Pharmacology

PHARMACOLOGY BASIC PHARMACOLOGY Pharmacology Greek “pharmakon” drug and “logos” knowledge Studies: Interaction of drugs within living organism Effects of drugs on function of living organism  action  mode of action  clinical use  adverse effect  fate of drug Clinical Pharmacology Evaluates:  Pharmacological Action of Drug  Preferred Route of Administration  Safe Dosage Drugs  Chemical substance other than nutrients (essential) dietary ingredient  When administered, will result in distinct biological outcome 1. Minerals 4. Synthetic Source  liquid paraffin  Aspirin  magnesium sulfate  Sulfoamides  magnesium trisilicate  Paracetamol  kaolin  Zidovudine 2. Animals 5. Microorganisms  Insulin  Penicillin  Thyroid Extract  Streptomycin  Heparin  Many other antibiotics 6. Genetic Engineering  Antitoxin Sera  Human Insulin 3. Plants  Morphine  Human Growth Hormone  Digoxin  Atropine  Castor oil  Effectivity depends upon administration o Oral o IV o IM, etc  There must be enough concentration within target tissue to achieve desired effect  Pharmacy  Science of  Identification  Standardization  Selection  Compounding and  Preservation  Dispensing of Medical Substances

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Pharmacodynamics – study of biological and therapeutic effect of drugs

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Pharmacokinetics – study of absorption, distribution metabolism, excretion (ADME) of drugs

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Pharmacotherapeutics – deals w/ proper selection and use of drugs for prevention & treatment of disease

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Toxicology – Science of POISONS; study the undesirable effect of chemicals and biological on cell function

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Poisons – substances that cause harmful, dangerous, or fatal symptoms in living substances

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Chemotherapy – study the effects of drugs upon microorganisms, parasites & neoplastic cells living and multiplying on living organism

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Pharmacopeia – official code containing a selected list of establishment of drugs & medical preparations

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With description of physical properties and test for o Identity o Purity o Potency PHARMACODYNAMICS – involves how drugs act on target cells to alter cellular function. Receptor and Non-receptor Mechanism Receptor – cell component where drugs interact o Molecules on the surface or w/in the cell o Most of the drugs produce their effects by binding with their specific receptors o Aluminum hydroxide & Magnesium trisilicate - Non-receptor Mechanism Similar drugs may bind to same receptor resulting to either BLOCKING or INTERACTIVE RESPONSE LOCK and KEY Principle Efficacy – ability of drug to produce an effect at a receptor Agonist o BOTH has the AFFINITY and EFFICACY o Stimulate a receptor o Outcome: Mimicry Antagonist o Has affinity but not efficacy or intrinsic activity o Outcome: Blocking o Prevent the natural chemical from acting on receptor Drug Binding – REVERSIBLE Forces – attraction of drug to its receptor o Hydrogen Bond o Ionic Bond o Covalent Bond – Strongest o Vander Waals Mechanism

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1st Messenger    

Receptors

Site of Drug Action Extracellularly Cell Surface Intracellulary

DrugReceptor Complex

Secondary Messenger

Mechanism of Drug Action

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Dose Response Relationship Relationship depends on biological object under observation & drug employed Minimal Dose – lowest concentration of a drug that elicits response Maximal Dose – largest concentration after which further increase in concentration will not change the response Graded Dose Effect o Direct relationship of DOSE & RESPONSE o EC50 or ED50 – concentration that is required to produce 50% of max. effect

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Quantal Dose – all or none response. Curve is characterized by stating the median effective dose and median lethal dose o Median Lethal Dose (LD50) – kills ½ of a population o Median Effect Dose (ED50) – desired response in 50% test population o Therapeutic Index  Approximate assessment of safety of the drug  Ratio of LD50 and ED50  Aka THERAPEUTIC WINDOW or SAFETY Structural Activity Relationship Drug activity is related to chemical structure Knowledge of chemical structure is useful for o Synthesis of new compounds w/ more specific actions and fewer adverse reactions o Synthesis of competitive antagonist o Understanding the mechanism of drug action Pharmacokinetics - It deals with: Absorption Distribution Metabolism Excretion of drugs in the body Biotransport of Drug – translocation of a solute from one side of a biological barrier to another Structural of Biological Membrane Outer – covered by thin membrane Proteins o Structure o Enzyme o Carrier o Receptors Plasma Membrane o Semipermeable o Allows passage of water, glucose, etc o Not allowing the passage of sucrose until converted to glucose and fructose Passage of Drug across a Membrane Passive Transfer o Simple diffusion  Movement from higher concentration to lower concentration  No need of energy  For highly lipid soluble drugs o Filtration  Water soluble drugs  Cross through pores  Facilitated by hydrodynamic pressure gradient across the membrane Specialized Transfer o Facilitated Diffusion  Passage across by carrier protein mediated system  Carrier mediated diffusion  Dependent on number of carrier o Active Transport  Pass often against their concentration gradient  Carrier + energy o Endocytosis – large molecules are engulfed by cell membrane & release them intracellularly

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Charac teristi c

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Simple diffusion

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Facilitated diffusion

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Active transport

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Incide nce Proces s Move ment

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Slow

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Very quick

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Along concentration gradient

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Against concentration gradient

Carrie r Energ y

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Along concentration gradient Not needed

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Not required

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Drug Absorption – process where drug enters to systemic circulation form site of administration through a biological carrier ALIMENTARY TRACT Advantages o Safe o Convenient o Economical Disadvanatages o Onset of action is slow o Irritant drugs cannot be administered o Not useful in vomiting and severe diarrhea o Gastric and digestive enzymes may destroy some drugs o Water soluble drugs are absorbed poorly Buccal Cavity - nitrates Stomach – aspirin, alcohol Intestine – most of non-ionized and ionized drugs Rectum – rectal suppositories, bisacodyl laxatives PARENTERAL Intradermal o Given into the layers of the skin o B.C.G Vaccine Subcutaneous o Non-irritant substances o Insulin Intramuscular o Soluble substances, mild irritants, suspension, colloids o Injected in deltoid or gluteal muscle o One of the more common routes (multivitamins, streptomycin) o Advantage  rate of absorption is uniform  Onset of action is faster than oral  Can be given in vomiting and diarrhea o Disadvantage  pain at local site of injection  Volume of injection should not exceed 10ml Intravenous o Direct o Produces rapid action o Can be given as bolus o Advantage - Production of desired blood concentration can be obtained with a well designed dose. o Disadvantage  Drug effect cannot be halted if once drug is injected  Expertise is needed to give injection Intrathecal - Injected into the subarachnoid space of spinal cord Intraperitoneal - Injected into the abdominal cavity Intra-articular - Injected directly into a joint

