Pharmacokinetics
The pharmacokinetics of barbiturates has been described in both
physiologic and compartmental models, with the latter gaining more support in recent
years.[33]
[41]
[300]
[301]
Physiologic
models of barbiturates describe rapid mixing of the drug with the central blood volume
followed by quick distribution of the drug to the highly perfused, low-volume tissues
(i.e., brain) and slower redistribution of the drug to lean tissue (muscle), which
terminates the effect of the induction dose. In these models, uptake by adipose
tissue and metabolic clearance (elimination) play only a minor role in termination
of the effects of the induction dose because of the minimal perfusion ratio in comparison
to other tissues and the slow rate of removal, respectively. Compartmental model
values for thiopental
and methohexital, the most commonly used barbiturates for induction, are given in
Table 10-1
. Both these pharmacokinetic
models describe rapid redistribution as the primary mechanism that terminates the
action of a single induction dose.[302]
The compartmental
model explains the delay in recovery when a continuous infusion of a barbiturate
is used. This model describes the phenomena whereby the termination of effect becomes
increasingly dependent on the slower process of uptake into adipose tissue and elimination
or clearance through hepatic metabolism. After prolonged infusions, the pharmacokinetics
of barbiturate metabolism is best approximated by nonlinear Michaelis-Menten metabolism.
In usual doses (4 to 5 mg/kg), thiopental exhibits first-order
kinetics (i.e., a constant fraction of drug is cleared
from the body per unit time); however, at very high doses of thiopental (300 to 600
mg/kg) with receptor saturation, zero-order kinetics occurs (i.e., a constant amount
of drug is cleared per unit time). Because the volume of distribution is slightly
larger in female patients, elimination half-lives are longer in this group.[42]
Pregnancy also increases the volume of distribution of thiopental, thereby prolonging
the elimination half-life.[303]
As noted earlier,
the clearance rate of thiopental is not altered in patients with cirrhosis because
the amount of protein available for the drug to bind to is still adequate even at
fairly advanced stages of the disease process.[304]
Because of its affinity for fat, relatively large volume of distribution,
and low rate of hepatic clearance, thiopental can accumulate in tissues, especially
if given in large doses over a prolonged period. Accumulation of thiopental was
shown to occur in studies conducted by Dundee and associates in which the plasma
drug level increased when repeat doses of drug were given.[305]
Obese patients are likely to have prolonged clearance half-lives of thiopental.
[306]
Approximately designed infusion schemes ensure
relatively constant blood levels, thus maintaining the hypnotic effect.
