Tranylcypromine Noradrenaline

Acute treatment with nonselective MAO inhibitors (iproniazid, tranylcypromine, phenelzine), as a consequence of inhibiting both forms of the enzyme, increase, brain levels of all monoamines (phenylethylamine, tryptamine, methylhistamine aminergic neurotransmitters (dopamine, noradr enaline, adrenaline and serotonin). By contrast MAO-A inhibitors (clorgyline) increase serotonin and noradrenaline, while MAO-B inhibitors (selegiline, rasagiline) increase brain levels... 

Fillenz, M and Stanford, SC (1981) Vesicular noradrenaline stores in peripheral nerves of the rat and their modification by tranylcypromine. Brit. J. Pharmacol. 73 401-404. 

Other indirect sympathetic mechanisms are the inhibition of the extra neuronal uptake of noradrenaline (uptake 2) by corticosteroids and meta-nephrine and the inhibition of MAO for example by moclobemide or tranylcypromine. 

Due to the frequent unwanted effects and, in case of tranylcypromine, the numerous and dangerous interactions MAO-inhibitors are more and more replaced by the much less problematic SSRIs. Compounds belonging to this group are citalopram, escitalopram, fluoxetine, paroxetine and sertraline. They are used clinically in the therapy of depression, bulimia and obsessive-compulsive disorders. All SSRIs show a slow onset of action (1-2 weeks). They may induce insomnia and weight loss. The antidepressant ven-lafaxine inhibits both, serotonin and noradrenaline re-uptake and might therefore additionally induce hypertension. 

The enzyme, monoamine oxidase, exists in two forms MAO-A (intestinal mucosa and intraneuronally in the brain) and MAO-B (platelets and mainly extraneuronally in the brain). Serotonin is preferentially metabolised by MAO-A and noradrenaline (NA norepinephrine), and dopamine and lyramine by both forms. The first generation MAOI antidepressants (phenelzine, tranylcypromine, and isocarboxazid) inhibit both MAO-A and MAO-B and are thought to work by increasing the availability of 5-HT and NA in the synapse—with longer-term adaptive effects occurring as for the TCAs. These MAOls are irreversible, i.e. they permanently inactivate MAO. Thus, recovery of activity occurs slowly, over days, as new MAO molecules are synthesised. 

In a randomised, double-blind, placebo-controlled study in 12 healthy subjects, phenelzine 15 mg three times daily for 7 days had no effect on the dose of intravenous noradrenaline (norepinephrine) required to raise the systolic blood pressure by 25 mmHg. In addition, phenelzine had no effect on the diastolic blood pressure rises and heart rate reductions seen with noradrenaline. In this study, phenelzine itself had no effect on blood pressure or heart rate. Similarly, in an earlier study in two healthy subjects given phenelzine 15 mg three times daily and two given tranylcypromine 10 mg three times daily for 7 days, there was no signifieant... 

In contrast, in a study in hypertensive patients who had postural hypotension after being given either pheniprazine (a formerly investigational older MAOI) (6 patients) or tranylcypromine (one patient), the dose of noradrenaline required to produce a 25 mmHg rise in systolic pressure was reduced by 62 to 87%. In three of these patients on pheniprazine the dose of methoxamine was reduced by 61 to 70% compared with that required in the absence of an MAOI. Three patients were later given nialamide augmentation of the pressor response of noradrenaline or methoxamine only occurred in the one patient who had developed postural hypotension. ... 

The situation in patients who show a reduced blood pressure due to the use of an MAOI is less clear. One early study found an increase in the pressor effects of noradrenaline and methoxamine in hypertensive patients who had developed orthostatic hypotension on pheniprazine or tranylcypromine. Bear this possibility in mind. 

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