Pimozide: side effects How Drug Causes Side Effects

• By blocking dopamine 2 receptors in the striatum, it can cause motor side effects

• By blocking dopamine 2 receptors in the pituitary, it can cause elevations in prolactin

• By blocking dopamine 2 receptors excessively in the mesocortical and mesolimbic dopamine pathways, especially at high doses, it can cause worsening of negative and cognitive symptoms (neuroleptic-induced deficit syndrome)

• Anticholinergic actions may cause sedation, blurred vision, constipation, dry mouth

• Antihistaminic actions may cause sedation, weight gain

• By blocking alpha 1 adrenergic receptors, it can cause dizziness, sedation, and hypotension

• Mechanism of weight gain and any possible increased incidence of diabetes or dyslipidemia with conventional antipsychotics is unknown

✽ Mechanism of potentially dangerous QTc prolongation may be related to actions at ion channels

Notable Side Effects

✽ Neuroleptic-induced deficit syndrome

✽ Akathisia

✽ Extrapyramidal symptoms, parkinsonism, tardive dyskinesia

✽ Hypotension

• Sedation, akinesia

• Galactorrhea, amenorrhea

• Dry mouth, constipation, blurred vision

• Sexual dysfunction

✽ Weight gain

Life-Threatening or Dangerous Side Effects

• Rare neuroleptic malignant syndrome

• Rare seizures

✽ Dose-dependent QTc prolongation

• Ventricular arrhythmias and sudden death

• Increased risk of death and cerebrovascular events in elderly patients with dementia-related psychosis

Weight Gain

• Occurs in significant minority

Sedation

• Occurs in significant minority

What to Do About Side Effects

• Wait

• Wait

• Wait

• For motor symptoms, add an anticholinergic agent

• Reduce the dose

• For sedation, give at night

• Switch to an atypical antipsychotic

• Weight loss, exercise programs, and medical management for high BMIs, diabetes, dyslipidemia

Best Augmenting Agents for Side Effects

✽ Augmentation of pimozide has not been systematically studied and can be dangerous, especially with drugs that can either prolong QTc interval or raise pimozide plasma levels

PIMOZIDE: DOSING AND USE

Usual Dosage Range

• Less than 10 mg/day

Dosage Forms

• Tablet 1 mg scored, 2 mg scored

How to Dose

• Initial 1–2 mg/day in divided doses; can increase dose every other day; maximum 10 mg/day or 0.2 mg/kg per day

• Children: initial 0.05 mg/kg per day at night; can increase every 3 days; maximum 10 mg/day or 0.2 mg/kg per day

Dosing Tips

✽ The effects of pimozide on the QTc interval are dose-dependent, so start low and go slow while carefully monitoring QTc interval

• Treatment should be suspended if absolute neutrophil count falls below 1,000/mm³

Overdose

• Deaths have occurred; extrapyramidal symptoms, EKG changes, hypotension, respiratory depression, coma

Long-Term Use

• Some side effects may be irreversible (e.g., tardive dyskinesia)

Habit Forming

• No

How to Stop

• Slow down-titration (over 6 to 8 weeks), especially when simultaneously beginning a new antipsychotic while switching (i.e., cross-titration)

• Rapid discontinuation may lead to rebound psychosis and worsening of symptoms

• If antiparkinson agents are being used, they should be continued for a few weeks after pimozide is discontinued

Pharmacokinetics

• Metabolized by CYP450 3A and to a lesser extent by CYP450 1A2

• Mean elimination half-life approximately 55 hours

Drug Interactions

• May decrease the effects of levodopa, dopamine agonists

• May enhance QTc prolongation of other drugs capable of prolonging QTc interval

• May increase the effects of antihypertensive drugs

✽ Use with CYP450 3A4 inhibitors (e.g., drugs such as fluoxetine, sertraline, fluvoxamine, and nefazodone; foods such as grapefruit juice) can raise pimozide levels and increase the risks of dangerous arrhythmias

• Use of pimozide and fluoxetine may lead to bradycardia

• Additive effects may occur if used with CNS depressants

• Some patients taking a neuroleptic and lithium have developed an encephalopathic syndrome similar to neuroleptic malignant syndrome

• Combined use with epinephrine may lower blood pressure