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{{drugbox
{{Drugbox
| IUPAC_name = N-[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxy-5-sulfamoyl-benzamide
| Watchedfields = changed
| image = Sulpiride.png
| verifiedrevid = 470474559
| CAS_number = 15676-16-1  
| IUPAC_name = (±)-5-(aminosulfonyl)-''N''-[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxybenzamide
| ATC_prefix = N05  
| image = Sulpiride2DACS3.svg
| ATC_suffix = AL01  
| width = 250
| ATC_supplemental = {{ATC|N05|AL07}}  
| image2 = Sulpiride3Dan.gif
| PubChem = 5355
 
| DrugBank = APRD00032
| width2 = 225
<!--Clinical data-->
| tradename =  Dolmatil, Sulparex (discontinued), Sulpor
| Drugs.com = {{drugs.com|international|sulpiride}}
| pregnancy_category = 
| legal_UK = POM
| legal_status = <br>Rx-only
| routes_of_administration = Oral
 
<!--Pharmacokinetic data-->
| bioavailability = 25–40%<ref name = EMC>{{cite web| title = Sulpiride Tablets 200mg, 400mg (SPC) | work = electronic Medicines Compendium (eMC) | publisher = Sanofi | date = 21 January 2010 | accessdate = 19 October 2013 | url = http://www.medicines.org.uk/emc/medicine/18936/SPC/Sulpiride+Tablets+200mg%2c+400mg/#PHARMACODYNAMIC_PROPS}}</ref><ref name = Pharm>{{cite journal| title = Absolute bioavailability, rate of absorption, and dose proportionality of sulpiride in humans| author = Bressolle, F; Brès, J; Fauré-Jeantis, A| journal=Journal of Pharmaceutical Sciences | pmid = 1619566 | volume = 81 | issue = 1 | pages = 26–32 | date = January 1992 | doi=10.1002/jps.2600810106}}</ref>
| metabolism = Not metabolised<ref>{{cite journal|title = Metabolism of sulpiride in man and Rhesus monkey| author = Imondi, AR; Alam, AS; Brennan, JJ; Hagerman, LM | journal = Archives Internationales de Pharmacodynamie et de Thérapie | volume = 232 | issue = 1 | pages = 79–91 | pmid = 96745 | date = March 1979}}</ref>
| protein_bound = <40%<ref name = EMC/>
| elimination_half-life = 6-8 hours<ref name = EMC/>
| excretion = [[Renal]] (70-90%),<ref name = Pharm/> [[Faeces|Faecal]] (~95% as the unchanged drug)<ref name = EMC />
 
<!--Identifiers-->
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 15676-16-1
| ATC_prefix = N05
| ATC_suffix = AL01
| PubChem = 5355
| IUPHAR_ligand = 5501
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00391
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5162
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 7MNE9M8287
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D01226
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 26
 
<!--Chemical data-->
| C=15 | H=23 | N=3 | O=4 | S=1  
| C=15 | H=23 | N=3 | O=4 | S=1  
| molecular_weight = 341.427 g/mol  
| molecular_weight = 341.427 g/mol
| bioavailability =  
| smiles = O=S(=O)(N)c1cc(c(OC)cc1)C(=O)NCC2N(CC)CCC2
| protein_bound =  
| InChI = 1/C15H23N3O4S/c1-3-18-8-4-5-11(18)10-17-15(19)13-9-12(23(16,20)21)6-7-14(13)22-2/h6-7,9,11H,3-5,8,10H2,1-2H3,(H,17,19)(H2,16,20,21)
| metabolism =  
| InChIKey = BGRJTUBHPOOWDU-UHFFFAOYAL
| elimination_half-life =  
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| pregnancy_category =  
| StdInChI = 1S/C15H23N3O4S/c1-3-18-8-4-5-11(18)10-17-15(19)13-9-12(23(16,20)21)6-7-14(13)22-2/h6-7,9,11H,3-5,8,10H2,1-2H3,(H,17,19)(H2,16,20,21)
| legal_status =  
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| routes_of_administration = }}
| StdInChIKey = BGRJTUBHPOOWDU-UHFFFAOYSA-N
'''Sulpiride''' (sold as '''Meresa''', '''Sulpirid Ratiopharm''', '''Sulpirid Neuraxpharm''', '''Bosnyl''', '''Dogmatil''', '''Eglonyl''') is an [[anti-psychotic]] drug used mainly in the treatment of [[psychosis]] (e.g. [[schizophrenia]]) and [[clinical depression|depression]]. It is a substituted benzamide. Sulpiride is more commonly used in Europe and Japan. So far it has not been approved in the US and Canada. The drug has strong chemical and clinical similarities to the novel anti-psychotic [[amisulpride]].
}}
 
