Introduction to Pharmacology & Pharmacodynamics PDF

Prof SBK, 2023 Aim/Objectives: To define pharmacology Distinguish between pharmacodynamics and pharmacokinetics Describe drug actions at the molecular, cellular, organ levels Describe different types of drug-receptor interactions Describe drug effects over time Describe dru...

Prof SBK, 2023 Aim/Objectives: To define pharmacology Distinguish between pharmacodynamics and pharmacokinetics Describe drug actions at the molecular, cellular, organ levels Describe different types of drug-receptor interactions Describe drug effects over time Describe drug safety indices and how they are measured Prof SBK, 2023 Outcomes/Expectation:  After this lecture, students should: know the definition of pharmacology as a medical science know the different types of pharmacological studies be able to briefly describe basic drug actions at molecular & cellular levels be able to describe different types of drug–receptor interactions. understand and be able to interpret dose-response relations under different conditions know drug effects or actions over time Be familiar with drug safety indices and how they are measured Prof SBK, 2023  The study of the effects of drug on physiological and pathophysiological processes  It is a branch of medical science that deals with the properties and characteristics of chemical agents (drugs) used for medicinal or other purposes.  Derives from Greek: Pharmacon(drug): logos (study or discourse)  Divided into TWO: Pharmacodynamics Pharmacokinetics Prof SBK, 2023  Pharmacodynamics: Greek: dynamis-power)  What the drug does to the body.  This includes physiological and biochemical effects of drugs and their mechanism of action at organ system/subcellular/macromolecular levels  Pharmacokinetics: (Greek: kinesis-movement)  What the body does to the drug.  This refers to movement of the drug in & alteration of the drug by the body; includes absorption, distribution, binding/localization/storage, biotransformation(metabolism) and excretion of the drug (ADME) Prof SBK, 2023  What is a drug? An active chemical entity present in a medical product that is used for diagnosis, prevention, or treatment/cure of a disease. This disease oriented definition of drug does not include contraceptives or use of drugs for improvement of health. The WHO (1966) gave a more inclusive definition—“Drug is any substance or product that is used or is intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient” A drug may be: Pharmacodynamic agent: Designed to have pharmacodynamic effects in the recipient. Chemotherapeutic agent: Designed to inhibit or kill invading parasite/malignant cell and have no/minimal P’dynamic effects in the recipient. Prof SBK, 2023  “Drugs”: Also used to refer to the use of illicit or inappropriate use of licit merely for physical or mental gratification-potential for dependance/addiction /abused.  Pharmacological Studies: Molecular (chemical molecules up to genes) (in vitro e.g signal transduction cascades, gene cloning & expression etc) Cellular- cells and reduced tissue (in vitro, ex vivo e.g. cancer cell lines, dissociated neurons/myocytes, slices) Organ (ex vivo- isolate heart, intestines, muscles, lungs etc) Whole animal (in vivo- disease models, genetic knock- in/knock-out, chemical lesioning etc)  TECHNIQUES: (Bio)chemistry, (Bio)physics, radiochemistry, microscopy etc Prof SBK, 2023  Other Aspects of Pharmacology:  Toxicology: Study of unwanted or poisonous & adverse effects of drugs and chemicals (household, environmental pollutant, industrial, agricultural, homicidal):detection, prevention and treatment of poisonings  Pharmacotherapeutics: The application of pharmacological information together with knowledge of the disease for its prevention, mitigation or cure. Involves selection of the most appropriate drug, dosage and duration (regimen) of treatment taking into account the specific features of a patient. Prof SBK, 2023  Aspects of Pharmacology: Clinical pharmacology: The scientific study of drugs (both old and new) in humans. includes pharmacodynamic and pharmacokinetic investigation in healthy volunteers and in patients:-Clinical Trials. Involves evaluation of efficacy and safety of drugs & comparative trials with other forms of treatment, surveillance of patterns of drug use, adverse effects, etc. Aims to generate data for optimum use of drugs and the practice of ‘evidence based medicine’. Subspecialties: Systems/Disease based e.g. Neuropharmacology, Respiratory Pharmacology, GI Pharmacology, Molecular Pharmacology, Cellular Pharmacology, Cardiovascular Pharmacology, Immunopharmacology, Cancer Pharmacology, Pharmacogenetics/genomics etc Prof SBK, 2023 Prof SBK, 2023  The study of the effects of the drug on the