Reversible inhibitors RIMAs

Figure 20.2 The chemical structure of some well-known MAO inhibitors. Most of these drugs irreversibly inhibit both MAOa and MAOb but reversible inhibitors (RIMAs), such as moclobemide, inhibit MAOa only...

The drug is found to show its aetion as an antidepressant as well as antimuscarinic activity. However, the antidepressant therapy has mainly been accomplished either via the monoamine oxidase (MAO) inhibitors or via the reversible inhibitors (RIMAs). 

Treatment of Major Depression. Dmgs commonly used for the treatment of depressive disorders can be classified heuristicaHy iato two main categories first-generation antidepressants with the tricycHc antidepressants (TCAs) and the irreversible, nonselective monoamine—oxidase (MAO) inhibitors, and second-generation antidepressants with the atypical antidepressants, the reversible inhibitors of monoamine—oxidase A (RIMAs), and the selective serotonin reuptake inhibitors (SSRIs). Table 4 fists the available antidepressants. 

Reversible Inhibitors of Monoamine Oxidase. Selective MAO-A inhibitors, which aie leveisible (so-called RIMAs), have also been developed, theiefoie substantially leduciag the potential foi food and dmg iateiactions. Indeed, the tyiamine-potentiating effects of these dmgs is much reduced compared with the irreversible MAO inhibitors. The RIMAs represent effective and safer alternatives to the older MAO inhibitors. The only marketed RIMAs ate toloxatone [29218-27-7] and moclobemide (55). The latter is used widely as an effective, weU-tolerated antidepressant. 

Because of their lack of selectivity and their irreversible inhibition of MAO, the first MAOIs to be developed presented a high risk of adverse interactions with dietary tyramine (see Chapter 20). However, more recently, drugs which are selective for and, more importantly, reversible inhibitors of MAO-A (RIMAs) have been developed (e.g. moclobemide). These drugs are proving to be highly effective antidepressants which avoid the need for a tyramine-free diet. 

Both these predictions are borne out by clinical experience despite the snag that only MAOb is found in serotonergic neurons (Saura et al. 1996). So far, there is no explanation for this anomaly. However, the lack of a tyramine-induced pressor effect with moclobemide probably owes more to the fact that it acts as a reversible inhibitor of MAOa (RIMA) than to its isoenzyme selectivity. Its reversible inhibition of MAOa means that, should tyramine ever accumulate in the periphery, it will displace... 

The reversible inhibitors of monoamine oxidase (RIMAs) brofaramine and meclobemide have been studied with mixed results.48 Neither is approved for use in the United States, but they are available in Canada. 

MAOI non-selective monoamine oxidase (A/B) inhibitors RIMA reversible inhibitor of monamine oxidase type A SSRI selective serotonin (5-HT) reuptake inhibitors SNRI serotonin/noradrenaline reuptake inhibitor SNARI selective noradrenaline (NA) reuptake inhibitor NA = 5-HT — DA potency of the drug is very similar in raising the level of both (or all three) monamines NA > 5-HT more selective for NA 5-HT>NA more selective for 5-HT NA increases the release of NA. 

Antidepressants of this class, such as moclobemide, have a high selectivity and affinity for MAO-A. Flowever, unlike the MAOIs, the RIMAs are reversible inhibitors of the enzyme and can easily be displaced from the enzyme surface by any primary amine which may be present in the diet. This means that the dietary amines are metabolized by MAO in the wall of the gastrointestinal tract while the enzyme in the brain and elsewhere remains inhibited. Thus the RIMAs have brought the MAOIs back into use as antidepressants in general practice. It is now evident that the RIMAs are not as potent as most currently available antidepressants. 

Based on some intriguing case reports (Jenike et al. 1983), a trial with a monoamine oxidase inhibitor (MAOI) may be an option in OCD patients who have comorbid panic disorder. In a double-blind trial, both phenelzine and clomipramine were found to be effective in reducing symptoms in OCD, as reflected on two of four OC measures [Vallejo et al. 1992). None of the patients in this study had panic disorder. This study suggests that MAOIs may be helpful in some patients with OCD even in the absence of panic disorder. However, in an earlier comparison trial, clomipramine, but not the MAOI clorgiline, resulted in significant reduction in OC symptoms [Insel et al. 1983b). Additional studies are needed to evaluate the place of MAOIs (including the newer reversible inhibitors of monoamine oxidase A [RIMAs], such as moclobemide) in the pharmacotherapy of OCD. 