'''Sulpiride''' (brand names '''Dogmatil''' <small>([[Hong Kong|HK]], [[Singapore|SG]], [[Philippines|PH]])</small>, '''Dolmatil''' <small>([[Ireland|IE]], [[United Kingdom|UK]])</small>, '''Eglonyl''' <small>([[Russia|RU]], [[South Africa|ZA]])</small>, '''Espiride''' <small>([[South Africa|ZA]])</small>, '''Modal''' <small>([[Israel|IL]])</small>, '''Sulpor''' <small>([[United Kingdom|UK]])</small> and others) is an [[atypical antipsychotic]] [[drug]] (although some texts have referred to it as a [[typical antipsychotic]]<ref>{{cite isbn|9780857110848}}</ref>) of the [[Benzamide|benzamide class]] used mainly in the treatment of [[psychosis]] associated with [[schizophrenia]] and [[major depressive disorder]], and sometimes used in low dosage to treat [[anxiety]] and [[dysthymia|mild depression]]. Sulpiride is commonly used in [[Europe]], [[Russia]] and [[Japan]]. [[Levosulpiride]] is its purified [[levo]]-[[isomer]] and is sold in [[India]] for similar purpose. So far it has not been approved in the [[United States]], [[Canada]] and [[Australia]]. The drug is chemically and clinically similar to [[amisulpride]].
 
== Medical uses ==
 
Sulpiride's primary use in medicine is in the management of the symptoms of [[schizophrenia]].<ref name = EMC/> It has been used as both a monotherapy and adjunctive therapy (in case of treatment-resistance) in schizophrenia.<ref name = EMC/><ref name = Maudsley>{{cite isbn|9780470979488}}</ref><ref name = Coch>{{cite journal|title = Sulpiride augmentation for schizophrenia|journal=The Cochrane Database of Systematic Reviews|issue=1|page=CD008125|date=January 2010|pmid=20091661|doi=10.1002/14651858.CD008125.pub2|author=Wang, J; Omori, IM; Fenton, M; Soares, B|url=http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008125.pub2/pdf}}</ref><ref>{{cite journal|title=Effectiveness of Sulpiride in Adult Patients With Schizophrenia|journal=Schizophrenia Bulletin|volume=39|issue=3|year=2013|pages=673–683|doi=10.1093/schbul/sbs002|author=Chia-Cheng Lai, E; Chang, CH; Yang, YHK; Lin, SJ; Lin, CY}}</ref><ref>{{cite journal|title=Sulpiride for schizophrenia|journal=The Cochrane Database of Systematic Reviews|issue=2|year=2000|pages=CD001162|pmid=10796605|doi=10.1002/14651858.CD001162 |author=Soares, BG; Fenton, M; Chue, P|url=http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001162/pdf}}</ref><ref>{{cite journal|title=Sulpiride versus other antipsychotics for schizophrenia (Protocol)|author=Omori, IM; Wang, J; Soares, B; Fenton, M|journal=The Cochrane Database of Systematic Reviews|issue=4|pages=CD008126|date=October 2009|doi=10.1002/14651858.CD008126}}</ref> It has also been used in the treatment of [[dysthymia]].<ref>{{cite journal|title=The substituted benzamides and their clinical potential on dysthymia and on the negative symptoms of schizophrenia|author=Pani, L; Gessa, GL|journal=Molecular Psychiatry|volume=7|issue=3|pages=247–253|pmid=11920152|year=2002|doi=10.1038/sj/mp/4001040|url=http://www.nature.com/mp/journal/v7/n3/pdf/4001040a.pdf}}</ref> Augmentation with sulpiride has also been tried as a strategy for accelerating antidepressant response in patients with [[major depressive disorder]].<ref>{{cite journal|title=Combined treatment with sulpiride and paroxetine for accelerated response in patients with major depressive disorder|journal=Journal of Clinical Psychopharmacology|author=Uchida, H; Takeuchi, H; Suzuki, T; Nomura, K; Watanabe, K; Kashima, H| volume = 25|issue=6|pages=545–551|date=December 2005|pmid=16282835|doi=10.1097/01.jcp.0000185425.00644.41}}</ref> There is also evidence of its efficacy in treating [[panic disorder]].<ref>{{cite journal|title=The response to sulpiride in social anxiety disorder: D2 receptor function|journal=Journal of Psychopharmacology|volume=27|issue=2|pages=146–151|date=February 2013|doi=10.1177/0269881112450778|pmid=22745189|author=Bell, C; Bhikha, S; Colhoun, H; Carter, F; Frampton, C; Porter, R}}</ref><ref>{{cite journal|title=Sulpiride and refractory panic disorder|author=Nunes, EA; Freire, RC; Dos Reis, M; de Oliveira, E; Silva, AC; Machado, S; Crippa, JA; Dursun, SM; Baker, GB; Hallak, JE; Nardi, AE|journal=Psychopharmacology|date=September 2012|volume=223|issue=2|pages=247–249|doi=10.1007/s00213-012-2818-6|pmid=22864966}}</ref>
 
