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SULPIRIDE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Sulpiride is a benzamide derivative, selective dopamine antagonist with antipsychotic and antidepressant activity. Amisulpride is a substituted benzamide atypical antipsychotic with properties similar to sulpiride. These agents are not available in the United States.

Specific Substances

    A) AMISULPRIDE
    1) 4-Amino-N- [(1-ethyl-2-pyrrolidinyl) methyl] -
    2) -5-(ethylsulphonyl)-2-methoxybenzamide; (RS)-
    3) -4-Amino-N-[(1-ethylpyrrolidin-2-yl) methyl] -5-
    4) -(ethylsulfonyl)-o-anisamide
    5) Molecular Formula: C17-H27-N3-O4-S
    6) CAS 71675-85-9
    7) Deniban
    8) Solian
    9) Sulamid
    SULPIRIDE
    1) N-(1-Ethylpyrrolidin-2-ylmethyl)-2-methoxy-5-
    2) sulphamoylbenzamide
    3) Molecular Formula: C15-H23-N3-O4-S
    4) CAS 15676-16-1
    TIAPRIDE
    1) FLO-1347
    2) Tiapridi Hydrochloridum
    3) N-(2-Diethylaminoethyl)-2-methoxy-5-methylsulphonylbenzamide hydrochloride
    4) Molecular Formula: C15-H24-N2-O4-S,HCl
    5) CAS 51012-32-9 (tiapride)
    6) CAS 51012-33-0 (tiapride hydrochloride)

Available Forms Sources

    A) FORMS
    1) Sulpiride is used in Europe and found in the Japanese pharmacopoeia.
    2) AMISULPRIDE: Similar to sulpiride and is available in the United Kingdom (Prod Info Solian(R), 1997).
    3) TIAPRIDE: Tiapride has been designated an orphan product for use in the treatment of Tourette's Syndrome.
    B) USES
    1) Sulpiride is a benzamide antipsychotic and mainly used in the treatment of psychoses such as schizophrenia. It has also been used in the management of Tourette's syndrome, anxiety disorders, vertigo, and benign peptic ulceration.
    2) Amisulpride, like sulpiride, is used primarily in the management of schizophrenia, and has been tried in the treatment of depression.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Sulpiride is a benzamide derivative, selective dopamine antagonist with antipsychotic and antidepressant activity. Amisulpride is a substituted benzamide atypical antipsychotic with properties similar to sulpiride. These agents are not available in the US.
    B) PHARMACOLOGY: These agents have a very high affinity for dopaminergic D2 and D3 receptors. In contrast to other neuroleptics (ie, haloperidol or clozapine) sulpiride does not have any affinity for other brain neurotransmitter receptor subtypes.
    C) EPIDEMIOLOGY: Overdose is uncommon, but significant cardiac toxicity has been observed. Deaths are rare.
    D) WITH THERAPEUTIC USE
    1) AMISULPRIDE
    a) Clinical events may include: mydriasis, drowsiness and sedation, seizures, coma, hypotension, bradycardia, agitation, hyperthermia and extrapyramidal symptoms. Neuroleptic malignant syndrome is a rare effect of therapy.
    2) SULPIRIDE
    a) Clinical events may include: palpitations, hypertension, tachycardia, blurred vision, sedation, and extrapyramidal effects, and dry mouth. Neuroleptic malignant syndrome is a rare effect of therapy.
    E) WITH POISONING/EXPOSURE
    1) AMISULPRIDE
    a) MILD TO MODERATE TOXICITY: Mydriasis, lethargy, drowsiness and sedation, bradycardia, agitation, hyperthermia and extrapyramidal symptoms have been reported.
    b) SEVERE TOXICITY: Seizures, coma, hypotension, and QTc prolongation have been reported after amisulpride overdose. Torsades de pointes and ventricular tachycardia have been reported in patients following intentional overdose.
    2) SULPIRIDE
    a) MILD TO MODERATE TOXICITY: Data limited. Clinical effects that may occur in overdose are: blurred vision, palpitations, hypertension, sedation, dizziness, extrapyramidal effects, dry mouth, vomiting, and sweating.
    b) SEVERE TOXICITY: Cardiac (ie, dysrhythmias, hypotension, and sinus tachycardia) and central nervous system effects (ie, agitation, hallucinations, and CNS depression) have occurred in some patients in overdose. Ventricular dysrhthymias and torsades de pointes have been reported rarely following overdose of sulpiride. Rhabdomyolysis has been reported in an adult following overdose.
    0.2.4) HEENT
    A) WITH THERAPEUTIC USE
    1) Blurred vision is possible with therapeutic use.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Laboratory Monitoring

