Perphenazine

Source: Wikipedia, the free encyclopedia.
Perphenazine
Clinical data
AHFS/Drugs.comMonograph
MedlinePlusa682165
Pregnancy
category
  • AU: C
IM
Drug classTypical antipsychotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability40%
Metabolismhepatic
Elimination half-life8-12 (up to 20) hours
Identifiers
  • 2-[4-[3-(2-chloro-10H-phenothiazin-10-yl) propyl]piperazin-1-yl]ethanol
JSmol)
  • Clc2cc1N(c3c(Sc1cc2)cccc3)CCCN4CCN(CCO)CC4
  • InChI=1S/C21H26ClN3OS/c22-17-6-7-21-19(16-17)25(18-4-1-2-5-20(18)27-21)9-3-8-23-10-12-24(13-11-23)14-15-26/h1-2,4-7,16,26H,3,8-15H2 checkY
  • Key:RGCVKNLCSQQDEP-UHFFFAOYSA-N checkY
  (verify)

Perphenazine is a typical antipsychotic drug. Chemically, it is classified as a piperazinyl phenothiazine. Originally marketed in the United States as Trilafon, it has been in clinical use for decades.

Perphenazine is roughly ten times as potent as chlorpromazine at the dopamine-2 (D2) receptor;[3] thus perphenazine is considered a medium-potency antipsychotic.[4][5]

Medical uses

In low doses it is used to treat

agitated depression (together with an antidepressant). Fixed combinations of perphenazine and the tricyclic antidepressant amitriptyline in different proportions of weight exist (see Etrafon below). When treating depression, perphenazine is discontinued as fast as the clinical situation allows.[citation needed] Perphenazine has no intrinsic antidepressive activity. Several studies show that the use of perphenazine with fluoxetine (Prozac) in patients with psychotic depression is most promising, although fluoxetine interferes with the metabolism of perphenazine, causing higher plasma levels of perphenazine and a longer half-life. In this combination the strong antiemetic action of perphenazine attenuates fluoxetine-induced nausea and vomiting
(emesis), as well as the initial agitation caused by fluoxetine. Both actions can be helpful for many patients.

Perphenazine has been used in low doses as a 'normal' or 'minor' tranquilizer in patients with a known history of addiction to drugs or alcohol, a practice which is now strongly discouraged.[citation needed]

Perphenazine has sedating and anxiolytic properties, making the drug useful for the treatment of agitated psychotic patients.

A valuable off-label indication is the short-time treatment of

teratogenic
and works very well, it is sometimes given orally in the smallest possible dose.

Effectiveness

Perphenazine is used to treat psychosis (e.g. in people with

poverty of speech, is unclear. Earlier studies found the typical antipsychotics to be ineffective or poorly effective in the treatment of negative symptoms,[6] but two recent, large-scale studies found no difference between perphenazine and the atypical antipsychotics.[7] A 2015 systematic review
compared perphenazine with other antipsychotic drugs:

Perphenazine compared with any antipsychotic drug for schizophrenia[8]
Summary
Although perphenazine has been used in randomized trials for more than 50 years, incomplete reporting and the variety of comparators used make it impossible to draw clear conclusions. All data for the main outcomes were of very low quality evidence. At best it can be said that perphenazine showed similar effects—including adverse events—as several of the other antipsychotic drugs.[8]

Side effects

As a member of the phenothiazine type of antipsychotics, perphenazine shares in general all allergic and toxic side-effects of

extrapyramidal side effects more often than placebo, and at a similar rate to other medium-potency antipsychotics[9] and the atypical antipsychotic risperidone.[10][11]

When used for its strong antiemetic or antivertignosic effects in cases with associated brain injuries, it may obscure the clinical course and interferes with the diagnosis. High doses of perphenazine can cause temporary dyskinesia. As with other typical antipsychotics, permanent or lasting tardive dyskinesia is a risk.

