Pharmacology at a Glance: Concepts and Calculations (Part 1) - University of Reading PDF

Pharmacology at a glance: concepts and calculations (Part 1) Prof David Leake 1  UNIVERSITY OF READING SCHOOL OF BIOLOGICAL SCIENCES...

Pharmacology at a glance: concepts and calculations (Part 1) Prof David Leake 1  UNIVERSITY OF READING SCHOOL OF BIOLOGICAL SCIENCES PART 2 SEMESTER 1 2024 PHARMACOLOGY AND TOXICOLOGY BI2BE4 Lecturer: Prof DS Leake (Module Convenor) Lectures: At various times in Slingo Lecture Theatre, JJ Thomson Building Practical: Week 1 or 2 in Hopkins G06 The definition and scope of pharmacology will be explained. The ways in which drugs act by binding to receptors for endogenous signalling molecules and the concepts of agonism and antagonism at receptors will be described. The principles of pharmacokinetics (i.e. the absorption, metabolism, distribution and elimination of drugs and other foreign compounds) will be explained. The mechanisms by which drugs can have toxic effects will be discussed. There is an organ bath practical on arterial vasodilatation (nitric oxide). Date Time Lecture Lectures Time Practicals theatre Weds 2 October 11am- Slingo, JJT Getting to grips with pharmacology: Concepts 1pm and calculations (Part 1) Getting to grips with pharmacology: Concepts and calculations (Part 2) Friday 4 October 1-3pm Group A Arterial vasodilatation (nitric oxide) practical Hopkins G06 Monday 7 Oct 1-3pm Group B Arterial vasodilatation (nitric oxide) practical Hopkins G06 Tuesday 8 Oct 1-3pm Group C Arterial vasodilatation (nitric oxide) practical Hopkins G06 Weds 9 October 11am- Slingo, JJT Receptor theory 1: Binding. affinity and 1pm agonists Receptor theory 2: Antagonists Thursday 10 Oct 1-3pm Group D Arterial vasodilatation (nitric oxide) practical Hopkins G06 Friday 11 October 2-4pm Group E Arterial vasodilatation (nitric oxide) practical Hopkins G06 Weds 16 Oct 11- Slingo, JJT Receptor theory 3: Efficacy & Partial Agonists 12noon 12noon- Calculation seminar for arterial vasodilatation 1pm (nitric oxide) practical (all groups; optional) Weds 23 Oct 11am- Slingo, JJT Pharmacokinetics: Absorption & Distribution 1pm Pharmacokinetics: Metabolism & Excretion Weds 30 Oct 11am- Slingo, JJT G protein-coupled receptors (GPCRs) 1pm Voltage and ligand-gated ion channels Weds 13 Nov 11am- Slingo, JJT Enzymes as drug targets 1pm Transporters as drug targets Weds 20 Nov 11am- Slingo, JJT Nuclear receptors 1pm From physiological systems to molecular drug targets 1 Weds 27 Nov 11am- Slingo, JJT From physiological systems to molecular drug 1pm targets 2 Biologicals and gene therapy Tues 10 Dec 4-6pm Slingo, JJT Drug toxicology 1 Drug toxicology 2 Assessment: Part II examinations 70%, practical report on nitric oxide practical 30% Recommended books (both in the library): Rang and Dale’s Pharmacology (2023) Ritter, J.M, Flower, R.J., Henderson, G., Yoke, Y.K, MacEwan, D., Robinson, E. & Fullerton, J., 10th edn, Churchill Livingstone, Edinburgh, ISBN 9780323873956, £56.99; Dale’s Pharmacology Condensed (2020) Page, C.P. & Pitchford, S., 3rd edn., Elsevier, ISBN 9780702078187, £31.99. A free electronic book on pharmacokinetics can be downloaded at http://bookboon.com/en/pharmacokinetics-ebook 16/9/24 2 Learning objectives After this lecture, and further reading as required, students will be able to: Define the terms pharmacology, drug, medicine, pharmacokinetics, pharmacodynamics. Explain the difference between a medicine and a drug. Explain the receptor concept for the action of drugs, and how it has developed. Explain how drugs can be classified according to class, chemical properties, therapeutic action. Explain the role of the human genome mapping project and molecular biological techniques identifying protein targets for drugs. Define the term drug target, and receptor and list the main types, namely receptors, enzymes, ion channels and transporters. 