|Molecular Weight:||400.474 g/mol|
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 glutaminergic N-methyl-D-aspartate receptors, while gamma-aminobutyric acid type A receptors are activated. Reports indicate that acamprosate only works with a combination of attending support groups and abstinence from alcohol. 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. Acamprosate should not be taken by people with kidney problems or allergies to the drug.
Acamprosate is thought to stabilize chemical signaling in the brain that would otherwise be disrupted by alcohol withdrawal. When used alone, acamprosate is not an effective therapy for alcoholism in most individuals; however, studies have found that acamprosate works best when used in combination with psychosocial support since it facilitates a reduction in alcohol consumption as well as full abstinence.
Serious side effects include allergic reactions, abnormal heart rhythms, and low or high blood pressure, while less serious side effects include headaches, insomnia, and impotence. Diarrhea is the most common side-effect. Acamprosate should not be taken by people with kidney problems or allergies to the drug.
Acamprosate is useful when used along with counselling in the treatment of alcohol dependence. Over three to twelve months it increases the number of people who do not drink at all and the number of days without alcohol. It appears to work as well as naltrexone.
Acamprosate is primarily removed by the kidneys and should not be given to people with severely impaired kidneys (creatinine clearance less than 30 mL/min). A dose reduction is suggested in those with moderately impaired kidneys (creatinine clearancebetween 30 mL/min and 50 mL/min). It is also contraindicated in those who have a strong allergic reaction to acamprosate calcium or any of its components.
Adverse effects that caused people to stop taking the drug in clinical trials included diarrhea, nausea, depression, and anxiety.
Other frequent adverse effects include headache, stomach pain, back pain, muscle pain, joint pain, chest pain, infections, flu-like symptoms, chills, heart palpitations, high blood pressure, fainting, vomiting, upset stomach, constipation, increased appetite, weight gain, edema, sleepiness, decreased sex drive, impotence, forgetfulness, abnormal thinking, abnormal vision, distorted sense of taste, tremors, runny nose, coughing, difficulty breathing, sore throat, bronchitis, and rashes.
The pharmacodynamics of acamprosate is complex and not fully understood; however, it is believed to act as an NMDA receptor antagonist and positive allosteric modulator of GABAA receptors.
Ethanol and benzodiazepines act on the central nervous system by binding to the GABAA receptor, increasing the effects of the inhibitory neurotransmitter GABA (i.e., they act as positive allosteric modulators at these receptors). In chronic alcohol abuse, one of the main mechanisms of tolerance is attributed to GABAA receptors becoming downregulated (i.e. these receptors become less sensitive to GABA). When alcohol is no longer consumed, these down-regulated GABAA receptor complexes are so insensitive to GABA that the typical amount of GABA produced has little effect, leading to physical withdrawal symptoms; since GABA normally inhibits neural firing, GABAA receptor desensitization results in unopposed excitatory neurotransmission (i.e., fewer inhibitory postsynaptic potentialsoccur through GABAA receptors), leading to neuronal over-excitation (i.e., more action potentials in the postsynaptic neuron). One of acamprosate’s mechanisms of action is the enhancement of GABA signaling at GABAA receptors via positive allosteric receptor modulation. It has been purported to open the chloride ion channel in a novel way as it does not require GABA as a cofactor, making it less liable for dependence than benzodiazepines. Acamprosate has been successfully used to control tinnitus, hyperacusis, ear pain and inner ear pressure during alcohol use due to spasms of the tensor tympani muscle.[medical citation needed]
In addition, alcohol also inhibits the activity of N-methyl-D-aspartate receptors (NMDARs). Chronic alcohol consumption leads to the overproduction (upregulation) of these receptors. Thereafter, sudden alcohol abstinence causes the excessive numbers of NMDARs to be more active than normal and to contribute to the symptoms of delirium tremensand excitotoxic neuronal death. Withdrawal from alcohol induces a surge in release of excitatory neurotransmitters like glutamate, which activates NMDARs. Acamprosate reduces this glutamate surge. The drug also protects cultured cells from excitotoxicity induced by ethanol withdrawal and from glutamate exposure combined with ethanol withdrawal.