=== 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 symptoms|extrapyramidal]] side effects have been reported.<ref name = EMC/>
* Lactation: Sulpiride is found in the milk of lactating women. Since the consequences are unclear, women should not breastfeed during treatment.<ref name = EMC/>
 
==Adverse effects==


==Pharmacology==
Sulpiride is usually well-tolerated, producing few adverse effects. Their incidences are as follows:<ref name = EMC/><ref name = Maudsley/><ref>{{cite journal|title=Sulpiride and perphenazine in schizophrenia. A double-blind clinical trial|journal=Acta Psychiatrica Scandinavica|volume=80|issue=1|date=July 1989|pages=92–96|pmid=2669445|author=Lepola, U; Koskinen, T; Rimón, R; Salo, H; Gordin, A|doi=10.1111/j.1600-0447.1989.tb01305.x}}</ref><ref>{{cite journal|title=Sulpiride versus haloperidol, a clinical trial in schizophrenia. A preliminary report|journal=Acta Psychiatrica Scandinavica Supplementum|volume=311|pages=31–41|author=Munk-Andersen, E; Behnke, K; Heltberg, J; Nielsen, H; Gerlach, J|pmid=6367362|year=1984}}</ref><ref>{{cite journal|journal=British Journal of Psychiatry|volume=147|pages=283–288|pmid=3904885|title=Sulpiride and haloperidol in schizophrenia: a double-blind cross-over study of therapeutic effect, side effects and plasma concentrations|author=Gerlach, J; Behnke, K; Heltberg, J; Munk-Anderson, E; Nielsen, H|date=Sep 1985|doi=10.1192/bjp.147.3.283}}</ref><ref>{{cite journal|title=A randomized double blind group comparative study of sulpiride and amitriptyline in affective disorder|journal=Psychopharmacology|year=1983|volume=81|issue=3|pages=258–260|pmid=6417717|author=Standish-Barry, HM; Bouras, N; Bridges, PK; Watson, JP|doi=10.1007/bf00427274}}</ref><ref>{{cite journal|title=A double blind trial of sulpiride in Huntington's disease and tardive dyskinesia|journal=Journal of Neurology, Neurosurgery and Psychiatry|author=Quinn, N; Marsden, CD|volume=47|issue=8|pages=844–847|pmid=6236286|pmc=1027949|date=August 1984|doi=10.1136/jnnp.47.8.844|url=http://jnnp.bmj.com/content/47/8/844.full.pdf}}</ref><ref>{{cite journal|title=Clinical trials of benzamides in psychiatry|journal=Advances in Biochemical Psychopharmacology|author=Peselow, ED; Stanley, M|volume=35|pages=163–194|year=1982|pmid=6756060}}</ref><ref>{{cite journal|title=Controlled trial of sulpiride in chronic schizophrenic patients|journal=The British Journal of Psychiatry|date=December 1980|pages=522–529|volume=137|pmid=7011469|author=Edwards, JG; Alexander, JR; Alexander, MS; Gordon, A; Zutchi, T|doi=10.1192/bjp.137.6.522}}</ref>
===Pharmacokinetics===
Sulpiride is absorbed slowly from the GI-Tract. Its oral bioavailability is only 25 to 35% with marked interindividual differences. The peak plasma concentration is reached 4.5 hours after oral dosing. The usual half-life is 6 to 8 hours. Ninety-two percent is excreted unchanged in the urine. Sulpiride is usually given in 2 or 3 divided doses.


