IM 6.3.7 Fundamentals of Pharmacology 1 (2024) PDF

6.3.7 Fundamentals of Pharmacology Ayman El-Sahar, PhD Pharmacology & Toxicology [email protected] 2024-2025 By the end of this lecture, the student should be able to: Identify historical approaches to the management of diseases through drug therapy. Define the scope o...

6.3.7 Fundamentals of Pharmacology Ayman El-Sahar, PhD Pharmacology & Toxicology [email protected] 2024-2025 By the end of this lecture, the student should be able to: Identify historical approaches to the management of diseases through drug therapy. Define the scope of pharmacology as the science dealing with drugs. Recall different sources for drugs Describe different molecular targets for drug action. Understand the concept of drug safety and health regulatory bodies 2024-2025 History Hippocrates: Father of Medicine First collection of medical texts (The Hippocratic Collection). Advice on how to observe & examine patients is still followed. Early form of patient history. Promoted exercise and a healthy diet. Understood that herbs and plants can be good medicines. e.g.: Willow bark (salicylates) extract relieves pain. 2024-2025 History Roman amputation saw Amputations & Anesthetics Patients with “gangrene” needing limb amputation often suffered a lot and some even died during the operation. Surgeons tried to anesthetize their patients with herbal drugs as Henbane OR mandrake to make Henbane Mandrake the operations easier. root CELSUS recipe: ✓ Boiled “ripe wild poppy heads with raisin wine” Ripe poppy head ✓ The cooled juice was used to make pills that would make the patient sleep. 2024-2025 Pharmacology Derived from the Greek word: “Pharmakon” meaning “drug”. Drugs were used to treat diseases in both humans and animals. The curative power of drugs was anticipated based on traditional knowledge. No mechanisms of action were assigned. No evidence-based medicine. 2024-2025 Pharmacology Pharmacology: Is the study of the interaction of drugs with living systems resulting in modification (= stimulation or inhibition) the function of these systems. A drug DOES NOT create a new condition, rather it modifies an already existing one. 2024-2025 Pharmacology Pharmacology is the study of how the drug works in the body “mechanism of action”. Pharmacology encounters effects on: ✓Single proteins ✓Cells ✓Tissues ✓Organs Example of drugs: Caffeine – Alcohol – Nicotine – Cannabis - Heroin 2024-2025 Drug Sources (3) A. Plants & natural products Atropine Digoxin Opiates Quinine (Atropa belladonna) (Digitalis purpurea) (Papaver somniferum) (Cinchona Bark) Cannabis Cocaine (Cannabis sativa) (Erythroxylum coca) 2024-2025  Drug Sources B. Microorganisms Penicillin Neomycin Vancomycin (Penicillium notatum) (Streptomyces fradiae) (Amycolatopsis orientalis) Botulinum toxin Cephalosporins (Clostridium botulinum) (Cephalosporium acremonium) 2024-2025 Drug Sources C. Animals 1. Insulin: Porcine or bovine pancreas – Islets of Langerhans – b-cells 2. Exenatide: Extracted from saliva of Gila monster It increases insulin release → used in ttt of type-2 diabetes 3. Allantoin: Extracted from maggots (fly larvae) Helps in wound debridment (necrotic tissue) 100 maggots remove 10-15g dead tissue/day 2024-2025 Drug Sources C. Animals 4. Human growth factor: Isolated from pituitary gland 5. Hirudin: Isolated from Leech Acts as an anticoagulant. 6. Teprotide: Extracted from snake venom Acts as an angiotensin-converting enzyme (ACE) inhibitor (famous antihypertensive drug class) 2024-2025 Important Factors in Pharmacology 1. Mechanism of action 2. Dose (ineffective – clinically effective – toxic) 3. Selectivity (drugs with only one target are rare) 4. Side effects (e.g.: Hypnotics as benzodiazepines→ anxiolytic, hypnotic, muscle relaxant, & amnesic) 5. Risk/benefit ratio (quality of life – age – seriousness of illness) 2024-2025 1-Mechanism of action of drugs in Pharmacology Physical mechanism of action as osmosis or adsorption [Minor]. e.g. Osmotic laxatives Chemical mechanism of action such as neutralization [Minor].e.g. Antacids Biological or cellular protein targets Most drugs produce their effect through interacting with cellular macromolecules [Major]. 