Metabolism
The barbiturates (with the exception of phenobarbital) are hepatically
metabolized. The metabolites that are formed are almost all inactive, water soluble,
and excreted in urine. Barbiturates are biotransformed by four processes: (1) oxidation
of the aryl, alkyl, or phenyl moiety at C5; (2) N-dealkylation; (3) desulfuration
of the thiobarbiturates at C2; and (4) destruction of the barbituric acid ring.[295]
[296]
Oxidation is the most important pathway,
and
it produces polar (charged) alcohols, ketones, phenols, or carboxylic acids. These
metabolites are readily excreted in urine or as glucuronic acid conjugates in bile.
The barbituric acid ring is so stable in vivo that hydrolytic cleavage of the ring
is a minimal contribution to the total metabolism of barbiturates. Drugs that induce
oxidative microsomes enhance the metabolism of barbiturates. Chronic administration
of barbiturates will also induce the enzymes.[296]
Thus, biotransformation of barbiturates may be enhanced in patients taking drugs
that are known to induce hepatic microsomes. The induction of hepatic enzymes by
barbiturates is responsible for the recommendation that they not be administered
to patients with acute intermittent porphyria. Barbiturates may precipitate an attack
by stimulating γ-aminolevulinic acid synthetase, the enzyme responsible for
the production of porphyrins.[297]
As mentioned earlier, hepatic metabolism accounts for elimination
of all the barbiturates with the exception of phenobarbital. Renal excretion is
important in the elimination of phenobarbital and accounts for 60% to 90% of the
drug being excreted in unchanged form.[298]
Thirty
percent of phenobarbital is excreted in urine, but only trivial amounts of other
barbiturates are excreted unchanged by the kidney. Alkalinization of urine with
bicarbonate enhances the renal excretion of phenobarbital. As the pH of urine increases
throughout the tubules, the concentration of the undissociated form of phenobarbital
decreases, thereby creating an increased gradient across the lipid tubular epithelium
that results in increased flow of the undissociated form of phenobarbital (lipophilic)
from the renal parenchyma into the tubular lumen.[298]
[299]
Methohexital is metabolized in the liver by oxidation to an alcohol;
N-dealkylation also occurs. When compared with thiopental, methohexital exhibits
similar distribution half-lives, volumes of distribution, and protein binding. A
marked difference exists, however, in plasma disappearance and elimination half-lives
(4 hours for methohexital and as many as 12 hours for thiopental). This difference
is due to the threefold greater rate of hepatic clearance of methohexital, with the
mean ranging from 7.8 to 12.5 mL/kg/min.[32]
The
hepatic extraction ratio of methohexital (clearance/hepatic blood flow) is approximately
0.5, thus indicating that the liver extracts 50% of the drug presented to it. In
contrast, the hepatic extraction ratio of thiopental is 0.15.