===Pharmacodynamic properties===
;Common (>1%) adverse effects:
Sulpiride is a selective antagonist at postsynaptic D2-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.
* 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 alpha-1 adrenergic, histamine and muscarinic acetylcholine receptor affinity)
* Insomnia
* Weight gain or loss
* [[Hyperprolactinaemia]] (elevated plasma levels of the hormone, [[prolactin]] which can, in turn lead to sexual dysfunction, galactorrhoea, amenorrhoea, gynaecomastia, etc.)
* Nausea
* Vomiting
* Nasal congestion
* [[Anticholinergic]] adverse effects such as:
:- Dry mouth
:- Constipation
:- Blurred vision
* Restlessness
* Impaired concentration


==Uses and dosage==
;Rare (<1% incidence) adverse effects:
* Productive psychosis: treatment with rather high doses&mdash;in excess of 600 mg daily.
* [[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.
* Long-term Treatment of negative (unproductive) psychosis: in moderate doses (approx. 600 mg daily)
* [[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.  
* Treatment of depression and [[Vertigo (medical)|vertigo]]: in low to moderate doses (50 to 200 mg daily)
* 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.
:- [[Neutropaenia]]
:- [[Leucopenia]]
:- [[Leukocytosis]]<ref>{{cite journal|title=Leukocytosis related to the therapeutic dosage of sulpiride|journal=Biological Psychiatry|volume=35|issue=12|pages=963|date=June 1994|authors=Levkovitz, H; Abramovitch, Y; Nitzan, I|pmid=8080896|doi=10.1016/0006-3223(94)91244-0}}</ref>
* Seizures
* [[Torsades de Pointes]]
 
;Unknown incidence adverse effects include:
* [[QTc interval]] prolongation which can lead to potentially fatal [[arrhythmias]].
* Cholestatic jaundice<ref>{{cite journal|title=Severe cholestatic jaundice due to sulpiride|journal=Israel Journal of Medical Sciences|author=Melzer, E; Knobel, B|volume=23|issue=12|pages=1259–1260|date=December 1987|pmid=3326861}}</ref>
* Elevated liver enzymes
* Primary biliary cirrhosis<ref>{{cite journal|title=Symptomatic primary biliary cirrhosis triggered by administration of sulpiride|journal=The American Journal of Gastroenterology|doi=10.1111/j.1572-0241.1999.01634.x|pmid=10606349|author=Ohmoto, K; Yamamoto, S; Hirokawa, M|volume=94|issue=12|pages=3660–3661|date=December 1999}}</ref>
* 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'''<ref name = EMC/>


==Contraindications and cautíons==
* Hypersensitivity to sulpiride
* Hypersensitivity to sulpiride
* Pre-existing breast cancer or other prolactin-dependent tumors
* Pre-existing breast cancer or other prolactin-dependent tumors
* Phaeochromocytoma
* [[Phaeochromocytoma]]
* Intoxication with other centrally active drugs
* Intoxication with other centrally active drugs
* Concomitant use of [[levodopa]]
* Concomitant use of [[levodopa]]
* Caution : Pre-existing Parkinson's Disease
* Acute porphyria
* Caution : Patients below 18 years of age (insufficient clinical data)
* Comatose state or CNS depression
* Caution : Pre-existing severe heart disease/bradycardia, or hypokalemia (predisposing to [[long QT syndrome]] and severe arrhythmias)
* Bone-marrow suppression
* Caution : Patients with pre-existing epilepsy. Anticonvulsant therapy should be maintained.


