Pinazepam: review of pharmacological properties and therapeutic efficacy

Pinazepam, a benzodiazepine derivative, differs from other drugs of its class by the presence of an unsaturated bond, the propargyl group, at the N-1 position. Its toxicity is less than that of diazepam. In animals, pinazepam controls anxiety and aggressiveness. This effect seems to be associated with a particularly low hypnotic effect and with a limited impairment of motor coordination. Pinazepam shows less cortical activity at the anxiolytic level than does diazepam on EEG. The drug's mechanism of action primarily involves modification in the region of the limbic system. Extensive pharmacokinetic studies have demonstrated rapid gastrointestinal absorption of pinazepam. The metabolic pathway is N-1 dealkylation and C-3 hydroxylation. In dogs, pinazepam reaches the steady state in one day and its main metabolite, depropargylpinazepam (N-desmethyldiazepam) in six days, thus achieving a much higher blood concentration than the parent drug. In rabbits, a first-pass effect is evident. Both compounds are converted to oxazepam, which is pharmacologically inactive and is eliminated in the urine. Pinazepam and depropargylpinazepam cross the placenta and appear in human milk. In dogs, accumulation could not be demonstrated at the end of treatment with 10 mg of pinazepam for 20 days. All the findings in animals were confirmed in humans. In clinical trials with open or controlled design, pinazepam, compared with diazepam, showed a significant and purely anxiolytic action in patients suffering from anxiety with or without somatic manifestations, particularly in gastrointestinal disorders. Even though it is not a specific hypnotic drug, it seems to help patients in whom the physiological course of the sleep is disturbed. The standard dosage is 10 mg daily, divided in two doses. Pinazepam is well tolerated in humans. About 5% of patients experience mild sedation. Other side effects are infrequent and minor. In the studies there was no evidence of impairment of motor coordination or of intellectual performance. There were no reports of a rebound phenomenon or drug dependence. These findings indicate that pinazepam is a pure anxiolytic agent devoid of hypnotic effect or motor disorders, characteristics that make it a useful drug for daytime use.