Carisoprodol

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Carisoprodol
Carisoprodol-2D-skeletal.png
Systematic (IUPAC) name
(RS)-2-{[(aminocarbonyl)oxy]methyl}-2-methylpentyl isopropylcarbamate
Clinical data
Trade namesSoma
AHFS/Drugs.commonograph
MedlinePlusa682578
Pregnancy cat.
  • C
Legal status
RoutesOral
Pharmacokinetic data
Protein binding60%
MetabolismHepatic (CYP2C19-mediated)
Half-life2 hours
ExcretionRenal
Identifiers
CAS number78-44-4 YesY
ATC codeM03BA02
PubChemCID 2576
DrugBankDB00395
ChemSpider2478 YesY
UNII21925K482H YesY
KEGGD00768 YesY
ChEBICHEBI:3419 YesY
ChEMBLCHEMBL1233 YesY
Chemical data
FormulaC12H24N2O4 
Mol. mass260.33 g/mol
 YesY (what is this?)  (verify)
 
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Carisoprodol
Carisoprodol-2D-skeletal.png
Systematic (IUPAC) name
(RS)-2-{[(aminocarbonyl)oxy]methyl}-2-methylpentyl isopropylcarbamate
Clinical data
Trade namesSoma
AHFS/Drugs.commonograph
MedlinePlusa682578
Pregnancy cat.
  • C
Legal status
RoutesOral
Pharmacokinetic data
Protein binding60%
MetabolismHepatic (CYP2C19-mediated)
Half-life2 hours
ExcretionRenal
Identifiers
CAS number78-44-4 YesY
ATC codeM03BA02
PubChemCID 2576
DrugBankDB00395
ChemSpider2478 YesY
UNII21925K482H YesY
KEGGD00768 YesY
ChEBICHEBI:3419 YesY
ChEMBLCHEMBL1233 YesY
Chemical data
FormulaC12H24N2O4 
Mol. mass260.33 g/mol
 YesY (what is this?)  (verify)

Carisoprodol is a centrally acting skeletal muscle relaxant. It is slightly soluble in water and freely soluble in alcohol, chloroform and acetone. The drug's solubility is practically independent of pH. Carisoprodol is manufactured and marketed in the United States by Meda Pharmaceuticals[1] under the brand name Soma, and in the United Kingdom and other countries under the brand names Sanoma and Carisoma. The drug is available by itself or mixed with aspirin, and in one preparation with codeine and caffeine, as well. Although carisoprodol has significant pharmacological activity, its benefit in therapy is likely due mostly to the meprobamate metabolite as meprobamate remains in the system significantly longer and reaches a higher peak plasma concentration than the parent drug a few hours following administration. This is further evidenced by carisoprodol's ability to maintain relevant benefits when administered 3-4 times a day despite its short half-life of only two hours.

History[edit]

On June 1, 1959 several American pharmacologists convened at Wayne State University in Detroit, Michigan to discuss a new drug. The drug, originally thought to have antiseptic properties, was found to have central muscle-relaxing properties.[2] It had been developed by Frank M. Berger at Wallace Laboratories and was named carisoprodol.

Carisoprodol was a modification of meprobamate, intended to have better muscle relaxing properties, less potential for abuse, and less risk of overdose.[3] The substitution of one hydrogen atom with an isopropyl group on one of the carbamyl nitrogens was intended to yield a molecule with new pharmacological properties.

Usage and legal status[edit]

Norway[edit]

Reports from Norway have shown carisoprodol has abuse potential[4] as a prodrug of meprobamate and/or potentiator of hydrocodone, dihydrocodeine, codeine and similar drugs. In May 2008 it was taken off the market in Norway.[5] It continues to be prescribed in North America, alongside orphenadrine and cyclobenzaprine (Flexeril). In Europe, doctors favor the safer cyclobenzaprine. In the United Kingdom, benzodiazepines are preferred, instead. All of the above, plus chlorzoxazone and tizanidine, are used in Canada.

Sweden[edit]

As of November 2007, carisoprodol (Somadril, Somadril comp.) has been taken off the market in Sweden due to problems with dependence and side effects. The agency overseeing pharmaceuticals considered other drugs used with the same indications as carisoprodol to have the same or better effects without the risks of the drug.[6]

European Union[edit]

In the EU, the European Medicines Agency issued a release recommending member states suspend marketing authorization for this product in the treatment of acute (not chronic) back pain.[7]

United States[edit]

Until December 12, 2011, when the Administrator of the Drug Enforcement Administration (DEA) issued the final ruling placing the substance carisoprodol into Schedule IV of the Controlled Substances Act (CSA), carisoprodol was not a controlled substance. The placement of carisoprodol into Schedule IV was effective January 11, 2012.[8]

Carisoprodol is available as a generic in 350 mg and, more recently, as 250 mg tablets. There is also a brand name formulation in 250 mg tablets.Compounded tablets with acetaminophen are also available. [9]

Canada[edit]

Federally, carisoprodol is a Prescription Drug (Schedule I, sub-schedule F1).[10] Provincial regulations may vary, e.g. for BC see library.bcpharmacists.org/D-Legislation_Standards. It is no longer readily available.[11] Now unscheduled, available in powder base as a Research Chemical

Indonesia[edit]

In September 2013, carisoprodol has been taken off the market in Indonesia due to problems with diversion, dependence and side effects.

