Phenelzine
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Phenelzine
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| Systematic (IUPAC) name | |
| (2-phenylethyl)hydrazine | |
| Identifiers | |
| CAS number | |
| ATC code | N06 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C8H12N2 |
| Mol. mass | 136.194 g/mol |
| SMILES | & |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | Liver |
| Half life | 1.2 hours |
| Excretion | Urine |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status | |
| Routes | Oral |
Phenelzine (sold as Nardil) is a psychoactive drug used widely as an antidepressant and anxiolytic/antipanic agent. It is a member of the monoamine oxidase inhibitor (MAOI) class of drugs. Phenelzine and the other MAOIs are typically considered to be significantly more effective against depression and anxiety in comparison to more mainstream antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), but they are usually reserved only as a last resort due to their prominent side effects and potentially hazardous food and drug interactions.
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[edit] Indications
Phenelzine is used primarily in the treatment of major depressive disorder. Patients with depressive symptomology characterized as "atypical," "nonendogenous," or "neurotic" have been reported to respond particularly well to phenelzine.[1] The medication has also been found to be useful in patients who do not respond favorably to first and second-line treatments for depression, or are said to be "treatment-resistant".[2] In addition to being a recognized treatment for major depressive disorder, phenelzine has been found in studies to be effective in treating dysthymia,[3] bipolar depression,[4] panic disorder,[5] social anxiety disorder,[6] bulimia,[7] and post traumatic stress disorder.[8]
[edit] Chemistry
Phenelzine, short for β-phenylethylhydrazine, as its name implies, is a hydrazine derivative. It is closely related on a structural level to the other hydrazine antidepressants, including iproclozide (Sursum), iproniazid (Marsilid), isocarboxazid (Marplan), nialamide (Niamid), and pheniprazine (Catron), all of which are also MAOIs.
Phenelzine is relatively easily made through the reaction of β-phenethylbromide (smells like roses) with hydrazine (a rocket propellant).
[edit] Pharmacology
Phenelzine is a nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO). It inhibits both of the respective isoforms of MAO, MAO-A and MAO-B, and does so almost equally, with slight preference for the former. By inhibiting MAO, phenelzine prevents the breakdown of the monoamine neurotransmitters serotonin, melatonin, norepinephrine, epinephrine, and dopamine, as well the trace amines such as phenethylamine and tyramine. This leads to an increase in the extracellular concentrations of these endogenous compounds and therefore an alteration in brain chemistry and neurotransmission. It is this action that is thought to be the primary mediator in phenelzine's antidepressant and anxiolytic properties.
Notably, although phenelzine inhibits the breakdown of norepinephrine and epinephrine which leads to increased levels of these two respective neurotransmitters, it actually decreases their levels overall with time via a complex interaction with another neurotransmitter known as octopamine. This is the cause of the commonly seen side effect of orthostatic hypotension with phenelzine and the other MAOIs. Though lowering adrenergic activity may have a beneficial effect on anxiety, it tends to exacerbate symptoms of depression, however the other effects of phenelzine typically more than overpower this loss.
Phenelzine also inhibits two other enzymes to a lesser extent, of which are alanine transaminase (ALA-T),[9] and γ-Aminobutyric acid transaminase (GABA-T),[10] the latter of which is not caused by phenelzine itself, but by its primary metabolite phenylethylidenehydrazine (PEH). By inhibiting ALA-T and GABA-T, phenelzine causes an increase in the alanine and GABA levels in the brain and body. GABA is the major inhibitory neurotransmitter in the mammalian central nervous system, and is very important for the normal suppression of anxiety and stress, as well as keeping depression at bay. It is thought that phenelzine's action in increasing GABA concentrations may significantly contribute to its antidepressant, and especially, anxiolytic/antipanic properties. As for ALA-T inhibition, though the consequences of disabling this enzyme are currently not well understood, there is some evidence to suggest that it is this action of the hydrazines (including phenelzine) which is responsible for the occasional incidence of hepatitis and liver failure.
Phenelzine has also been shown to partially metabolize to the trace amine phenethylamine (PEA). PEA is a norepinephrine and dopamine releasing agent which is very similar to amphetamine and may contribute further to phenelzine's overall antidepressant effects, the extent of which is however currently unknown.
[edit] Pharmacokinetics
Phenelzine is administered orally in the form of phenelzine sulfate and is rapidly absorbed from the gastrointestinal tract. Although phenelzine has a relatively short half-life (approximately 1.2 hours), unlike most other drugs, phenelzine irreversibly disables MAO, and as a result, it does not necessarily need to be present in the blood at all times for its effects to be sustained. Because of this, upon phenelzine treatment being ceased, its effects typically do not actually wear off until the body replenishes its enzyme stores, a process which can take as long as 2-3 weeks. Phenelzine is metabolized primarily in the liver and its metabolites are excreted in the urine.
Dosages typically range from 45 mg to 90 mg, but may be pushed as high as 150 mg if necessary.
