Biology:Phenelzine

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Phenelzine, sold under the brand name Nardil among others, is a non-selective and irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine family which is primarily used as an antidepressant and anxiolytic to treat depression and anxiety.[1][2] Along with tranylcypromine and isocarboxazid, phenelzine is one of the few non-selective and irreversible MAOIs still in widespread clinical use.[1][3]

Medical uses

Phenelzine is primarily used in the treatment of major depressive disorder. Patients with atypical depression respond particularly well to phenelzine,[4] but evidence suggests phenelzine can also be effective in melancholic depressions.[5] The medication is also useful in treatment-resistant depression,[6] where patients do not respond favorably to first and second-line treatments for depression.[7] In addition to being a recognized treatment for major depressive disorder, phenelzine is also effective in treating dysthymia,[8] bipolar depression,[9] panic disorder,[10] social anxiety disorder,[11] bulimia nervosa,[12] post-traumatic stress disorder (PTSD),[13] and obsessive–compulsive disorder (OCD).[14][15]

Side effects

Common side effects of phenelzine may include dizziness, blurry vision, dry mouth, headache, lethargy, sedation, somnolence, insomnia, anorexia, weight gain or loss, small fiber neuropathy, nausea and vomiting, diarrhea, constipation, urinary retention, mydriasis, muscle tremors, hyperthermia, sweating, hypertension 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 include hypomania or mania, psychosis, and acute liver failure, the last of which is usually only seen in people with pre-existing liver damage, old age, long-term effects of alcohol consumption, or viral infection.[16]

Interactions

The MAOIs have certain dietary restrictions and drug interactions. A hypertensive crisis may result from the overconsumption of tyramine-containing foods, although it is a rare occurrence.[17][18] Serotonin syndrome may result from an interaction with certain drugs which increase serotonin activity such as selective serotonin reuptake inhibitors, serotonin releasing agents, and serotonin agonists.[19][20]

Phenelzine has also been linked to vitamin B6 deficiency.[21] Transaminases such as GABA-transaminase have been shown to be dependent upon vitamin B6[22] and may be involved in a potentially related process, since the phenelzine metabolite phenylethylidenehydrazine (PEH) is a GABA-transaminase inhibitor. Both phenelzine and vitamin B6 are rendered inactive upon these reactions occurring. The pyridoxine form of B6 is recommended for supplementation, since this form has been shown to reduce hydrazine toxicity from phenelzine and, in contrast, the pyridoxal form has been shown to increase the toxicity of hydrazines.[23]

Pharmacology

Pharmacodynamics

Phenelzine is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase. It inhibits both of the respective isoforms of monoamine oxidase (MAO), MAO-A and MAO-B, and does so almost equally, with a slight preference for the former. By inhibiting MAO, phenelzine prevents the breakdown of the monoamine neurotransmitters serotonin, melatonin, norepinephrine, epinephrine, and dopamine, as well as trace amine neuromodulators such as phenethylamine, tyramine, octopamine, and tryptamine. Consequently, the amount of these neurochemicals in the synaptic cleft increases, ultimately affecting neurotransmission. This action is thought to be the primary mediator in phenelzine's therapeutic benefits.[24]

Phenelzine and its metabolites also inhibit other enzymes to a lesser extent, two of which are alanine transaminase (ALA-T),[25] and γ-aminobutyric acid transaminase (GABA-T),[26] the latter of which is not caused by phenelzine itself, but by phenylethylidenehydrazine (PEH), which is a phenelzine metabolite. By inhibiting GABA-T and ALA-T, phenelzine causes an increase in the alanine and GABA levels in the brain and body.[27] GABA is the major inhibitory neurotransmitter in the central nervous system of mammals, and is very important for the normal suppression of anxiety, stress, and depression. Phenelzine's action in increasing GABA concentrations may significantly contribute to its antidepressant, and especially, anxiolytic/antipanic properties, the latter of which have been considered superior to those of other antidepressants. 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 may be responsible for the occasional incidence of hepatitis and liver failure.[28]

