Pharmacodynamics I Lecture Notes (PHRMSCI 170A) PDF
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Uploaded by GainfulPalladium5508
University of California, Irvine
2025
Benita Sjögren
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Summary
These lecture notes cover pharmacodynamics, including the mechanisms of drug action, different types of drug targets, and signal transduction pathways. The notes are well-structured with clear diagrams and definitions, and are suitable for a pharmaceutical sciences undergraduate student course.
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PHRMSCI 170A: Molecular Pharmacology I Pharmacodynamics I January 13, 2025 Benita Sjögren Pharmaceutical Sciences [email protected] What the body does to the drug What the drug does to the body Learning Objectives - Pharmacodynamics: Distin...
PHRMSCI 170A: Molecular Pharmacology I Pharmacodynamics I January 13, 2025 Benita Sjögren Pharmaceutical Sciences [email protected] What the body does to the drug What the drug does to the body Learning Objectives - Pharmacodynamics: Distinguish between pharmacokinetics Effect of drug action and pharmacodynamics Affinity – KD Potency – EC50, IC50 (LD50) Drug targets Efficacy Classes of drug targets (types of receptors, enzymes, ion channels etc.) Underlying mechanisms of tolerance and dependence Types of ligands/drugs Receptor desensitization Agonists – Full vs. Partial Receptor internalization Antagonists – Full vs. partial Allosteric modulators – PAMs, NAMs Signal transduction What pathways are initiated by receptors? Ligand-gated ion channels GPCRs TRK Reading assignments: Goodman & Gilman, Chapter 3. Nuclear receptors Traditional Drug Development Pipeline Preclinical Studies: Use animal/ex vivo/in vitro models Toxicity Affinity/selectivity of target Pharmacokinetics/pharmacodynamics Physical properties – stability/solubility/formulation Synthesis/purification Structure Activity Relationship – SAR From L1, Monday, Jan 6 Classes of drug targets A brief history of receptors as drug targets The cloning era begins! Maehle et al., Nat. Rev. Drug Disc. (2002) 1:637-641. Nobel Prizes for G Protein-coupled Receptors! 1967. Ragnar Granit, Haldan Keffer Hartline and George Wald – Physiological and chemical processes underlying photoreception. 1970. Sir Bernard Katz, Ulf von Euler and Julius Axelrod – Acetycholine and noradrenaline in nerve terminals and the mechanism for their storage, release and inactivation. 1971. Earl W. Sutherland, Jr. – cyclic AMP (cAMP). 1988. Sir James W. Black – Discovery of propranolol, which blocks the β-adrenergic receptor, and the H2 histamine receptor blocker cimetidine. 1994. Martin Rodbell and Alfred G. Gilman – Heterotrimeric G-proteins. 2000. Arvid Carlsson, Paul Greengard and Eric R. Kandel – Discoveries concerning signal transduction in the nervous system - Dopamine 2004. Linda B. Buck and Richard Axel – Odorant receptors. 2012. Brian Kobilka and Robert Lefkowitz – Studies of G-protein coupled receptors. 7 Step 1 of cell signaling: Reception Ligand - Agonists activates receptors - Antagonists blocks ligand actions on receptors Step 2 of cell signaling: Transduction Ligand - Agonists activates receptors - Antagonists blocks ligand actions on receptors Step 3 of cell signaling: Response Ligand - Agonists activates receptors - Antagonists blocks ligand actions on receptors Pharmacodynamics – Mechanism of drug action Requirements for a drug: 1. If the drug isn’t there, you don’t get any effect. 2. Adding more of the drug (up to a certain point) causes an incremental change in effect 3. Taking the drug away (or masking its action with a molecule that blocks the drug) means there is no effect. A typical Dose-response curve demonstrates the effects of what happens (the vertical Y-axis) when more and more drug is added to the experiment (the horizontal X-axis). Dose response curves Effect 100% 50% SIGNAL EC50 Concentration (linear scale) SIGNAL NO SIGNAL 14 Dose response curves EC50: The concentration of agonist needed to cause 50% of maximal response. Other “50s”: IC50: Concentration of an antagonist needed to achieve 50% inhibition. ED50: Dose needed to produce 50% of the maximal effect (similar to EC50) LD50: Lethal dose 15 Parameters of drug action Efficacy: What is the maximal response? KD Affinity: How strong is the Potency: What is the concentration of receptor ligand interaction? drug needed for effect? Affinity How strong is the binding of the ligand to the drug target? k+1 k+1 [L][R] Ligand L+R LR Dissociation constant = KD = = k-1 k-1 [LR] Receptor Binding Binding Binding Potency Batrachotoxin:
