Phenelzine

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Phenelzine
Phenelzine2DACS.svg
Phenelzine3Dan2.gif
Clinical data
Trade names Nardil, others
Other names2-Phenylethylhydrazine; β-Phenylethylhydrazine; Phenethylhydrazine; Phenylethylhydrazine; Phenylethylamine hydrazide; Phenethylamine hydrazide; β-Hydrazinoethylbenzene; Fenelzine; 1-(2-Phenylethyl)hydrazine
AHFS/Drugs.com Monograph
MedlinePlus a682089
License data
Pregnancy
category
Routes of
administration 		By mouth
Drug class Monoamine oxidase inhibitor; Antidepressant
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • BR: Class C1 (Other controlled substances) [2]
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Metabolism Liver
Elimination half-life 11.6 hours
Excretion Urine
Identifiers
  • 2-phenylethylhydrazine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.108 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C8H12N2
Molar mass 136.198 g·mol−1
3D model (JSmol)
Boiling point 74 °C (165 °F)
  • N(N)CCc1ccccc1
  • InChI=1S/C8H12N2/c9-10-7-6-8-4-2-1-3-5-8/h1-5,10H,6-7,9H2 Yes check.svgY
  • Key:RMUCZJUITONUFY-UHFFFAOYSA-N Yes check.svgY
   (verify)

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. [3] Along with tranylcypromine and isocarboxazid, phenelzine is one of the few non-selective and irreversible MAOIs still in widespread clinical use. [4]

Contents

Synthesis of phenelzine was first described by Emil Votoček and Otakar Leminger in 1932. [5] [6]

Medical uses

Phenelzine is primarily used in the treatment of major depressive disorder. Patients with atypical depression respond particularly well to phenelzine. [7] The medication is also useful in treatment-resistant depression, where patients do not respond favorably to first and second-line treatments for depression. [8] In addition to being a recognized treatment for major depressive disorder, phenelzine is also effective in treating dysthymia, [9] bipolar depression, [10] panic disorder, [11] social anxiety disorder, [12] bulimia nervosa, [13] post-traumatic stress disorder (PTSD), [14] and obsessive–compulsive disorder (OCD). [15] [16]

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 peripheral 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. [17]

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. [18] [19] 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. [20] [21]

Phenelzine has also been linked to vitamin B6 deficiency. [22] Transaminases such as GABA-transaminase have been shown to be dependent upon vitamin B6 [23] 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. [24]

Pharmacology

Pharmacodynamics

Phenelzine is a non-selective 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 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 the trace amine neuromodulators such as phenethylamine, tyramine, octopamine, and tryptamine. This leads to an increase in the extracellular concentrations of these neurochemicals and, therefore, an alteration in neurochemistry and neurotransmission. This action is thought to be the primary mediator in phenelzine's therapeutic benefits. [25]

Phenelzine and its metabolites also inhibit at least two other enzymes to a lesser extent, of which are alanine transaminase (ALA-T), [26] and γ-aminobutyric acid transaminase (GABA-T), [27] the latter of which is not caused by phenelzine itself, but by a phenelzine 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. [28] GABA is the major inhibitory neurotransmitter in the mammalian central nervous system, 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. [29]

Phenelzine has also been shown to metabolize to phenethylamine (PEA). [30] 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). [31]

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. [32]

Pharmacokinetics

Phenelzine 15 mg tablets. NardilTablets.jpg
Phenelzine 15 mg tablets.

Phenelzine is administered orally in the form of phenelzine sulfate [4] and is rapidly absorbed from the gastrointestinal tract. [33] The time to peak plasma concentration is 43 minutes, and the half-life is 11.6 hours. [34] 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. [4]

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. [35] [36] Phenelzine may also interact with cytochrome P450 enzymes, inactivating these enzymes through the formation of a heme adduct. [37] Two other minor metabolites of phenelzine, as mentioned above, include phenylethylidenehydrazine and phenethylamine. [38]

Chemistry

Phenelzine, also known as 2-phenylethylhydrazine or phenylethylamine hydrazide, is a phenethylamine and hydrazine derivative. [39] [40] It is the hydrazide of β-phenethylamine and can also be referred to as N-aminophenethylamine. [39] [40]