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TRANSCUTANEOUS Iontophoresis o Galvanic current is used o Salicylates Inunctions o Rubbed into the skin o Nitroglycerin Jet injection o With the help of high velocity jet produced through a microfine orifice o No need of needle o Mass inoculation programs o Adhesive units  a transdermal therapeutic system produce prolonged systemic effect  Scopolamine for motion sickness TOPICAL/LOCAL Absorption through skin is a passive process Absorption occurs more easily through cell lining Dusting powder, paste, lotion, drops, ointment, suppository for vagina and rectum INHALATION Dry powders, nebulized particles Sprayed as fine droplets deposited over mucus membrane Produce local effects Salbutamol spray (bronchial asthma), volatile general anaesthetics PHARMACOKINETICS ABSORPTION: drug absorption from the site of administration permits entry of the therapeutic agent (either directly or indirectly) into plasma. DISTRIBUTION: drug may then reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids. METABOLISM: drug may be biotransformed by metabolism by the liver, or other tissues. ELIMINATION: Finally, drug and its metabolites are eliminated from the body in urine, bile, or feces. To design and optimize treatment regimens Make decisions as to the: • route of administration, • amount and frequency of dose, and • duration of treatment Oral – Aspirin Enteric-coated preparations: o Chemical envelope that resists the action of the fluids and enzymes in the stomach o Omeprazole o Delivering them instead to the less acidic intestine, where the coating dissolves and allows the drug to be released. Extended-release preparations: o Special coatings or ingredients that control how fast the drug is released from the pill into the body. o Having a longer duration of action may improve patient compliance o Maintain concentrations within an acceptable therapeutic range over a long period of time o For drugs with short half-lives. o Oral morphine o Only two doses are needed when controlled-release tablets are used. o Developed to create a marketing advantage over conventional-release products o Obtain the required dosage when a dosage form of the required strength is unavailable o Begin therapy with the lowest possible dose Sublingual Placement under the tongue Advantages, including:

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o rapid absorption, o convenience of administration, o low incidence of infection, o bypass of the harsh GI environment, and o avoidance of first-pass metabolism The buccal route (between cheek and gum) is similar to the sublingual route. Parenteral Introduces drugs directly across the body’s barrier defenses into the systemic circulation. Parenteral administration is used for drugs: o that are poorly absorbed from the GI tract (for example, heparin) and o for agents that are unstable in the GI tract (for example, insulin). Treatment of unconscious (rapid onset of action) Highest bioavailability Most control over the actual dose of drug delivered to the body. Irreversible and may cause pain, fear, tissue damage, and infections. 1. IV (Intravascular) Most common parenteral route. For drugs that are not absorbed orally IV delivery permits a rapid effect Delivered to the systemic circulation almost immediately. Longer time, decrease in the peak plasma concentration and an increase in the time the drug is present in the circulation. IV injection is advantageous for administering chemicals that may cause irritation when administered via other routes, because the substance is rapidly diluted by the blood. Contamination at the site of injection. It may also precipitate blood constituents, induce hemolysis, or cause other adverse reactions Carefully monitored for unfavorable drug reactions, and the rate of infusion must be carefully controlled. 2. IM (Intramuscular) Drugs administered IM can be in: o aqueous solutions o specialized depot preparations Depot preparations o often consist of a suspension of the drug in a nonaqueous vehicle o As the vehicle diffuses out of the muscle, the drug precipitates at the site of injection. o The drug then dissolves slowly o Haloperidol and Depot medroxyprogesterone 3. SC (Subcutaneous) Like IM injection, requires absorption via simple diffusion and is somewhat slower than the IV route. Minimizes the risks of hemolysis or thrombosis associated with IV injection May provide constant, slow, and sustained effects. This route should not be used with drugs that cause tissue irritation. Minute amounts of epinephrine are sometimes combined with a drug administered subcutaneously to restrict its area of action Solids, such as a single rod containing the contraceptive etonogestrel that is implanted for longterm activity Programmable mechanical

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Others 1. Oral Inhalation Rapid delivery of a drug across the large surface area of the mucous membrane Producing an effect almost as rapidly as does IV injection. Drugs that are gases (for example, some anesthetics) and those that can be dispersed in an aerosol. This route is particularly effective and convenient for patients with respiratory complaints Albuterol, and Fluticasone.

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2. Nasal Inhalation

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Drugs directly into the nose. Oxymetazoline, and Mometasone furoate. Desmopressin Salmon calcitonin

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3. Intrathecal / Intraventricular The blood-brain barrier typically delays or prevents the absorption of drugs into the central nervous system When local, rapid effects are needed Intrathecal amphotericin B

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4. Topical Local effect of the drug is desired. Clotrimazole 5. Transdermal This route of administration achieves systemic effects via transdermal patch The rate of absorption can vary markedly - lipid solubility of the drug. This route is most often used for the sustained delivery of drugs 6. Rectal Biotransformation of drugs by the liver is minimized with rectal administration. Like the sublingual route of administration Useful if the drug induces vomiting when given orally, if the patient is already vomiting, or if the patient is unconscious. [Note: The rectal route is commonly used to administer antiemetic agents.] On the other hand, rectal absorption is often erratic and incomplete, and many drugs irritate the rectal mucosa.

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ABSORPTION Factors influencing Absorption 1. pH • Most drugs are either weak acids or weak bases. • A drug passes through membranes more readily if it is uncharged • Therefore, the effective concentration of the permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms. • Distribution equilibrium is achieved when the permeable form of a drug achieves an equal concentration in all body water spaces. • [Note: Highly lipid-soluble drugs rapidly cross membranes and often enter tissues at a rate determined by blood flow.] 2. Blood flow to the absorption site • Absorption from the intestine is favored over that from the stomach. • [Note: Shock severely reduces blood flow to cutaneous tissues, thereby minimizing the absorption from SC administration.] 3. Total Surface Area available for absorption • With a surface rich in brush borders containing microvilli, the intestine has a surface area about 1000-fold that of the stomach, making absorption of the drug across the intestine more efficient. 4. Contact time at the absorption surface • If a drug moves through the GI tract very quickly • Delays the transport of the drug from the stomach to the intestine delays the rate of absorption of the drug. • Parasympathetic input increases the rate of gastric emptying, • Sympathetic input, anticholinergics delays gastric emptying. • Food in the stomach both dilutes the drug • Therefore, a drug taken with a meal is generally absorbed more slowly 5. Expression of P-glycoprotein • A multidrug transmembrane transporter protein responsible for transporting various molecules, including drugs, across cell membranes • It is expressed throughout the body, and its functions include: • Liver • Kidneys • Placenta • Intestines • Brain capillaries

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BIOAVAILABILITY - fraction of administered drug that reaches the systemic circulation

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Determining bioavailability is important for calculating drug dosages for non-intravenous routes of administration. The route by which a drug is administered, as well as the chemical and physical properties of the agent, affects its bioavailability.