living system What the drug does when it gets there. Prof SBK, 2023  Effects are produced by: Non-receptor mechanisms Receptor interactions  Drugs mostly act by binding to protein targets such as: 1. Enzymes 2. Carrier molecules 3. Ion channels 4. Receptors Prof SBK, 2023  Actions on Enzymes Enzymes = Biological catalysts Speed chemical reactions Drugs that alter enzyme activity alter processes catalyzed by the enzyme Examples  Non steroidal anti-inflammatory agents - NSAIDs (Ibuprofen) & Paracetamol  Monoamine oxidase inhibitors (phenelzine) Prof SBK, 2023  Changing Physical Properties Mannitol (Changes osmotic balance across membranes, causes osmotic diuresis)  Changing Cell Membrane Permeability to ions Lidocaine Blocks sodium channels Verapamil Block calcium channels Prof SBK, 2023  Combining With Other Chemicals Antacids Chelation of heavy metals (Deferoxamine with Fe)  Anti-metabolites Compete with normal substrates in biochemical pathways May result in biologically inactive product e.g.: Antineoplastic agents (eg. methotrexate competes with folate for dihydrofolate reductase , interferes with the formation of thymidylate from 2-deoxyuridylate. Thymidylate is used in the synthesis of DNA) Antimicrobials (sulphonamides competes with dihydropteroate synthetase , interferes with synthesis of folic acid in bacteria) Prof SBK, 2023 Prof SBK, 2023 Prof SBK, 2023  Receptors Macromolecular components of a cell (on the surface or inside the cytoplasm) with which a drug interacts to produce a response or effect. There is usually a conformational change  Binding- site specificity & drug usefulness  No complete/absolute specificity,(selectivity, side-effects)  Affinity : this is the tendency of a drug to bind to the receptor  Intrinsic activity (a): ability of a drug to induce or cause a response after it is bound to the receptor (a = +1 to -1)  Efficacy: ability of a drug to produce (the maximum possible) physiological response (a= +1= full agonist) Prof SBK, 2023   A.J. Clark (1926 &1937): Pharmacological response of a drug (D) depends on the proportion of receptors (R) occupied, and maximum response is observed when all the receptors are occupied..?. Relationship between the number of receptors occupied and the response observed is linear..?. B=Partial agonism  D+R #DR ∞ Response (A) C=“Spare receptors” A B C Ariens (1954) & Stephenson (1956) Prof SBK, 2023 I: Channel-linked receptors (Voltage/ligand-gated ion channels) Ligand binds to receptor, causes opening or closing of an ion channel pores in the same receptor. E.gs drugs  Ca2+ channel blockers (Nifedipine, Amlodipine)  Local anesthetics (Lignocaine),  Anticonvulsants (Clonazepam, Carbamazepine, Phenytoin)  Antiarrhythmics (Amiodarone)  They produce very fast response on interacting with these receptors- from microseconds (10-6) to millisecond (10-3) Prof SBK, 2023  G (guanosine triphosphate)-protein coupled receptors are 7- transmembrane receptors,  They contain an intermediate transducing molecule, called the GTP- binding protein (or G-protein).  The G-protein is bound to the inner membrane of the cell and consists of three subunits: alpha, beta and gamma.  The G-protein binds to the receptor when the ligand activates the receptor  This causes the alpha subunit to exchange a GDP (guanosine diphosphate) molecule on it for a GTP molecule.   Alpha subunit together with GTP breaks from the beta and gamma subunits  Alpha subunit, free to move along the inner membrane, contacts another membrane-bound protein (eg. the enzyme adenylyl cyclase), which is the "primary effector."  The enzyme converts ATP (Adenosine Triphosphate) to cAMP (Cyclic adenosine monophosphate)  cAMP further activates other proteins or enzymes (so referred to as a second messenger). Prof SBK, 2023 Prof SBK, 2023  Examples of second messengers include: Derivatives of phosphatidylinositol bisphosphates (PIP2) inositol 1,4,5 triphosphate (IP3) diacylglycerol (DAG) Ca2+ cAMP cGMP Prof SBK, 2023  Usually transmembrane receptors with part inside the cytoplasm, linked to inactivated enzymes, majority being protein kinases especially tyrosine kinases  ligand binds to receptor, to activate the enzymes leading to addition of phosphate groups to other proteins inside the cytoplasm (phosphorylation).  This leads to changes in the physiological function of the cell.  Examples include receptor for growth factors and insulin receptors. Prof SBK, 2021 Prof SBK, 2023  Receptors are located inside the cell rather than on cell membrane.  Their ligands are usually the second messengers as well as extracellular lipophilic hormones (steroidal hormones as well as vitamin D, and thyroid hormone).  Ligands bind to receptors, activated receptor moves into nucleus and interacts with nuclear DNA, affecting gene expression (production of new mRNA and then protein synthesis in the target cell).  