-6 students. In examination, these can be given on cards and a short viva can be conducted. They can also be given this activity with prescription writing as is done usually. A short viva can be held on the answer written by the student. This can be done in labs where students are doing experiments. Examples of problem based drug interactions: 1. A 35-year-male was prescribed astemizole and erythromycin together for sore throat. Next day he was admitted in cardiac casualty with arrhythmias. a) What happened to the patient? b) Which other drugs can lead to similar situation? c) How this can be prevented?

2. A 35-year-male on taking MAO inhibitors. He consumed cheese tomato during a wedding party of his friend. Next day he was admitted in casualty with a BP of 190/ 110 mm of Hg. a) Why his BP increased? b) How this can be prevented? c) How this can be treated?

Problem Based Drug Interactions  169 3. A 26-year-female was using oral contraceptive pill for the last 2 years. He was prescribed antitubercular drugs for the tuberculosis. She became pregnant after 2 months. a) Why she became pregnant even when she was on oral contraceptives? b) How this can be prevented? c) Which other drugs can produce similar situation?

4. A 4-year-old child was prescribed iron syrup for anemia (Hb 9.5 gm). To avoid bad taste, his mother used to give milk with iron syrup. After 4 months of iron therapy the Hb was still 9.5 gm. a) Why there was no increase in Hb? b) How this can be prevented?

170  Practical Manual of Pharmacology 5. A 30-year-male patient was stable with warfarin therapy. He was prescribed cimetidine. After 1 week he was admitted to hospital with intracranial bleeding. a) What happened to patient? b) Which other drugs can lead to similar situation? c) How this can be prevented?

6. A 40-year-male epileptic patient was stable with phenytoin. He was prescribed ketoconazole. After 1 week he was admitted to hospital with slurred speech and dizziness. a) What happened to patient? b) Which other drugs can lead to similar situation? c) How this can be prevented?

Problem Based Drug Interactions  171 7. A 50-year-male was taking azathioprine for the last 2 months. He was prescribed allopurinol for gout. After 1 week he was admitted to hospital with bleeding from gums. a) What happened to patient? b) Which other drugs can lead to similar situation? c) How this can be prevented?

8. A 30-year-lady was taking oral contraceptives for the last 1 year. She was prescribed ampicillin for an infection. She became pregnant after 1 month inspite of taking oral contraceptives regularly. a) What she became pregnant? b) Which other drugs can lead to similar situation? c) How this can be prevented?

172  Practical Manual of Pharmacology 9. A cardiac CHF patient was taking metoprolol. He was prescribed verapamil by another cardiologist without asking what he was already taking. Next day patient was admitted in ICCU with severe bradycardia. a) What happened to patient? b) Which other drugs can lead to similar situation? c) How this can be prevented?

10. A 45-year-old male hypertensive patient was stable on metoprolol for the last one year. He was prescribed diclofenac for joint pains. After 2 months his BP increased even when he was taking metoprolol regularly. a) What happened to patient? b) Which other drugs can lead to similar situation? c) How this can be prevented?

Problem Based Drug Interactions  173 11. A 45-year-old male epileptic patient was stable on carbamazepine for the last one year. He was prescribed clarithromycin for throat infection. After 1 month he complained of diplopia and ataxia. a) What happened to patient? b) Which other drugs can lead to similar situation? c) How this can be prevented?

12. A 55-year-old male patient was stable on lithium for the last 6 months. He was prescribed chlorthiazide for CHF. After 1 month his complained of persistent nausea/ vomiting and blurred vision. a) What happened to patient? b) Which other drugs can lead to similar situation? c) How this can be prevented?

174  Practical Manual of Pharmacology 13. A 45-year-old male hypertensive patient was stable on enalapril for the last one year. He was prescribed spironolactone for CHF. After 5 days he complained of palpitations and restlessness. a) What happened to patient? b) Which other drugs can lead to similar situation? c) How this can be prevented?

14. A 34-year-old male consumed alcohol during a wedding party. He felt abdominal discomfort in the morning and took metronidazole. In the evening he developed a rash on the body, throbbing headache and respiratory difficulty and nausea. a) What happened to patient? b) Which other drugs can lead to similar situation? c) How this can be prevented?

Problem Based Drug Interactions  175 15. A 65-year-old male Parkinsonian patient was stable on L-dopa last one year. He was prescribed pyridoxine. After 1 month his condition deteriorated. a) What happened to patient? b) How this can be prevented?

16. A 40-year-old male diabetic patient was stable on chlorpropamide for the last one year. He was prescribed probenecid. After 1 month he was admitted in ICU with in unconscious state. a) What happened to patient? b) Which other drugs can lead to similar situation? c) How this can be prevented?

176  Practical Manual of Pharmacology 17. A 40-year-old male diabetic patient was stable on gliclazide for the last one year. He was prescribed chlorthiazide for hypertension. After one month his fasting blood sugar increased to 180 mg/dl. a) What happened to patient? b) Which other drugs can lead to similar situation? c) How this can be prevented?

18. A 45-year-old male diabetic patient was stable on glibenclamide for the last 6 months. He was prescribed propranolol for migraine. After one week he was admitted in ICU with in unconscious state. a) What happened to patient? b) Which other drugs can lead to similar situation? c) How this can be prevented?

Problem Based Drug Interactions  177 19. A 52-year-old male was taking nitrates for angina for the last one year. He was prescribed sildenafil for erectile dysfunction. On next day, at 11pm he was admitted in ICU with aggravation of angina. a) What happened to patient? b) Which other drugs can lead to similar situation? c) How this can be prevented?

CHAPTER

20

Adverse Drug Reaction (ADR) Monitoring

It took many decades before the deleterious effects of aspirin on the gastro-intestinal tract became apparent and almost as long before it was recognised that the protracted abuse of phenacetin could produce renal papillary necrosis; 35 years elapsed before it became clear that amidopyrine could cause agranulocytosis; and several years before the association of phocomelia with thalidomide became obvious. The recent withdrawal of a very successful drug 'Rofecoxib' highlights the importance of ADR monitoring. Hence, systematic collection of information on adverse drug reactions is essential to provide much needed information regarding patients at risk, drug interactions and adverse reactions to new drugs not detected in studies conducted before marketing of the drug. The ADR monitoring is also known as pharmacovigilance. WHO defines pharmacovigilance as "the science and activities relating to the detection, assessment, understanding and prevention of ADRs or any other, medicinerelated problem". Pharmacovigilance plays a major role in pharmacotherapy decision-making, be it individual, regional, national or international. What is an adverse drug reaction? 1. Adverse reaction: A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or modifying a physiological function. 2. Side effects: Any unintended effect of a pharmaceutical product occurring at doses normally used in man which is related to pharmacological properties of the drug. 3. Toxic effect: A direct action of the drug, often at high dose damaging cells, e.g. liver damage from paracetamol overdose. Types of ADRs: A. (Augmented)—directly related to pharmacolgical action of drug, e.g. hypokalaemia with digoxin B. (Bizarre)—idiosyncratic and genetically determined, e.g. acute intermittent porphyria due to sulphonamides in patients with G-6 PD deficiency. C. (Continues use)—associated with long term use of drugs tardive dyskinesia with neuroleptics.

Adverse Drug Reaction (ADR) Monitoring  179 D. (Delayed)—Teratogenicity or carcinogenicity, e.g. phenytoin-teratogenicity E. (End of dose)—abrupt stoppage of drug, e.g. beta blockers, corticosteroids. Severity: Minor : Moderate :

no treatment/antidote or hospitalization required. Drug is continued. change in drug therapy required, specific treatment, increase in hospitalization by at least for one day. Severe : potentially life threatening, caused permanent damage or require intensive medical care. Lethal : directly or indirectly contributed to death of the patient. Causality: It is determination that the event is due to drug and that there is no other alternative explanation for it. The Naranjo algorithm is one means to assign the likelihood of a drug causing an untoward event. This simple ten-item questionnaire uses specifically assigned numerical values to arrive at an overall total score for probability assignment. Probability is assigned via a score termed: 1. definite 2. probable 3. possible or 4. doubtful. Advantages of the Naranjo algorithm include its ease and widespread use. However, tests of its reliability as a tool for serious cases of adverse drug reactions have not been performed. The Naranjo algorithm can be used to assess the likelihood that a change in clinical status is the result of an ADR rather than the result of other factors such as progression of disease. Answer each of the ten items in the assessment and enter the value of the answer in the column labeled Score. Sum the scores of the ten items to determine the total score, and apply the interpretation rules that appear at the bottom of the page (available at http:// mqa.dhs.state.tx.us/QMWeb/MedSim/Naranjo.htm). Health professionals are in the best position to report on suspected ADRs observed in their every day patient care. All healthcare providers (physicians, pharmacists, nurses, dentists and others) should report ADRs as part of their professional responsibility, even if they are doubtful about the precise relationship with the given medication. You can reduce the suffering and save thousands of patients lives by doing this. ADR monitoring is to help ensure that patients obtain safe and efficacious products. The results of ADR monitoring have also a very important educational value. The aim is to obtain data of scientific quality for rational and safe use of drugs. Several methods used for collection of information on adverse reactions to drugs have been reported in literature. The main methods are as follows:

180  Practical Manual of Pharmacology A. Premarketing Clinical trials Before marketing of drug, animal studies and human trials (Phase I, II, III and IV) are done to detect ADRs. Animal studies include acute, subacute, chronic toxicity studies and specialized toxicity studies. But, it has been proved again and again that tests in animals are insufficient to predict human safety. Clinical trial done in humans to look for ADRs, but number of patients is limited and there trials detect ADR with an incidence of 1:200 only. The declared purpose of 'pre-marketing' clinical trials is to discover: • If a drug works and how well • If it has any harmful effects • If there is potential harm how serious is it and how does it weigh against the benefits. There are concerns about these premarketing studies because of two reasons: 1. Before marketing drugs are evaluated for toxicity in animals. These studies produce an overall picture of toxicology of the drug and indicate organs which are at highest risk of damage. However, it is difficult to draw direct parallels between toxicity in animal models and potential risks to man. 2. After animal toxicity studies drug undergoes clinical trials in humans. For a new drug pre-marketing clinical trials are generally carried out in less than 3000 patients. Type A reactions can thus be identified. Subgroups at particular risks are occasionally identified. However, type B reactions with incidence of 1:1000 are generally missed. By the time of licensing, exposure of less than 5000 human subjects to a drug allows only the more common ADR to be detected. At least 30,000 people need to be treated with a drug to be sure that you do not miss at least one patient with an ADR which has an incidence of 1 in 10,000 exposed individuals. Susceptible population like elderly, children, lactating mothers are unlikely to be included in these studies. However, within a short time after entering the market, the drug may be administered to several million patients. That means that for drugs that cause rare toxicity, their toxicity can only be detected after, not before, marketing. So, the safety profile for new drugs that come into the market is never totally defined because new drugs are studied only in relatively small and homogenous patient populations. The complete safety profile of a new drug will be defined only after it has been approved and is in use in the market. Clinical trials generally do tell a good deal about how well a drug works for a defined disease and what potential harm it may cause. However, they provide no information for larger populations with different characteristics from the trial group—age, gender, state of health, ethnic origin and so on. Therefore, for many medicines and particularly new, complex products, safety monitoring does not stop at the manufacturing stage, it must be followed by careful patient monitoring and by further scientific data collection. This aspect of drug monitoring is called postmarketing B. Postmarketing methods In these methods ADRs are observed epidemiologically under conditions of normal use in the community. Thus, post-marketing surveillance is important to permit detection of less

Adverse Drug Reaction (ADR) Monitoring  181 common, but sometimes very serious ADRs. Therefore, health professionals worldwide should report on ADRs as it can save lives of their patients and others. The various methods used are: Case Reports: This has the advantage of speed and sensitivity, however, the reports need to be validated. Case reports have been the first means by which some of the type B reactions have been identified, e.g. Practolol induced dermatitis and keratoconjunctivitis, benoxaprofen induced photosensitivity which is dose related. Cohort Studies: Cohort of patients receiving a drug under investigation are prospectively studied and compared with control population. The cohort studies are excellent methods of quantifying ADRs, e.g. Royal College of General Practitioner's oral contraceptive study. The contraceptive study quantified the risk of cardiovascular diseases and excess mortality due to oral contraceptives. However, cohort studies are expensive and slow and do not necessarily, prove causal link. Prescription event monitoring: Patients who have received specific drugs are identified from prescription (in UK prescription pricing authority). The general practitioner is then asked to report any adverse event detected. The method has the advantage of enhancing detection of new adverse reactions and incidence of event can be calculated. Prescription event monitoring has identified deafness associated with enalapril. Case control studies (Retrospective): In this prospective method patients who have the identified disease are matched with a control group who have similar potentially confounding factors but who do not have the disease. The drug histories are then compared. The association between aspirin and Reye's syndrome was confirmed using this method and resulted in recommending removal of the pediatric formulation of aspirin from the market. Spontaneous Reporting-Yellow card system: Spontaneous reporting of ADRs to a central body was started in UK in 1964. However, it is estimated that out of even serious and fatal ADRs, only 10% are reported so there is gross underreporting. Reporting may be biased and limited to serious ADRs. Advantages of this system are that numbers are large, personal details are kept confidential and early alerts are available. The yellow card system identified the risk of urticaria and confirmed the occurrence of cough due to captopril and enalapril. It is recommended that a physician for newer drugs a physician must report all suspected ADRs and for established drugs, he should report all serious suspected ADRs. Advantages of this system are that it acts as early alerting system. 1. Record linkage: The health records of a defined population are correlated with data on the use of drugs. This technique is not very sensitive compared to other methods but can generate hypotheses for further investigation. This method covers large sample size and there is no recall bias. Phase-IV clinical studies (Post Marketing surveillance): Post marketing surveillance (PMS) is a regulatory requirement and done for all the drugs after marketing. This surveillance provides information of long term safety of drug, safety in extremes of ages, safety in special population, e.g. pregnant and lactating females. Severe ADRs may lead to withdrawal of drugs. In India it is now mandatory to submit results of postmarketing surveillance within 2

182  Practical Manual of Pharmacology years of marketing the drug. Sometimes after this surveillance warnings on ADRs are inserted on labels of drugs. This monitoring can be done as regional or national level. Other way to monitor is to monitor disease, rather than drugs, especially in case of Type B bizarre ADRs, that will help in identifying many serious adverse effects in different subspecialties of medicine and surgery, e.g. carcinoma in young females showed unusual clear cell carcinoma like histopathological features, only in these mothers who received stilbesterol during pregnancy, similarly biopsy revealed pseudomembranous colitis in those treated with tetracycline lead to the path of drugs induced adverse effect in the gastroenterology department, while ophthalmic department could observe a different kind of dry eye in those treated with controlled care studies. Thus, orientation and participation of physicians can help identifying the new drugs reaction, as well as minimizing the adverse effect of dugs through regularly updating their own knowledge. WHO promotes drug safety through its International Drug Monitoring Programme, which began to operate in 1968. Initially a pilot project in 10 countries with established national reporting systems for ADRs, the network has expanded significantly as more countries worldwide develop national pharmacovigilance centers for the recording of ADRs. Currently, 81 countries are members in the programme. The Uppsala Monitoring Centre (UMC, WHO), Sweden is maintaining the international database of adverse drug reaction (ADR) reports received from several National Centers. By June 2006, the database had 3.67 million adverse drug reaction reports. Vigibase online (web based) system is used for submission of ADR reports. Although, India is participating in this programme, its contribution to UMC database is very little. This is essentially due to the absence of a vibrant ADR monitoring system and also the lack of a reporting culture among health care workers. Special need for ADR monitoring in India Due to huge population, unorganized health sector, use of alternative medicine there is an urgent need for monitoring ADRs in India. There is variation in ADRs between different countries on account of variation in genetic, environmental, dietary factors and disease patterns and drug used. The reported incidence of drug induced hepatotoxicity is low in India compared to developed countries. The common drugs incriminated were antitubercular drugs in India as opposed to halothane reported to be the commonest in the Danish registry. In India, in rural areas, over 50% of children are malnourished and 45-70% of population is iron deficient, which may affect incidence of ADR. There are very few functioning ADR centers in India. Adequate information is not available even on adverse reactions to old drugs. There is lack of data on ADR in specialised populations like pregnant, women and children. Due to the increased prevalence of certain diseases in this country certain drugs are used in a population where they are not recommended, e.g. Ciprofloxacin in children. Many patients tend to use modern drugs along with traditional remedies. Interactions that can result could

Adverse Drug Reaction (ADR) Monitoring  183 lead to adverse reaction and loss of efficacy. Traditional drugs are considered safe but may not necessarily be safe. Organization of ADR monitoring system in India Appreciating the importance and benefits of pharmacovigilance, Central Drugs Standard Control Organization (CDSCO), Ministry of Health and Family Welfare, Govt. of India launched the National Pharmacovigilance Programme (NPP) in November, 2004. It is largely based on the recommendations made in the WHO document titled "Safety monitoring of medicinal products-guidelines for setting up and running a pharmacovigilance centre". The immediate aim of NPP is to foster the culture of ADR notification by health care workers in India. Subsequently, it seeks to generate broad based ADR data on the Indian population and share this with WHO database. This would ensure optimum safety of drugs in the Indian market. Under this programme, the whole country is divided into zones and regions for operational efficiency. CDSCO, New Delhi is at the top of the hierarchy followed by two zonal pharmacovigilance centers, Seth GS Medical College, Mumbai and AIIMS, New Delhi. There are 5 regional pharmacovigilance centers located at Kolkata (IPGMR-SSKM Hospitals), Mumbai (TN Medical College & BYL Nair Charitable Hospital), Nagpur (Indira Gandhi Medical College), New Delhi (Lady Hardinge Medical College) and Pondicherry (JIPMER). Twenty eight peripheral centers, spread country-wide, are attached to their nearest peripheral centers. ADR reports can be sent only by health care workers (doctors including dentists, nurses, pharmacists) to any one of the nearest pharmacovigilance centre. The full list of centers is available at CDSCO website (www.cdsco.nic.in). ADR reports sent by lay public are not acceptable. Data received at the peripheral centers are forwarded to the respective regional centers which will carry out the causality analysis. This information will be forwarded to the zonal centers. From there the data will be forwarded to the CDSCO and UMC database. The ADR form for reporting ADRs in India is given in Appendix-III. The various factors contribute to poor ADR reporting from India. Doctors feel that they are trained to treat patients and not monitor ADRs. There is no guarantee of confidentiality of a reported ADR by a doctor and government has no effective machinery to monitor ADRs. Patient communities can not report an ADR and population is not educated about ADRs and interprets it as doctor's negligence. How to recognize ADRs? Since ADRs may occur through the same physiological and pathological pathways as different diseases, they are difficult and sometimes impossible to distinguish. However, the following step-wise approach may be helpful in assessing possible drug-related ADRs: 1. Ensure that the medicine ordered is the medicine received and actually taken by the patient at the dose advised. 2. Verify that the onset of the suspected ADR was after the drug was taken, not before and discuss carefully the observation made by the patient.

184  Practical Manual of Pharmacology 3. Determine the time interval between the beginning of drug treatment and the onset of the event. 4. Evaluate the suspected ADR after discontinuing the drugs or reducing the dose and monitor the patient's status. If appropriate, restart the drug treatment and monitor recurrence of any adverse events (dechallenge and rechallenge). 5. Analyse the alternative causes (other than the drug) that could on their own have caused the reaction. 6. Use relevant up-to-date literature and personal experience as a health professional on drugs and their ADRs and verify if there are previous conclusive reports on this reaction. The National Pharmacovigilance Centre and Drug Information Centers are very important resources for obtaining information on ADR. The manufacturer of the drug can also be a resource to consult. 7. Report any suspected ADR to the person nominated for ADR reporting in the hospital or directly to the National ADR Centre. What should be reported? • For "new" drugs - report all suspected reactions, including minor ones. (In many countries drugs are still considered "new" up to five years after marketing authorization) • For established or well-known drugs - report all serious or unexpected (unusual) suspected ADRs • All life threatening and serious adverse effects • Report all suspected ADRs associated with drug-drug, drug-food or drug-food supplements (including herbal and complementary products) interactions • Report ADRs in special fields of interest such as drug abuse and drug use in newborns, pregnancy and during lactation • All reactions to vaccines, report ADRs occurring from overdose or medication error • All drug interactions. Thus, report all suspected adverse reactions that you consider of clinical importance as soon as possible! How to report ADRs? ADR reporting usually occurs retrospectively. Local case report forms (CRF) should be obtained from the National Drug Regulatory Authority. Some countries have included CRF in their National Formularies (British National Formulary, Formularies of South Africa, Zimbabwe, etc.). There are different Case Report Forms in different countries. The ADR reporting form for India is attached as Appendix I. Send filled form to regional centre. In any case of doubt, you may send this form to the National Pharmacovigilance Centre at: Central Drugs Standard Control Organization, Directorate General of Health Services, Ministry of Health and Family Welfare, Nirman Bhawan, New Delhi-110 011. All forms have at least four sections which should be completed.

Adverse Drug Reaction (ADR) Monitoring  185

Sample ADR format 1. Patient information • Patient identifier • Age at time of event or date of birth • Gender • Weight 2. Adverse event or product • Problem date of event date of this report • Description of event or problem • Relevant tests/laboratory data (if available) • Other relevant patient information/history • Outcomes attributed to adverse event 3. Suspected medication(s): • Name (INN and brand name) dose frequency route used • • • •

Therapy date Diagnosis for use Event abated after use stopped or dose reduced Batch number expiration date

• Event reappeared after • Reintroduction of the treatment • Concomitant medical products and therapy dates 4. Reporter • Name, address and telephone number • Specialty and occupation

OBJECTIVES At the end of the practical group work the student shall be able to: 1. Appreciate the importance of ADR monitoring 2. Enumerate methods used for ADR monitoring

186  Practical Manual of Pharmacology 3. 4. 5. 6.

Identify which adverse effects should be reported Find out severity and causality Fill ADR monitoring form Report an ADR to a monitoring centre.

Exercises in class: Simulated cases can be given for exercises: The form in Appendix II can be given as exercise to students. The students are divided into batches and sent to hospital to investigate and report ADR on preselcted cases. The information collected can be discussed in a larger group explaining the importance of all parameters of ADR monitoring. Example The patient is a 42-year-old woman who presents to the emergency department with an erythematous rash and audible wheezing. She presented to the medicine OPD days ago for a second evaluation for elevated blood pressure. She was started on benazepril 5 mg po bd. After taking the second dose, she noticed a rash on her torso and upper arms. Shortly thereafter, she began experiencing difficulty in breathing as well as some facial swelling. Her past medical history was notably only for high blood pressure for 4 years that was previously controlled by diet and exercise. She has no history of tobacco use or alcohol use. She has no known drug or food allergies. Her current medication is benazepril and she has not taken any other prescription or OTC medications for more than 3 weeks. On physical exam, she is a well developed, well nourished woman in moderate distress. Her vital signs are as follows: blood pressure 100/80 mmHg, heart rate 78 beats per minute, respiratory rate 32 beats per minute and afebrile. She weighs 62 kg and is 5 feet 5 inches. On examination, she had notable edematous swollen face, inspiratory and expiratory wheezing and a red, maculopapular rash on trunk and upper extremities. She was alert and oriented. Her serum chemistries and complete blood count were within normal limits. Exercise: 1. Has the patient suffered an ADR? If yes, explain severity and causality. 2. Did a drug precipitate a reaction in this patient? 3. Let's complete an ADR form on this patient.

