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What is ‘biochemical pharmacology’? • A fancy way of saying ‘pharmacology’, and of hiding the fact that we are sneaking a subject of medical interest into the UW biochemistry curriculum. • An indication that we are not going to discuss prescriptions for your grandmother’s aching knee; we will focus on the scientific side of things but not on whether to take the small blue pill before or after the meal. What is it not? • A claim that we accurately understand the mechanism of action of each practically useful drug in biochemical terms. • A claim that enzyme mechanisms and receptor structures, or even cell biology suffice as a basis to understand drug action. | Biochemical Pharmacology Lecture Notes Michael Palmer Department of Chemistry University of Waterloo Canada Third edition January 2007 Contents About these notes . vi Chapter 1. Introduction. 1 1.1. What are drugs . 1 1.2. Drugs and drug target molecules . 2 1.3. Drug molecules may or may not have physiological counterparts. 3 1.4. Synthetic drugs may exceed the corresponding physiological agonists in selectivity . 4 1.5. Metabolism of physiological mediators and of drugs. 5 1.6. Strategies of drug development. 5 Chapter 2. Pharmacokinetics. 9 2.1. Drug application and uptake. 9 2.1.1. Oral drug application . 9 2.1.2. Intravenous drug application . 10 2.1.3. Other routes of drug applicaton . 11 2.2. Drug distribution. 12 2.2.1. Vascular permeability the blood brain barrier . 12 2.2.2. Drug hydrophobicity and permeation across membranes . 12 2.2.3. L-DOPA as an example of drug distribution facilitated by specific transport . 14 2.2.4. The volume of distribution . 14 2.2.5. Protein binding. 15 2.2.6. Kinetics of drug distribution. 15 2.3. Drug elimination Kidneys . 16 2.3.1. Kidney anatomy and function . 16 2.3.2. Filtration secretion reuptake. 18 2.3.3. Examples. 20 2.4. Drug elimination Metabolism . 21 2.4.1. Example Metabolism of phenobarbital and of morphine . 21 2.4.2. Cytochrome P450 enzymes. 22 2.4.3. Overview of drug conjugation reactions . 23 2.4.4. Glucuronidation. 24 2.4.5. Glutathione conjugation . 24 2.4.6. Acetylation . 25 2.4.7. Other reactions in drug metabolism . 25 Chapter 3. Pharmacodynamics. 27 3.1. Classes of drug receptors . 27 3.2. Mechanisms and kinetics of drug receptor interaction. 28 3.2.1. Mass action kinetics of drug-receptor binding . 28 3.2.2. Reversible inhibition. 28 3.2.3. Irreversible inhibition. 29 3.2.4. Example Inhibition of a-adrenergic receptors by tolazoline and phenoxybenzamine . 30 3.3. Drug dose-effect relationships in biochemical cascades . 31 3.4. Spare receptors. 33 3.5. Potency and efficacy . 33 3.6. Partial agonism and
