Mechanisms responsible for disproportional sedation resulting from triazolam administration to patients with cirrhosis were investigated. Ordinary sedative doses (0.26 mg) were given p.0. to 8 cirrhotics and 18 controls. Plasma concentrations of unbound drug were assessed by capillary gas chromatography and equilibrium dialysis. Median apparent oral clearances of unbound triazolam were 14.8 ml per min per kg in cirrhotics and 23.9 ml per min per kg in controls (p < 0.01). Clearances were significantly correlated with severity of liver disease as 898888ed by the aminopyrine breath test (Rs = 0.77, n = 17, p < 0.001). At a time when plasma concentrations of unbound triazolam were the same in both groups, i.e., 2.25 hr after dosing, flicker sensitivity at 5 Hz which was used as an index of CNS performance was impaired by a factor of 3.2 in cirrhotics and 1.4 in controls (p < 0.01 for group difference). Performance was also significantly lower in cirrhotics with the digit symbol substitution test (p < 0.05). It is concluded that, in patients with cirrhosis, disproportional sedation after b e d a z e p i n e administration may be due not only to impaired drug elimination, but also to hypersensitivity of the brain.
In patients with cirrhosis, adequate treatment of insomnia and anxiety, e.g., associated with endoscopy, has remained controversial. Generally, hepatologists agree that in some cirrhotics ordinary doses of sedatives may lead to disorientation and coma (1). Several studies seem to support this contention: investigations with morphine (8 mg s.c.) (2), chlorpromazine [l mg per kg p.0. (3) and 25 mg i.v. (4)], and diazepam [variable i.v. doses ( 5 ) and 0.25 mg per kg i.v. (6)] and midazolam (0.075 mg per kg i.v.) (7) have demonstrated that some cirrhotics suffer from disproportional drug responses as assessed by clinical observation, psychometric testing and EEG. A history of hepatic encephalopathy or abnormalities in predrug measurements tended to be associated with oversedation. Murray-Lyon et al. (8), however, found neither a tendency to develop increased slow wave activity in the