indication

For use in the management of the manifestations of psychotic disorders and for the control of severe nausea and vomiting in adults.

pharmacology

Perphenazine is a piperazinyl phenothiazine, acts on the central nervous system, and has a greater behavioral potency than other phenothiazine derivatives whose side chains do not contain a piperazine moiety. It is a member of a class of drugs called phenothiazines, which are dopamine D1/D2 receptor antagonists. Perphenazine is 10 to 15 times as potent as chlorpromazine; that means perphenazine is a highly potent antipsychotic. In equivalent doses it has approximately the same frequency and severity of early and late extrapypramidal side-effects compared to Haloperidol.

mechanism of action

Binds to the dopamine D1 and dopamine D2 receptors and inhibits their activity. The mechanism of the anti-emetic effect is due predominantly to blockage of the dopamine D2 neurotransmitter receptors in the chemoreceptor trigger zone and vomiting centre. Perphenazine also binds the alpha andrenergic receptor. This receptor's action is mediated by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.

toxicity

Symptoms of overdose include stupor or coma, and children may have convulsive seizures. Signs of arousal may not occur for 48 hours. Oral LD₅₀=318 mg/kg (rat); IPR LD₅₀=64 mg/kg (mouse)

biotransformation

Hepatic.

absorption

Absolute bioavailability is 40% following oral administration.

half life

8-12 hours, but ranges up to 20 hours.

route of elimination

Perphenazine is extensively metabolized in the liver to a number of metabolites by sulfoxidation, hydroxylation, dealkylation, and glucuronidation.

drug interactions

Amphetamine: Decreased anorexic effect, may increase psychotic symptoms

Atomoxetine: The CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine

Benzphetamine: Antipsychotics may diminish the stimulatory effect of Amphetamines. Monitor effectiveness of amphetamine therapy when altering concurrent antipsychotic therapy as antipsychotic agents may impair the stimulatory effect of amphetamines.

Bromocriptine: The phenothiazine decreases the effect of bromocriptine

Cisapride: Increased risk of cardiotoxicity and arrhythmias

Dexfenfluramine: Decreased anorexic effect, may increase psychotic symptoms

Dextroamphetamine: Decreased anorexic effect, may increase psychotic symptoms

Diethylpropion: Decreased anorexic effect, may increase psychotic symptoms

Donepezil: Possible antagonism of action

Fenfluramine: Decreased anorexic effect, may increase psychotic symptoms

Galantamine: Possible antagonism of action

Gatifloxacin: Increased risk of cardiotoxicity and arrhythmias

Grepafloxacin: Increased risk of cardiotoxicity and arrhythmias

Guanethidine: Perphenazine may decrease the effect of guanethidine.

Levofloxacin: Increased risk of cardiotoxicity and arrhythmias

Mazindol: Decreased anorexic effect, may increase psychotic symptoms

Methamphetamine: Decreased anorexic effect, may increase psychotic symptoms

Metrizamide: Increased risk of convulsions

Phendimetrazine: Decreased anorexic effect, may increase psychotic symptoms

Phenmetrazine: Decreased anorexic effect, may increase psychotic symptoms

Phentermine: Decreased anorexic effect, may increase psychotic symptoms

Phenylpropanolamine: Decreased anorexic effect, may increase psychotic symptoms

Rivastigmine: Possible antagonism of action

Sparfloxacin: Increased risk of cardiotoxicity and arrhythmias

Tacrine: The therapeutic effects of the central acetylcholinesterase inhibitor (AChEI), Tacrine, and/or the anticholinergic/antipsychotic, Perphenazine, may be reduced due to antagonism. This interaction may be beneficial when the anticholinergic action is a side effect. AChEIs may also augment the central neurotoxic effect of antipsychotics. Monitor for extrapyramidal symptoms and decreased efficacy of both agents.

Terbinafine: Terbinafine may reduce the metabolism and clearance of Perphenazine. Consider alternate therapy or monitor for therapeutic/adverse effects of Perphenazine if Terbinafine is initiated, discontinued or dose changed.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Tetrabenazine: May cause dopamine deficiency. Monitor for Tetrabenazine adverse effects.

Trimethobenzamide: Trimethobenzamide and Perphenazine, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Triprolidine: The antihistamine, Triprolidine, may increase the arrhythmogenic effect of the phenothiazine, Perphenazine. Monitor for symptoms of ventricular arrhythmias. Additive anticholinergic and CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.

Trospium: Trospium and Perphenazine, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.