Phenelzine

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Phenelzine
Clinical data
Trade namesNardil
AHFS/Drugs.comMonograph
MedlinePlusa682089
License data
Pregnancy
category
Routes of
administration		By mouth
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
MetabolismLiver
Elimination half-life11.6 hours
ExcretionUrine
Identifiers
  • 2-phenylethylhydrazine
JSmol)
Boiling point74 °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 checkY
  • Key:RMUCZJUITONUFY-UHFFFAOYSA-N checkY
  (verify)

Phenelzine, sold under the brand name Nardil, among others, is a

irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class which is primarily used as an antidepressant and anxiolytic.[3] Along with tranylcypromine and isocarboxazid, phenelzine is one of the few non-selective and irreversible MAOIs still in widespread clinical use.[4]

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

Medical uses

Phenelzine is primarily used in the

obsessive-compulsive disorder (OCD).[15][16]

Pharmacology

Pharmacodynamics

Phenelzine is a non-selective and

therapeutic benefits.[17]

Phenelzine and its metabolites also inhibit at least two other enzymes to a lesser extent, of which are

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.[21]

Phenelzine has also been shown to metabolize to phenethylamine (PEA).

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 (though with markedly different pharmacokinetics such as a far shorter duration of action).[23]
Although this is indeed the same mechanism to which some (but not all) of amphetamine's effects are attributable, this is not all that uncommon a property among phenethylamines in general, many of which do not have psychoactive properties comparable to amphetamine. Amphetamine is different in that it binds with high affinity to the reuptake pumps of dopamine, norepinephrine, and serotonin, which phenethylamine and related molecules may as well to some extent, but with far less potency, such that it is insignificant in comparison—and often being metabolized too quickly or not having the solubility to enable it to have a psychostimulant effect in humans. Claims that phenethylamine has comparable or roughly similar effects to psychostimulants such as amphetamine when administered are misconstrued. When administered to humans, phenethylamine has no noticeable, easily discernible, reliably induced effects. Phenelzine's enhancement of PEA levels may contribute further to its overall antidepressant effects to some degree. In addition, phenethylamine is a substrate for MAO-B, and treatment with MAOIs that inhibit MAO-B, such as phenelzine, has been shown to consistently and significantly elevate its concentrations.

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

serotonin N-acetyltransferase. Typically, a therapeutic response to MAOIs is associated with an inhibition of at least 80-85% of monoamine oxidase activity.[24]

Pharmacokinetics

Phenelzine 15 mg tablets.

Phenelzine is administered orally in the form of phenelzine sulfate[4] and is rapidly absorbed from the gastrointestinal tract.[25] The time to peak plasma concentration is 43 minutes, and the half-life is 11.6 hours.[26] 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. Phenelzine may also interact with cytochrome P450 enzymes, inactivating these enzymes through the formation of a heme adduct. Two other minor metabolites of phenelzine, as mentioned above, include phenylethylidenehydrazine and phenethylamine.

Adverse effects

Common side effects of phenelzine may include

viral infection.[27]

Interactions

See also: Monoamine oxidase inhibitor § Dangers
See also:
Foods containing tyramine

The MAOIs have certain dietary restrictions and drug interactions.

selective serotonin reuptake inhibitors, serotonin releasing agents, and serotonin agonists.[medical citation needed
]

Phenelzine has also been linked to vitamin B6 deficiency.[30] Transaminases such as GABA-transaminase have been shown to be dependent upon vitamin B6[31] 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.[32]

Research

Phenelzine showed promise in a phase II clinical trial from March 2020 in treating prostate cancer.[33] Phenelzine has also been shown to have neuroprotective effects in animal models.[34][35][36]

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". medlineplus.gov. Retrieved 27 October 2023.
  4. ^
    PMID 32119395
    . Retrieved 23 November 2023.
  5. The Merck Index
    (12th ed.). Whitehouse Station: Merck & Co. 7181.
  6. 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. PMID 15552546
    .
  9. S2CID 145651628
    .
  10. S2CID 32909169
    .
  11. PMID 3542985
    .
  12. S2CID 12296484
    .
  13. PMID 3282482
    .
  14. PMID 3048121
    .
  15. S2CID 36232956
    .
  16. S2CID 235395484
    .
  17. PMID 1362653
    .
  18. S2CID 20655821
    .
  19. PMID 7931216. {{cite book}}: |journal= ignored (help
    )
  20. OCLC 46576166
    .
  21. PMID 8607601
    .
  22. PMID 4004908
    .
  23. PMID 23539642
    .
  24. PMID 7231652
    .
  25. ^ "Phenelzine". go.drugbank.com. Retrieved 23 November 2023.
  26. ^ "Phenelzine: Package Insert". Drugs.com. Retrieved 23 November 2023.
  27. S2CID 43020372
    .
  28. doi:10.13140/RG.2.2.11909.40165. Archived from the original on 8 January 2022. Retrieved 8 January 2022.[self-published source?
    ]
  29. S2CID 206312008
    .
  30. PMID 7803366
    .
  31. PMID 14534310
    .
  32. PMID 13818307
    .
  33. S2CID 212681980
    .
  34. S2CID 75140657
    .
  35. S2CID 233211407
    .
  36. PMID 27750484
    .
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