CHAPTER

21

Therapeutic Drug Monitoring (TDM)

Therapeutic drug monitoring is a branch of clinical chemistry that specialises in the measurement of medication levels in blood. It is also part of chemical pharmacology. Its main focus is on drugs with a narrow therapeutic index, i.e. drugs that can easily be under or overdosed. In pharmacology, many medications are used without monitoring of blood levels, as their dosage can generally be varied according to the clinical response that a patient gets to that substance, e.g. dosage adjustment can be done by monitoring the blood pressure for antihypertensives (pharmacodynamic monitoring). However, in a small group of drugs, this is impossible, as insufficient levels will lead to undertreatment or resistance and excessive levels can lead to toxicity and tissue damage. But for some drugs, there is either no readily available measure of effect or it is not sufficiently sensitive. For example, clinical effects do not serve as a good guidance indicator when drugs are used prophylactically (e.g. anticonvulsants) or when drug effects develop slowly (e.g. antidepressants) or when drug effect cannot be differentiated from the complications of disease process (e.g. digoxin). For such drugs, measurement of plasma concentration is very useful (pharmacokinetic monitoring). For these drugs, plasma concentration indicates the dose required to achieve therapeutic levels for safe and effective outcome. Thus, TDM involves measurement of drug concentration in body fluids and adjusting the dose in individual patients. TDM is defined as "individualization of dosage by maintaining plasma or blood concentrations within a target range (therapeutic range/therapeutic window). It is pragmatic manipulation of the dose of a drug using plasma concentration as a guide to optimize its efficacy, to avoid or identify toxicity and to detect or confirm poor compliance." The characteristics of drugs which make them suitable for, or make them require, therapeutic drug monitoring are: • marked pharmacokinetic variability • concentration related therapeutic and adverse effects • narrow therapeutic index • defined therapeutic (target) concentration range • desired therapeutic effect difficult to monitor.

188  Practical Manual of Pharmacology The indications for TDM are listed in Table 21.1. Table 21.1: Indications for TDM Indication

Drug/s

Narrow therapeutic range drugs

Lithium

Drugs with non-linear (zero order) pharmacokinetics

Phenytoin

Drugs showing interindividual variation in metabolism

Tricyclic antidepressants

Prophylactic use

Antiepileptics

To check toxicity

Aspirin

To check compliance

Antiepileptics, antidepressants

To check bioequivalence

Two or more brands of the same drug

To check drug interactions

Two or more drugs

To check effect of concomitant pathological/physiological condition on drugs, e.g. pregnancy, organ dysfunction

Phenytoin

Efficacy failure

Antiepileptics

The important steps in TDM are

TIME OF SAMPLING Drug concentrations are usually measured in serum or whole blood. Saliva can be used if it is difficult to get blood sample. For example, in children for phenytoin. The timing of sampling influences the interpretation of a drug concentration measurement. Hence, the correct time of sampling is very important. Drug concentrations vary over the dosing interval and with the duration of dosing in relation to achieving a steady state. This is unlike most physiological parameters such as serum creatinine or serum sodium which change relatively slowly. Generally, samples are collected after the steady state levels have been reached which takes approximately five half-lives. This does not apply to drugs such as amiodarone and perhexiline with very long half-lives and which can cause severe toxicity. Steady state may take months to be reached and dose adjustments need to be made along the way. With all drugs, if a sample is taken before steady state is reached, allowance needs to be made for this in interpreting the concentration. The pre-dose or trough concentration is commonly used for antiepileptics and peak concentrations may be used for antimicrobials. Antimicrobials are classed as "time dependent" where the aim is to maintain concentration above minimum inhibitory concentration (MIC) throughout the dosage or "concentration dependent" where the aim is to achieve peak

Therapeutic Drug Monitoring (TDM)  189 concentration, but allow the concentration to fall to low levels in between doses. Vancomycin exhibit time dependant activity, hence steady state levels are measuresd. Aminoglycosides are concentration dependant, hence sampling is recommended 1 hour after dose (peak concentration). Immediate sampling is recommended in cases of suspected toxicity. In general for therapeutic failure, sample should be taken half an hour before next dose and for toxicity sample should be taken half an hour after the last dose. Drug estimation methods The sensitivity, specificity and reproducibility of the laboratory method are important. Most high-volume drug assays are now carried out by automated immunoassay methods which have these characteristics. The most commonly used methods are: 1. High performance liquid chromatography (HPLC, e.g. antiepileptics) 2. Liquid Chromatography Mass Spectroscopy [LC-MS] 3. Gas Chromatography Mass Spectroscopy [GC-MS, GC/MS] 4. Gas liquid chromatography (GLC, e.g. amiodarone, perhexiline) 5. Immunoassay (e.g. antiepileptics) 6. Spectrophotometry (e.g. Salicylates). All methods if used correctly are acceptable. Participation in international quality control programmes will ensure laboratory validity. Recurring cost for HPLC is least of all. However, it requires technical expertise. Usually, plasma or serum is used for drug assays, depending on the equipment used. However, with cyclosporin there are large shifts of drug between red cells and plasma with storage and temperature change so whole blood is assayed. Some blood collecting tubes, especially those containing a gel to separate cells and plasma, may not be suitable for all drugs due to drug adsorption by the gel or other components in the tube. All analytical methods estimate total drug (free + bound) levels. Although it is the free drug which has direct access to the site of action. In patients with normal plasma protein levels, total drug concentration correlates well with drug effects. However, sometimes it is necessary to estimate metabolites especially when the metabolite is active and the concentration is high (e.g. carbamazepine epoxide in children). Interpretation of plasma concentration data The concentration measured must always be interpreted in the light of clinical response, the demographic and clinical status of individual patient, dosage regimen and concomitant drugs used. Ideally interpretation and advice should be there with each report. If the levels exceed 90% of therapeutic concentration, the dosage is halved. Dosage is further reduced by 50% if plasma levels exceed therapeutic concentrations at 4 half-life interval. If the first concentration is not too high, one can proceed with the same dose. With this procedure undue toxicity can be avoided. Therapeutic concentrations are average values and individual patients will show satisfactory drug response at levels above and below the average values. Plasma concentration data must always be considered along with the patient's clinical response.

190  Practical Manual of Pharmacology Dosage adjustment For drugs with linear kinetics increasing the dose leads to proportionate increase in plasma concentration and can be safely carried out. Revised dose rate =

Previous dose rate × target Css Measured Css

For drugs with nonlinear pharmacokinetics, relatively small increase in dosage can result in disproportionately large increase in plasma concentrations (e.g. phenytoin) for such a drug it is advisable to use a nomogram. A list of drugs for which therapeutic drug monitoring is commonly used is shown in Table 21.2 with the target or therapeutic ranges. The ranges used are in most cases derived from observation of therapeutic and adverse effects in small groups of patients. Therefore, when applied to a wider population of patients, there will be individuals who achieve adequate effects at lower concentrations or experience adverse events within the 'therapeutic range'. Table 21.2. Drugs and therapeutic range Drug Digoxin Amiodarone Lignocaine Salicylate Theophylline Phenytoin Carbamazepine Sodium valproate Gentamicin Amikacin Vancomycin Lithium

Time to steady state 7 days 2-6 months 12 hours 2-5 days 1-2 days 2-4 weeks 2 weeks 2-3 days 8 hours 8 hours 24 hours 3-6 days

Therapeutic range mg/L 0.5 - 2.1 1.0 - 2.5 2.0 - 5.0 150 - 300 10 - 20 10 - 20 5.0 - 12 50 - 100 trough 1-2; peak 5-10 trough 3-5; peak 20-30 trough 5-10; steady state 15-25 0.6 - 1.2

For rational therapeutics TDM can be followed in a stepwise pattern as:

Therapeutic Drug Monitoring (TDM)  191 Flow chart 21.1: TDM process at a glance

TDM procedure at a glance With this background information let us now consider the important aspects of therapeutic drug monitoring keeping in mind Flow chart 21.1. Antiepileptic Drugs (AED) Most antiepileptic drugs have a narrow margin of safety and there is considerable interindividual variation in pharmacokinetics, dosage requirement and response obtained. Phenytoin Measurement of plasma levels, commuting with effect, and adjusting the dose as per requirement is very important and rewarding for phenytoin. Phenytoin has a narrow margin of safety. Levels below l0 μg/ml do not give good seizure control and those above 20 μg/ml are usually associated with toxicity. However, do not consider plasma levels in isolation. It is seen that about 20% patients achieve good seizure control despite phenytoin levels below 10 μg/ml on the other hand 3-5% patients are well controlled only with levels above 20 μg/ ml and show no sign of toxicity. Patient compliance is a very important variable in AED treatment. When a patient shows subtherapeutic levels despite standard doses, compliance must be checked before increasing the dose. In majority of the patients receiving 300 mg phenytoin per day levels below 5 μg/ml were found to be simply due to non compliance. Patient counseling, simpler drug and dosage regimens, and recording intake helps to control seizures effectively in many patients.

192  Practical Manual of Pharmacology Phenytoin has nonlinear kinetics and dose increments result in proportionately large increases in plasma concentrations leading to toxicity. Hence, it is necessary to use a nomogram for calculating dose requirement. One of the limitations of phenytoin tablets and capsules available in India is their dosage strength, all are of 100 mg strength (and syrup is 125 mg/5ml). On account of the nonlinear kinetics, dose increments of 100 mg may lead to toxic levels in some patients. It is observed that nearly 20% of the patients need dose increments of only 25 or 50 mg to achieve desired therapeutic concentrations. Appropriate dosage adjustment and achieving therapeutic concentration results in over 70% of patients getting good seizure control. Carbamazepine Therapeutic range of carbamazepine is 4-12 μg/ml. Samples should be collected after steady state levels are reached. Some reduction in plasma concentration thereafter is to be expected on account of autoinduction. In adults, fluctuations in carbamazepine plasma levels between dosing intervals are not large and blood sample can be collected at trough or peak time. In children due to short half-life and specially with liquid formulations which can be rapidly absorbed, the difference between peak and trough levels can be substantial, requiring measurement of both levels depending on indication. Drug monitoring is most useful in deciding the extent to which dose can be increased in patients who are not responding to standard dose inspite of good compliance. Phenobarbitone Therapeutic range for phenobarbitone is 10-40 μg/ml and monitoring is mainly useful for deciding maximum increase in dose (side effect of drowsiness experienced by the patient is most important limiting factor). Is TDM cost-effective? Therapeutic drug monitoring is has become very important in managing the difficulties in using some drugs. While the digoxin therapeutic range is somewhat 'loose', the advent of monitoring resulted in a far greater appreciation of the toxicity of digoxin and of the need for rational dosing. Similarly, theophylline, while now falling out of favour for other reasons, was rescued from oblivion when the advent of therapeutic drug monitoring in the 1970s allowed its use largely without the serious toxicity previously associated with it. The use of any of the drugs in Table 21.2 without monitoring would be difficult and often dangerous. Emphasis should be placed not so much on whether monitoring is necessary as on how to use it in the most cost-effective and clinically effective manner possible.

OBJECTIVES At the end of the session the student shall be able to: 1. Understand and define therapeutic drug monitoring 2. List indications for TDM with examples

Therapeutic Drug Monitoring (TDM)  193 3. Suggest the timing of sampling for TDM depending on the given clinical situation. 4. Suggest modification of dosage/treatment by interpreting given plasma levels of drugs. Exercises: Exerices can be given in small groups to students. These exercises can be in the form of cases on cards. Then the cases can be discussed in a bigger group. Exercises: 1. When samples should be collected for following clinical conditions: a) Failure of antiepileptic therapy

b) Suspected aspirin toxicity

c) Cyclosporine in organ transplantation

d) Starting gentamicin therapy

2. A 35-year-old male was given Tab. Theophylline 300 mg bd for bronchial asthma. There was good clinical response as evidenced by pulmonary function tests, but patient complained of tremor, anxiety and palpitations. What would you advise the doctor on duty? Investigations – Theophylline blood levels–7 mg/l (Normal 5-15 μg/ml).

3. A 49-year-old male was prescribed phenytoin for seizure prophylaxis. After receiving a 400 mg loading dose of phenytoin, the patient received 200 mg phenytoin qid, but experienced disturbance in sensorium. You are approached by neurologist to comment on. What you would advise? Investigations-phenytoin blood levels 26 μg/ml. (Normal levels of phenytoin 10-20 μg/ml, Toxic levels > 20 μg/ml).

C H A P T E R

22

Drug Use in Special Population/ Diseases/Physiological Conditions

Certain pathological and physiological condition can change pharmacokinetics of a drug affecting its action. Hence, dose adjustment is needed in these conditions. Let us discuss them one by one.

A. CHILDREN Very old are very young patients are more prone to adverse drug reactions (ADRs). When the drug manufacturer does not provide adequate information about pediatric dosage, there can be substantial risk in deriving a dose for children and infants from an adult dose. Children and particularly neonates, differ from adults in their response to drugs. Special care is needed in the neonatal period (first 30 days of life) and doses should always be calculated with care. At this age, the risk of toxicity is increased by inefficient renal function, relative enzyme deficiencies, differing target organ sensitivity and inadequate metabolism systems causing delayed elimination. Factors affecting drug disposition in children • Absorption o Variable gastric and intestinal transit time: in young infants, gastric emptying time is prolonged and only approaches adult values at around 6 months of age. In older infants, intestinal hurry may occur. o Increased gastric pH: gastric acid output does not reach adult values until the second year of life. o Other factors: gastrointestinal contents, posture, disease states and therapeutic interventions, such as drug therapy, can also affect the absorption process. o Bioavailability of rifampicin, gentamicin, phenytoin, phenobarbitone and acetaminophen is increased in children. o Topical drugs are absorbed promptly in children. • Distribution: o Increased total body water: as a percentage of total body weight, the total body water and extracellular fluid volume decrease with increasing age. Neonates require higher doses of water soluble drugs on an mg/kg basis than adults.

Drug Use in Special Population/Diseases/Physiological Conditions  195 o Decreased plasma protein binding: plasma protein binding in neonates is reduced as a result of low levels of albumin and globulins and an altered binding capacity, e.g. increased free levels of aspirin. High circulating bilirubin levels in neonates may displace drugs from albumin. • Metabolism o Enzyme systems mature at different times and may be absent at birth, or present in considerably reduced amounts. Phase 2 reactions are not well developed, e.g. Gray baby syndrome with Chloramphenicol in neonates. o Altered metabolic pathways may exist for some drugs. o Metabolic rate in children is often greater than in adults. Compared with adults, children may require more frequent dosing or higher doses on an mg/kg basis. • Excretion o Complete maturation of renal function is not reached until 6-8 months of age. Similarly pharmacodynamic vary in children. There is immaturity in receptor and neurotransmitter development. Similarly ciprofloxacin can lead to tendon damage and rupture and it is not recommended for children, but in our country there is no restriction for its use in children. Children are not mini-adults. Always calculate the appropriate dose for the child. Dose can be calculated based on body weight, age or surface area. The commonly used method is based on weight but the most accurate method is based on surface area. The following methods can be used to calculate dose in children: 1. Young's formula Dose in child =

Age × Adult dose Age + 12

2. Clark's rule Dose in child =

Adult dose × Weight (Pounds) 150

3. Fried's rule Dose in child =

Adult dose × Age in months 150

4. Based on surface area Dose in child =

Adult dose × Body surface area (m 2 ) Adult body surface area (1.7 m 2 )

Dosage form, compliance, vomiting, shaking of suspensions, measurements with household measures, taste of drugs are some of the practical issues in children.

196  Practical Manual of Pharmacology Golden rules in children are: • Always calculate appropriate dose • Do not use newer drugs, use only well established drugs • Avoid polytherapy Some drugs should be avoided as far as possible. These are given in Table 22.1: Table 22.1. Drug to be avoided in children S. No. 1 2 3 4 5 6

Drug Aspirin Chloramphenicol Fluoroquinolones Tetracyclines Stunned growth Aminoglycosides

Adverse effect Reye's syndrome Gray baby syndrome Arthropathy Teeth and bone abnormalities Corticosteroids Ototoxicity

B. ELDERLY It is estimated that by the year 2020 elderly people will constitute 11-12% of total population. In treatment of the elderly (geriatric) many variations are required from standard recognized treatment due to both aging itself and common age related diseases. Variations occur in pharmacokinetics and pharmacodynamic with age. Moreover elderly people often suffer from multiple diseases and are treated with multiple drugs. Multiple drug use and altered responsiveness expose elderly more to adverse drug reactions making it difficult to prescribe rationally. Providing safe, effective drug therapy is one of the greatest challenges in geriatrics. The following changes happen in the elderly: Pharmacokinetic changes Decreased first pass metabolism can lead to increased levels of propranolol. Decreased lean body mass can lead to increased level of water soluble drugs, e.g. digoxin. Decreased plasma protein binding can cause increased activity of highly plasma protein bound drugs, e.g. warfarin. Impaired renal elimination can cause accumulation of digoxin. Impaired hepatic elimination can lead to increased levels of theophylline. Pharmacodynamic changes Physiologic changes and loss of homeostatic resilience can result in increased sensitivity to unwanted effects of drugs, such as hypotension from psychotropic medications and hemorrhage from anticoagulants, even if dosage is appropriately adjusted to account for the age. Drugs that depress the central nervous system produce increased effects at any given plasma concentration.

Drug Use in Special Population/Diseases/Physiological Conditions  197 In addition, drug therapy should be employed only after nonpharmacologic means have been considered or tried and only when the benefit clearly outweighs the risk. Once pharmacotherapy has been decided upon, it should begin at less than the usual adult dosage and the dose should be increased slowly. However, given the marked variability in pharmacokinetics and pharmacodynamics in the elderly, dose escalation should continue until either a successful endpoint is reached or an intolerable side effect is encountered. The final dosage schedule should be kept as simple as possible, and the number of pills should be kept as low as possible. Other factors which affect therapy: • Impaired memory • Impaired eyesight • Tremors in hands • Constipation. Compliance is often poor (60%) in the old patients particularly in persons taking too many drugs. This may be due to forgetfulness, confusion (the patient takes too many doses), deliberate and immobility lethargy. Be careful about following drug groups in elderly: Sedative-Hypnotics If nonpharmacologic treatment of insomnia is unsuccessful, use intermediate-acting agent whose metabolism is not affected by age (e.g. oxazepam, 10 to 30 mg/d). Antibiotics Serum creatinine is not a good index of renal function in old people, concentrations of relevant antibiotics should be measured directly. Cardiac Drugs In older patients, digitalis, procainamide and quinidine have prolonged half-lives and narrow therapeutic windows. Toxicity is common at the usual dosages. Antipsychotics and Tricyclic Antidepressants These drugs can produce anticholinergic side effects in old people (e.g. confusion, urinary retention, constipation, dry mouth. The newer potent antipsychotics (e.g. risperidone, olanzapine, quetiapine, and clozapine) are relative exceptions to this rule. Analgesics Of the NSAIDs, indomethacin is most likely to induce confusion, fluid retention and gastrointestinal bleeding. Each of these agents should be avoided in the elderly. Cyclooxygenase 2 (COX-2) inhibitors are safer than nonselective NSAIDs for older adults. However, they are more expensive and can cause fluid retention with consequent worsening of hypertension and nocturnal incontinence.

198  Practical Manual of Pharmacology Avoidance of Overtreatment Drugs are frequently not indicated in some common clinical situations in elderly. For instance, antibiotics need not be given for asymptomatic bacteriuria unless obstructive uropathy, other anatomic abnormalities or stones are also present. Ankle edema is often due to venous insufficiency, drugs such as NSAIDs or some calcium antagonists or even inactivity or malnutrition in chairbound patients. Diuretics are usually not indicated unless edema is associated with heart failure. Fitted, pressure gradient stockings are often helpful. For claudication, regular exercise should be prescribed before cilostazol. Golden rules in treatment of elderly are: • • • • • • •

Start slow, go slow One drug, one dose Start at right time, stop at right time Avoid certain drugs Think about necessity of drug Think about drug dose and dosage form Check compliance.

C. PREGNANCY Drugs given during pregnancy may affect fetus. Thalidomide is a classical example of teratogenic effects. It was synthesized in 1954 in Germany and four years later was marketed as sedative. It was widely used by pregnant females for nausea and vomiting. It was considered safe because in toxicity studies in rodents, it did not produce any toxic effect. Thalidomide led to birth of babies with seal like limbs (phocomelia). It is estimated that approximately 20,000 babies suffered toxicity of thalidomide. It was withdrawn in 1961. There are so many physiological changes during pregnancy which can affect drug action. In pregnant state pharmacokinetics and pharmacodynamic of a drug change considerably. Total body water increases by 8%, diluting the drugs in the body. Plasma protein binding undergoes a considerable change. Some metabolic pathways may be induced. Renal plasma flow is doubled during 3rd trimester, so clearance of some drurg may increase. This predisposes a pregnant female to adverse drug reactions. An important aspect of human teratology is that teratogenic medications administered after the vulnerable period will not usually cause structural malformations but may induce functional adversity. Thus, the timing of drug intake is crucial: (a) Conception to about 17 days of gestation: It is likely that the deleterious effects on the zygote will lead to abortion. (b) From is 18 to 55 days of intra-uterine life: It is the most susceptible period for adverse effects. The rapidly multiplying and differentiating cells are vulnerable to any agent (Table 22.2) affecting division, enzymes, protein synthesis or replication. As many organs are for concurrently, it is not surprising

Drug Use in Special Population/Diseases/Physiological Conditions  199 that a dysmorphogenic agent interferes with simultaneous organization of many systems may produce a multiplicity of malformation various sites. It is recommended that no drug should be given in first trimester of pregnancy. (c) By the day-56 of gestation, most organs are well formed and drugs can no longer produce malformations, but they may still impair the growth, development and functioning particularly in organs which are not yet fully differentiated. Drug given prior to labour: drugs can lead to adverse postnatal effects in infants, e.g. CNS depressants can lead to neurological, respiratory or muscular dysfunction in the neonate. Drugs given during labour: Anaesthetics, analgesics, etc. used during labour can suppress foetal respiration and prolong labour. Drugs which are considered safe in pregnancy are: penicillin, pyrimethamine, thiazides, atenolol, ACE inhibitors and prazocin. According to their effect on fetus drug are classified into categories. CATEGORY A: Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities to the fetus in any trimester of pregnancy, e.g. Folic acid Thyroxine B: Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate and well-controlled studies in pregnant women. Or, Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester, e.g. Amoxycillin, Paracetamol. C: Animal studies have shown an adverse effect and there are no adequate and wellcontrolled studies in pregnant women. Or, No animal studies have been conducted and there are no adequate and wellcontrolled studies in pregnant women, e.g. Morphine, Atropine. D: Adequate well-controlled or observational studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective, e.g. Aspirin, Phenytoin. E: Adequate well-controlled or observational studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities or risks. The use of the product is contraindicated in women who are or may become pregnant, e.g. Isotretinoin, Ergometrine. You must assess the benefit/risk ratio for the condition being treated.