==Pregnancy and lactation==
'''Cautions'''<ref name = EMC/>
* Pregnancy: Animal studies did not reveal any embryo- or fetotoxic properties 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.
* 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 [[arrhythmia]]s)
* Patients with pre-existing [[epilepsy]]. [[Anticonvulsant]] therapy should be maintained.
* Lithium use — increased risk of neurological side effects of both drugs


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


==Side effects==
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 [[benztropine]]. All patients should be closely monitored for signs of [[long-QT syndrome]] and severe arrhythmias.
Sulpiride has fewer [[extrapyramidal]] side effects ([[dystonia]], [[parkinsonism]], [[tardive dyskinesia]] and [[akathisia]]) than many of the older antipsychotic medications. Most of these do not seem to occur in a dose related manner. Other side effects occur infrequently (hypotension, rarely long-QT syndrome, dry mouth, sweating, nausea, activation or sedation, insomnia, allergic rash or pruritus). Isolated cases of the potentially life-threatening [[Neuroleptic malignant syndrome|NMS]] (neuroleptic malignant syndrome) have been reported. Sulpiride should not be taken after 4 p.m. in order to avoid insomnia. The foremost problem with sulpiride is a strong stimulation of prolactin-secretion; whether this may contribute to the development of breast-cancer in women is currently not known.


==Synthesis==
Sulpiride can be synthesized from 5-aminosulfo[[salicylic 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.


* Levodopa : Sulpiride and levodopa have antagonistic effects.
[[File:Sulpiride synthesis.png|800px|center|thumb|Sulpiride synthesis: E.L. Engelhardt, Ch.S. Miller, {{Cite patent|DE|1595915}} (1965)E.L. Engelhardt, Ch.S. Miller, {{Cite patent|DE|1795723}} (1965) E.L. Engelhardt, M.L. Thominet, {{US Patent|3342826}} (1969) G. Bulteau, J. Acher, {{US Patent|4077976}} (1978) F. Mauri, {{Cite patent|DE|2903891}} (1979).]]
* Alcohol : Sedation and hypotension may be potentiated.
* Antihypertensive agents : Hypotension may be potentiated (risk of postural collapse).
* Other central depressants : Increased sedation with negative impact on the capacity to drive or operate machinery.


==Overdose==
== Pharmacology ==
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 [[trism]]. 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 [[Benztropine]]. All patients should be closely monitored for signs of long-QT syndrome and severe arrhythmias.
 
Sulpiride is a [[binding selectivity|selective]] [[receptor antagonist|antagonist]] at [[dopamine]] [[D2 receptor|D<sub>2</sub>]] and [[D3 receptor|D<sub>3</sub> receptor]]s. This action dominates in doses exceeding 600&nbsp;mg daily. In doses of 600 to 1,600&nbsp;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&nbsp;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 [[GHB receptor|gamma-hydroxybutyrate receptor]] in vivo at therapeutic concentrations.<ref>{{cite journal |author=Maitre M, Ratomponirina C, Gobaille S, Hodé Y, Hechler V |title=Displacement of [3H] gamma-hydroxybutyrate binding by benzamide neuroleptics and prochlorperazine but not by other antipsychotics |journal=Eur J Pharmacol. |volume=256 |issue=2 |pages=211–4 |date=Apr 1994 |pmid=7914168 |doi=10.1016/0014-2999(94)90248-8 }}</ref> Sulpiride was found in one study in rats to [[upregulate]] GHB receptors.<ref>{{cite journal |author=Ratomponirina C, Gobaille S, Hodé Y, Kemmel V, Maitre M |title=Sulpiride, but not haloperidol, up-regulates gamma-hydroxybutyrate receptors in vivo and in cultured cells |journal=Eur J Pharmacol. |volume=346 |issue=2–3 |pages=331–7 |date=Apr 1998 |pmid=9652377 |url=http://linkinghub.elsevier.com/retrieve/pii/S0014-2999(98)00068-5 |doi=10.1016/S0014-2999(98)00068-5}}</ref> 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.<ref>{{cite journal|title=Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation|author=Dong, E; Nelson, M; Grayson, DR; Costa, E; Guidotti, A|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=105|issue=36|pages=13614–13619|doi=10.1073/pnas.0805493105|date=August 2008|pmid=18757738|url=http://www.pnas.org/content/105/36/13614.full.pdf|pmc=2533238}}</ref>
 
