Selegiline MAOIs

The discovery that MAO has two isoenzymes with different distributions, substrate specificity and inhibitor sensitivity has helped to rehabilitate the MAOIs to some extent. These isoenzymes are the products of different genes on the X-chromosome and share about 70% sequence homology. Whereas noradrenaline and 5-HT are metabolised preferentially by MAOa, tyramine and dopamine can be metabolised by either isoenzyme. Selective inhibitors of MAOa (e-g- moclobemide Da Prada et al. 1989) should therefore be safe and effective antidepressants whereas the selective MAOb inhibitor, selegiline, should not have any appreciable antidepressant activity (Table 20.5). 

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. 

Accordingto the FDA-approved prescribing information for the transdermal selegiline patch, patients receiving the 6 mg/24 hour dose are not required to modify their diet. However, patients receiving the 9 or 12 mg/24 hour dose are still required to follow the dietary restrictions similar to the other monoamine oxidase inhibitors (MAOIs). 

Yet another MAOI is selegiline (Eldepryl). Unlike the other MAOls, selegiline is seldom used to treat depression. At low doses, selegiline only inhibits the M AO-B enzyme. Therefore, it increases dopamine activity but does not have any pronounced effect on norepinephrine or serotonin. For this reason, it has been less useful as an antidepressant however, its primary use has been to treat Parkinson s disease. Of course, this selectivity for dopamine suggests that it may be helpful for ADHD as well. 

Iproniazid, an MAOI no longer available because of its hepatotoxicity, was the first effective antidepressant to be discovered it was introduced shortly before the discovery of imipramine. All MAOIs are presumed to have a similar mode of action, namely to inhibit the intra- and interneuronal metabolism of the biogenic amine neurotransmitters (noradrenaline, dopamine and serotonin). These amines are primarily metabolized by MAO-A (noradrenaline and serotonin) or MAO-B (dopamine). The irreversible MAOIs are inhibitors of MAO-A while selegiline (deprenyl), used as an adjunctive treatment for Parkinson s disease, is a selective, irreversible inhibitor of MAO-B. 

Dmg-induced serotonin syndrome is generally mild and resolves when the offending drugs are stopped. However, it can be severe and deaths have occurred. A large number of drugs have been implicated including tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), selective serotonin re-uptake inhibitors (SSRIs), pethidine, lithium, and dextromethorphan. The most severe type of reaction has occurred with the combination of selective serotonin re-uptake inhibitors and monoamine oxidase inhibitors. Both non-selective MAOIs such as phenelzine and selective MAOIs such as moclobemide and selegiline have been implicated. 

MAOIs had been reserved as a last line of treatment, used only when other classes of antidepressant drugs had failed, because of the mentioned potentially lethal dietary and drug interactions. However, in 2006 a patch form of the drug selegiline, called Emsam, was approved for use by the FDA. When applied transdermally the drug does... 

The MAOIs are as effective as the heterocyclic antidepressants and the newer agents, such as the SSRIs. However, at least two forms of life-threatening toxicity (hepatotoxicity and dietary tyramine-induced hypertensive crisis ) have been associated with their chronic use. For this reason, the MAOIs are not considered first-line agents in the treatment of depression. They are generally reserved for treatment of depressions that resist therapeutic trials of the newer, safer antidepressants. However, a new transdermal formulation of selegiline undergoing clinical trials demonstrates antidepressant efficacy without concerns of liver toxicity or dietary tyramine-induced hypertension. 

In the United States, the three MAOIS available for the treatment of psychiatric conditions are phenelzine (Nardil), tranylcypromine (Parnate), and isocarboxazid (Marplan). All three agents have indications for adult major depression (>16 years old) and, more specifically, atypical depression (anergia, hypersomnia, hy-perphagia, somatization, and anxiety symptoms). Although not indicated for anxiety, the MAOIs can also be particularly helpful in treatment of these disorders. Selegiline or L-deprenyl (Eldepryl) is also available in the United States and indicated for symptoms of Parkinson s disease and depression. 

Preliminary studies suggest that MAOIs are effective in juvenile and adult ADHD. In a controlled trial of clorygline (MAOI-A) and tranylcypromine sulfate (mixed), Zametkin et al. (1985) reported a significant reduction in ADHD symptoms with minimal adverse effects. Eeigin et al. (1996) conducted a controlled trial of 10 mg of selegiline (which at low doses is a specific MAOI-B) in children with ADHD and Tourette s syndrome. Selegiline was well tolerated and was associated... 

In open studies of adult ADHD, moderate improvements were reported in studies with pargyline and selegiline (MAOI-Bs) (Wender et ah, 1983, 1985). In a controlled study of selegiline in adult ADHD (Ernst 1996), use of active drug failed to produce results different from those with placebo however, the placebo response was unusually high in that study. In addition, a high dose (60 mg) was more effective than a low dose (20 mg), which suggests that MAOI-A effects may be more helpful in the treatment of ADHD. 