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1. Determining Bioavailabilty

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Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration with plasma drug levels achieved by IV injection, in which the total agent rapidly enters the circulation. When the drug is given orally, only part of the administered dose appears in the plasma

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2. Factors that influence bioavailability

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IV – 100 % Bioavailability Oral undergoes first pass mechanism This biotransformation, in addition to the drug’s chemical and physical characteristics, determines the amount of the agent that reaches the circulation and at what rate.

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2.a. First-Pass Hepatic Metabolism

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When a drug is absorbed across the GI tract, it first enters the portal circulation before entering the systemic circulation

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If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the amount of unchanged drug that gains access to the systemic circulation is decreased. [Note: First-pass metabolism by the intestine or liver limits the efficacy of many drugs when taken orally. (Nitroglycerin)

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2.b. Solubility of Drug

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Very hydrophilic drugs are poorly absorbed Extremely hydrophobic are also poorly absorbed, because they are totally insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. Weak acids or weak bases

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2.c. Chemical Instability

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Penicillin G, are unstable in the pH of the gastric contents. Insulin, are destroyed in the GI tract by degradative enzymes.

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2.d. Nature of the Drug Formulation

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Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, o particle size, o salt form, o crystal polymorphism, o enteric coatings, and the o presence of excipients (such as binders and dispersing agents)  Can influence the ease of dissolution and, therefore, alter the rate of absorption.

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Bioequivalence - two related drug preparations are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations

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Therapeutic Equivalence - Two similar drug products are therapeutically equal if they are pharmaceutically equivalent with similar clinical and safety profiles

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DISTRIBUTION

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Drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and then the cells of the tissues For a drug administered IV, when absorption is not a factor, the initial phase represents the distribution phase o during which a drug rapidly disappears from the circulation and enters the tissues This is followed by the elimination phase, when drug in the plasma is in equilibrium with drug in the tissues. The delivery of a drug from the plasma to the interstitium primarily depends on o cardiac output and regional blood flow, o capillary permeability, the o tissue volume, the o degree of binding of the drug to plasma and tissue proteins, and the o relative hydrophobicity of the drug.

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A. Blood Flow

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The rate of blood flow to the tissue capillaries varies widely as a result of the unequal distribution of cardiac output to the various organs. Blood flow to the brain, liver, and kidney is greater than that to the skeletal muscles. Adipose tissue, skin, and viscera have still lower rates of blood flow. Variance in blood flow partly explains the short duration of hypnosis produced by a bolus IV injection of propofol High blood flow, together with the high lipid solubility of thiopental, permits it to rapidly move into the CNS and produce anesthesia. A subsequent slower distribution to skeletal muscle and adipose tissue lowers the plasma concentration sufficiently so that the higher concentrations within the CNS decrease, and, thus, consciousness is regained.

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B. Capillary Permeability

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Determined by capillary structure and by the chemical nature of the drug. Capillary structure varies widely in terms of the fraction of the basement membrane that is exposed by slit junctions between endothelial cells. To enter the brain, drugs must pass through the endothelial cells of the capillaries of the CNS or be actively transported.

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C. Binding of drugs to plasma proteins and tissues

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Binding to Plasma Proteins o Reversible binding to plasma proteins sequesters drugs in a nondiff usible form and slows their transfer out of the vascular compartment. o Binding is relatively nonselective regarding chemical structure o Plasma albumin is the major drug-binding protein and may act as a drug reservoir o This maintains the free-drug concentration as a constant fraction of the total drug in the plasma. Binding to Tissue Proteins o Numerous drugs accumulate in tissues, o Drugs may accumulate as a result of binding to lipids, proteins or nucleic acids. o Drugs may also be actively transported into tissues. o These tissue reservoirs may serve as a major source of the drug and prolong its actions or, on the other hand, can cause local drug toxicity. o [For example, acrolein, the metabolite of cyclophosphamide is toxic to the kidney because of its accumulation in renal cells.]

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D. Hydrophobicity

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The chemical nature of a drug strongly influences its ability to cross cell membranes. Hydrophobic drugs readily move across most biologic membranes. These drugs can dissolve in the lipid membranes and, therefore, permeate the entire cell’s surface. The major factor influencing the hydrophobic drug’s distribution is the blood flow to the area. By contrast, hydrophilic drugs do not readily penetrate cell membranes and must pass through the slit junctions.

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E. Volume of Distribution

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The fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma. It is calculated by dividing the dose that ultimately gets into the systemic circulation by the plasma concentration at time zero (C0) Although Vd has no physiologic or physical basis, it can be useful to compare the distribution of a drug with the volumes of the water compartments in the body

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E. 1. Distribution into the Water Compartments in the Body

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Once a drug enters the body, from whatever route of administration, it has the potential to distribute into any one of three functionally distinct compartments of body water or to become sequestered in a cellular site. Plasma Compartment o If a drug has a very large molecular weight or binds extensively to plasma proteins, it is too large to move out through the endothelial slit junctions of the capillaries and, thus, is effectively trapped within the plasma (vascular) compartment. o As a consequence, the drug distributes in a volume (the plasma) that is about 6 percent of the body weight. Extracellular Fluid o If a drug has a low molecular weight but is hydrophilic, it can move through the endothelial slit junctions of the capillaries into the interstitial fluid. o However, hydrophilic drugs cannot move across the lipid membranes of cells to enter the water phase inside the cell. o Therefore, these drugs distribute into a volume that is the sum of the plasma water and the interstitial fluid Total Body Water

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If a drug has a low molecular weight and is hydrophobic, not only can it move into the interstitium through the slit junctions, but it can also move through the cell membranes into the intracellular fluid. The drug, therefore, distributes into a volume of about 60 percent of body weight

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DRUG CLEARANCE THROUGH METABOLISM

