Phenelzine Isocarboxazid

Isocarboxazid, phenelzine, and tranylcypromine are irreversible nonselective inhibitors of both MAO-A and MAO-B. However, it appears that inhibition of MAO-A, not MAO-B, is important to the antidepressant action of these agents. 

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. 

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

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

The relative activities of iproniazid, nialamide, isocarboxazid, phenelzine, pheniprazine, and tranylcypromine are shown in Table IV, which is taken from the work of Maxwell, Gray, and Taylor (72). The method employed was the in vitro and in vivo potentiation of tryptamine. 

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. 

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... 

MAO inhibitors (MAOIs), which include irreversible MAOIs (isocarboxazid, phenelzine, and tranylcypromine) and reversible inhibitors of MAO type A (RIMAs befloxatone, moclobemide, and toloxatone). ... 

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. 

Not fully understood. Mebanazine, iproniazid, isocarboxazid, phenelzine, and tranylcypromine have all been shown to reduce blood glucose levels in the absence of conventional antidiabetics, possibly due to some direct action on the pancreas, which causes the release of insulin. It would seem that this can be additive with the effects of the conventional hypoglycaemics. 

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. 

Monoamine—Oxidase Inhibitors. In the mid-1950s, tuberculosis patients with depression being treated with iproniazid (42) were occasionally reported to become euphoric. This observation led to the discovery of irreversible monoamine—oxidase (MAO) inhibiting properties. Hydrazine and nonhydrazine-related MAO inhibitors were subsequentiy shown to be antidepressants (122). Three other clinically effective irreversible MAO inhibitors have been approved for treatment of major depression phenelzine (43), isocarboxazid (44), and tranylcypromine (45). 

With the exception of tranylcypromine (a phenylcycloalkylamine), the first MAOIs (e.g. iproniazid, isoniazid, phenelzine, isocarboxazid) were derivatives of hydrazine (originally used as a rocket fuel) (Fig. 20.2). All are irreversible inhibitors of the enzyme and restoration of MAO activity requires the synthesis of new enzyme. 

With most psychedelics, their activity can probably be considerably enhanced by prior (or possibly concomitant) use of a monoamine oxidase inhibitor (e.g., isocarboxazid (Marplan), nialamide (Niamid), phenelzine (Nardil), and tranylcypromine (Parnate)). Some compounds (e.g., DMT) which have no oral activity, can probably become orally active. These compounds are often prescribed as antidepressants, but it is not a good idea to use them frequently or in large doses. For antidotes to the hallucinogens see Amer. J. Hosp. Pharm. 30,80(1973). 

Increased bilirubin levels are caused due to the intake of large doses of such drugs as chloroquine, vitamin K, sulpha-drugs, tetracyclines, paracetamol, nicotinic acid and monoamine oxidase inhibitors (e.g., iproniazid RP 1.0 nialamide RP 1.8 isocarboxazid RP 3.1 phenelzine RP 18 pheniprazine RP31 and tranylcypromine RP 45), where RP designates the Relative Potency based on the tiyptamine potentiation test. The elevated levels are due to hepatic injury, and... 

All the commonly used MAOIs (monoamine oxidase inhibitors), exemplified by phenelzine, isocarboxazid and pargyline, are irreversible inhibitors of both forms of the enzyme, forming covalent bonds with the active sites... 

There are four classes of antidepressants tricyclic antidepressants (imipramine, trimipramine, amitriptyline, doxepin, desipramine, protriptyline, nortriptyline, amoxapine, maprotiline) monoaminooxidase (MAO) inhibitors (phenelzine, isocarboxazid, tranylcypromine) second-generation antidepressants or atypical antidepressants, which are a chemically dissimilar group of recently proposed drugs (bupropion, trazodone, fluoxetine) and amphetamines and other stimulators of the CNS (dextroamphetamine, methylphenidate). 

Isocarboxazid is a powerful MAO inhibitor. As with phenelzine, isocarboxazid is used for depressions that do not respond to other drugs. Marplan is a synonym of isocarboxazid. 

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. 

