Pharmacology for Anaesthesia and Intensive Care

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Section IVOther important drugs

Table 17.1.Kinetics of some benzodiazepines.

Diazepam Midazolam Lorazepam

Protein binding (%) 95 95 95

Elimination half-life (h) 20–45 1–4 10–20

Volume of distribution (l.kg−^1 ) 1.0–1.5 1.0–1.5 0.75–1.30

Active metabolites yes yes no

Clearance (ml.kg−^1 .min−^1 ) 0.2–0.5 6–10 1.0–1.5

Uses

Midazolam is used intravenously to sedate patients for minor procedures and has

powerful amnesic properties. It is also used to sedate ventilated patients in intensive

care.

Kinetics

Midazolam may be given orally (bioavailability approximately 40%), intranasally or

intramuscularly as premedication. It has a short duration of action due to distribu-

tion. It is metabolized by hydroxylation to the active compound 1-αhydroxymidazo-

lam, which is conjugated with glucuronic acid prior to renal excretion. Less than 5%

is metabolized to oxazepam. It is highly protein bound (approximately 95%) and has

an elimination half-life of 1–4 hours. At 6–10 ml.kg−^1 .min−^1 its clearance is larger than

that of diazepam and lorazepam so that its effects wear off more rapidly following

infusion.

Alfentanil is metabolized by the same hepatic P450 isoenzyme (3A3/4), and when

administered together their effects may be prolonged.

Diazepam

Diazepam has a high lipid solubility, which facilitates its oral absorption and its

rapid central effects. It is highly protein bound (approximately 95%) to albumin

and is metabolized in the liver by oxidation to desmethyldiazepam, oxazepam and

temazepam all of which are active. It does not induce hepatic enzymes. The glu-

curonide derivatives are excreted in the urine. It has the lowest clearance of the

BDZs discussed here and its half-life is hugely increased by its use as an infusion (cf.

context-sensitive half-time, p.77).

Itmay cause some cardiorespiratory depression. Liver failure and cimetidine will

prolong its actions by reducing its metabolism. When administered with opioids or

alcohol, respiratory depression may be more pronounced. In common with other

BDZs it reduces the MAC of co-administered anaesthetic agents.

Lorazepam

Lorazepam shares similar pharmacokinetics and actions to other BDZs although its

metabolites are inactive. It is used for premedication as an anxiolytic and amnesic.