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Once a drug enters the body, the process of elimination begins. The three major routes involved are: 1. hepatic metabolism, 2. elimination in bile, and 3. elimination in urine. Together, these elimination processes cause the plasma concentration of a drug to decrease exponentially. That is, at any given time, a constant fraction of the drug present is eliminated in a unit of time Most drugs are eliminated according to first-order kinetics Metabolism leads to products with increased polarity, which will allow the drug to be eliminated. Clearance (CL) estimates the amount of drug cleared from the body per unit of time. Total CL is a composite estimate reflecting all mechanisms of drug elimination 1. First-order kinetics: The metabolic transformation of drugs is catalyzed by enzymes, and most of the reactions obey Michaelis-Menten kinetics.  That is, the rate of drug metabolism and elimination is directly proportional to the concentration of free drug, and first-order kinetics are observed  This means that a constant fraction of drug is metabolized per unit of time (that is, with every half-life the concentration reduces by 50%).  First-order kinetics is sometimes referred to clinically as linear kinetics 2. Zero-order Kinetics • With a few drugs, such as aspirin, ethanol , and phenytoin, the doses are very large. • Therefore [C] is much greater than Km, and the velocity • The enzyme is saturated by a high free-drug concentration, and the rate of metabolism remains constant over time. • This is called zeroorder kinetics (sometimes referred to clinically as nonlinear kinetics). • A constant amount of drug is metabolized per unit of time, and the rate of elimination is constant and does not depend on the drug concentration.

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Reactions of Drug Metabolism

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The kidney cannot efficiently eliminate lipophilic drugs that readily cross cell membranes and are reabsorbed in the distal convoluted tubules. Therefore, lipid-soluble agents must first be metabolized into more polar (hydrophilic) substances in the liver using two general sets of reactions, called Phase I and Phase II o o Phase I  Phase I reactions convert lipophilic molecules into more polar molecules by introducing or unmasking a polar functional group, such as –OH or –NH2.  Phase I metabolism may increase, decrease, or leave unaltered the drug’s pharmacologic activity. o Phase II  This phase consists of conjugation reactions.  If the metabolite from Phase I metabolism is sufficiently polar, it can be excreted by the kidneys.  However, many Phase I metabolites are too lipophilic to be retained in the kidney tubules.  Glucuronidation is the most common and the most important conjugation reaction.  Neonates are deficient in this conjugating system, making them particularly vulnerable to drugs such as chloramphenicol, which is inactivated by the addition of glucuronic acid, resulting in gray baby syndrome.  [Note: Drugs already possessing an –OH, –NH2, or –COOH group may enter Phase II directly and become conjugated without prior Phase I metabolism.]  The highly polar drug conjugates may then be excreted by the kidney or in bile.

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Drug Clearance by the Kidney

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Elimination of drugs from the body requires the agents to be sufficiently polar for efficient excretion. Removal of a drug from the body occurs via a number of routes, the most important being through the kidney into the urine. A patient in renal failure may undergo extracorporeal dialysis, which removes small molecules such as drugs. Glomerular Filtration • Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus. • Free drug (not bound to albumin) flows through the capillary slits into Bowman’s space as part of the glomerular filtrate. • The glomerular filtration rate (125 mL/min) is normally about 20 percent of the renal plasma flow (600 mL/min) Proximal Tubular Secretion • Drugs that were not transferred into the glomerular filtrate leave the glomeruli through efferent arterioles, which divide to form a capillary plexus surrounding the nephric lumen in the proximal tubule. • Secretion primarily occurs in the proximal tubules by two energy-requiring active transport (carrier requiring) systems: one for anions (for example, deprotonated forms of weak acids) and one for cations (for example, protonated forms of weak bases). • Each of these transport systems shows low specificity and can transport many compounds. Thus, competition between drugs for these carriers can occur within each transport • [Note: Premature infants and neonates have an incompletely developed tubular secretory mechanism and, thus, may retain certain drugs in the glomerular filtrate.] Distal Tubular Reabsorption • As a drug moves toward the distal convoluted tubule, its concentration increases and exceeds that of the perivascular space. • The drug, if uncharged, may diffuse out of the nephric lumen, back into the systemic circulation. • Manipulating the pH of the urine to increase the ionized form of the drug in the lumen may be done to minimize the amount of back-diffusion and, hence, increase the clearance of an undesirable drug. • As a general rule, weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine. • This process is called “ion trapping.” • For example, a patient presenting with phenobarbital (weak acid) overdose can be given bicarbonate , which alkalinizes the urine and keeps the drug ionized, thereby decreasing its reabsorption. • If overdose is with a weak base, such as amphetamine, acidification of the urine with NH4Cl leads to protonation of the drug (that is, it becomes charged) and an enhancement of its renal excretion. Rule of Drug Metabolism Most drugs are lipid soluble and, without chemical modification, would diffuse out of the kidney’s tubular lumen when the drug concentration in the filtrate becomes greater than that in the perivascular space To minimize this reabsorption, drugs are modified primarily in the liver into more polar substances using two types of reactions: o Phase I reactions, which involve either the addition of hydroxyl groups or the removal of blocking groups from hydroxyl, carboxyl, or amino groups, and o Phase II reactions that use conjugation with sulfate, glycine, or glucuronic acid to increase drug polarity. o The conjugates are ionized, and the charged molecules cannot back-diffuse out of the kidney lumen (Figure 1.21).

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CLEARANCE BY OTHER ROUTES

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Other routes of drug clearance include via: o intestines, o the bile,

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o the lungs, and o milk in nursing mothers, among others The feces are primarily involved in elimination of unabsorbed orally ingested drugs or drugs that are secreted directly into the intestines or in bile. While in the intestinal tract, most compounds are not reabsorbed and eliminated in the feces. The lungs are primarily involved in the elimination of anesthetic gases (for example, halothane and isoflurane). Elimination of drugs in breast milk is clinically relevant as a potential source of undesirable side effects to the infant. A suckling baby will be exposed, to some extent, to medications and/or its metabolites being taken by the mother. Excretion of most drugs into sweat, saliva, tears, hair, and skin occurs only to a small extent. However, deposition of drugs in hair and skin has been used as a forensic tool in many criminal cases. Total body clearance, the culmination of all clearance methods, and drug half-life are important measures of drug clearance calculated to prevent drug toxicity

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A. Total Body Clearance

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The total body (systemic) clearance, CLtotal or CLt, is the sum of the clearances from the various drug-metabolizing and drug-eliminating organs. The kidney is often the major organ of excretion; however, the liver also contributes to drug loss through metabolism and/or excretion into the bile. A patient in renal failure may sometimes benefit from a drug that is excreted by this pathway, into the intestine and feces, rather than through the kidney. Some drugs may also be reabsorbed through the enterohepatic circulation, thus prolonging their half-lives. Total clearance can be calculated by using the following equation: CLtotal = CLhepatic + CLrenal + CLpulmonary + CLother where CLhepatic + CLrenal are typically the most important.