Reversible inhibitor of monoamine oxidase activity (RIMA). (Atypical agent. 

Another approach is to develop selective and reversible MAOIs. The goal again is to produce agents with a minimal risk of tyramine reactions and thus markedly diminish the need for the dietary restrictions that have plagued the use of nonselective and irreversible A, B inhibitors. Collaborative clinical trials of the reversible inhibitors of monoamine oxidase A (RIMAs) in Europe have included more than 2,000 patients, many hospitalized for more severe, endogenous depressive episodes (183). In comparison trials with the TCAs, the onset of effect with RIMAs was also more rapid in some cases. 

One Type B MAOl (i.e., selegiline) has a low propensity to cause hypertensive and hyperpyrexic reactions, but there is scant information on its use for PD. On the other hand, among the selective and reversible inhibitors of monoamine oxidase A (RIMAs) such as brofaromine, some may be as effective as phenelzine without posing the same risks. 

Reversible inhibitors of MAO-A (RIMAs) affinity for cardiac muscle. 

A newer class of MAO inhibitors, which has entered clinical practice for the treatment of depression, is known as reversible inhibitors of MAO A (RIMAs). This is a very welcome development in new drug therapeutics for depression, because it has the potential of making MAO A inhibition for the treatment of depression much safer. That is, the suicide inhibitors are associated with the dangerous hypertensive episodes mentioned above, which are caused when patients eat food rich in tyramine (such as cheese). This so-called cheese reaction occurs when the tyramine in the diet releases norepinephrine and other sympathomimetic amines (Fig. 5—23). When MAO is inhibited irreversibly, the levels of these amines rise to a dangerous level... 

In the case of a reversible inhibitor of MA0(1), the NE released by tyramine can displace the RIMA (2), allowing for normal destruclon of the extra NE(3). 

FIGURE 6-24. Shown in this figure also is the combination of a monoamine oxidase (MAO) inhibitor and tyramine. However, in this case the MAO inhibitor is of the reversible type (reversible inhibitor of MAO A, or RIMA). In contrast to the situation shown in the previous figure (Fig. 6— 23), the accumulation of norepinephrine (NE) caused by tyramine (indicated in red circle 1) can actually strip the RIMA off MAO (arrow 2). MAO, now devoid of its inhibitor, can merrily do its job, which is to destroy the NE (red circle 3) and thus prevent the dangerous accumulation of NE. Such a reversal of MAO by NE is only possible with a RIMA and not with the classical MAO inhibitors, which are completely irreversible. 

Monoamine Oxidase (MAO) Inhibitors. The classical irreversible MAO inhibitors are effective in treating panic disorder, with anecdotal observations suggesting that they may be even more effective than imipramine. Clinical experience with reversible inhibitors of MAO A (RIMAs) (see Chapter 6) is also favorable for the treatment of panic disorder. However, the RIMAs may be somewhat less effective than the irreversible MAO inhibitors, but this is not well established. The disadvantages of the MAO inhibitors make them second- or third-line treatments for panic disorder these include orthostatic hypotension, weight gain, sexual dysfunction, and dietary restrictions (low tyramine diet), with the potential for a tyramine-induced hypertensive crisis. The RIMAs appear safer, with lessened potential for side effects, as discussed in Chapter 6, but also possibly with less efficacy. 

Reversible inhibitors of monoamine oxidase A Clinical experience with RIMAs in those countries where these agents are approved for marketing or testing suggests potential utility as antipanic agents. Further research is required to determine the relative advantages and relative efficacy of these compounds as compared with available antipanic agents. 

After reuptake of it NE is stored again or it is degraded. The major metabolic pathway of NE is its oxidation into 3,4-dihydroxymandelic acid by the type A of the enzyme monoamine oxidize (MAO). Numerous drugs have MAO as their primary target. Their can be divided into two groups non-reversible MAO inhibitors (MAOIs) and reversible MAO inhibitors (RIMAs). Respective examples for these groups are phenelzine and moclobemide (Blier and de Montigny 1985 Blier et al., 1986). 

Within each class or subclass drugs are listed in order of frequency of prescription in the United Kingdom (1997 data). Abbreviations RIMA—reversible inhibitor of monoamine oxidase NaRI—noradrenaline reuptake inhibitor SNRI—serotonin and noradrenaline reuptake inhibitor NaSSA—noradrenaline and specific serotonergic antidepressant. 

Of greater application to the treatment of depression are the reversible inhibitors of monomnineoxidase-Aor RIMAs. Brofaromine... 

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