RIMAs Reversible inhibitors of monoamine oxidase

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. 

RIMA Reversible inhibitor of monoamine oxidase type A... 

Some of the newer and more recently developed drugs with MAO inhibitory activity (see Table 32.1 , (below)) interact to a lesser extent than the older MAOIs. This is because they are largely selective. One group of these selective inhibitors targets MAO-A, and are relatively rapidly reversible inhibition of this enzyme is responsible for the antidepressant effect. These selective MAO-A inhibitors (moclobemide, toloxatone) have been given the acronym RIMAs (Reversible Inhibitors of Monoamine oxidase A). They leave MAO-B largely uninhibited so that there is still a metabolic pathway available for the breakdown of amines, such as... 

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. 

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. 

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. 

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 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. 

Selective serotonin reuptake inhibitors (SSRIs) are regarded as first-line treatment in social phobia. Fluvoxamine, paroxetine, and sertraline have been shown to be effective in double-blind placebo-controlled studies. - The irreversible monoamine oxidase inhibitor (MAOI) phenelzine shows robust results in terms of efficacy and has demonstrated (at least anecdotally), its efficacy in improving some of the cognitive aspects associated with SAD. However, phenelzine is usually less well tolerated than alternative treatments due to its associated dietary restrictions and adverse side-effect profile, including sedation and postural hypotension. Results with the reversible inhibitor of monoamine oxidase type A (RiMA) mociobemide are inconsistent. 

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. 

The modest improvements achieved in selectivity with respect to serotonin reuptake inhibition may also have been achieved with an isoenzyme system. Moclobemide, which was introduced in Sweden, reversibly inhibits monoamine oxidase A (RIMA). It is likely that this eliminates the severe hypertensive drug and food interactions that so severely limit the usefulness of the very effective earlier MAO inhibitors, since tyramine is now metabolized. An additional benefit of such agents may be a lack of cholinergic and cardiovascular effects. 

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