Introduction to Pharmacology 2025 PDF

Introduction to Pharmacology Dr Linda King  Learning outcomes 1. Review the basic principles of pharmacology 2. Describe the pharmacodynamics, pharmacokinetics and pharmacogenomics of drugs 3. Briefly explain how drugs are discovered and developed 4. Review a class of...

Introduction to Pharmacology Dr Linda King  Learning outcomes 1. Review the basic principles of pharmacology 2. Describe the pharmacodynamics, pharmacokinetics and pharmacogenomics of drugs 3. Briefly explain how drugs are discovered and developed 4. Review a class of drugs (NSAIDs) with respect to discovery, development, uses, and potential toxicity  Session Outline What is pharmacology? Pharmacodynamics Pharmacokinetics Pharmacogenomics and personalised medicine Drug discovery Case study: NSAIDs  Definitions Drugs - chemicals that interact with molecules in living systems Exogenous – mimic original molecules Endogenous – replace original molecules Pharmacy - preparing, dispensing Pharmaceutical - relating to pharmacy/industry developing/synthesizing drugs – ‘Big pharma’ Pharmacology - study of interaction of drugs with living systems Underpinned by understanding of physiology and pathology, chemistry, genetics, cell biology…  Domains of pharmacology Pharmacotherapy: application of drugs in prevention, treatment or diagnosis of disease Pharmacodynamics: action of drug on body Drug-receptor, dose-response, mechanisms Pharmacokinetics: action of body on drug absorption, distribution, metabolism, excretion (ADME) Toxicology: study of harmful effects Pharmacogenomics: genes modify efficacy Aim of a good drug - to of drugs be safe and effective 5  The nature of drugs: Size Small molecules - molecular weight 1000 Da usually administered parenterally 6  The nature of drugs: Shape Drugs fits receptors about half of all drugs racemic mixtures of stereoisomers, mostly chiral enantiomers differ in ability to bind to and alter function of receptors (Michaelis-Menten kinetics), rates of elimination, toxicity, effect on target tissue Drug names: Brand vs generic  Session Outline What is pharmacology? Pharmacodynamics Pharmacokinetics Pharmacogenomics and personalised medicine Drug discovery Case study: NSAIDs  Pharmacodynamics Dose response curve Action of drug on the body Response to given concentration – therapeutic/toxic action dependent on amount of drug at site of action concentration in vicinity of receptors plateau at high concentrations  Properties of drug targets Most drug targets are proteins enzymes, hormone/neurotransmitter receptors, transport systems Proteins evolved to bind endogenous molecules drugs mimic/block their effects Orthosteric: drugs compete with endogenous ligand binding site Allosteric: drug binds other sites on target  Types of drug-receptor interactions Agonists: drugs activate receptors they bind to mimic endogenous regulators of receptor, elicit biological response  Types of drug-receptor interactions Antagonists: prevent effect of endogenous agonists on receptor usually competitive inhibitors (same binding site) – reversible, irreversible do not elicit biologic response effects of competitive pharmacologic antagonist overcome by adding more agonist  Factors governing drug action Affinity: measure of tightness of drug binding to receptor Intrinsic activity: measure of ability of binding to generate effect independent of each other Agonists have both affinity and intrinsic activity Antagonists only have affinity for receptor  Affinity of binding Binding of drug (D) to receptor (R) determined by: Hydrophobicity Hydrogen bonds Ionic bonds Van der Waals forces Covalent bonds  Receptor occupancy and affinity Fractional saturation (E/Emax) 100% occupancy [DR]/[RT] Kd [Drug] Strength of binding - Michaelis-Menten enzyme kinetics more receptor sites occupied as ligand concentration increases dissociation constant Kd - tendency to bind  Intrinsic activity (efficacy) Drugs once bound to receptor differ in ability to initiate change in receptor conformation and physiological response - intrinsic activity (e) Occupation Intrinsic activity (affinity) (efficacy) k +1 Drug (D)  R DR DR* response k -1 (Agonist) (Receptor) Affinity + efficacy→ drug’s potency Log transformation of MM curve Intrinsic activity – maximum 1 (100%) ED50 – dose for 50% effect = potency Highly potent drugs can also be highly toxic (e.g. cancer drugs) Tissue response Competitive antagonist Prazosin (alpha blocker) – competitive antagonist of Phenylephrine (PE) - shifts PE curve to the right i.e. more drug needed to overcome inhibition, but maximal effect still reached  Partial agonists Partial agonists activate receptors but unable to elicit maximal response Tissue response Clonidine has higher affinity but lower intrinsic activity than methoxamine (both alpha agonists) – affects magnitude of response 21  Session Outline What is pharmacology? Pharmacodynamics Pharmacokinetics Pharmacogenomics and personalised medicine