Tranylcypromine Phenelzine

Monoamine oxidase inhibitors (phenelzine, tranylcypromine, possibly linezolicl)... 

MAOls Brofaromine Isocarboxizide Moclobemide Phenelzine Tranylcypromine... 

Examples of monoamine oxidase inhibitors are phenelzine, tranylcypromine, isocarboxazid and mo-clobemide. They are indicated for atypical depression. Changes in the neurotransmitter levels are seen in several days but the clinical effect may lag by several weeks. Phenelzine is a non-selective hydrazine-type monoamine oxidase inhibitor while the also non-selective inhibitor tranylcypromine is of the non-hydrazine-type. Phenelzine, tranylcypromine and isocarboxazid are irreversible inhibitors. Phenelzine is partly metabolized by acetylation and slow acetylators are more prone to toxicity. It has anxiolytic properties and superior efficiacy in treating severe anxiety. 

In adults, phenelzine, tranylcypromine, and isocarboxazid are rapidly absorbed and have short half-lives, requiring more than once-a-day dosing. For example, the half-life of phenelzine ranges from 1.5 to 4 hours and the half-life for tranylcypromine ranges from 1.54 to 3.15 hours (Mallinger and Smith, 1991). 

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). 

Only minimal information is available about the pharmacokinetics of the traditional MAOIs (e.g., phenelzine, tranylcypromine) ( 308). Such data are probably less critical for these versus other antidepressants, because MAOIs are consumed by their mechanism of action (i.e., irreversible inhibition of MAO by covalently binding to the enzyme). This mechanism accounts for the fact that traditional MAOIs have half-lives of only 2 to 4 hours, but their effects persist for an extended period because of their irreversible inactivation of their target. These MAOIs undergo presystemic or first pass degradation, and, thus, genetic or acquired alterations in this metabolism could alter their bioavailability and hence their effects. 

It is well-established that the MAOIs available in the United States (e.g., phenelzine, tranylcypromine) are effective antipanic and antiphobic agents. Of these, phenelzine has been the most extensively studied. As with the other nonselective MAOIs, however, it also carries the risk of hypertensive and hyperpyrexic reactions (see also Chapter 5). 

The enzyme, monoamine oxidase, exists in two forms MAO-A (intestinal mucosa and intraneuronally in the brain) and MAO-B (platelets and mainly extraneuronally in the brain). Serotonin is preferentially metabolised by MAO-A and noradrenaline (NA norepinephrine), and dopamine and lyramine by both forms. The first generation MAOI antidepressants (phenelzine, tranylcypromine, and isocarboxazid) inhibit both MAO-A and MAO-B and are thought to work by increasing the availability of 5-HT and NA in the synapse—with longer-term adaptive effects occurring as for the TCAs. These MAOls are irreversible, i.e. they permanently inactivate MAO. Thus, recovery of activity occurs slowly, over days, as new MAO molecules are synthesised. 

Antidepressants MAO-I (e.g., isocarboxazid, phenelzine, tranylcypromine) Tricyclic antidepressants (e.g., amitriptyline, desipramine, nortriptyline, etc.)... 

Clinically important, potentially hazardous interactions with furazolidone, MAO inhibitors, oxprenolol, phenelzine, tranylcypromine... 

Inhibitors of MAO (e.g., phenelzine, tranylcypromine) may increase prejunctional levels of NE. Note that MAO type A, the enzyme form that metabolizes NE, also metabolizes tyramine and serotonin (5HT). 

MAOIs phenelzine, tranylcypromine TCAs amitriptyline, imipramine, clomipramine... 

Monoamine Oxidase Inhibitors Isocarboxazid, Phenelzine, Tranylcypromine, Selegiline, Moclobemide... 

