Usage
Pimozide is prescribed primarily for the management of severe motor and phonic tics associated with Tourette’s syndrome in patients who have not responded to or cannot tolerate other treatments. It is classified as a first-generation (typical) antipsychotic. Pimozide’s mechanism of action involves blocking dopamine D2 receptors, which reduces dopaminergic neurotransmission believed to contribute to the manifestation of tics.
Alternate Names
- International/Regional Variations: No significant variations.
- Brand Name(s): Orap
How It Works
Pharmacodynamics: Pimozide primarily acts as a dopamine D2 receptor antagonist in the brain. This action leads to a decrease in dopaminergic activity, which is thought to be responsible for its therapeutic effect in reducing tics associated with Tourette’s syndrome. It has a high affinity for D2 receptors and a relatively low affinity for other dopamine receptor subtypes and other neurotransmitter receptors.
Pharmacokinetics:
- Absorption: Pimozide is well-absorbed orally.
- Metabolism: Primarily metabolized in the liver by CYP3A4 and CYP2D6 enzymes.
- Elimination: Excreted mainly in the urine and feces. The elimination half-life is highly variable, ranging from approximately 29 to 150 hours, with some genetic variations influencing metabolism speed.
Mode of Action: Pimozide binds to and blocks dopamine D2 receptors, thus inhibiting dopamine’s effects in the brain. This dopamine blockade results in the reduction of tics.
Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Pimozide is a potent dopamine D2 receptor antagonist. It also has weak anticholinergic and antihistaminic properties. It is metabolized by CYP3A4 and CYP2D6 enzymes.
Elimination Pathways: Excreted in urine and feces.
Dosage
Standard Dosage
Adults:
Initial: 1-2 mg orally once daily.
Increase the dose every other day, as needed.
Maximum: Do not exceed 10 mg/day or 0.2 mg/kg/day, whichever is less.
Children:
- <2 years: Safety and efficacy not established.
- 2-12 years:
- Initial: 0.05 mg/kg/day orally at bedtime.
- Increase every 3 days, as needed.
- Maximum: 0.2 mg/kg/day (not to exceed 10 mg/day) or 2-4mg/day, whichever is less.
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12 years: Same as adult dosing.
Special Cases:
- Elderly Patients: Start with half the usual adult initial dose.
- Patients with Renal Impairment: Dosage adjustments may be necessary. Close monitoring is recommended.
- Patients with Hepatic Dysfunction: Dosage adjustments may be necessary. Close monitoring is recommended.
- Patients with Comorbid Conditions: Carefully consider potential drug interactions and adjust dosage as needed.
Clinical Use Cases
Pimozide is not typically used in the clinical scenarios you listed (intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations). Its primary indication is for Tourette’s syndrome.
Dosage Adjustments
Dose modifications may be necessary for patients with renal or hepatic impairment, metabolic disorders, or genetic polymorphisms affecting CYP2D6 or CYP3A4 activity. For CYP2D6 poor metabolizers, the maximum recommended dose is 4 mg/day for adults and 0.05 mg/kg/day for children.
Side Effects
Common Side Effects:
Drowsiness, dizziness, dry mouth, blurred vision, fatigue, weakness, headache, restlessness, constipation, extrapyramidal symptoms (EPS) such as Parkinsonism, dystonia, akathisia, and tardive dyskinesia.
Rare but Serious Side Effects:
Neuroleptic malignant syndrome (NMS), tardive dyskinesia, QT prolongation, torsades de pointes, agranulocytosis, leukopenia, seizures.
Long-Term Effects:
Tardive dyskinesia can be a long-term side effect, potentially irreversible in some cases.
Adverse Drug Reactions (ADR): NMS, QT prolongation, torsades de pointes, severe EPS.
Contraindications
Hypersensitivity to pimozide, concurrent use of drugs that prolong the QT interval (e.g., certain antiarrhythmics, some antibiotics), congenital long QT syndrome, history of cardiac arrhythmias, severe CNS depression, comatose states, uncorrected hypokalemia or hypomagnesemia, concurrent use of CYP3A4 or CYP2D6 inhibitors.