    A) Monitor vital signs and CNS function.
    B) Monitor electrolytes, liver enzymes and kidney function tests after a significant overdose.
    C) Institute continuous cardiac monitoring and obtain an ECG after a significant overdose. QT prolongation and ventricular dysrhthymias (including torsades de pointes) have developed in some cases.
    D) Drug concentrations are not widely available or useful to guide clinical management.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor blood pressure, pulse rate and rhythm. Monitor neurologic function. Institute continuous cardiac monitoring and obtain a baseline ECG. HYPOTENSION: IV fluids, dopamine, norepinephrine, as indicated. VOMITING: Administer IV fluids and electrolyte repletion, if significant vomiting occurs.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor CNS function. Institute continuous cardiac monitoring. Torsades has been observed in a limited number of cases. Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium and/or atrial overdrive pacing. MAGNESIUM SULFATE: ADULT: DOSE: 2 g IV over 1 to 2 minutes, repeat 2 g bolus and begin infusion of 0.5 to 1 g/hr, if dysrhythmias recur. CHILD: DOSE: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 minutes. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia) and hypoxia, if present. Avoid class Ia (eg, quinidine, disopyramide, procainamide), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol). SEIZURES: Initially treat with benzodiazepines, barbiturates. BRADYCARDIA: Administer atropine for symptomatic bradycardia.
    C) DECONTAMINATION
    1) PREHOSPITAL: GI decontamination is not recommended because of the risk of cardiac instability, CNS depression or seizures after significant overdose and the potential for aspiration.
    2) HOSPITAL: Administer activated charcoal if given soon after ingestion if the patient is alert and the airway is protected.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary following a mild to moderate exposure, but may be necessary if cardiac instability (ie, ventricular dysrhythmias, torsades de pointes) or CNS effects (ie, seizures, coma) occur.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be useful because of the large volume of distribution of these agents.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic adult with an inadvertent minor exposure (eg, a single extra dose) may be monitored at home.
    2) OBSERVATION CRITERIA: Patients with significant or deliberate amisulpride overdose should be observed for at least 16 hours after ingestion with continuous cardiac monitoring and serial ECGs. If no dysrhythmias or QT prolongation develop, they may be discharged after psychiatric evaluation if indicated
    3) ADMISSION CRITERIA: Patients with dysrhythmias or QT prolongation on ECG should be admitted to an intensive care setting for continuous cardiac monitoring and therapy.
    4) CONSULT CRITERIA: Contact a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.
    H) PHARMACOKINETICS
    1) AMISULPRIDE: Plasma protein binding is reportedly low; volume of distribution is 5.8 L/kg; terminal half life is approximately 12 hours. Metabolites appear to be inactive. Amisulpride is eliminated unchanged in the urine.
    2) SULPIRIDE: Less than 40% bound to plasma proteins; volume of distribution is 1 to 2.7 L/kg following IV administration; a plasma half-life of 6 to 9 hours and may be up to 20 to 26 hours after an IV dose in patients with renal failure. Metabolites have not been identified. Following an IV dose 70% to 90% of the dose is excreted unchanged in the urine, while 15% to 30% of an oral dose is excreted unchanged in the urine.
    I) DIFFERENTIAL DIAGNOSIS
    1) Other agents that may produce cardiac dysrhthymias or QT prolongation. Avoid class Ia (eg, quinidine, disopyramide, procainamide), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol).
    J) PITFALLS
    1) Early discharge prior to a sustained normalized cardiac rhythm. Coingestion of other agents that may produce cardiac dysrhthymias.

Range Of Toxicity

    A) TOXICITY: AMISULPRIDE: The toxic dose has not been established. Eighty-one adults ingested between 1.2 to 120 g of amisulpride, all patients except one who ingested 24 g, survived. Two adults developed QT prolongation and hypocalcemia after the ingestion of 5 g and 3.6 g of amisulpride, respectively. Both patients recovered following supportive care. In adults, torsades de pointes has developed after ingestion of 4 g of amisulpride or more. THERAPEUTIC DOSE: SULPIRIDE: ADULT: ORAL: 200 to 400 mg twice daily, to a maximum of 1200 mg daily. AMISULPRIDE: ADULT: ORAL: 400 to 800 mg/day are usually recommended for acute psychotic episodes; maximum dose is 1200 mg/day.

