DELHI PSYCHIATRY JOURNAL Vol. 10 No.2 OCTOBER 2007 Drug Review Levosulpiride : A Review Sparsh Gupta, Gobind Rai Garg, Sumita Halder, Krishna Kishore Sharma Department of Pharmacology, University College of Medical Sciences & G.T.B. Hospital, Dilshad Garden, Delhi-110095 Dopamine is a neurotransmitter known to be Mechanism of action involved in the regulation of mood and behavior. Levosulpride is an atypical antipsychotic agent Psychotic illness is thought to be caused due to that blocks the presynaptic dopaminergic D 2 disturbance of neurotransmitters (chiefly dopamine) receptors.1 Like its parent compound, levosulpiride in the brain. Schizophrenia is a psychotic illness shows antagonism at D and D receptors present 3 2 characterized by dopamine over activity in the brain presynaptically as well as postsynaptically in the and so anti dopaminergic drugs are a useful rat striatum or nucleus accumbens2. The preferential component of the therapy for the management of binding of the presynaptic dopamine receptors this disease. decreases the synthesis and release of dopamine at Levosulpiride is the levo enantiomer of low doses whereas it causes postsynaptic D 2 sulpiride. It is a substituted benzamide which is receptor antagonism at higher dose. This receptor meant to be used for several indications: depression, profile of the drug along with its limbic selectivity psychosis, somatoform disorders, emesis and explains its effectiveness in the management of both dyspepsia. It is physically present as a white positive and negative symptoms of schizophrenia.3 crystalline powder with the chemical structure as follows: Pharmacokinetics The parent drug is given in a dose of 400-1800 mg orally daily although a much lower dose is effective for producing antidepressant effect (about 50-300 mg).The plasma t of the drug is about 6-8 1/2 hours. The drug is chiefly excreted through the renal The levo enantiomer shows better/similar route. pharmacological actions and lower incidence of Indications toxic effects than both dextro as well as the racemic 1. Psychiatric illness: the primary indication of forms of the drug. this drug is in the management of both positive Amisulpride is a substituted benzamide which and negative symptoms of schizophrenia. It is is also used for various psychiatric indications. It also used in patients of depression. has a half life of 12 hours and its bioavailability is 2. Burning mouth syndrome: Burning mouth 48%. It is weakly metabolized by liver and is syndrome (BMS) is a condition of unknown primarily eliminated through the renal route. Its etiology where there is a complaint of a burning chemical structure is as follows : sensation in the mouth in the absence of any underlying medical or dental cause. The pain CONNCH N 2 is predominantly localized to tongue or lips with OCH CH2 6 3 minimal oral signs. Levosulpiride at a dose of 100 mg/day demonstrated beneficial effect CHOS 2 5 2 (decreased burning or stinging oral sensation) 4 NH2 Clinical Structure of Amisulpride in BMS. 144 Delhi Psychiatry Journal 2007; 10:(2) © Delhi Psychiatric Society OCTOBER 2007 DELHI PSYCHIATRY JOURNAL Vol. 10 No.2 3. Acute unilateral labyrinthine dysfunction: etc.) of hands, leg, tongue and facial levosulpiride has been shown to induce muscles. recovery in unilateral labyrinthine dysfunction. Sedation or drowsiness (because of When the drug was administered at a dose of decrease in sensory inputs to reticular 25 mg three times a day for a period of 10 days, activating system) it produced lesser residual labyrinthine Increase in plasma prolactin levels mani- dysfunction and reduction in the recurrence of fested by breast enlargement, production attacks.5 of milk and stopping of menstrual periods. 4. Cataplexy: Animal studies have demonstrated This can be taken care of with the use of the beneficial effects of levosulpiride in the lower dose of this drug.4 management of cataplexy without much Neuroleptic malignant syndrome (characte- adverse effects. Another advantage with the use rized by hyperpyrexia, muscle rigidity, this drug is non reduction of the REM sleep.6 increased myoglobin and creatine kinase; Earlier canine studies have already suggested the last two suggestive of muscle damage. the role of D /D receptors in the regulation of Akathisia (uncontrollable desire to move 2 3 cataplexy.7 about without any anxiety). 