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Pharmacokinetics of Intravenous Anaesthetics: Implications for Clinical Use

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Summary

Intravenous anaesthetics comprise a variety of drugs that differ in chemical structure but share a suitable combination of physical properties that confer ready penetration of the blood-brain barrier. Lipid solubility is particularly important in this respect. Rapid entry into the brain is associated with rapid distribution and redistribution in the body for most of these drugs. They all readily cross the placenta to the fetus. Rate of metabolism varies between the rapidly biotransformed drugs like propanidid to the slowly metabolised ones like thiopentone. The liver is the main site of biotransformation, with the exception of propanidid which is hydrolysed by plasma pseudocholinesterase. Recovery of mental and psychomotor functions is protracted compared with inhalation anaesthetics, except after propanidid.

Thiopentone confers a two- or three-compartment open model system on the body, with an average elimination half-life of 6.2 hours: Rapid initial recovery is due to redistribution to the muscle mass. Distribution is modified by the stale ofionisalion of the drug and its magnitude of binding to plasma proteins.

Melhohexilone has an elimination half-life of 70 to 125 minutes, which is the result of a high plasma clearance rate. However, complete psychomotor recovery seems to lake the same length of time after the use of thiopentone and methohexitone in equianeasthetic doses.

Droperidol exhibits two-compartment open model kinetics with a mean elimination half-life of 2.2 hours. It is 85 to 90% bound to plasma proteins at therapeutic levels and accumulates in certain brain areas. Fentanyl has a half-life of 1 to 4 hours or more, depending on the dosage given. The drug can therefore accumulate in the body after large or multiple doses, in spile of its reputation as a short-acting narcotic.

Ketamine has a half-life of 4 hours or longer. It is poorly bound to plasma proteins. Some of its metabolites are pharmacologically active. The relation between the plasma levels of the drug and its metabolites and incidence of post-drug hallucinations and dreams need to be studied.

The kinetics of propanidid follow a one-compartment open model. It is rapidly hydrolysed in plasma and the duration of anaesthesia is influenced by pseudocholinesterase activity.

Althesin (alphadione) is a mixture of 2 steroids (alphaxalone and alphadolone). Alphaxalone is rapidly metabolised in the liver and then excreted in the urine. The pharmacokinetics of alphadolone have not been studied. The accumulation of Althesin after repealed doses and late impairment of driving skills have initial recovery may suggest the formation of pharmacologically active metabolites.

Plasma level data of intravenous diazepam can be fitted with a three-compartment open model system. It has an elimination half-life of 21 to 37 hours which is age dependent and is prolonged in patients with liver disease. It is highly bound to plasma proteins and occasionally fluctuations in plasma concentrations may coincide with subjective recurrence of drowsiness.

Etomidate is a new carboxylated imidazole derivative. Return of the drug to the central compartment from the deep peripheral compartment may be the rate controlling step in elimination of the drug. The major metabolic pathway is hydrolysis of the ethyl ester, which probably occurs mainly in the liver.

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  1. Department of Anesthesia, University of Iowa Hospitals, Iowa City, Iowa, IA 52242, USA

    M. M. Ghoneim & K. Korttila

  2. University of Helsinki, Helsinki, Finland

    M. M. Ghoneim & K. Korttila

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Ghoneim, M.M., Korttila, K. Pharmacokinetics of Intravenous Anaesthetics: Implications for Clinical Use. Clin Pharmacokinet 2, 344–372 (1977). https://doi.org/10.2165/00003088-197702050-00003

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