Monoamine oxidase inhibitors nonselective

Monoamine Oxidases and their Inhibitors. Table 4 Nonselective and selective monoamine oxidase inhibitors... 

The monoamine oxidase inhibitors (MAOIs) phenelzine and tranylcypromine increase the concentrations of NE, 5-HT, and DA within the neuronal synapse through inhibition of the monoamine oxidase (MAO) enzyme system. Both drugs are nonselective inhibitors of MAO-A and MAO-B. Selegiline is available as a transdermal patch for treatment of major depression. It inhibits MAO-A and MAO-B in the brain, but has reduced effects on MAO-A in the gut. 

Drugs that may affect nateglinide include nonsteroidal anti-inflammatory agents (NSAIDs), salicylates, monoamine oxidase inhibitors, rifamycins, MAOIs, and nonselective beta-adrenergic blocking agents, thiazides, corticosteroids, thyroid products, and sympathomimetics. 

Monoamine oxidase inhibitors. The monoamine oxidase inhibitors (MAOIs) inhibit the intracellular catabolic enzyme monoamine oxidase. There are two types of monoamine oxidase MAO-A and MAO-B, both of which metabolize tyramine and dopamine. In addition, MAO-A preferentially metabolizes norepinephrine, epinephrine, and serotonin, and MAO-B preferentially metabolizes phenylethylamine (an endogenous amphetamine-like substance) and N-methylhistamine (Ernst, 1996). Some MAOIs are selective for A or B and some are nonselective (mixed). In addition, irreversible MAOIs (e.g., phenelzine, tranylcypromine) are more susceptible to the cheese effect than are the reversible agents (e.g., moclobemide). 

Note. MAOI=monoamine oxidase inhibitor MAO=monoamine oxidase. Selective at lower doses, nonselective at higher doses. 

Postural hypotension is common and often asymptomatic, and tends to diminish with continuing treatment. Hypertension may also occur, especially in the presence of nonselective monoamine oxidase inhibitors or sympathomimetics or when massive doses of levodopa are being taken. 

Interactions. With nonselective monoamine oxidase inhibitors (MAOI), the monoamine dopamine formed from levodopa is protected from destruction it accumulates and also follows the normal path of conversion to noradrenaline (norepinephrine), by dopamine (J-hydroxylase severe hypertension results. The interaction with the selective MAO-B inhibitor, selegiline, is possibly therapeutic (see below). Tricyclic antidepressants are safe. Levodopa antagonises the effects of antipsychotics (dopamine receptor blockers). Some antihypertensives enhance hypotensive effects of levodopa. Metabolites of dopamine in the urine interfere with some tests for phaeochromocytoma, and in such patients it is best to measure the plasma catecholamines directly. 

As with other sympathomimetic agents, theoretical drug interactions with ephedra alkaloids are possible. Despite this potential, only a handful of adverse drug interactions have been reported. This is especially pertinent when considering the extensive use of both ephedra-containing supplements and ephedrine- or pseudoephedrine-containing OTC products. The most notable interaction exists between nonselective monoamine oxidase inhibitors and ephedra- or ephedrine-containing products. 

The ephedra alkaloids are all sympathomimetic amines, which means that a host of drug interactions are theoretically possible. In fact, only a handful of adverse drug interactions have been reported in the peer-reviewed literature. The most important of these involve the monoamine oxidase inhibitors (MAOI). Irreversible, nonselective MAOIs have been reported to adversely interact with indirectly acting sympathomimetic amines present in many cough and cold medicine. In controlled trials with individuals taking moclobemide, ephedrine s effects on pulse and blood pressure were potentiated, but only at higher doses than those currently provided in health supplements (137). Ephe-drine-MAOI interaction may, on occasion, be severe enough to mimic pheo-... 

