Isocarboxazid toxicity

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. 

The potential for toxicity that is associated with the administration of the MAOIs restricts their use in major depression. Hepatotoxicity is likely to occur with isocarboxazid or phenelzine, since hydrazine compounds can cause damage to hepatic parenchymal cells. This is true particularly for patients identified as slow acetyla-tors (see Chapter 4) of hydrazine compounds. Fortunately, the incidence of hepatotoxicity is low with the available agents. 

Iproniazic was the first widely prescribed MAOI. Realization that this drug can produce rare but dangerous liver toxicity led to the synthesis of the other hydrazine MAOIs, such as isocarboxazid, nialamide, and phenelzine, as well as the nonhydrazine MAOIs, tranylcypromine, and pargyline. 

If a patient does not respond to one MAO I, or if there appears to be a loss of efficacy over time, it may be reasonable to try a second. When switching from a hydrazine-based MAOl (e.g., phenelzine or isocarboxazid) to a nonhydrazine MAOl (e.g., tranylcypromine), one should wait at least 2 weeks. This is because the nonhydrazine MAOl, tranylcypromine, produces NE uptake inhibitory and sympathomimetic effects similar to dextroamphetamine and may cause a toxic reaction if initiated within 2 weeks following MAO inhibition by another agent (261). 

During clinical studies of iproniazid (201) in the treatment of tuberculosis it was found to have a mood-elevating effect. It was later found to be an inhibitor of monoamine oxidase (MAO), the enzyme which oxidatively deaminates such neurotransmitters as noradrenaline and serotonin, and it was tried in the treatment of depression in 1957. Other MAO inhibitors were introduced later, most of them being hydrazine derivatives. Heterocyclic examples include isocarboxazid (202) and nialamide (203). They are toxic and cause dangerous hypertensive crises if food with a high tyramine content is eaten, and on this account their use is limited. 

Patients should not use dextromethorphan if they are taking any drug in the class known as monoamine oxidase inhibitors (MAOI), including phenelzine (Nardil), isocarboxazid (Marplan), and tranylcypromine (Parnate), which are used in the treatment of depression. The combination of MAOIs with dextromethorphan can lead to toxic levels of dextromethorphan in the blood. 

These two classes of drugs are subject to life-threatening interactions (e.g., mania, convulsions, hypertension, heart arrythmias) with monoamine oxidase (MAO) inhibitors, such as isocarboxazide, phenelzine, selegiline, and tranylcypromine, because they inhibit the metabolism of serotonin and sympathomimetic amines (19,120). This interaction is one of the earliest toxic drug-drug interactions to be recognized however, these interactions are not often observed because the MAO inhibitors are now used sparingly. 

The literature on a withdrawal syndrome (SEDA-10, 17) has been expanded by further reports. One of these (33) involved the development of an acute toxic delirium 3 days after withdrawal of phenelzine, and another (34) concerned patients who became manic after withdrawal of isocarboxazid. A withdrawal state similar to that caused by withdrawal from amphetamines has been described after withdrawal of tranylcypromine (SEDA-16, 8) (SEDA-18,14). 

Insomnia and daytime somnolence and fatigue have been reported with tranylcypromine, phenelzine, and isocarboxazid (SEDA-16, 8) (SEDA-17, 16). In a comparison of phenelzine and imipramine (15) there were important and significant differences between the drugs 19% of the patients taking phenelzine reported drowsiness compared with none of those taking imipramine moreover, 18 patients taking phenelzine had to be withdrawn, compared with one taking imipramine (who developed urinary retention). Central nervous system toxicity was also reported after an abrupt switch from phenelzine to isocarboxazid (SEDA-17, 17). 

The monamine oxidase inhibitor, iproniazid, was the first useful antidepressant drug. Unfortunately, it proved too toxic for clinical use. Since its effect was observed, many monamine oxidase inhibitors have been prepared. Most have shown an antidepressant effect, but unfortunately, many of the newer agents also exhibited serious toxic effects. At present, the most commonly employed monoamine oxidase inhibitors are isocarboxazid, phenelzine, and nialamide. These agents exert a highly useful effect in the depressed patient. 

Acute CNS toxicity, hypertension, tachycardia, tremor and urinary retention occurred in a woman 48 hours after phenelzine was abruptly stopped and isocarboxazid started. In this patient, phenelzine was poorly tolerated causing hypertension and headache. ... 

KlysnerR, Larsen JK, ScirensenP, HyUestedM, Pedersen BD. Toxic interaction of venlafec-ine and isocarboxazide. Lancet (1995) 346,1298-9. 

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