{| class="wikitable"
|-
! Protein !! Binding affinity (K<sub>i</sub> [nM]) towards cloned human receptors<ref>{{cite web|title=PDSP Ki Database|author=Roth, BL; Driscol, J|work=Psychoactive Drug Screening Program (PDSP)|publisher=University of North Carolina at Chapel Hill and the United States National Institute of Mental Health|date=12 January 2011|accessdate=19 October 2013|url=http://pdsp.med.unc.edu/pdsp.php}}</ref>
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || >10000
|-
| [[Dopamine D1 receptor|D<sub>1</sub>]] || >10000
|-
| [[Dopamine D2 receptor|D<sub>2</sub>]] || 9.8
|-
| [[Dopamine D3 receptor|D<sub>3</sub>]] || 8.05
|-
| [[Dopamine D4 receptor|D<sub>4</sub>]] || 54
|-
| [[Arginine vasopressin receptor 1B|V<sub>3</sub>]] || >10000
|}
 
== See also ==
* [[Atypical antipsychotic]]
* [[Benzamide]]


== References ==
== References ==
* British National Formulary, 2005
{{Reflist|2}}


{{Antipsychotics}}
{{Antipsychotics}}
{{Dopaminergics}}
{{GHBergics}}


<!--Categories-->
[[Category:Atypical antipsychotics]]
[[Category:Atypical antipsychotics]]
 
[[Category:Pyrrolidines]]
<!--Other languages-->
[[Category:Sulfonamides]]
[[de:Sulpirid]]
[[Category:Benzamides]]
[[ja:スルピリド]]
[[Category:Phenol ethers]]
[[pl:Sulpiryd]]
[[Category:GHB receptor ligands]]
[[ru:Сульпирид]]

Revision as of 20:08, 6 April 2015

Sulpiride
File:Sulpiride2DACS3.svg
Clinical data
Trade namesDolmatil, Sulparex (discontinued), Sulpor
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)

  • Rx-only
Pharmacokinetic data
Bioavailability25–40%[2][3]
Protein binding<40%[2]
MetabolismNot metabolised[1]
Elimination half-life6-8 hours[2]
ExcretionRenal (70-90%),[3] Faecal (~95% as the unchanged drug)[2]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC15H23N3O4S
Molar mass341.427 g/mol
3D model (JSmol)
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Sulpiride (brand names Dogmatil (HK, SG, PH), Dolmatil (IE, UK), Eglonyl (RU, ZA), Espiride (ZA), Modal (IL), Sulpor (UK) and others) is an atypical antipsychotic drug (although some texts have referred to it as a typical antipsychotic[4]) of the benzamide class used mainly in the treatment of psychosis associated with schizophrenia and major depressive disorder, and sometimes used in low dosage to treat anxiety and mild depression. Sulpiride is commonly used in Europe, Russia and Japan. Levosulpiride is its purified levo-isomer and is sold in India for similar purpose. So far it has not been approved in the United States, Canada and Australia. The drug is chemically and clinically similar to amisulpride.

Medical uses

Sulpiride's primary use in medicine is in the management of the symptoms of schizophrenia.[2] It has been used as both a monotherapy and adjunctive therapy (in case of treatment-resistance) in schizophrenia.[2][5][6][7][8][9] It has also been used in the treatment of dysthymia.[10] Augmentation with sulpiride has also been tried as a strategy for accelerating antidepressant response in patients with major depressive disorder.[11] There is also evidence of its efficacy in treating panic disorder.[12][13]

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.[2]
  • Lactation: Sulpiride is found in the milk of lactating women. Since the consequences are unclear, women should not breastfeed during treatment.[2]

Adverse effects

Sulpiride is usually well-tolerated, producing few adverse effects. Their incidences are as follows:[2][5][14][15][16][17][18][19][20]

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 alpha-1 adrenergic, histamine and muscarinic acetylcholine receptor affinity)
  • Insomnia
  • Weight gain or loss
  • Hyperprolactinaemia (elevated plasma levels of the hormone, prolactin which can, in turn lead to sexual dysfunction, galactorrhoea, amenorrhoea, gynaecomastia, etc.)
  • Nausea
  • Vomiting
  • Nasal congestion
  • Anticholinergic adverse effects such as:
- Dry mouth
- Constipation
- Blurred vision
  • Restlessness
  • 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.
- Neutropaenia
- Leucopenia
- Leukocytosis[21]
Unknown incidence adverse effects include
  • QTc interval prolongation which can lead to potentially fatal arrhythmias.
  • Cholestatic jaundice[22]
  • Elevated liver enzymes
  • Primary biliary cirrhosis[23]
  • 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[2]

  • 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[2]

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 benztropine. 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.