Because of undesirable side effects associated with monoamine oxidase inhibitor therapy (see section 2.3.2), pharmaceutical companies nearly abandoned research on new analogs in the 1960s. The early MAO inhibitors were nonselective and irreversible. Today, efforts toward the development of monoamine oxidase inhibitors are focused on selective MAQA or MAOB inhibitors. Selective MAOB inhibitors are being examined in the treatment of, for example, schizophrenia, Alzheimer s disease, and Parkinson s disease. MAO-B inhibitors might be effective in the treatment of depression, but relatively little woik has been done in this area. Selegiline... 

Unfortunately, this blocking action is nonselective it enables numerous other substances to score as well. So when MAO defenses are blocked, the body is vulnerable to many potentially dangerous chemical reactions. Obviously, the main problem. with the use of any monoamine oxidase inhibitor is that if it is not used wisely, which is to say sha-manically, one could very easily wind up dead. Dietary restrictions are therefore mandatory when ingesting any AAAO-inhibiting substance, a discipline strictly adhered to by all South American shamans using... 

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. 

Monoamine oxidase (MAO) inhibitors MAO and COMT are the 2 major enzyme systems involved in the metabolism of catecholamines. Do not treat patients concomitantly with entacapone and a nonselective MAO inhibitor. 

Nonselective and Irreversible Inhibitors of Monoamine Oxidase A and Monoamine Oxidase B... 

Monoamine oxidase A (MAO A) acts selectively on the substrates norepinephrine and serotonin, whereas monoamine oxidase B (MAO B) preferentially affects phenylethylamine. Both MAO A and MAO B oxidize dopamine and tyramine. MAO A inhibition appears to be most relevant to the antidepressant effects of these drugs. Drugs that inhibit both MAO A and MAO B are called non-selective. The MAOI antidepressants currently available in the United States are nonselective inhibitors. Because tyramine can be metabolized by either MAO A or MAO B, drugs that selectively inhibit one of these enzymes but not the other do not require dietary... 

Monoamine oxidase (MAO) inhibitors, nonselective (Types A,B) phenelzine sulfate tranylcypromine sulfate... 

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. 

The combined administration of levodopa and an inhibitor of both forms of monoamine oxidase (ie, a nonselective inhibitor) must be avoided, because it may lead to hypertensive crises, probably because of the peripheral accumulation of norepinephrine. 

Monoamine oxidase exists in two subtypes, A and B. Both forms are inhibited by the original MAO inhibitors, which are therefore nonselective. The A form metabolizes the neurotransmitter monoamines most closely linked to depression (serotonin and norepinephrine). 

Monoamine Oxidase (MAO) Inhibitors. Inhibitors of the catabolic enzyme MAO increase both catecholamine and serotonin brain levels, which in turn produce significant and prolonged decrease in REM sleep. This is especially the case with phenelzine and nialamide nonselective MAO inhibitors and less pronounced with the reversible MAO-A inhibitor moclobemide. In normal subjects, moclobemide reduces REM sleep period during the first night, but by the third night, REM sleep returns to normal levels (37). 

A different approach to Parkinsonism would be the use of inhibitors of monoamine oxidase (MAO), the enzyme that oxidatively deaminates catechol and other monamines, including DA, NE, and EP (see subsequent discussion of metabolism and other uses). Such a drug would tend to preserve brain DA and be effective itself and/or potentiate levodopa. Early attempts at such combinations produced hypertension. Subsequently, with the discovery that two MAO isozymes, A and B, exist (more discussion later), it was realized that the drugs tested were nonselective. It is now understood that MAO B primarily metabolizes DA. Selegiline (Eldepryl) appears to be a specific type B MAO inhibitor, and does extend the duration and increase the efficacy of levodopa. The drug is promising, probably as an adjunct to levodopa or in levodopa refractory patients. 

Remember that levodopa is a precursor of norepinephrine and epinephrine as well as dopamine and that norepinephrine and epinephrine are metabolized primarily by monoamine oxidase type A. In the presence of nonselective inhibitors of monoamine oxidases, levodopa may cause a hypertensive crisis. Though not contraindicated in Parkinson s disease, tricyclic antidepressants may interfere with the effectiveness of levodopa. The answer is (D). 

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