MD214 U1L1 2022 Pharmacology Lecture Notes PDF

MD214 Introduction to to Pharmacology Unit 1 Lecture 1 Dr Louise Rabbitt MRCPI Email: [email protected] Specialist Registrar, Clinical Pharmacology and Therapeutics, Galway University Hospitals; NUI Galway University ofGalway.ie MD214 Unit 1 1. Introduction to drugs. Drug tar...

MD214 Introduction to to Pharmacology Unit 1 Lecture 1 Dr Louise Rabbitt MRCPI Email: [email protected] Specialist Registrar, Clinical Pharmacology and Therapeutics, Galway University Hospitals; NUI Galway University ofGalway.ie MD214 Unit 1 1. Introduction to drugs. Drug targets and receptor families 2. Agonists and antagonists. Dose and concentration responses 4. Adverse drug reactions and poisoning 3. Mechanisms and dose responses of selected drugs. Clinical trials, systematic reviews and meta analysis Practical Session: Drug Profiles Unit 1, Week 1: Drug Action What are drugs? Sources Classification What are drugs targets? Proteins Others What is the nature of drug interactions? Agonists Antagonists How are drug effects measured? Receptor occupancy Dose response Names Receptors Ion channels Enzymes Transporters Full Partial Inverse Biased Competitive Noncompetitive Kd and Bmax Potency EC50 and Emax Efficacy Learning Outcomes 1. Introduction to the discipline of pharmacology 2. What are drugs a. Drug sources b. Drug classification 3. Drug Targets a. Ligands b. Receptors c. ligand specificity 4. Receptor Families – online mini-lecture University ofGalway.ie Picture credit: University subject profile: pharmacy and pharmacology | University guide | The Guardian Definitions Pharmacology: Study of the effect of drugs on the function of living systems A Drug: “A chemical substance of known structure, other than a nutrient or essential dietary ingredient, which, when administered to a living organism, produces a biological effect” (From Rang and Dale’s Pharmacology) University ofGalway.ie The Drug perspective The “Pharmacology” of a drug The Drug perspective The “Pharmacology” of a drug Harmful effects Pharmacodynamics Pharmacokinetics The Drug perspective The “Pharmacology” of a drug Pharmacodynamics Sources Classes Biochemical Mechanisms Dose response Physiological Harmful effects Pharmacokinetics The Drug perspective The “Pharmacology” of a drug Pharmacodynamics Sources Classes Biochemical Mechanisms Harmful effects Dose response Pharmacokinetics Physiological Absorption Distribution Metabolism Elimination The Drug perspective The “Pharmacology” of a drug Pharmacodynamics Sources Classes Biochemical Mechanisms Harmful effects Dose response Pharmacokinetics ADRs Physiological Absorption Distribution Metabolism Elimination Toxicity Risk: benefit Disease perspective Physiology “Balance” Pathophysiology Successful drug intervention “Imbalance” Age Diagnosis Genetics Renal function Interacting diseases Interacting drugs Drugs: sources and classification University ofGalway.ie Naming Drugs Unfortunately, any one drug may have many names 1. exact or abbreviated chemical name 2. official generic name 3. brand or commercial name • The IUPAC (International Union of Pure and Applied Chemistry) allow for exact chemical description of a drug. • All new drugs are given official names. • These are now global, but in the past were national. • Pharmaceutical companies also use brand names to describe their drugs, and thus there can be more than one brand name for a single drug. University ofGalway.ie An example Chemical Name: methyl({3-phenyl-3-[4(trifluoromethyl)phenoxy]propyl})amine Official Name: Fluoxetine (hydrochloride) Brand Name: Prozac Molecular Formula: C17H19ClF3NO Molecular Weight: 345.79 The first successfully marketed highly specific serotonin uptake inhibitor, used as an antidepressant University ofGalway.ie Source: https://pubchem.ncbi.nlm.nih.gov/compound/62857 Naming and Classifying drugs 1 Acetylsalicylic acid 2 Atorvastatin 3 Levothyroxine sodium 4 Bisoprolol 5 Paracetamol 6 Esomeprazole 7 Salbutamol 8 Rosuvastatin 9 Ramipril 10 Amlodipine 11 Metformin 12 Lansoprazole 13 Pantoprazole 14 Prednisolone 15 Omeprazole 16 Pregabalin 17 Furosemide 18 Warfarin 19 Citalopram/escitalopram 20 Zopiclone Increasing use of common