Sulpiride

Medical uses

Sulpiride's primary use in medicine is in the management of the symptoms of schizophrenia. It has been used as both a monotherapy and adjunctive therapy (in case of treatment-resistance) in schizophrenia. It has also been used in the treatment of dysthymia. Augmentation with sulpiride has also been tried as a strategy for accelerating antidepressant response in patients with major depressive disorder. There is also evidence of its efficacy in treating panic disorder.

Pregnancy and lactation

Pregnancy: Animal studies did not reveal any embryotoxicity or fetotoxicity, nor did limited human experience. Due to insufficient human data, pregnant women should be treated with sulpiride only if strictly indicated. Additionally, the newborns of treated women should be monitored, because isolated cases of extrapyramidal side effects have been reported.

Lactation: Sulpiride is found in the milk of lactating women. Since the consequences are unclear, women should not breastfeed during treatment.

Adverse effects

Sulpiride is usually well-tolerated, producing few adverse effects. Their incidences are as follows:

Common (>1%) adverse effects

Dizziness

Headache

Extrapyramidal side effects

- Tremor- Dystonia- Akathisia — a sense of inner restlessness that presents itself with the inability to stay still- Parkinsonism

Somnolence (not a very prominent adverse effect considering its lack of α₁ adrenergic, histamine and muscarinic acetylcholine receptor affinity)

Insomnia

Weight gain or loss

Hyperprolactinemia (elevated plasma levels of the hormone, prolactin which can, in turn lead to sexual dysfunction, galactorrhea, amenorrhea, gynecomastia, etc.)

Nausea

Vomiting

Nasal congestion

Anticholinergic adverse effects such as:

- Dry mouth- Constipation- Blurred vision

Impaired concentration

Rare (<1% incidence) adverse effects

Tardive dyskinesia — a rare, often permanent movement disorder that, more often than not, results from prolonged treatment with antidopaminergic agents such as antipsychotics. It presents with slow (hence tardive), involuntary, repetitive and purposeless movements that most often affect the facial muscles.

Neuroleptic malignant syndrome — a rare, life-threatening complication that results from the use of antidopaminergic agents. Its incidence increases with concomitant use of lithium (medication) salts

Blood dyscrasias — rare, sometimes life-threatening complications of the use of a number of different antipsychotics (most notably clozapine) which involves abnormalities in the composition of a person's blood (e.g. having too few white blood cells per unit volume of blood). Examples include:

- Agranulocytosis — a significant drop in white blood cell count, leaving individuals wide open to life-threatening opportunistic infections- Neutropenia- Leucopenia- Leukocytosis

Seizures

Torsades de pointes

Unknown incidence adverse effects include

QTc interval prolongation which can lead to potentially fatal arrhythmias.

Cholestatic jaundice

Elevated liver enzymes

Primary biliary cirrhosis

Allergic reactions

Photosensitivity — sensitivity to light

Skin rashes

Depression

Catatonia

Palpitations

Agitation

Diaphoresis — sweating without a precipitating factor (e.g. increased ambient temperature)

Hypotension — low blood pressure

Hypertension — high blood pressure

Venous thromboembolism (probably rare)

Contraindications and cautions

Contraindications

Hypersensitivity to sulpiride

Pre-existing breast cancer or other prolactin-dependent tumors

Phaeochromocytoma

Intoxication with other centrally-active drugs

Concomitant use of levodopa

Acute porphyria

Comatose state or CNS depression

Bone-marrow suppression

Cautions

Pre-existing Parkinson's Disease

Patients below 18 years of age (insufficient clinical data)

Pre-existing severe heart disease/bradycardia, or hypokalemia (predisposing to long QT syndrome and severe arrhythmias)

Patients with pre-existing epilepsy. Anticonvulsant therapy should be maintained

Lithium use — increased risk of neurological side effects of both drugs

Overdose

Sulpiride has a relatively low order of acute toxicity. Substantial amounts may cause severe but reversible dystonic crises with torticollis, protrusion of the tongue, and/or trismus. In some cases all the classical symptoms typical of severe Parkinson's disease may be noted; in others, over-sedation/coma may occur. The treatment is largely symptomatic. Some or all extrapyramidal reactions may respond to the application of anticholinergic drugs such as biperiden or benzatropine. All patients should be closely monitored for signs of long QT syndrome and severe arrhythmias.

Synthesis

Sulpiride can be synthesized from 5-aminosulfosalicylic acid. Methylating this with dimethylsulfate gives 2-methoxy-5-aminosulfonylbenzoic acid, which is transformed into an amide using 2-aminomethyl-1-ethylpyrrolidine as the amine component and carbonyldiimidazole (CDI) as a condensing agent.

Pharmacology

Sulpiride is a selective antagonist at dopamine D₂ and D₃ receptors. This action dominates in doses exceeding 600 mg daily. In doses of 600 to 1,600 mg sulpiride shows mild sedating and antipsychotic activity. Its antipsychotic potency compared to chlorpromazine is only 0.2 (1/5). In low doses (in particular 50 to 200 mg daily) its prominent feature is antagonism of presynaptic inhibitory dopamine receptors accounting for some antidepressant activity and a stimulating effect. Therefore, it is in these doses used as a second line antidepressant. Additionally, it alleviates vertigo.

The benzamide neuroleptics (including sulpiride, amisulpride, and sultopride) have been shown to activate the endogenous gamma-hydroxybutyrate receptor in vivo at therapeutic concentrations. Sulpiride was found in one study in rats to upregulate GHB receptors. GHB has neuroleptic properties and it is believed binding to this receptor may contribute to the effects of these neuroleptics.

Sulpiride, along with clozapine, has been found to activate DNA demethylation in the brain.

History

Sulpiride discovered as a result of a research program by Justin-Besançon and C. Laville at Laboratoires Delagrange who were working to improve the anti-dysrhythmic properties of procainamide; the program led first to metoclopramide and later to sulpiride. Laboratoires Delagrange was acquired by Synthelabo in 1991 which eventually became part of Sanofi.