Acamprosate is not metabolized by the human body. Acamprosate’s absolute bioavailability from oral administration is approximately 11%. Following administration and absorption of acamprosate, it is excreted unchanged (i.e., as acamprosate) via the kidneys.
It was approved by the FDA in July 2004.
The first generic versions of acamprosate were launched in the US in 2013.
As of 2015 acamprosate was in development by Confluence Pharmaceuticals as a potential treatment for fragile X syndrome. The drug was granted orphan status for this use by the FDA in 2013 and by the EMA in 2014.
Society and culture
It is sold under the brand name Campral.
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 the effects of alcohol withdrawal, and possibly other causes of neurotoxicity).
- “Campral label” (PDF). FDA. January 2012. Retrieved 27 November2017. For label updates see FDA index page for NDA 021431
- Plosker, GL (July 2015). “Acamprosate: A Review of Its Use in Alcohol Dependence”. Drugs. 75 (11): 1255–68. doi:10.1007/s40265-015-0423-9. PMID 26084940.
- Williams, SH. (2005). “Medications for treating alcohol dependence”. American Family Physician. 72 (9): 1775–1780. PMID 16300039.
- Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). “Chapter 16: Reinforcement and Addictive Disorders”. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. ISBN 9780071827706.
It has been hypothesized that long-term ethanol exposure alters the expression or activity of specific GABAA receptor subunits in discrete brain regions. Regardless of the underlying mechanism, ethanol-induced decreases in GABAA receptor sensitivity are believed to contribute to ethanol tolerance, and also may mediate some aspects of physical dependence on ethanol. … Detoxification from ethanol typically involves the administration of benzodiazepines such as chlordiazepoxide, which exhibit cross-dependence with ethanol at GABAA receptors (Chapters 5 and 15). A dose that will prevent the physical symptoms associated with withdrawal from ethanol, including tachycardia, hypertension, tremor, agitation, and seizures, is given and is slowly tapered. Benzodiazepines are used because they are less reinforcing than ethanol among alcoholics. Moreover, the tapered use of a benzodiazepine with a long half-life makes the emergence of withdrawal symptoms less likely than direct withdrawal from ethanol. … Unfortunately, acamprosate is not adequately effective for most alcoholics.
- Mason, BJ (2001). “Treatment of alcohol-dependent outpatients with acamprosate: a clinical review”. The Journal of Clinical Psychiatry. 62 Suppl 20: 42–8. PMID 11584875.
- Nutt, DJ (2014). “Doing it by numbers: A simple approach to reducing the harms of alcohol”. JOURNAL OF PSYCHOPHARMACOLOGY. 28: 3–7. doi:10.1177/0269881113512038. PMID 24399337.
- “Acamprosate”. drugs.com. 2005-03-25. Archived from the original on 22 December 2006. Retrieved 2007-01-08.
- Wilde, MI; Wagstaff, AJ (June 1997). “Acamprosate. A review of its pharmacology and clinical potential in the management of alcohol dependence after detoxification”. Drugs. 53(6): 1038–53. doi:10.2165/00003495-199753060-00008. PMID 9179530.
- “Acamprosate Oral – Who should not take this medication?”. WebMD.com. Retrieved 2007-01-08.
- Saivin, S; Hulot, T; Chabac, S; Potgieter, A; Durbin, P; Houin, G (Nov 1998). “Clinical Pharmacokinetics of Acamprosate”. Clinical Pharmacokinetics. 35 (5): 331–345. doi:10.2165/00003088-199835050-00001. PMID 9839087.
- “Acamprosate: Biological activity”. IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 26 November 2017.
Due to the complex nature of this drug’s MMOA, and a paucity of well defined target affinity data, we do not map to a primary drug target in this instance.
