Relationship between tyramine potentiation and monoamine oxidase (MAO) inhibition: comparison between moclobemide and other MAO inhibitors

The pharmacodynamic properties of moclobemide, a reversible inhibitor of MAO-A (RIMA), were compared with the properties of other reversible as well as older irreversible MAO inhibitors in human subjects. All the substances supposed to have MAO-A-inhibitory activity, with the exception of toloxatone, were shown by the decrease in plasma DHPG or MHPG levels to cause inhibition ranging between 50% and 85%. Toloxatone and low doses of deprenyl (a MAO-B inhibitor) caused 20% and 17% inhibition respectively; higher doses of deprenyl, however, strongly inhibited MAO-A. MAO-B inhibition was confirmed for all nonselective and selective MAO-B inhibitors. Moclobemide and clorgyli-ne were found to be the most highly selective MAO-A inhibitors, although both also inhibited 30% of platelet MAO-B activity. Potentiation of the tyramine pressor effect is mainly influenced by the irreversibility and degree of MAO-A inhibition. Tyramine sensitivity was raised (a factor of 10–30) by all irreversible MAO inhibitors in doses inhibiting MAO-A; it diminished with increasing reversibility. In therapeutic doses, moclobemide potentiated the intravenous tyramine pressor effect 3 times less than the old irreversible MAO inhibitors; with the highest therapeutic dose, the tyramine sensitivity factor for moclobemide is only one-seventh to one-tenth that of tranylcypromine or phenelzine. Duration of action is obviously also closely related to the reversibility of inhibition: it ranged from up to 2 days with high doses of moclobemide to 3 weeks with tranylcypromine; clorgyline and phenelzine have been shown to maintain their action for several months. The new generation of RIMAs represents a significant progress in safety. Among the RIMAs having significant pharmacodynamic activity, moclobemide appears to be the safest, the most selective and the most readily reversible.