Acamprosate

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Acamprosate
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Systematic (IUPAC) name
3-Acetamidopropane-1-sulfonic acid
Identifiers
CAS number 77337-76-9
ATC code N07BB03
PubChem CID 155434
DrugBank APRD00661
ChemSpider 136929
Chemical data
Formula C5H11NO4S 
Mol. mass 181.211 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 11%[1]
Protein binding Negligible[1]
Metabolism Nil[1]
Half-life 20 to 33 hours[1]
Excretion Renal[1]
Therapeutic considerations
Pregnancy cat. C[1] (US) B2 (AU)
Legal status POM (UK) -only (US)
Routes Oral (333mg tablets of acamprosate calcium)[1]
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Acamprosate, also known by the brand name Campral, is a drug used for treating alcohol dependence.

Acamprosate is thought to stabilize the chemical balance in the brain that would otherwise be disrupted by alcoholism, possibly by blocking glutamatergic N-methyl-D-aspartate receptors, while gamma-aminobutyric acid (GABA) type A receptors are activated.[2] Reports indicate that acamprosate only works with a combination of attending support groups and abstinence from alcohol.[3] Certain serious side effects include allergic reactions, irregular heartbeats, and low or high blood pressure, while less serious side effects include headaches, insomnia, and impotence.[4] Acamprosate should not be taken by people with kidney problems or allergies to the drug.[5]

Campral is manufactured and marketed in the United States by Forest Laboratories, while Merck KGaA markets it outside the US. It is sold as 333 mg white and odorless tablets of acamprosate calcium, which is the equivalent of 300 mg of acamprosate.[1]

Contents

Approval

While the Food and Drug Administration (FDA) in the United States approved this drug in July 2004, it has been legal in Europe since 1989. After it approved the drug, the FDA released this statement:

"While its mechanism of action is not fully understood, Campral is thought to act on the brain pathways related to alcohol abuse. Campral was demonstrated to be safe and effective by multiple placebo-controlled clinical studies involving alcohol-dependent patients who had already been withdrawn from alcohol, (i.e., detoxified). Campral proved superior to placebo in maintaining abstinence (keeping patients off alcohol consumption), as indicated by a greater percentage of acamprosate-treated subjects being assessed as continuously abstinent throughout treatment. Campral is not addicting and was generally well-tolerated in clinical trials. The most common adverse events reported for patients taking Campral included headache, diarrhea, flatulence, and nausea."[6]

Study results

The Scripps Research Institute conducted a double blind study comparing the effectiveness between using acamprosate and placebos in combination with psychotherapy. The primary end-point evaluated was percentage of alcohol-free days. The researchers concluded that acamprosate is "safe and effective".[7]

Another study was conducted by Princess Alexandra Hospital in Brisbane comparing the use of acamprosate, naltrexone, and both drugs at once in a twelve-week study.[8] Three groups of 59 patients were tested with cognitive behavioral therapy; each group with each form of treatment outlined for this study. The results are outlined below.

Percentage attending program Abstinence rates Average number of days abstinence1 Days until first breach of abstinence1

Acamprosate group 66.1% 50.8% 45.07 days 26.79 days
Naltrexone group 79.7% 66.1% 49.95 days 26.7 days
Drug combination group 83.1% 67.8% 53.58 days 37.32 days
1 This statistic applies to patients who could not remain abstinent throughout the entire 84-day period.

This study concluded that a combination of medications was generally more popular and yielded better results than using either drug alone.

Physiological action

Alcohol inhibits activity of biochemical receptors called N-methyl-D-aspartate receptors, or NMDARs, so that chronic alcohol consumption leads to the overproduction of these receptors. Thus, sudden alcohol abstinence causes these excessive numbers of NMDARs to be more active than normal and to produce the symptoms of delirium tremens and excitotoxic neuronal death.[9] Withdrawal from alcohol induces a surge in release of excitatory neurotransmitters like glutamate, which activates NMDARs.[10] Acamprosate reduces this glutamate surge.[11] The drug also protects cultured cells in excitotoxicity induced by ethanol withdrawal.[12] and by glutamate exposure combined with ethanol withdrawal.[13]

