Intravenous Anaesthetic Agents: Pharmacokinetic-Pharmacodynamic Relationships

The number and variety of intravenous anaesthetics available has increased dramatically in recent years. In order to administer these agents safely and rationally in the operating theatre, the anaesthesiologist needs to have a detailed understanding of their dose-response behaviour. The pharmacokinetic and pharmacodynamic profiles of these anaesthetics underlie this behaviour. In understanding and applying this information, an integrated approach involving combined pharmacokinetic and pharmacodynamic modelling has proved tremendously helpful. This approach has provided significant insight into the pharmacology of these drugs under conditions of normal and abnormal physiology. Intravenous anaesthetics may be classified as hypnotics, narcotics, or muscle relaxants. Through quantitative measures or drug effect, as provided by the electroencephalogram (EEG) in the former two classes or electromyography in the latter class, precise measures of end-organ (brain or neuromuscular junction) sensitivity have been generated using integrated modelling techniques. These values not only allow for dose potency comparisons within an anaesthetic class but, furthermore, may explain changes in drug response with ageing and disease. Incorporation within these models of an effect compartment, characterised by a rate constant for equilibration with plasma (k_eo), has proved to be essential in accurately describing the temporal lag between drug administration and effect. Quantitating the size of this lag has direct implications for the design of anaesthetic bolus and infusion regimens. Combined pharmacokinetic and pharmacodynamic modelling of intravenous anaesthetics provides a precise, rational basis for the clinical use of these classes of drugs.