200  Practical Manual of Pharmacology Table 22.2. Common drugs that are teratogenic ACE inhibitors Alcohol Amantadine Antithyroid Androgens Anticonvulsants Aspirin and other salicylates (third trimester) Benzodiazepines Chloramphenicol (third trimester) Cyclophosphamide Diazoxide Diethylstilbestrol Disulfiram Ergotamine Estrogens Griseofulvin Isotretinoin

Lithium Methotrexate Misoprostol NSAIDs (third trimester) Opioids (prolonged use) Oral hypoglycemics Progestins Radioiodine Reserpine Ribavirin Sulfonamides (third trimester) Tetracycline (third trimester) Thalidomide Tobacco smoking Trimethoprim (third trimester) Warfarin and other coumarin anticoagulants

Dosage adjustment and plasma level monitoring Points to remember while prescribing in pregnancy: • Dosage adjustment becomes difficult due to changes in pharmacokinetics and complex nature of maternal-placental-fetal complex (Fig. 22.1). Be careful when narrow therapeutic index drugs are given, e.g. phenytoin levels tend to fall during pregnancy, hence dosage has to be increased. • If possible counselling of women before a planned pregnancy should be carried out including discussion of risks associated with specific drugs. • Drugs should be prescribed in pregnancy only if the expected benefits to the mother are thought to be greater than the risk to the fetus. • All drugs should be avoided if possible during the first trimester. • Drugs which have been used extensively in pregnancy and appear to be usually safe should be prescribed in preference to new drugs and the smallest effective dose should be used. • Well known single component drugs should usually be Fig. 22.1: Fetus in uterus with placenta preferred to multidrug therapy.

Drug Use in Special Population/Diseases/Physiological Conditions  201 D. LACTATION Most drugs are secreted in breast milk in very small quantities. These do not affect suckling infant. However, there are few drugs, which readily enters breast milk and adversely affect nursing infant. Care should be taken while prescribing drugs to lactating mothers. Drugs may be classified as per the following criteria: a. Drugs undetected in breast milk: aminoglycosides b. Drugs reach the baby but insignificant dose: non-narcotic analgesics, penicillin c. Drugs reach the baby with significant dose: aspirin, benzodiazepines, barbiturates, tetracyclines, carbimazole. The following principles should be followed when prescribing for breastfeeding mothers: • Avoid unnecessary drug use and limit use of over-the-counter (OTC) products, e.g. opiates, benzodiazepines, Isoniazid, anticancer drugs • Breastfeeding mothers should seek advice on the suitability of OTC products • Avoid use of drugs known to cause serious toxicity in adults or children • Neonates (and particularly premature infants) are at greater risk from exposure to drugs via breast milk, because of immature excretory functions and the consequent risk of drug accumulation • Choose a regimen and route of administration which presents the minimum amount of drug to the infant • It is best to avoid long-acting preparations, especially those of drugs likely to cause serious side effects (e.g. antipsychotic agents). • Multiple drug regimens may pose an increased risk especially when adverse effects such as drowsiness are additive • Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms • Avoid new drugs if a therapeutically equivalent alternative that has been more widely used is available. A robust assessment of the balance of benefit to risk requires data both on the drug's passage into breast milk and its effects in infants: there is rarely enough information available for new drugs to allow such an assessment to be made • Assess the benefit/risk ratio for both mother and infant.

E. HEPATIC DISEASE Drugs which are mainly eliminated by liver are affected. There can be accumulation of drug or failure to get converted to active moiety (prodrug). Hence, Dose adjustment is needed. Unfortunately, unlike renal disease where creatinine clearance can provide an indication of the extent of renal dysfunction, there is no simple test to assess hepatic functions. Most of the conventional liver function tests do not reflect the capacity of the liver to metabolise. Hepatic blood supply: this decreases in old age and with use of beta blockers. Dosage of drugs with high extraction ratio need to be decreased in this case, e.g. lignocaine, imipramine. First pass metabolism: dosage of drugs undergoing extensive first pass metabolism need to be decreased, e.g. propranolol.

202  Practical Manual of Pharmacology Prodrugs: these drugs get activated by metabolism in liver, hence in hepatic dysfunction they might become ineffective, e.g. captopril. Hepatotoxic drugs: avoid all drugs which are hepatotixic, e.g. tetracyclines, methotrexate. Hypoalbiminaemia: this leads to increased concentration of highly plasma protein bound drugs, e.g. warfarin. Remember that in while prescribing for patients with hepatic disease: • Avoid drugs which undergo extensive first pass metabolism • Measure plasma levels • Be careful about drug interactions • Drugs mainly metabolized by kidneys can be used.

F. RENAL DISEASES Drugs which are eliminated from body through kidneys are mainly affected. There can be accumulation of drug at therapeutic doses, leading to toxicity. Elimination of a drug is linearly and hence, predicably related to GFR (Table 22.3) which is best expressed clinically as the creatinine clearance. Dose adjustment is done according to creatinine clearance (CLcr). Creatinine clearance is calculated as (Cockroft Gault formula): Wt ml/min 72 140 CLcr– Age 100Ccr Wt Female = 0.85 × ml/min × 72 Ccr is serum creatinine concentration in mg/dl This formula is invalid with Ccr > 5 mg/dl The loading dose is not changed. The maintenance dose is altered based on the clinical condition. The maintenance dose of a drug can be reduced either by reducing the individual dose amount leaving the normal interval between doses unchanged or by increasing the interval between doses without changing the dose. The interval extension method may provide the benefits of convenience and decreased cost, while the dose reduction method provides more constant plasma concentration. Male =

×

Based on CLcr, 2 methods to calculate the dosage can be used a. Clearance method b. Dose fraction method a. Clearance method It is the most accurate method, but clearance data of drug is needed. This method can be used to determine: i. Dose amount DRF = D ×

Drug Use in Special Population/Diseases/Physiological Conditions  203 DRF – dose in renal failure D – standard dose ii. Dosage interval DI (revised) = DI (standard) × iii. Infusion rate DRF = CLRF × Cp iv. Oral dose DRF/F (fraction of absorption). b. Dose Fraction method It is less accurate as it uses renal clearance only, but it is more user friendly. DRF = D × The known dose fraction (KRF/K) of a drug (at CLcr zero) is plotted on the Nomograsm, against estimated CLcr and the required dose fraction in renal failure is obtained. In adjusting the dosage for patients with renal failure the initial loading dose usually needs little or no reduction. A few notable exceptions to this principle are digoxin and morphine (because of changes in distribution volume and sensitivity). After the initial dose CL KRF achieves the peak plasma concentration, the plasma level will decrease more slowly, i.e. the Clrf K half life will be prolonged in proportion to the severity of renal failure as reflected by the plasma creatinine concentration. The prolonged half life means that the plasma concentration will be higher than usual when the next dose is due. A marked reduction in dosage will be required when the kidney is the only route of excretion of a drug and renal failure is severe. Obviously the half lives of those drugs eliminated predominantly by extrarenal routes will be affected little by renal failure and intermediate effects will result when elimination is partially renal. The fractional elimination by the kidney (the renal clearance as a fraction of total plasma clearance) determines the extent of dosage adjustment required in renal failure. Avoid all nephrotoxic drugs, e.g. aminoglycosides, NSAIDs Remember that in while prescribing for patients with renal disease: • Avoid/adjust dosage of drugs which undergo extensive renal elimination • Measure plasma levels • Be careful about drug interactions • Drugs mainly metabolized in liver can be used. For patients in whom renal function is compromised, dosing nomograms have been developed to help achieve the usual therapeutic plasma concentrations of a drug. Renal impairment is usually divided into three grades: Mild—GFR 20 – 50 ml/minute Moderate—GFR 10 – 20 ml/minute Severe—GFR < 10 ml/minute

204  Practical Manual of Pharmacology Table 22.3. Drugs requiring dose/interval adjustment in renal dysfunction Drug Aminoglycosides Cefazolin Amoxicillin Lithium Atenolol Spironolactone Famotidine

Adjustment Dose reduction Interval extension Interval extension Dose reduction Dose reduction Interval extension Dose reduction

> 50

GFR (ml/min) 10-50 < 10

60-90% 8h 1h 100% 100% 6-12 h 100%

30-70% 12 h 6h 50-75% 50% 12-24 h 75%

20-30% 24-48 h 6-12 h 25-50% 25% avoid 25-50%

G. GENETIC VARIATIONS Sometimes dose adjustment is required due to genetic variations (Table 22.4). Table 22.4. Drugs causing hemolysis in glucose 6 phosphate dehydrogenase deficient individuals o Definite association: primaquine, sulfanilamide, sulfacetamide, dapsone, nitrofurantoin, nalidixicacid, niridazole, methylene blue, phenazopyridine, naphthalene, toluidine blue. o Probable association: chloroquine, quinine,sulfadiazine, sulfisoxazole, aspirin, paracetamol, phenacitin, ciprofloxacin, norfloxacin, L-dopa, chloramphenicol, vitamin K analogs, probenecid,vitamin C

OBJECTIVES At the end of the session the student will be able to: 1. Understand the modification in the pharmacokinetics of some common drugs in children, elderly, pregnancy, lactation, hepatic and renal disease. 2. List and choose drugs based on efficacy, suitability, tolerability and cost in these conditions. 3. Calculate dose of a given drug in children and in renal disease. Exercises in class: Exercises can be given in small groups. The problem is then discussed in a larger group.

Drug Use in Special Population/Diseases/Physiological Conditions  205 Examples: a) Which drugs you will choose in following conditions. Explain with reasons. 1. Pregnant woman suffering from grand mal epilepsy.

2. Hyperthyroid pregnant female.

3. 70-year-old suffering from insomnia.

4. 40-year-old hypertensive with impaired renal function.

5. 42-year-old lady with hepatic dysfunction and suffering from tuberculosis.

6. 35-year-old male suffering from gram negative infection with renal dysfunction.

7. The creatinine clearance of a patient with renal failure is 35 ml/min. How would you adjust the normal dosage of gentamicin for this patient using the nomogram provided. (dose of gentamicin 80 mg three times a day).

8. Seven year child suffering from status epilepticus.

9. Can tetracycline be prescribed to children and pregnant females.

10. 70-year-old diabetic patient.

206  Practical Manual of Pharmacology b) The parenteral dose of erythromycin injection is 10 mg/kg/24 hours. Calculate the daily dose of this drug for a 20 kg child.

c) A 23 kg, 7-year-old girl of average height is to begin Griseofulvin therapy. The dose of this drug is 10 mg/kg/24 -4 doses, orally. The average adult dose is 500 mg daily in divided doses.

d) Each numbered term in column A below indicates a method of solving the daily child's dose for the given data. Once you have solved the child's dose according to each method, find it in column B and enter the corresponding letter in the blank. Column A Column B (Method) (Daily Dose) 1. Clark's Rule. 2. Young's Rule. 3. Calculation using mg/kg dose 4. Calculation as fraction of adult 5. Calculate based on surface area.

e) The child has a body surface area of 0.67 M2. The adult dose of drug A is 40 mg/day. The physician prescribed 8 mg. Is the dosage correct?

C H A P T E R

23

Critical Appraisal of Drug Promotional Literature

There seems to be a glamour about anything new. A new car or a new movie, you know these days how these things are advertised. Similarly, pharmaceutical Industry has multitrack approach for providing information to physicians. This is the commonest source of drug information for physicians and available through all channels of communication, i.e. verbal, written and computerised. These channels also include professional meeting, advertising in journals, direct mailing, medical representatives, etc. Advertising is paid, one-way communication through a medium in which the sponsor is identified and the message is controlled. 15-20% of budget of a pharmaceutical industry is for promotion of products. Out of those > 50% is spent on medical representatives. 90% of the physicians see medical representatives (MRs). This is the easiest way to gather new drug information. A substantial percentage of physicians heavily rely on representatives as source of information about drugs (and gifts!). But, it has been observed that these representatives emphasize only the positive aspects of products and overlook or give little coverage to the negative aspects (ADRs). Most of the information is commercially driven. These advertisements highlight the advantages of the drug in question and the disadvantages or the limitations of the drug being suppressed. The general principles of advertising are also applied to drug advertising. There is a huge difference in criteria when you want to select a vehicle or mobile phone as compared to selecting a drug. Ethically speaking the criteria for selection of drug should be entirely driven by patient's disorder or disease. For that a doctor do not need advertisement but a scientifically validated information about drugs. Whenever you are shown an advertisement about drugs by MRs, look carefully for the size of the letters used for brand name, generic names, efficacy, and adverse effects. Critically analyse the given advertisements for: a) Validity of scientific claims b) Content of scientific information c) Relevance of references cited d) Appropriateness of illustrations. The following sources of drug information can be used for this purpose:

208  Practical Manual of Pharmacology Source of drug information Although pharma houses provide knowledge about the drug and their hazardous events that may occur during their use in therapeutic indications with recommended dosage the information given by these houses is often incomplete and hence the data loses its reliability. There should be pooled information given by drug safety committee to be backed by WHO and a regular update must appear especially on the adverse effect of newer drugs in the leading medical journals, so that physicians remain comprehensively updated to face any eventuality. The typical example of how the information provided can change the concepts and beliefs of the patients, doctors and community is information on new selective COX-2 inhibitor NSAIDs. Many doctors also gained the false impression that selective drugs were also less likely than conventional NSAIDs to have adverse effects on blood pressure and the kidneys. This view was also held by some key opinion leaders, people who always have a major influence on prescribing patterns and, for this reason, are invited by pharmaceutical companies to talk to groups of prescribers. To complicate the situation, the media persuaded consumers that the new 'wonder' drugs were more efficacious than older medications. Word of mouth completed a marketer's dream situation. Certainly the drugs were heavily promoted by both industry and the media, but why did prescribers fail to follow ethical principles? The facts were all there in many independent sources of information. The present status is that Cox-2 inhibitors are either being banned (nimesulide) or withdrawn voluntary by manufacturer (rofecoxib). The manufacture is paying heavy claims to the patients who suffered from adverse effects. There is no merit in being among the first to prescribe a new drug whatever the pressures from patients and drug companies. Of course industry puts the best possible spin on its marketing messages, but doctors should be smart enough to see through the hype created. They need to know that when a drug first appears on the market only limited safety data are available and long term outcomes, both good and bad, can only emerge with time and appropriately designed, prospective safety studies. It is well established that most prescribers obtain the majority of their information from the pharmaceutical industry and they, therefore need more training in how to evaluate the information and what questions to ask drug representatives. How doctors can get updated about drugs? Knowledge and ideas about drugs are constantly changing. More and more new drugs are coming on the market. New experience with existing drugs is expanding (side effects, new indications/ways of using). A Physician is expected to know about new developments in drug therapy. However, in many parts of the world, objective and unbiased information about drugs is a luxury which is difficult for most of the physicians to access. It is difficult for busy physicians to have satisfactory knowledge of all these drugs. Hence, selection and use of right drug in an appropriate manner becomes a challenge. How you can keep up-to-date about drug information inspite of your busy schedule?

Critical Appraisal of Drug Promotional Literature  209 The sources of information are: 1. Written form-journals, reference books, drug bulletins, books 2. Verbally-through discussions in CMEs, meetings, journal clubs in institutions 3. Tape/video/online-journals, CDs 4. Drug Information Centers 5. Pharmaceutical industry 6. Internet. Others written forms which can be used are: 1. Drug compendia—these list the drugs available on the market 2. National list of essential drugs and standard treatment guidelines 3. General Pharmacological reference—Goodman and Gilman's: The Pharmacological basis of Therapeutics 4. Martindale's The extra Pharmacopoeia—excellent reference book, gives all information on all chemicals used with references 5. Avery' drug treatment—more specialised 6. Meyler's side effects of drugs 7. MIMS—monthly index of medical specialties—these provide information on: • Generic/brand names • Chemical composition • Indications/contraindications • Side effects, interactions • Price. [Current Index of Medical Specialties (CIMS), Indian Drug Review (IDR), Drug Index (DI), Drugs Today, etc.] Drug bulletins are preferred because they are: • Critical source of new drug information • Promote rational drug therapy • Appear at frequent intervals • Sponsors—government agencies, university departments, professional bodies, nonindustry sponsored. Some drug bulletins available In India are: Drug bulletins Australian prescriber is available free of charge Others are: Drugs and therapeutic bulletin (UK) Medical letter (USA)

210  Practical Manual of Pharmacology Medical Journals The important ones are: The Lancet, New England Journal of Medicine, and British Medical Journal. Tons of information is available in these journals. Thousands are published and they vary enormously in quality. • Only a small proportion publish scientifically validated articles • Good journal are peer reviewed by independent experts, usually no advertisements are there • Define range of drugs available to prescriber • Consensus on the treatment of choice for the most common diseases and complaints • Index Medicus has list of major reputable journals. Symposia/conferences Symposia are useful for disseminating information. The objective scientific content of such meetings should be paramount, and presentations by independent scientists and health professionals are helpful to this end. DIC (Drug Information Centre) • Very useful • Prescribers and general public can call • Use reference books online. Examples • DIC-Philippines-Dept. of Pharmacology • DIC-Kathmandu, Nepal 2 Clinical pharmacologists 1 Pharmacist. Internet Adverse effects are the prime health hazards of drugs. In order to manage an adverse drug reaction it is important to be aware of all possible drug reactions and drug interactions. However, given the current scenario of introduction of new drugs into market, it is impossible to keep track of all reports of reactions. This is where the web comes to the rescue. Internet is another source of drug information, but all the information available is not authentic. Check the authenticity of the website. Advantages • A large number of sources • Quick and easy.

Critical Appraisal of Drug Promotional Literature  211 Disadvantages • Illegal advertising and complaints have increased • Use catchy slogans, e.g. Scientific breakthrough, miraculous cure, secret formula, ancient ingredients, antiageing, all natural • Use case histories of successful consumers, authenticity of whom is questionable Keeping up-to-date should not be too difficult for physicians in developed countries, but it can be far from easy in some parts of the world where access to independent sources of drug information is very limited. But wherever you live and work it is important to develop a strategy to maximize your access to key information you need for optimal benefit of the drugs you prescribe. Ethical criteria for drug promotion WHO has formulated ethical criteria for medicinal drug promotion. The main objective of ethical criteria for medicinal drug promotion is to support and encourage the improvement of health care through the rational use of medicinal drugs. The essential features are: 1. Ethical criteria for drug promotion provides the foundation for proper behaviour concerning the promotion of medicinal drugs, consistent with the search for truthfulness and righteousness. These criteria constitute general principles for ethical standards which could be adapted by governments to national circumstances as appropriate to their political, economic, cultural, social, educational, scientific and technical situation, laws and regulations, disease profile, therapeutic traditions and the level of development of their health system. They apply to prescription and non-prescription medicinal drugs ("over-the-counter drugs"). They also apply generally to traditional medicines as appropriate, and to any other product promoted as a medicine. 2. "Promotion" refers to all informational and persuasive activities by manufacturers and distributors, the effect of which is to induce the prescription, supply, purchase and/or use of medicinal drugs. All promotion making claims concerning medicinal drugs should be reliable, accurate, truthful, informative, balanced, up-to-date, capable of substantiation and in good taste. They should not contain misleading or unverifiable statements or omissions likely to induce medically unjustifiable drug use or to give rise to undue risks. The word "safe" should only be used if properly qualified. Comparison of products should be factual, fair and capable of substantiation. Scientific data in the public domain should be made available to prescribers and any other person entitled to receive it, on request, as appropriate to their requirements. Scientific and educational activities should not be deliberately used for promotional purposes. 3. Information that such advertisements should usually contain, among others includes: • The name(s) of the active ingredient(s) using either international nonproprietary names (INN) or the approved generic name of the drug. • Brand name. • Content of active ingredient(s) per dosage form or regimen;

212  Practical Manual of Pharmacology

4.

5.

6.

7. 8.

• Name of other ingredients known to cause problems; • Approved therapeutic uses; • Dosage form or regimen; • Side-effects and major adverse drug reactions; • Precautions, contraindications and warnings; • Major interactions; • Name and address of manufacturer or distributor; • Reference to scientific literature as appropriate. To fight drug addiction and dependency, scheduled narcotic and psychotropic drugs should not be advertised to the general public. While health education aimed at children is highly desirable, drug advertisements should not be directed at children. Medical representatives should have an appropriate educational background. They should be adequately trained. They should possess sufficient medical and technical knowledge and integrity to present information on products and carry out other promotional activities in an accurate and responsible manner. Exposure of medical representatives and trainees to feedback from the medical and allied professions and from independent members of the public, particularly regarding risks, can be salutary. Medical representatives should make available to prescribers and dispensers complete and unbiased information for each product discussed, such as an approved scientific data sheet or other source of information with similar content. Free samples of legally available prescription drugs may be provided in modest quantities to prescribers, generally on request. Free samples of non-prescription drugs to the general public for promotional purposes. Postmarketing scientific studies and surveillance should not be misused as a disguised form of promotion. Appropriate information being important to ensure the rational use of drugs, all packaging and labeling material should provide information consistent with that approved by the country's drug regulatory authority. Adequate information on the use of medicinal drugs should be made available to patients.

Should you avoid representatives? Medical representatives are criticized a lot, but there network is very huge and now they have become an integral part of medical infrastructure in the country. Hence, make best use of this huge network for getting drug information in a desirable way! Ask about publication of drug safety in an authentic medical journal. Optimize the time spent with medical representatives. Remember following points while dealing with a representative: • Take control of the discussion • You get the information you need • Ask for officially registered drug information and compare it with what industry has got printed

Critical Appraisal of Drug Promotional Literature  213 • • • •

Comparison with standard treatment use Particularly look for side effects and contraindications Ask for published references on efficacy and safety If it is 'me too' drug (analogue of same class, e.g. new proton pump inhibitor) ask about price • Do not start by using free samples on a few patients or family members • Do not base your conclusions on the treatment of a few patients.

OBJECTIVES At 1. 2. 3. 4. 5.

the end of the practical class the student shall be able to: Understands concept of advertisement. Critically analyze a given drug advertisement. Identify unethical points in advertisement. Enumerate authentic sources of drug information. Appreciate the merits and limitations of the various sources.

