1_PHAR0004_9_7_Introduction_Drug_TSS_2023.pdf

Pharmacology pharmakon – from “poison” to “DRUG” logia – “knowledge/study of” From describing what drugs do... to... Explaining how they work – the Mechanism of Drug Action Pharmacology PHAR0004/9/7 Introductory lecture How are drugs named? What are the targets of drug action? How...

Pharmacology pharmakon – from “poison” to “DRUG” logia – “knowledge/study of” From describing what drugs do... to... Explaining how they work – the Mechanism of Drug Action Pharmacology PHAR0004/9/7 Introductory lecture How are drugs named? What are the targets of drug action? How selective are drugs for their targets? How can the ratio of beneficial to unwanted effects be measured? Classification and names of drugs Please spend a few minutes writing down the names of any drugs that you can think of. These may be drugs used for diseases, medical conditions or operative procedures or alternatively those taken for non-medical purposes. Classification and names of drugs … … … … … … Classification and names of drugs Therapeutic use: Antihypertensive Antiepileptic Molecular mechanism of action: - blocker Monoamine oxidase inhibitor Ca2+ channel blocker Chemical structure: Benzodiazepine Catecholamine Names of drugs Approved name: Brand name / proprietary name: Caprin ( Sinclair) Aspirin Aspro (Roche) Disprin (Reckitt & Colman) Disprin Extra (aspirin + paracetamol) Paracetamol Calpol (GSK) (acetaminophen) Panadol (Sterling-Winthrop Tylenol (Johnson & Johnson) Solpadeine (paracetamol +codeine, SKB) Propranolol Inderal (AstraZeneca) Syprol (Rosemont) Targets of drug action Important concept of “SELECTIVE TOXICITY”. Drugs will often bind to sites in addition to their main site of action. Such binding may result in unwanted or toxic effects. Drug molecule Different binding sites Targets of drug action Important concept of “SELECTIVE TOXICITY”. Drugs will often bind to sites in addition to their main site of action. Such binding may result in unwanted or toxic effects. Ehrlich was one of first to realise the importance of a drug’s selectivity. - the concept of a “MAGIC BULLET” - the idea that a drug might act selectively where its action is wanted. Targets of drug action Important concept of “SELECTIVE TOXICITY”. Drugs will often bind to sites in addition to their main site of action. Such binding may result in unwanted or toxic effects. "In order to use chemotherapy successfully we must search for substances which have an affinity for the cells of the parasite and a power of killing them greater than the damage such substances cause to the organism itself, so that the destruction of the parasite will be possible without seriously hurting the organism. This means we must strike the parasites and the parasites only, if possible, and to do this we must learn to aim, learn to aim with chemical substances!" How can selective action be achieved? Aim to achieve a higher concentration of drug at the desired site of action. E.g. eye drops, bronchodilator aerosols, local anaesthetics – Pharmacokinetics – “Drug Motion” Design drug to have a higher affinity for desired site of action. E.g. selective MAO inhibitors, cardioselective  – blockers – Pharmacodynamics – “Drug Power” Drug targets Note: the target may be the patients own tissues (normal or diseased) or an invading organism (bacterium, malaria parasite etc.) The latter may be very effectively treated by vaccination (immune attack) and antibiotics. Drug targets 1 Drug action at a specific binding site e.g. Protein, DNA 2 Action not involving a specific binding site e.g. osmotic diuretic 1. Drug targets Specific macromolecular targets – may exhibit high affinity for drug and high specificity (due to stereochemistry of substrate cofactor binding: Hormone/neurotransmitter receptors – antagonists or agonists Enzymes – cholinesterases, monoamine oxidase Transporters – e.g. cardiac glycosides acting on Na+ /K+ pump. Ion channels – e.g. local anaesthetics at Na+ channels DNA – some anticancer agents 2. Drug targets Drugs without identifiable binding sites - generally act at higher concentrations: The general anaesthetic ether produces surgical anaesthesia only at concentrations above 20mM The action of these drugs is less affected by changes in chemical structure. A wide variety of molecules (including N2) produce general anaesthesia.  Benefit and risk The amount of risk acceptable is influenced by the severity of the medical condition. Significant side effects may be tolerated for life threatening conditions such as cancer. Ehrlich’s THERAPEUTIC INDEX: Maximum non-toxic dose = Minimum effective dose Difficulties with measurements due to individual variations or sensitivity to drug. Benefit and risk An improved measure uses the better defined doses producing effects in 50% of subjects: TD50 (Toxic dose) Therapeutic index = ED50 (Effective dose) Benefit and risk Benefit and risk In animal studies death may be used as a measure of toxicity, so: LD50 (Lethal dose) Therapeutic index = ED50 (Effective dose)  Pharmacokinetics and Pharmacodynamics Pharmacokinetics “Drug Motion” How does the drug concentration change as it moves through the compartments of the body, i.e. what does the body do the drug? Pharmacodynamics “Drug Power” Potency Drug Receptor Interaction Affinity Efficacy How does a drug exert its effect, i.e. what does the drug do to the body? Specifying Drug Activity RECEPTORS....drug targets