Effects[edit]

Side effects[edit]

The usual dose of 350 mg is unlikely to engender prominent side effects other than somnolence, and mild to significant euphoria or dysphoria, but the euphoria is generally short lived. The medication is well tolerated and without adverse effects in the majority of patients for whom it is indicated. In some patients, however, and/or early in therapy, carisoprodol can have the full spectrum of sedative side effects and can impair the patient's ability to operate a firearm, motor vehicles, and other machinery of various types, especially when taken with medications containing alcohol, in which case an alternative medication would be considered. The intensity of the side effects of carisoprodol tends to lessen as therapy continues, as is the case with many other drugs.

The interaction of carisoprodol with essentially all opioids, and other centrally acting analgesics, but especially those of the codeine-derived subgroup of the semisynthetic class (codeine, ethylmorphine, dihydrocodeine, hydrocodone, oxycodone, nicocodeine, benzylmorphine, the various acetylated codeine derivatives including acetyldihydrocodeine, dihydroisocodeine, nicodicodeine and others) which allows the use of a smaller dose of the opioid to have a given effect[citation needed], is useful in general and especially where injury and/or muscle spasm is a large part of the problem. The potentiation effect is also useful in other pain situations and is also especially useful with opioids of the open-chain class, such as methadone, levomethadone, ketobemidone, phenadoxone and others. In recreational drug users, deaths have resulted from carelessly combining overdoses of hydrocodone and carisoprodol. Another danger of misuse of carisoprodol and opiates is the potential to aspirate while unconscious, which usually requires quick intervention and long hospital stays, if death can even be avoided.

Meprobamate and other muscle-relaxing drugs often were subjects of misuse in the 1950s and 1960s.[12][13] Overdose cases were reported as early as 1957, and have been reported on several occasions since then.[14][15][16][17][18][19][20]

Carisoprodol, meprobamate, and related drugs such as tybamate, have the potential to produce physical dependence with prolonged use. Withdrawal of the drug after extensive use may require hospitalization in medically compromised patients.

Because of potential for more severe side effects, this drug is on the list to avoid in the elderly.[21]

Recreational use and abuse[edit]

Recreational users of carisoprodol usually seek its potentially heavy sedating, relaxant, and anxiolytic effects.[22] Also, because of its potentiating effects on narcotics, it is often abused in conjunction with many opioid drugs. Also it is not detected on standard drug testing screens. On March 26, 2010 the DEA issued a Notice of Hearing on proposed rule making in respect to the placement of carisoprodol in schedule IV of the Controlled Substances Act.[23] Carisoprodol is sometimes mixed with date rape drugs.[24]

Overdose[edit]

As with other gabaminergic drugs, combination with other gabaminergic drugs, including alcohol, as well as with sedatives in general, possess a significant risk to the user in the form of overdose. Overdose symptoms are similar to those of other gabaminergics including excessive sedation, severe ataxia, amnesia, confusion, agitation, intoxication and inappropriate (potentially violent) behavior. Severe overdoses may present with respiratory depression, coma, and death. Carisoprodol is not detected on all toxicology tests which may delay diagnosis of overdose. Overdose symptoms in combination with opiates are similar but distinguished by miosis. Carisoprodol (as with its metabolite meprobamate) is particularly dangerous in combination with alcohol. Flumazenil may be used to counteract the effects of carisoprodol but its use is restricted by the potential for severe side effects and is contraindicated in mixed overdoses such as when it has been co-ingested with opiates.

Pharmacokinetics[edit]

Carisoprodol has a rapid, 30-minute onset of action, with the aforementioned effects lasting about two to six hours. It is metabolized in the liver via the cytochrome P450 oxidase isozyme CYP2C19, excreted by the kidneys and has about an eight-hour half-life. A considerable proportion of carisoprodol is metabolized to meprobamate, which is a known drug of abuse and dependence; this could account for the abuse potential of carisoprodol (meprobamate levels reach higher peak plasma levels than carisoprodol itself following administration).

Chemistry[edit]

Carisoprodol is a carbamic acid ester. It is a racemic mixture of two stereoisomers.

Carisoprodol synthesis: F.M. Berger, B.J. Ludwig, Carter Prod Inc; U.S. Patent 2,937,119 (1960).

