Pharmacology for Anaesthesia and Intensive Care

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Section IBasic principles

Applied pharmacokinetics

Propofol

The intravenous anaesthetic propofol has become more popular than thiopental for

induction of anaesthesia as many of its properties approximate to those of the ideal

anaesthetic agent. It can be used both for induction and maintenance of anaesthesia,

and it has become accepted as the anaesthetic agent of choice in daycase surgery

due to its favourable ‘wake up’ profile. Although it is possible to give a bolus dose of

propofol without understanding its pharmacokinetic properties, to use it sensibly

byinfusion requires some understanding of its disposition in the body.

Structure

Propofol is a sterically hindered phenol: the potentially active hydroxyl (-OH) group

is shielded by the electron clouds surrounding the attached isopropyl ((CH 3 ) 2 CH-)

groups, which reduces its reactivity. So, unlike phenol, propofol is insoluble in water

but highly soluble in fat and requires preparation as a lipid emulsion.

Pharmacokinetics

The usual induction dose of propofol is 1.5–2.5 mg.kg−^1 ,which when given intra-

venously is extensively bound to plasma proteins (98% bound to albumin). Following

an induction dose there is rapid loss of consciousness as the lipid tissue of the cen-

tral nervous system (CNS) takes up the highly lipophilic drug. Over the next few

minutes propofol then distributes to peripheral tissues and the concentration in the

CNS falls, such that in the absence of further doses or another anaesthetic agent

the patient will wake up. Its distribution half-life is 1–2 minutes (with distribution to

the lipid tissues) and accounts for the rapid fall in plasma levels with a short duration

of action. The terminal elimination half-life is very much longer (5–12 hours) and

plays little or no role in offset of clinical action following a bolus dose.

Propofol causes peripheral vasodilatation, possibly through nitric oxide release in

asimilar manner to nitrates, so that when used in the elderly or hypovolaemic patient

it may cause profound hypotension. This may be avoided by giving the drug as a slow

infusion, however this results in the plasma concentration rising more slowly and

onset of anaesthesia is delayed.

Context-sensitive half-time

Context-sensitive half-time is discussed above. When propofol is used by infusion

it steadily loads the peripheral compartments; the longer the duration of the infu-

sion, the more peripheral compartment loading will occur. Therefore, following a

prolonged infusion, there will be more propofol to re-distribute from the peripheral

compartments back into the central compartment, which will tend to maintain the

plasma concentration and duration of action. In practice, the longer the duration

of the infusion, the longer the time required before the plasma level falls below that