roots and name endings constituting a means of classification. Cholesterol lowering drugs (Statins, …..statin) Anti-ulcer drugs (proton pump inhibitors, …..prazole) Classification of Drugs Can be based on: 1. Chemical structure 2. Mechanism of action 3. Response produced University ofGalway.ie 1. Chemical Structure Beta lactam antibiotics (penicillin, etc.) O R-C-NH S N O COOH University ofGalway.ie 2. Mechanism of Action • Beta blocker (propranolol) • Drugs for lowering blood pressure • Block beta adrenoceptors University ofGalway.ie 3. Response produced • Antihypertensive agents • Physiological response is to lower BP • Examples (3 classes based on mechanism) • Beta blockers • ACE inhibitors • Diuretics • All reduce blood pressure but by different mechanisms University ofGalway.ie Classification of most prescribed drugs, Ireland 2015 Class No. Cardiovascular Central Nervous System Pain Miscellaneous Endocrine Respiratory Gastrointestinal Genitourinary Anti-infective Total 29 20 11 10 8 8 5 5 4 100 University ofGalway.ie Sources of drugs 1. 2. 3. 4. 5. Plants Microorganisms Animals Synthetic Products of genetic engineering University ofGalway.ie Plants Digitalis from Foxglove Modern pharmacology can be considered to date from Withering's book, An Account of the Foxglove, published in 1785. With this book, Withering introduced Digitalis for the therapy of congestive heart failure, or dropsy, as he knew the condition. University ofGalway.ie Morphine from Opium Poppy Morphine was purified from opium in 1805 by Frederich Sertürner. The active agent was ten times as potent as opium University ofGalway.ie Microorganisms University ofGalway.ie University ofGalway.ie Penicillin from Penicillium mould In 1928, Fleming discovered the first antibiotic called (Benzyl) Penicillin, and by 1943 Penicillin was mass produced and available by injection. University ofGalway.ie Animals University ofGalway.ie University ofGalway.ie Insulin from Pancreatic extracts In the 1920s, Banting and Best found that injection of pancreatic extracts reversed effects of experimental diabetes in dogs Insulin was purified from such extracts and marketed to treat human diabetes University ofGalway.ie Antitoxins University ofGalway.ie https://www.nlm.nih.gov/exhibition/fromdnatobeer/exhibition-interactive/illustrations/diphtheria-alternative.html Synthetic University ofGalway.ie Sulphanilamide and sulphonamides In 1932, Domagk discovered that the dye prontosil had antagonistic properties against a wide range of bacteria, and in 1935 it was found that the sulphanilamide portion of the prontosil molecule was responsible for its antibacterial effect. University ofGalway.ie Genetic Engineering University ofGalway.ie Recombinant Insulin from E. coli Insulin was purified from bovine and porcine sources Side effects including blindness Because cow and pig insulin differs slightly from human insulin Since 1982, recombinant insulin has been produced by inserting the human insulin gene into E. coli, which then produces insulin in culture University ofGalway.ie Drug Targets University ofGalway.ie University ofGalway.ie How do drugs work? Drug Targets: • • • • Receptors Ion channels Enzymes Transporters • All protein in nature • Exceptions are targets of chemotherapyoften bind DNA University ofGalway.ie Mechanism of action of most prescribed drugs, Ireland 2015 Target Enzyme Inhibitor Receptor Agonist Receptor Antagonist Transporter Blocker Ion Channel Blocker Miscellaneous/complex Total No 27 28 22 9 5 9 100 University ofGalway.ie What are receptors? • Recognition molecules for chemical mediators • Receptors are large proteins • Specialised structure • Linked to other molecules within the cell • Trigger a response in that cell • Found on • Cell membrane surface • Cytosol • Nucleus University ofGalway.ie Endogenous ligands The body’s own ‘drugs’ Drugs bind to receptors in the same way that endogenous ligands bind to receptors For example, adrenaline is the endogenous ligand for beta receptors. Isoprenaline (isoproterenol) is a synthetic drug that binds to this same receptor. University ofGalway.ie Ligand specificity “Lock and key” Receptors are specific for a particular ligand or drugs