Phenelzine has also been shown to metabolize to phenethylamine (PEA).[29] PEA acts as a releasing agent of norepinephrine and dopamine, which occurs in a similar manner to amphetamine by being taken up into vesicles, displacing and causing the release of those monoamines, and reversing monoamine flux through their respective transporters (though with markedly shorter pharmacokinetics).[30]

Like many other antidepressants, phenelzine usually requires several weeks of treatment to achieve full therapeutic effects. The reason for this delay is not fully understood. Still, it is believed to be due to many factors, including achieving steady-state levels of MAO inhibition and the resulting adaptations in mean neurotransmitter levels, the possibility of necessary desensitization of autoreceptors which generally inhibit the release of neurotransmitters like serotonin and dopamine, and also the upregulation of enzymes such as serotonin N-acetyltransferase. Typically, a therapeutic response to MAOIs is associated with an inhibition of at least 80–85% of monoamine oxidase activity.[31]

Pharmacokinetics

Phenelzine 15 mg tablets.

Phenelzine is administered orally in the form of phenelzine sulfate[3] and is rapidly absorbed from the gastrointestinal tract.[32] The time to peak plasma concentration is 43 minutes, and the half-life is 11.6 hours.[33] Unlike most other drugs, phenelzine irreversibly disables MAO. 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 wear off until the body replenishes its enzyme stores, a process which can take as long as 2–3 weeks.[3]

Phenelzine is metabolized primarily in the liver, and its metabolites are excreted in the urine. Oxidation is the primary routine of metabolism, and the major metabolites are phenylacetic acid and parahydroxyphenylacetic acid, recovered as about 73% of the excreted dose of phenelzine in the urine over 96 hours after single doses. Acetylation to N2-acetylphenelzine is a minor pathway.[34][35] Phenelzine may also interact with cytochrome P450 enzymes, inactivating these enzymes through the formation of a heme adduct.[36] Two other minor metabolites of phenelzine, as mentioned above, include phenylethylidenehydrazine and phenethylamine.[37]

Chemistry

File:Phenelzinehydrochloride.png
Phenelzine hydrochloride powder.

Phenelzine, also known as 2-phenylethylhydrazine or phenylethylamine hydrazide, is a phenethylamine and hydrazine derivative.[38][39] It is the hydrazide of β-phenethylamine and can also be referred to as N-aminophenethylamine.[38][39]

Synthesis

The chemical synthesis of phenelzine has been described.[1]

Analogues

Close analogues of phenelzine include the amphetamine and hydrazine derivatives pheniprazine (α-methylphenelzine; the corresponding amphetamine analogue) and metfendrazine (α,N-dimethylphenelzine; the corresponding methamphetamine analogue), among others.[40][41] Other analogues of phenelzine are its deuterated isotopologues α,α-dideuterophenelzine (d2-phenelzine) and α,α,β,β-tetradeuterophenelzine (d4-phenelzine), which show strongly potentiated pharmacological activity compared to phenelzine.[42][43][44][45][46][47]

History

Synthesis of phenelzine was first described by Emil Votoček and Otakar Leminger in 1932.[48][49]

Research

Phenelzine showed promise in a phase II clinical trial from March 2020 in treating prostate cancer.[50] Phenelzine has also been shown to have neuroprotective effects in animal models.[51][52][53]