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B. Clinical Situation resulting in changes in drug half-life • • •

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When a patient has an abnormality that alters the half-life of a drug, adjustment in dosage is required. It is important to be able to predict in which patients a drug is likely to have a change in halflife. The halflife of a drug is increased by o diminished renal plasma flow or hepatic blood flow, for example, in cardiogenic shock, heart failure, or hemorrhage; o decreased ability to extract drug from plasma, for example, as seen in renal disease; and o decreased metabolism, for example, when another drug inhibits its biotransformation or in hepatic insuffi ciency, as with cirrhosis. half-life of a drug may decrease by o 1) increased hepatic blood flow, o 2) decreased protein binding, and o 3) increased metabolism.

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DRUGS AFFECTING CNS

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Bipolar Disorder

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Mental illness marked by extreme shifts in mood ranging from a manic to a depressive state. Bipolar disease or manic depression. A person with mania will feel excited, impulsive, euphoric, and full of energy.

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Treat Bipolar Disorder

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Treat Bipolar Disorder Medication is the cornerstone on bipolar disorder treatment.

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Taking a mood stabilizing medication can help minimize the highs and lows of bipolar disorder and keep symptoms under control.

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Mood Stabilizer

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A mood stabilizer is a psychiatric medication used to treat mood disorders characterized by intense and sustained mood shifts, typically bipolar disorder. Suppress swings between mania and depression. People with bipolar disorder usually try mood stabilizers first.

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Lithium

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Very effective mood stabilizer. It was the first mood stabilizer approved by the FDA in the 1970's; for treating both manic and depressive episodes.

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Anticonvu lsant medicatio ns

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Originally developed to treat seizures, but they were found to help control moods as well. One anticonvulsant commonly used as a mood stabilizer is valproic acid, also called divalproex sodium. For some people, it may work better than lithium. Other anticonvulsants used as mood stabilizers are carbamazepine, lamotrigine and oxcarbazepine.

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Atypical Antipsychotics

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Atypical antipsychotic medications are sometimes used to treat symptoms of bipolar disorder. Often, antipsychotics are used along with other medications. 

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Olan zapi ne Aripi praz ole Zipra sido ne Cloz apin e Lura sido ne Risp erido ne

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Helps people with severe or psychotic depression, Often is accompanied by a break with reality, hallucinations, or delusions Can be taken as a pill or as a shot

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Often used for people who do not respond to lithium or anticonvulsants.

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Antidepressants

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Antidepressants are sometimes used to treat symptoms of depression in bipolar disorder. People with bipolar disorder should not take an antidepressant on its own. Doing so can cause the person to rapidly switch from depression to mania, which can be dangerous

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Antidepressa nts Fluoxetine

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Paroxetine

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Sertraline

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To prevent this problem, doctors give patients a mood stabilizer or an antipsychotic along with an antidepressant. Research on whether antidepressants help people with bipolar depression is mixed. An NIMH-funded study found that antidepressants were no more effective than a placebo to help treat depression in people with bipolar disorder. Side Effects

Lithium

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Loss of coordination Excessive thirst Frequent urination Blackouts Seizures Slurred speech Fast, slow, irregular, or pounding heartbeat Hallucinations (seeing things or hearing voices that do not exist) Changes in vision Itching, rash Swelling of the eyes, face, lips, tongue, throat, hands, feet, ankles, or lower legs.

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If a person with bipolar disorder is being treated with lithium, he or she should visit the doctor regularly to check the levels of lithium in the blood, and make sure the kidneys and the thyroid are working normally.

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Valproic acid/divalproex sodium

Side effects of Antidepressants

Changes in weight Nausea Stomach pain Vomiting Anorexia Loss of appetite.

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Lamotrigine

Rare but serious skin rash that needs to be treated in a hospital.

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May cause damage to the liver or pancreas Valproic acid may affect young girls and women in unique ways. Sometimes, valproic acid may increase testosterone (a male hormone) levels in teenage girls and lead to a condition called polycystic ovarian syndrome (PCOS) . PCOS is a disease that can affect fertility and make the menstrual cycle become irregular, but symptoms tend to go away after valproic acid is stopped. It also may cause birth defects in women who are pregnant. In some cases, this rash can cause permanent disability or be life-threatening.

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DRUGS for SEIZURE DISORDERS Carbmazepine (Carbatrol or Tegretol) Diazepam (Valium) Lorazepam (Ativan) Tranquilizers/ Clonazepam (Klonopin)

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Eslicarbazepin e (Aptiom)

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Ethosuximide (Zarontin) Lacosamide (VIMPAT)

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Lamotrigine (Lamictal)

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First choice for partial, generalized tonic-clonic and mixed seizures Effective in short-term treatment of all seizures; used often in the emergency room to stop a seizure, particularly status epilepticus Tolerance develops in most within a few weeks, so the same dose has less effect over time. Valium can also be given as rectal suppository. This drug is a once-a-day medication used alone or in combination with other anti-seizure drugs to treat partial-onset seizures.

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Used to treat absence seizures

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nausea, vomiting, decreased appetite, and weight loss.

This drug is approved to treat partial-onset seizures in adults with epilepsy. VIMPAT can be used alone or with other drugs. The drug comes as tablets, an oral solution, or injection. Treats partial, some generalized seizures and mixed seizures.

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dizziness, headache, and nausea.

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(RARE) dizziness, insomnia, or rash.

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Common adverse effects include fatigue, vision changes, nausea,dizziness, rash. Tiredness, unsteady walking, nausea, depression and loss of appetite. In children, they can cause drooling and hyperactivity

dizziness, nausea, headache, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor.