Exercise in class Drug promotional literature is given to batch of 4-5 students. They are given 15 minutes to analyse and write their points. The group leader gets 5 minute to speak about advertisement which is projected through LCD projector in front of whole class. In this way you can cover a large number of advertisements and all aspects of advertisements. Exercises Find out the following information from the appropriate books and mention the source of information:

1. What is the plasma half life of atenolol?

2. Does the clearance of gentamicin get altered in the renal insufficiency?

3. What is the Vd of amiodarone?

214  Practical Manual of Pharmacology 4. What is dose of paracetamol in children?

5. Select the cheapest preparation of ciprofloxacin (500 mg tablet).

6. Select the cheapest and costliest preparation of diclofenac (50 mg tablet).

7. What is the incidence of anaphylaxis with penicillin injection?

8. Can nimesulide be prescribed to a 3-year-old child?

9. What are precautions while taking doxycyline tablet?

10. Name 3 new antiepileptic drugs.

11. Why rofecoxib was withdrawn from market?

12. Write 5 brand names of enalapril tablet.

CHAPTER

24

Therapeutic Follow-up Cases/Problems

Cases are identified in the hospital. Students are divided into batches. Each batch has 4-5 students. They are allotted cases. They go to their respective cases and work up on the case and fill the following required information. Clinical Pharmacology Exercise Form (Therapeutic follow-up for any case) Student's Name MBBS 2nd Prof.(Year)

Semester

Roll No. Clinical Assignment of

INSTRUCTIONS 1. Fill up the Performa with appropriate data. 2. Write down the presenting complaint, chief complaints and other symptoms of disease in this patient. 3. Write down the various parameters to follow improvement in this disease and enter the observation daily/ periodically in the columns provided. 4. Write the name of the drug, dose, route, and frequency of administration. Tick (√) in the appropriate date column when each drug is started and put (X) when the drug is discontinued. 5. Any fresh sign/ symptom appearing during the treatment should be recorded. Tick (√) when these appear and put (X) when these disappear. Salient Features of the case: Clinical Department Registration No. DOA/DOD Name of patient. Body weight

Ht.

Age and Sex, Pregnant Smoking Y/N Alcohol Y/N

Lactating

216  Practical Manual of Pharmacology Major Sign and Symptoms: (Write down all the symptoms in chronological order) Symptoms

Signs/ Diagnostic test

1. 2. 3. 4. 5. 6. Drugs used Name of drug

Dose

Route

Frequency

Res. Rate

BP

Change/Date

Daily cost

Parameters monitored (General) Day/time

Temp

Pulse

Others

Others

Others

Others

Therapeutic Follow-up Cases/Problems  217 Specific parameters Investigation

Date

Day-

Day-

Day-

Day-

1 2 3 4 5 C. Investigations during treatment with date and rational/ reasons 1. 2. 3. 4. 5. D. Fresh signs and symptoms/adverse effects (developed during treatment) 1. 2. 3. 4. E. Comment on: Common trade names of the drugs used Cost Shelf life/Storage Schedule (H/X, etc.) Method of administration (With/without food, milk, other drugs, posture, inhalation, Dilution/Infusion, etc.) Information to patient (About expected side effects which are not serious/when consultation should be sought) Specific Antidote (In case of poisoning) Advice to attendant/family members to ensure compliance and assess improvement F. Therapeutic follow-up G. Advice on discharge

218  Practical Manual of Pharmacology H. Other alternative drugs available for this case II. Alternatives to be used in old/Children/Pregnant/presence of concurrent hepatic or renal disease III. Non-Pharmacological Measures to be taken. (Diet, exercise, smoking, alcohol, etc.)

OBJECTIVES 1. Complete few therapeutic follow-up cases 2. Present these cases and highlight drug management. Students will fix the copies of this performa in their practical notebook. The case will be discussed during the presence of full class. The student will present the case and other students would be allowed to comment/ask questions. The number of cases covered can vary from 20 to 40 depending upon the schedule. Later on problem based questions can be taken out from these cases. Put them on card along with 3-4 questions and make them as one of the OSPE stations. Example: This is taken from history of a parkinsonism patient. A 60-year-male was on phenothiazines therapy for psychotic illness. He developed parkinsonism disease. He was given L-dopa 250 mg OD but there was no improvement. The dose of which then increased to 750 mg OD but still there was no improvement. Q1. Why he developed parkinsonism? Q2. Why he was not benefited by increasing the L-dopa dose even? Q3. What alternate should be given?

CHAPTER

25

New Drug Development

New drug development involves animal toxicity studies followed by clinical trial in humans. Potentially useful compounds are studied in animals to evaluate desired effects and toxicity. Animal toxicity studies are done to see whether the chemical is safe or not. Compounds that appear effective and safe are candidates for human studies. For all new drugs, it is mandatory to do toxicity studies in animals. After that the drug enters various phases of clinical trials. The various phases of drug development are:

Drug development is an extremely arduous, highly technical, time-consuming and very expensive process. The investment to produce one marketed drug is approximately US$800 million and 12-15 years. The idea starts from folklore or screening of natural products. But nowadays drugs are designed on computer keeping in view the target, e.g. agonists and antagonists are synthesized for receptors. Chemical synthesis is done by chemists by using computer models these days. Various combinations are designed using CADD (computer assisted drug designing) and then best molecules are chosen for study in animals. They are given code numbers, e.g. M1001-M1210.

220  Practical Manual of Pharmacology The molecules are synthesized and a formulation is made. It is tested in animals. Various screening methods are available depending on the disease condition. Selected molecules from screening are further subjected to animal toxicity studies. If the molecule is found to be safe it enters clinical trials. It is estimated that to have one successful drug we need to start with 10,000 molecules. Clinical trial is defined as “a carefully and ethically designed experiment with the aim of answering some precisely framed questions. To carry out each phase of clinical trial in India, permission from Drug Controller General of India (DCGI) is required. In US the regulatory authority is Food and Drug Administration’s (FDA). Clinical trial is systematic study of pharmaceutical products on human subjects (whether patients or non patient volunteers) in order to discover or verify the clinical, pharmacological (including pharmacodynamics/pharmacokinetics) and/or adverse effects, with the object of determining their safety and/or efficacy. There are five phases of clinical trials. Phase 0 Phase 0 is a recent designation for exploratory, first-in-human trials conducted in accordance with the FDA 2006 guidelines. Phase 0 trials are designed to expedite the development of promising therapeutic or imaging agents by establishing very early on whether the agent behaves in human subjects as was anticipated from preclinical studies. Distinctive features of Phase 0 trials include the administration of single subtherapeutic doses of investigational agent to a small number of subjects (10 to 15) to gather preliminary data on the agent’s pharmacokinetic and pharmacodynamic properties and mechanism of action. Phase I The objective of phase I of trials is to determine the maximum tolerated dose in humans, pharmacodynamic effect, adverse reactions, if any, with their nature and intensity and pharmacokinetic behaviour of the drug as far as possible. These studies are often carried out in healthy adult volunteers (20-25) using clinical, physiological and biochemical observations. The main aim is to find out the safety of the drug in humans. Phase I trials are usually carried out by investigators trained in clinical pharmacology and having the necessary facilities to closely observe and monitor the subjects. These may be carried out at one or two centres. The perquisite to start phase I trials is submission of results of animal toxicity studies. Phase II-Exploratory trials In phase II trials a limited number of patients (20-200) are studied carefully to determine possible therapeutic uses, effective dose range and further evaluation of safety and pharmacokinetics. Normally 10-12 patients should be studied at each dose level. These studies are usually limited to 3-4 centres and carried out by clinicians specialized on the concerned therapeutic areas and having adequate facilities to perform the necessary investigations for efficacy and safety. The perquisite to start phase II trials is submission of results of phase I.

New Drug Development  221 Phase III-Confirmatory trials The purpose of these trials is to obtain sufficient evidence about the efficacy and safety of the drug in a larger number of patients (250-1000), generally in comparison with a standard drug and/or a placebo as appropriate. These are real life situations. These trials may be carried out by clinicians in the concerned therapeutic areas, having facilities appropriate to the protocol. Data on ADRs observed during clinical use of the drug should be reported along with a report on its efficacy in the prescribed format. The perquisite to start phase III trials is submission of results of phase II. However, if the drug is already approved/marketed in other countries, then you need to carry on directly phase III study (known as bridging study) on at least 100 patients distributed over 3-4 centres primarily to confirm the efficacy and safety of the drug, in Indian patients. The prerequisite is submission of data of marketed drug in other countries. In this case you need to conduct bioequivalence studies also. Phase IV These are studies performed after marketing of the pharmaceutical product. Trials in phase IV are carried out on the basis of the product characteristics on which the marketing authorization was granted and are normally in the form of postmarketing surveillance, assessment of therapeutic value, treatment strategies used and safety profile. Phase IV studies should use the same scientific and ethical standards as applied in pre-marketing studies. This phase has now become mandatory in India under Schedule Y. After a product has been placed on the market, clinical trials designed to explore new indications, new methods of administration or new combinations, etc. are normally considered as trials for new pharmaceutical products. A protocol for clinical trials has following information: • Title: • Introduction: (brief, justification and problem definition) • Hypothesis: • Aims and Objectives: • Materials and Methods: (a) Type of Study: prospective, observational (b) Setting: (c) Subjects: patients, healthy volunteers (d) No. of Groups: Randomisation, blinding (e) Sample size calculation: power of study (f) Study design: (g) Treatment: (h) Primary outcome measures: (i) Secondary outcome measures:

222  Practical Manual of Pharmacology (j) Stopping rule: (k) Analysis: (l) Ethics:

OBJECTIVES At the end of the session a student shall be able to: 1. Understand concept of new drug development. 2. Understand various phases of clinical trials.

C H A P T E R

26

Calculation of Drug Doses and Dilutions

Posology is the science of dosage. It deals with the amount of drug necessary to produce a desired physiological, therapeutic, or prophylactic effect. Dose It is the appropriate amount of a drug required to produce a certain degree of response in a patient given at a time and which can be repeated at an appropriate interval to produce a desired therapeutic effect or it is quantity of drug which is sufficient to diagnose, prevent or cure a disease. Dosage It is schedule of dose, frequency and duration of administration of drug. Dose may be: 1. Standard dose The same average dose is given to all the patients, e.g. diclofenac 50 mg three times a day. a. The minimum dose is the smallest dose that produces a therapeutic effect. b. The maximum dose is the largest dose that can be safely administered. c. The toxic dose is the dose that produces harmful effects. d. The lethal dose is the dose that will result in death. The minimum lethal dose (MLD) is the smallest amount that will cause death. e. The single dose is the amount of a drug taken at one time. f. The daily dose is the total amount of a drug taken in 24 hours. g. A continuous dose consists of small doses taken at short intervals. 2. Regulated or Titrated dose Dose is adjusted based on measurement of a body function. For example: antihypertensive drugs as per BP measurement Antidiabetic drugs as per blood glucose measurement.

224  Practical Manual of Pharmacology 3. Target level dose Plasma concentration of a drug is monitored for adjustment of dose, e.g. Phenytoin in epilepsy based on plasma level achieved. Target concentration is 10-20 microgrms/dl. Fixed-Dose Combinations (FDC) The concomitant use of two or more drugs adds to the complexity of individualization of drug therapy of a disease. The dose of each drug should be adjustable to achieve optimal benefit. But patient compliance is more difficult to achieve. To obviate the latter problem, many fixed-dose drug combinations have been marketed. The use of such combinations is beneficial only if the ratio of the fixed doses of drugs corresponds to the needs of the individual patient. Most of the FDCs are banned in India and other countries. Drug doses may also be calculated based on body weight or surface area in adults. Anticancer drugs are calculated based on body surface area. Ratio-proportions Ratios indicate a relationship between two numbers with a colon between the numbers. The colon represents division. For example 3:4 = 3/4. A ratio is the relation between like numbers or values, or a way to express a fractional part of a whole. Ratios may be written: As a fraction:

2 3

1.0 11 gm 200 1000 3 ml

As a division: 2 ÷ 3 The strength or concentration of various drugs can be expressed as a ratio. First, read the label of the drug and find the strength or concentration. Express this strength as a ratio in fractional form, as in the following examples. Kanamycin injection, 1.0 gm/3 ml = Isoproterenol inhalation, 1:200 = Epinephrine injection, 1:1000 = Proportions are equations containing ratios of equal value. A proportion consists of two equal ratios and is essentially a statement of equality between two ratios. For example 3:4 = 6:8. This may also be written as fractions, 3/4 = 6/8. The value of the ratio on the right must always equal the value of the ratio on the left. A proportion may be written with the double colon, or proportion sign (::), or with the sign of equality (=).

Calculation of Drug Doses and Dilutions  225 Means 2 :5 :: 4: 10

or

Extremes In a proportion, there are four numbers. The two middle numbers are known as MEANS and the two end numbers are known as EXTREMES. Example: You find a 10-ml vial of Aminophylline in supply labeled "25 mg per ml." Thus, there are 250 mg of drug in this 10-ml vial. (extreme) 25 mg = 250 mg (mean) (mean) 1 ml = 10 ml (extreme) Notice that when you multiply the two extremes and the two means, the products are equal. For example: 25 × 10 = 250 × 1. Multiply the extremes: 25 × 10 = 250 Multiply the means: 1 × 250 = 250 In a proportion, the product of the means is always equal to the product of the extremes. Therefore, when you do not know one value (x), you can determine it, if the other three values are known. When setting up a ratio, the known factor (on hand) is stated first, the 2=4 desired is stated second. 5 = 10 When doing calculation, use the following steps to solve for X. (1) Step 1. State problem in "if-then" form. (2) Step 2. Convert the problem to an equation. (a) Known information (labeled strength, and so forth) should be your IF ratio. (b) The unknown ratio including X will be your THEN ratio. (c) Put like units on the same side of each ratio. (For example, if the left side of the equation is expressed in mg/ml, then the right side must also be expressed in mg/ml). (3) Step 3. Cross multiply means and extremes. (4) Step 4. Solve for X. Example 1: Prescribed: 600,000 units of penicillin po q6h Available: 400,000 units per scored tablet How many tablets will you administer? 400,000 units : 1 tablet = 600,000 units : x 600,000 = 400,000x 600,000 = x = 1.5 tablets

226  Practical Manual of Pharmacology 400,000 or the formula method can be used: D/H X Q = X D - dosage desired or ordered H - what is on hand (available) Q - unit of measure that contains the available dose. When using solid products (tablets, capsules) Q is always 1 and can be eliminated. Q varies when using liquid measures. X - the unknown dosage you need to administer. Example 2: Prescribed: Potassium Chloride 20 mEq added to the IV. Available: 40 mEq per 10 cc. How much potassium will you add? D = 20 mEq H = 40 mEq Q = 10 cc 20 mEq X 10 cc = X 40 mEq 0.5 X 10 = X = 5 cc It doesn't matter if you use ratios, fractions or the formula, the answer will be the same Calculating dosages in units (insulin, heparin, pitocin, vitamins, some antibiotics). Example 3: Prescribed: Ampicillin 400 mg IM q6h Available: Vial with powder. Label reads: For IM injection, add 3.5 ml diluent (read accompanying circular). Resulting solution contains 250 mg Ampicillin per ml. Use solution within one hour. How many ml will you administer Ratio-proportion method: 250 mg : 1 ml = 400 mg : x 400 = 250 x 400÷250 = 1.6 ml Formula method: D/H X Q = X 400 mg X 1 ml = X 250 mg 1.6 ml = X.

Calculation of Drug Doses and Dilutions  227 Example 4: Prescribed: Heparin 8000 units subcutaneous q12h Available: Heparin 10,000 units per ml How much will you administer? Formula: 8000 units X 1 ml = 0.8 ml 10,000 units Ratio: 10,000 units : 1 ml = 8000 units : x 8000 units X 1 ml = 10,000 units x 8000/10,000 = x 0.8 ml = x. Conversion within the metric system To convert a quantity in the metric system to a larger unit, we divide or move the decimal point to the left. To convert to a smaller unit, we multiply or move the decimal point to the right. Alternatively, we can use ratio and proportion as illustrated in the following examples: Example 1: Convert 0.3 mg to grams. (There are 1000 mg in 1 gram.) IF 1000 mg THEN 0.3 mg 1 gm = X gm 1000 x X = 0.3 x 1 1000X = 0.3 X = 0.0003 gm (answer). Example 2: Express 30 liters in terms of milliliters. (There are 1000 ml in 1liter.) IF 1000 ml THEN X ml. 1 liter = 30 liters 1 x X = 1000 x 30 liters X = 30,000 ml (answer). The labeled strength of a 30 ml vial of Meperidine injection is 50 mg/ml. How many milliliters must be injected to provide a 75 mg dose? IF 50 mg THEN 75 mg 1 ml = X ml 50 x X = 1 x 75 50X = 75 X = 1.5 ml.

228  Practical Manual of Pharmacology Calculate drop rate: Example 1: Prescribed: Infuse 2 L of Lactated Ringers solution in 24 hours. The administration set has 12 gtts/ml. How many gtts/min will you administer the IV? 2000 ml X 12 gtts/ml = x 24 hr 60 min/hr 24000 = x 1440 16.7 gtts/min or 17 gtts/min = x. Example 2: Ordered: Gentamicin 100 mg/100 ml IV q8h. The IV handbook states that it should be given over 90 min. What rate will you set on your IV pump? 100 ml = x 90 min 60 min 90 x = 6000 x = 6000/90 x = 66.7 or 67 ml/hr. Liquids Example 1: A three-month old boy who is 24.5 inches long and weighs 11 pounds, 8 ounces, is to receive Phenobarbital elixir labeled 20 mg/5 ml. The anticonvulsant dose of Phenobarbital is 125 mg/m² dose. (1) Calculate the single dose of Phenobarbital in mg. SURFACE AREA = 0.31 m² CHILD'S DOSE = 0.31 x 125 mg = 40 mg, approximately (2) How many milliliters will be administered for each single dose? IF 20 mg THEN 40 mg 5 ml = X ml 20 x X = 5 _ 40 X = 200 = 10 ml (answer) 20. Example 2: How many grams of potassium permanganate should be used in preparing 500 ml of a 1:2500 solution? 1:2500 = 0.04%

Calculation of Drug Doses and Dilutions  229 500x0.0004 = 0.2 gm or 1:2500 means 1gm in 2500 ml 2500:500 = 1xX X = 0.2 gm.

OBJECTIVES At the end of the session the student shall be able to: 1. Calculate the quantity of drug present in a given solution. 2. Appreciate the importance of calculating the total quantity of drug and its conversion from percentage and molar solutions for individualization of therapy. 3. Calculate number of tablets, quantity of solution, drip rate for given condition. Exercises in class: These can be given to small groups on cards. Later on these cards can be used as one of the stations in OSPE. 1. How many milliliters of promethazine hydrochloride injection labeled 25 mg/ml must be administered to provide a dose of 12.5 mg?

2. A patient is prescribed 30 milligrams of furosemide intravenously. 10 milligrams in 1 millilitre of liquid for IV. Injection is available. How many millilitres will you administer?

3. A patient is prescribed 22 milligrams of gentamicin sulphate by intramuscular injection. 20 milligrams in 2 millilitres of liquid for IM. Injection is available. How many millilitres will you administer?

4. A patient is prescribed 75 micrograms of fentanyl citrate intravenously. 0.1 milligrams in 1 millilitre of liquid for IV. Injection is available. How many millilitres will you administer?

5. A patient is prescribed 50 milligrams of sodium valproate orally. 200 milligrams in 5 millilitres of syrup is available. How many millilitres will you administer?

230  Practical Manual of Pharmacology 6. A patient is prescribed 200 milligrams of Amoxicillin trihydrate orally. 250 milligrams in 5 millilitres of Syrup is available. How many millilitres will you administer?

7. A patient is prescribed 15 mg of stemetil. You have 2 ml of solution on hand which contains 25 mg Stemetil. What volume of solution would you give?

8. A dose of 75 mg of pethidine has been prescribed. It is available in ampoules containing 100 mg in 2 ml. What volume must be administered?

9. Calculate the drip rate for 100 mls of IV fluids to be given over a half hour via a giving set which delivers 10 drops/ml.

10. Calculate the drip rate for 500 ml of normal saline to be given over 4.5 hours via a giving set which delivers 15 drops/ml.

11. Calculate the drip rate for 500 ml of dextrose 5% in water to be given over 4 hours via a giving set which delivers 15 drops/ml.

12. A patient is prescribed 50 milligrams of amitriptyline. 25 milligram tablets are available. How many tablets will you give?

13. A patient is prescribed 300 milligrams of carbamazepine. 200 milligram tablets are available. How many tablets will you give?

Calculation of Drug Doses and Dilutions  231 14. A child weighing 12 kg has been prescribed syrup chloroquine (one bottle of 60 ml, each ml containing 10 mg of chloroquine base). The initial dose of chloroquine is 10 mg/kg. Calculate the amount of syrup to be administered to the child.

15. A patient is prescribed 2.5 grams of neomycin sulphate. 500 milligram tablets are available. How many tablets will you give?

16. Convert 93074 milligrams to grams.

17. Convert 64343 millilitres to litres.

18. Convert 97.196 micrograms to milligrams.

CHAPTER

27

Evaluation of Drug Formulations

Rational therapeutics is an important clinical aspect of applied pharmacology. Formulation is an integral part of therapeutics. Hence, following aspects of formulation for a given disease will be discussed 1. Labeling: 2. Cost: 3. Rational Therapeutic: 4. Essential drug concept: Pharmaceutical companies manufacture the drugs. They usually provide the information sheets/package inserts/brochures for their products. Though, they should provide the scientific information for their products, largely such information is prepared from commercial angle and for marketing of their products rather than giving scientific information. Often the companies provide the information which is incomplete, irrelevant and having tall claims. Therefore, it is necessary that these information sheets/brochures/literature provided by the pharmaceutical companies should be evaluated on the basis of above points. In addition to this one should pay special attention to the following points: 1. Physical presentation: quality of paper, print, colour, etc. 2. Figures, diagrams, tables, pictures, cartoon, etc. 3. Quality of statements made, i.e. broken, convenient statements and their source 4. References: their authenticity, time of publication, etc. 5. Cost, if mentioned. The following aspects of labeling and package inserts should be considered: 1. Consumer information which is simple and not confusing 2. Indication of the item as a medicinal product 3. Composition of the product including international nonproprietary name (INN)/generic name of the active substance 4. Uses for which the product is intended

Evaluations of Drug Formulations  233 5. Mode of use, including route of administration (systemic or local), maximum single dose, maximum daily dose and duration of treatment 6. The product is intended for (children or adults) 7. Presentation of the most important precautions, contraindications and adverse effects clearly stated in easily understandable language. The size of letters. 8. Specific warnings and information for use during physiological/pathological variations such as pregnancy, lactation, the elderly, or in patients with renal or hepatic failure. 9. When medical advice should be sought 10. Duration of use 11. Information on storage conditions and shelf-life 12. Inactive ingredients listed 13. Expected benefit when the drug is used properly 14. Expiry date 15. Overdosage: Brief clinical description of symptoms, non-drug treatment and supportive therapy and specific antidotes Many developing countries including India, have a limited budget allocated to health care especially for drug procurement. Therefore, it is imperative to optimize expenditures for drug purchases by selecting an essential drug list and promoting the rational use of drugs. Rational drug use: RUD means use of a right medicine, in the right manner (dose, route and frequency of administration, duration of therapy), in right type of a patient, at a right cost, i.e. the rule of right. Rational drug use also means using the drug when necessary (chloroquine in malaria) and more importantly, not using it when unnecessary (expectorant mixture in common cold). When the word 'right' is replaced by the word 'wrong' it becomes irrational drug therapy which is more frequent than assumed. Irrational use of medicines is a major problem worldwide. WHO estimates that more than half of all medicines are prescribed, dispensed or sold inappropriately and that half of all patients fail to take them correctly. Inappropriate, ineffective and inefficient use of drugs commonly occurs at health facilities in developing and developed countries. Common types of irrational use of drugs include: • Non-compliance with health worker prescription • Self-medication with prescription drugs • Overuse and misuse of antibiotics • Overuse and misuse of antidiarrhoeals for non-specific childhood diarrhea • Multiple or overprescription • Overuse of injections and overuse of relatively safe drugs • Use of unnecessary expensive drugs and poor patient compliance • Unnecessary use of tonics and multivitamins • Short consulting time.