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. [41] [42]

Research

Phenelzine showed promise in a phase II clinical trial from March 2020 in treating prostate cancer. [43] Phenelzine has also been shown to have neuroprotective effects in animal models. [44] [45] [46]

References

  1. ↑ "Phenelzine (Nardil) Use During Pregnancy". Drugs.com. 3 March 2020. Retrieved 11 July 2020.
  2. ↑ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  3. ↑ "Phenelzine". MedlinePlus Drug Information. U.S. National Library of Medicine. Retrieved 27 October 2023.
  4. 1 2 3 Sidhu G, Marwaha R (2023). "Phenelzine". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID   32119395 . Retrieved 23 November 2023.
  5. ↑ Budavari S, O'Neil, Smith A, Heckelman PE, Kinneary JF (1996). "Phenelzine". The Merck Index (12th ed.). Whitehouse Station: Merck & Co. 7181.
  6. ↑ Votoček E, Leminger O (1932). "Sur la β-phenoéthylhydrazine" [On the [preparation and properties of] β-phenoethylhydrazine]. Collection of Czechoslovak Chemical Communications (in French). 4: 271–281. doi:10.1135/cccc19320271.
  7. ↑ Parke-Davis Division of Pfizer Inc. (2007). "Nardil(R) (Phenelzine sulfate tablets, USP), labeling information" (PDF). U.S. Food and Drug Administration's. Archived (PDF) from the original on 27 November 2009. Retrieved 14 December 2009.
  8. ↑ Fiedorowicz JG, Swartz KL (July 2004). "The role of monoamine oxidase inhibitors in current psychiatric practice". Journal of Psychiatric Practice. 10 (4): 239–248. doi:10.1097/00131746-200407000-00005. PMC   2075358 . PMID   15552546.
  9. ↑ Vallejo J, Gasto C, Catalan R, Salamero M (November 1987). "Double-blind study of imipramine versus phenelzine in Melancholias and Dysthymic Disorders". The British Journal of Psychiatry. 151 (5): 639–642. doi:10.1192/bjp.151.5.639. PMID   3446308. S2CID   145651628.
  10. ↑ Quitkin FM, McGrath P, Liebowitz MR, Stewart J, Howard A (March 1981). "Monoamine oxidase inhibitors in bipolar endogenous depressives". Journal of Clinical Psychopharmacology. 1 (2): 70–74. doi:10.1097/00004714-198103000-00005. PMID   7028797. S2CID   32909169.
  11. ↑ Buigues J, Vallejo J (February 1987). "Therapeutic response to phenelzine in patients with panic disorder and agoraphobia with panic attacks". The Journal of Clinical Psychiatry. 48 (2): 55–59. PMID   3542985.
  12. ↑ Blanco C, Schneier FR, Schmidt A, Blanco-Jerez CR, Marshall RD, Sánchez-Lacay A, et al. (2003). "Pharmacological treatment of social anxiety disorder: a meta-analysis". Depression and Anxiety. 18 (1): 29–40. doi:10.1002/da.10096. PMID   12900950. S2CID   12296484.
  13. ↑ Walsh BT, Gladis M, Roose SP, Stewart JW, Stetner F, Glassman AH (May 1988). "Phenelzine vs placebo in 50 patients with bulimia". Archives of General Psychiatry. 45 (5): 471–475. doi:10.1001/archpsyc.1988.01800290091011. PMID   3282482.
  14. ↑ Frank JB, Kosten TR, Giller EL, Dan E (October 1988). "A randomized clinical trial of phenelzine and imipramine for posttraumatic stress disorder". The American Journal of Psychiatry. 145 (10): 1289–1291. doi:10.1176/ajp.145.10.1289. PMID   3048121.
  15. ↑ Vallejo J, Olivares J, Marcos T, Bulbena A, Menchón JM (November 1992). "Clomipramine versus phenelzine in obsessive-compulsive disorder. A controlled clinical trial". The British Journal of Psychiatry. 161 (5): 665–670. doi:10.1192/bjp.161.5.665. PMID   1422616. S2CID   36232956.