Monoamine oxidase inhibitors have a low therapeutic index. Adverse effects include orthostatic hypotension, impotence and insomnia. Overdoses become manifest by symptoms of agitation, hyper-reflexia followed by convulsions. Rare but serious cases of hepatotoxicity have been associated with the use of isocarboxazid and of phenelzine. 

MAOI agents was synthesized and tested for antidepressant properties. Three MAOI agents are approved in the United States for use in major depression isocarboxazid (Marplan), phenelzine Nardil), and tranylcypromine (Parnate). 

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. 

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. 

Structurally, all MAOIs are either hydralazines or nonhydralazines. Iproniazid, the first MAOI used for depression, is a hydralazine. There are currently two hydralazines available, phenelzine and isocarboxazid. Tranylcypromine is a nonhydralazine with a unique structure. Although tranylcypromine is considered to be a reversible inhibitor of MAO, clinically, the return of normal enzymatic activity is delayed, similar to phe-... 

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). 

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. 

Most presently available MAOIs are irreversible inhibitors of the enzyme, forming a chemical bond with part of the enzyme or the flavin adenine dinucleotide cofactor. When treatment is stopped, inhibition continues for a time until MAO levels return to normal as the new enzyme is synthesized. Thus, phenelzine, isocarboxazid, and tranylcypromine are all irreversible, nonselective MAOIs. Clorgyline, however, is an irreversible, selective MAO-A inhibitor moclobemide is a reversible, selective MAOI l-deprenyl and pargyline are relatively selective, irreversible MAO-B inhibitors. 

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). 

This is an uncommon reaction, most frequently associated with iproniazid, a hydrazine-based MAOl that has been removed from general use. The reaction seemed to be related to the liberation of free hydrazine and does not occur with nonhydrazine MAOIs. The risk of hepatotoxicity with currently available hydrazine MAOIs (phenelzine, isocarboxazid) is extremely low. 

Inhibition of MAO types A+B and thus reduce metabolism Isocarboxazid of 5-HT and NA Phenelzine... 

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. 

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. 

Monoamine oxidase inhibitors such as phenelzine and isocarboxazid (Fig. 5.37) are used clinically for the treatment of depression. These compounds also form complexes with... 

Figure 5.37 Structures of the enzyme inhibitors iproniazid, BNPP, isocarboxazid, and phenelzine. Abbreviation BNPP, bis-p-nitrophenyl phosphate.

Classical MAO inhibitors—irreversible and nonselective phenelzine (Nardil) tranylcypromine (Parnate) isocarboxazid (Marplan)... 

OFFICIAL NAMES Amitriptyline (Elavil), amoxapine (Asendin), bupropion (Wellbutrin), citalopram (Celexa), clomipramine (Anafranil), desipramine (Norpramin), doxepin (Sinequan), fluoxetine (Prozac), imipramine (Norfranil, Tofranil), isocarboxazid (Marplan), maprotiline (Ludiomil), mirtazapine (Remeron), nefazodone (Serzone), nortriptyline (Aventyl, Pamelor), paroxetine (Paxil), phenelzine (Nardil), protriptyline (Vivactil), sertraline (Zoloft), thioridazine (Mellaril), tranylcypromine (Parnate), trazodone (Desyrel), trimipramine (Sur-montil), venlafaxine (Effexor) the herb St. John s wort (Hypericum perforatum) is sold over-the-counter without prescription STREET NAMES Happy pills... 

Because of neurotoxicity and overdose concerns, 2C-B may have potentially dangerous interactions with users taking monoamine oxidase inhibitors (MAOIs). MAOIs are most commonly found in the prescription antidepressants Nardil (phenelzine), Parnate (tranylcypromine), Marplan (isocarboxazid), Eldepryl (1-deprenyl), and Aurorex or Manerix (moclobemide). Ayahuasca also contains MAOIs (harmine and harmaline). 

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. 

C-B should not be taken by persons who use a specific category of antidepressants called monoamine oxidase (MAO) inhibitors. These include phenelzine (Nardil), isocarboxazid (Marplan), tranylcypromine (Parnate), and moclobemide (Aurorix, Manerix). It also should not be used by diabetics. 

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