Monoamine oxidase inhibitors (MAOI) in clinical use have an irreversible action on MAO, and this persists until the enzyme has been resynthesized. The effects of small daily doses of MAOI are therefore cumulative. The biochemical effects of these drugs will involve several substrates of MAO, e.g. dopamine, tyramine, serotonin and, to a lesser extent, noradrenaline and adrenaline. MAO probably regulates the metabolism of catecholamines and serotonin in tissues, while catechol-O-methyltransferase is responsible for the metabolism of circulating noradrenaline and adrenaline. Certain pharmacological effects of MAOI are related to the accumulation of monoamines in various tissues that follows the decrease of intraneuronal deamination. Among these effects are reversal of the reserpine syndrome in animals and augmentation of the pharmacological action of monoamines. Other effects are unrelated to the inhibition of MAO, e.g. immediate desynchronization of EEG and initial pressor effects. MAOI may potentiate or change the action of several other drugs and even certain foods. The mechanisms involved are usually reasonably predictable from animal experiments. Substrates of MAO, e.g. dopamine and tyramine, evoke augmented and prolonged effects in patients treated with MAOI. This is partly due to an impaired metabolism of the circulating amines. In addition, inhibition of intestinal and hepatic MAO largely increases the absorption of tryamine from cheeses and other foods. Usually innocuous amounts of tyramine may therefore cause hypertensive reactions in patients treated with MAOI. Indirectly acting sympathomimetic amines, such as amphetamines, ephedrine and MAOI with amphetamine-like properties, can be potentiated, because they may release increased amounts of nor-adrenaline from sympathetic nerve endings after MAO inhibition. The effects of any amine, whether a substrate of MAO or not, may be enhanced by MAO inhibitors producing postganglionic block. This is due to ‘denervation’ supersensitivity of adrenergic receptors. Harmful pharmacological interaction is also possible between MAO inhibitors and agents which release (reserpine) or replete (amine precursors, e.g. L-DOPA in broad beans) monoamines centrally and peripherally. Drugs that sensitize adrenergic and tryptaminergic receptors to the action of monoamines, e.g. imipramine-like compounds, may be greatly potentiated by MAO inhibitors. The anti-hypertensive effects of thiazides and ganglion-blocking agents may be enhanced by MAOI. A few drugs are known to exert prolonged effects in occasional patients treated with MAOI, e.g. pethidine, phenothiazines and pentobarbital. MAOI may possibly decelerate the metabolism of these compounds by a nonspecific inhibition of liver microsomal enzymes. Finally, a great number of agents have been found empirically to evoke augmented effects after inhibition of MAO, e.g. insulin and anti-Parkinson drugs.
Inhibition of monoamine oxidase–A activity in rat brain by synthetic hydrazines: Structure-activity relationship (SAR)
