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Pharmacology for Anesthesia I Introduction What is a Drug? Pharmacokinetics (PK) What the body does to the drug • • • • Absorption Distribution Metabolism Excretion Absorption The process of diffusion or transport of a drug from the site of administration to the plasma Skipped by administering drugs parenterally Inhaled agents require special considerations Fick’s Law concentration gradient x surface area x diffusion coefficient Rate of Diffusion = membrane thickness Diffusion coefficient = Permeability Size Ionization State Henderson – Hasselbalch Equation log concentration (protonated) = pKa - pH concentration (unprotonated) Trapping Distribution The process of diffusion of a drug throughout the body Generally governed by the same characteristics as absorption Vd = volume of distribution Protein Binding Metabolism • The enzymatic modification of the drug molecule by the body – Often occurs in liver – May occur elsewhere Hepatic Metabolism Example of Phase II prior to Phase I CYP Enzymes Pharmacogenetics of Drug Metabolism Examples of Drug-Drug Interactions Elimination • The removal of the drug from the body – Renal – Hepatic – Respiratory – Cutaneous Clearance • Used to describe our ability to eliminate the active ingredient – Combination of metabolism and excretion Example of Zero order kinetics Distribution and Clearance First Order Kinetics • Single compartment model • Double compartment model • Three compartment model • Etc. Absorption and Clearance Effect Not Always Governed by Plasma Concentration Dosing Regimens Can speed accumulation time by administering a loading dose Routes of Administration ROUTE Intravenous Subcutaneous ABSORPTION PATTERN SPECIAL UTILITY Absorption circumvented Valuable for emergency use Increased risk of adverse effects Potentially immediate effects Permits titration of dosage Must inject solutions slowly as a rule Suitable for large volumes and for irritating substances, or complex mixtures, when diluted Usually required for high-molecular- Not suitable for oily solutions or poorly weight protein and peptide drugs soluble substances Prompt, from aqueous solution Suitable for some poorly soluble suspensions and for instillation of slow-release implants Slow and sustained, from repository preparations Intramuscular Oral ingestion LIMITATIONS AND PRECAUTIONS Not suitable for large volumes Possible pain or necrosis from irritating substances Prompt, from aqueous solution Suitable for moderate volumes, oily vehicles, and some irritating substances Precluded during anticoagulant therapy Slow and sustained, from repository preparations Appropriate for self-administration (e.g., insulin) May interfere with interpretation of certain diagnostic tests (e.g., creatine kinase) Variable, depends on many factors (see Most convenient and economical; text) usually more safe Requires patient compliance Bioavailability potentially erratic and incomplete Pharmacodynamics • What the drug does to the body – Typically receptor mediated What factors affect the ability of a drug to interact with a receptor? Drug size • Large enough to be specific • Not so large as to be unable to interact with the receptor Drug Shape Some drugs do not appear to fit into these categories • Osmotic agents • Transport regulators Agonists Antagonists Competitive Noncompetitive Allosteric Activators Potentiators Partial agonists Inverse agonists Antagonists Noncompetitive Antagonist and Spare Receptors Full and Partial Agonists Cellular Receptors Different Drugs Similar Effects Potency vs. Efficacy Population Variation and Therapeutic Window