Nighttime Dosing of Triazolam in Patients with Liver Disease and Normal Subjects: Kinetics and Daytime Effects

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Abstract
This study was designed to determine whether the severity of liver dysfunction in cirrhosis affects the kinetics and next‐day effects of triazolam after bedtime administration of a single oral dose. Eight patients with biopsy‐proven cirrhosis and seven normal subjects matched for age, weight, and sex participated as paid volunteers. The first night was the control night, when no nighttime sedative was administered. The next day, psychomotor testing was performed at 8:30 am, 2 pm, and 5 pm. Triazolam 0.25 mg was administered at 10:30 pm that evening. Psychomotor testing was repeated on the posttriazolam day in the same manner as on the control day. Blood samples were obtained from a venous catheter at 11 predetermined times in the 14 hours after triazolam administration. Memory testing was also performed. Apparent oral clearance of triazolam was directly related to albumin concentration and indocyanine‐green elimination rate constant, and inversely related to partial thromboplastin time expressed as seconds over control. Clearance was 6.69 ± 2.52 mL/min/kg in the normal subjects and 4.99 ± 3.14 in the subjects with cirrhosis. There were no significant differences in Cmax between normal subjects (1.43 ± 0.44 ng/mL) and subjects with cirrhosis (1.62 ± 0.31 ng/mL) or in tmax (2.0 ± 1.0 vs 2.5 ± 1.9 hr) between normal and cirrhosis subjects, respectively. Posttriazolam, cirrhotic subjects took significantly longer to sort cards at 8:30 am than on the control day. There was a significant correlation between extent of impairment on 8:30 am card sorting by suit and AUC0–8 (r = 0.687; P = 0.0046). For all tests other than card sorting, there was less than a 15% change from control day performance. Both normal and cirrhosis subjects recalled significantly fewer items from the two‐hour posttriazolam presentation of items than they did on the control night. Thus, the presence of cirrhosis decreases the clearance of triazolam, with the extent of the reduction depending on the severity of the liver dysfunction. Most subjects had minimal daytime psychomotor impairment after receiving triazolam 0.25 mg at bedtime. However, compared with controls and subjects with minimal liver dysfunction, subjects with severe liver disease have greater psychomotor impairment at 8:30 am, which is explained by higher concentrations of triazolam during the night. Whether cirrhotic patients are additionally more sensitive than control subjects cannot be determined from this study. If nighttime sedation with triazolam is deemed appropriate, patients with severe liver dysfunction should receive 0.125 mg as the starting dose.