Amisulpride

Usage

Amisulpride is an atypical antipsychotic medication primarily prescribed for the treatment of schizophrenia, including acute exacerbations and maintenance therapy of both positive (e.g., hallucinations, delusions, disorganized thought) and negative symptoms (e.g., social withdrawal, flattened affect). It is also used for the treatment of dysthymia, a chronic form of depression. Its pharmacological classification is as an atypical antipsychotic or second-generation antipsychotic (SGA).

Amisulpride’s mechanism of action involves selective binding to dopamine D2 and D3 receptors in the limbic system, with preferential binding to presynaptic receptors at lower doses. This selectivity for presynaptic receptors may contribute to its efficacy in treating negative symptoms.

Alternate Names

Amisulpride is also known as Solian (a common brand name). Barhemsys is the brand name for the intravenous formulation used in postoperative nausea and vomiting (PONV).

How It Works

Pharmacodynamics: Amisulpride primarily acts as an antagonist at dopamine D2 and D3 receptors in the limbic system, a part of the brain involved in emotion and behavior regulation. At lower doses, it preferentially binds to presynaptic D2/D3 receptors, leading to increased dopamine release and improvement of negative symptoms. At higher doses, it also blocks postsynaptic D2 receptors, resulting in antipsychotic effects on positive symptoms. Amisulpride has a lower affinity for other receptor types like serotonin, histamine, and muscarinic receptors, resulting in a reduced incidence of some side effects associated with other antipsychotics.

Pharmacokinetics: Amisulpride is well-absorbed orally, reaching peak plasma concentration in about 1-2 hours. It is weakly metabolized in the liver, primarily by CYP3A4, but also by CYP2D6 and CYP2C19. This weak metabolism means dosage adjustments are usually unnecessary in patients with hepatic impairment. The majority of the drug is eliminated unchanged in the urine via renal excretion. The elimination half-life is approximately 12 hours. In patients with renal impairment, systemic clearance is reduced, necessitating dose adjustments.

Mode of Action: Amisulpride preferentially binds to presynaptic dopamine D2 and D3 receptors at lower doses, enhancing dopamine release. At higher doses, it also blocks postsynaptic D2 receptors. It also exhibits some serotonin 5-HT7 receptor antagonism.

Elimination Pathways: Primarily renal excretion; minimal hepatic metabolism via CYP3A4, CYP2D6, and CYP2C19.

Dosage

Standard Dosage

Adults:

• For Schizophrenia:
  • Initially, 400-800 mg orally per day, divided into two doses if greater than 400 mg.
  • Maximum dose: 1200 mg/day.
  • Predominantly Negative Symptoms: 50-300 mg/day, usually given as a single daily dose. Optimal dose is around 100 mg/day.
• For PONV (Barhemsys IV formulation):
  • Prevention: 5 mg as a single IV dose at anesthesia induction.
  • Treatment: 10 mg as a single IV dose for PONV after prophylaxis with a different antiemetic or when no prophylaxis was given.

Children:

Amisulpride is contraindicated in children up to puberty due to lack of safety and efficacy data. Its use is not recommended in adolescents (puberty to 18 years).

Special Cases:

• Elderly Patients: Start with a lower dose and titrate cautiously due to increased risk of hypotension and sedation.
• Patients with Renal Impairment: Reduce the dose based on creatinine clearance (CrCl):
  • CrCl 30-60 ml/min: Reduce dose by half.
  • CrCl 10-30 ml/min: Reduce dose to one-third.
  • CrCl < 10 ml/min: Amisulpride is contraindicated.
• Patients with Hepatic Dysfunction: Dosage adjustment is usually not necessary.
• Patients with Comorbid Conditions: Exercise caution in patients with cardiovascular disease, diabetes, or seizure disorders.

Clinical Use Cases

The intravenous formulation (Barhemsys) is used specifically for the prevention and treatment of postoperative nausea and vomiting (PONV) in adults. It is not indicated for use in intubation, surgical procedures other than PONV prevention/treatment, mechanical ventilation, general ICU use, or emergency situations like status epilepticus or cardiac arrest.

Dosage Adjustments

Dose modifications may be necessary based on renal function, age, and individual response. Therapeutic drug monitoring and careful observation are essential.

Side Effects

Common Side Effects:

Insomnia, anxiety, agitation, somnolence, weight gain, constipation, nausea, vomiting, dry mouth, dizziness, hyperprolactinemia (increased prolactin levels), tremor, extrapyramidal symptoms (EPS) including acute dystonia (spasm, torticollis, trismus), akathisia (restlessness), parkinsonism (rigidity, bradykinesia), tardive dyskinesia (involuntary movements, usually after long-term use).