References

  1. ↑ 1.0 1.1 1.2 "Classics in Chemical Neuroscience: Selegiline, Isocarboxazid, Phenelzine, and Tranylcypromine". ACS Chem Neurosci 14 (23): 4064–4075. December 2023. doi:10.1021/acschemneuro.3c00591. PMID 37966854. 
  2. ↑ "Phenelzine" (in en). MedlinePlus Drug Information. U.S. National Library of Medicine. https://medlineplus.gov/druginfo/meds/a682089.html. 
  3. ↑ 3.0 3.1 3.2 "Phenelzine". StatPearls. Treasure Island (FL): StatPearls Publishing. 2023. https://www.ncbi.nlm.nih.gov/books/NBK554508/. Retrieved 23 November 2023. 
  4. ↑ Parke-Davis Division of Pfizer Inc. (2007). "Nardil(R) (Phenelzine sulfate tablets, USP), labeling information". U.S. Food and Drug Administration's. http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/011909s038lbl.pdf. 
  5. ↑ "On the Origins of MAOI Misconceptions: Reaffirming their Role in Melancholic Depression". Psychopharmacology Bulletin 53 (3): 35–54. August 2023. doi:10.64719/pb.4466. PMID 37601082. 
  6. ↑ "The prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression". CNS Spectrums 28 (4): 427–440. August 2023. doi:10.1017/S1092852922000906. PMID 35837681. 
  7. ↑ "The role of monoamine oxidase inhibitors in current psychiatric practice". Journal of Psychiatric Practice 10 (4): 239–248. July 2004. doi:10.1097/00131746-200407000-00005. PMID 15552546. 
  8. ↑ "Double-blind study of imipramine versus phenelzine in Melancholias and Dysthymic Disorders". The British Journal of Psychiatry 151 (5): 639–642. November 1987. doi:10.1192/bjp.151.5.639. PMID 3446308. 
  9. ↑ "Monoamine oxidase inhibitors in bipolar endogenous depressives". Journal of Clinical Psychopharmacology 1 (2): 70–74. March 1981. doi:10.1097/00004714-198103000-00005. PMID 7028797. 
  10. ↑ "Therapeutic response to phenelzine in patients with panic disorder and agoraphobia with panic attacks". The Journal of Clinical Psychiatry 48 (2): 55–59. February 1987. PMID 3542985. 
  11. ↑ "Pharmacological treatment of social anxiety disorder: a meta-analysis". Depression and Anxiety 18 (1): 29–40. 2003. doi:10.1002/da.10096. PMID 12900950. 
  12. ↑ "Phenelzine vs placebo in 50 patients with bulimia". Archives of General Psychiatry 45 (5): 471–475. May 1988. doi:10.1001/archpsyc.1988.01800290091011. PMID 3282482. 
  13. ↑ "A randomized clinical trial of phenelzine and imipramine for posttraumatic stress disorder". The American Journal of Psychiatry 145 (10): 1289–1291. October 1988. doi:10.1176/ajp.145.10.1289. PMID 3048121. 
  14. ↑ "Clomipramine versus phenelzine in obsessive-compulsive disorder. A controlled clinical trial". The British Journal of Psychiatry 161 (5): 665–670. November 1992. doi:10.1192/bjp.161.5.665. PMID 1422616. 
  15. ↑ "Time to Reconsider Monoamine Oxidase Inhibitors for Obsessive Compulsive Disorder?: A Case Series Using Phenelzine". Journal of Clinical Psychopharmacology 41 (4): 461–464. July 2021. doi:10.1097/JCP.0000000000001418. PMID 34108430. https://eprints.soton.ac.uk/450147/1/OCD_phenelzine_3_27_21.docx. 
  16. ↑ "Phenelzine-induced fulminant hepatic failure". Annals of Internal Medicine 124 (7): 692–693. April 1996. doi:10.7326/0003-4819-124-7-199604010-00014. PMID 8607601. 
  17. ↑ "The risk of harm from acute tyramine-induced hypertension: how significant?". PsychoTropical Commentaries 5: 1–10. January 2019. doi:10.13140/RG.2.2.11909.40165. https://psychotropical.com/risk_of_harm_from_acute_tyr_hypertension/. Retrieved 8 January 2022. [self-published source?]