  16. ↑ Grant JE, Baldwin DS, Chamberlain SR (July 2021). "Time to Reconsider Monoamine Oxidase Inhibitors for Obsessive Compulsive Disorder?: A Case Series Using Phenelzine". Journal of Clinical Psychopharmacology. 41 (4): 461–464. doi:10.1097/JCP.0000000000001418. PMID   34108430. S2CID   235395484.
  17. ↑ Gómez-Gil E, Salmerón JM, Mas A (April 1996). "Phenelzine-induced fulminant hepatic failure". Annals of Internal Medicine. 124 (7): 692–693. doi:10.7326/0003-4819-124-7-199604010-00014. PMID   8607601. S2CID   43020372.
  18. ↑ Gillman PK (January 2019). "The risk of harm from acute tyramine-induced hypertension: how significant?". PsychoTropical Commentaries. 5: 1–10. doi:10.13140/RG.2.2.11909.40165. Archived from the original on 8 January 2022. Retrieved 8 January 2022.[ self-published source? ]
  19. ↑ Grady MM, Stahl SM (March 2012). "Practical guide for prescribing MAOIs: debunking myths and removing barriers". CNS Spectrums. 17 (1): 2–10. doi:10.1017/S109285291200003X. PMID   22790112. S2CID   206312008.
  20. ↑ Scotton WJ, Hill LJ, Williams AC, Barnes NM (2019). "Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions". International Journal of Tryptophan Research. 12: 1178646919873925. doi:10.1177/1178646919873925. PMC   6734608 . PMID   31523132.
  21. ↑ Volpi-Abadie J, Kaye AM, Kaye AD (2013). "Serotonin syndrome". Ochsner Journal. 13 (4): 533–540. PMC   3865832 . PMID   24358002.
  22. ↑ Malcolm DE, Yu PH, Bowen RC, O'Donovan C, Hawkes J, Hussein M (November 1994). "Phenelzine reduces plasma vitamin B6". Journal of Psychiatry & Neuroscience. 19 (5): 332–334. PMC   1188621 . PMID   7803366.
  23. ↑ PDB: 1OHW ​; Storici P, De Biase D, Bossa F, Bruno S, Mozzarelli A, Peneff C, et al. (January 2004). "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. doi: 10.1074/jbc.M305884200 . PMID   14534310.
  24. ↑ Dubnick B, Leeson GA, Scott CC (July 1960). "Effect of forms of vitamin B6 on acute toxicity of hydrazines". Toxicology and Applied Pharmacology. 2 (4): 403–409. doi:10.1016/0041-008X(60)90007-7. PMID   13818307.
  25. ↑ Baker GB, Coutts RT, McKenna KF, Sherry-McKenna RL (November 1992). "Insights into the mechanisms of action of the MAO inhibitors phenelzine and tranylcypromine: a review". Journal of Psychiatry & Neuroscience. 17 (5): 206–214. PMC   1188458 . PMID   1362653.
  26. ↑ Tanay VA, Parent MB, Wong JT, Paslawski T, Martin IL, Baker GB (August 2001). "Effects of the antidepressant/antipanic drug phenelzine on alanine and alanine transaminase in rat brain". Cellular and Molecular Neurobiology. 21 (4): 325–339. doi:10.1023/A:1012697904299. PMC   11533834 . PMID   11775064. S2CID   20655821.
  27. ↑ McKenna KF, McManus DJ, Baker GB, Coutts RT (1994). "Chronic administration of the antidepressant phenelzine and its N-acetyl analogue: Effects on GABAergic function". In Tipton KF, Youdim MB, Barwell CJ, Callingham BA, Lyles GA (eds.). Amine Oxidases: Function and Dysfunction. Journal of Neural Transmission. Supplementum. Vol. 41. pp. 115–122. doi:10.1007/978-3-7091-9324-2_15. ISBN   978-3-211-82521-1. PMID   7931216.
  28. ↑ 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.
  29. ↑ Gómez-Gil E, Salmerón JM, Mas A (April 1996). "Phenelzine-induced fulminant hepatic failure". Annals of Internal Medicine. 124 (7): 692–693. doi:10.7326/0003-4819-124-7-199604010-00014. PMID   8607601.