Rare but Serious Side Effects:

Neuroleptic malignant syndrome (NMS), characterized by fever, muscle rigidity, altered mental status, and autonomic instability; QT prolongation, seizures, stroke, hypersensitivity reactions (rash, hives, angioedema), severe liver toxicity, hyperglycemia, neutropenia, agranulocytosis, venous thromboembolism.

Long-Term Effects:

Tardive dyskinesia, weight gain, metabolic disturbances, sexual dysfunction.

Adverse Drug Reactions (ADR):

NMS, QT prolongation, severe hypersensitivity reactions, agranulocytosis, stroke.

Contraindications

• Hypersensitivity to amisulpride.
• Pheochromocytoma.
• Prolactin-dependent tumors (e.g., prolactinoma, breast cancer).
• Children up to puberty.
• Concomitant use with levodopa or dopamine agonists.

Drug Interactions

• Drugs that prolong the QT interval (e.g., antiarrhythmics, some antibiotics, some antipsychotics).
• Dopamine agonists (e.g., levodopa, bromocriptine).
• Central nervous system depressants (e.g., alcohol, benzodiazepines).
• Antihypertensives.
• CYP3A4 inhibitors and inducers.

Pregnancy and Breastfeeding

Amisulpride is not recommended during pregnancy unless the benefit outweighs the risk. It is excreted in breast milk and can cause side effects in infants. Breastfeeding is generally not recommended while taking amisulpride.

Drug Profile Summary

• Mechanism of Action: Dopamine D2 and D3 receptor antagonist, preferentially presynaptic at lower doses.
• Side Effects: EPS, hyperprolactinemia, somnolence, weight gain, insomnia, QT prolongation.
• Contraindications: Pheochromocytoma, prolactin-dependent tumors, children before puberty.
• Drug Interactions: QT prolonging drugs, dopamine agonists, CNS depressants.
• Pregnancy & Breastfeeding: Not recommended.
• Dosage: 400-800 mg/day for schizophrenia; 5-10 mg IV for PONV.
• Monitoring Parameters: Prolactin levels, EPS, QT interval, weight, blood glucose, liver function tests, complete blood count.

Popular Combinations

Amisulpride is sometimes used in combination with mood stabilizers (e.g., lithium, valproate) or antidepressants (e.g., SSRIs) in the treatment of bipolar disorder or schizoaffective disorder. Combination use requires careful monitoring for potential drug interactions and additive side effects.

Precautions

• Monitor for EPS, NMS, QT prolongation, hyperprolactinemia, and metabolic changes.
• Caution in elderly patients due to increased risk of hypotension and sedation.
• Avoid abrupt discontinuation to minimize withdrawal symptoms.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Amisulpride?

A: For schizophrenia: 400-800mg/day in adults, divided into two doses if above 400 mg. For predominantly negative symptoms: 50-300mg/day. For PONV (IV): 5mg for prevention, 10 mg for treatment.

Q2: What are the common side effects of Amisulpride?

A: Common side effects include insomnia, anxiety, agitation, drowsiness, weight gain, extrapyramidal symptoms (EPS) like tremor and rigidity, hyperprolactinemia.

Q3: What are the contraindications for Amisulpride?

A: Contraindications include pheochromocytoma, prolactin-dependent tumors, hypersensitivity to Amisulpride, and use in children before puberty.

Q4: Can Amisulpride be used during pregnancy and breastfeeding?

A: It is generally not recommended, as it can cross the placenta and is excreted in breast milk.

Q5: How does Amisulpride differ from other antipsychotics?

A: It has higher selectivity for dopamine D2/D3 receptors, with preferential binding to presynaptic receptors at lower doses. This may contribute to its efficacy in treating negative symptoms and potentially reduced EPS.

Q6: How should Amisulpride be administered?

A: Amisulpride tablets are administered orally, usually before meals. The IV formulation (Barhemsys) is administered as a single bolus injection.

Q7: What should I monitor in patients taking Amisulpride?

A: Monitor for EPS, NMS, QT prolongation, weight gain, metabolic changes (blood glucose, lipids), prolactin levels, complete blood count and liver function tests.

Q8: Does Amisulpride interact with other medications?

A: Yes. Significant drug interactions can occur with QT interval prolonging drugs, dopamine agonists, and CNS depressants.

Q9: How is Amisulpride metabolized and eliminated?

A: Amisulpride is weakly metabolized by the liver (mainly CYP3A4) and is predominantly eliminated unchanged in the urine.

Q10: Can Amisulpride be used in elderly patients?

A: Yes, but with caution and at lower doses. Start with a lower dose due to an increased risk of hypotension and sedation. Renal function should also be carefully considered.