It should also be noted that like many other antidepressants, phenelzine usually requires about 2-6 weeks of constant dosing before its therapeutic benefits fully kick in. The reason for this delay has not fully been elucidated, but it is believed to be due to the necessity of desensitization of pre-synaptic autoreceptors which normally inhibit the release of neurotransmitters like serotonin and dopamine.
[edit] Side Effects
Common side effects of phenelzine may include changes in dizziness, blurry vision, dry mouth, headache, lethargy, sedation, somnolence, insomnia, anorexia, weight gain or loss, nausea and vomiting, diarrhea, constipation, urinary retention, mydriasis, muscle tremors, increased body temperature or hyperthermia, sweating, decreased blood pressure or hypotension, orthostatic hypotension, paresthesia, hepatitis, and sexual dysfunction (consisting of loss of libido and anorgasmia). Rare side effects usually only seen in susceptible individuals may inlcude hypomania or mania, psychosis, and acute liver failure, the latter of which is usually only seen in people with pre-existing liver damage, old age, alcohol consumption, or viral infection.[11]
Phenelzine has been linked to vitamin B6 deficiency. It reacts with vitamin B6 via an unknown enzyme to form a biologically inert metabolite. Both phenelzine and vitamin B6 are rendered inactive upon this reaction occurring. For this reason, it is recommended to supplement with vitamin B6 while taking phenelzine. It should be noted, however, that too high of doses of vitamin B6 may significantly lower phenelzine levels and subsequently inhibit its therapeutic benefits; thus, excess quantities of vitamin B6 should be avoided. It is also advisable to dose them separately during different times of the day to avoid interaction as much as possible.
[edit] Interactions
The MAOIs are infamous for their problematic food restrictions and drug interactions. Hypertensive crisis may result from the overconsumption of tyramine-containing foods. As a result, patients on phenelzine and other MAOIs must avoid excess quantities of certain foods that contain tyramine such as aged cheeses and cured meats, among others. Serotonin syndrome may result from an interaction with certain drugs which increase serotonin activity. See the monoamine oxidase inhibitor main article for more information and a complete list of the contraindicated drugs. Several deaths have been reported due to drug interaction-related serotonin syndrome such as the case of Libby Zion.
[edit] References
- ^ Parke-Davis Division of Pfizer Inc. (2003). Nardil(R) (Phenelzine sulfate tablets, USP), labeling information. Retrieved January 13, 2006, from the U.S. Food and Drug Administration's Web site: http://www.fda.gov/cder/foi/label/2003/11909slr033_nardil_lbl.pdf
- ^ Fiedorowicz, J.G., & Swartz, K.L. (2004). The role of monoamine oxidase inhibitors in current psychiatric practice. Journal of Psychiatric Practice, 10, 239-248.
- ^ Vallejo, J., Gasto, C., Catalan, R., & Salamero, M. (1987). Double-blind study of imipramine versus phenelzine in melancholias and dysthymic disorders. British Journal of Psychiatry, 151, 639-642
- ^ Quitkin, F.M., McGrath, P., Liebowitz, M.R., Stewart, J., & Howard, A. (1981). Monoamine oxidase inhibitors in bipolar endogenous depressives. Journal of Clinical Psychopharmacology, 1, 70-74.
- ^ Buigues, J. & Vallejo, J. (1987). Therapeutic response to phenelzine in patients with panic disorder and agoraphobia with panic attacks. Journal of Clinical Psychiatry, 48, 55-59.
- ^ Blanco, C., Schneier, F.R., Schmidt, A., Blanco-Jerez, C., Marshall, R.D., Sanchez-Lacay, A., et al. (2003). Pharmacological treatment of social anxiety disorder: A meta-analysis. Depression and Anxiety, 18, 29-40.
- ^ Walsh, B.T., Gladis, M., Roose, S.P., Stewart, J.W., Stetner, F., & Glassman, A.H. (1988). Phenelzine vs placebo in 50 patients with bulimia. Archives of General Psychiatry, 45, 471-475.
- ^ Frank, J.B., Kosten, T.R., Giller, E.L., & Dan, E. (1988). A randomized clinical trial of phenelzine and imipramine for posttraumatic stress disorder. American Journal of Psychiatry, 145, 1289-1291.
- ^ Tanay, V.A.I., Parent, M.B., Wong, J.T.F., Paslawski, T., Martin, I.L., & Baker, G.B. (2001). Effects of the antidepressant/antipanic drug phenelzine on alanine and alanine transaminase in rat brain. Cellular and Molecular Neruobiology, 21, 325-339.
- ^ McKenna, K.F., McManus, D.J., Baker, G.B., & Coutts, R.T. (1994). Chronic administration of the antidepressant phenelzine and its N-acetyl analogue: Effects on GABAergic function. Journal of Neural Transmission, 41, Suppl, 115-122.
- ^ Phenelzine-Induced Fulminant Hepatic Failure. Annals of Internal Medicine; 4/01/96, Vol. 124 Issue 7, p692-693, 2p
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