Clinical Effects

Summary Of Exposure

    A) USES: Sulpiride is a benzamide derivative, selective dopamine antagonist with antipsychotic and antidepressant activity. Amisulpride is a substituted benzamide atypical antipsychotic with properties similar to sulpiride. These agents are not available in the US.
    B) PHARMACOLOGY: These agents have a very high affinity for dopaminergic D2 and D3 receptors. In contrast to other neuroleptics (ie, haloperidol or clozapine) sulpiride does not have any affinity for other brain neurotransmitter receptor subtypes.
    C) EPIDEMIOLOGY: Overdose is uncommon, but significant cardiac toxicity has been observed. Deaths are rare.
    D) WITH THERAPEUTIC USE
    1) AMISULPRIDE
    a) Clinical events may include: mydriasis, drowsiness and sedation, seizures, coma, hypotension, bradycardia, agitation, hyperthermia and extrapyramidal symptoms. Neuroleptic malignant syndrome is a rare effect of therapy.
    2) SULPIRIDE
    a) Clinical events may include: palpitations, hypertension, tachycardia, blurred vision, sedation, and extrapyramidal effects, and dry mouth. Neuroleptic malignant syndrome is a rare effect of therapy.
    E) WITH POISONING/EXPOSURE
    1) AMISULPRIDE
    a) MILD TO MODERATE TOXICITY: Mydriasis, lethargy, drowsiness and sedation, bradycardia, agitation, hyperthermia and extrapyramidal symptoms have been reported.
    b) SEVERE TOXICITY: Seizures, coma, hypotension, and QTc prolongation have been reported after amisulpride overdose. Torsades de pointes and ventricular tachycardia have been reported in patients following intentional overdose.
    2) SULPIRIDE
    a) MILD TO MODERATE TOXICITY: Data limited. Clinical effects that may occur in overdose are: blurred vision, palpitations, hypertension, sedation, dizziness, extrapyramidal effects, dry mouth, vomiting, and sweating.
    b) SEVERE TOXICITY: Cardiac (ie, dysrhythmias, hypotension, and sinus tachycardia) and central nervous system effects (ie, agitation, hallucinations, and CNS depression) have occurred in some patients in overdose. Ventricular dysrhthymias and torsades de pointes have been reported rarely following overdose of sulpiride. Rhabdomyolysis has been reported in an adult following overdose.

