Pharmacokinetics of Anesthetic Agents

Pharmacokinetics describes the time course of a drug in the body: how it is absorbed, distributed to tissues, metabolised and eliminated. In anesthesia, where drugs are titrated against a moment-to-moment surgical stimulus, pharmacokinetic reasoning explains why an agent acts quickly, how its effect spreads and wanes, and how rapidly a patient recovers after the drug is stopped.

Definition

Pharmacokinetics is the quantitative study of drug absorption, distribution, metabolism and elimination over time; applied to anesthetic agents, it characterises how the concentration of a drug at its site of action rises and falls and thereby governs the onset, magnitude and duration of its effect.

Scope

This topic covers the four classical processes of absorption, distribution, metabolism and elimination (ADME) as applied to anesthetic drugs, the compartmental models used to represent their disposition, and the derived parameters that anesthetists use to reason about onset and offset, including clearance, volume of distribution, elimination half-life and the context-sensitive half-time. It is an educational account of how drug disposition is modelled, not a guide to drug dosing.

Core questions

• How do absorption, distribution, metabolism and elimination shape the concentration of an anesthetic drug over time?
• What do compartmental models and parameters such as clearance and volume of distribution tell us about a drug's behaviour?
• Why does the time to recover from an intravenous anesthetic depend on how long it has been infused?

Key concepts

• Absorption, distribution, metabolism and elimination (ADME)
• Compartmental (multicompartment) models
• Clearance and volume of distribution
• Elimination half-life
• Context-sensitive half-time
• Redistribution
• Effect-site concentration and equilibration delay

Key theories

Context-sensitive half-time

Hughes, Glass and Jacobs showed that for intravenous anesthetic drugs the time for plasma concentration to fall by half after stopping an infusion is not the fixed elimination half-life but depends on the duration of the infusion, because redistribution among compartments changes the apparent decay; this concept reframed how the offset of anesthetic drugs is predicted.

Mechanisms

After administration a drug distributes from the blood into tissues according to perfusion, lipid solubility and protein binding, then is cleared by hepatic metabolism, renal excretion or, for some agents such as remifentanil, by widespread esterase hydrolysis. Multicompartment models represent the body as a central compartment in rapid equilibrium with plasma and one or more peripheral compartments, and they capture the fact that the decline in concentration after an infusion reflects both elimination and redistribution. Because of redistribution, the practically important measure of offset is the context-sensitive half-time, which lengthens with infusion duration for most drugs but remains short and almost constant for agents with very rapid clearance such as remifentanil.

Clinical relevance

Pharmacokinetic understanding underlies the rational comparison and selection of anesthetic agents and the anticipation of how quickly a patient will recover; it also explains why drugs accumulate during prolonged infusions. This entry describes these principles for reference and education and does not provide dosing schemes or individualized treatment recommendations.

Evidence & guidelines

The pharmacokinetics of individual anesthetic agents have been characterised in numerous controlled human studies and population pharmacokinetic analyses, and the underlying concepts are codified in clinical-pharmacology textbooks. The context-sensitive half-time framework and rational-selection reasoning summarised by Hughes, Glass and Jacobs (1992) and by Shafer and Varvel (1991) remain reference points for the field.

History

Classical pharmacokinetics developed compartmental modelling and parameters such as clearance and volume of distribution across the twentieth century. Their application to anesthesia matured when computer-based simulation allowed the disposition of intravenous anesthetics to be modelled directly; Shafer and Varvel (1991) reframed opioid selection around simulated effect-site behaviour, and Hughes, Glass and Jacobs (1992) introduced the context-sensitive half-time, shifting attention from the static elimination half-life to a duration-dependent measure of offset.

Key figures

• Steven L. Shafer
• Peter S. A. Glass
• Thomas D. Egan

Seminal works

• hughes-1992
• shafer-varvel-1991

Frequently asked questions

What is the difference between elimination half-life and context-sensitive half-time?

Elimination half-life is a fixed property describing how fast a drug is ultimately cleared, whereas the context-sensitive half-time is the time for concentration to fall by half after an infusion is stopped and depends on how long the infusion ran, because redistribution between tissue compartments influences the early decline.

Why does remifentanil behave differently from most anesthetic drugs?

Remifentanil is hydrolysed by non-specific esterases throughout the body, giving it a very rapid clearance and an almost constant, short context-sensitive half-time regardless of infusion duration, as described in its pharmacokinetic characterisation by Egan (1995).