Section A The pharmacology of lorazepam, a broad-spectrum tranquillizer

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Abstract
Lorazepam (Wy 4036; 7-chloro-5-[o-chlorophenyl]-3-hydroxy-1, 3-dihydro-2H-1, 4-benzodiazepin-2-one) is a new minor tranquillizer of the benzodiazepine class. Compared with a number of other benzodiazepines, lorazepam was the most potent agent tested in a variety of potentially predictive anti-anxiety tests: i.e. treadmill avoidance studies, fighting mice and conditioned suppression learning tests. In addition, lorazepam exhibited potent anticonvulsant activity against metrazol convulsions and electroshock seizures. Motor inco-ordination or ataxia was a prominent feature of the benzodiazepine drugs, but the separation of 'effective' and depressive doses of lorazepam, in the above tests, suggested there is likely to be a wide separation of anti-anxiety and sedative doses in man. The demonstration that lorazepam was the most effective benzodiazepine tested in suppressing fear-conditioning in rats means that the drug is likely to cause amnesia for unpleasant, essentially painful experiences. This action was not associated with analgesia. These results provide good evidence for the 'specificity' of lorazepam's anti-anxiety potential, and support the lack of toxicity of the compound. In behavioural studies in monkeys, lorazepam produced long periods of obvious sedation at doses which caused only minimal initial episodes of pronounced depression, as measured by the animal's toleration of being placed in lateral recumbency. Since in man it has been shown that only minimal cardiovascular effects occur at doses of lorazepam causing long periods of hypnosis, the pronounced cardiovascular depression observed in animal experiments is probably of little importance. The results of drug-interaction experiments between lorazepam and thiopentone sodium suggest that although potentiation occurs, a change in the amount of thiopentone required to induce anaesthesia is likely to be necessary only after doses of lorazepam are used which are larger than those envisaged for clinical use. Whilst lorazepam exhibited muscle relaxant properties in its own right, intermediate in potency between that of diazepam and oxazepam, in whole animal experiments, there was no evidence in decerebrate cats to show that lorazepam or diazepam either potentiate or reduce the effects of the skeletal neuromuscular blocking agents, suxamethonium or gallamine, with regard to either their intensity or duration of action. In other experiments, it was found that alteration of the analgesic action of morphine by lorazepam is unlikely to be of practical significance when these agents are used concurrently in man. In addition, observations in rats and mice provided evidence that an interaction of lorazepam given initially and morphine subsequentially is unlikely with therapeutic doses in man. In fact, the results indicate that any interaction of excessive doses of lorazepam is likely to be beneficial or protective rather than adverse.

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