Lack of effect of nitrendipine on the pharmacokinetics and pharmacodynamics of midazolam during steady state.
1. The possible interaction (as indicated by rat experiments) between calcium channel blocking agents and benzodiazepines has been evaluated in nine healthy subjects. 2. Subsequently to an intravenous loading dose (0.07 mg kg-1) midazolam was infused for 6 h (0.035 mg kg-1 h-1) and steady state plasma levels between 54 to 114 micrograms l-1 were achieved. Two hours after the bolus of midazolam a solution of 20 mg nitrendipine or placebo was administered in a randomized, double-blind crossover fashion. 3. The marked sedative-hypnotic effects of midazolam as assessed by visual analogue scales (about four fold increase in the sedation index) and choice reaction time (100% prolongation) indicated some form of adaptation or tolerance towards the end of the infusion. However, the midazolam-induced impairments were not affected by nitrendipine. 4. EEG-data indicated stabile benzodiazepine-like effects during the complete infusion period of midazolam (e.g. decrease in alpha activity, increase in sigma, delta 2 and beta 1 activity). Again, these alterations were not modified by nitrendipine. 5. There was also no pharmacokinetic interaction between both agents, since elimination of midazolam (t 1/2 = 2.5 +/- 0.8 h; CL = 548 +/- 143 ml min-1) was in close agreement with control values (t 1/2 = 2.4 +/- 0.6 h; CL = 512 +/- 102 ml min-1). Likewise, plasma levels of nitrendipine were comparable to literature data. 6. Thus, it could be concluded that nitrendipine does not affect the action of midazolam and therefore a direct involvement of calcium at the benzodiazepine receptor site is unlikely under our clinical conditions.
Handel
J
J
Dr Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart FRG.
Ziegler
G
G
Gemeinhardt
A
A
Stuber
H
H
Fischer
C
C
Klotz
U
U
D000328:Adult; D004347:Drug Interactions; D004569:Electroencephalography; D005260:Female; D006801:Humans; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics* / Q000494:pharmacology; D009568:Nitrendipine / Q000493:pharmacokinetics / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects
D009568:Nitrendipine; D008874:Midazolam