  30. ↑ Dyck LE, Durden DA, Boulton AA (June 1985). "Formation of beta-phenylethylamine from the antidepressant, beta-phenylethylhydrazine". Biochemical Pharmacology. 34 (11): 1925–1929. doi:10.1016/0006-2952(85)90310-7. PMID   4004908.
  31. ↑ Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN   978-0-470-11790-3. OCLC   181862653. OL   18589888W.
  32. ↑ Raft D, Davidson J, Wasik J, Mattox A (1981). "Relationship between response to phenelzine and MAO inhibition in a clinical trial of phenelzine, amitriptyline and placebo". Neuropsychobiology. 7 (3): 122–126. doi:10.1159/000117841. PMID   7231652.
  33. ↑ "Phenelzine". go.drugbank.com. Retrieved 23 November 2023.
  34. ↑ "Phenelzine: Package Insert". Drugs.com. Retrieved 23 November 2023.
  35. ↑ "NARDIL- phenelzine sulfate tablet, film coated" (PDF). DailyMed . Archived (PDF) from the original on 20 May 2024. Retrieved 20 May 2024.
  36. ↑ Kallem RR, Jillela B, Ravula AR, Samala R, Andy A, Ramesh M, et al. (June 2016). "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. doi:10.1016/j.jchromb.2016.04.006. PMID   27085800.
  37. ↑ Polasek TM, Elliot DJ, Somogyi AA, Gillam EM, Lewis BC, Miners JO (May 2006). "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. doi:10.1111/j.1365-2125.2006.02627.x. PMC   1885050 . PMID   16669850.
  38. ↑ Matveychuk D, MacKenzie EM, Kumpula D, Song MS, Holt A, Kar S, et al. (January 2022). "Overview of the Neuroprotective Effects of the MAO-Inhibiting Antidepressant Phenelzine". Cellular and Molecular Neurobiology. 42 (1): 225–242. doi:10.1007/s10571-021-01078-3. PMC   8732914 . PMID   33839994.
  39. 1 2 Shulgin A, Manning T, Daley DF (2011). The Shulgin Index: Psychedelic Phenethylamines and Related Compounds . Vol. 1. Transform Press. ISBN   978-0-9630096-3-0. [...] phenelzine (N-amino-phenethylamine, an anxiolytic) [...]
  40. 1 2 "PiHKAL·info". Isomer Design. 4 August 2024. Retrieved 12 August 2024.
  41. ↑ Secci D, Bolasco A, Chimenti P, Carradori S (2011). "The state of the art of pyrazole derivatives as monoamine oxidase inhibitors and antidepressant/anticonvulsant agents". Curr Med Chem. 18 (33): 5114–5144. doi:10.2174/092986711797636090. PMID   22050759.
  42. ↑ Yáñez M, Padín JF, Arranz-Tagarro JA, Camiña M, Laguna R (2012). "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. doi:10.2174/156802612805220011. PMID   23231399.
  43. ↑ Stone L (April 2020). "MAOA inhibitor phenelzine efficacious in recurrent prostate cancer". Nature Reviews. Urology. 17 (4): 192. doi: 10.1038/s41585-020-0307-y . PMID   32203303. S2CID   212681980.
  44. ↑ Baker G, Matveychuk D, MacKenzie EM, Holt A, Wang Y, Kar S (May 2019). "Attenuation of the effects of oxidative stress by the MAO-inhibiting antidepressant and carbonyl scavenger phenelzine". Chemico-Biological Interactions. 304: 139–147. Bibcode:2019CBI...304..139B. doi: 10.1016/j.cbi.2019.03.003 . PMID   30857888. S2CID   75140657.
  45. ↑ Matveychuk D, MacKenzie EM, Kumpula D, Song MS, Holt A, Kar S, et al. (January 2022). "Overview of the Neuroprotective Effects of the MAO-Inhibiting Antidepressant Phenelzine". Cellular and Molecular Neurobiology. 42 (1): 225–242. doi: 10.1007/s10571-021-01078-3 . PMC   8732914 . PMID   33839994. S2CID   233211407.
  46. ↑ Cebak JE, Singh IN, Hill RL, Wang JA, Hall ED (April 2017). "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. doi:10.1089/neu.2016.4624. PMC   5385448 . PMID   27750484.
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