Butyrophenones

by David Rosenblum November,18

Butyrophenones

Butyrophenones

They are typical antipsychotics. The three butyrophenones are:

  • Haloperidol
  • Trifluperidol
  • Penfluridol

Pharmacological actions

1. Effect on CNS-

  • Effects differ in normal and psychotic individuals.
  • They have potent dopamine D2 receptor blocking property and produce extrapyramidal motor side effects. They are also called ‘Neuroleptic drugs’.
  • The effects are perceived as neutral or unpleasant by most normal individuals.
  • In a psychotic they reduces irrational behaviour, agitation, anxiety and aggressiveness and controls psychotic symptomatology.
  • Hyperactivity, hallucinations and delusions are suppressed.
  • The sedative effect is produced promptly, while antipsychotic effect takes weeks to develop.
  • Moreover, tolerance develops to the sedative but not to the antipsychotic effect. Thus, the two appear to be independent actions.
  • Vigilance is impaired.
  • The disturbed sleep pattern is normalized in psychotic patient.
  • Lower seizure threshold and can precipitate fits in untreated epileptics.
  • Temperature control is knocked off at relatively higher doses.
  • They have potent antiemetic action exerted through the CTZ.

Mechanism of action

  • They have potent dopamine D2 receptor blocking property.
  • Blockade of dopaminergic projections to the temporal and prefrontal areas constituting the limbic system and in mesocortical areas is probably responsible for the antipsychotic action.
  • Only the positive symptoms (hallucination, aggression, etc.) appear to be closely linked to DA overactivity in mesolimbic areas, but not the negative symptoms (apathy, cognitive deficit, withdrawal, etc.)
  • Other monoaminergic (5-HT) as well as aminoacid (glutamate) neurotransmitter systems may also be affected.

2. ANS

  • They have lesser α blocking activity compared to phenothiazines.
  • Mild anticholinergic activity and weak H1-antihistaminic and anti-5HT actions as well.

3.  CVS

  • Hypotension (by a central as well as  peripheral action on sympathetic tone).
  • More prominent after paenteral administration.
  • Accentuated by hypovolemia.
  • Partial tolerance to hypotensive action develop after chronic use.
  • Reflex tachycardia accompanies hypotension.

4.  Skeletal muscle

  • They reduce certain types of spasticity.

5. Endocrine

  • They consistently increase prolactin release by blocking the inhibitory action of DA on pituitary lactotropes.
  • This may result in galactorrhoea and gynaecomastia.
  • They reduce gonadotropin secretion, but amenorrhoea and infertility occur only occasionally.
  • ACTH release in response to stress is diminished.
  • Release of GH is also reduced.
  • Decrease release of ADH.

Tolerance and dependence

  • Tolerance to the sedative and hypotensive actions develops within days or weeks .
  • The antipsychotic, extrapyramidal and other actions based on Da antagonism do not display tolerance.
  • No physical and psychological dependence.

Haloperidol –

  • It is a potent antipsychotic.
  • It produces few autonomic effects.
  • It is less epileptogenic.
  • Does not cause weight gain
  • Jaundice is rare.
  • It is preferred drug for acute schizophrenia, Huntington’s disease and Gilles de la Tourette’s syndrome.
  • It is metabolised by CYP3A4 and 2D6 both.
  • Elimination t1/2 averages 24 hours.
  • Haloperidol does not modifies the duration of delirium in critically ill patients. (1)
  • Haloperidol induce the functional changes in neural networks accounting for selective and involuntary attention, suggesting modulation of these functions by dopamine D2 receptors. (2)
  • Injected intramuscularly, haloperidol is safe and has a good tranquilizing and anti-emetic effect. It enhance the course of normal labor and does not cause apparent fetal depression. (3)
  • Haloperidol can be used in palliative care especially in case of nausea and vomiting and delirium. The adverse effect include EPS and QT prolongation. (4)
  • Downregulation of D1 receptor activity in the prefrontal cortex and an upregulation of D2 receptors contribute to the generation of cognitive loss observed in haloperidol treated monkeys. Reduced excitatory inputs due to hampered cortico-striatal D1 dopaminergic activity and stronger inhibtion at the synapse of excitatory input site by upregulated striatal D2 receptor activity could promote the side effects associated with haloperidol. (5)
  • Intravenous haloperidol is drug of choice to treat delirium in ICU patients. Self limited dyskinesia can occur during withdrawal of high dose IV haloperidol therapy. (6)
  • Torsades de pointes ventricular tachycardia can occur with use of haloperidol. The QT interval is prolonged and shortened after cessation of medication and infusion of isoproterenol. (7)
  • Haloperidol can be effective for the treatment of ketamine induced emergence delirium. (8)
  • Haloperidol along with promethazine is effective in psychosis induced aggression. (9)
  • Haloperidol,olanzapine and risperidone are superior to aripiprazole, quetiapine and ziprasidone for acute treatment of psychosis in hospitalized patients with schizophrenia, schizoaffective disorder and schizophreniform disorder. (10)
  • Haloperidol is an antipsychotic used in the treatment of adult schizophrenia and mania. It is used in children with neurological disorders like chorea and developmental disorders like hyperactivity. Sometimes accidental haloperidol poisoning can occur in children. (11)
  • Haloperidol induces apoptosis via the sigma2 receptor system and bcl-XS which is associated with clinical risk of haloperidol particularly following chronic regimens or in the elderly. (12)
  • Cinnarizine improves the haloperidol induced brain oxidative stress and impairment of learning and memory in the water maze test in mice. (13)