Possible neuroprotection

In addition to its apparent ability to help patients refrain from drinking, some evidence suggests that acamprosate is neuroprotective (that is, it protects neurons from damage and death caused by effects of alcohol withdrawal and possibly other insults).[11] For example, acamprosate has been found to protect cultured cells from damage induced by ischemia (inadequate blood flow).[14] Also, the drug protected infant hamsters from brain damage induced by injections of the toxin ibotenic acid, which exacerbates excitotoxicity (the harmful overactivation of glutamate receptors.[15]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 "Campral Description" (PDF). http://www.fda.gov/cder/foi/label/2004/21431lbl.pdf. Retrieved 2006-04-02. 
  2. Williams SH. (2005). "Medications for treating alcohol dependence". American Family Physician 72 (9): 1775-1780. PMID 16300039
  3. Mason BJ. "Treatment of alcohol-dependent outpatients with acamprosate: a clinical review". J Clin Psychiatry 2001;62(suppl 20):42-8. PMID 11584875
  4. "Acamprosate". drugs.com. 2005-03-25. http://www.drugs.com/mtm/acamprosate.html. Retrieved 2007-01-08. 
  5. "Acamprosate Oral - Who should not take this medication?". WebMD.com. http://www.webmd.com/drugs/drug-91488-Acamprosate+Oral.aspx?drugid=91488&drugname=Acamprosate+Oral&pagenumber=5. Retrieved 2007-01-08. 
  6. "FDA Approves New Drug for Treatment of Alcoholism". FDA Talk Paper. Food and Drug Administration. 2004-07-29. Archived from the original on 2008-01-17. http://web.archive.org/web/20080117175319/http://www.fda.gov/bbs/topics/answers/2004/ANS01302.html. Retrieved 2009-08-15. 
  7. Mason, BJ; Goodman AM, Chabac S, Lehert P (2006). [Expression error: Missing operand for > "Effect of oral acamprosate on abstinence in patients with alcohol dependence in a double-blind, placebo-controlled trial: The role of patient motivation"]. J Psychiatr Res 40 (5): 383–393. doi:10.1016/j.jpsychires.2006.02.002. PMID 16546214. 
  8. Feeney, GF; Connor JP, Young RM, Tucker J, McPherson A (2006). [Expression error: Missing operand for > "Combined acamprosate and naltrexone, with cognitive behavioural therapy is superior to either medication alone for alcohol abstinence: A single centre's experience with pharmacotherapy"]. Alcohol Alcohol 41 (3): 321–327. doi:10.1093/alcalc/agl007. PMID 16467406. 
  9. Tsai G, Coyle JT. 1998. The role of glutamatergic neurotransmission in the pathophysiology of alcoholism. Annual Review of Medicine, 49: 173-184. PMID 9509257. Retrieved on March 4, 2007.
  10. Tsai GE, Ragan P, Chang R, Chen S, Linnoila VM, Coyle JT. (1998). "Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal." American Journal of Psychiatry, 155 (6): 726-732. PMID 9619143. Retrieved on March 4, 2007.
  11. 11.0 11.1 De Witte P, Littleton J, Parot P, Koob G. (2005). "Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action." CNS Drugs 19 (6): 517-537. PMID 15963001. Retrieved on March 4, 2007.
  12. Mayer S, Harris BR, Gibson DA, Blanchard JA, Prendergast MA, Holley RC, Littleton J. (2002). "Acamprosate, MK-801, and ifenprodil inhibit neurotoxicity and calcium entry induced by ethanol withdrawal in organotypic slice cultures from neonatal rat hippocampus." Alcoholism, Clinical and Experimental Research, 26 (10): 1468-1478. PMID 12394279. Retrieved on March 4, 2007.
  13. al Qatari M, Khan S, Harris B, Littleton J. (2001). "Acamprosate is neuroprotective against glutamate-induced excitotoxicity when enhanced by ethanol withdrawal in neocortical cultures of fetal rat brain." Alcoholism, Clinical and Experimental Research 25 (9): 1276-1283. PMID 11584146. Retrieved on March 4, 2007.
  14. Engelhard, K; Werner C, Lu H, Mollenberg O, Zieglgansberger W, Kochs E (2006). [Expression error: Missing operand for > "The neuroprotective effect of the glutamate antagonist acamprosate following experimental cerebral ischemia. A study with the lipid peroxidase inhibitor u-101033e"]. Anaesthesist 49 (9): 816–821. PMID 11076270. 
  15. Adde-Michel, C; Hennebert O, Laudenbach V, Marret S, Leroux P (2005). [Expression error: Missing operand for > "Effect of acamprosate on neonatal excitotoxic cortical lesions in in utero alcohol-exposed hamsters"]. Neuroscience Letters 374 (2): 109–112. doi:10.1016/j.neulet.2004.10.037. PMID 15644274. 

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