Opipramol

Opipramol has high affinity for the sigma binding sites (type 1 and type 2) and has an antagonistic effect at the type 1 histamine receptors. The affinity for the type 2A serotonin receptors, type 2 dopamine receptors and the α-adrenergic receptors is lower. In contrast to the structurally related tricyclic antidepressants, opipramol has only slight anticholinergic activity and does not inhibit the reuptake of serotonin or noradrenaline.

Opipramol has a modulating effect on the NMDA system through the sigma receptors; protective effects against neuron loss due to ischaemia in the hippocampus region were demonstrated in animal experiments.

The dopamine turnover is increased. Similar modulating effects are described for sigma ligands in the serotoninergic and noradrenergic system also. Opipramol, like other more selective sigma ligands, is active in pharmacologic behavioural models, which are indicative of anxiolysis, and has comparatively lower activity in the swimming test in the rat, which is used as a screening method for potential antidepressants.

In humans, opipramol has sedating, anxiolytic and slight mood-elevating effects.

Following oral ingestion, opipramol is absorbed rapidly and completely. Partial metabolism to dehydroxyethyl-opipramol takes place during its passage through the liver. The plasma protein binding is about 91%, the distribution volume is approx. 10 l/kg and the elimination half-life is about 11 hours.

Opipramol is essentially metabolised by the CYP2D6 isoenzyme. In patients with CYP2D6 deficiency (“poor metabolisers”) the maximum plasma concentration of opipramol can be up to 2.5 times higher than with normal metabolism. However, the elimination half-life is not prolongated with chronic use, so that accumulation of opipramol is not to be expected even in slow metabolisers.

The acute toxicity is relatively low. Intoxication symptoms affect the CNS predominantly. Subchronic and chronic administration of very high doses causes CNS symptoms, liver and lung damage, skin and coat changes and cataract formation in certain species.

In vitro and in vivo studies gave no evidence of mutagenic potential. Animal experiments yielded no evidence of an impairment of fertility by opipramol. In embryotoxicity studies no teratogenic effects occurred but embryotoxic effects were observed in the maternal toxic dose range. Studies of peri- and postnatal toxicity were not performed.