G Tranylcypromine

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). 

That depends on the drug. Effects of drugs that reversibly bind to MAO (e.g., tranylcypromine) immediately cease upon withdrawal. Effects of drugs that bind irreversibly (e.g.. phenelzine) continue until new enzyme is formed, which may take as long as several weeks. 

Procarbazine can cause a disulfiram-like reaction and is a monoamine oxidase inhibitor. Thus, ingestion of alcohol, foods containing tyramine (e.g., cheese), drugs that increase sympathetic activity, and MAOl-type antidepressants (e.g., tranylcypromine) should be avoided. 

The MAOIs can be classified as hydrazines (e.g., phenelzine) and nonhydrazines (e.g., tranylcypromine), which can block the oxidative deamination of naturally occurring monoamines. MAOIs can also be classified according to their ability to selectively or nonselectively inhibit MAO. The currently available MAOl antidepressants (phenelzine and tranylcypromine) (Fig. 21.25) are considered to be irreversible nonselective inhibitors of MAO. The mechanism of antidepressant action of the MAOIs suggests that an increase in free 5-HT and NE and/or alterations in other amine concentrations within the CNS is mainly responsible for their antidepressant effect. 

Patients taking the non-seiective MAOIs (e.g. tranylcypromine, phenelzine) can suffer a serious hypertensive reaction if they drink tyramine-rich drinks (some beers or iagers, including low-aicohoi brands, or wines), but no serious interaction is likely with the RIMAs (e.g. mociobemide). The hypotensive adverse effects of the MAOIs may be exaggerated in a few patients by aicohoi, and they may experience dizziness and faintness after drinking reia-tiveiy modest amounts. Mociobemide does not appear to aiter the psychomotor effects of aicohoi to a ciinicaiiy reievant extent. 

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... 

Sherry RL, Rauw G, McKenna KF, Paetsch PR, Courts RT, et al. 2000. Failure to detect amphetamine or 1-amino-3-phenylpropane in humans or rats receiving the MAO inhibitor tranylcypromine. J Affect Disord 61 23. 

E.M. Shepard, FI. Fleather, G.A. Juda, D.M. Dooley, Inhibition of six copper-containing amine oxidases by the antidepressant drug tranylcypromine, Biochim. Biophys. Acta 1647 (2003) 252-259. 

K. White, J. Razani, B. Cadow, R. Gelfand, R. Palmer, G. Simpson, R.B. Sloane, Tranylcypromine vs. nortriptyline vs. placebo in depressed out patients A controlled trial, Psychopharmacology 82 (1984) 258-262. 

L.FI. Price, D.S. Charney, G.R. Fleninger, Efficacy of lithium-tranylcypromine treatment in refractory depressison, Am. J. Psychiatry 142 (1985) 619-623. 

A.J. Greenshaw, T.S. Rao, A.J. Nazarali, G.B. Baker, R.T. Courts, Chronic effects of tranylcypromine and 4-fluorotranylcypromine on regional brain monoamine metabolism in rats A comparison with clorgyline, Biol. Psychiatry 25 (1989) 1014-1020. 

G.B. Baker, H.R. McKim, D.G. Caiveriey, W.G. Dewhurst, Effects of the monoamine oxidase inhibitors tranylcypromine, phenelzine and pheniprazine on the uptake of catecholamines in slices from rat brain regions, Proc. Eur. Soc. Neurochem. 1 (1978) 536. 

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). 

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. 

Tranylcypromine causes irreversible inhibition of the two isozymes MAOa and 0 2% Therefore, presystemic elimination in the liver of biogenic amines, such as tyramine, that are ingested in food (e. g., in aged cheese and Chianti) is impaired (with danger of a diet-induced hypertensive crisis). The compound is obsolete in some countries. 

Razani J, White KL, White J, Simpson G, Sloane RB, Rebal R, Palmer R. The safety and efficacy of combined amitriptyline and tranylcypromine antidepressant treatment. A controlled trial. Arch Gen Psychiatry 1983 40(6) 657-61. 

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

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). 

Metoclopramide increases gastric transit time, enhancing the absorption of substances absorbed in the small intestine (e.g., ethanol, cyclosporin) and decreasing the absorption of substances absorbed in the stomach (e.g., cimetidine, digoxin). Anticholinergic drugs and dopamine-function-enhancing substances such as levodopa reduce the effectiveness of metoclopramide. Because metoclopramide releases catecholamine, it should be used cautiously with monoamine oxidase inhibitors such as tranylcypromine. Because metoclopramide inhibits plasma cholinesterase, it increases the effectiveness of succinylcholine, a skeletal muscle relaxant. 

It was initially believed that the antidepressant effectiveness of MAOIs was the direct result of MAO inhibition. This acute effect decreases degradation of monoamines (e.g., norepinephrine, serotonin, or dopamine) stored in presynaptic neurons, thereby resulting in an increased amount of these neurotransmitters available at the synapse. More recent research indicates that this model does not fully explain the mechanism of MAOIs efficacy. For example, the positive (h-) stereoisomer of tranylcypromine is a poor antidepressant despite inhibiting MAO. The main pharmacologic difference between the negative (-) and + isomers of tranylcypromine is that the former has much weaker effects as a norepinephrine reuptake inhibitor in relation to its potency as an MAOI. The other MAOIs may also block the reuptake of selected neurotransmitters. However, like the non-MAOI uptake inhibitors, these acute effects often precede clinical antidepressant effects by weeks. More consistent with the 2- to 4-week lag in therapeutic effect, chronic treatment with a diverse number of MAOIs has been shown to reduce the number of a2- and P-adrenergic and serotonin (5-HT2) postsynaptic binding sites in the brain. 

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. 

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