Interaction of H₂‐receptor antagonists and benzodiazepine sedation

Abstract

SummaryH,-receptor antagonists differentially inhibit cytochrome P450 and this may affect the rate at which benzodiazepines are metabolised. However, it is not known whether this delayed clearance results in prolonged psychomotor impairment. In a randomised double-blind trial 28 healthy volunteers received two single doses of midazolam (0.07 mg.kg-') at an interval of one week during which they took cimetidine 400 mg, ranitidine 150 mg or placebo, each twice daily. Recovery from the benzodiazepine was monitored on each occasion over a 12 h period using a battery of psychometric tests. There was wide individual variation in performance; however, an overall measure of impairment indicated a significant difference at 2.5 h ( p < 0.05), the cimetidine group having a high impairment score. This decrement appeared to be in cognitive and psychomotor functions and was not rejected in the subjective assessment. Key wordsHistamine; cimetidine, ranitidine. Recovery; psychometric tests. Hypnotics, benzodiazepines; midazolam.Cimetidine and ranitidine aid peptic ulcer healing by reducing the gastric acid output as a result of their H,-receptor blocking action. They may also relieve heartburn in peptic oesophagitis, in high doses reduce gastric acid output in the Zollinger-Ellison syndrome, and inhibit acid breakdown of pancreatic enzyme supplements. Patients with these symptoms are routinely referred for day-case endoscopy for which benzodiazepines are used as sedation. It is essential to establish which factors will affect the rate of recovery after sedation in order to predict the extent of residual functional impairment in patients released into the community.It is well known that cimetidine inhibits cytochrome P450 [I] and thus slows the metabolism of diazepam [2] and midazolam [3]. Ranitidine also inhibits P450, but to much less an extent than cimetidine [4] and studies of its effect on the metabolism of these benzodiazepines have provided contradictory results [5-71.Theoretically, those patients taking cimetidine will metabolise benzodiazepines more. slowly than those receiving ranitidine. If the rate of metabolism of the sedatives may be differentially affected by those two H,-receptor blockers, then it is necessary to determine whether the rate of psychomotor recovery is also differentially affected. It has not been established whether this reduced hepatic metabolism of the benzodiazepines results in prolonged psychomotor impairment. Studies which have used psychometric tests have not provided conclusive evidence. Dundee and colleagues [5] found no significant effect of ranitidine on a single dose of midazolam on observer assessment of sedation. Although Gough and colleagues [S] found a significant difference in the plasma concentrations and of the elimination half-life of diazepam after cimetidine compared to placebo, they found no significant difference in cognitive impairment using the Digit Symbol Substitution Test (DSST) and visual analogue scales (VAS). Similarly Greenblatt and colleagues [9] administered cimeti...

Drugs That Disturb Sleep and Wakefulness

“…163 Similarly, cimetidine has been shown to increase levels of theophylline, carbamazepine, and beta-blockers, with resultant increases in the CNS effects of these drugs. 166 One crossover study comparing 1-week administration of cimetidine, famotidine, ranitidine, and placebo in normal subjects reported no differences in nocturnal sleep or daytime MSLT latencies, although cimetidine produced a slight increase in subjective estimates of sleepiness.…”

Adverse drug interactions in dentistry

“…Similarly, cimetidine (Tagamet ® ) may inhibit CYP3A4 oxidative metabolism of diazepam, triazolam, and alprazolam. Half‐life increases of 30–63% have been reported (4, 79, 206). Elevations of these benzodiazepine blood concentrations would be associated with increased sedation and psychomotor performance deficits.…”