Heent

    3.4.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Blurred vision is possible with therapeutic use.
    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Anticholinergic activity associated with sulpiride therapy may cause blurred vision (Gerlach et al, 1985; Peselow & Stanley, 1982).
    B) WITH POISONING/EXPOSURE
    1) Mydriasis has been reported in one patient following overdose with amisulpride (Tracqui et al, 1995).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TORSADES DE POINTES
    1) WITH POISONING/EXPOSURE
    a) AMISULPRIDE
    1) INCIDENCE: In a 5-year prospective study of 83 amisulpride ingestions of greater than 1 g among 81 patients with a median age of 29 years, torsades de pointes (TdP) developed 5 to 19 hours after ingestion in 6 (7%) cases associated with doses of 4 g, 4.6 g, 18 g, 24 g, 32 g, and 80 g. TdP led to cardiac arrest and death in one patient who ingested 24 g of amisulpride. In 2 cases, TdP degenerated into ventricular fibrillation. Patients who survived recovered from TdP spontaneously or received defibrillation. Magnesium infusions were initiated after resolution. Coingestants known to cause QT prolongation were reported in 4 cases with only 2 cases developing a prolonged QT interval (560 mg citalopram, 50 to 100 g valproate) (Isbister et al, 2010).
    B) PALPITATIONS
    1) WITH THERAPEUTIC USE
    a) Palpitations were seen in sulpiride-treated patients (Munk-Andersen et al, 1984; Gerlach et al, 1985).
    C) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Sulpiride has been associated with hypertensive episodes in patients with pheochromocytoma (Corvol et al, 1974).
    b) CASE SERIES
    1) Sulpiride 100 mg by mouth caused hypertension in 6 of 26 hypertensive patients. In 4 of these it induced a rise in urinary excretion of vanillylmandelic acid and catecholamines.
    2) Three patients with pheochromocytoma had a transient rise in blood pressure and catecholamines after administration of sulpiride, another patient probably had this condition.
    3) The mechanism of action for provoking hypertension is not known. It is thought to be due to a noradrenergic effect (Corvol et al, 1974; S Sweetman , 2001).
    D) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) AMISULPRIDE: Hypotension and bradycardia have occurred occasionally at therapeutic dose (Prod Info Solian (R) amisulpride, 1997).
    2) WITH POISONING/EXPOSURE
    a) Hypotension has been reported in overdose with sulpiride (Capel et al, 2000).
    b) AMISULPRIDE
    1) INCIDENCE: In a 5-year prospective study of 83 amisulpride ingestions of greater than 1 g (median ingestion 6 g) among 81 patients with a median age of 29 years, 19 (23%) cases of hypotension (systolic blood pressure less than 90 mmHg) occurred. Coingestants were associated with 8 of the occurrences. In most cases, hypotensive episodes responded to volume replacement (Isbister et al, 2010).
    E) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) QT PROLONGATION
    1) AMISULPRIDE: QT prolongation is a rare event following therapeutic administration (Prod Info Solian (R) amisulpride, 1997).
    2) TIAPRIDE: A 76-year-old man with atrial fibrillation and mild congestive heart failure, developed prolonged QTc interval (600 msec) and torsades de pointes one day after taking tiapride (300 mg/daily) for agitation. The 24-hour Holter monitoring revealed polymorphic ventricular tachycardia and QTc-interval prolongation. Following the discontinuation of tiapride, the QTc interval returned to baseline values (440 msec at a heart rate of 47 bpm) within 4 days (Iglesias et al, 2000).
    2) WITH POISONING/EXPOSURE
    a) QT PROLONGATION
    1) AMISULPRIDE
    a) INCIDENCE: Among 440 ECG recordings involving 83 amisulpride ingestions of greater than 1 g, 4 cases involved coingestants of drugs known to cause QT prolongation. In 2 of these cases, QT prolongation did not occur. However, in the other 2 cases, a prolonged QT interval was observed with coingestants of citalopram 560 mg and valproate 50 to 100 mg (Isbister et al, 2010).
    b) CASE SERIES: Four adults developed QT prolongation following intentional overdose of amisulpride (dose range 4.6 g to 32 g amisulpride) (Isbister et al, 2006).
    1) One patient ingested 24 g amisulpride along with nitrazepam and diazepam. She had a QT interval of 560 msec on arrival 7 hrs after ingestion, and developed wide complex tachycardia without hypotension 12 hrs after ingestion. QRS normalized 4 hrs later and QT interval remained abnormal for 12 more hours
    2) Another patient ingested 32 g amisulpride along with mirtazapine (300 mg), valproate (7 g), amitriptyline (1.25 g) and omeprazole. ECG showed a QT interval of 460 msec and bifid T waves on arrival. About 12.5 hrs after ingestion he developed wide complex tachycardia (120 beats/minute) without hypotension. He developed pulseless torsades de pointes 29 hrs after ingestion and again 32.5 hrs after ingestion and ventricular tachycardia 34 hrs after ingestion. QT interval was 360 msec 5 days after ingestion.
    3) Another adult ingested 4.6 g amisulpride and 7 hrs after ingestion had an episode of pulseless torsades de pointes, with a second episode 24 hrs after ingestion despite isoprenaline infusion. QT interval was 600 msec 7 hrs after ingestion, 460 msec 62 hrs after ingestion, and 360 msec 3 weeks after ingestion.
    4) A 39-year-old woman presented 12 hours after ingesting 16 to 24 g amisulpride, with a heart rate of 59 beats/min, blood pressure 81/44 mmHg, and QT interval of 600 msec. Two hours later she deteriorated with GCS of 7 but normal blood pressure. She was intubated, and afterward developed bradycardia without detectable pulses. Resuscitation attempts were unsuccessful. Postmortem amisulpride concentration was 140 mg/L with a fluoxetine level of 0.2 mg/L (Isbister et al, 2006)
    c) Two patients developed QT prolongation (QTc peaked at 557 ms in patient 1 and peaked at 625 ms in patient 2) and hypocalcemia after ingesting 5 g and 3.6 g of amisulpride, respectively; patient one also ingested 4 g of paracetamol. In patient 1, the lowest serum calcium level, corrected for albumin, and serum magnesium level were 1.96 mmol/L and 0.66 mmol/L, respectively. In patient 2, the lowest serum calcium level, corrected for albumin, was 2.25 mmol/L. Although the magnesium level was 0.76 mmol/L on presentation to the hospital, a repeat measurement could not be done. Both patients were treated with intravenous calcium gluconate (20 mL of 10%) and magnesium sulfate (10 mL of 50%). Following several hours of supportive care, both patients recovered without further sequelae (Ward, 2005).
    2) SULPIRIDE
    a) CASE REPORT: A 22-year-old woman intentionally ingested 1.5 g of sulpiride (30 over-the-counter sleeping aid tablets containing 50 mg sulpiride per tablet) and was admitted to the Emergency Department 2 hours after exposure complaining of nausea and muscle cramps. Approximately 7 hours after exposure, the patient developed a short run of wide complex ventricular dysrhythmia, which terminated without treatment. Subsequent frequent premature ventricular contractions occurred, which were treated with amiodarone. About 5 hours later, a long QT interval (QT peaked at 600 ms; corrected QT 670 ms) was observed and torsades de pointes developed; amiodarone was stopped. Treatment included 2 g magnesium sulfate and 50 mg lidocaine with an infusion of 50 mcg/kg per minute. Fifty-eight hours after exposure, the QT had decreased to 440 ms. No further dysrhythmias occurred and the patient was discharged on day 3; follow-up 3 weeks later revealed a normal ECG (Chang et al, 2009).
    b) QT - HEART RATE AT-RISK PAIR
    1) AMISULPRIDE
    a) INCIDENCE: Among 440 ECG recordings involving 83 amisulpride ingestions of greater than 1 g, 61 (73%) recordings showed at-risk QT interval-heart rate pairs. Coingestants were associated with 27 of these recordings (Isbister et al, 2010).
    2) WIDE QRS
    a) INCIDENCE: Among 440 ECG recordings involving 83 amisulpride ingestions of greater than 1 g, 2 episodes of QRS greater than 120 msec were observed. In both cases coingestants were not a factor and there was no relationship between dose and QRS width (Isbister et al, 2010).
    3) BUNDLE BRANCH BLOCK
    a) INCIDENCE: Transient, rate-dependent bundle branch block (BBB) was observed on 3 out of 440 ECG recordings involving 83 amisulpride ingestions of greater than 1 g. Two of the 3 cases with BBB were associated with coingestants and one occurred 60 hours after ingestion (Isbister et al, 2010).
    F) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) SULPIRIDE
    1) Sinus tachycardia has been reported in overdose with sulpiride (Capel et al, 2000).
    b) AMISULPRIDE
    1) INCIDENCE: Tachycardia occurred in 19 (23%) cases among 83 amisulpride ingestions of greater than 1 g (median ingestion 6 g) (Isbister et al, 2010).
    G) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) An adult developed asymptomatic sinus bradycardia (40 bpm during waking hours), while receiving 800 mg of amisulpride daily. The dose was decreased to 600 mg daily and the rate increased to the low 60's (Pedrosa Gil et al, 2001).
    2) WITH POISONING/EXPOSURE
    a) AMISULPRIDE
    1) INCIDENCE: Bradycardia (less than 60 beats/min) occurred in 20 (24%) cases among 83 amisulpride ingestions of greater than 1 g. Coingestants were associated with 6 of the occurrences (Isbister et al, 2010).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Sedation, dizziness, depression, sleep disturbances, headache, restlessness, and impaired concentration have been seen with therapeutic administration (Gerlach et al, 1985; Peselow & Stanley, 1982; Munk-Andersen et al, 1984a; Standish-Barry et al, 1983; Lepola et al, 1989; Robertson et al, 1990).
    b) Extrapyramidal effects are relatively common with sulpiride and may occur with amisulpride (Prod Info Solian (R) amisulpride, 1997).
    2) WITH POISONING/EXPOSURE
    a) Agitation, hallucinations, and CNS depression can occur following a sulpiride overdose (Capel et al, 2000).
    b) AMISULPRIDE
    1) INCIDENCE: In a 5-year prospective study of 83 amisulpride ingestions of greater than 1 g (median ingestion 6 g) among 81 patients with a median age of 29 years, Glasgow Comma Scale (GCS) scores of less than 15 occurred in 25 cases. GCS scores of less than 9 occurred in 7 (8%) cases; sedative coingestants were associated with 4 ingestions resulting in scores of less than 9 (Isbister et al, 2010).
    2) Transient CNS depression (Glasgow coma score of 8 and 13) was reported in 2 patients who ingested 5 and 3.6 g amisulpride, respectively (Ward, 2005).
    B) DROWSY
    1) WITH THERAPEUTIC USE
    a) SULPIRIDE: Sedation is common with therapy; 25% of patients experienced symptoms during clinical therapy (Peselow & Stanley, 1982).
    C) EXTRAPYRAMIDAL DISEASE
    1) WITH THERAPEUTIC USE
    a) AMISULPRIDE
    1) Extrapyramidal effects appear dose dependent; a lack of symptoms were reported at doses of 50 to 300 mg/day (Prod Info Solian (R) amisulpride, 1997).
    b) SULPIRIDE
    1) Extrapyramidal effects are commonly reported with therapy (ie, an estimated incidence of 30%), despite selective dopamine receptor activity (Edwards et al, 1980; Bratfos & Haug, 1979; Cassano et al, 1975; Munk-Andersen et al, 1984).
    2) Parkinsonian symptoms (Quinn & Marsden, 1984; Peselow & Stanley, 1982; Gerlach et al, 1985), acute dystonias (Linazasoro et al, 1991), akathisia (Gerlach et al, 1985; Robertson et al, 1990), tardive dyskinesia (Achiron et al, 1990), and tardive dystonia (Miller & Jankovic, 1990) have all occurred.
    3) CASE REPORT: Parkinsonism, orolingual dyskinesia, and tardive akathisia were observed following sulpiride administration in a 56-year-old woman; well-tolerated symptoms of akathisia and dyskinesia remained 2 months after therapy was stopped (Lopez de Munain et al, 1994).
    2) WITH POISONING/EXPOSURE
    a) AMISULPRIDE
    1) INCIDENCE: Dystonic reactions were reported in 2 cases among 83 cases of amisulpride ingestions of greater than 1 g (median ingestion 6 g). Risperidone (60 mg) was coingested in one of these cases (Isbister et al, 2010).
    D) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) AMISULPRIDE
    1) Seizures were reported in 2 cases among 83 cases of amisulpride ingestions of greater than 1 g (median ingestion 6 g). No coingestants were involved with either case (Isbister et al, 2010).
    E) NEUROLEPTIC MALIGNANT SYNDROME
    1) WITH THERAPEUTIC USE
    a) One patient has developed neuroleptic malignant syndrome (Kashihara & Ishida, 1988). It is also a rare event during amisulpride administration (Prod Info Solian (R) amisulpride, 1997).
    b) Clinical features resembling neuroleptic malignant syndrome were reported in patients receiving sulpiride and penfluridol. Both cases involved elderly women, with a history of mental disturbances. Severe rigidity and fever (39.5 degrees celsius and 39.8 degrees celsius, respectively) occurred within days (up to 2 weeks in one case) of beginning sulpiride therapy, no infection was found in either case (Luhdorf et al, 1987).
    F) IMPAIRED COGNITION
    1) WITH THERAPEUTIC USE
    a) Sulpiride has been shown not to significantly impair psychomotor and cognitive functions after a single dose of 200 milligrams or multiple doses of 150 mg/day (Liljequist et al, 1975) (Bartfai & Wiesel, 1986). However, a higher dose of 400 mg delayed rapid information processing in the absence of subjective sedation (McClelland et al, 1990).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) APTYALISM
    1) WITH THERAPEUTIC USE
    a) Dry mouth (an anticholinergic-related effect) may occur with sulpiride or amisulpride therapy (Prod Info Solian (R) amisulpride, 1997).
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation (an anticholinergic-related effect) can occur with therapeutic administration of sulpiride or amisulpride (Prod Info Solian (R) amisulpride, 1997).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) SULPIRIDE
    1) Cholestatic jaundice is an idiosyncratic event.
    2) CASE REPORT: Cholestatic jaundice occurred after daily doses of 150 mg for 3 months. Serum bilirubin levels declined gradually following sulpiride withdrawal.
    3) CASE REPORT: A 30-year-old developed cholestatic hepatitis following month long exposure to an herbal product adulterated with sulpiride (Chang et al, 1995). Liver function returned to normal within one month of drug cessation.