2024-2025  Biological Cellular (protein) Targets 1. Ion channels (Voltage-gated ion channels) 2. Enzymes 3. Carrier molecules 4. Receptors The four main targets for drug action: ion channels, enzymes, carrier molecules, and receptors. In each of these four cases, most drugs are effective because they bind to particular target proteins. 2024-2025  I- Ion Channels (Voltage-gated Ion Channels) e.g. Local anesthetics are drugs that act on (block) Na+ channel (Ion channels). Local anesthetics are also called Na+ channel blockers. 2024-2025  II- Enzymes e.g. Captopril (Angiotensin-converting enzyme inhibitor [ACEI]) inhibits ACE enzyme → Vasodilation → used in treating hypertension. e.g. Sildenafil → A phosphodiesterase inhibitor → Vasodilation → used for the treatment of erectile dysfunction. 2024-2025 II- Enzymes 2024-2025  III- Carrier molecules What are carrier molecules in the cell? A carrier molecule is typically involved in the transport of other biological compounds such as proteins, DNA or RNA, electrons, or protons including ions. e.g. Sodium-potassium pump (Na+/K+ pump) 2024-2025  III- Carrier molecules e.g. Digoxin (Cardiac glycosides) binds to and inhibits the sodium/potassium-ATPase pump of cardiac myocytes used in the treatment of congestive heart failure 2024-2025 IV- Receptors “Definition“ receptor is a specialized target macromolecule that binds a drug and mediates its pharmacological action. 2024-2025 IV- Receptors “Key-Lock model“ The drug “key” which is able to fit onto a receptor “lock“ is said to have an affinity for that receptor and if it can initiate a response ( open the lock) after fitting to it, it’s said to have an intrinsic activity or efficacy. 2024-2025 Classification of drugs acting on specific receptors: Drugs may be Agonists: fully activate a given receptor Partial agonists: partially activate a given receptor Antagonists: block a given receptor 2024-2025 Receptors Many membrane receptors are made of a ligand-binding domain (the site where endogenous neurotransmitters, hormones or drugs bind) and an effector domain (the site that mediates intracellular signaling inside the cell). 2024-2025 Classification of receptors according to the effector domain (4 main types) 1. Ligand-gated ion channels. 2. Enzyme-linked receptors. 3. G-protein coupled receptors. 4. Nuclear receptors. 2024-2025 1-Receptors: Ligand-gated Ion Channels Receptor: Nicotinic (N) Receptor Effector domain: Ion channel 2024-2025 2-Receptors: Enzyme-linked Receptors Receptor: Insulin Receptor Effector domain: Enzymes (Tyrosine Kinase). 2024-2025 3- Receptors: G-protein-coupled Receptors Receptor: a-adrenergic Receptor Receptor: b-adrenergic Receptor Effector domain: G-protein. 2024-2025 4-Receptors: Nuclear or DNA receptors Receptor: Glucocorticoid Receptor Receptor: Vitamin D Receptor Effector domain: DNA. 2024-2025 2024-2025 Milestones in Drug Therapy Date Event 1600 BC Egyptian medical papyrus 200 AD Galen theory of disease (blood – Phlegm – yellow bile – black bile) 1516 Van Hohenheim – active principles in natural products, Questioned Galen’s ideas. 1804 Sertürner – Isolated morphine – first pure drug 1909 Ehrlich – Organic synthesis of arsenical compounds – syphilis 1935 Domagk – Antibacterials, sulphonamides, first selective antimicrobials 1945 Fleming, Chain & Florey – introduction of penicillin – first antibiotic 1960s Black – Structure-function studies of drugs, b-blockers (propranolol), H2 antagonists (cimetidine) 2000s Biologics – Antibodies used to treat disease e.g.: rheumatoid arthritis Etanercept, Infliximab 2024-2025 Drug Safety Teratogenicity It refers to drug-induced fetal malformations In 1940s: Rubella infection caused fetal abnormality In 1960s: Thalidomide (hypnotic & anti-morning sickness) caused limb malformations. Now, it’s used as an anticancer under strict precautions. Drug regulatory bodies: Central Administration of Pharmaceutical Affairs (CAPA) … (EG) Egyptian Drug Authority (EDA) … [EG] Medicines & Healthcare Regulatory Agency (MHRA) … [UK] Committee for Safety of Medicines (CSM) …[UK] 2024-2025 Suggested Reference Lippincott Illustrated Reviews: Pharmacology 6th edition 2024-2025 QUESTIONS 2024-2025