However, a drug may bind to more than one receptor (see case of amitriptyline) University ofGalway.ie The case of amitriptyline • Amitriptyline is a tricyclic antidepressant • Mechanism of action is inhibition of the neuronal reuptake of noradrenaline and serotonin • But also binds to other targets such as the muscarinic and histamine H1 receptor • What would be the consequences of binding to multiple targets? Noradrenaline reuptake site Serotonin reuptake site Adrenergic receptors Muscarinic receptors Histamine H1 receptor 5-HT2A receptor High High Highmoderate High V. high V. high University ofGalway.ie Specificity depends on shape Adrenaline binding to the b2 receptor • Protein shape depends on folding in response to pH, water, lipid etc • Drug-Receptor binding • Multiple chemical interactions • Sum of these provides specificity • No drug is completely specific • Favourability of the interactions = AFFINITY (thus, amitriptyline has a University high affinity for a number of drug targets) ofGalway.ie Drug-Receptor Bonds Mainly van der Waals and hydrogen bonds Characteristics that affect binding Physical nature: solid, liquid or gaseous, organic, inorganic Drug size: range from v. small (lithium, MW 7) to v. large (alteplase, MW 59,000) Most lie between 100 and 1000 Drug reactivity: electrostatic bonds with target Drug shape: Chirality (stereoisomerism), more than half of drugs are chiral molecules (exist as enantiomeric pairs) University ofGalway.ie Example of Imatinib • Imatinib is a highly selective inhibitor of the BCR-Ab1 tyrosine kinase fusion protein • Imatinib interacts with specific amino acid residues that possess hydrophobic side chains via van der Waals forces and hydrogen bonding • The binding causes a conformational change in the active site of the enzyme, inhibiting its catalytic activity University ofGalway.ie Affinity • The strength of the reversible interaction between a drug and its receptor • Tendency of a drug to bind to a receptor • Measured by Kd • This measurement enables us to compare the affinities ofUniversity drugs, i.e. how avidly they bind to their target receptor ofGalway.ie Occupancy • AJ Clarke (1926) proposed that • the rate at which drugs (D) combine with their receptors (R) depends on the concentration of drug and receptor. • The rate of dissociation depends on the number of complexes (DR) formed. • This is the Law of Mass Action University ofGalway.ie Law of mass action D Drug + R Receptor K +1 K -1 • K+1 = association rate constant • K-1 = dissociation rate constant • K-1 / K+1 = Kd = equilibrium constant DR Complex Drug-receptor occupancy curves • As the concentration of drug in the vicinity of its receptor is increased, then the proportion of receptors occupied increases • As there are a finite number of receptors, a concentration point will be reached when all of these receptors are occupied • A drug-receptor occupancy curve can be graphically depicted and certain parameters can be derived • The following graphs depict such a curve, the second using a log scale to create a sigmoid (s-shaped) curve University ofGalway.ie No. of Occupied Receptors Bmax 50% Kd Drug Concentration No. of Occupied Receptors Bmax = density of receptors at maximum binding Bmax Kd (equilibrium constant) = concentration of drug required to occupy 50% of receptors 50% Kd Log Drug Concentration How does the cell respond? University ofGalway.ie University ofGalway.ie Receptor Families Receptors are divided into 4 superfamilies 1. Ion channels 2. G-protein coupled receptors 3. Kinase-linked receptors 4. Nuclear (intracellular receptors) Each has a different mechanism, but all share the property of activation by a ligand, which can be exploited by drugs Watch Blackboard mini-lecture for further information on receptor families University ofGalway.ie Summary • Drugs come from a variety of natural and synthetic sources • Drugs can be classified in many ways (structurally, effect produced) • Drug targets are largely protein in nature • The main target of drugs is receptors • The law of mass action helped to explain the way in which drugs form complexes with receptors University ofGalway.ie Thank you Questions? University ofGalway.ie