Phenelzine metabolism

Amantidine, bromocriptine, mazindol, pergolide, cabergoline, L-dopa/carbidopa, pramipexole, ABT-431, catecholamine metabolism inhibitors (disulfiram, phenelzine, selegiline), amineptine Methylphenidate, /-amphetamine, tropanes, GBR-12909 (partial agonist that may also act as antagonist), modafinil, coca tea... 

WARNING Cases of fulminant liver failure resulting in death have occurred Uses Adjunct to carbidopa/levodopa in Parkinson Dz Action COMT inhibitor slows levodopa metabolism Dose 100 mg PO tid w/ 1st daily levodopa/carbidopa dose, then dose 6 12 h later -1- w/ renal impair Caution [C, ] Contra Hqjatic impair, w/ nonselective MAOI Disp Tabs SE Constipation, XCTOstomia, vivid dreams, hallucinations, anorexia, N/D, orthostasis, liver failure, Rhabdomyolysis Interactions T Effects OF CNS dqjressants, SSRIs, TCAs, warfarin, EtOH t risk of hypotensive crisis W/ nonselective MAOIs (phenelzine, tranylc5 promine) EMS Has been associated w/ liver failure and death may experience hallucinations concurrent EtOH use can T CNS dqjression T effects of warfarin severe D is common sevoal wks afto starting OD May cause NA and dizziness... 

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. 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). 

Although the half-life of an MAOI is short (hours), the half-life of MAO inhibition is about 2 weeks because it takes that long for the new enzyme to be synthesized. Some have speculated that phenelzine may be metabolized by acetylation and that there are two hereditary types (i.e., slow and fast acetylators), with slow acetylators presumably having a greater degree of MAO inhibition. There is limited support for the theory that slow acetylators have a better response, whereas other investigators find no difference (179). More importantly, there is no evidence that phenelzine is indeed acetylated. 

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. 

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

The different MAOIs are metabolized via different pathways but tend to have extensive first-pass effects that may substantially decrease bioavailability. Tranylcypromine is ring hydroxylated and /V-acetylated, whereas acetylation appears to be a minor pathway for phenelzine. Selegiline is /V-demethylated and then hydroxylated. The MAOIs are well absorbed from the gastrointestinal tract. 

Runge-Morris, M., Feng, Y, Zangar, R.C. Novak, R.F. (1996) Effects of hydrazine, phenelzine, and hydralazine treatment on rat hepatic and renal drug-metabolizing enzyme expression. DrugMetab. Disp., 24, 734-737... 

After reuptake of it NE is stored again or it is degraded. The major metabolic pathway of NE is its oxidation into 3,4-dihydroxymandelic acid by the type A of the enzyme monoamine oxidize (MAO). Numerous drugs have MAO as their primary target. Their can be divided into two groups non-reversible MAO inhibitors (MAOIs) and reversible MAO inhibitors (RIMAs). Respective examples for these groups are phenelzine and moclobemide (Blier and de Montigny 1985 Blier et al., 1986). 

Muakkassah S, Yang W. Mechanism of the inhibitory action of phenelzine on microsomal drug metabolism. J Pharmacol Exp Ther 1981 219 147-155. 

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. 

Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, interact with drugs including clarithromycin, warfarin, phenelzine, benzotropine, chlorpromazine, diazepam, and cyproheptadine. Cigarette smokers metabolize SSRIs faster. 

Correct answer = D. Carbidopa inhibits the peripheral decarboxylation of levodopa, permitting lower dosage. Chlorpromazine blocks the dopamine receptor site in the brain and therefore blocks the beneficial effects of levodopa. Vitamin B6 enhances the peripheral decarboxylation of levodopa. Dopamine does not itself cross the blood-brain barrier. Phenelzine inhibits the metabolism of norepinephrine and serotonin and may produce a hypertensive crisis. 

Tranylcypromine is a non-hydrazine monoamine oxidase (MAO) inhibitor with actions and uses similar to those of phenelzine, but with less prolonged inhibition. Its half-life is 90-190 minutes. It is structurally related to amfetamine, to which it is metabolized in overdose (1). 

MDMA MAOIs Risk of severe and life-threatening hypertension. Risk is greatest with non-selective MAOIs. At least four deaths have been reported following the ingestion of MDMA and modobemide. Another death was reported after phenelzine co-ingestion MAO is an enzyme that metabolizes dopamine, norepinephrine and other amines Avoid concurrent use... 

Anise 2. Asian ginseng 3. Cereus 4. Ephedra 5. Ginseng 6. Parsley 7. Shepherds purse 8. Verbena (vervain) 9. Capsicum 1. Phenelzine 2. Tranylcypromine 3. Modobemide May cause T blood pressure with anise and ephedra. T risk of side-effects such as psychosis and hallucinations with Asian ginseng. Headache, tremulousness and manic episodes have been reported with ginseng and phenelzine Unknown mechanism (anise, Asian ginseng) Inhibits metabolism of ephedra (MAOIs inhibit the metabolism of ephedra) Avoid concomitant use... 

Several other genetically determined metabolic pathways affect the rate and degree of metabolism of phenelzine (Nardil) and certain benzodiazepines. Unpredicted medication responses to these agents are potentially linked to altered metabolism. 

The biotransformation of hydrazine and hydrazide derivatives also proceeds by acetylation. The antihypertensive hydralazine (Apresoline) " ""and the MAO inhibitor phenelzine (Nardil) " are two representative hydrazine compounds that are metabolized by this pathway. The initially formed N-acetyl derivative of hydralazine is unstable and cyclizes intramolecularly to form 3-methyl-s-triazolo 3.4-a phtha-lazine as the major isolable hydralazine metabolite in humans. " The antituberculosis drug isoniazid or isonicoli-nic acid hydrazide (INH) is metabolized extensively to N-acetylisoniazid. " ... 

The clinically u.scful MAOl antidepre.ssanls are nonselec-tive between inhibiting metabolism of NE and S-HT. AgenLs selective for a MAO that degrades. S-HT have been under study for some lime. The structures of phenelzine and tranylcypromine are given in Table IS-4... 

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). 

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