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Felbamate (Felbatol)

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Levetiracetam (Keppra)

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Oxcarbazepine (Oxtellar XR, Trileptal )

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Perampanel (Fycompa)

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Phenobarbitol

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Phenytoin (Dilantin)

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Tiagabine (Gabitril)

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Pregabalin ( Lyrica) 

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Topiramate (Topamax) 

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Treats partial seizures alone and some partial and generalized seizures in LennoxGastaut Syndrome; is used rarely and only when no other medications have been effective. Therefore, the use of the drug is limited and patients taking it must have blood cell counts and liver tests regularly during therapy. It is combined with other epilepsy drugs to treat partial seizures, primary generalized seizures and myoclonic (shock-like jerks of muscle) seizures. Used to treat partial seizures, it is a once-daily medicine used alone or with other medications to control seizures. The drug is approved to treat partial onset seizures and primary generalized tonic-clonic seizures in those age 12 and older. Oldest epilepsy medicine still in use. It is used to treat most forms of seizures and is known for its effectiveness and low cost. Controls partial seizures and generalized tonicclonic seizures; also can be given by vein (intravenously) in the hospital to rapidly control active seizures, although if the drug is being delivered by IV, fosphenytoin (Cerebyx) is usually used. Used with other epilepsy drugs to treat partial seizures with or without generalized seizures

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Used with other epilepsy drugs to treat partial seizures, but is used more often to treat neuropathic pain. Used with other drugs to treat partial or generalized tonic-clonic seizures. It is also used with absence seizures.

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decreased appetite, weight loss, inability tosleep, headache, and depression. Although rare, the drug may cause bone marrow or liver failure.

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Side effects include tiredness, weakness, and behavioral changes.

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Common side effects include dizziness, sleepiness, headache, vomiting, double vision , and balance problems.

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The label carries a warning of potential serious events including irritability, aggression, anger, anxiety, paranoia, euphoric mood, agitation, and changes in mental status. Side effects can be sleepiness or changes in behavior.

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dizziness, fatigue, slurred speech, acne, rash, gum thickening, and increased hair (hirsutism). Over the long term, the drug can cause bone thinning.

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dizziness, fatigue, weakness, irritability, anxiety, and confusion.

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Side effects include dizziness, sleepiness (somnolence), dry mouth, peripheral edema, blurred vision, weight gain, and difficulty with concentration/ attention sleepiness, dizziness, speech problems, nervousness, memory problems, visions problems, weight loss.

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Anesthesia

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A way to control pain during a surgery or procedure by using medicine called anesthetics. It can help control your breathing, blood pressure, blood flow, and heart rate and rhythm. Anesthesia may be used to: o Relax you. o Block pain. o Make you sleepy or forgetful. o Make you unconscious for your surgery. Other medicines may be used along with anesthesia, such as ones to help you relax or to reverse the effects of anesthesia

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Types of Anesthesia

1. Local Anesthesia • Numbs a small part of the body for minor procedures. • For example, you may get a shot of medicine directly into the surgical area to block pain. • You may stay awake during the procedure. 2. Regional Anesthesia • Blocks pain to a larger part of your body. You may also get medicine to help you relax or sleep. Types of regional anesthesia include: • Peripheral nerve blocks. • This is a shot of anesthetic to block pain around a specific nerve or group of nerves. • Blocks are often used for procedures on the hands, arms, feet, legs, or face. • Epidural and spinal anesthesia. • This is a shot of anesthetic near the spinal cord and the nerves that connect to it. • It blocks pain from an entire region of the body, such as the belly, hips, or legs. 3. General Anesthesia • affects your brain and the rest of your body. • You may get some anesthetics through a vein (intravenously, or IV), and you may breathe in some anesthetics. • With general anesthesia, you're unconscious and you don't feel pain during the surgery. 

What determines the type of Anesthesia used?

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Past and Current Health o affects your brain and the rest of your body. o You may get some anesthetics through a vein (intravenously, or IV), and you may breathe in some anesthetics. o With general anesthesia, you're unconscious and you don't feel pain during the surgery. Type of Surgery o For example, you may need general anesthesia to ensure your comfort and safety during certain types of surgery. Results of Tests o such as blood tests or an electrocardiogram(EKG, ECG).

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What are the Risks and Complications of Anesthesia?

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Major side effects and other problems of anesthesia aren't common, especially in people who are in good health. But all anesthesia has some risk. For example: o After general anesthesia heart problems, pneumonia, sore throat, or vomiting can occur. With high doses of local anesthesia o the anesthetic can go into the rest of the body and affect your brain or heart. After spinal anesthesia - some people get headaches

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How can you prepare for anesthesia?

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Your doctor or nurse will let you know what to do the night before and the day of the procedure. Know when to stop eating and drinking. o If you take any medicines regularly, ask your doctor or nurse about changes to your medicine routine for the day before or the day of your surgery. Try to stay calm. o Many people are nervous before they have anesthesia and surgery.

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Mental relaxation methods, such as guided imagery or meditation, can help you relax. And some medicines can help you relax. Plan ahead for going home. o Ask a friend or a family member to drive you home. Don't plan to drive yourself. o

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Ketalar (Ketamine)

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Diprivan (propofol)

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Pentothal

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Inapsine

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Psychological effects ranging from pleasant, dream-like states to delirium have occurred as Ketalar wears off. Be sure to have a responsible adult to monitor and assist you for up to 24 hours after you receive Ketalar. Slows the activity of your brain and nervous system. Diprivan is used to help you relax before and during general anesthesia for surgery or other medical procedures. Propofol is also used in critically ill patients who require a breathing tube connected to a ventilator (a machine that moves air in and out of the lungs when a person cannot breathe on their own). Causing drowsiness or sleep before surgery or certain medical procedures. It is also used to stop seizures. It may also be used for other conditions as determined by your doctor. Pentothal is a barbiturate. It works by depressing the central nervous system, causing mild sedation or sleep, depending on the dose. Reducing nausea and vomiting during surgeries and diagnostic procedures. Inapsine is a tranquilizer. It is unknown exactly how Inapsine works. 

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ANTIHYPERTENSIVE DRUGS

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Hypertension

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Hypertension is defined as either a sustained systolic blood pressure. Increased peripheral vascular arteriolar smooth muscle tone à o increased arteriolar resistance o reduced capacitance of the venous system. Chronic hypertension (either systolic or diastolic) can to: o cerebrovascular accidents (strokes) o congestive heart failure o myocardial infarction o renal damage. Hypertension is classified into four categories for the purpose of treatment management.

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Etiology

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Secondary to other disease processes. More than 90 percent of patients have essential hypertension o disorder of unknown origin affecting blood pressure– regulating mechanisms o incidence of essential hypertension is four-fold more frequent among blacks than among whites o more often among middle-aged males than among middleaged females, and its prevalence increases with age and obesity. Pre-disposing factors: o Family history o Stressful lifestyle o High dietary intake of sodium o Smoking

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Mechanisms for Controlling Blood Pressure

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Arterial blood pressure is regulated within a narrow range to provide adequate perfusion of the tissues without causing damage to the vascular system, particularly the arterial intima (endothelium). Arterial blood pressure is directly proportional to cardiac output and peripheral vascular resistance (Figure 19.3).