Discontinuation

The

discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[12] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[13] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[13] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[13] Symptoms generally resolve after a short period of time.[13]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[14] It may also result in reoccurrence of the condition that is being treated.[15] Rarely tardive dyskinesia can occur when the medication is stopped.[13]

Pharmacology

Pharmacodynamics

Perphenazine has the following binding profile towards cloned human receptors unless otherwise specified:[16][17]

Molecular target Binding affinity (Ki[nM]) for perphenazine Binding affinity (Ki[nM]) for dealkylperphenazine Binding affinity (Ki[nM]) for 7-hydroxyperphenazine
5-HT1A 421 - -
5-HT2A 5.6 54 38
5-HT2C 132 - -
5-HT6 17 - -
5-HT7 23 - -
α1A 10 - -
α2A 810 - -
α2B 104.9 - -
α2C 85.2 - -
M1 2000 130 3400
M3 1848 - -
D1
 29.9 (RS) - -
D2
 0.765 - -
D2L receptor 3.4 85 4.1
D3
 0.13 - -
D4
 17 - -
D4.4 receptor 140 690 620
H1 8 - -
σ 18.5 (RB) - -


Acronyms:
RS — Rat striatum receptor.
RB — Rat brain receptor.

Pharmacokinetics

Perphenazine has an oral bioavailability of approximately 40% and a half-life of 8 to 12 hours (up to 20 hours), and is usually given in 2 or 3 divided doses each day. It is possible to give two-thirds of the daily dose at bedtime and one-third during breakfast to maximize hypnotic activity during the night and to minimize daytime sedation and hypotension without loss of therapeutic activity.

Pharmacokinetics of long-acting injectable antipsychotics
Medication Brand name Class Vehicle Dosage Tmax t1/2 single t1/2 multiple logPc Ref
Aripiprazole lauroxil Aristada Atypical Watera 441–1064 mg/4–8 weeks 24–35 days ? 54–57 days 7.9–10.0
Aripiprazole monohydrate
 Abilify Maintena Atypical Watera 300–400 mg/4 weeks 7 days ? 30–47 days 4.9–5.2
Bromperidol decanoate Impromen Decanoas Typical Sesame oil 40–300 mg/4 weeks 3–9 days ? 21–25 days 7.9 [18]
Clopentixol decanoate
 Sordinol Depot Typical Viscoleob 50–600 mg/1–4 weeks 4–7 days ? 19 days 9.0 [19]
Flupentixol decanoate
 Depixol Typical Viscoleob 10–200 mg/2–4 weeks 4–10 days 8 days 17 days 7.2–9.2 [19][20]
Fluphenazine decanoate
 Prolixin Decanoate Typical Sesame oil 12.5–100 mg/2–5 weeks 1–2 days 1–10 days 14–100 days 7.2–9.0 [21][22][23]
Fluphenazine enanthate
 Prolixin Enanthate Typical Sesame oil 12.5–100 mg/1–4 weeks 2–3 days 4 days ? 6.4–7.4 [22]
Fluspirilene Imap, Redeptin Typical Watera 2–12 mg/1 week 1–8 days 7 days ? 5.2–5.8 [24]
Haloperidol decanoate Haldol Decanoate Typical Sesame oil 20–400 mg/2–4 weeks 3–9 days 18–21 days 7.2–7.9 [25][26]
Olanzapine pamoate
 Zyprexa Relprevv Atypical Watera 150–405 mg/2–4 weeks 7 days ? 30 days –
Oxyprothepin decanoate Meclopin Typical ? ? ? ? ? 8.5–8.7
Paliperidone palmitate
 Invega Sustenna Atypical Watera 39–819 mg/4–12 weeks 13–33 days 25–139 days ? 8.1–10.1
Perphenazine decanoate Trilafon Dekanoat Typical Sesame oil 50–200 mg/2–4 weeks ? ? 27 days 8.9
Perphenazine enanthate Trilafon Enanthate Typical Sesame oil 25–200 mg/2 weeks 2–3 days ? 4–7 days 6.4–7.2 [27]
Pipotiazine palmitate
 Piportil Longum Typical Viscoleob 25–400 mg/4 weeks 9–10 days ? 14–21 days 8.5–11.6 [20]
Pipotiazine undecylenate
 Piportil Medium Typical Sesame oil 100–200 mg/2 weeks ? ? ? 8.4
Risperidone Risperdal Consta Atypical
Microspheres
 12.5–75 mg/2 weeks 21 days ? 3–6 days –
Zuclopentixol acetate
 Clopixol Acuphase Typical Viscoleob 50–200 mg/1–3 days 1–2 days 1–2 days 4.7–4.9
Zuclopentixol decanoate
 Clopixol Depot Typical Viscoleob 50–800 mg/2–4 weeks 4–9 days ? 11–21 days 7.5–9.0
Note: All by
fractionated coconut oil with medium-chain triglycerides). c = Predicted, from PubChem and DrugBank
. Sources: Main: See template.

