Pharmacology

Basic principles

Principles of pharmacology

Pharmacodynamics is the drug acting on the body. Pharmacokinetics is the body acting on the drug.

-1-

half life.

Inhalation

Patches (transdermal)

Sublingual

Rectal

Types

10% delivery

Administration and formulation

Dry powder Aerosols Nebulisers

Good absorption Patient doesnʼt need to swallow tablet Oil base which melts in rectum

Slow absorption Avoids first-pass effect

Oral

Getting into the body

Administration

-2-

Formulations

Preparations

Subcutaneous

Intravenous

Intramuscular

Topical

Solutions

Suspensions

Liquid

Tablets

Capsules

Tasteless

Less damage to stomach

Controlled-release

Vascular dermis

Simple for self-administration

Depot effect

For lipid-insoluble and non-polar drugs

Potential bleeding problems

Less accuracy required for injection

Unpredictable absorption patterns

Long-term release possible

Direct on site

Avoids systemic absorption

insulin

Absorption

Passive absorption

Fick’s law

Gastric emptying

Rate of diffusion depends on:

Empty stomach = quicker absorption. Fed stomach = slower absorption.

Concentration difference, Surface area, Permeability.

Polar groups Polar groups

Non-polar groups

More lipid soluble Less water soluble

Less lipid soluble More water soluble

Better absorption

Worse absorption

Ionisation Ionised

Neutral

More lipid soluble

Less lipid soluble

Better absorption

Worse absorption

How does this relate to weak acids?

More importantly, how does this relate to pregnant babies?

Membranes are just lipids.

Active absorption

Requires energy.

-3-

Brain

Muscle

Distribution patterns after IV injection

Blood

Distribution

Fat

Think perfusion of tissues.

Watch out for pH changes.

slightly lower

-4-

Easy.

Cytochrome P450 SUBSTRATES

2C9

3A4 Quinidine

Omeprazole

Furafylline

2D6 1A2

Disulfiram

Ethanol Isoniazid

P-glycoprotein

Orphenadrine

2E1 2B6

Caffeine Nifedipine Phenacetin Cyclosporine Mephenytoin Theophylline Erythromycin Taxol Terfenadine Debrisoquine Chlorzoxazone S-Warfarin Metoprolol Phenytoin Dextromethorphan Tolbutamide Ifosphamide

Coumarin

2A6 2C19 2C8

INHIBITORS

INDUCERS Rifampicin

Quercetin Tranylcypromine Ketoconazole 8MeOPsoralen Sulphaphenazole

Phenobarbitone

An example.

Effects

Many substrates/inhibitors/inducers are also of CYP3A4.

Decreased CNS penetration

Decreased absorption in gut

Reduced excretion through bile/urine

Reactions between terfenidine and ketoconazole

Removes AIs from cells

Metabolism

Reactions

Really really complex.

Massive problem for MDR cancers

Coded from ABCB1 gene

-5-

Phase 2

Phase 1

Exposes polar groups

Lignocaine

Aromatic hydroxylation

Amide hydrolysis

Glucuronyl-

Varying specificity

oxidation

Nitrogen-dealkylation

Cytochrome P450 enzymes

Glucuronide

Sulpho-

Methyl-

Acetyl-

Sulphate

Acetyl

Glutathione conjugation

Methyl

10% metabolised in phase 1 - toxic

Sulphate conjugation

Glucuronide conjugation

Attachment of endogenous molecule to drug or Phase I metabolite

Paracetamol

Transferases

Fever

Starvation

GENETIC

FACTORS

Drugs

Alcohol Intake

Herbals

Disease

Sex

Age

Cigarette Smoking

Cysteine and mercapturic acid conjugates

Depleted in overdose

plus a stack of genetics.

Cardiovascular Function Liver Function

Renal Function Gastrointestinal Function

Dietary Factors

Prescribing factors Factors affecting prescribing 1. Pharmacokinetic 2. Pharmacodynamic 3. Impact on the patient 4. Cost a. previous treatments?

5. Patient factors

a. Familiarity with drug

6. Doctor factors

Benoxaprofen

Prescribing

Bad times

You prescribe for a: Cure for symptoms, Relief from symptoms, Prevention of symptoms.

Post-marketing surveillance by yellow card system

Treated arthritis Small premarketing trial - 3000 people Type B side-effects

-6-

Sold over the counter

Badly labelled

Badly trialled

Malformities.

All of the COX, none of the GI bleed

2005 − 92% increased risk of thombotic events

Uncertain from trials.

Type A adverse effects are predictable. Type B aren’t. Can you titrate the dose?

Thalidomide

COX-2 inhibitors