234  Practical Manual of Pharmacology Many individuals or factors influence the irrational use of drugs such as patients, prescribers, the workplace environment, the supply system including industry influences, government regulation, drug information and misinformation. In addition to optimizing the use of limited budget, promoting the rational use of drugs aims to improve quality, increase accessibility and equity of health and medical care for the community. Essential drug concept: The concept of essential drugs was first time mooted by the World Health Organisation (WHO) in 1977 and the first list of essential list was published in 1977. The list is revised every two years. Currently the 15th list (March, 2007) is in use (http://www.whoindia.org/ LinkFiles/Essential_Medicine_List_EML15.pdf). The essential drug list of India was formulated in 1996 and revised in 2003. It has 354 drugs (Appendix IV). Many drugs included in the list are preceded by a box in WHO list to indicate that they represent an example of a therapeutic group and that various drugs could serve as alternatives. It is imperative that this is understood when drugs are selected at national level, since choice is then influenced by the comparative cost and availability of equivalent products. Definition: Essential medicines are those that satisfy the priority health care needs of the population. Selection criteria: Essential medicines are selected with due regard to disease prevalence, evidence on efficacy and safety and comparative cost-effectiveness. Essential drugs are selected to fulfill the real needs of the majority of the population in diagnostic, prophylactic, therapeutic and rehabilitative services using criteria of risk-benefit ratio, cost-effectiveness, quality, practical administration as well as patient compliance and acceptance. Purpose: Essential medicines are intended to be available within the context of functioning health systems at all times, in adequate amounts, in the appropriate dosage forms, with assured quality and at a price the individual and the community can afford. Implementation: The implementation of the concept of essential medicines is intended to be flexible and adaptable to many different situations; exactly which medicines are regarded as essential remains a national responsibility. Clinical guidelines and a list of essential medicines lead to better patient care and effective prevention. The principle of the concept is that a limited number of drugs lead to: • • • • • •

Better supply of drugs More rational prescribing Procurement of good quality drugs at lower costs Easier storage, distribution and dispensing Focused training and drug information Prescribers gain more experience with fewer drugs and recognize ADR better.

Evaluations of Drug Formulations  235 Essential drugs are selected based on: • • • • • • • •

Morbidity pattern Evidence of efficacy and safety Relative cost effectiveness Local manufacturing facilities Pharmacokinetics considerations Ensured quality, bio-availability, stability Single compounds preferred over FDC FDCs only if proven advantage of combination, decreasing emergence of resistance, i.e. malaria, tuberculosis, HIV/AIDS.

Essential drug list should be: • Evidence Based Best balance of efficacy, safety, quality and cost • Efficient Focuses therapeutic, decision, professional training, public information, finances • Flexible Implemented from primary to tertiary health care • Forward Looking Regularly updated in accordance with new needs and information. Rational drug use and essential drug concept are interdependent and interlinked. Availability of essential drugs will undoubtedly lead to more rational drug use and rational use of drugs shall promote more production and supply of essential drugs. There are three broad categories of interventions to improve rational drug use. These have been classified as educational approaches, managerial approaches and regulatory approaches. Educational approaches attempt to inform or persuade prescribers, dispensers or patients to use drugs in the proper, rational and efficient way. There are many types of this approach such as inservice training, face-to-face education, small group discussions, seminars, workshops and printed education materials. Managerial strategies attempt to improve drug decision-making by a variety of techniques including use of specific processes, forms, packages and monetary incentives. The interventions using this approach include developing and implementing Essential Drug Lists or Drug Formularies, Standard Treatment Guidelines, implementing drug supply kit system, monitoring and feedback, establishing representative Pharmacy and Therapeutics Committees, establishing structured drug prescribing form, providing cost information, and set-up financing. Essential Drug Lists or Drug Formularies provide prescribers with a list of the drugs felt to be most effective and economic in treating important health problems. Regulatory approaches attempt to restrict allowable decisions by placing absolute limits on availability of drugs. These strategies rely on rules or regulations to change behavior.

236  Practical Manual of Pharmacology Interventions using this approach are limiting or banning registration, changing product registration status as well as prescribing and dispensing controls. In general a combined intervention is likely to have a synergistic effect Fixed-dose Drug Combinations (FDCs): They are produced and used to meet the following objectives: 1. To produce drug synergism in order to achieve a better therapeutic response than each drug used alone. Atleast they must have additive effect, for example, cotrimoxazole. 2. To reduce the incidence/severity of adverse effects of one drug by the other, for example, atenolol + amlodipine, combinations of antitubercular drugs. 3. To provide convenience of administration and to reduce cost of drug, leading to better patient compliance, for example, levodopa + carbidopa. As against these, following are the demerits of majority of the currently available FDCs in India. 1. dosage alteration of one drug is not possible without alternation of other drugs. 2. differing pharmacokinetics of constituent drugs pose the problem of frequency of administration of the formulation. 3. overprescribing and polypharmacy leading to consumption of unnecessary drugs. 4. increased chance of adverse drug effects and drug interactions. 5. increased cost. 6. when an FDC has large number of ingredients (4 or more), as in the case of tonics, haematinics and cough mixtures, a doctor may not know what are the ingredients in the formulation he is prescribing. WHO essential drug list has only 2.1% FDCs. As against this, according to a rough estimate, approximately 1,00,000 drug formulations are marketed in India. According to a conservative estimate nearly 70% of them are FDCs. A large majority of these FDCs are nonessential or useless at the best and irrational or harmful at the worst. In India, doctors get information about various drugs largely from the medical representatives visiting them or from the promotional literature mailed to them by the pharmaceutical industry. More often a doctor consults various indexes like, Monthly Index of Medical Specialties (MIMS), Current Index of Medical Specialties (CIMS), Indian Drug Review (IDR) or Drug Index (DI) to get information on drugs. The claimed objective of these publications is to share information but hidden agenda is to promote the commercial interest. One gets lost in the 'therapeutic jungle'. It becomes virtually impossible to choose the right medicine from plethora of drugs. Therefore, it is essential for a doctor to develop the skill of critically evaluating the available drug formulations for their rationality based on efficacy, safety, cost and convenience of administration before embarking on their use.

Evaluations of Drug Formulations  237

OBJECTIVES 1. Work out the cost of drug treatment for the given condition. Compare the drug cost for different brands. 2. Assign the status as rational/semirational/irrational to the given drug formulation as a whole and giving reason(s) for the same. 3. Comment on the following FDC a) Paracetamol + aspirin b) Paracetamol + Nimesulide c) Amoxycillin + clavulanic acid.

CHAPTER

28

Ethics and Humans

ETHICS • • • •

A discipline dealing with what is good and bad and with moral duty and obligation A set of moral principles or values A theory or system of moral values The principles of conduct governing an individual or a group. Ethics is the study of right conduct and a rational process for determining the best course of action in the face of conflicting choices. Medical ethics is the science of moral values that guides a medical practitioner in their relationship with their patients, the state and professional brethren. It also includes ethical issues associated with providing health care or perusing biomedical research. The four essential principles of ethics are: 1. Autonomy of Patients: Patients body is his/her own. He/she has right to decide about operations and procedures. When patients come to you it is implied consent for routine procedures. It is better to explain patient about every procedure and them perform. When special procedures are done stated/special consent is taken. Physician must guide patients to take right decision. 2. Beneficence: One must remember that whatever we do, it should be done for benefit of patients. 3. Non-maleficence: Do no harm. 4. Justice: Patient should get the best treatment and justice should be done to all as far as possible. You need not have ethical worries if you behave in a beneficent, nonmaleficant, just manner, protecting autonomy and following consistent moral code. Since ethics is an integral part of practice of medicine, its study should parallel that of study of medicine. The purpose of this session is to make students start understanding of principal moral values governing medical ethics. It should subsequently develop awareness of frequent existence of ethical issues and dilemmas help develop the capacity for resolution

Ethics and Humans  239 of these issues through ethical reasoning and acquire understanding of the function of institutional bodies concerned with ethics. As in every sphere of life, medical profession has also moral duty and obligations, and so is in the field of pharmacology. Ethics in pharmacology are most important when it comes to research on humans and the interaction of doctors and medical representatives. Earlier human beings were being used in research without their consent. History is full of examples showing unethical use of human beings. Nurember code (1947) was the first attempt to integrate ethics into research. The main emphasis of this code was to protect the integrity of the research subject. This was followed by declaration of Helsinki in 1964 by World Medical Association and International Guidelines for biomedical research involving human subjects by WHO (1982). In India, there are guidelines from ICMR, New Delhi (2000)for conduct of research on human beings. As per these guidelines it is mandatory to take written informed consent from any human who is going to be involved in research. This consent form is considered to be document of faith and trust. It safeguards autonomy, respect patient's right to dignity. Written Informed consent has following components: 1. Patient Information Sheet Provides information to patient about the research work where he is going to be involved. 2. Consent Form Used to document consent in writing Informed consent emerged from the ethical principle of Respect for Persons. These principles state that: • Individuals be treated as capable of taking decisions for themselves ("autonomy") • Those with diminished autonomy be protected • Language: The informed consent and information sheet must be available in local languages in validated format. Informed consent is a PROCESS and involves: • • • • • •

Providing all relevant information to the volunteer/patient The patient/volunteer understanding the information provided Voluntarily agreeing to participate It should be in writing, there is no value of verbal consent Basic right Maintaining confidentiality.

The information on consent form includes: a) Name and designation of investigator b) Institute where the study will be carried out

240  Practical Manual of Pharmacology c) d) e) f) g) h) i) j)

Name and address of the patient Age, sex and hospital registration number Title of the study Procedure in layman's language Option to opt out of the study without reason Care will not suffer if he opts out Adverse effects (known and unknown) Signatures.

Written informed consent is needed in following circumstances: 1. All research projects involving human beings. Special care has to be taken about, double blinding, randomization, serious adverse effects, whether to give placebo or not, cost of treatment, washout period, informed consent form in writing, treatment after end of trial, insurance of subjects, randomization, etc. 2. Cancer chemotherapy 3. Invasive procedures 4. HIV testing 5. Thalidomide prescription. It is necessary to stress that taking informed consent should satisfy the letter and spirit of the procedure. Special groups like pregnant women, children, mentally ill patients were previously excluded from clinical trials. However, now the trend has changed to include these groups in clinical trials so as not to deprive them of the benefits of new drugs and therapies. Therefore, whenever possible the procedure is explained to the subject (during a lucid interval or to a child using pictorial representations) and receiving the individuals consent in addition to the guardian's consent is mandatory. Example of an informed consent form: PATIENT CONSENT DOCUMENT Example 1 I_________________________ exercising my free power of choice, hereby give my consent to be included in this study of "Drug A" and understand that I will be treated with this drug for the disorder I am suffering from. I have been informed to my satisfaction by the attending physician, the purpose of this and follow up including the laboratory investigations required to monitor and safeguard my body functions. I, have also been explained the risk profile of the drug and am giving consent that I be included in the study. I am also aware of my right to opt out of the study at any time during the course of the study without having to give reasons for doing so. Patient Signature: Date: Signature of investigator: Date:

Ethics and Humans  241 PATIENT CONSENT DOCUMENT Example 2 Patient Consent Form I exercising my free power of choice, hereby give my consent to be included in the study "Comparison of safety of Drug A and Drug B in Indian patients." I have been informed to my satisfaction by the doctor, the purpose of this study. I will not be given any new medication. I am diagnosed to be suffering from and will be receiving standard treatment for this disease. I understand that I will be evaluated for adverse effects of drugs in the OPD only. The information will be kept confidential and will be used only for scientific purpose. I am also aware of my right to opt out of the study at any time without having to give any reason for doing so. Patient Signature: Date: Signature of investigator: Date: Consent form need to be signed by a relative/guardian for mentally ill patients. Other ethical issues are: • • • • • • • •

Meeting drug medical representatives (MRs) Acceptance of gifts of equipment, travel, or accommodation from MRs Attending at sponsored dinners and social or recreational events Attending at sponsored educational events, continuing medical education, workshops, conferences or seminars Conducting drug company sponsored research Company funding for medical schools, academic chairs, or lecture halls Undertaking paid consultancy work for drug companies Giving medication during pregnancy/lactation.

OBJECTIVES At the end of the session a student shall be able to: 1. Understand importance of ethical issues in clinical research. 2. Understand the components of a written informed consent form and realize its medicolegal implications. 3. To recognize the specific groups (children, mentally ill patients, etc.) where informed consent has to be sought from the legal guardian. Example 1: A new selective Cox-II NSAID has been launched to the market. You are invited on its launch in a five star hotel in Mumbai. You deliver a lecture in its favour. Its adverse effect

242  Practical Manual of Pharmacology profile has not been investigated adequately. The drug company marketing the NSAID gives you 500 tablets as sample and asks you to try out the drug on 30 patients. You are also informed that you can present your findings at an international conference to be held after 3 months in USA. There is no DCGI permission. The travel arrangement (along with family) will be sponsored by drug company. You agree and start using the drug on patients who attend the dispensary where you work but not on patients who come to your private clinic. Comment on ethical issues.

Example 2: You are conducting a clinical trial in Punjab on hypertension. The informed consent are in English language and there is no information sheet attached to it. The patient is just told to sign on it without giving any explanation. The patient is paying for all investigations done during the trial. Comment on ethical issues.

CHAPTER

29

Management of Some Common Poisonings

How apt is the statement that, "A medicine in large dose can act like a poison, a poison in small dose can act like a medicine" A poison or toxin is a substance that can cause temporary or permanent damage if taken into the body in sufficient quantity. A poison may be swallowed, inhaled, injected, instilled in the eye or absorbed through the skin. Once introduced into the body, a poison can quickly be carried to all the tissues via the bloodstream. Signs and symptoms vary, depending on the poison and its method of entry. Vomiting is common to many cases, with the attendant risk of inhalation of the stomach contents. Acute poisoning requires accurate assessment and prompt therapy may be needed. Hazard is associated not only with the potency of the poison but also with the quantity ingested, the duration of exposure and the presence of other ingredients in preparations, including solvents. General principles: It should be determined if the poisoning: 1. Is life-threatening and already compromising vital functions; 2. Poses a potential hazard or 3. Is essentially harmless. Early identification of the toxic substance (or ingredients and their potential toxicities) can save time and decrease the risk of toxicity and complications, particularly in instances where a specific antidote could be lifesaving or prevent serious organ damage, e.g. methanol, paracetamol, arsenic, iron poisoning, etc. Early collection of blood, urine and other body fluid samples to establish baseline values for monitoring the toxin, glucose, electrolytes, acid/base status and organ damage may be valuable in the management of the poisoned patient. Obtaining the original toxic substance or container is more valuable and reliable for rapid and positive identification of the poison than depending on laboratory analysis of blood, urine or other body fluids alone.

244  Practical Manual of Pharmacology Supportive care: • Contaminated clothing should be removed and the skin washed with soap and water. If contaminated, the hair should be shampooed. • Reliable venous access should be established in comatose patients. Hypoventilation can be avoided by ensuring an adequate airway with suction, oxygen, insertion of an airway and mechanical ventilation as required. Most poisons that depress consciousness also impair respiration. An obstructed airway needs immediate attention. Dentures and oral secretions should be removed and the jaw held forward with the patient turned in a left semiprone position. Volume depletion secondary to vomiting, diarrhoea and sweating is common and should be corrected. Hypoglycemia must be excluded in any comatose patient. If present, 50 ml of a 50% dextrose solution should be administered intravenously. Hypoglycemia should be suspected particularly in intoxication with oral hypoglycemics, salicylates and ethyl alcohol. Hypotension is most common in severe barbiturate poisoning and whether due to volume depletion or venous pooling, frequently necessitates monitoring of central venous pressure to determine fluid requirements. Hypothermia (< 35° C) may develop in comatose patients. Cardiac conduction defects and arrhythmias may occur in acute poisoning with various substances. ECG monitoring is advisable and attention should be given to aggravating factors such as acidosis, hypoxia and electrolyte/fluid disturbances. Specific treatment will depend on the toxin ingested and the type of arrhythmia. Convulsions that are single and short-lived do not require immediate anticonvulsive therapy. Diazepam, given slowly intravenously, should be administered if convulsions are protracted or recur frequently, keeping in mind that it may produce CNS and particularly respiratory depression. Terminating exposure to ingested toxins: The stomach should be emptied after the ingestion of most poisons, (there are some notable exceptions, e.g. corrosives, volatile hydrocarbons and convulsants). Gastric emptying is clearly unnecessary if the risk of toxicity is small or if the patient presents too late. Emptying the stomach more than 4 hours after ingestion is of questionable value, although worthwhile recovery of tricyclic antidepressants (and other drugs which delay gastric emptying, e.g. anticholinergics, opiates, antihistamines and sympathomimetic amines) can be achieved 4-12 hours after ingestion. Induced emesis may be preferred to lavage in alert patients with an active gag reflex and is usually more efficient than lavage especially when large tablets or capsules have been swallowed. Emesis is best induced with ipecacuanha. Gastric lavage via a large-bore orogastric tube (32-40 F in adults and 16-28 F in children) is preferred in patients with a depressed level of consciousness, but only after a cuffed

Management of Some Common Poisonings  245 endotracheal tube has been inserted to prevent aspiration. Warm water is instilled and after a minute the water is removed. The procedure may have to be repeated 5-6 times until no further drug is obtained. Stomach emptying should be followed by the administration of activated charcoal, which reduces absorption of many substances. Activated charcoal (WHO essential therapeutic group) Activated charcoal is a powerful adsorbent of a wide spectrum of drugs and poisonous substances thereby reducing absorption from the gut. It is used in cases of overdosage or accidental poisoning by drugs and other non-corrosive substances, usually after the stomach has been emptied by lavage or emesis and plays an important role in the management of poisoning. Since charcoal adsorbs ipecacuanha it should not be given before the emetic. Current opinion favours the use of larger and more frequent doses of charcoal in all instances where a potential for adsorbing intoxicants exists. Binding of drugs in the lumen also creates a concentration gradient so that the drug or poison passes continuously from the circulation into the gut lumen. There are indications that this 'gastrointestinal dialysis' is valuable in hastening the elimination of numerous drugs or toxins that have already been absorbed into the bloodstream. It is recommended that 2-4 additional doses of 20-50 g be administered in severely poisoned patients, in cases where slow release tablets have been ingested (e.g. theophylline), in poisoning with drugs that are excreted into the bile, undergoing entero-hepatic recycling (e.g. tricyclic antidepressants, estrogens and progestogens, digitoxin) as well as those secreted into the intestine (e.g. digoxin, pethidine). It is of no value in poisoning with strong acids or alkalis, iron salts, lithium, petroleum products (including kerosene) and of questionable value in cyanide ingestion. Activated charcoal may be mildly constipating, but is essentially safe and innocuous. Mixing the suspended dose with 20 ml lactulose and 50% syrup (or sorbitol 70%) makes it more palatable and prevents the constipating effect. Adult dose: Usually oral or via gastric tube, 50-100 g, prepared as a thick slurry in 200500 ml water. Paediatric dose: Under 6 years, 10 g in 50-100 ml water; older children, 20-50 g in 100-300 ml water. Osmotic laxatives, e.g. saline purgatives (such as sodium sulphate), sorbitol 70% or lactulose may usefully assist in clearing the bowel of potentially absorbable poisonous material. Rough estimates of the dose, the time elapsed since exposure and the physical state of the patient determine whether emesis, gastric lavage, supportive care, or specific therapy is required, as well as the sequence of such interventions.

246  Practical Manual of Pharmacology Poisoning with drugs 1. Paracetamol poisoning It is the commonest ingested toxin in UK causing > 300 deaths in the UK each year. It is rarely taken alone. The liver is the main target organ in paracetamol poisoning. Doses of 7.515 g in an adult may cause severe centrilobular hepatic necrosis. Renal tubular necrosis may also develop. Hepatic and renal failure typically manifest only after 3-5 days. Clinical features: Within a few hours after the overdose (0.5-24 hours) patients experience symptoms of gastrointestinal irritability with anorexia, nausea, vomiting, abdominal pain, as well as pallor, malaise and increased sweating. During this phase the patient may, however, appear normal or asymptomatic. During the next 24-48 hours symptoms and signs may become less pronounced, but the blood chemistry starts to become abnormal. Very rarely coma and severe metabolic acidosis develop in patients who have extremely high plasma paracetamol concentrations (usually > 800 mg/L). Loin pain, haematuria and proteinuria after the first 24 hours strongly suggest incipient renal failure. Features of hepatic necrosis with right subcostal pain and tenderness, recurrence of nausea, vomiting and jaundice can occur after 2-3 days. Management Start treatment depending on time elapsed since ingestion of paracetamol: • If within 1 hour give activated charcoal. • If < 4 hours wait for blood levels. • If > 4 hours and >150 mg/kg don't wait for levels. Emesis or gastric lavage is indicated if less than 6 hours have elapsed since ingestion. Activated charcoal should be administered if the specific antidote is given by the i.v. route, but is contraindicated if the antidote is given orally. Acetylcysteine is the antidote of choice and is usually given intravenously. Although more effective when administered within 8-12 hours of ingestion of paracetamol, recent studies have indicated benefit if antidote therapy is initiated up to 96 hours after the overdose. Acetylcysteine has not been shown to contribute to hepatic injury that is already present. Acetylcysteine: Use with caution in patients with asthma or a history of asthma. Patients should be observed carefully for the emergence of hypersensitivity reactions. The hypersensitivity-type adverse reactions often tend to be due to histamine release and are not necessarily true allergic reactions. Therefore, acetylcysteine may not need to be discontinued in mild reactions. These reactions may be overcome by temporary cessation of the infusion, IV administration of an antihistamine, followed by a slower infusion rate of acetylcysteine. Acetylcysteine is incompatible with rubber and metals, silicone rubber and plastic should be used. Plasma potassium should be monitored. Hypokalaemia and ECG changes have been associated with paracetamol overdosage irrespective of the treatment. Considered to be relatively safe during pregnancy and breast feeding.