DA agonists levodopa, bromocriptine, ropinirole, pramipexole, selegiline AAAD inhibitor carbidopa M-blockers benztropine, trihexiphenidyl MAOIs phenelzine, tranylcypromine TCAs amitriptyline, imipramine, clomipramine SSRIs fluoxetine, paroxetine, sertraline Others bupropion, mirtazapine, nefazodone, trazodone... 

MAO INHIBITORS (isocarboxazid, phenelzine, tranylcypromine) Hypotension restlessness insomnia daytime sleepiness mania urinary retention tremors sexual disturbances paresthesias dry mouth nausea constipation anorexia weight gain edema rash hepatitis tinnitus muscle spasm lupus-like reaction leukopenia hyperthermia hypertension interactions with other drugs or foods may be severe MAPROTILINE... 

Selective inhibitors of these two isozymes are available (see Chapter 17). Irreversible antagonists ofMAO(e.g., phenelzine, tranylcypromine, and isocarboxazidj enhance the bioavailability of tyramine contained in many foods by inhibiting MAO-A tyramine-induced NE release from sympathetic neurons may lead to markedly increased blood pressure (hypertensive crisis) selective MAO-B inhibitors (e.g., selegiUnej or reversible MAO-A—selective inhibitors (e.g., moclobe-midej are less likely to cause this potential interaction. MAO inhibitors are useful in the treatment of Parkinson s disease and mental depression (see Chapters 17 and 20). 

SELECTIVE MAO-B INHIBITORS Two isozymes of MAO (MAO-A and MAO-B) oxidize monoamines and both are present in the periphery and GI tract MAO-B is the predominant form in the striatum and is responsible for most of the oxidative metabolism of dopamine in the brain. At low-to-moderate doses (10 mg/day or less), selegiline (eldepryl) selectively and irreversibly inhibits MAO-B. Unlike nonspecific inhibitors of MAO (e.g., phenelzine, tranylcypromine, isocarboxazid), selegiline does not inhibit peripheral metabolism of catecholamines and can be taken safely with levodopa. Selegihne does not cause the lethal potentiation of indirectly acting sympathomimetic amines such as dietary tyramine. Doses of selegiline higher than 10 mg daily can produce inhibition of MAO-A and should be avoided. 

Monoamine oxidase inhibitors (MAOIs) Phenelzine, tranylcypromine, and moclobemide have no clinically significant interactions with carbamazepine. 

Anecdotal data describe marked hypotension and impaired consciousness when morphine is added to tranylcypromine. Many studies have shown no clinically significant interactions with isocarboxazid, phenelzine, tranylcypromine, and morphine, including in patients with known adverse reactions to meperidine. 

MAO inhibitors (MAOIs) These drugs (eg, phenelzine, tranylcypromine, isocarboxazid) are stmcturally related to amphetamines and are orally active. They inhibit both MAO-A (which metabolizes norepinephrine, serotonin, and tyramine) and MAO-B (which metabolizes dopamine). Tranylcypromine is the fastest in onset of effect but has a shorter duration of action (about a week) than do other MAO inhibitors (with durations of 2-3 weeks). In spite of these prolonged actions, the MAO inhibitors are given daily. These drugs are inhibitors of hepatic drug-metabolizing enzymes and cause many drug interactions. 

Monoamine oxidase inhibitors used in depressive disorders (phenelzine, tranylcypromine) increase the stores of norepinephrine in sympathetic nerve endings. They also inhibit the metabolism of tyramine, which at high levels in the blood can act as an indirect sympathomimetic to release norepinephrine. The answer is (L). 

Table 21.15. Pharmacokinetics of the Monoamine Oxidase Inhibitors (MAOIs) Phenelzine Tranylcypromine Parameters (Nardil) (Parnate) Meclobemide ...

Serious and potentially life-threatening reactions (the serotonin syndrome) can develop if venlafaxine and non-selective MAOIs (isocarboxazid, phenelzine, tranylcypromine) are given concurrently, or even sequentially if insufficient time is left in between. The situation with moclobemide, in therapeutic doses, is uncertain. 

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