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) AMENORRHEA
    1) WITH THERAPEUTIC USE
    a) Amenorrhea has been reported during sulpiride therapy (Lepola et al, 1989; Quinn & Marsden, 1984).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) Diaphoresis has occasionally been reported during therapy (Gerlach et al, 1985; Munk-Andersen et al, 1984).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) HYPERREFLEXIA
    1) WITH POISONING/EXPOSURE
    a) Increased muscle tone, hyperreflexia, and extensor plantar reflex have been reported in sulpiride overdose (Capel et al, 2000).
    B) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) A 22-year-old woman complained of muscle cramps following an intentional ingestion of 1.5 g of sulpiride. Laboratory evidence of rhabdomyolysis was present (creatine phosphokinase 6798 International Units/L) on admission, which was treated with urinary alkalinization and intravenous sodium bicarbonate. No long-term effects were reported (Chang et al, 2009).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) LACTATION
    1) WITH THERAPEUTIC USE
    a) Galactorrhea and breast enlargement may occur with therapy (Payne et al, 1985; Standish-Barry et al, 1983; Lepola et al, 1989).
    b) CASE REPORT: Sulpiride therapy was stopped after 3 weeks, due to galactorrhea and weight gain (Sandyk, 1984).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Concentrations of sulpiride in breast milk have been low (about 1 ng/mL) with maternal oral administration of 100 mg daily, suggesting a low propensity for prolactin release or other adverse effects in the infant (Ylikorkala et al, 1982).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and CNS function.
    B) Monitor electrolytes, liver enzymes and kidney function tests after a significant overdose.
    C) Institute continuous cardiac monitoring and obtain an ECG after a significant overdose. QT prolongation and ventricular dysrhthymias (including torsades de pointes) have developed in some cases.
    D) Drug concentrations are not widely available or useful to guide clinical management.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes, including calcium and magnesium, after significant overdose.
    2) Monitor liver enzymes and kidney function tests in symptomatic patients and following a significant overdose.
    3) PEAK PLASMA CONCENTRATIONS: After a 100 mg dose have varied considerably, ranging from 0.05 to 0.2 mcg/mL (Wiesel et al, 1980). After a 200 mg dose, range was 0.2 to 2 mcg/mL (Bressolle et al, 1992).
    4.1.4) OTHER
    A) OTHER
    1) Institute continuous cardiac monitoring and obtain an ECG after significant overdose.