Management of Some Common Poisonings  247 Adult dose: i.v. infusion, initially 150 mg/kg in 200 mL 5% dextrose over 15 minutes; then 50 mg/kg in 500 mL 5% dextrose over the next 4 hours by continuous infusion; followed by 100 mg/kg in 1 litre 5% dextrose over 16 hours. The manufacturer's dosage regimen covers only the first 20-24 hours. The recommended dose for the second 24 hours is 150 mg/kg in 1 litre 5% dextrose water over 24 hours. The above represents a minimum dosage requirement and is exceeded in some investigational regimens. Oral acetylcysteine is proven to be effective in the treatment of paracetamol overdose. Loading dose of 140 mg/kg followed by 70 mg/kg 4 hourly for 17 doses (over a period of 72 hours). Solutions should be diluted to 5% in water or fruit juice/soft drink. Capsules or powder should be taken with adequate amounts of fluid (250 mL). If the initial paracetamol level is in the toxic range, full antidote therapy is necessary. Liver damage is likely to occur in 90% of patients with paracetamol levels > 300 mcg/mL at 4 hours or > 45 mcg/mL at 15 hours post ingestion. Levels below 120 mcg/mL at 4 hours are unlikely to cause hepatotoxicity. For reliable hepatotoxicity risk assessment, blood for plasma levels must be drawn after the drug has peaked (at least 4 hours post ingestion). Patients presenting 24 hours or later after an overdose of paracetamol and having detectable plasma levels or biochemical evidence of hepatotoxicity must be given acetylcysteine. Patients taking drugs that induce hepatic enzymes, e.g. barbiturates, phenytoin, carbamazepine, rifampicin and meprobamate, or alcohol abusers may develop paracetamol toxicity at lower plasma concentrations; a lower threshold for instituting specific antidote therapy should be used (50-70% of the potential toxic levels). If paracetamol levels are in the potentially toxic range, liver and kidney function tests should be performed daily. Fatality at below mentioned levels < 150 mg/kg Unlikely > 250 mg/kg Likely > 12 g total Potentially fatal Carbocysteine and methionine can be used as alternative to acetylcysteine. 2. Opioid poisoning Respiratory depression is the most important toxic effect of the opioid analgesics. Death from morphine poisoning is nearly always due to respiratory arrest. Clinical features: Poisoning with morphine and other opioids produces central nervous system depression ranging from drowsiness to deep coma, respiratory depression with shallow respiration or apnoea, cyanosis, miosis (pin-point pupils), hypotension and hypothermia. If hypoxia is severe, the pupils may be dilated. In some cases there is spasticity, muscle twitching, convulsions and non-cardiogenic pulmonary oedema. The onset of pulmonary oedema may be rapid, but in the comatose patient it may be delayed for up to 24 hours after recovery from coma (following administration of an opioid antagonist).

248  Practical Manual of Pharmacology Management Stomach emptying using gastric lavage should be performed in the comatose patient via an orogastric tube after a cuffed endotracheal tube has been inserted to prevent aspiration. (Gastric emptying may be delayed because of opioid-induced pylorospasm.) Activated charcoal should be administered to adsorb opioid in the intestine and may be followed by a saline cathartic such as sodium sulphate, magnesium citrate or magnesium sulphate. Sorbitol 70% or lactulose are also useful cathartics. Immediate attention to an adequate airway, and artificial ventilation, may be indicated. Naloxone, an opioid antagonist, is administered intravenously or intramuscularly (preferably IV). The initial adult dose is 0.4-2 mg. If improvement does not occur immediately with IV administration, it may be repeated at 2-3 minute intervals to a maximum of 10 mg. The diagnosis should be reconsidered if 2-3 doses fail to produce a response. In children, the initial dose is 0.01 mg/kg, followed if necessary by a dose of 0.1 mg/kg. Intramuscular naloxone is an alternative in the event that IV access is not possible, or if the patient is threatening to self-discharge. Naloxone may precipitate a severe withdrawal syndrome in an addict that cannot be readily suppressed during the period of action of the antagonist. The duration of action of naloxone is shorter than that of most opioids. Patients should be observed carefully; repeated doses may be required after initial improvement. Opioid induced pulmonary oedema should be treated with positive- pressure ventilation using positive end expiratory pressure (PEEP). Intravenous infusions of naloxone may be useful where repeated doses are required. An infusion of 60% of the initial dose per hour is a useful starting point (dose adjusted to clinical response). Infusions are not a substitute for frequent review of the patient's clinical state. 3. Aspirin and other salicylates Toxic doses disturb the acid/base balance and uncouple oxidative phosphorylation which may result in metabolic acidosis or compensated respiratory alkalosis. In overdose, salicylates may be retained in the stomach for 4-8 hours or longer. Ingestion of large amounts may form concretions in the stomach which may delay absorption. Clinical features These may include restlessness, hyperventilation, tinnitus, deafness, tachycardia, nausea, vomiting, sweating, hyperthermia, dehydration, pulmonary oedema, acute renal failure, hypokalaemia, hypoglycemia and hypoprothrombinaemia. Stupor and coma indicate severe poisoning. Management Therapeutic plasma salicylate level lies between 0.7 to 2.2 mmol/L or 100-300 mcg/mL. Severity can be determined by measuring blood salicylate levels 6 or more hours after acute ingestion, but may be misleading in severe acidosis. Emesis or lavage should be followed by activated charcoal. Studies have indicated that repeated doses, 50-100 g every 4 hours, increase clearance significantly by a process termed `gastrointestinal dialysis'.

Management of Some Common Poisonings  249 Dehydration, acidosis, hypoglycemia and electrolyte disturbances should be corrected. Hyperthermia is managed by external cooling. Alkalinisation of the urine (pH 7.5-8.5) by administering sodium bicarbonate orally or by infusion is recommended to increase excretion of salicylates. Care must be taken to avoid fluid overload and renal function closely monitored. In severe poisoning with decreased urinary flow, pulmonary oedema or progressive deterioration, charcoal haemoperfusion or haemodialysis should be considered. Antacids may be administered to counteract gastric irritation and vitamin K to correct deranged coagulation mechanisms. 4. Methanol The potentially fatal human dose of methanol is 30 ml of a 40% solution, although fatalities have been reported with 15 ml. Clinical features Initially symptoms include those of minor inebriation followed by a latent period of 12-30 hours when methanol is metabolised to the toxic products formaldehyde and formic acid. Co-ingestion of alcohol delays the toxic effects. Severe acidosis is due to formic acid and lactic acidosis and the severe retinal toxicity is caused by formaldehyde. Further symptoms and signs include headache, confusion, vertigo, nausea, vomiting, abdominal pain, blurred vision, blindness, Kussmaul's respiration, restlessness, delirium, convulsions and coma. Management Gastric lavage or emesis as early as possible. (Charcoal does not absorb methanol well and is of little value.) Ethanol in all cases, while awaiting methanol determination. To maintain a blood level of 100 mg/dl of ethanol begin with a loading dose of 0.6 g/kg, followed by an ethanol infusion of 66 mg/kg/hour (for non-drinkers) to 154 mg/kg/hour (for chronic ethanol drinkers). Particular attention should be directed towards the correction of metabolic acidosis with sodium bicarbonate. Haemodialysis, if the blood-methanol level is greater than 50 mg/dl, continue until the level is in the range of 20 mg/dl. The administration of folate, in the form of leucovorin, may have a therapeutic advantage (1 mg/kg, up to 50 mg/dose, followed by the same dose 4 hourly for 6 doses). Methanol, formic acid and formaldehyde are effectively removed by haemodialysis which is about 8 times more effective than peritoneal dialysis. Other indications for haemodialysis include any visual impairment, metabolic acidosis not correctable with bicarbonate, and renal failure. Ethanol blood levels should be maintained between 100 and 150 mg/dl. Note that ethanol prolongs the elimination half-life of methanol to 24-30 hours so that several days may be required to reduce methanol levels to < 20 mg/dl if haemodialysis is not used.

250  Practical Manual of Pharmacology 5. Tricyclic antidepressants (TCAs) Cardiovascular toxicity is the principal cause of fatalities from TCA overdose. It is caused by the blockade of noradrenalin uptake as well as the anticholinergic, membrane stabilising and alpha-blocking effects of TCAs. Clinical Features Overdosage can produce central nervous system, anticholinergic and cardiovascular effects. Nervous system toxic effects include drowsiness, agitation, hallucinations, hyperactive reflexes, myoclonus, choreoathetosis, muscle twitching and rigidity, convulsions, respiratory depression and coma. Anticholinergic effects include flushing, dry mouth, dilated pupils, hyperpyrexia, and bladder and bowel paralysis. Cardiovascular toxic effects include sinus tachycardia, hypotension, conduction abnormalities and arrhythmias, e.g. PR and QRS prolongation, ST and T wave changes, heart block, atypical and regular ventricular tachycardia, and ventricular fibrillation. Patients may develop respiratory complications similar to those seen in barbiturate overdose, which may include respiratory depression, aspiration pneumonia, adult respiratory distress syndrome and pulmonary edema. Management Ensure a clear airway and adequate ventilation. Check arterial blood gases and correct any hypoxia. If hypercapnia is present assisted ventilation is indicated. Gastric lavage is useful as late as 8 hours after ingestion (gastric emptying is delayed by the TCAs). Lavage should be followed by activated charcoal and further doses, given, e.g. every 4-6 hours, may effectively remove enterorecycling drug. Blood pH must be checked and acidosis adequately corrected with bicarbonate to enhance protein binding and decrease the concentration of free drug in the plasma. Observe for 6 hours if asymptomatic. Patients who remain asymptomatic and have normal ECG by 6 hours are unlikely to develop late complications. Perform 12 lead ECG and monitor cardiac rhythm. Repeat ECG if symptomatic. Check urea and electrolytes and monitor urine output. Resist the temptation to treat arrhythmias with drugs. Arrhythmia is best treated by correction of hypoxia and acidosis. Otherwise, phenytoin and lignocaine are the antiarrhythmic drugs of choice. Seizures may be treated with diazepam (0.1-0.3 mg/kg body weight) or lorazepam (4 mg). Alkalinisation (with sodium bicarbonate) will usually benefit both convulsive activity and cardiotoxicity 0.5-2 mEq/kg IV bolus followed by i.v. infusion to maintain blood pH of 7.5 has been suggested. Both sodium and potassium levels should be monitored closely. Disopyramide, procainamide and quinidine are contraindicated because of their additive cardiac depressant effect. Physostigmine has been used for delirium, coma, choreo-athetosis, myoclonus and some resistant cardiotoxic effects, but must be used with caution because of potentially serious cholinergic effects. It should always be administered under close ECG monitoring.

Management of Some Common Poisonings  251 Prolonged monitoring is needed in severe poisoning as the half-lives of the TCAs vary from 24 to 72 hours, and may be increased in overdose. 6. OPC poisoning The organophosphates and carbamates are cholinesterase inhibitors, indirectly causing a stimulation of muscarinic and nicotinic receptors. They can be absorbed by ingestion, inhalation or via the skin. While the organophosphates form an irreversible complex with cholinesterase, the carbamyl-enzyme complex is reversible, leading to a less severe intoxication with a much shorter duration. The carbamates also penetrate the blood-brain barrier poorly, producing fewer CNS effects. Clinical Features The onset of features may be delayed for 12-24 hours after skin exposure. Early features include anxiety, restlessness, insomnia, tiredness, dizziness, headache, nausea, vomiting, abdominal colic, diarrhoea, sweating, hypersalivation, chest tightness and miosis. Muscle weakness and fasciculation may develop. Severe poisoning causes widespread flaccid paralysis (including ocular and respiratory muscles), convulsions, coma, pulmonary oedema with copious bronchial secretions, bronchospasm and cardiac dysrhythmias. Hyperglycaemia and glycosuria occur without ketonuria. Plasma cholinesterase activity is usually reduced to < 50% with clinical poisoning and to < 10% in severe cases. Management Supportive measures are vitally important to prevent further absorption according to route of exposure. Remove soiled clothing and wash contaminated skin with soap and water (see skin decontamination). Be sure that any cuts on your hands or face are protected. Pesticides penetrate broken skin more readily than intact skin. Avoid contaminating yourself. Wear protective clothing. In one report three emergency department staff suffered toxicity requiring treatment after exposure to a contaminated patient!! Consider gastric lavage if a substantial amount has been ingested within 1-2 hours. Care should be taken to protect the airway, particularly if a hydrocarbon solvent is involved or if consciousness is depressed. If there is bronchorrhoea and/or bronchospasm give atropine. Very large doses are occasionally required. An initial intravenous 'test dose' of 1 mg in adults and 0.01 mg/kg in children provides a measure of severity. The dose of atropine in organophosphate poisoning is 0.05 mg/kg (2-4 mg in adults) every 15 minutes until full atropinisation is reached. For maintenance therapy, an intermittent or continuous intravenous infusion of 0.05 mg/kg/hr may be given. High doses of atropine are sometimes required initially (4-5 mg every 15 minutes). The criterion of adequate therapy is control of excessive bronchial and oral secretions. In severe poisoning ensures a clear airway, adequate ventilation and removal of bronchial secretions. Give high inspired oxygen concentration.

252  Practical Manual of Pharmacology In moderate or severe poisoning give pralidoxime mesylate (P2S) to reactivate cholinesterase. Dosage instructions follow. Intravenous diazepam (5-10 mg for an adult, 0.02 mg/kg body weight for a child) will control twitching and may reduce morbidity and mortality. In moderate or severe poisoning give pralidoxime 30 mg/kg by intravenous injection (over 5-10 minutes) to reactivate cholinesterase—improvement should be apparent within 30 minutes. Repeat doses at 4-6 hourly intervals may be necessary or an intravenous infusion of 8 mg/kg/hour can be given. Atropine administration should be initiated as soon as possible. Close observation during this stage is essential, as rebound effects of organophosphate toxicity (due to their lipid solubility) may occur. Parameters to monitor Presence of hypersecretion, ECG, pupil size, blood pressure and pulse, serial measurement of vital capacity (preferred to peak flow measurements) to detect respiratory insufficiency, and plasma cholinesterase. Normal levels of plasma cholinesterase are 3000-8500 U/L in adults. Although cholinesterase reactivators such as obidoxime are widely regarded as valuable adjuvants in the early management of moderate to severe organophosphate poisoning (if given within 24 hours of exposure), it is not clear if their use alters the outcome. Therapy should be in conjunction with atropine and other supportive measures. Cholinesterase reactivators, e.g. obidoxime, are contraindicated in carbamate poisoning. Several complications may follow organophosphate poisoning: • Since most of these substances have a petroleum base, aspiration may cause a chemical aspiration pneumonitis. • Potential toxicity of the vehicle should be taken into account. • Ventricular arrhythmias (with a prolonged QT interval) may occur. • Confusion and convulsions, due to the effects of the organophosphate or to excess atropine, are best controlled with diazepam. • Aminoglycosides and succinylcholine should be avoided in organophosphate poisoning because of their blocking effect on the neuromuscular junction. • Phenothiazines, reserpine and theophylline are also contraindicated.

OBJECTIVES At the end of the session the student will be able to: 1. List the general supportive measures to be extended to a patient with poisoning. 2. Understand the principles of treatment of a patient with poisoning. 3. List the steps in the management of a patient with: (a) Organophorous poisoning. (b) Opioid poisoning.

CHAPTER

30

Objective Structured Practical Examination (OSPE)

One of the most important aspects of training of a doctor is acquisition of practical skills. Objective assessment of practical (psychomotor skills) is thus a challenge for examiners. OSPE is a method of examination which evaluates student's wide range of skills uniformly and objectively. An OSPE consists of a number of predetermined stations (spots) through which each student rotates. An examiner (observer) may be present on each spot to score the student's performance using a predetermined checklist or scoring is done after conduct of OSPE. OSPE fulfills all the requirements of a good evaluation method 1. Validity—it measures what it is supposed to measure. 2. Reliability— Is the examination objective assessment? Are results accurate and consistent? There is same station and predetermined checklist, so interobserver variation is decreased to minimum. The difference in marks obtained in OSPE is because of ability of the student, rather than due to extraneous factors. 3. Feasibility Is it feasible to put into practice? The requirements for the staff and accommodation can be met. It can cope with sufficient no. of students. If 1 minute is given for each station, in total 50 minutes you can objectively examine 50 students. So, in nutshell OSPE is a form of practical examination which is objective and which owes its objectivity to a structured marking scheme. The OSPE converts subjectivity into objectivity, leading to fair and equal evaluation of students. Approximately 20-50 spots can be chosen for OSPE. They can be from all branches of pharmacology, for example: Problem based therapeutics Problem based drug interaction Prescription correction Correct use of inhaler

254  Practical Manual of Pharmacology Filling injection from vial Calculate pharmacokinetic parameter, e.g. Vd Calculation of dose Identify instrument/apparatus Indication of a drug combination New drug delivery system Pharmacy preparation Dosage forms, etc. Hence, there is wide inexpensive variety of spots you can choose in your department. The various spots can be put serial wise in a room. There can be a list of questions for that spot on each serial number. You need to appoint observers and give them a check list for observatory spots, e.g. correct use of inhaler. The various spots can be: 1. Starling heart lever: a. Identify. b. Where it is used? c. Write 1 advantage over simple lever. 2. Frontal writing lever a. Identify. b. Where it is used? c. Write 1 advantage over simple lever. 3. Inhaler a. Identify. b. Write 2 indications. c. Demonstrate how it is used. 4. Lignocaine 2% a. Identify. b. Write 2 indications. c. Write 1 adverse effect. 5. Calculate Vd a. Plasma conc. 20 mg/L. b. Drug administered 1000 mg. c. Write 1 clinical significance of Vd. 6. Advertisement of a drug a. Write 2 good points of this advertisement. b. Write 2 bad points of this advertisement.

Objective Structured Practical Examination (OSPE)  255 7. Combination of amoxycillin and clavulanic acid a. Write 1 advantage of this combination. b. Write 2 adverse effects of this combination. 8. Fill in the blanks from the sample given a. Manufacturing date----------b. IP means----------------------9. Vial of heparin a. Write 1 indication. b. Write 2 adverse effects of this. 10. Skin patch of diclofenac a. Write 1 advantage of this. b. Write 1 adverse effect of this combination. 11. Combination of amoxycillin and clavulanic acid a. Write 1 advantage of this combination. b. Write 2 adverse effects of this combination. 12. Informed consent form a. Write 1 reason why it is used in clinical studies in humans. b. Informed consent in clinical trials is mandatory True/False. 13. IV set a. Identify. b. Write 2 drug given by this. 14. Rotahaler a. Write 1 advantage of this. b. Write 2 adverse effects of this. c. How it is used? 15. Analgesiometer a. Which drugs are screened by this instrument? b. Which animals are used in this experiment? 16. Set up iv infusion on given model a. Write name of 2 drugs given by this route. 17. Inject im in given model a. Write name of 2 drugs given by this route. 18. Inject iv in given model a. Write name of 2 drugs given by this route. 19. Aspirate drug from ampoule. 20. Reconstitute solution for injection.

256  Practical Manual of Pharmacology 21. Ciprofloxacin strip a. Write 2 brand names of this drug. b. Which is the cheapest brand? 22. OPC poisoning a. Write antidote. b. What is the dose? 23. A 40-year-old woman had a renal failure. She was not able to stick to a salt and protein restricted diet. She developed an upper respiratory tract infection and comes to the hospital breathless, coughing up with purulent sputum. She got edema and her blood urea is raised. The intern on duty treated the infection with minocycline and edema with furosemide. After a week patient complaint improved but now she complained of deafness. a. What is the reason of deafness? b. Why was her blood urea raised? c. What alternate would you choose?

Appendix I

PROPOSED REVISED CURRICULUM Skills to be acquired in pharmacology practicals as per proposed revised curriculum: Psychomotor skills 1. Dosage forms: Oral, Parenteral, Topical and Others 2. Routes of drug administration, setting up an intravenous drip—Administer the required dose of different drug formulations using appropriate devices and techniques (e.g. hypodermic syringes, inhalers, transdermal patches, etc.) 3. Calculation of drug dosage using appropriate formulae for an individual patient. 4. Sources of drug information—how to retrieve information 5. ADR monitoring—recognize and report adverse drug reactions to suitable authorities. 6. Therapeutic Drug Monitoring—advice and interpret the therapeutic monitoring reports of important drugs 7. Critical appraisal of drug promotional literature— a. Analyse critically, drug promotional literature for proprietary preparations, in terms of the (a) pharmacological actions of their ingredients (b) claims of pharmaceutical companies (c) economics of use (d) rational or irrational nature of fixed dose drug combinations b. Retrieve drug information from appropriate sources, especially electronic resources 8. Essentials of Clinical trials 9. Communicating to patients on the proper use of medication 10. Selection of P drug 11. Prescription writing, prescription auditing and standard treatment protocols—Write a correct, complete and legible prescription for common ailments including the conditions in the National Health Programmes 12. Essential drugs list 13. Use of drugs in pregnancy, lactation children and elderly 14. Use of drugs in liver disease and renal disease

258  Practical Manual of Pharmacology 15. 16. 17. 18. 19.

Ethics in clinical trials, therapy Preparation of test dose for penicillin solution Preparation and use of oral rehydration solution Informed Consent Form Computer assisted learning (CAL).

Attitudes and Communication skills 1. Communicate to patients regarding the optimal use of drug formulations, devices and storage of medicines. 2. Follow the drug treatment guidelines laid down for diseases covered under the National Health Programmes and be capable of initiating, monitoring treatment, recording progress, and assessing outcomes. 3. Motivate patients with chronic diseases to adhere to the line of management outlined by the health care provider. 4. Appreciate the relationship between cost of drugs and patient compliance. 5. Exercise caution in prescribing drugs likely to produce dependence and recommend the line of management. 6. Understand the legal aspects of prescribing drugs. 7. Evaluate the ethics, scientific procedures and social implications involved in the development and introduction of new drugs.

Appendix II

260  Practical Manual of Pharmacology

Appendix III

Schedule of practicals for MBBS 2nd Prof (18 months) (Effective period 15 months) Theory Lectures

Practicals

General pharmacology teaching

Clinical pharmacy simultaneously

Pharmacokinetics part of general pharmacology ANS When about to finish ANS CVS Antihypertensives CNS

Chemotherapy GIT Endocrinology

Respiratory Miscellaneous

Pharmacokinetic parameters in between clinical pharmacy Continue clinical pharmacy Introduction to experimental pharmacology Experimental pharmacology Effect of drugs on dog BP Short experiments Ethics Introduction to prescription writing, P drug concept Prescription examples of ANS, CVS, CNS ADR, TDM, Therapeutic follow-up, dose calculation Drug use in special population, new drug development Promotional literature, drug interactions, rest of prescriptions and analysis of prescriptions Formulation evaluation, ethics Revision

Appendix IV

ESSENTIAL DRUG LIST (INDIA) 2003 The names of drugs are followed by the following letters to indicate their need at various levels of medical care: P-Primary health care S-Secondary health care T-Tertiary health care U-Universal. The information is given as: • Name of the Drug Category • Medicine Category • Route of Administration/ Strengths • Dosage Form.