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Cardiac output and peripheral resistance, in turn, are controlled mainly by two overlapping control mechanisms: the barorefl exes and the renin-angiotensin-aldosterone system (Figure 19.4). Most anti hypertensive drugs lower blood pressure by reducing cardiac output and/or decreasing peripheral resistance.

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A. Baroreceptors and The Sympathetic Nervous System

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Baroreflexes act by changing the activity of the sympathetic nervous system. Responsible for the rapid, moment-tomoment regulation of blood pressure. A fall in blood pressure à send fewer impulses to cardiovascular centers in the spinal cord à reflex response of increased sympathetic and decreased parasympathetic output à vasoconstriction and increased cardiac output. The baroreflex is the fastest mechanism to regulate acute blood pressure changes via controlling heart rate, contractility, and peripheral resistance.

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B. Renin-angiotensin-aldosterone system

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This peptidase converts angiotensinogen to angiotensin I, which is converted, in turn to angiotensin II, in the presence of angiotensin-converting enzyme (ACE). Angiotensin II is a potent circulating vasoconstrictor, constricting both arterioles and veins, causing an increase in blood pressure. Angiotensin II exerts a preferential vasoconstrictor action on the eff erent arterioles of the renal glomerulus, increasing glomerular filtration. Furthermore, angiotensin II stimulates aldosterone secretion, leading to increased renal sodium reabsorption and increased blood volume, which contribute to a further increase in blood pressure. These eff ects of angiotensin II are mediated by stimulation of angiotensin II–AT1 receptors.

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Treatment STRATEGIES

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If blood pressure is inadequately controlled, a second drug is added o β-blocker may be added if the initial drug was a diuretic and vice versa. o Vasodilator can be added as a third drug for those patients who still fail to achieve goal blood pressure. o When angiotensin II–converting enzyme inhibitors or angiotensin II–AT1 receptor blockers are used to initiate therapy, a diuretic is the most common second drug added.

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A. Individualized Care

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Certain subsets of the hypertensive population respond better to one class of drug than they do to another Furthermore, hypertension may coexist with other diseases that can be aggravated by some of the antihypertensive drugs. In such cases, it is important to match antihypertensive drugs to the particular patient.

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B. Patient compliance in antihypertensive therapy

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Lack of patient compliance is the most common reason for failure of antihypertensive therapy. The hypertensive patient is usually asymptomatic and is diagnosed by routine screening before the occurrence of overt end-organ damage. Thus, therapy is generally directed at preventing future disease sequelae rather than relieving the patient’s current discomfort. The adverse effects associated with the hypertensive therapy may influence the patient more than the future benefits. For example, β-blockers can decrease libido and induce erectile dysfunction in males, particularly middleaged and elderly men. This druginduced sexual dysfunction may prompt the patient to discontinue therapy. Thus, it is important to enhance compliance by carefully selecting a drug regimen that both reduces adverse effects and minimizes the number of doses required daily. Combining two or three drug classes in a single pill, at a fixed-dose combination, has been shown to improve patient compliance and the number of patients achieving goal blood pressure. •

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Diuretics

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Diuretics can be used as first-line drug therapy for hypertension. Low-dose diuretic therapy is safe, inexpensive, and effective: o stroke o myocardial infarction o congestive heart failure Recent data suggest that diuretics are superior to β-blockers for treating hypertension in older adults.

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ADRENOCEPTOR–BLOCKERS

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The β-blockers reduce blood pressure primarily by decreasing cardiac output They may also decrease sympathetic outflow from the central nervous system (CNS) and inhibit the release of renin. The prototype β-blocker is propranolol, which acts at both β1 and β2 receptors. Selective blockers of β1 receptors, such as metoprolol and atenolol, are among the most commonly prescribed β-blockers. Nebivolol is a selective blocker of β1 receptors, which also increases the production of nitric oxide leading to vasodilation. The selective β-blockers may be administered cautiously to hypertensive patients who also have asthma. The nonselective β-blockers, such as propranolol and nadolol, are contraindicated due to their blockade of β2-mediated bronchodilation. The β-blockers should be used cautiously in the treatment of patients with acute heart failure or peripheral vascular disease. Therapeutic Use

1. Subsets of the hypertensive population • Conditions that discourage the use of β-blockers: • severe chronic obstructive lung disease • chronic congestive heart failure • severe symptomatic occlusive peripheral vascular disease 2. Hypertensive patients with concomitant diseases • The β-blockers are useful in treating conditions that may coexist with hypertension: • supraventricular tachyarrhythmia • previous myocardial infarction • angina pectoris • chronic heart failure 

Pharmacokinetics

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The β-blockers are orally active. Propranolol undergoes extensive and highly variable first-pass metabolism. The β-blockers may take several weeks to develop their full effects.

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Adverse Effects

1. Common Effects • The β-blockers may cause bradycardia and CNS side effects such as fatigue, lethargy, insomnia, and hallucinations, and these drugs can also cause hypotension • The β-blockers may decrease libido and cause impotence. 2. Alterations in Serum Lipid Patterns • The β-blockers may disturb lipid metabolism, decreasing high-density lipoprotein cholesterol and increasing plasma triglycerides. 3. Drug Withdrawal • Abrupt withdrawal may induce angina, myocardial infarction, and even sudden death in patients with ischemic heart disease. • Therefore, the dose of these drugs must be tapered over 2 to 3 weeks in patients with hypertension and ischemic heart disease. 

ACE INHIBITORS

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Enalapril and Lisinopril Recommended when the preferred first-line agents (diuretics or β-blockers) are contraindicated or ineffective.

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Actions

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The ACE inhibitors lower blood pressure by reducing peripheral vascular resistance without reflexively increasing cardiac output, rate, or contractility. These drugs block the ACE that cleaves angiotensin I to form the potent vasoconstrictor angiotensin II. The converting enzyme is also responsible for the breakdown of bradykinin, which increases the production of nitric oxide and of prostacyclin by the blood vessels. Both nitric oxide and prostacyclin are potent vasodilators. ACE inhibitors decrease angiotensin II and increase bradykinin levels. Vasodilation of both arterioles and veins occurs as a result of the combined effects of lower vasoconstriction caused by diminished levels of angiotensin II and the potent vasodilating effect of increased bradykinin. By reducing circulating angiotensin II levels, ACE inhibitors also decrease the secretion of aldosterone, resulting in decreased sodium and water retention. ACE inhibitors reduce both cardiac preload and afterload, thereby decreasing cardiac work.

