Phenelzine toxicity

Phenelzine Toxic symptoms headache, insomnia, irritability... 

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. 

D PP, Tam YK, Young LT, et al Dthium decreases Gs, Gi-1 and Gi-2 alpha-subunit mRNA levels in rat cortex. Eur J Pharmacol 206 165-166, 1991 Debhch I, Yirmiya R Naltrexone reverses a long term depressive effect of a toxic lithium injection on saccharin preference. Physiol Behav 39 547-550, 1987 DebowitzMR Social phobia. Mod Probl Pharmacopsychiatry 22 141-173, 1987 Debowitz MR, Quitkin EM, Stewart JW, et al Phenelzine vs. imipramine in atypical depression a preliminary report. Arch Gen Psychiatry 41 669-677, 1984 liebowitz MR, Quitkin EM, Stewart JW, et al Antidepressant specificity in atypical depression. Arch Gen Psychiatry 45 129-137, 1988 Liebowitz MR, Schneier F, Campeas R, et al Phenelzine vs atenolol in social phobia. Arch Gen Psychiatry 49 290-300, 1992... 

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). 

Phenelzine Blockade of MAO-A and MAO-B (phenelzine, nonselective) MAO-B irreversible selective MAO-B inhibition (low dose selegiline) Transdermal absorption of selegiline achieves levels that inhibit MAO-A Major depression unresponsive to other drugs Very slow elimination Toxicity Hypotension, insomnia Interactions Hypertensive crisis with tyramine, other indirect sympathomimetics serotonin syndrome with serotonergic agents, meperidine... 

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). 

There have been previous reports of serotonin toxicity when venlafaxine was combined with therapeutic doses of conventional MAO inhibitors (SEDA 20, 21). The serotonin syndrome has been reported in four patients who were switched from the MAO inhibitor phenelzine to venlafaxine (83). In two of the subjects, the 14-day washout period recommended when switching from phenelzine to other antidepressant drugs had elapsed. 

These cases suggest that even after the recommended 2-week washout from MAO inhibitors, venlafaxine can provoke serotonin toxicity in some patients. In principle it should be possible to switch from one conventional MAO inhibitor to another without a washout period. However, there have been reports that patients who switched from phenelzine to tranylcypromine had hypertensive reactions, with disastrous consequences (84). Whenever possible, a 2-week washout period when switching MAO inhibitors or when introducing serotonin re-uptake inhibitors seems advisable. 

PHENELZINE DRUG DEPENDENCE THERAPIES-BUPROPION t acute toxicity of bupropion Uncertain Be aware... 

A few (hugs have distinctive odours md this can provide a clue to the compoimd or at least to the type of preparation. A yeast-like or meaty smell may indicate a harmless vitamin preparation, an odour of peppermint may indicate a non-toxic indigestion remedy. Antibiotics, especially of the penicillin group, sometimes have a rather unpleasant sulphide-type smell. Other drugs with characteristic odours are chlormethiazole, phenelzine, ethchlorvynol, chloral hydrate, and methylpentynol. 

Slow acetylator Isoniazid Hydralazine, procainamide Phenelzine, sulfasalazine Increased incidence of peripheral neuropathy SLE-like syndrome and more prone to phenytoin toxicity Increased incidence of SLE-like syndrome More prone to side effects... 

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). 

Acetylation of drugs is also associated with genetically determined interindividual and interethnic differences. Differences in isoniazid toxicity between Asians and Caucasians are due to acetylation enzyme polymorphism. The majority (78%-93%) of Chinese and East Asians are fast acetylators, whereas only 50% of whites and African Americans are fast acetylators (Weber 1987). This is clinically important, because several psychoactive compounds (e.g., caffeine, clonazepam, nitrazepam, and phenelzine) are metabolized through acetylation (Sjoqvist et al. 1997). 

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. 

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