- “Acamprosate: Summary”. IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 26 November 2017.
Acamprosate is a NMDA glutamate receptor antagonist and a positive allosteric modulator of GABAA receptors.
Marketed formulations contain acamprosate calcium
- “Acamprosate”. DrugBank. University of Alberta. 19 November 2017. Retrieved 26 November 2017.
Acamprosate is thought to stabilize the chemical balance in the brain that would otherwise be disrupted by alcoholism, possibly by blocking glutaminergic N-methyl-D-aspartate receptors, while gamma-aminobutyric acid type A receptors are activated. … The mechanism of action of acamprosate in maintenance of alcohol abstinence is not completely understood. Chronic alcohol exposure is hypothesized to alter the normal balance between neuronal excitation and inhibition. in vitro and in vivostudies in animals have provided evidence to suggest acamprosate may interact with glutamate and GABA neurotransmitter systems centrally, and has led to the hypothesis that acamprosate restores this balance. It seems to inhibit NMDA receptors while activating GABA receptors.
- Malenka RC, Nestler EJ, Hyman SE (2009). “Chapter 15: Reinforcement and Addictive Disorders”. In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 372. ISBN 9780071481274.
- Möykkynen T, Korpi ER (July 2012). “Acute effects of ethanol on glutamate receptors”. Basic & Clinical Pharmacology & Toxicology. 111 (1): 4–13. doi:10.1111/j.1742-7843.2012.00879.x. PMID 22429661.
- Tsai, G; Coyle, JT (1998). “The role of glutamatergic neurotransmission in the pathophysiology of alcoholism”. Annual Review of Medicine. 49: 173–84. doi:10.1146/annurev.med.49.1.173. PMID 9509257.
- Tsai, GE; Ragan, P; Chang, R; Chen, S; Linnoila, VM; Coyle, JT (1998). “Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal”. The American Journal of Psychiatry. 155 (6): 726–32. doi:10.1176/ajp.155.6.726. PMID 9619143.
- 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): 517–37. doi:10.2165/00023210-200519060-00004. PMID 15963001.
- 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): 1468–78. doi:10.1097/00000374-200210000-00003. PMID 12394279.
- 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): 1276–83. doi:10.1111/j.1530-0277.2001.tb02348.x. PMID 11584146.
- Berfield, Susan (27 May 2002). “A CEO and His Son”. Bloomberg Businessweek.
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- Use:alcohol-abuse deterrent
- Chemical name:3-(acetylamino)-1-propanesulfonic acid calcium salt (2:1)
- MW:400.49 g/mol
- LD50:>10 g/kg (M, p.o.)
- MW:181.21 g/mol
Substances Referenced in Synthesis Path
|CAS-RN||Formula||Chemical Name||CAS Index Name|
|3687-18-1||C3H9NO3S||3-aminopropane-1-sulfonic acid||1-Propanesulfonic acid, 3-amino-|
|GB||Campral EC||Merck Serono|
- tabl. 50 mg, 100 mg, 333 mg
- DE 3 019 350 (Lab. Meram; appl. 21.5.1980; F-prior. 23.5.1979).
- US 4 355 043 (Lab. Meram; 19.10.1982; F-prior. 23.5.1979).
synthesis of 3-aminopropane-1-sulfonic acid:
- Fujii, A. et al.: J. Med. Chem. (JMCMAR) 18, 502 (1975).
- JP 46 002 012 (Kowa; appl. 19.1.1971).
- WO 8 400 958 (Mitsui; appl. 15.3.1984; J-prior. 7.9.1982, 19.7.1983, 8.9.1982).
|Trade names||Campral EC|
|Synonyms||N-Acetyl homotaurine, Acamprosate calcium (JAN JP), Acamprosate calcium (USANUS)|
|Elimination half-life||20 h to 33 h|
|Chemical and physical data|
|Molar mass||181.211 g/mol|
|3D model (JSmol)|
|(what is this?)|
////////////////Acamprosate calcium, アカンプロセート