File:Sulpiride synthesis.png
Sulpiride synthesis: E.L. Engelhardt, Ch.S. Miller, DE 1595915  (1965)E.L. Engelhardt, Ch.S. Miller, DE 1795723  (1965) E.L. Engelhardt, M.L. Thominet, Template:US Patent (1969) G. Bulteau, J. Acher, Template:US Patent (1978) F. Mauri, DE 2903891  (1979).

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.[24] Sulpiride was found in one study in rats to upregulate GHB receptors.[25] 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.[26]

Protein Binding affinity (Ki [nM]) towards cloned human receptors[27]
5-HT1A >10000
D1 >10000
D2 9.8
D3 8.05
D4 54
V3 >10000

See also

References

  1. ↑ Imondi, AR; Alam, AS; Brennan, JJ; Hagerman, LM (March 1979). "Metabolism of sulpiride in man and Rhesus monkey". Archives Internationales de Pharmacodynamie et de Thérapie. 232 (1): 79–91. PMID 96745.
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 "Sulpiride Tablets 200mg, 400mg (SPC)". electronic Medicines Compendium (eMC). Sanofi. 21 January 2010. Retrieved 19 October 2013.
  3. ↑ 3.0 3.1 Bressolle, F; Brès, J; Fauré-Jeantis, A (January 1992). "Absolute bioavailability, rate of absorption, and dose proportionality of sulpiride in humans". Journal of Pharmaceutical Sciences. 81 (1): 26–32. doi:10.1002/jps.2600810106. PMID 1619566.
  4. ↑ Template:Cite isbn
  5. ↑ 5.0 5.1 Template:Cite isbn
  6. ↑ Wang, J; Omori, IM; Fenton, M; Soares, B (January 2010). "Sulpiride augmentation for schizophrenia". The Cochrane Database of Systematic Reviews (1): CD008125. doi:10.1002/14651858.CD008125.pub2. PMID 20091661.
  7. ↑ Chia-Cheng Lai, E; Chang, CH; Yang, YHK; Lin, SJ; Lin, CY (2013). "Effectiveness of Sulpiride in Adult Patients With Schizophrenia". Schizophrenia Bulletin. 39 (3): 673–683. doi:10.1093/schbul/sbs002.
  8. ↑ Soares, BG; Fenton, M; Chue, P (2000). "Sulpiride for schizophrenia". The Cochrane Database of Systematic Reviews (2): CD001162. doi:10.1002/14651858.CD001162. PMID 10796605.
  9. ↑ Omori, IM; Wang, J; Soares, B; Fenton, M (October 2009). "Sulpiride versus other antipsychotics for schizophrenia (Protocol)". The Cochrane Database of Systematic Reviews (4): CD008126. doi:10.1002/14651858.CD008126.
  10. ↑ Pani, L; Gessa, GL (2002). "The substituted benzamides and their clinical potential on dysthymia and on the negative symptoms of schizophrenia" (PDF). Molecular Psychiatry. 7 (3): 247–253. doi:10.1038/sj/mp/4001040. PMID 11920152.
  11. ↑ Uchida, H; Takeuchi, H; Suzuki, T; Nomura, K; Watanabe, K; Kashima, H (December 2005). "Combined treatment with sulpiride and paroxetine for accelerated response in patients with major depressive disorder". Journal of Clinical Psychopharmacology. 25 (6): 545–551. doi:10.1097/01.jcp.0000185425.00644.41. PMID 16282835.
  12. ↑ Bell, C; Bhikha, S; Colhoun, H; Carter, F; Frampton, C; Porter, R (February 2013). "The response to sulpiride in social anxiety disorder: D2 receptor function". Journal of Psychopharmacology. 27 (2): 146–151. doi:10.1177/0269881112450778. PMID 22745189.
  13. ↑ Nunes, EA; Freire, RC; Dos Reis, M; de Oliveira, E; Silva, AC; Machado, S; Crippa, JA; Dursun, SM; Baker, GB; Hallak, JE; Nardi, AE (September 2012). "Sulpiride and refractory panic disorder". Psychopharmacology. 223 (2): 247–249. doi:10.1007/s00213-012-2818-6. PMID 22864966.
