To study the effects of cirrhosis of the liver on the pharmacokinetics of midazolam single IV (7.5 mg as base) and p.o. (15.0 mg as base) doses of midazolam were administered to seven patients with cirrhosis of the liver and to seven healthy control subjects. One cirrhotic patient did not receive the oral dose. The distribution of midazolam in both study groups was alike as indicated by similar values of t1/2 alpha, V1 and Vss. Also the plasma protein binding of midazolam was unchanged in the patients with cirrhosis. The elimination of midazolam was significantly retarded in the patients as indicated by its lower total clearance (3.34 vs. 5.63 ml/min/kg), lower total elimination rate constant (0.400 vs. 0.721 h-1), and longer elimination half-life (7.36 vs. 3.80 h). The bioavailability of oral midazolam was significantly (P less than 0.05) higher in patients than controls (76% vs. 38%). The antipyrine-half-life was 32.4 h in the patients and 11.8 h in the controls. There were statistically significant (P less than 0.01) correlations between the clearances of the two drugs (r = 0.680) and between their half-lives (r = 0.755). The hypnotic effects of midazolam were similar in both groups. However, on a pharmacokinetic basis a reduced dosage of midazolam to patients with advanced cirrhosis of the liver is recommended.
The comparative pharmacodynamics of midazolam and diazepam were examined by use of the electroencephalogram as a measure of drug effect on the central nervous system. Intravenous doses of 7.5, 15, and 25 mg midazolam and 15, 30, and 50 mg diazepam were given on repeated occasions to three volunteers. Arterial plasma concentration and electroencephalogram voltage were related with nonparameteric and parametric pharmacodynamic models. The peak increases in voltage (maximal effect) and the slopes of the plasma concentration versus effect curve were similar for both drugs. The half-time of blood:brain equilibration was significantly longer for midazolam than diazepam (4.8 minutes versus 1.6 minutes). Midazolam was found to have an intrinsic steady-state potency that was approximately five times greater than that of diazepam (152 ng/ml versus 958 ng/ml).
1 In a double-blind, cross-over study in six healthy volunteers, the effects of different oral doses of midazolam (10, 20 and 40 mg), or 0.15 mg kg-'midazolam administered intravenously and of placebo were investigated. Plasma concentrations of midazolam and of its active a-hydroxy metabolite were measured at the same time. 2 The effect was assessed using objective and subjective methods (reaction time, tracing test, subjects' self-assessment and investigator's subjective assessment). 3 The respective time courses of the plasma concentration and of the effect (reaction time, number of errors in the tracing test) were almost identical. Peak plasma levels and maximum effects were attained within 30 min. In general, the effect after intravenous injection of 0.15 mg kg-' and after an oral dose of 10 mg midazolam lasted for 2 h following administration and its duration was doubled (i.e. to 4 h) after the 20 mg oral dose. Between the logarithm of the plasma concentration and the effect, there is a sigmoidal relationship that is virtually time independent. 4 Particularly in the first few hours after oral administration the effect is intensified by the a-hydroxy metabolite of midazolam which is formed by first-pass metabolism. 5 At identical plasma concentrations of midazolam, the oral dose produced more marked effects than did the intravenous administration. 6 Correlation of the measured effects with the total (midazolam + a-hydroxy midazolam) plasma concentration reveals a closer sigmoidal relationship.
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