Phenelzine

UNDER REVIEW (September 2016)

Mechanism of Action:

A non-selective monoamine oxidase (MAO) inhibitor used as an antidepressant. MAO metabolises catecholamines, which are important as neurotransmitters in the central nervous system. There are two MAO isoenzymes – MAO-A primarily oxidises noradrenaline and serotonin (5-HT) while MAO-B oxidises phenylethylamine. Both oxidise dopamine and tyramine. Phenelzine is a derivative of hydrazine, which is phenylethylamine-like moiety and similar to normal substrates of MAO. When MAO tries to oxidize phenelzine, this hydrazine-moiety binds covalently to the enzyme, thus inactivating it irreversibly. Therefore, phenelzine is a non-competitive, long-lasting inhibitor of the MAO enzymes. Inhibiting MAO raises the levels of the substrates of MAO in synapses, like 5-HT, dopamine and noradrenaline. Accumulation of catecholamines mean increased transmitter release during an action potential, thereby increasing the probability of activating postsynaptic receptors for the particular neurotransmitter. Furthermore, primarily through its primary metabolite, PEH (phenylethylidenehydrazine), phenelzine elevates levels of GABA in the caudate-putamen and nucleus accumbens. This may contribute to its anxiolytic properties and superior efficiacy in treating severe anxiety.

Lecture and CAL materials:

• Lecture: Neuropharmacology Introduction
• Lecture: Drugs affecting mood and cognition

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Drug specifics

Alternative drug name	not specified
Effects	Monoamine oxidase inhibitors (MAOIs) are a powerful class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression. The potentially serious dietary and drug interactions mean that they are now reserved as third line treatment when other classes of antidepressant drugs (tricyclic antidepressants and selective serotonin reuptake inhibitors) have been tried unsuccessfully. MAOIs potentiate the effects of catecholamine neurotransmitters which are ‘excitatory’, and are associated with feelings of excitement, euphoria, and anxiety.
Adverse actions	Common side-effects include orthostatic hypotension and dizziness mainly due to decreased noradrenaline action as a result of accumulation of dopamine in synaptic vesicles. Others are headache, fatigue, insomnia, sexual difficulty, hesitant urination. Most of these side effects dissipate after adjusting to the medication. As with other MAOIs, tyramine-containing foods have the potential to cause a serious hypertensive crisis therefore users of phenelzine should adhere to certain dietary guidelines, primarily consisting of avoiding certain aged wines and spirits, and certain aged cheeses.
Dose	Phenelzine is administered orally as phenelzine sulphate. Although phenelzine itself has a fairly short half-life in the body before hepatic acetylation and urinary excretion, its clinical effect lasts for several weeks (because of irreversible covalent binding to the receptor), until new functional MAO-enzymes have been produced by the body.
Interactions	All patients should avoid eating fermented foods (e.g. cheese, yeast products such as Marmite). MAO inhibition means that tyramine (an amine produced during fermentation) cannot be metabolized, leading to acute and severe hypertension – which could cause headaches, cardiac abnormalities, and even intracranial bleeding (a ‘cheese’ or ‘tyramine’ reaction). MAOIs should not be administered alongside tricyclic antidepressants or 5-HT reuptake inhibitors (SSRIs) because of the risk of excessive seizures, restlessness and even coma (serotonin reaction). There are many other significant drug-drug interactions - refer to eBNF.
Contraindications	not specified
Comments	MAOIs are prescribed less frequently now because of the dangers of interactions with drugs and diet. However, they can be prescribed to patients who are unresponsive to other antidepressants. Patients should be advised to take fresh food wherever possible and avoid alcohol. They should also be warned about possible drowsiness (especially when driving). Avoid sudden withdrawal of MAOIs. MAOIs are coming to attention again because of recent discoveries of reversible, isozyme specific drugs.
Contributors