Treatment

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital GI decontamination is not recommended because of the risk of cardiac instability, CNS depression or seizures after significant overdose and the potential for aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. No specific antidote is recommended.
    B) MONITORING OF PATIENT
    1) Monitor pulse rate and rhythm. Several cases of sinus tachycardia and alterations in blood pressure (hypo- and hypertension) have been reported following therapeutic use and in several overdose cases with sulpiride and amisulpride.
    2) Perform an ECG and institute continuous cardiac monitoring. Monitor serum electrolytes, including calcium and magnesium, after significant overdose.
    3) Monitor liver enzymes and kidney function tests in symptomatic patients or following a significant exposure.
    C) BRADYCARDIA
    1) Asymptomatic bradycardia (rate in the 40's) was associated with amisulpride therapy. Monitor pulse rate. Atropine may be considered in patients that become symptomatic.
    2) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    D) ECG FINDING
    1) Hypocalcemia with associated QTc prolongation have been reported after amisulpride overdose (Ward, 2005). Administer IV calcium and magnesium if patients develop QTc prolongation, hypocalcemia or hypomagnesemia.
    E) TORSADES DE POINTES
    1) Two patients developed pulseless torsades de pointes following a mixed ingestion with amisulpiride and amisulpiride only. The first patient with a mixed ingestion had a prolonged QT interval of 560 ms for approximately 29 hours when pulseless torsades occurred, which responded to direct cardioversion. The other patient ingested 4.6 g amisulpride only and developed an episode of pulseless torsades approximately 7 hours later which also responded to cardioversion (Isbister et al, 2006).
    a) Patients may require prolonged cardiac monitoring of at least 16 hours following a significant amisulpride exposure, or if the QT is prolonged. Cardiac monitoring should be performed until the conduction intervals have normalized (Isbister et al, 2006).
    2) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    3) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    4) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    5) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    6) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    7) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    8) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

