Posted by DSCH on September 30, 2003, at 0:32:08
In reply to Guide Errata: MAOI/RIMA, corrections soon, posted by DSCH on September 27, 2003, at 17:38:14
Source:
Perrine, Daniel M.
"The Chemistry of Mind-Altering Drugs: History, Pharmacology, and Cultural Context"
American Chemical Society, 1996, p. 233-5.[Note: Brofaromine appears to have been dropped just short of marketing by Ciba-Geigy]
Monoamine Oxidase Inhibitors.
Discovery. Monoamine Oxidase (MAO) inhibitors (MAOI) were discovered by accident during clinical trials of the antitubercular drug iproniazid during the 1950s. Isolated from family, friends, and their ordinary occupations and confronted with a life-threatening disease, many of the patients in the tuberculosis sanatoria of the day were understandably depressed [40], and it was soon noticed at several centers that the mood of those patients taking the antitubercular drug iproniazid was improved. It was hypothesized that iproniazid had an antidepressant effect because it blocks the enzyme MAO, which metabolizes excess epinepherine and serotonin (see Chapter 1) within the presynapse. Inhibiting the action of this enzyme would make more epinepherine and serotonin available.
Mode of Action. These early MAOIs are all "suicide substrate" irreversible inhibitors of MAO, a flavin-containing enzyme found in the mitochondria of neurons, intestinal mucosa, the liver, etc. Iproniazid contains a hydrazine (-NHNH2) function that is oxidized by MAO to a reactive intermediate that binds irreversibly to the flavin prosthetic group of the enzyme, rendering it inactive. Maximal inhibition of MAO activity is usually achieved in a few days (although, as with all antidepressants, psychological effects are not seen for 2-3 weeks), and after medication is discontinued, it requires 1-2 weeks for MAO activity to be restored to normal.
Side Effects. Iproniazid was replaced with better MAOIs, but all MAOIs still share common awkward side effects: orthostatic hypotension, sexual dysfunction (impotence, delayed ejaculation, loss of libido), and an unusual food/drug interaction: any foods or beverages containing large amounts of tyramine can cause a hypertensive crisis (headache, tachycardia, nausea and occasionally subarachnoid hemorrage). Foods containing tyramine are aged cheeses, wines, beers, dried meats and fish, and fava beans. The tyramine (4-hydroxyphenethylamine, also called tyrosamine) in these foods does not normally affect us because it is rapidly converted by MAO in the intestines to tyrosine, a common amino acid; absent this protective mechanism, tyramine enters the storage vessels for norepinepherine (NE) and displaces the NE, causing a drastic rise in blood pressure.
Phenelzine, Isocarboxazid, and Tranylcypromine. Phenelzine (Nardil, 5-30, Figure 5.7), isocarboxazid (Marplan, 5-31), and Tranylcypromine (Parnate, 5-32), are all used for clinical depression, panic disorder, and phobic disorders. Phenelzine, developed by Warner-Lambert, represents a simple substitution of hydrazine for the amine function of phenethylamine. Phenelzine also may improve eating behavior in some bulimics, but controlled clinical trials have not yet confirmed this. Isocarboxazid is an elaboration of the phenelzine structure, and is probably converted to it in vivo. Tranylcypromine can be seen either as a modification of phenethylamine or as an amphetamine with the side chain cyclized into a cyclopropane ring; in larger doses than those used to treat depression, it can cause psychomotor stimulation, and the development of dependence occasionally has been reported.
Reversible Inhibitors of Monoamine Oxidase A.
More recent research shows that there are two types of MAO enzyme, MAOA and MAOB. Whereas MAOB is more active in the peripheral system and metabolizes dietary tyramine, it is the inhibition of MAOA enzyme in the CNS that is responsible for the antidepressant efficacy of the MAOIs [41]. Older drugs such as phenelzine, isocarboxazid, and tranylcypromine irreversibly inhibit both enzyme types, but some newer drugs used in Europe are selective for MAOA. These reversible inhibitors of MAOA (RIMAs) are active antidepressants but do not induce a "cheese effect" hypertensive crisis if tyramine-containing foods are eaten.
Moclobemide. Moclobemide (Aurorix, 5-33, Figure 5.8) was first marketed by Hoffman-LaRoche in Sweden in 1990,and was subsequently approved for marketing in about 50 countries. It was the first of the RIMA class of drugs, and it shows good promise. In a randomized multicenter study comparing its efficacy to that of tranylcypromine, moclobemide was equally efficacious but had the clear advantage of a safer profile and slightly better tolerability [42]. However, studies from the Danish University Antidepressant Group have indicated that moclobemide, citalopram, and paroxetine are all somewhat less effective than clomipramine [43]. In a comparitive study of moclobemide and fluoxetine, tolerance of both drugs was quite good and efficacy statistically identical; whereas sedation, nausea, and vomiting were reported more frequently with fluoxetine, insomnia was more common with moclobemide [44].
Brofaromine, 5-34. In a randomized, double-blind Canadian study, this new RIMA drug was compared to clomipramine in patients with panic disorder with or without agoraphobia [45]. The drugs proved to be of equal efficacy, and the much more favorable safety and reduced side effects of the RIMA will most likely make it prefferable to clomipramine. In a review of trials using brofaromine for patients with major depression who did not respond to current antidepressant medications, brofaromine was judged equally effective but better tolerated and safer to use [46].
References and Notes.
40. Thomas Mann's The Magic Mountain provides an unforgettable impression of the psychological atmosphere prevading these institutions.
41. It is perhaps the reversability of the newer MAO agents rather than the selectivity that leads to their improved profile: the predominant enzyme active in metabolizing tyramine in the human intestine is MAO-A: Anderson, M.C.; Hasan, F,; et al. "Monoamine oxidase inhibitors and the cheese effect," Neurochem. Res., 1993, 18, 1145-1149.
42. Heinze, G.; Rossel, L. et al., "Double-blind comparison of moclobemide and tranylcypromine in depression," Pharmacopsychiatry, 1993, 26, 240-245.
43. (a) Vestergard, P.; Gram, L.F.; et al., "Therapeutic potentials of recently introduced antidepressants," Psychopharmacol. Ser., 1993, 10, 190-198. (b) Danish University Antidepressant Group, "Moclobemide a reversible MAO-A inhibitor showing weaker antidepressant effect than clomipramine in a controlled multicenter study," J. Affect. Disord., 1993, 28, 105-116.
44. Williams, R; Edwards, R.A.; et al., "A double-blind comparison of moclobemide and fluoxetine in the treatment of depressive disorders," Int. Clin. Psychopharmacol., 1993, 7, 155-158.
45. Bakish, D.; Saxena, B.M.; et al., "Reversible monoamine oxidase-A inhibitors in panic disorder," Clin. Neuropharmacol., 1993, 16, Suppl. 2, S77-S82.
46. Nolen, W.A.; Hoencamp, E; et al., "Reversible monoamine oxidase-A inhibitors in resistant major depression," Clin. Neuropharmacol., 1993, 16, Suppl. 2, S69-S76.
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