  18. ↑ "Practical guide for prescribing MAOIs: debunking myths and removing barriers". CNS Spectrums 17 (1): 2–10. March 2012. doi:10.1017/S109285291200003X. PMID 22790112. 
  19. ↑ "Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions". International Journal of Tryptophan Research 12. 2019. doi:10.1177/1178646919873925. PMID 31523132. 
  20. ↑ "Serotonin syndrome". Ochsner Journal 13 (4): 533–540. 2013. PMID 24358002. 
  21. ↑ "Phenelzine reduces plasma vitamin B6". Journal of Psychiatry & Neuroscience 19 (5): 332–334. November 1994. PMID 7803366. 
  22. ↑ PDB: 1OHW​; "Structures of gamma-aminobutyric acid (GABA) aminotransferase, a pyridoxal 5'-phosphate, and [2Fe-2S] cluster-containing enzyme, complexed with gamma-ethynyl-GABA and with the antiepilepsy drug vigabatrin". The Journal of Biological Chemistry 279 (1): 363–373. January 2004. doi:10.1074/jbc.M305884200. PMID 14534310. 
  23. ↑ "Effect of forms of vitamin B6 on acute toxicity of hydrazines". Toxicology and Applied Pharmacology 2 (4): 403–409. July 1960. doi:10.1016/0041-008X(60)90007-7. PMID 13818307. 
  24. ↑ "Insights into the mechanisms of action of the MAO inhibitors phenelzine and tranylcypromine: a review". Journal of Psychiatry & Neuroscience 17 (5): 206–214. November 1992. PMID 1362653. 
  25. ↑ "Effects of the antidepressant/antipanic drug phenelzine on alanine and alanine transaminase in rat brain". Cellular and Molecular Neurobiology 21 (4): 325–339. August 2001. doi:10.1023/A:1012697904299. PMID 11775064. 
  26. ↑ "Chronic administration of the antidepressant phenelzine and its N-acetyl analogue: Effects on GABAergic function". Amine Oxidases: Function and Dysfunction. Journal of Neural Transmission. Supplementum. 41. 1994. pp. 115–122. doi:10.1007/978-3-7091-9324-2_15. ISBN 978-3-211-82521-1. 
  27. ↑ Paslawski TM (1998). The Antipanic Drug Phenelzine and Its Effects on GABA and Related Amino Acids (Ph.D. thesis). University of Alberta. ISBN 978-0-612-29091-4. OCLC 46576166.
  28. ↑ "Phenelzine-induced fulminant hepatic failure". Annals of Internal Medicine 124 (7): 692–693. April 1996. doi:10.7326/0003-4819-124-7-199604010-00014. PMID 8607601. 
  29. ↑ "Formation of beta-phenylethylamine from the antidepressant, beta-phenylethylhydrazine". Biochemical Pharmacology 34 (11): 1925–1929. June 1985. doi:10.1016/0006-2952(85)90310-7. PMID 4004908. 
  30. ↑ "Dopamine-releasing agents". Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. July 2008. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf. 
  31. ↑ "Relationship between response to phenelzine and MAO inhibition in a clinical trial of phenelzine, amitriptyline and placebo". Neuropsychobiology 7 (3): 122–126. 1981. doi:10.1159/000117841. PMID 7231652. 
  32. ↑ "Phenelzine" (in en). https://go.drugbank.com/drugs/DB00780. 
  33. ↑ "Phenelzine: Package Insert" (in en). https://www.drugs.com/pro/phenelzine.html. 
  34. ↑ "NARDIL- phenelzine sulfate tablet, film coated" (PDF). https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=513a41d0-37d4-4355-8a6d-a2c643bce6fa&type=pdf. 
  35. ↑ "Highly sensitive LC-MS/MS-ESI method for determination of phenelzine in human plasma and its application to a human pharmacokinetic study". Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences 1022: 126–132. June 2016. doi:10.1016/j.jchromb.2016.04.006. PMID 27085800. 
  36. ↑ "An evaluation of potential mechanism-based inactivation of human drug metabolizing cytochromes P450 by monoamine oxidase inhibitors, including isoniazid". British Journal of Clinical Pharmacology 61 (5): 570–584. May 2006. doi:10.1111/j.1365-2125.2006.02627.x. PMID 16669850. 