5. Gastroparesis and glycemic control in Tardive dyskinesia, it occurs late in the diabetics: the selective antagonistic action of therapy and its features include involuntary levosulpiride on the D receptors also makes it rhythmical movements of face, mouth and 2 useful as a prokinetic drug. Its use in a dose of jaw. The reason for tardive dyskinesia is 25 mg tds orally for a period of 6 months has synthesis of newer DA receptors which are been shown to increase glycemic control in supersensitive to even a small amount of IDDM subjects by effectively managing DA. This causes a decrease in cholinergic gastroparesis in them.8 Administration of activity in the striatum followed by levosulpride in a dose of 25 mg four times a decrease in GABA release. This decreased day produces beneficial effect in patients with in inhibitory GABA is responsible for diabetic cholecystoparesis as evidenced by increased involuntary motor activity. reduction of basal mean gall bladder volume.9 Postural hypotension (because of autono- 6. Premature ejaculation: Premature ejaculation mic blockade), tolerance develops to this is defined as a failure of the normal voluntary effect after some time. control over ejaculation. It is usually managed Weight gain. with the use of antidepressants and other Elevated liver transaminases. adjuvant drugs. In a double blind study, Drug interactions administration of levosulpiride 25 mg once daily for 60 days provided significant 1. Antacids and Sucralfate: They can decrease improvement in control over ejaculation the absorption of the drug from the intestine. (76.47% drug treated patients as compared to So, these medicines should not be taken along 26.66% patients receiving placebo). Dopamine with levosulpiride. There should be a minimum has been shown to be facilitate sexual arousal 2 hour time lag between the two medicines. and in decreasing ejaculatory threshold. So, 2. Alcohol : there is increased chance of sedation. levosulpiride being a dopamine antagonist may 3. Smoking: increased metabolism of the drug be responsible for the beneficial effect by this may require higher dose. mechanism.10 4. Antihypertensive medications: concomitant use may enhance the hypotensive effect seen Side effects with the drug. The following side effects can occur with the 5. Anticholinergics: increased incidence of use of this drug; anticholinergic side effects. Acute muscular dystonia characterized by 6. Levo dopa: It may oppose the antipsychotic abnormal movements (twitching, tremor action of the drug, conversely levosulpiride can Delhi Psychiatry Journal 2007; 10:(2) © Delhi Psychiatric Society 145 DELHI PSYCHIATRY JOURNAL Vol. 10 No.2 OCTOBER 2007 cause decrease the efficacy of levo-dopa in the 2. Schoemaker H, Claustre Y, Fage D, Rouquier management of Parkinsonism. L, Chergui K, et al. Neurochemical 7. Arrhythmia especially prolonged QT interval characteristics of amisulpiride, an atypical with the concurrent use of dopamine D /D receptor antagonist with both 2 3 Atomoxetine presynaptic and limbic selectivity. J Pharmacol Antiarrhythmics Exp Ther 1997 Jan; 280 : 83-97. Terfenadine 3. Danien JM, Rein W, Fleurot O. Improvement Chloroquine, quinine of schizophrenic patients with primary negative Cisapride symptoms treated with amisulpiride. Am J Drugs causing hypokalemia (corticosteroids, Psychiatry 1999 Apr; 156 : 610-6. laxatives, diuretics like furosemide) 4. Demarosi F, Tarrozi M, Lodi G, Canegallo L, Rimondini L, Sardella A. The effect of Contraindications levosulpiride in burning mouth syndrome. The following are the conditions where the Minerva Stomatol 2007; 56 : 21-6. drug should either be used cautiously or is 5. Zanetti D, Civiero N, Balzanelli C, Tonini M, contraindicated: Antonelli AR. Improvement of vestibular Elderly people compensation by Levo-sulpiride in acute Children less than 14 years of age unilateral labyrinthine dysfunction. Acta Parkinson disease Otorhinolaryngol Ital. 2004 Apr; 24 : 49-57. Severe renal or hepatic insufficiency 6. Okura M, Reihl J, Mignot E, Nishino S. History of epilepsy Sulpiride, a D /D blocker reduces cataplexy 2 3 Porphyrias but not REM sleep in canine narcolepsy. Breast cancer Neuropsychpharmacology 2000; 23 : 528-38. Alcohol intoxication 7. Honda K, Reihl J, Mignot E, Nishino S. Certain tumors like phaeochromocytoma and Dopamine D agonists into the substantia nigra 3 pituitary prolactinoma aggravate cataplexy but do not modify sleep Hypokalemia Neuroreport. 1999; 10 : 31111-8. The drug should be used cautiously in 8. Melga P, Mansi C, Ciuchi E, Giusti R, Sciaba pregnancy (only when it is expected to L, Prando R. Chronic administration of benefit the mother more than the possibility levosulpiride and glycemic control in IDDM of risking the fetus). patients with gastroparesis Diabetes Care; 21: The drug is known to be secreted in breast 55-8. milk, so, its use should be restricted in 9. Mansi C, Savarino V, Vigneri S, Sciaba L, breastfeeding women. Perilli D, Mele MR, et al. Effect of D dopamine 2 References receptor antagonist levosulpiride on diabetic cholecystoparesis Aliment Pharmacol and Ther 1. Rossi F, Forgione A. Pharmacotoxocological 1995; 9 : 185-9. aspects of levosulpiride. Pharmacol Res 1995; 10. Grecco E, Polonio Balbi P, Speranza JC. 31 : 81-94. Levosulpiride – a new solution for premature ejaculation? Int J Impotence Res 2002; 14 : 308- 9. 146 Delhi Psychiatry Journal 2007; 10:(2) © Delhi Psychiatric Society.