Clozapine

Title: Clozapine
CAS Registry Number: 5786-21-0
CAS Name: 8-Chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine
Manufacturers' Codes: HF-1854
Trademarks: Clozaril (Novartis); Leponex (Novartis)
Molecular Formula: C18H19ClN4
Molecular Weight: 326.82
Percent Composition: C 66.15%, H 5.86%, Cl 10.85%, N 17.14%
Literature References: Combined serotonin (5HT2) and dopamine (D2) receptor antagonist. Prepn: FR 1334944 (1963 to Wander); Schmutz, Hunziker, US 3539573 (1970); NL 293201 (1965 to Wander), C.A. 64, 8221a (1966); Hunziker et al., Helv. Chim. Acta 50, 1588 (1967). Structure-activity studies: Schmutz et al., Chim. Ther. 2, 424 (1967). Pharmacology: Stille et al., Farmaco Ed. Prat. 26, 603 (1971). Metabolism: Gauch, Michaelis, ibid. 667. Toxicology: Lindt et al., ibid. 585. Review: A. C. Sayers, H. A. Amsler, in Pharmacological and Biochemical Properties of Drug Substances vol. 1, M. E. Goldberg, Ed. (Am. Pharm. Assoc., Washington, DC, 1977) pp 1-31. Review of pharmacology and clinical use: R. J. Baldessarini, F. R. Frankenburg, N. Engl. J. Med. 324, 746-754 (1991). Comprehensive description: M. J. McLeish et al., Anal. Profiles Drug Subs. Excip. 22, 145-184 (1993). Overview of mechanism of action: H. Y. Meltzer, J. Clin. Psychiatry 55, Suppl. B, 47-52 (1994). Clinical trial in suicide prevention in schizophrenia: H. Y. Meltzer et al., Arch. Gen. Psychiatry 60, 82 (2003). Review of safety and tolerability: J. Fitzsimons et al., Expert Opin. Drug Saf. 4, 731-744 (2005).
Properties: Yellow crystals from acetone-petr ether, mp 183-184°. Soly w/w at 25° (%): acetone >5; acetonitrile 1.9; chloroform >20; ethyl acetate >5; abs ethanol 4.0; water <0.01. pKa1 3.70; pKa2 7.60. Partition coefficient (octanol/water): 0.4 (pH 2); 600 (pH 7); 1000 (pH 7.4); 1500 (pH 8). uv max (ethanol): 215, 230, 261, 297 nm (e 27400, 25800, 16800, 10500). LD50 in mice, rats (mg/kg): 61, 58 i.v.; 199, 260 orally (Lindt).
Melting point: mp 183-184°
pKa: pKa1 3.70; pKa2 7.60
Log P: Partition coefficient (octanol/water): 0.4 (pH 2); 600 (pH 7); 1000 (pH 7.4); 1500 (pH 8)
Absorption maximum: uv max (ethanol): 215, 230, 261, 297 nm (e 27400, 25800, 16800, 10500)
Toxicity data: LD50 in mice, rats (mg/kg): 61, 58 i.v.; 199, 260 orally (Lindt)
Therap-Cat: Antipsychotic.
Keywords: Antipsychotic; Other Tricyclics; Serotonin-Dopamine Antagonist.
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Clozapine
Clozapine2DACS.svg
Clozapine3DanBS.gif
Systematic (IUPAC) name
8-Chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine
Clinical data
Trade names Clozaril
AHFS/Drugs.com monograph
MedlinePlus a691001
Pregnancy cat. C (AU) B (US)
Legal status Prescription Only (S4) (AU) -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability 60 to 70%
Metabolism Hepatic, by several CYP isozymes
Half-life 6 to 26 hours (mean value 14.2 hours in steady state conditions)
Excretion 80% in metabolized state: 30% biliary and 50% renal
Identifiers
CAS number 5786-21-0 YesY
ATC code N05AH02
PubChem CID 2818
IUPHAR ligand 38
DrugBank DB00363
ChemSpider 10442628 YesY
UNII J60AR2IKIC YesY
KEGG D00283 YesY
ChEBI CHEBI:3766 YesY
ChEMBL CHEMBL42 YesY
Chemical data
Formula C18H19ClN4 
Mol. mass 326.823 g/mol
Physical data
Melt. point 183 °C (361 °F)
Solubility in water 0.1889[1] mg/mL (20 °C)
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Clozapine is an atypical antipsychotic medication used in the treatment of schizophrenia, and is also sometimes used off-label for the treatment of bipolar disorder. The first of the atypical antipsychotics to be developed, it was first introduced in Europe in 1971, but was voluntarily withdrawn by the manufacturer in 1975 after it was shown to cause agranulocytosis, a condition involving a dangerous decrease in the number of white blood cells, that led to death in some patients. In 1989 after studies demonstrated that it was effective in treating treatment-resistant schizophrenia[2] the United States Food and Drug Administration (FDA) approved the use of clozapine solely for that use, requiring regular white blood cell and absolute neutrophil counts.[3][4] The FDA also requires clozapine to carry five black box warnings for agranulocytosis, seizures, myocarditis, for "other adverse cardiovascular and respiratory effects", and for "increased mortality in elderly patients with dementia-related psychosis."[5] In 2002 the FDA approved clozapine for reducing the risk of suicidal behavior for patients with schizophrenia.

Clozapine is usually used only in patients that have not responded to other anti-psychotic treatments due to its danger of causing agranulocytosis as well as the costs of having to have blood tests continually during treatment. It is, however, one of the very effective anti-psychotic treatment choices.[6] Patients are monitored weekly for the first six months. If there are no low counts the patient can be monitored every two weeks for an additional six months. Afterwards, the patient may qualify for every four-week monitoring.[7] Clozapine has numerous severe side effects including agranulocytosis, bowel infarction,[8] and seizures,[9] and has been associated with myocarditis[10] and diabetes[11] though those relationships have not been confirmed. Additionally, it also often causes less serious side effects such as hypersalivation and weight gain.