1. ANAESTHETICS 1.1 General anaesthetics and Ether Halothane Isoflurane* Ketamine HCl Nitrous Oxide Oxygen Thiopentone Na 0.5%, 0.5% + 7.5% Glucose 1.2 Local Anaesthetics Bupivacaine HCL Ethyl Chloride Lignocaine HCl * Complementary

Oxygen S, T S, T S, T U U U S, T S, T

Inhalation Inhalation Inhalation Injection 10 mg/ml 50 mg/ml Inhalation Inhalation Injection 0.5 g, 1 g powder Injection 0.25%

U U

Spray 1% Topical Forms 2-5%

Appendix IV  263 Injection 1-2% Spinal 5% + 7.5% Glucose Lignocaine HCl + Adrenaline U Injection 1%, 2% + adrenaline 1:200,000 in vial 1.3 Preoperative medication and sedation for short term procedures Atropine Sulphate U Injection 0.6 mg/ml Diazepam U Tablets 5 mg Injection 5 mg/ml Midazolam U Injection 1 mg/ml 5 mg/ml Morphine Sulphate S, T Injection 10 mg/ml Promethazine U Syrup 5 mg/5 ml 1.4 Postoperative respiratory stimulant Doxapram* T Injection 4 mg/ml

2. ANALGESICS, ANTIPYRETICS, NSAIDS, MEDICINES IN GOUT AND RHEUMATOID DISORDERS 2.1 Non-opioid analgesics, antipyretics and nonsteroidal antiinflammatory medicines Acetyl Salicylic Acid U Tablets 300-350 mg Diclofenac T Tablets 50 mg, 100 mg Injection 25 mg/ml Ibuprofen U Tablets 200 mg, 400 mg Paracetamol U Injection 150 mg/ml Syrup 125 mg/5ml Tablets 500 mg 2.2 Opioid Analgesics Morphine Sulphate S, T Injection 10 mg/ml Tablets 10 mg Pentazocine S, T Tablets 25 mg, Injection 30 mg/ml Pethidine HCl S, T Injection 50 mg/ml 2.3 Medicines used to treat Gout Allopurinol S, T Tablets 100 mg Colchicine S, T Tablets 0.5 mg 2.4 Disease modifying agents used in rheumatoid disorders Azathioprine S, T Tablets 50 mg Chloroquine Phosphate S, T Tablets 150 mg Methotrexate S, T Tablets 2.5 mg Sulfasalazine S, T Tablets 500 mg * Complementary

264  Practical Manual of Pharmacology 3. ANTIALLERGICS AND MEDICINES USED IN ANAPHYLAXIS Adrenaline Bitartrate U Chlorpheniramine Maleate U Dexchlorpheniramine Maleate Dexamethasone U Hydrocortisone Sodium Succinate U Pheniramine Maleate U Prednisolone S Promethazine U

Injection 1 mg/ml Tablets 4 mg Syrup 0.5 mg/5 ml Tablets 0.5 mg Injection 4 mg/ml Injection 100 mg Injection 22.75 mg/ml Tablets 5 mg Tablets 10 mg, 25 mg Syrup 5 mg/5 ml

4. ANTIDOTES AND OTHER SUBSTANCES USED IN POISONINGS 4.1 Nonspecific Activated Charcoal U Atropine Sulphate U 4.2 Specific Antisnake Venom U solution/ Lyophilyzed Polyvalent serum Calcium Gluconate S,T Desferrioxamine Mesylate S, T Dimercaprol S, T Flumazenil* T Methylthioninium Chloride (Methylene blue) S, T Naloxone S, T Penicillamine S, T Pralidoxime Chloride (2-PAM) S, T Sodium Nitrite S, T Sodium Thio S, T

Powder Injection 0.6 mg/ml Injection Polyvalent Injection 100 mg/ml Injection 500 mg Injection in oil 50 mg/ml Injection 0.1 mg/ml Injection 10 mg/ml Injection 0.4 mg/ml Tablets or Capsules 250 mg Injection 25 mg/ml Injection 30 mg/ml Injection 250 mg/ml

5. ANTIEPILEPTICS Carbamazepine

U

Diazepam

U

* Complementary

Tablets 100 mg, 200 mg Syrup 20 mg/ml Injection 5 mg/ml

Appendix IV  265 Magnesium Sulphate Phenobarbitone Phenytoin Sodium

T U ST U

Sodium Valproate

U

Injection 500 mg /ml Tablets 30 mg, 60 mg Injection 200 mg/ml Capsules or Tablets 50 mg, 100 mg, Syrup 25 mg/ml, Injection 50 mg/ml Tablets 200 mg, 500 mg Syrup 200 mg/5 ml

6. ANTIINFECTIVES 6.1 Anthelminthics 6.1.1 Intestinal Anthelminthics Albendazole U Mebendazole

U

Niclosamide Pyrantel Pamoate

U U

6.1.2 Antifilarials Diethylcarbamazine Citrate U 6.1.3 Antischistosomals and Antitrematode Praziquantel S, T 6.2 Antibacterials 6.2.1 Beta lactam medicines Amoxicillin U Ampicillin

U

Benzathine Benzylpenicillin Benzylpenicillin Cefotaxime* Ceftazidime* Ceftriaxone* Cefuroxime* Cloxacillin

U U S, T S, T S, T S, T U

* Complementary

Tablets 400 mg Suspension 200 mg/5 ml Tablets 100 mg Suspension 100 mg/5 ml Chewable Tablets 500 mg Tablets 250 mg Suspension 250 mg/5 ml Tablets 50 mg Tablets 600 mg

Powder for suspension 125 mg/5 ml, Capsules 250 mg, 500 mg Capsules 250 mg, 500 mg Powder for suspension 125 mg/5 ml Injection 500 mg Injection 6 lacs, 12 lacs, 24 lacs units Injection 5 lacs,10 lacs units Injection 125, 250, 500 mg Injection 250 mg, 1g Injection 250 mg, 1 g Injection 250 mg, 750 mg Capsules 250 mg, 500 mg

266  Practical Manual of Pharmacology

Procaine Benzylpenicillin U (1 lac units) +Procaine penicillin (3 lacs units) 6.2.2 Other antibacterials Amikacin* S, T Azithromycin* S, T

Injection 250 mg, Liquid 125 mg/5 ml Injection Crystalline penicillin

Injection 250 mg/2 ml Capsules or Tablets 100 mg, 250 mg, 500 mg Suspension 100 mg/5 ml Injection 500 mg Cephalexin* U Syrup 125 mg/5 ml Capsules 250 mg, 500 mg Clarithromycin* S, T Capsules 500 mg Chloramphenicol S, T Injection 1 g S, T Suspension 125 mg/5 ml S, T Capsules, Tablets 250 mg, 500 mg Ciprofloxacin HCl U Injection 200 mg /100 ml Tablets 250 mg, 500 mg Co-Trimoxazole U Tablets 40 + 200 mg (Trimethoprim 80 + 400 mgSulphamethoxazole) Suspension 40 +200 mg/5 ml Doxycycline U Capsules 100 mg Erythromycin Estolate U Syrup 125 mg/5 ml Tablets 250 mg, 500 mg. Gentamicin U Injection 10 mg/ml 40 mg/ml Metronidazole U Tablets 200 mg, 400 mg Injection 500 mg /100 ml Nalidixic Acid U Tablets 250 mg, 500 mg Nitrofurantoin U Tablets 100 mg Norfloxacin U Tablets 400 mg Roxithromycin* S, T Tablets 50 mg, 150 mg Sulphadiazine* S, T Tablets 500 mg Tetracycline U Tablets or Capsules 250 mg Vancomycin HCL* T Injection 500 mg, 1 g 6.2.3 Antileprosy Clofazimine S, T Capsules 50 mg, 100 mg Dapsone U Tablets 50 mg, 100 mg Rifampicin U Capsules or Tablets 150, 300 mg * Complementary

Appendix IV  267 6.2.4 Antituberculosis medicines Ethambutol U Isoniazid U Ofloxacin* S, T Pyrazinamide

U

Rifampicin

U

Streptomycin Sulphate Thiacetazone + Isoniazid 6.3 Antifungal medicines Amphotericin Clotrimazole Fluconazole Flucytosine Griseofulvin Ketoconazole Nystatin

U S, T B S, T U S, T S, T U S, T U

6.4 Antiviral medicines 6.4.1 Antiherpes medicines Acyclovir* S, T

Tablets 200 mg, 400 mg, 600 mg, 800 mg Tablets 50 mg, 100 mg, 300 mg Tablets 100 mg, 200 mg Syrup 50 mg/5 ml Tablets 500 mg, 750 mg, 1000 mg, 1500 mg Capsules/Tablets 50 mg, 150 mg, 300 mg, 450 mg Syrup 100 mg/5 ml Injection 0.75 g, 1 g Tablets 150 mg + 300 mg Injection 50 mg Pessaries 100 mg,200 mg Gel 2% Capsules or Tablets 50 mg, 100 mg, 150 mg, 200 mg Capsules 250 mg Capsules or Tablets 125,250 mg Tablets 200 mg Tablets 500,000 IU Pessaries 100,000 IU

Tablets 200 mg, 400 mg Injection 250 mg, 500 mg Suspension 400 mg/5 ml

6.4.2 Antiretroviral medicines* 6.4.2.1 Nucleoside reverse transcriptase inhibitors Didanosine* S, T Tablets 250 mg, 400 mg Lamivudine* S, T Tablets 150 mg Lamivudine +Nevirapine + Stavudine* S, T Tablets 150 mg + 200 mg + 30 mg Lamivudine + Zidovudine* S, T Tablets 150 mg + 300 mg Stavudine* S, T Capsules 15 mg, 30 mg, 40 mg Zidovudine* S, T Tablets 100 mg, 300 mg * Complementary

268  Practical Manual of Pharmacology 6.4.2.2 Non-nucleoside reverse transcriptase inhibitors Efavirenz* S, T Capsules 200 mg, 600 mg Nevirapine* S, T Capsules 200 mg Suspension 50 mg/5 ml 6.4.2.3 Protease inhibitors Indinavir* S, T Capsules 200 mg, 400 mg Nelfinavir* S, T Capsules 250 mg Ritonavir* S, T Capsules 100 mg Syrup 400 mg/ml Saquinavir* S, T Capsules 200 mg 6.5 Antiprotozoal 6.5.1 Antiamoebic and antigiardiasis Diloxanide Furoate U Tablets 500 mg Metronidazole U Tablets 200 mg, 400 mg Injection 500 mg/100 ml Tinidazole U Tablets 500 mg 6.5.2 Antileishmaniasis Amphotericin B S, T Injection 50 mg Pentamidine Isothionate S, T Injection 200 mg Sodium Stibogluconate S,T Injection 100 mg/ml 6.5.3 Antimalarial medicines 6.5.3.1 For curative treatment Artesunate T Injection 60 mg Chloroquine Phosphate base U Tablets 150 mg Injection 40 mg/ml, Syrup 50 mg/5 ml Primaquine U Tablets 2.5 mg, 7.5 mg Pyrimethamine U Tablets 25 mg Quinine Sulphate U Tablets 300 mg S, T Injection 300 mg/ml Sulfadoxine + Pyrimethamine U Tablets 500 mg + 25 mg 6.5.3.2 For Prophylaxis Chloroquine Phosphate base U Tablets 150 mg Syrup 50 mg/5 ml 6.5.4 Antipneumocystosis and Antitoxoplasmosis Co-Trimoxazole (Trimethoprim+ Sulphamethoxazole) U Tablets 40 + 200 mg, 80 mg + 400 mg Suspension 40 + 200 mg/5 ml * Complementary

Appendix IV  269 Pentamidine Isothionate Trimethoprim

S, T U

Injection 200 mg Tablets 100 mg

7. ANTIMIGRAINE MEDICINES 7.1 For Treatment of acute attack Acetyl Salicylic Acid U Dihydroergotamine S, T Paracetamol U 7.2 For prophylaxis Propranolol HCl U

Tablets 300 - 350 mg Tablets 1 mg Tablets 500 mg Tablets 10 mg, 40 mg

8. ANTINEOPLASTIC, IMMUNOSUPPRESSIVES AND MEDICINES IN PALLIATIVE CARE 8.1 Immunosuppressive medicines Azathioprine* T Cyclosporine T 8.2 Cytotoxic medicines Actinomycin D* Alpha Interferon* Bleomycin* Busulphan* Cisplatin* Cyclophosphamide*

T T T T T T

Cytosine Arabinoside*

T

Danazol* Doxorubicin* Etoposide*

T T T

Flutamide* 5-Fluorouracil* Folinic Acid* Gemcitabine HCl* L- Asparaginase* Melphalan*

T T T T T T

* Complementary

Tablets 50 mg Capsules 10 mg, 25 mg, 50 mg, 100 mg Concentrate for Injection 100 mg/ml Injection 0.5 mg Injection 3 million IU Injection 15 mg Tablets 2 mg Injection 10 mg/vial 50 mg/vial Tablets 50 mg Injection 200 mg, 500 mg Injection 100 mg/vial 500 mg/vial, 1000 mg/vial Capsules 50 mg,100 mg Injection 10 mg, 50 mg Capsules 100 mg Injection 100 mg/5 ml Tablet 250 mg Injection 250 mg/5 ml Injection 3 mg/ml Injection 200 mg, 1 g Injection 10000 KU Tablets 2 mg, 5 mg

270  Practical Manual of Pharmacology Mercaptopurine*

T

Methotrexate*

T

Mitomycin-C* T Paclitaxel* T Procarbazine* T Vinblastine Sulphate* T Vincristine T 8.3 Hormones and antihormones Prednisolone* S, T

Raloxifene* T Tamoxifen Citrate* T 8.4 Medicines used in palliative care Morphine Sulphate* T Ondansetron* S, T

Tablets 50 mg, Injection 100 mg/ml Tablets 2.5 mg Injection 50 mg/ml Injection 10 mg Injection 30 mg/5 ml Capsules 50 mg Injection 10 mg Injection 1 mg/ml Tablets 5 mg Injection 20 mg 25 mg (as sodium phosphate or succinate) Tablets 60 mg Tablets 10 mg, 20 mg Tablets 10 mg Tablets 4 mg, 8 mg Injection 2 mg/ml Syrup 2 mg/5 ml

9. ANTIPARKINSONISM MEDICINES Bromocriptine Mesylate Levodopa+ Carbidopa

S, T U

Trihexyphenidyl HCl

U

Tablets 1.25 mg, 2.5 mg Tablets 100 mg + 10 mg, 250 mg + 25 mg, 100 mg + 25 mg Tablets 2 mg

10. MEDICINES AFFECTING BLOOD 10.1 Antianemia medicines Cyanocobalamin Ferrous Salt

U U

Oral solution 25 mg elemental iron (as sulphate)/ml Folic Acid U Iron Dextran S, T Pyridoxine U * Complementary

Injection 1 mg/ml Tablets Equivalent to 60 mg elemental iron

Tablets 1 mg, 5 mg Injection 50 mg iron/ml Tablets 5 mg

Appendix IV  271 10.2 Medicines affecting coagulation Acenocoumarol 4 mg Heparin Sodium S, T Menadione Sodium Sulphite S, T Protamine Sulphate S, T Phytomenadione S, T Warfarin Sodium S, T

Injection 1000 IU/ml 5000 IU/ml Tablets 10 mg Injection 10 mg/ml Injection 10 mg/ml Tablets 5 mg

11. BLOOD PRODUCTS AND PLASMA SUBSTITUTES 11.1 Plasma substitutes Dextran-40 U Injection 10% Dextran-70 U Injection 6% Fresh Frozen Plasma* T Injection Hydroxyethyl Starch (Hetastarch) S, T Injection 6% Polygeline S, T Injection 3.5% 11.2 Plasma fractions for specific use Albumin S, T Injection 5%, 20% Cryoprecipitate S, T Injection Factor VIII Concentrate* S, T Injection Dried Factor IX Complex (Coagulation Factors II,VII, IX, X) * S, T Injection Dried Platelet Rich Plasma S, T Injection

12. CARDIOVASCULAR MEDICINES 12.1 Antianginal medicines Acetyl Salicylic Acid* Diltiazem Glyceryl Trinitrate

U S, T U

Isosorbide 5 Mononitrate/Dinitrate U Metoprolol* U Propranolol

* Complementary

U

Tablets 75 mg, 100 mg, 350 mg Tablets 30 mg, 60 mg Sublingual Tablets 0.5 mg, Injection 5 mg/ml Tablets 10 mg, 20 mg Tablets 25 mg, 50 mg Injection 1 mg/ ml Tablets 10 mg, 40 mg Injection 1 mg/ml

272  Practical Manual of Pharmacology 12.2 Antiarrhythmic medicines Adenosine* S, T Amiodarone S, T Bretylium Tosylate* Diltiazem Diltiazem Esmolol* Isoprenaline HCl* Lignocaine HCl Mexiletine HCL

T S, T T T T S, T S, T

Procainamide HCl

T

Quinidine Verapamil

T S, T

12.3 Antihypertensive medicines Amlodipine U Atenolol U Chlorthalidone* U Clonidine HCl* S, T Enalapril Maleate U

Injection 3 mg/ml Tablets 100 mg, 200 mg Injection 150 mg Injection 1 mg, 2 mg 4 mg/ml Tablets 30 mg, 60 mg Injection 5 mg/ml Injection 10 mg/ml Injection 2 mg/ml Injection 1%, 2% Capsules, 50 mg,150 mg Injection 25 mg/ml Tablets 250 mg Injection 100 mg/ml* Tablets 100 mg Tablets 40 mg, 80 mg Injection 2.5 mg/ml

Tablets 2.5 mg, 5 mg,10 mg Tablets 50 mg, 100 mg Tablets 25 mg, 50 mg Tablets 100 mg, 150 mg Tablets 2.5,5,10 mg Injection 1.25 mg/ml Losartan Potassium* S, T Tablets 25, 50 mg Methyldopa U Tablets 250 mg Nifedipine S, T Capsules 5, 10 mg tablets 10 mg, 20 mg, Sustained release capsules 10 mg, or tablets 20 mg, Propranolol U Tablets 10 mg, 40 mg Sodium Nitroprusside* T Injection 50 mg/ 5 ml Terazosin* S, T Tablets 1, 2, 5 mg 12.4 Medicines used in heart failure Digoxin S, T Tablets 0.25 mg Injection 0.25 mg/ml Elixir 0.05 mg/ml Dobutamine* S,T Injection 50 mg/ml Dopamine HCl S,T Injection 40 mg/ml

* Complementary

Appendix IV  273 12.5 Antithrombotic medicines Acetyl Salicylic Acid U Heparin Sodium* S, T StreptokinaseST Injection 750,000,15,00,000IU, Urokinase T

Tablets 75, 100 mg Injection 1000, 5000 IU/ml Injection 500,000 IU/ml 10,00,000 IU/ml

13. DERMATOLOGICAL MEDICINES (TOPICAL) 13.1 Antifungal medicines Benzoic Acid + Salicylic Acid Miconazole 13.2 Antiinfective medicines Acyclovir Framycetin Sulphate Methylrosanilinium Chloride

U U

Ointment or Cream 6% + 3% Ointment or Cream 2%

S, T Cream 5% U Cream 0.5% (Gentian Violet) U Aqueous solution 0.5% Neomycin+Bacitracin U Ointment 5 mg + 500 IU Povidone Iodine U Solution or Ointment 5% Silver Nitrate U Lotion 10% Silver Sulphadiazine U Cream 1% 13.3 Antiinflammatory and antipruritic Betamethasone Dipropionate U Cream/Ointment 0.05% Calamine U Lotion 13.4 Astringent medicines Zinc Oxide U Dusting Powder 13.5 Medicines affecting skin differentiation and proliferation Coal Tar U Solution 5% Dithranol* T Ointment 0.1-2% Glycerin U Solution Salicylic Acid U Solution 5% 13.6 Scabicides and pediculicides Benzyl Benzoate U Lotion 25% Gamma Benzene Hexachloride U Lotion 1%

* Complementary

274  Practical Manual of Pharmacology 14. DIAGNOSTIC AGENTS 14.1 Ophthalmic medicines Fluorescein Lignocaine Tropicamide 14.2 Radiocontrast media Barium Sulphate Calcium Ipodate Iopanoic Acid Meglumine Iothalamate

S, T S, T S, T

Eye drops 1% Eye drops 4% Eye drops 1%

S, S, S, S,

Suspension 100% w/v 250% w/v Injection 3 g Tablets 500 mg Injection 60% w/v (iodine = 280 mg/ml) Solution 5-8 g iodine in 100-250 ml Oily, suspension 500-600 mg/ml Injection 70% w/v (Iodine = 420 mg/ml)

T T T T

Meglumine Iotroxate

S, T

Propyliodone Sodium Iothalamate

S, T S, T

Sodium Meglumine Diatrizoate S, T

Injection 60% w/v(Iodine conc. = 292 mg/ml) 76% w/v (Iodine conc. = 370 mg/ml)

15. DISINFECTANTS AND ANTISEPTICS 15.1 Antiseptics Acriflavin+Glycerin Benzoin Compound Cetrimide Chlorhexidine Ethyl Alcohol 70% Gentian Violet Hydrogen Peroxide Povidone Iodine 15.2 Disinfectants Bleaching Powder Formaldehyde IP Glutaraldehyde Potassium Permanganate

U U U U U U U U

Solution Tincture Solution 20% (conc. for dilution) Solution 5% (conc. for dilution) Solution Paint 0.5%, 1% Solution 6% Solution 5%, 10%

U U S,T U

Powder Solution Solution 2% Crystals for solution

Appendix IV  275 16. DIURETICS Furosemide

U

Hydrochlorothiazide Mannitol* Spironolactone

U U U

Injection, 10 mg/ ml, Tablets 40 mg Tablets 25 mg, 50 mg Injection 10%, 20% Tablets 25 mg

17. GASTROINTESTINAL MEDICINES 17.1 Antacids and other antiulcer medicines Aluminium Hydroxide + Magnesium Hydroxide U Tablet Suspension Omeprazole U Capsules 10, 20, 40 mg Ranitidine HCl U Tablets 150, 300 mg Injection 25 mg/ml 17.2 Antiemetics Domperidone U Tablets 10 mg Syrup 1 mg/ml Metoclopramide U Tablets 10 mg Syrup 5 mg/ml Injection 5 mg/ml Prochlorperazine U Tablets 5, 25 mg Promethazine U Tablets 10 mg, 25 mg Elixir or Syrup 5 mg/5 ml Injection 25 mg/ml 17.3 Antihaemorrhoidal medicines Local Anaesthetic, Astringent and Antiinflammatory Medicines U Ointment/suppository 17.4 Antiinflammatory medicines Sulfasalazine T Tablets 500 mg 17.5 Antispasmodic medicines Dicyclomine HCl U Tablets 10 mg Injection 10 mg/ml Hyoscine Butyl Bromide U Tablets or 10 mg Injection 20 mg/ml 17.6 Laxatives Bisacodyl U Tablets/suppository 5 mg Isphaghula U Granules * Complementary

276  Practical Manual of Pharmacology 17.7 Medicines used in diarrhoea 17.7.1 Oral rehydration salts U 17.7.2 Antidiarrhoeal medicines Furazolidone S, T Loperamide* S, T (Contraindicated for paediatric use)