Given the unique efficacy of MAOIs, there have been several attempts to develop kinder and gentler versions. A transdermal form of selegiline is one promising approach. Another approach is the development of selective and reversible MAOIs (180). 

Arguably the first modern class of antidepressants, monoamine oxidase inhibitors (MAOIs) were introduced in the 1950s but are now rarely used in clinical practice because of toxicity and potentially lethal food and drug interactions. Their primary use now is in the treatment of depression unresponsive to other antidepressants. However, MAOIs have also been used historically to treat anxiety states, including social anxiety and panic disorder. In addition, selegiline is used for the treatment of Parkinson s disease (see Chapter 28). 

Current MAOIs include the hydrazine derivatives phenelzine and isocarboxazid and the non-hydrazines tranylcypromine, selegiline, and moclobemide (the latter is not available in the USA). The hydrazines and tranylcypromine bind irreversibly and nonselectively with MAO-A and -B, whereas other MAOIs may have more selective or reversible properties. Some of the MAOIs such as tranylcypromine resemble amphetamine in chemical structure, whereas other MAOIs such as selegiline have amphetamine-like metabolites. As a result, these MAOIs tend to have substantial CNS-stimulating effects. 

The different MAOIs are metabolized via different pathways but tend to have extensive first-pass effects that may substantially decrease bioavailability. Tranylcypromine is ring hydroxylated and /V-acetylated, whereas acetylation appears to be a minor pathway for phenelzine. Selegiline is /V-demethylated and then hydroxylated. The MAOIs are well absorbed from the gastrointestinal tract. 

MAOIs are classified by their specificity for MAO-A or -B and whether their effects are reversible or irreversible. Phenelzine and tranylcypromine are examples of irreversible, nonselective MAOIs. Moclobemide is a reversible and selective inhibitor of MAO-A but is not available in the USA. Moclobemide can be displaced from MAO-A by tyramine, and this mitigates the risk of food interactions. In contrast, selegiline is an irreversible MAO-B-specific agent at low doses. Selegiline is useful in the treatment of Parkinson s disease at these low doses, but at higher doses it becomes a nonselective MAOI similar to other agents. 

Summary of some amine-containing foods which could interact with MAOIs, particularly irreversible inhibitors (e.g. phenelzine, isocarboxazid, tranycypromine, selegiline)... 

Drugs and chemicals are known to cause activated interaction. The depressant action of opioid drugs is enhanced by drugs acting on the central nervous system (CNS) such as alcohol, anesthetics, anxiolytics, hypnotics, tricyclic antidepressants, and antipsychotics. Concomitant administration of opioid analgesics and monoamine oxidase inhibitors (MAOIs) should be avoided, or extra care should be taken if such a therapy is inevitable. Fatal reactions are reported when treated along with selegiline. Interactions also are reported with cyclizine, cimetidine, mexiletine, cisapride, metoclopramide, or domperidone. 

Monamine oxidase inhibitors (MAOIs) Phenelzine (Nardil) Selegiline transdermal (Emsam) Tranylcypromine (Parnate)... 

MAOIs TCAs-AMITRIPTYLINE CLOMIPRAMINE DESIPRAMINE IMIPRAMINE NORTRIPTYLINE t risk of stroke, hyperpyrexia and convulsions, t plasma concentrations of TCAs, with risk of toxic effects, t risk of serotonin syndrome and of adrenergic syndrome with older MAOIs. Clomipramine may trigger acute confusion in Parkinson s disease when used with selegiline TCAs are believed to also act by inhibiting the reuptake of serotonin and norepinephrine, increasing the risk of serotonin and adrenergic syndromes. The combination of TCAs and antidepressants can t risk of seizures Very hazardous interaction. Avoid concurrent use and consider the use of an alternative antidepressant. Be aware that seizures occur with overdose of TCAs just before cardiac arrest... 

MAOIs BETA-2 AGONISTS t occurrence of headache, hypertensive episodes. Unlikely to occur with modobemide and selegiline Due to impaired metabolism of these sympathomimetic amines because of inhibition of MAO. Modobemide is involved in the breakdown of serotonin, while selegiline is mainly involved in the breakdown of dopamine Be aware. Monitor BP closely... 

LEVODOPA, SELEGILINE, POSSIBLY RASAGILINE, ENTACAPONE, TOLCAPONE MAOIs Risk of adrenergic syndrome -hypertension, hyperthermia, arrhythmias - and dopaminergic effects with selegiline Levodopa and related drugs are precursors of dopamine. Levodopa is predominantly metabolized to dopamine, and a smaller proportion is converted to epinephrine and norepinephrine. Effects are due to inhibition of MAOI, which breaks down dopamine and sympathomimetics Avoid concurrent use. Onset may be 6-24 hours after ingestion. Carbidopa and benserazide, which inhibit dopa decarboxylase that converts L-dopa to dopamine, is considered to minimize this interaction. However, MAOIs should not be used in patients with Parkinson s disease on treatment with levodopa. Imipramine and amitriptyline are considered safer by some clinicians... 

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