Enhanced Elimination

    A) EFFICACY
    1) Hemodialysis is unlikely to be effective due to the large volume of distribution of these agents.

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with dysrhythmias or QT prolongation on ECG should be admitted to an intensive care setting for continuous cardiac monitoring (Isbister et al, 2006).
    6.3.1.2) HOME CRITERIA/ORAL
    A) An asymptomatic adult with an inadvertent minor exposure (eg, a single extra dose) may be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with significant or deliberate amisulpride overdose should be observed for at least 16 hours after ingestion with continuous cardiac monitoring and serial ECGs. If no dysrhythmias or QT prolongation develop, they may be discharged after psychiatric evaluation if indicated (Isbister et al, 2006).

Monitoring

    A) Monitor vital signs and CNS function.
    B) Monitor electrolytes, liver enzymes and kidney function tests after a significant overdose.
    C) Institute continuous cardiac monitoring and obtain an ECG after a significant overdose. QT prolongation and ventricular dysrhthymias (including torsades de pointes) have developed in some cases.
    D) Drug concentrations are not widely available or useful to guide clinical management.

Range Of Toxicity

Summary

    A) TOXICITY: AMISULPRIDE: The toxic dose has not been established. Eighty-one adults ingested between 1.2 to 120 g of amisulpride, all patients except one who ingested 24 g, survived. Two adults developed QT prolongation and hypocalcemia after the ingestion of 5 g and 3.6 g of amisulpride, respectively. Both patients recovered following supportive care. In adults, torsades de pointes has developed after ingestion of 4 g of amisulpride or more. THERAPEUTIC DOSE: SULPIRIDE: ADULT: ORAL: 200 to 400 mg twice daily, to a maximum of 1200 mg daily. AMISULPRIDE: ADULT: ORAL: 400 to 800 mg/day are usually recommended for acute psychotic episodes; maximum dose is 1200 mg/day.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) AMISULPRIDE-
    a) ORAL/ACUTE EPISODE - 400 to 800 milligrams/day are recommended for acute episodes with the maximum dose being 1200 milligrams/day (Prod Info Solian(R), 1997).
    1) Note: doses above 1200 mg/daily have not been extensively studied for safety.
    b) For patients with predominantly negative symptoms, oral doses between 50 milligrams/day and 300 milligrams/day are recommended (Prod Info Solian(R), 1997).
    c) Amisulpride can be given at oral doses up to 300 milligrams/day with higher doses given twice daily (Prod Info Solian(R), 1997).
    2) SULPIRIDE-
    a) IM DOSE - 200 to 800 milligrams daily for acute schizophrenia (S Sweetman , 2001).
    b) ORAL - 200 to 400 milligrams twice daily for acute schizophrenia. The dose may be increased gradually to a maximum of 1200 milligrams daily (S Sweetman , 2001).
    1) It has been found that patients with mainly positive symptoms respond to higher doses, while doses at the lower end have a greater alerting effect and patients with predominantly negative symptoms respond to doses below 800 mg daily (S Sweetman , 2001).
    c) Lower doses are recommended with renal failure (Besssolle et al, 1989):
    CREATININE CLEARANCE (mL/min)DOSE
    30 to 6070% of normal dose
    10 to 3050% of normal dose
    Under 1034% of normal dose

    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) AMISULPRIDE - The safety and effectiveness in children less than 15 years has not been established (Prod Info Solian(R), 1997).
    2) SULPIRIDE - For children over 14 years of age, a daily oral dose of 3 to 5 milligrams/kilogram may be given (S Sweetman , 2001).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) SULPIRIDE
    a) After a 100 mg dose the peak plasma concentration of sulpiride has varied considerably, ranging from 0.05 to 0.2 mcg/mL (Wiesel et al, 1980). After a 200 mg dose, range was 0.2 to 2 mcg/mL (Bressolle et al, 1992).
    b) There does not appear to be a correlation between plasma concentration and therapeutic effect (Gerlach et al, 1985).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) AMISULPRIDE
    a) SURVIVAL: A patient developed generalized seizures followed by coma, tachycardia, motor restlessness, and a slight prolonged QT interval following a 3 g ingestion of amisulpride and an unknown amount of dothiepin; blood-amisulpride concentration was 9.63 mcg/mL (S Sweetman , 2001).
    b) FATALITY: A patient was found dead with a blood-amisulpride concentration of 41.7 mcg/mL (S Sweetman , 2001).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) AMISULPRIDE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 175 mg/kg ((RTECS, 2001))
    2) LD50- (ORAL)MOUSE:
    a) 1024 mg/kg ((RTECS, 2001))
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 224 mg/kg ((RTECS, 2001))
    B) SULPIRIDE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 170 mg/kg ((RTECS, 2001))
    2) LD50- (ORAL)MOUSE:
    a) 1700 mg/kg ((RTECS, 2001))
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 290 mg/kg ((RTECS, 2001))
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 210 mg/kg ((RTECS, 2001))
    5) LD50- (ORAL)RAT:
    a) 9800 mg/kg ((RTECS, 2001))
    6) LD50- (SUBCUTANEOUS)RAT:
    a) 360 mg/kg ((RTECS, 2001))