Powder for solution As per IP Tablets 100 mg Syrup 25 mg/5 ml Capsules 2 mg

18. HORMONES, OTHER ENDOCRINE MEDICINES AND CONTRACEPTIVES 18.1 Adrenal hormones and synthetic substitutes Dexamethasone S, T Tablets 0.5 mg Injection 4 mg/ml Hydrocortisone Sodium Succinate U Injection 100 mg/ml Methylprednisolone S, T Injection 40 mg/ ml Prednisolone U Tablets 5 mg, 10 mg 18.2 Androgens Testosterone T Capsules 40 mg (as undecanoate) T Injection 25 mg/ml (as propionate) 18.3 Contraceptives 18.3.1 Hormonal contraceptives Ethinylestradiol + Levonorgesterol U Tablets 0.03 mg + 0.15 mg Ethinylestradiol + Norethisterone U Tablets 0.035 mg + 1.0 mg Hormone Releasing IUD T Levonorgesterol Releasing IUD 18.3.2 Intrauterine devices IUD containing Copper U 18.3.3 Barrier mMethods Condoms U 18.3.4. Non hormonal contraceptives Centchroman U Tablets 30 mg 18.4 Estrogens Ethinylestradiol U Tablets 0.01, 0.05 mg * Complementary

Appendix IV  277 18.5 Antidiabetics and hyperglycaemics 18.5.1 Insulins and other antidiabetic Agents Glibenclamide U Tablets 2.5 mg, 5 mg Insulin Injection (Soluble) U Injection 40 IU/ml Intermediate Acting Insulin (Lente/NPHInsulin) U Injection 40 IU/ml Metformin U Tablets 500 mg 18.5.2 Hyperglycaemics Glucagon* T Injection 1 mg/ml 18.6 Ovulation inducers Clomiphene Citrate* T Tablets 25, 50, 100 mg 18.7 Progestogens Medroxy Progesterone Acetate U Tablets 5, 10 mg Norethisterone U Tablets 5 mg 18.8 Thyroid and antithyroid medicines Carbimazole S, T Tablets 5 mg, 10 mg Levothyroxine S, T Tablets 0.1 mg Iodine S, T Solution 8 mg/5 ml

19. IMMUNOLOGICALS 19.1 Diagnostic agents Tuberculin, Purified Protein Derivative U 19.2 Sera and Immunoglobulins Anti-D S, Immunoglobulin(Human) T Antisnake Venom U Antitetanus Human Immunoglobin U Diphtheria Antitoxin S, T Rabies Immunoglobulin U 19.3 Vaccines 19.3.1 For universal immunisation BCG Vaccine U DPT Vaccine U Hepatitis B vaccine U * Complementary

Injection

Injection 250, 300 mg Injection 10 ml Injection 250 IU, 500 IU Injection 10,000 IU Injection 150 IU/ml

Injection Injection Injection

278  Practical Manual of Pharmacology Measles Vaccine U Oral Poliomyelitis Vaccine (Live Attenuated) U 19.3.2 For Specific group of individuals Rabies Vaccine U Tetanus Toxoid U

Injection Solution Injection Injection

20. MUSCLE RELAXANTS (PERIPHERALLY ACTING) AND CHOLINESTERASE INHIBITORS Atracurium Besylate* Neostigmine

S, T S, T

Pancuronium Bromide Pyridostigmine Bromide

S, T S, T

Succinyl Choline Chloride

S,T

Injection 10 mg/ml Tablets 15 mg Injection 0.5 mg/ml Injection 2 mg/ml Tablet 60 mg Injection 1 mg/ml Injection 50 mg/ml

21. OPHTHALMOLOGICAL PREPARATIONS 21.1 Antiinfective Agents Chloramphenicol U Ciprofloxacin HCl U Gentamicin U Miconazole U Povidone Iodine S, T Sulphacetamide Na U Tetracycline HCl U 21.2 Antiinflammatory agents Prednisolone Acetate U Prednisolone Sodium Phosphate U Xylometazoline U 21.3 Local anaesthetics Tetracaine HCl U 21.4 Miotics and antiglaucoma medicines Acetazolamide S, T Betaxolol HCl S, T Physostigmine Salicylate* S, T * Complementary

Drops/Ointment 0.4%, 1% Drops/Ointment 0.3% Drops 0.3% Drops 1% Drops 0.6% Drops 10%, 20%, 30% Ointment 1% Drops 0.1% Drops 1% Drops 0.05%, 0.1% Drops 0.5% Tablets 250 mg Drops 0.25%, 0.5% Drops 0.25%

Appendix IV  279 Pilocarpine S, T Timolol Maleate S, T 21.5 Mydriatics Atropine Sulphate U Homatropine U Phenylephrine U 21.6 Ophthalmic Surgical Aids Methyl Cellulose* T

Drops 2%, 4% Drops 0.25%, 0.5%, Drops/Ointment 1% Drops 2% Drops 5% Injection 2%

22. OXYTOCICS AND ANTIOXYTOCICS 22.1 Oxytocics Methyl Ergometrine Mifepristone Oxytocin 22.2 Antioxytocics Isoxsuprine HCl Terbutaline Sulphate

U T S, T S, T S, T

Tablets 0.125 mg Injection 0.2 mg/ml Tablets 200 mg Injection 5, 10 IU/ml Tablets 10 mg Injection 5 mg/ml Tablets 2.5 mg Injection 0.5 mg/ml

23. PERITONEAL DIALYSIS SOLUTION Intraperitoneal Dialysis Solution (of approximate composition)

24. PSYCHOTHERAPEUTIC MEDICINES 24.1 Medicines used in psychotic disorders Chlorpromazine HCl U

Haloperidol

S, T

Tablets 25, 50, 100 mg Syrup 25 mg/5 ml Injection 25 mg/ml Tablets 1.5, 5, 10 mg Injection 5 mg/ml Tablet 5 mg, 10 mg

Trifluoperazine S, T 24.2 Medicines used in mood disorders 24.2.1 Medicines used in depressive disorders Amitriptyline U Tablets 25 mg Fluoxetine HCl U Capsules 20 mg Imipramine U Tablets 25 mg, 75 mg * Complementary

280  Practical Manual of Pharmacology 24.2.2 Medicines used in bipolar disorders Lithium Carbonate T Tablets 150 mg 24.3 Medicines used for generalized anxiety and sleep disorders Alprazolam U Tablets 0.25, 0.5 mg Diazepam U Tablets 2, 5, 10 mg Nitrazepam U Tablets 5 mg, 10 mg 24.4 Medicines used for obsessive compulsive disorders and panics attacks Clomipramine HCl S, T Tablets 10, 25 mg

25. MEDICINES ACTING ON THE RESPIRATORY TRACT 25.1 Antiasthmatic medicines Aminophylline U Beclomethasone Dipropionate U Hydrocortisone Sodium Succinate U Salbutamol Sulphate U

Theophylline Compounds 25.2 Antitussives Codeine Phosphate Dextromethorphan

U U U

Injection 25 mg/ml Inhalation 50 mg, 250 mg/dose Injection 100, 200, 400 mg Tablets 2 mg, 4 mg Syrup 2 mg/5 ml Inhalation 100 mg/dose Tablets 100, 200 mg Tablets 10 mg Syrup 15 mg/5 ml Tablets 30 mg

26. SOLUTIONS CORRECTING WATER, ELECTROLYTE AND ACID-BASE DISTURBANCES 26.1 Oral Oral Rehydration Salts

U

Powder for Solution As per IP

26.2 Parenteral Glucose

U

Injection 5% isotonic 50% hypertonic

Glucose with Sodium Chloride U Normal Saline U N/2 Saline S, T N/5 Saline S, T Potassium Chloride U

Injection 5% + 0.9% Injection 0.9% Injection Injection Injection 11.2% Sol.

Appendix IV  281 Ringer Lactate Sodium Bicarbonate 26.3 Miscellaneous Water for Injection

U U

Injection Injection

U

Injection 2, 5, 10 ml

27. VITAMINS AND MINERALS Ascorbic Acid Calcium salts Multivitamins

U U U

Tablets 100, 500 mg Tablets 250, 500 mg Tablets

(Having composition as per schedule v of drugs and cosmetics act, 1940) Nicotinamide Pyridoxine Riboflavine Thiamine Vitamin A

U U U U U

Vitamin D 3 (Ergocalciferol)

S, T

Tablets 50 mg Tablets 25 mg Tablets 5 mg Tablets 100 mg Tablets 5000 IU, Capsules 10,000 IU 50,000 IU Injection 50,000 IU/ml Capsules 0.25 mg, 1 mg

Terminologies Used in Pharmacology

PHARMACOLOGY Pharmacology is the science that deals with study of drugs and their action on living organisms. It consists of detailed study of drugs, including their actions on living animals, organs or tissues. The actions may be beneficial or harmful. Pharmacology is combination of two words: Pharmacon = an active principle (drug) Logos = a discourse or treatise

DRUG The name is derived from Drogue, a French word (means Dry herb). The name is derived from the fact that most of the drugs earlier were obtained by drying plant or animal parts. Definition of Drug According to WHO “A drug is any substance/product that is used/ intended to be used to modify/explore physiological systems/pathological states for benefit of the recipient.” Drug is also defined as any chemical substance which is used for prevention, treatment or diagnosis of a disease. Examples: • Antibiotics for treatment of infection • Vaccines for prevention of disease • Radioactive iodine for diagnosis of thyroid cancer. Branches of Pharmacology: Pharmacology has expanded to much wider areas, so now it has a number of branches or subdivisions.

PHARMACY It is the art of preparing, compounding and dispensing drugs in such a way so as to make the medication suitable for easy, effective and palatable administration in the treatment of a disease.

284  Practical Manual of Pharmacology Experimental Pharmacology It is the study of drugs in animals. It usually involves research on animals using drugs. Clinical Pharmacology It is the scientific study of drugs in human being. It includes clinical trials/studies of new drugs in human beings, identifying and reporting adverse drug reactions, rational drug use and essential drug concept. This area of pharmacology is most demanding these days. With the shift of a number of clinical trials of new drugs to India, the training, demand and recruitment has increased tremendously in clinical pharmacology.

CLINICAL PHARMACY It deals with patient care with particular emphasis on drug therapy. In practice it is patient oriented and includes not only the dispensing of required drug but also giving advice to the patient on the proper use of all drugs, both prescribed and over the counter drugs. It usually utilizes the services of a pharmacist as an information source for members of the medical and other health professions on all matters pertaining to drugs and their dosage forms. This practice is quite common and also mandatory in developed countries. In India it has just started in few metropolitan cities. A number of good pharmacy stores have come up in major cities in India, which are following all aspects of clinical pharmacy. Molecular Pharmacology It deals with study of actions of drugs at molecular level. Pharmacodynamics It is the study of action of drugs on the body (what the drug does to the body). Pharmacokinetics It is the study of absorption, distribution, metabolism and excretion (ADME) of drugs (what the body does to the drug). Pharmacognosy It is the study of identification of source and physical properties of natural medicinal substances, i.e. drugs obtained from plants. Pharmacotherapeutics It is a branch of medicine concerned with the cure of disease or relief of symptoms using drugs. (It deals with the use of drugs in clinical practice). It is also called Drug therapy or pharmacotherapy. Poison A poison is a substance which when absorbed or ingested into the body may alter physiology to a mild or a critical extent by damaging body tissues or cells.

Terminologies Used in Pharmacology  285 TOXICOLOGY It is the science of poisons dealing with their detection, measurement and management of poisons. (Poisons are substances that cause harmful, dangerous or fatal symptoms in animals and human beings.) Pharmaceutics It is an adjective which means pertaining to pharmacy. It deals in technique of calculation, preparation and dispensing required dosage forms. Pharmaceutical chemistry It is the application of organic and inorganic chemistry to pharmaceutics and relation of these principles to drug use. Pharmacoeconomics It involves the cost of drug therapy, including those of purchasing, dispensing (e.g. salaries of pharmacists, pharmacy technicians), storage, administration (e.g. salaries of nurses, costs of supplies), laboratory, other tests used to monitor client responses and losses from expiration. Length of illness or hospitalization is also considered. Pharmacovigilance It involves adverse drug event monitoring, detection, reporting and remedial measures.

Index A

C

Acute abdomen 126 Acute asthma 120 Acute attack of migraine 128 Acute gouty arthritis 137 Acute severe asthma 121 Adverse drug reaction (ADR) 178 types 178 augmented 178 bizarre 178 continues use 178 delayed 179 end of dose 179 Adverse effects of drugs on mice using rota rod apparatus 96 Allergic conjunctivitis 129 Analgesic effect of drugs on rats using tail flick method 94 Anemia (microcytic hypochromic) 118 Angina pectoris 119 Animal toxicity studies 98 Antidepressant effect of drugs on mice 95 Antipsychotics and tricyclic antidepressants 197 Aphthous ulcer 154 Aspirate drug from ampoule into syringe 41 requirements 41 technique 41 Aspirate drug from vial into syringe 42 requirements 42 technique 42 AUC 106 Autonomic nervous system pharmacology 74

Calculation of drug doses and dilutions 223 Cerebral malaria 143 Chloroquine resistant malaria 142 Chloroquine sensitive malaria 141 Chronic simple glaucoma 153 Clark’s rule 195 Clearance 109 clinical significance 110 salient features 109 Commercial preparations of drugs 13 Common errors in prescription writing 157 Conversion between systems 8 Creams 61 advantage 61 disadvantage 61 Cytochrome P450 isoenzymes 165

B Bipolar disorder 148

D Depression 147 Dilator pupillae 75 Dissolve dry medicine in vial aspirate drug solution into syringe 43 requirements 43 technique 43 Domestic weights and measures 8 Dosage adjustment and plasma level monitoring 200 Dosage forms for injections 40 Drug characteristics 36 Drug interaction 162 pharmaceutical 162 pharmacokinetic 163 Drug nomenclature 16 Drug schedules 18 Drugs and solutions used in dog BP experiment 91 Drugs and solutions used in rabbit intestine experiment 87

Drugs classified into various categories 14 over-the counter (OTC) drugs 14 prescription-only drugs 14 Drugs on the rabbit eye 75 drugs and solutions 76 procedure 76 corneal reflex 77 light reflex 77 size of pupil 76 requirements 76 Drugs schedules and acts 17 Dusting powder 59 advantages 60 disadvantages 60 Dysmenorrhoea 127

E Ear drops 55 advantage 55 disadvantage 55 procedure 56 Effect of drugs on dog BP 92 Effect of drugs on frog heart 80 Effect of drugs on rabbit intestine 88 Effect of drugs on rats using hole board test 97 Erectile dysfunction 152 Essential drug concept 234 implementation 234 purpose 234 selection criteria 234 Essential drug list (India) 2003 262 anaesthetics 262 general anaesthetics and oxygen 262 local anaesthetics 262

288  Practical Manual of Pharmacology analgesics, antipyretics, NSAIDs, medicines in gout and rheumatoid disorders 263 disease modifying agents used in rheumatoid disorders 263 medicines used to treat gout 263 non-opioid analgesics, antipyretics and nonsteroidal antiinflammatory medicines 263 opioid analgesics 263 antiallergics and medicines used in anaphylaxis 264 antidotes and other substances used in poisonings 264 antiepileptics 264 antiinfectives 264 antimigraine medicines 269 antineoplastic immunosuppressives and medicines in palliative care 269 antiparkinsonism medicines 270 blood products and plasma substitutes 271 cardiovascular medicines 271 dermatological medicines (topical) 273 diagnostic agents 274 disinfectants and antiseptics 274 diuretics 275 gastrointestinal medicines 275 hormones, other endocrine medicines and contraceptives 276 immunologicals 277 medicines acting on the respiratory tract 280 medicines affecting blood 270 muscle relaxants (peripherally acting) and cholinesterase inhibitors 278 ophthalmological preparations 278 oxytocics and antioxytocics 279 peritoneal dialysis solution 279 psychotherapeutic medicines 279

solutions correcting water, electrolyteand acid-base disturbances 280 vitamins and minerals 281 Ethical criteria for drug promotion 211 Ethics 238 principles 238 Ethics and humans 238 Evaluation of drug formulations 232 Eye drops 54 advantages 54 disadvantages 54 procedure 54 Eye ointment 55 advantage 55 disadvantage 55 procedure 55

F Factors affecting drug disposition in children 194 Factors affecting oral route of administration 35 Facts about frog heart 81 FDA (USA) schedules 18 Food-drug interactions 167 Formulations 10 Fried’s rule 195

G Generalized tonic clonic and partial seizures 146 Genetic variations 204 Golden rules in treatment of elderly 198

H Half-life 108 clinical significance 109 salient features 108 Hepatic amoebiasis 133 Hepatic disease 201 first pass metabolism 201 hepatic blood supply 201 prodrugs 201 Herpes zoster 130

Hypertension (essential hypertension with no associated disease) 122

I Imperial system 7 apothecary system (UK)/troy system 8 avoirdupois system 7 Importance of ethics 100 Inject drugs subcutaneously 47 procedure 48 requirements 48 Injection by intramuscular route 46 procedure 46 requirements 46 Injections by intramuscular route in an orange model 46 procedure 46 requirements 46 Injections by intravenous route 43 procedure 43 requirements 43 Inscription 113 Insomnia 151 Instruments in pharmacy 4 containers 5 dispensing balance 4 measuring cylinders and flask 4 mortar and pestle 4 pill tile 5 spatulas 5 wash bottle 5 weights 4 Intestinal amoebiasis 134

L Label 19 primary label 19 secondary label 19 Liniments 60 advantage 60 disadvantage 60 procedure 60 Loading dose 110 maintenance dose 111 Local anaesthetics (Las) 79 Local-inhalation 62 advantages 63 care of for the rotahaler 64

Index  289 disadvantages 63 procedure (for rotahaler) 64 procedure for correct use (for MDI) 63 Local-oral 64 gargles and mouthwashes 64 advantage 65 disadvantage 65 procedure 65 Lotions 60 advantage 60 disadvantage 60 procedure 60

M Medical journals 210 Metabolism 164 Metric system 7 Miotics and mydriasis 78 classification 78 indications 78 Model for IV injections for students in laboratory 44 general principles 44 requirements 44 Multibacillary leprosy 138 Myasthenia gravis 150

N Naranjo algorithm 179 Nasal drops 56 advantage 56 disadvantages 56 procedure 56 Nasal sprays 56 advantages 56 disadvantage 56 procedure 57 NDDS-oral 66 advantages 66 prodrugs 66 New drug development 219 New techniques for drug delivery 65 NIDDM 125

O Objective structured practical examination (OSPE) 253 Ointments 60 advantages 61

disadvantages 61 procedure 61 Oral candidiasis (thrush) 131 Oral-capsules 32 advantages 33 disadvantages 33 type 32 hard gelatin type 32 soft gelatine type 32 Oral-liquids 34 advantages 34 disadvantages 34 Oral-pills 33 advantages 33 disadvantages 33 Oral-powder 33 advantages 33 disadvantages 33 Oral-special preparations 36 coated preparations 36 sustained release (SR) preparations 37 advantages 37 disadvantages 37 Oral-tablets 31 disadvantages 32 Organization of ADR monitoring system in India 183

P Paints 61 advantage 62 disadvantage 62 Parameters of prescription audit 159 Parenteral 40 intravenous injections (IV) advantages 41 disadvantages 41 Parenteral-IM 45 intramuscular injections 45 advantages 45 disadvantages 45 precautions 45 Parenteral-intradermal injection 48 epidural injections 48 intra-arterial injections 48 intra-articular injections 49 intra-thecal injections 48 Parenteral-SC 46 advantages 47 disadvantages 47

Parenteral-sublingual 49 advantages 49 disadvantages 49 Parenteral-transdermal 49 advantages 51 disadvantages 51 types 50 matrix controlled 50 membrane controlled 50 sandwich type 50 Parkinsonism 149 Patient consent document 240 Paucibacillary leprosy 139 Peptic ulcer 124 Pharmaceutical calculations 8 percent calculation 8 percent by volume (%v/v) 9 percent by weight (%w/w) 9 percent weight in volume (%w/v) 8 proportion calculation 9 Pharmaceutical containers 6 Pharmacopoeia 16 Poisoning with drugs 246 aspirin and other salicylates 248 clinical features 248 management 248 methanol 249 clinical features 249 management 249 OPC poisoning 251 clinical features 251 management 251 opioid poisoning 247 clinical features 247 management 248 paracetamol poisoning 246 clinical features 246 management 246 tricyclic antidepressants (TCAs) 250 clinical features 250 management 250 Postmarketing methods 180 case control studies (retrospective) 181 case reports 181 cohort studies 181 prescription event monitoring 181 spontaneous reporting-yellow card system 181 Premarketing clinical trails 180

290  Practical Manual of Pharmacology Prepare and dispense 1:5000 solution of potassium permanganate 24 adverse effects 26 labeling 25 pharmacological actions 25 procedure 24 storage conditions 25 therapeutic uses 25 Prepare and dispense 25 ml of Mandle’s throat paint 23 labeling 23 pharmacological actions 24 iodine 24 potassium iodide 24 precautions 24 procedure 23 therapeutic uses 24 Prepare and dispense 50 ml of calamine lotion 21 labeling 22 pharmacological actions 22 bentonite 22 calamine 22 glycerine 22 liquefied phenol 22 sodium citrate 22 zinc oxide 22 precautions 23 procedure 21 therapeutic uses 23 Prepare and dispense one dose of oral rehydration powder for 1000 ml of oral rehydration solution (ORS) 26 home made ORS 28 new WHO ORS 29 objective of ORS 26 pharmacological action of salts 27 glucose 27 sodium chloride 27 pharmacological actions 27 precautions 29 procedure 26 reduced osmolarity ORS 29 super-ORS 28 therapeutic uses 28 WHO formula (for 1 litre ORS) 26 Prescription 112

Primary syphilis 135 Principles of ethics 100 Process of pharmacokinetics 104 absorption of drugs 104 distribution of drugs 104 elimination of drugs 104 bioavailability 104 clinical significance 105 salient features 105 metabolism of drugs 104

R Rational drug 233 Rectal 37 advantages 37 disadvantages 38 Renal diseases 202 Routes of drug administration 11

S Source of drug information 208 Sources of drugs 30 animals 30 biosynthetic 30 microorganisms 30 minerals 30 plants 30 semisynthetic 30 synthetic 30 Special need for ADR monitoring in India 182 Special toxicity studies 99 Sphincter pupillae 75 Sprays 61 advantage 61 disadvantage 61 Starling heart lever 80 Status epilepticus 123 Subscription 113 Suppositories 57 advantages 57 disadvantages 57 procedure 58 Suspected adverse drug reaction reporting form 260 Sustained vs. controlled release 66 Syme’s cannula 80 Symposia/conferences 210

T Terminologies used in pharmacology 283 Therapeutic drug monitoring (TDM) 187 characteristics 187 cost-effective 192 indications 188 steps 188 dosage adjustment 190 drug estimation methods 189 interpretation of plasma concentration data 189 time of sampling 188 TDM procedure 191 antiepileptic drugs (AED) 191 carbamazepine 192 phenobarbitone 192 phenytoin 191 Therapeutic follow-up cases/ problems 215 Time of drug administration 10 Tips for writing a good prescription 159 Tuberculosis 140 Typhoid 136

U Upper respiratory tract infection 144

V Vaginal candidiasis (vulvovaginitis) 132 Vaginal pessaries 58 advantages 58 disadvantages 58 procedure 58 Volume of distribution (VD) 106

W Written informed consent 240

Y Young’s formula 195