Drug Interactions
Numerous drug interactions exist. Some clinically significant interactions include:
- CYP3A4 Inhibitors: Increase pimozide levels and risk of adverse events.
- CYP2D6 Inhibitors: Increase pimozide levels and risk of adverse events.
- QT Prolonging Drugs: Increase the risk of torsades de pointes.
- Dopamine Agonists: May decrease the efficacy of pimozide.
- Anticholinergic Drugs: May exacerbate anticholinergic side effects.
Pregnancy and Breastfeeding
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Pregnancy Safety Category: C (US) - Animal studies show adverse effects. Use only if the potential benefit justifies the potential risk to the fetus. Avoid use during the first trimester. Neonates exposed in the third trimester are at risk of extrapyramidal and/or withdrawal symptoms.
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Breastfeeding: Not recommended. It is unknown if pimozide is excreted in breast milk.
Drug Profile Summary
- Mechanism of Action: Dopamine D2 receptor antagonist.
- Side Effects: Drowsiness, dizziness, dry mouth, EPS, NMS, QT prolongation, tardive dyskinesia.
- Contraindications: Hypersensitivity, long QT syndrome, concurrent QT prolonging drugs, CYP3A4/2D6 inhibitors.
- Drug Interactions: CYP3A4/2D6 inhibitors, QT prolonging drugs, dopamine agonists.
- Pregnancy & Breastfeeding: Category C; not recommended during breastfeeding.
- Dosage: Adults: 1-2 mg/day initially, up to 10 mg/day. Children: Dose adjustments needed.
- Monitoring Parameters: ECG, electrolytes, CBC, liver function tests.
Popular Combinations
Pimozide is not generally used in combination with other medications for Tourette’s syndrome. Other treatments may be added if pimozide alone is insufficient.
Precautions
- General: Baseline ECG, electrolyte levels, and CBC recommended. Monitor for EPS, NMS, and tardive dyskinesia.
- Specific Populations: As noted in the “Special Cases” section above.
- Lifestyle Considerations: Avoid alcohol. May cause drowsiness; caution with driving or operating machinery.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Pimozide?
A: Adults: Initial dose is 1-2 mg/day, increased every other day as needed, not to exceed 10 mg/day or 0.2mg/kg/day, whichever is less. Pediatric dosing varies based on age (see above).
Q2: What are the most serious side effects of Pimozide?
A: Neuroleptic malignant syndrome (NMS), tardive dyskinesia, QT prolongation, torsades de pointes, and blood dyscrasias (agranulocytosis, leukopenia).
Q3: What are the common side effects of Pimozide?
A: Drowsiness, dizziness, dry mouth, blurred vision, EPS (Parkinsonism, dystonia, akathisia).
Q4: What should I do if a patient develops NMS while taking Pimozide?
A: Discontinue pimozide immediately and provide supportive care. Manage hyperthermia and muscle rigidity.
Q5: Is Pimozide safe to use during pregnancy?
A: Pimozide is Pregnancy Category C. Use only if the benefits outweigh the risks. Avoid in the first trimester. Neonatal complications may occur with third-trimester exposure.
Q6: Can Pimozide be used in children?
A: Yes, but with careful dosage adjustments based on age and weight. Not recommended for children under 2.
Q7: What are the drug interactions I should be aware of with Pimozide?
A: Avoid concurrent use with CYP3A4/2D6 inhibitors, QT-prolonging drugs, and dopamine agonists. Many other potential interactions exist; consult a drug interaction database for a comprehensive list.
A: Primarily by CYP3A4 and CYP2D6 enzymes in the liver.
Q9: What monitoring is recommended for patients taking Pimozide?
A: Baseline and periodic ECGs, electrolyte monitoring, complete blood counts (CBCs), and liver function tests.
Q10: What patient education should be provided for Pimozide?
A: Advise patients about potential side effects, including EPS, NMS, and the risk of tardive dyskinesia. Emphasize the importance of reporting any unusual symptoms. Counsel on avoiding alcohol and caution with driving.