3  Pharmacology: the study of the effect of drugs on the function of living systems Pharmacodynamics: the effects of the drug on the body Example: Paracetamol- mechanism of action is dependent on the inhibition of prostaglandin synthesis. Pharmacokinetics: the effects of the body on the drug (relates to Absorption, Distribution, Metabolism, Excretion (ADME)) Drug or medicine? B A C D Drug: A biologically active compound (other than a nutrient or essential dietary ingredient) taken with the intent to produce a change in the body. Medicine: A chemical preparation which usually contains one or more drugs administered with the purpose of producing a therapeutic effect. Medicines usually contain other substances to make them more convenient to use. Timeline 3x Paul Ehrlich (1854-1915) Interested in staining cellular components. Pioneered treatment of syphilis. It took him three years’ and three hundred syntheses to produce ‘salvarsan’. 8 Receptor concept Ehrlich proposed the ‘magic bullet’ theory. Whereby a drug would have selectively toxicity e.g. against a microbial agent or cancer cell. Ideally with little action on the host cell even at high doses = therapy without toxicity. 9 Receptor concept At the same time, Langley described drug action (at the neuromuscular junction) in terms of interaction with a “receptor” substance. Receptors represent a major target for drug ‘bullets’. Drugs act through ‘receptors’ Extracellular Intracellular Cell membrane 11 Drug classes Problems: Drugs cannot be classified according to a single rational system because of the need of chemists, pharmacologists, doctors differ. Nomenclature- it is not always practical to present each drug under a single name as formulations vary widely. Any drug therefore may have names in 3 different classes. 12  One drug…several classes Small molecule Therapeutic class: Cardiovascular Anti-arrhythmia Anti-hypertensive vasodilator Chemical class: napthalene or phenoxypropanolamine IUPAC name: (RS)-1-(isopropylamino)-3-(1-baphthyloxy)propan-2-ol drug name: propranolol trade name: Propranolol (non-proprietary, “generic” trade name) Inderal (trade name for an intravenous preparation of propranolol supplied by Wyeth)  The word ‘target’ in the context of drug discovery has several meanings. A working definition for this module is the molecular recognition site to which a drug will bind. The majority of known ‘targets’ are proteins, most commonly receptors but NOT always (e.g. enzymes). Drug targets Human (approx. 73%) Microbial, viral (approx. 16%) Miscellaneous (approx. 11%) Identified by exploring disease mechanisms (classical) Identified by analysing genetic basis or susceptibility to disease (post- genomic) Not all disease mechanisms are “druggable” Question time How many drugs were FDA approved in 2021? 1. 12 2. 39 3. 50 4. 67 Was this higher of lower than 2020? 1. Lower 2. Higher Identifying drug targets Conventional routes Analysis pathophysiology Analysis of mechanism of action of existing therapeutic drugs. Novel routes Trawl the genome Rethinking drug discovery Logical starting point for a drug is to understand the mechanisms of disease. Pioneers on this front were Hitchings and Elion (1944) and their unravelling of the synthesis of DNA. Drugs accredited to their work: Anti-tuberculosis-pyrimethamine Anti-bacterial- trimethoprim Anti-cancer -6-mercaptopurine Anti-gout- allopurinol Accidental discoveries Amphetamine Observed to Ritalin was trialled as decrease developed for headache agitation in ADHD remedy (1937) children Trawling the genome Disease genes: Genes, mutations of which cause or predispose to the development of human disease Disease modifying genes: Genes whose altered expression may be involved in the development of the disease state OR genes that encode functional proteins, whose activity is altered in disease state 20 Trawling the genome ✓Success: Imatinib, highly specific tyrosine kinase inhibitor. Treats chronic myeloid leukaemia. ×Frustrations: Alzheimer's disease 21 Transgenic models  Drug and genes Human genome 30,000 Disease modifying ‘Druggable’ genome genes 3000 3000 Drug targets Approx. 600-1500 Source: Hopkins and Groom, 2002 Next up Pharmacology at a glance: concepts and calculations (Part 2)