Sedative/Hypnotic Drugs

Thiopental has a small hepatic extraction ratio, and therefore its metabolism and clearance should be adversely affected in patients with liver disease. However, available data suggest that the elimination half-life of thiopental is unchanged in cirrhotic patients, possibly because of a large volume of distribution. ^{[60] [61]} A prolonged effect from standard doses of thiopental thus seems unlikely in this patient population. In contrast, other intravenous anesthetics, including methohexital, ketamine, etomidate, and propofol, are highly lipid soluble, are metabolized by the liver, have a large hepatic extraction ratio, and would be expected to have diminished clearance in the presence of advanced liver disease.^[62] Despite this pharmacokinetic profile, limited data indicate that etomidate clearance is unchanged in cirrhotic patients, although increased volumes of distribution may prolong the elimination half-life and result in unpredictable recovery times.^[63] Methohexital and propofol also have an elimination kinetic profile in cirrhotic individuals that is similar to that in normal patients,^[62] both after single-bolus administration of propofol^[64] and after propofol infusion.^[65] However, mean clinical recovery times may be longer after discontinuation of propofol infusions in cirrhotic patients.^[65] The reduced clearance of midazolam in patients with end-stage liver disease produces prolonged elimination half-lives.^{[66] [67]} In conjunction with reduced protein binding and increased free fractions of midazolam, a prolonged duration of action and an enhanced sedative effect should be anticipated in patients with severe liver disease, especially after multiple doses or prolonged infusions. Similar changes have also been observed with diazepam.^[67]

Dexmedetomidine, an α₂ -adrenergic agonist with sedative and analgesic properties, is primarily metabolized in the liver with minimal renal clearance. Preliminary data from patients with hepatic failure of varying severity demonstrated significantly decreased clearance, prolonged half-lives, and lower bispectral index (BIS) values than in normal control patients.^[68] Dosage adjustments are therefore indicated when dexmedetomidine is used in patients with significant hepatic dysfunction. This evidence mirrors, in part, findings from dexmedetomidine use in individuals with renal dysfunction, where prolonged sedation despite unchanged pharmacokinetics has been attributed to altered protein binding, a factor that also applies to patients with hepatic dysfunction.^{[69] [70]}

In summary, despite substantial hepatic metabolism of most intravenous anesthetic induction agents, limited evidence from single-dose pharmacokinetic studies suggests that cirrhosis generally has minimal impact on the pharmacokinetic profile of sedative/hypnotic drugs. However, the clinical effect and duration of action of benzodiazepines are more pronounced in the presence of severe liver disease. It is probably prudent to administer all these drugs cautiously when using repeated dosing or prolonged infusions, either in the operating room or in the intensive care unit, where drug accumulation, prolongation of effects, and increased risk of hepatic encephalopathy can be anticipated.