  14. ↑ Lepola, U; Koskinen, T; Rimón, R; Salo, H; Gordin, A (July 1989). "Sulpiride and perphenazine in schizophrenia. A double-blind clinical trial". Acta Psychiatrica Scandinavica. 80 (1): 92–96. doi:10.1111/j.1600-0447.1989.tb01305.x. PMID 2669445.
  15. ↑ Munk-Andersen, E; Behnke, K; Heltberg, J; Nielsen, H; Gerlach, J (1984). "Sulpiride versus haloperidol, a clinical trial in schizophrenia. A preliminary report". Acta Psychiatrica Scandinavica Supplementum. 311: 31–41. PMID 6367362.
  16. ↑ Gerlach, J; Behnke, K; Heltberg, J; Munk-Anderson, E; Nielsen, H (Sep 1985). "Sulpiride and haloperidol in schizophrenia: a double-blind cross-over study of therapeutic effect, side effects and plasma concentrations". British Journal of Psychiatry. 147: 283–288. doi:10.1192/bjp.147.3.283. PMID 3904885.
  17. ↑ Standish-Barry, HM; Bouras, N; Bridges, PK; Watson, JP (1983). "A randomized double blind group comparative study of sulpiride and amitriptyline in affective disorder". Psychopharmacology. 81 (3): 258–260. doi:10.1007/bf00427274. PMID 6417717.
  18. ↑ Quinn, N; Marsden, CD (August 1984). "A double blind trial of sulpiride in Huntington's disease and tardive dyskinesia" (PDF). Journal of Neurology, Neurosurgery and Psychiatry. 47 (8): 844–847. doi:10.1136/jnnp.47.8.844. PMC 1027949. PMID 6236286.
  19. ↑ Peselow, ED; Stanley, M (1982). "Clinical trials of benzamides in psychiatry". Advances in Biochemical Psychopharmacology. 35: 163–194. PMID 6756060.
  20. ↑ Edwards, JG; Alexander, JR; Alexander, MS; Gordon, A; Zutchi, T (December 1980). "Controlled trial of sulpiride in chronic schizophrenic patients". The British Journal of Psychiatry. 137: 522–529. doi:10.1192/bjp.137.6.522. PMID 7011469.
  21. ↑ Levkovitz, H; Abramovitch, Y; Nitzan, I (June 1994). "Leukocytosis related to the therapeutic dosage of sulpiride". Biological Psychiatry. 35 (12): 963. doi:10.1016/0006-3223(94)91244-0. PMID 8080896.
  22. ↑ Melzer, E; Knobel, B (December 1987). "Severe cholestatic jaundice due to sulpiride". Israel Journal of Medical Sciences. 23 (12): 1259–1260. PMID 3326861.
  23. ↑ Ohmoto, K; Yamamoto, S; Hirokawa, M (December 1999). "Symptomatic primary biliary cirrhosis triggered by administration of sulpiride". The American Journal of Gastroenterology. 94 (12): 3660–3661. doi:10.1111/j.1572-0241.1999.01634.x. PMID 10606349.
  24. ↑ Maitre M, Ratomponirina C, Gobaille S, Hodé Y, Hechler V (Apr 1994). "Displacement of [3H] gamma-hydroxybutyrate binding by benzamide neuroleptics and prochlorperazine but not by other antipsychotics". Eur J Pharmacol. 256 (2): 211–4. doi:10.1016/0014-2999(94)90248-8. PMID 7914168.
  25. ↑ Ratomponirina C, Gobaille S, Hodé Y, Kemmel V, Maitre M (Apr 1998). "Sulpiride, but not haloperidol, up-regulates gamma-hydroxybutyrate receptors in vivo and in cultured cells". Eur J Pharmacol. 346 (2–3): 331–7. doi:10.1016/S0014-2999(98)00068-5. PMID 9652377.
  26. ↑ Dong, E; Nelson, M; Grayson, DR; Costa, E; Guidotti, A (August 2008). "Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation" (PDF). Proceedings of the National Academy of Sciences of the United States of America. 105 (36): 13614–13619. doi:10.1073/pnas.0805493105. PMC 2533238. PMID 18757738.
  27. ↑ Roth, BL; Driscol, J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 19 October 2013.
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