Drug discovery Case study: NSAIDs  Pharmacokinetics: An effective drug A ‘good’ drug easily administered (e.g. orally) reach target at sufficient concentrations to be effective therapeutic benefits outweigh toxic effects fewer side effects the better ADMET criteria Absorption – from site of administration to blood stream Distribution – from blood stream to tissues Metabolism – transformation to facilitate elimination Excretion – to bring drugs/metabolites out of body Toxicity – unwanted, unpleasant (or dangerous) side effects, balanced against therapeutic effects See videos available in Resources and Activities page  Slow Absorption Orally (swallowed) If drug taken orally (tablet), consider liberation - disintegration (from solid tablets), dispersal, dissolution, survival in acidic conditions of GI Significant ‘first-pass’ effect Mucus Membranes – Oral Mucosa (e.g. sublingual) – Nasal Mucosa (e.g. insufflated) – Topical/Transdermal (through skin) – Rectally (suppository)  Faster Absorption Parenterally (injection) Intravenous (IV) Intramuscular (IM) Subcutaneous (SC) Intraperitoneal (IP) Inhaled (through lungs) General Principle: The faster the absorption, the quicker the onset, but the shorter the duration  Distribution From bloodstream to tissues – three ‘compartments’ Hydrophobic compounds – may bind to proteins e.g. Albumin Effective drug reaches target compartment in sufficient quantity - effective concentration reduced if distributed more widely Some targets hard to reach e.g. blood-brain barrier 27  Bioavailability of a drug Bioavailability - fraction of administered drug that appears in plasma Determined by administering drug, measuring concentration in plasma over time (AUC - area under the curve is how much drug has been available over time) Blood levels determine dosage  Xenobiotic Metabolism Body’s defense mechanism against foreign (xenobiotic) compounds alters drug effectiveness – (decreases drug’s conc.) if rapidly metabolised, drug must be administered more frequently/at higher doses pro-drugs – drugs need to be metabolised to be active (e.g. levodopa > dopamine for Parkinson’s disease) First-pass metabolism - alters drug before reaching full circulation (oral route) The liver: main site of xenobiotic metabolism oral topical IV IM inhalation Liver Kidney IV - intravenous Lung Intestine IM – intramuscular Skin Gonads  Xenobiotic metabolism: two phases preparing compounds for elimination Phase I transformations: Oxidation by CYP450 enzymes Increases water solubility of foreign compounds to aid excretion Add on functional groups (e.g. hydroxyl) to participate in subsequent metabolic steps – about 57 cytochrome P450 (CYP) genes – P450 – wavelength of absorption peak – more than 20 involved in drug metabolism Membrane-bound proteins – other CYPs involved in cholesterol Located primarily in smooth ER metabolism etc. (“microsomal” enzymes) Principal component of active site - haem moiety - central coordinated Fe atom makes redox reactions possible  Cytochrome P450 superfamily Gene family members different isoenzymes - families, subfamilies on basis of degree of amino acid similarity most significant in human drug metabolism - CYP1, CYP2, CYP3 divided into subfamilies - CYP2D, CYP3A, etc. isoenzymes identified with second number e.g.. CYP3A4 CYP3A4: the most important cytochrome P450 in drug metabolism CYP3A4 isoenzyme in liver, enterocytes (GI tract) Drug metabolism starts in enterocytes  Phase I reaction Hydroxylation - chief phase I reaction NADPH-P450 reductase DRUG-H + O2 + NADPH + H+ DRUG-OH + H2O + NADP+ Cytochrome P450 Lipophilic More drug hydrophilic drug Mono-oxygenation of one atom of oxygen into substrate; other oxygen atom reduced to water with reducing equivalents derived from NADPH  Factors affecting metabolism by CYP450 Disease states affecting drug metabolism – hepatic disease Age and sex – congestive heart failure - decreased blood flow Pathological status to liver Diet and nutrition Babies and older people need lower doses of drugs Hormonal – newborns have only partially developed systems to metabolise drugs Genetic differences – as people age, decreases in hepatic blood flow, enzyme activity, liver mass alter Drug-drug interactions metabolism of drugs The cytochrome P450 system is more affected by ageing than any other metabolic pathway  Genetic polymorphisms of CYPs Rate of drug metabolism affected by single nucleotide polymorphisms (SNPs) of CYP isoenzymes – type/amount of isoenzyme available – highly significant for pharmacotherapy – missing/reduced enzymatic activity results in extended retention time of drugs in body Two well-know genetic polymorphisms in drug oxidation – sparteine/debrisoquine (CYP2D6) polymorphism – mephenytoin oxidation (CYP2C19) polymorphism Two extremes of phenotypes in population – poor metabolisers - prone to adverse reactions to drugs with narrow therapeutic range (more toxic drugs) – extensive metabolisers - drug rapidly metabolised - reduced