Acamprosate calcium

3-acetamidopropane-1-sulfonic acid

Acamprosate, sold under the brand name Campral, is a medication used along with counselling to treat alcohol dependence.^[1][2]

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.^[3] When used alone, acamprosate is not an effective therapy for alcoholism in most individuals;^[4] 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.^[2][5][6]

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.^[7] Diarrhea is the most common side-effect.^[8] Acamprosate should not be taken by people with kidney problems or allergies to the drug.^[9]

Until it became a generic in the United States, Campral was manufactured and marketed in the United States by Forest Laboratories, while Merck KGaA markets it outside the US.

Medical uses

Acamprosate is useful when used along with counselling in the treatment of alcohol dependence.^[2] Over three to twelve months it increases the number of people who do not drink at all and the number of days without alcohol.^[2] It appears to work as well as naltrexone.^[2]

Contraindications

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).^[1][10] It is also contraindicated in those who have a strong allergic reaction to acamprosate calcium or any of its components.^[10]

Adverse effects

The US label carries warnings about increased of suicidal behavior, major depressive disorder, and kidney failure.^[1]

Adverse effects that caused people to stop taking the drug in clinical trials included diarrhea, nausea, depression, and anxiety.^[1]

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.^[1]

Pharmacology

Pharmacodynamics

The pharmacodynamics of acamprosate is complex and not fully understood;^[11][12][13] however, it is believed to act as an NMDA receptor antagonist and positive allosteric modulator of GABA_A receptors.^[12][13]

Ethanol and benzodiazepines act on the central nervous system by binding to the GABA_A receptor, increasing the effects of the inhibitory neurotransmitter GABA (i.e., they act as positive allosteric modulators at these receptors).^[12][4] In chronic alcohol abuse, one of the main mechanisms of tolerance is attributed to GABA_A receptors becoming downregulated (i.e. these receptors become less sensitive to GABA).^[4] When alcohol is no longer consumed, these down-regulated GABA_A receptor complexes are so insensitive to GABA that the typical amount of GABA produced has little effect, leading to physical withdrawal symptoms;^[4] since GABA normally inhibits neural firing, GABA_A receptor desensitization results in unopposed excitatory neurotransmission (i.e., fewer inhibitory postsynaptic potentialsoccur through GABA_A 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 GABA_A receptors via positive allosteric receptor modulation.^[12][13] 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).^[14][15] 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.^[16] Withdrawal from alcohol induces a surge in release of excitatory neurotransmitters like glutamate, which activates NMDARs.^[17] Acamprosate reduces this glutamate surge.^[18] The drug also protects cultured cells from excitotoxicity induced by ethanol withdrawal^[19] and from glutamate exposure combined with ethanol withdrawal.^[20]

Pharmacokinetics

Acamprosate is not metabolized by the human body.^[13] Acamprosate’s absolute bioavailability from oral administration is approximately 11%.^[13] Following administration and absorption of acamprosate, it is excreted unchanged (i.e., as acamprosate) via the kidneys.^[13]

History

Acamprosate was developed by Lipha, a subsidiary of Merck KGaA.^[21] and was approved for marketing in Europe in 1989.^{[citation needed]}

In October 2001 Forest Laboratories acquired the rights to market the drug in the US.^[21][22]

It was approved by the FDA in July 2004.^[23]

The first generic versions of acamprosate were launched in the US in 2013.^[24]

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.^[25]

Society and culture

“Acamprosate” is the INN and BAN for this substance. “Acamprosate calcium” is the USAN and JAN. It is also technically known as N-acetylhomotaurine or as calcium acetylhomotaurinate.

It is sold under the brand name Campral.^[1]

Research

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).^[18][26]

References

 Acamprosate calcium

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-
156-87-6	C3H9NO	3-amino-1-propanol	1-Propanol, 3-amino-

Trade Names

Country	Trade Name	Vendor	Annotation
D	Campral	Merck
F	Aotal	Merck Lipha
GB	Campral EC	Merck Serono
USA	Campral	Forest

Formulations

• tabl. 50 mg, 100 mg, 333 mg

References

• • 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).

Acamprosate

Clinical data
Trade names	Campral EC
Synonyms	N-Acetyl homotaurine, Acamprosate calcium (JAN JP), Acamprosate calcium (USANUS)
Pregnancy category	C[1]> (US) B2 (AU)
Routes of administration	Oral [1]
ATC code	N07BB03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	11%[1]
Protein binding	Negligible[1]
Metabolism	Nil[1]
Elimination half-life	20 h to 33 h[1]
Excretion	Renal[1]
Identifiers
IUPAC name[show]
CAS Number	77337-76-9
PubChem CID	155434
IUPHAR/BPS	7106
DrugBank	DB00659
ChemSpider	136929
UNII	N4K14YGM3J
KEGG	D07058
ChEBI	CHEBI:51042
ChEMBL	CHEMBL1201293
ECHA InfoCard	100.071.495
Chemical and physical data
Formula	C5H11NO4S
Molar mass	181.211 g/mol
3D model (JSmol)	Interactive image
SMILES[hide] [Ca+2].O=C(NCCCS(=O)(=O)[O-])C.[O-]S(=O)(=O)CCCNC(=O)C
InChI[hide] InChI=1S/2C5H11NO4S.Ca/c2*1-5(7)6-3-2-4-11(8,9)10;/h2*2-4H2,1H3,(H,6,7)(H,8,9,10);/q;;+2/p-2  Key:BUVGWDNTAWHSKI-UHFFFAOYSA-L
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////////////////Acamprosate calcium, アカンプロセート

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CC(=O)NCCCS(=O)(=O)[O-].CC(=O)NCCCS(=O)(=O)[O-].[Ca+2]