Drugs that act on intracellular receptors are slow acting because gene transcription takes time, but endure hours after the drug has been eliminated from the body. Prof SBK, 2023 Intracellular receptors Prof SBK, 2023 Summary Receptor types Prof SBK, 2023   A.J. Clark (1926 &1937): Pharmacological response of a drug (D) depends on the proportion of receptors (R) occupied, and maximum response is observed when all the receptors are occupied..?. Relationship between the number of receptors occupied and the response observed is linear..Is it?. B=Partial agonism  D+R #DR ∞ Response (A) C=“Spare receptors” A B C Ariens (1954) & Stephenson (1956) Prof SBK, 2023  Binding- site specificity & drug usefulness  No complete/absolute specificity,(selectivity, side-effects)  Affinity : this is the tendency of a drug to bind to the receptor  Intrinsic activity (a): ability of a drug to induce or cause a response after it is bound to the receptor (a = +1 to -1)  Efficacy: ability of a drug to produce (the maximum possible) physiological response (a= +1= full agonist) Prof SBK, 2023  EC50 – Index of potency  Emax - the ultimate achievable response,  Potency- a measure of the amount of drug necessary to produce a responses of a given size ( amount in relation to effect)  Efficacy – the ability of a drug to illicit a physiological response ( or the strength of response induced by receptor occupancy by an agonist)-Intrinsic activity (ranging from +1 to -1)  A full agonist has greater efficacy than a partial agonist independent of potency, e.g. morphine (full agonist) is a better analgesic than buprenorphine (partial agonist).  Which is more potent? ◦ buprenorphine (usual oral dose 0.2 mg) ◦ morphine (usual oral dose 10 mg)  BUPRENORPHINE Prof SBK, 2023  Lock and key mechanism Agonist Receptor Agonist- Receptor Interaction Prof SBK, 2023 Induced Fit Receptor Perfect Fit! Prof SBK, 2023  Agonists: Exogenous substances(xenobiotics) often of related chemical structure can mimic/replicate/produce pharmacological effects usually produced by endogenous substance such as hormones and neurotransmitters Drugs that bind to a receptor to produce similar pharmacological effects - AGONISTS Prof SBK, 2023  Bind to receptor sites and inhibit or blocks the endogenous substances or agonists from occupying a receptor, preventing normal cellular functions. Antagonist-receptor interaction may be reversible, irreversible, competitive and non-competitive Prof SBK, 2023  Reversible In this situation, antagonist and agonist compete for the same receptor site Increasing in the dose of either will displace the other thereby decreasing or increasing the activity of the agonist  Irreversible competitive ◦ When an increasing dose of an agonist does not displace the antagonist because it does not dissociate or dissociates slowly from the receptor, interaction is said to be irreversible competitive. Prof SBK, 2023 Antagonist Receptor Antagonist- DENIED! Receptor Complex Prof SBK, 2023  Here, antagonist either prevents the binding of the receptor with the agonist or blocks the agonist from producing a response  Antagonist binds to a site other than the agonist-binding domain, induces a conformational change in the receptor such that the agonist no longer “recognizes” the agonist binding site.  High doses of the agonist do not overcome the antagonist here Prof SBK, 2023  Antagonist Agonist Receptor DENIED! ‘Inhibited’-Receptor Prof SBK, 2023  A B Therapeutic Effect Effect A! Why? Dose Which drug is more potent? Prof SBK, 2023  B A Therapeutic Effect Effect Dose Which drug has the lower threshold dose? A Which has the greater maximum effect? B Prof SBK, 2023  Time Response  Dose Response Prof SBK, 2023 Effect/Response Maximal (Peak) Effect Latency Duration of Response Time Prof SBK, 2023 Effect/Response IV IM SC Time Prof SBK, 2023  Drug’s safety margin  Must be >1 for drug to be usable  Digitalis has a TI of 2  Penicillin has TI of >100  Also used in the context of adverse drug reactions LD50 TI = ED50 Prof SBK, 2023 Prof SBK, 2023  Why don’t we use a drug with a TI LD50 = Very Bad! NOTE: caution with chemotherapeutic agents e.g. anticancer!! Prof SBK, 2023 Prof SBK, 2023 Sources 1. Udaykumar P.(2009) Textbook of Medical Pharmacology 2. Rang H.P., Dale M.M., Ritter J.M., Moore P.K. (2003). Pharmacology 3. Howland R.D, Mycek M.J(2006) Pharmacology. Lippincott’s Illustrated reviews. 4. Tripathi K.D.(2008). Essentials of Medical Pharmacology 5. Stein C. (2007). Handbook of Experimental pharmacology 6. Kandel et al, (2014) Principles of Neural Sciences 5th Edition. 7. On-line Google images 8. https://www.mayoclinic.org/diseases-conditions/ Prof SBK, 2023