  37. ↑ "Overview of the Neuroprotective Effects of the MAO-Inhibiting Antidepressant Phenelzine". Cellular and Molecular Neurobiology 42 (1): 225–242. January 2022. doi:10.1007/s10571-021-01078-3. PMID 33839994. 
  38. ↑ 38.0 38.1 The Shulgin Index: Psychedelic Phenethylamines and Related Compounds. 1. Transform Press. 2011. ISBN 978-0-9630096-3-0. "[...] phenelzine (N-amino-phenethylamine, an anxiolytic) [...]" 
  39. ↑ 39.0 39.1 "PiHKAL·info". 4 August 2024. https://isomerdesign.com/pihkal/explore/10642. 
  40. ↑ "The state of the art of pyrazole derivatives as monoamine oxidase inhibitors and antidepressant/anticonvulsant agents". Curr Med Chem 18 (33): 5114–5144. 2011. doi:10.2174/092986711797636090. PMID 22050759. 
  41. ↑ "History and therapeutic use of MAO-A inhibitors: a historical perspective of MAO-A inhibitors as antidepressant drug". Curr Top Med Chem 12 (20): 2275–2282. 2012. doi:10.2174/156802612805220011. PMID 23231399. 
  42. ↑ "Potentiation of the biochemical effects of beta-phenylethylhydrazine by deuterium substitution". Biochem Pharmacol 32 (9): 1519–1522. May 1983. doi:10.1016/0006-2952(83)90475-6. PMID 6860370. 
  43. ↑ "Potentiation of the behavioural effects of the antidepressant phenelzine by deuterium substitution". Psychopharmacology (Berl) 81 (2): 122–125. 1983. doi:10.1007/BF00429005. PMID 6415742. 
  44. ↑ "Involvement of brain trace amines in the behavioural effects of phenelzine". Neurochem Res 13 (2): 113–119. February 1988. doi:10.1007/BF00973322. PMID 3362290. 
  45. ↑ "Effect of chronic deuterated and non-deuterated phenelzine on rat brain monoamines and monoamine oxidase". Naunyn Schmiedebergs Arch Pharmacol 337 (3): 279–283. March 1988. doi:10.1007/BF00168839. PMID 3393230. 
  46. ↑ "Effect of deuterium substitution on the penetration of beta-phenylethylhydrazine into the rat brain". Biochem Pharmacol 37 (13): 2703–2704. July 1988. doi:10.1016/0006-2952(88)90266-3. PMID 3390229. 
  47. ↑ "Deuterium isotope effect of phenelzine on the inhibition of rat liver mitochondrial monoamine oxidase activity". Biochem Pharmacol 38 (23): 4245–4251. December 1989. doi:10.1016/0006-2952(89)90522-4. PMID 2597196. 
  48. ↑ "Phenelzine". The Merck Index (12th ed.). Whitehouse Station: Merck & Co. 1996. 7181. 
  49. ↑ "Sur la β-phenoéthylhydrazine." (in French). Collection of Czechoslovak Chemical Communications 4: 271–281. 1932. doi:10.1135/cccc19320271. 
  50. ↑ "MAOA inhibitor phenelzine efficacious in recurrent prostate cancer". Nature Reviews. Urology 17 (4): 192. April 2020. doi:10.1038/s41585-020-0307-y. PMID 32203303. 
  51. ↑ "Attenuation of the effects of oxidative stress by the MAO-inhibiting antidepressant and carbonyl scavenger phenelzine". Chemico-Biological Interactions 304: 139–147. May 2019. doi:10.1016/j.cbi.2019.03.003. PMID 30857888. Bibcode: 2019CBI...304..139B. 
  52. ↑ "Overview of the Neuroprotective Effects of the MAO-Inhibiting Antidepressant Phenelzine". Cellular and Molecular Neurobiology 42 (1): 225–242. January 2022. doi:10.1007/s10571-021-01078-3. PMID 33839994. 
  53. ↑ "Phenelzine Protects Brain Mitochondrial Function In Vitro and In Vivo following Traumatic Brain Injury by Scavenging the Reactive Carbonyls 4-Hydroxynonenal and Acrolein Leading to Cortical Histological Neuroprotection". Journal of Neurotrauma 34 (7): 1302–1317. April 2017. doi:10.1089/neu.2016.4624. PMID 27750484. 



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