Minimum Lethal Exposure

    A) SUMMARY
    1) AMISULPRIDE: An adult was found dead with a blood-amisulpride concentration of 41.7 mcg/mL (S Sweetman , 2001).
    2) A 39-year-old woman died after ingesting 16 to 24 g amisulpride (Isbister et al, 2006).
    3) An adult died after ingesting 24 g amisulpride from a cardiac arrest associated with torsades de pointes (Isbister et al, 2010).

Maximum Tolerated Exposure

    A) AMISULPRIDE
    1) In a 5-year prospective study of 83 amisulpride ingestions ranging from 1.2 to 120 g among 81 patients with a median age of 29 years, all patients except one who ingested 24 g, survived. Torsades de pointes developed in 6 (7%) cases associated with doses of 4, 4.6, 18, 24, 32, and 80 g (Isbister et al, 2010).
    2) An adult developed generalized seizures followed by coma, motor restlessness, tachycardia and slight prolongation of the QT interval after ingesting 3 grams of amisulpride and an unknown amount of dothiepin. Serum amisulpride concentration was 9.63 mcg/mL; the patient recovered within 48 hours following supportive care (Tracqui et al, 1995).
    3) Two patients developed QT prolongation (QTc peaked at 557 ms in patient 1 and peaked at 625 ms in patient 2) and hypocalcemia after ingesting 5 g and 3.6 g of amisulpride, respectively; patient one also ingested 4 g of paracetamol. In patient 1, the lowest serum calcium level, corrected for albumin, and serum magnesium level were 1.96 mmol/L and 0.66 mmol/L, respectively. In patient 2, the lowest serum calcium level, corrected for albumin, was 2.25 mmol/L. Although the magnesium level was 0.76 mmol/L on presentation to the hospital, a repeat measurement could not be done. Both patients were treated with intravenous calcium gluconate (20 mL of 10%) and magnesium sulfate (10 mL of 50%). Following several hours of supportive care, both patients recovered without further sequelae (Ward, 2005).
    4) Torsades de pointes developed in two adults after ingestion of 4.6 and 32 g amisulpride, both recovered with supportive care. QT prolongation and QRS widening developed in another adult after ingestion of 24 g amisulpride (Isbister et al, 2006).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) SUMMARY: Sulpiride is a neuroleptic which blocks dopamine receptors. It is a specific dopamine (D2 - D3) antagonist in vivo and in vitro (Gerlach et al, 1985). It lacks the effects on norepinephrine, acetylcholine, serotonin, histamine, or gamma- aminobutyric acid receptors (Gerlach et al, 1985).
    1) Sulpiride has a very high affinity for dopaminergic D2 and D3 receptors and, in contrast to other neuroleptics, such as haloperidol or clozapine, it does not have any affinity for other brain neurotransmitter receptor subtypes. Studies of deplacement of 3H-spiperone binding by sulpiride from different brain structures confirm that sulpiride binding occurs in regions rich in dopaminergic receptors: the corpus stratum and the limbic system, in particular the nucleus accumbens. PET-scan data on a small number of patients indicated that sulpiride at doses of 600 to 1200 mg/day resulted in a striatal occupancy of 33% to 43% (Martinot et al, 1996).
    B) ANTIDEPRESSANT EFFECT: Low doses of sulpiride (50 to 150 mg/day) may exert an antidepressant effect, whereas doses of 800 to 1000 mg/day are antischizophrenic. The antidepressant effects may be due to preferential blockade of dopamine autoreceptors, with activation of dopamine transmission (Serra et al, 1990).
    C) PROLACTIN: Sulpiride stimulates prolactin secretion (Payne et al, 1985; Aono et al, 1982).
    D) ANTIULCER ACTIVITY: Sulpiride improves blood flow and mucus secretion in the gastroduodenal mucosa. It is being investigated as treatment for duodenal ulcer (Tatsuta et al, 1986).
    E) ANTIEMETIC: Sulpiride is being investigated as treatment for vertigo and migraine headaches (S Sweetman , 2001).

Physicochemical

Molecular Weight

    A) SULPIRIDE - 341.4

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