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Therapeutic uses

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Along with the ARBs, ACE inhibitors slow the progression of diabetic nephropathy and decrease albuminuria. Beneficial effects on renal function may result from decreasing intraglomerular pressures, due to efferent arteriolar vasodilation. ACE inhibitors are a standard in the care of a patient following a myocardial infarction and first-line agents in the treatment of patients with systolic dysfunction. Therapy is started 24 hours after the end of the infarction. Chronic treatment with ACE inhibitors achieves sustained blood pressure reduction, regression of left ventricular hypertrophy, and prevention of ventricular remodeling after a myocardial infarction. ACE inhibitors are first-line drugs for treating heart failure, to treat hypertensive patients with chronic renal disease, and for patients with increased risk for coronary artery disease.

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Adverse Effects

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The dry cough, which occurs in about 10 percent of patients, is thought to be due to increased levels of bradykinin in the pulmonary tree. It occurs more frequently in women and nonsmokers and with longeracting ACE inhibitors. It resolves a few days after therapy discontinuation. Potassium levels must be monitored, and potassium supplements, high-potassium diets, and use of potassium-sparing diuretics are contraindicated. Serum creatinine levels should also be monitored, particularly in patients with underlying renal disease. Angioedema is a rare but potentially life-threatening reaction and may also be due to increased levels of bradykinin. Reversible renal failure can occur in patients with bilateral renal artery stenosis who take ACE inhibitors. ACE inhibitors can induce fetal malformations and should not be used by women who are pregnant.

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ANGIOTENSIN-RECEPTOR BLOCKERS

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The ARBs are alternatives to the ACE inhibitors. These drugs block the AT1 receptors, decreasing the activation of AT1 receptors by angiotensin II. Losartan is the prototypic ARB, and, currently, there are six additional ARBs. Their pharmacologic effects are similar to those of ACE inhibitors in that they produce arteriolar and venous dilation and block aldosterone secretion, thus lowering blood pressure and decreasing salt and water retention. ARBs do not increase bradykinin levels. ARBs decrease the nephrotoxicity of diabetes, making them an attractive therapy in hypertensive diabetics. Their adverse effects are similar to those of ACE inhibitors, although the risks of cough and angioedema are significantly decreased. ARBs are also fetotoxic and should not be used by women who are pregnant.

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RENIN INHIBITORS

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A selective renin inhibitor, aliskiren is available for the treatment of hypertension. Aliskiren directly inhibits renin and, thus, acts earlier in the renin-angiotensin-aldosterone system than do ACE inhibitors or ARBs. It lowers blood pressure about as effectively as ARBs, ACE inhibitors, and thiazides. It can also be combined other antihypertensives, such as diuretics, ACE inhibitors, ARBs, and calciumchannel blockers. Aliskiren can cause diarrhea, especially at higher doses. Aliskiren can also cause cough and angioedema but probably less often than ACE inhibitors. As with ACE inhibitors and ARBs, aliskiren is contraindicated during pregnancy. Aliskiren is available in a fixed-dose combination with valsartan as well as with hydrochlorothiazide. Hyperkalemia is significantly more common in patients who received both valsartan and aliskiren. Aliskiren is metabolized by CYP 3A4 and is, thus, subject to drug interactions.

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CALCIUM-CHANNEL BLOCKERS

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Recommended when the preferred first-line agents are contraindicated or ineffective. They are effective in treating hypertension in patients with angina or diabetes. High doses of short-acting calcium-channel blockers should be avoided because of increased risk of myocardial infarction due to excessive vasodilation and marked reflex cardiac stimulation.

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Classes 1. Diphenylalkylamines  Verapamil is the only member of this class that is currently approved in the United States.  Verapamil is the least selective of any calcium-channel blocker and has significant effects on both cardiac and vascular smooth muscle cells.  It is also used to treat angina, supraventricular tachyarrhythmias, and to prevent migraine and cluster headaches.  First-degree atrioventricular block and constipation are dose-dependent common side effects of verapamil. 2. Benzothiazepines  Diltiazem is the only member of this class that is currently approved in the United States.  Like verapamil, diltiazem affects both cardiac and vascular smooth muscle cells, but it has a less pronounced negative inotropic effect on the heart compared to that of verapamil.  Diltiazem has a favorable side effect profile 3. Dihydropyridines  This rapidly expanding class of calcium-channel blockers includes:  first-generation nifedipine  five second-generation agents for treating cardiovascular disease:  (amlodipine, felodipine, isradipine, nicardipine, and nisoldipine) These second-generation calcium-channel blockers differ in pharmacokinetics, approved uses, and drug interactions. All dihydropyridines have a much greater affinity for vascular calcium channels than for calcium channels in the heart. The dihydropyridines have the advantage in that they show little interaction with other cardiovascular drugs, such as digoxin or warfarin, which are often used concomitantly with calcium-channel blockers.

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Actions

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The intracellular concentration of calcium plays an important role in maintaining the tone of smooth muscle and in the contraction of the myocardium. Calcium enters muscle cells through special voltage-sensitive calcium channels. This triggers release of calcium from the sarcoplasmic reticulum and mitochondria, which further increases the cytosolic level of calcium. Calcium-channel antagonists block the inward movement of calcium by binding to L-type calcium channels in the heart and in smooth muscle of the coronary and peripheral arteriolar vasculature. This causes vascular smooth muscle to relax, dilating mainly arterioles. Calcium-channel blockers do not dilate veins.

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Therapeutic Uses

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Calcium-channel blockers have an intrinsic natriuretic effect and, therefore, do not usually require the addition of a diuretic. These agents are useful in the treatment of hypertensive patients who also have asthma, diabetes, angina, and/or peripheral vascular disease.

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Pharmacokinetics

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Most of these agents have short half-lives (3–8 hours) following an oral dose. Sustained-release preparations are available and permit once-daily dosing. Amlodipine has a very long half-life and does not require a sustained-release formulation. E.

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Adverse Effects

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Constipation occurs in approximately 10 percent of patients treated with verapamil. Dizziness, headache, and a feeling of fatigue caused by a decrease in blood pressure are more frequent with dihydropyridines Verapamil should be avoided in patients with congestive heart failure or with atrioventricular block due to its negative inotropic (force of cardiac muscle contraction) and dromotropic (velocity of conduction) effects. Nifedipine has caused gingival enlargement.