Trifluperidol

  • Similar but slightly more potent than haloperidol.
  • Trifluperidol may be the drug of choice in schizophrenia patients. (14)
  • Trifluperidol reduce the secretion of tumor necrosis factor-α and nitirc oxide by rat rat microglial cells, thus may be used in the treatment of CNS disease associated with excessive TNF-α and NO release. (15)
  • Trifluperidol reduce interleukin-1 beta and interleukin-2 release by rat mixed glial and microglial cell cultures. (16)
  • Trifluperidol along with haloperidol can be used in the treatment of acute schizophrenia. (17)
  • Trifluperidol is effective in the treatment of chronic schizophrenia. (18)

Penfluridol

  • An exceptionally long acting neuroleptic, recommended for chronic schizophrenia, affective withdrawal and social maladjustment.
  • Dose is 20-60 mg oral (max 120 mg) once weekly.
  • Penfluridol is a suitable drug for maintenance therapy in schizophrenic patients. (19)
  • Penfluridol is effective in acute psychosis. (20)
  • The major biotransformation pathways of penfluridol are oxidative N-dealkylation followed by beta oxidation, conjugation of penfluridol and conjugation of the acidic metabolites. (21)
  • Penfluridol, administered orally once a week is well tolerated and is effective in treating and maintaining schizophrenic patients. (22)
  • Penfluridol can be used as a maintenance treatment for schizophrenic patients who relapse. (23)
  • The long term treatment of rats with penfluridol produces an increase in the sensitivity of the dopamine receptors in the nucleus accumbens and corpus striatum and the nucleus accumbens may play a role in locomotor activity. (24)
  • Penfluridol reversed halofantrine resistance in T9.96HF halofantrine resistant strain of Plasmodium falciparum (originally chloroquine sensitive parasites). (25)
  • Penfluridol is not only cytotoxic to cancer cells in vitro but can also inhibit tumor growth in vivo. Dysregulation of cholestrol homeostasis by penfluridol may be involved in its anti-tumor mechanisms. (26)

Adverse effects

  • CNS:- sedation,seizures
  • CVS:- postural hypotension, palpitation
  • Anticholinergic:- Dry mouth, blurring of vision, constipation, etc.
  • Endocrine :- hyperprolactinemia
  • Extrapyramidal side effects:-Akthasia, dystonia, parkinsonism, tremor, malignant neuroleptic syndrome, tardive dyskinesia
  • Hypersensitivity reactions-rashes, urticaria etc

Interactions

  • Neuroleptics potentiate all CNS depressants.
  • Neuroleptics block the action of levodopa and direct DA agonists in parkinsonism.
  • Antihypertensive action of clonidine and methyldopa is reduced, probably due to central α2 adrenergic blockade
  • Enzyme inducers can reduce blood levels of neuroleptics.

References:

