VM522P / VM7522 Pharmacology WIMU Fall WIMU Regional Program in Veterinary Medicine Fundamentals of Pharmacology VM522P, VM7522 Handouts of Pharmacology Lectures by Washington State University and Utah State University faculty, Drs. Suzy Appleyard, Steve Simasko, Nicolas Villarino, Mirella Meyer‐Ficca, and Ralph Meyer 1 VM522P / VM7522 Pharmacology WIMU Fall Table of Contents PART1 – Pharmacodynamics (S. Appleyard) .................................................................................................................5 L1: PHARMACODYNAMICS – TARGETS ......................................................................................................................5 I. Specific Drug Targets .....................................................................................................................................5 II. Non‐targeted mechanisms ............................................................................................................................9 L2: PHARMACODYNAMICS – RECEPTOR ‐ DRUG INTERACTIONS ........................................................................... 10 I. Drug‐Receptor Interactions – General Concepts ....................................................................................... 11 II. Measurement of Binding Affinity ............................................................................................................... 12 III. Measurement of Effective Concentration. ............................................................................................. 13 IV. Relationship between binding and effect .............................................................................................. 14 V. Potency ....................................................................................................................................................... 16 VI. Selectivity: The Structure‐Activity Relationship .......................................................................................... 17 L3: PHARMACODYNAMICS – AGONISTS AND ANTAGONISTS ................................................................................ 19 I. Receptors .................................................................................................................................................... 19 II. Agonists ...................................................................................................................................................... 19 III. Antagonists ............................................................................................................................................. 20 IV. Partial agonists ....................................................................................................................................... 23 L4: POPULATION PHARMACOLOGY ....................................................................................................................... 26 I. Quantal Dose‐Response Curves ................................................................................................................. 26 II. Therapeutic Index (TI) ................................................................................................................................ 27 III. LD50 ........................................................................................................................................................ 28 IV. Adverse Reactions .................................................................................................................................. 29 PART2 – Pharmacokinetics (S. Simasko) .................................................................................................................... 32 L5: Absorption ........................................................................................................................................................ 32 L6: Pharmacokinetics: Distribution ........................................................................................................................ 39 L7: Pharmacokinetics: Metabolism ........................................................................................................................ 44 L8: Pharmacokinetics: Excretion ............................................................................................................................ 53 L9: Pharmacokinetic Models .................................................................................................................................. 59 A. One‐Compartment Open Model .................................................................................................................... 59 B. Two‐Compartment Open Model .................................................................................................................... 63 C. Multi‐Compartment Models .......................................................................................................................... 66 L10‐12: Pharmacokinetic Variables ........................................................................................................................ 68 a) Clearance ........................................................................................................................................................ 69 b) Volume of Distribution ................................................................................................................................... 70 c) Bioavailability ................................................................................................................................................. 71 d) Half‐life ........................................................................................................................................................... 73 2 VM522P / VM7522 Pharmacology WIMU Fall L13: Dosing regimens ‐ Infusions ............................................................................................................................ 74 L14: Dosing regimens – Intermittent dosing .......................................................................................................... 82 L15: TOLERANCE AND DRUG INTERACTIONS ......................................................................................................... 94 I. Tolerance .................................................................................................................................................... 94 II. Drug‐Drug Interactions ............................................................................................................................... 96 L16: Pharmacokinetics: Adjustments ..................................................................................................................... 99 L16: Clinical Pharmacokinetics ............................................................................................................................. 105 Drug label or package ........................................................................................................................................... 105 Drug label or package: sections ........................................................................................................................... 105 PK section of the label .......................................................................................................................................... 105 Labels are specific for products and formulations ............................................................................................... 105 How to use/interpret a PK section? ..................................................................................................................... 105 Specific pharmacokinetic parameters .................................................................................................................. 107 List of key works for interpreting labels ........................................................................................................... 109 Part 3 – Neuropharmacology (S. Appleyard) ............................................................................................................ 110 L17: Review of Neurotransmission ....................................................................................................................... 110 I. Steps in Neurotransmission ..................................................................................................................... 111 II. Examples of how drugs modulate Neurotransmission ............................................................................ 115 III. Modulation of Neurotransmission ...................................................................................................... 117 L18: Overview of the Autonomic Nervous System (ANS) .................................................................................... 120 I. Divisions and Structure of the ANS .......................................................................................................... 121 II. Chemical Mediators and Receptors within the ANS ................................................................................ 125 III. Function of the ANS .............................................................................................................................. 129 IV. Somatic efferent nervous system (motor neurons) ............................................................................ 131 L19, 20: Cholinergic Pharmacology .....................................................................................................................