bioavailability; clinically significant interactions between drugs metabolised by same isoenzyme  Drug-drug interactions: altering CYP activity Increased drug toxicity, reduced pharmacological effect, adverse drug reactions – Inducers of CYP enzymes - accelerate metabolism, reduce bioavailability – Inhibitors of CYP enzymes - slow down metabolism, increased side-effects/toxicity – Opposite for pro-drugs (e.g. inducers increase their metabolism and activation – more toxicity?) Drug-drug interactions: clinical considerations Must prevent clinically significant interactions from occurring – avoid co-administration, anticipate potential problems – adjust patient's drug regimen early in course of therapy – optimal response with minimal adverse side-effects  Phase II transformations: Conjugation Addition of polar groups to xenobiotic compound Addition increases water solubility - labels for excretion Glutathione Glucuronic acid Sulfate group Major endogenous antioxidant - Drugs, pollutants, bilirubin, Breakdown of neurotransmitters; reduced (GSH) and oxidised (GSSG androgens, oestrogens, detoxification of phenolic drugs - disulfide) states; essential for mineralocorticoids, (e.g. beta blockers), alcohol immune system glucocorticoids, fatty acid Fundamental role in many metabolic derivatives, retinoids, bile acids and biochemical reactions Detoxifies many xenobiotics, carcinogens  Hepatotoxicity Chemical-driven liver damage Hepatocytes exposed to reactive metabolites of drugs formed by CYP450 enzymes >600 xenobiotics with hepatotoxic effects in man or lab animals Cell damage/death - metabolites interacting covalently or non-covalently with target molecules Covalent interactions - adduct formation between metabolite and cellular macromolecules (eg. paracetamol, alcohol) Non-covalent interactions - generation of cytotoxic ROS, modifications of sulfhydryl groups on key enzymes and proteins Activation - may lead to centrilobular (Zone III) toxicity/necrosis (eg. paracetamol)  CYP system and alcohol metabolism: potentially toxic products generated Alcohol dehydrogenase - reacts with other proteins in cell, generating harmful hybrid adducts Adducts impede function of original proteins may induce harmful immune responses HER - hydroxyethyl radical MDA - malondialdehyde HNE - 4–hydroxy–2–nonenal MAA - mixed MDA–acetaldehyde–protein adducts CYP activity - generates acetaldehyde, highly reactive oxygen free radicals Oxygen free radicals interact with lipids (lipid peroxidation) - form reactive molecules - react with proteins to form harmful adducts  Excretion: bile Compounds actively transported into bile then to intestine Drugs and metabolites further degraded by digestive enzymes excreted in faeces reabsorbed into bloodstream - enterohepatic cycling affects rate of excretion of some compounds  Excretion: kidneys Drugs passed through glomerular filter and excreted in urine compounds MW < 60 000 many metabolites and water are reabsorbed if drugs not reabsorbed, they will be excreted Excretion affects half life of a drug and dosage  Therapeutic Index Therapeutic Index (TI): comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity Dose Effective for 50% of subjects 𝐸 𝐷 50 𝑇𝐼= 𝑇 𝐷 50 Dose Toxic for 50% of subjects Used to measure the relative safety of a drug Therapeutic index: examples  Session Outline What is pharmacology? Pharmacodynamics Pharmacokinetics Pharmacogenomics and personalised medicine Drug discovery Case study: NSAIDs  Genetic variability Most SNPs neutral, but some associated with diseases Drug’s target molecule may vary with genetics 1% of single nucleotide polymorphisms impact directly on protein function Proteins involved in transport or metabolism may be genetically altered predictive/diagnostic to select optimum treatment determine‘safe-responder’ vs ‘non-responder/toxic response’ patients CYP450 genetic variation Drug’s metabolism can be significantly altered – changes in efficacy and safety/toxicity  Personalised medicine Therefore: genotype individuals before administering a particular drug – particularly relevant with respect to pharmacokinetics  Warfarin (coumarin) - a case study Used as an anticoagulant (blood thinner, e.g. to treat stroke) Blocks vitamin K epoxide reductase which reactivates vitamin K If vitamin K is not reactivated, blood clotting ability is reduced Warfarin side effect is bleeding and may include tissue damage Narrow therapeutic window Metabolism via CYP2C9 Patients with CYP2C9*2 and CYP2C9*3 allelic variants are poor metabolisers Require lower doses of warfarin (higher risk of bleeding)  Interested in Pharmacology? Choose Pharmacology and Translational Medicine as your optional module next year  Session Outline What is pharmacology? Pharmacodynamics Pharmacokinetics Pharmacogenomics and personalised medicine Drug discovery Case study: NSAIDs  Further reading Basic pharmacology textbook (several in the library) See Canvas and readinglists@Anglia for additional reading material