  1. Valerief J Page, W Wesley Ely, Simon Gates, Xiao Bei Zhao, Timothy Alce, Ayumi Shintani, Jim Jackson, Gavin D Perkins, Daniel F McAuley. Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double blind, placebo controlled trial. The Lancet Respiratry Medicine. The Lancet Respiratory Medicine. Sept 2013;1(7):515-523. 
  2. Seppo Kahkonen, Jyrki Ahveninen, Liro P Jaaskelainen, Seppo Kaakkola, Risto Naatanen, Juha Huttunen, Eero Pekkonen. Effects of haloperidol on selective attention: A combined whole-head MEG and High resolution EEG study. Neuropsychopharmacology. Oct 2001;25(4):498-504. 
  3. JC Staples. The use of haloperidol in obstetrics. Can Fam Physician. Oct 1967;13(10):23-24. 
  4. Jane Vella Brincat, AD (Sandy) Macleod. Haloperidol in palliative care. Palliat Med. April 2004;18(3):195-201. 
  5. Irene Navarro-Lobato, Mariam Masmudi-Martin, Manuel F Lopez-Aranda et al. A correlation of haloperidol-induced cognitive deficit with dysfunctional dopamine receptor activity in nonhuman primate. Open Access Animal Physiology. May 2010;2:1-8. 
  6. Richard R Riker, Gilles L Fraser, Peter Richen. Movement disorders associated with withdrawal from high dose intravenous haloperidol therapy in delrious ICU patients. Chest 1997;111(6):1778-1781. 
  7. M Kriwisky, GY Perry, D Tarchitsky, Y Gutman, Y Kishon. Haloperidol-induced torsades de pointes. Chest 1990;98(2):482-484. 
  8. Glen M Atlea, Maano Milles. Haloperidol for the treatment of ketamine induced emergence delirium. J Anesth Clin Pharmacology. 2007;23(1):65-67. 
  9. Haloperidol plus promethazine effective for psychosis induced aggression. Evid Based Mental Health. 2010;13:23. 
  10. Robert E McCue, Rubina Waheed, Leonel Urcuyo, Geraldine Orendain, Michel D Joseph, Richard Charles, Syed M Hasan. Comparative effectiveness of second generation antipsychotics and haloperidol in acute schizophrenia. The British Journal of Psychiatry. 2006;189:433-440. 
  11. Mona P Gajre, Dimple Jain, Alka Jadhav. Accidnetal haloperidol poisoning in children. Indian Journal of Pharmacology. 2012;44(6):803-804. 
  12. Z Wei, DD Mousseau, Y Dai, X Cao, X-M Li. Haloperidol induces apoptosis via the sigma2 receptor system and Bcl-XS. The Pharmacogenomics Journal. 2006;6:279-288. 
  13. Omar ME Abdel Salam, Marwa El Sayed El Shamarka, Naveen A Salem, Aliaa EMK El Mosallamy, Amany A Sleem. Amelioration of the haloperidol induced memory impairment and brain oxidative stress by cinnarizine. EXCLI Journal 2012;11:517-530. 
  14. DM Gallant, MP Bishop, WM Nesselhof, DJ Sprehe. Further observations on trifluperidol: a butyrophenone derivative. Psychopharmacologia. 1965;7(1):37-43. 
  15. Jan Kowalski, Krzysztof Labuzek, Zbigniew S Herman. Flupentixol and trifluperidol reduce secretion of tumor necrosis factor-α and nitirc oxide by rat microglial cells. Neurochemistry International. July 2003;43(2):173-178. 
  16. Kowalski J, Labuzek K, Herman ZS. Flupentixol and trifluperidol reduce interleukin-1 beta and interleukin-2 release by rat mixed glial and microglial cell cultures. Polish Journal of Pharmacology. 2004;56(5):563-570. 
  17. JP Pratt, MP Bishop, DM Gallant. Trifluperidol and haloperidol in the treatment of acute schizophrenia. Am J Psychiatry. 1964;121:592-594. 
  18. Mervin L Clark, Wolfgang K Huber, Adrian A Kyriakopoulos, Thomas S Ray, John P Colmore, H Ruby Ramsey. Evaluation of trifluperidol in chronic schizophrenia. Psychopharmacologia. Feb 1968;12(3):193-203. 
  19. SM Channabasavanna, Albert Michael. Penfluridol maintenance therapy in schizophrenia: a controlled study. Indian J Psychiatry. Oct-Dec 1987;29(4):333-336. 
  20. HM van Praag, T Schut, L Dols, R van Schilfgaarden. Controlled trial of penfluridol in acute psychosis. Br Med J 1971;4. 
  21. JM Grindel, BH Migdalof, WA Cressman. The comparative metabolism and disposition of penfluridol-3H in the rat, rabbit, dog and man. Drug metabolism and disposition. Sept 1979;7(5):325-329. 
  22. Richard IH Wang, Craig Larson, Sharon J Treul. Study of penfluridol and chlorpromazine in the treatment of chronic schizophrenia. The Journal of Pharmacology. May-June 1982;22(5-6):236-242. 
  23. E Kingstone, P Grof, W Furlong, W Jacques, L Virc, L Daigle. Penfluridol, a peroral long acting neuroleptic, for themaintenance treatment of schizophrenic patients who relapse. The Journal of Clinical Pharmacology. April 1977;17(4):252-258. 
  24. David M Jackson, Nils-Erik Anden, Jorgen Engel, Sture liljequist. The efefct of long term penfluridol treatment on the sensitivity of dopamine receptors in the nucleus accumbens and in the corpus striatum. Psychopharmacologia. 1975;45(2):151-155. 
  25. M Nateghpour, RE Howells, SA Ward. Revresal of halofantrine resistance in plasmodium falciparum by penfluridol in vitro. Iranian Journal of Public Health. 1998;27(3-4):7-14. 
  26. Lu Wu, Yan Yang Liu, Zhi Xi Li, Qian Zhao, Xia Wang, Yang Yu, Yu Yi Wang, Yi Qin Wang, Feng Luo. Anti-tumor effects of penfluridol through dysregulation of cholestrol homeostasis. Asian Pac J Cancer Prev. 2014;15(1):489-494.
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