Formulations

It is sold under the brand names Trilafon (single drug) and Etrafon/Triavil/Triptafen[28] (contains fixed dosages of amitriptyline). A brand name in Europe is Decentan pointing to the fact that perphenazine is approximately 10-times more potent than chlorpromazine. Usual oral forms are tablets (2, 4, 8, 16 mg) and liquid concentrate (4 mg/ml).

The 'Perphenazine injectable USP' solution is intended for deep

intramuscular
(i.m.) injection, for patients who are not willing to take oral medication or if the patient is unable to swallow. Due to a better bioavailability of the injection, two-thirds of the original oral dose is sufficient. The incidence of hypotension, sedation and extrapyramidal side-effects may be higher compared to oral treatment. The i.m.-injections are appropriate for a few days, but oral treatment should start as soon as possible.

In many countries, depot forms of perphenazine exist (as

perphenazine decanoate). One injection works for 1 to 4 weeks depending on the dose of the depot-injection. Depot-forms of perphenazine should not be used during the initial phase of treatment as the rare neuroleptic malignant syndrome
may become more severe and uncontrollable with this form. Extrapyramidal side-effects may be somewhat reduced due to constant plasma-levels during depot-therapy. Also, patient compliance is sure, as many patients do not take their oral medication, particularly if feeling better once improvement in psychosis is achieved.

Interactions

Fluoxetine causes higher plasma levels and a longer elimination half-life of perphenazine, therefore a dose reduction of perphenazine might be necessary.

Perphenazine intensifies the central depressive action of drugs with such activity (tranquilizers, hypnotics, narcotics,

antihistaminics, OTC-antiemetics
etc.). A dose reduction of perphenazine or the other drug may be necessary.

In general, all

neuroleptics may lead to seizures in combination with the opioid tramadol
(Ultram).

Perphenazine may increase the

blood glucose levels
of insulin-dependent patients regularly during long-term treatment.

References

  1. FDA
    . Retrieved 22 Oct 2023.
  2. ^ Anvisa (2023-03-31). "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 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  3. PMID 14436902
    .
  4. PMID 16504026
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  5. ISBN 978-0-7817-8543-3
    . Retrieved 2009-06-22.
  6. S2CID 37692796
    .
  7. PMID 17015808
    .
  8. ^
    PMID 25749632
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  9. ISBN 978-0-471-25401-0
    . Retrieved 2009-06-22.
  10. S2CID 11934011
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  11. PMID 7508675
    .
  12. ISBN 978-0-85369-845-6
    . Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.
  13. ^
    ISBN 9780198527480
    .
  14. S2CID 6267180
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  15. ISBN 9788847026797
    .
  16. ^ National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Oct 3]. Chapel Hill (NC): University of North Carolina. 1998-2013. Available from: "PDSP Database - UNC". Archived from the original on 2013-11-08. Retrieved 2013-11-03.
  17. PMID 10770456
    .
  18. ^ Parent M, Toussaint C, Gilson H (1983). "Long-term treatment of chronic psychotics with bromperidol decanoate: clinical and pharmacokinetic evaluation". Current Therapeutic Research. 34 (1): 1–6.
  19. ^
    PMID 6931472
    .
  20. ^ a b Reynolds JE (1993). "Anxiolytic sedatives, hypnotics and neuroleptics.". Martindale: The Extra Pharmacopoeia (30th ed.). London: Pharmaceutical Press. pp. 364–623.
  21. PMID 6143748
    .
  22. ^
    PMID 444352
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  23. ^ Young D, Ereshefsky L, Saklad SR, Jann MW, Garcia N (1984). Explaining the pharmacokinetics of fluphenazine through computer simulations. (Abstract.). 19th Annual Midyear Clinical Meeting of the American Society of Hospital Pharmacists. Dallas, Texas.
  24. PMID 4992598
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  25. PMID 3545764
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  27. ^ Larsson M, Axelsson R, Forsman A (1984). "On the pharmacokinetics of perphenazine: a clinical study of perphenazine enanthate and decanoate". Current Therapeutic Research. 36 (6): 1071–88.
  28. ^ "Triptafen | Mind, the mental health charity - help for mental health problems". www.mind.org.uk. Retrieved 2017-03-19.