Carisoprodol is synthesized by reacting 2-methyl-2-propylpropane-1,3-diol with 1 molar equivalent of phosgene, forming the chloroformate, from which carbamate is formed by reacting it with isopropylamine. Reacting this with either urethane or sodium cyanate gives carisoprodol.

Notes[edit]

  1. ^ Meda Pharmaceuticals Inc. of Somerset, New Jersey is the U.S. subsidiary of Meda AB of Solna, Sweden "Meda Pharmaceuticals Inc.". Retrieved June 22, 2010. 
  2. ^ Miller JG, ed. The pharmacology and clinical usefulness of carisoprodol. Detroit:Wayne State University; 1959.
  3. ^ Berger F, Kletzkin M, Ludwig B, Margolin S. The history, chemistry, and pharmacology of carisoprodol. Annals of the New York Academy of Sciences. 1959;86:90-107
  4. ^ Bramness JG, Furu K, Engeland A, . (2007). "Carisoprodol use and abuse in Norway. A pharmacoepidemiological study". Br J Clin Pharmacol 64 (2): 210–218. doi:10.1111/j.1365-2125.2007.02847.x. PMC 2000626. PMID 17298482. 
  5. ^ "Somadril trekkes fra markedet". 20 April 2008. Retrieved 12 March 2010. 
  6. ^ "Marknadsföringen av Somadril och Somadril comp rekommenderas upphöra tillfälligt". 16 Nov 2007. Retrieved 9 May 2009. 
  7. ^ "Carisprodol press release" (PDF). EMEA. Retrieved 2008-05-12. 
  8. ^ US Department of Justice (2011). "Schedules of Controlled Substances: Placement of Carisoprodol into Schedule IV" (PDF). Federal Register 76 (238): 77330–77360. Retrieved 2012-02-01. 
  9. ^ http://www.the-rheumatologist.org/details/article/1246915/High_Cost_No_Benefit.html
  10. ^ "NAPRA - Search National Drug Schedule" (ASP). National Association of Pharmacy Regulatory Authorities. 2009. Retrieved 2014-01-07. 
  11. ^ Personal communication from a pharmacist
  12. ^ Kamin I, Shaskan D. (1959). "Death due to massive overdose of meprobamate". Am J Psychiatry 115 (12): 1123–1124. PMID 13649976. 
  13. ^ Hollister LE (1983). "The pre-benzodiazepine era". J Psychoactive Drugs 15 (1–2): 9–13. doi:10.1080/02791072.1983.10472117. PMID 6350551. 
  14. ^ Gaillard Y, Billault F, Pepin G (1997). "Meprobamate overdosage: a continuing problem. Sensitive GC-MS quantitation after solid phase extraction in 19 fatal cases". Forensic Sci.Int 86 (3): 173–180. doi:10.1016/S0379-0738(97)02128-2. PMID 9180026. 
  15. ^ Allen MD, Greenblatt DJ, Noel BJ (1977). "Meprobamate overdosage: a continuing problem". Clin Toxicol 11 (5): 501–515. doi:10.3109/15563657708988216. PMID 608316. 
  16. ^ Kintz P, Tracqui A, Mangin P, Lugnier AA (1988). "Fatal meprobamate self-poisoning". Am J Forensic Med Pathol 9 (2): 139–140. doi:10.1097/00000433-198806000-00009. PMID 3381792. 
  17. ^ Eeckhout E, Huyghens L, Loef B, Maes V, Sennesael J (1988). "Meprobamate poisoning, hypotension and the Swan-Ganz catheter". Intensive Care Med 14 (4): 437–438. doi:10.1007/BF00262904. PMID 3403779. 
  18. ^ Lhoste F, Lemaire F, Rapin M (1977). "Treatment of hypotension in meprobamate poisoning". N Engl J Med 296 (17): 1004. doi:10.1056/NEJM197704282961717. PMID 846530. 
  19. ^ Bedson H (1959). "Coma due to meprobamate intoxication. Report of a case confirmed by chemical analysis". Lancet 273 (1): 288–290. doi:10.1016/S0140-6736(59)90209-0. PMID 13632000. 
  20. ^ Blumberg A, Rosett H, Dobrow A (1959). "Severe hypotension reactions following meprobamate overdosage". Ann Intern Med 51 (3): 607–612. doi:10.7326/0003-4819-51-3-607. PMID 13801701. 
  21. ^ NCQA’s HEDIS Measure: Use of High Risk Medications in the Elderly
  22. ^ "DEA Drugs & Chemicals of Concern "Carisoprodol"". Retrieved 29 April 2011. 
  23. ^ http://www.pharmcast.com/FederalRegistrar/Yr2010/Mar2010/032210/Carisoprodol032610.htm
  24. ^ Knock-Out Drugs: Their Prevalence, Modes of Action, and Means of Detection Burkhard Madea, Prof. Dr. med.*1 and Frank Mußhoff, Prof. Dr. Rer. Nat.

External links[edit]