Pharmacology for Anesthesia I Introduction

What is a Drug?

Pharmacokinetics (PK) What the body does to the drug Absorption Distribution Metabolism Excretion

Absorption Skipped by administering drugs parenterally Inhaled agents require special considerations The process of diffusion or transport of a drug from the site of administration to the plasma

Fick’s Law concentration gradient x surface area x diffusion coefficient membrane thickness Rate of Diffusion = Diffusion coefficient = Permeability Size

Ionization State Henderson – Hasselbalch Equation log concentration (protonated) concentration (unprotonated) = pK a - pH

Trapping

Distribution The process of diffusion of a drug throughout the body Generally governed by the same characteristics as absorption V d = 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

First Order Kinetics Single compartment model Double compartment model Three compartment model Etc. Distribution and Clearance

Absorption and Clearance

Effect Not Always Governed by Plasma Concentration

Dosing Regimens

Can speed accumulation time by administering a loading dose

Routes of Administration

ROUTEABSORPTION PATTERNSPECIAL UTILITYLIMITATIONS AND PRECAUTIONS IntravenousAbsorption circumventedValuable for emergency use Increased risk of adverse effects Potentially immediate effectsPermits titration of dosageMust inject solutions slowly as a rule Suitable for large volumes and for irritating substances, or complex mixtures, when diluted Usually required for high-molecular- weight protein and peptide drugs Not suitable for oily solutions or poorly soluble substances SubcutaneousPrompt, from aqueous solution Suitable for some poorly soluble suspensions and for instillation of slow-release implants Not suitable for large volumes Slow and sustained, from repository preparations Possible pain or necrosis from irritating substances IntramuscularPrompt, 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) Oral ingestion Variable, depends on many factors (see text) Most convenient and economical; 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