Acamprosate

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Acamprosate
Acamprosate structure.svg
Acamprosate molecule ball.png
Clinical data
Pronunciation /əˈkæmproʊseɪt/
Trade names Campral, Campral EC
Other namesN-Acetyl homotaurine, Ca2+ bis-acetyl-homotaurinate, acamprosate calcium (JAN JP), acamprosate calcium (USAN US)
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • AU:B2
Routes of
administration 		By mouth [1]
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 11% [1]
Protein binding Negligible [1]
Metabolism Nil [1]
Elimination half-life 20 h to 33 h [1]
Excretion Kidney [1]
Identifiers
  • 3-Acetamidopropane-1-sulfonic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.071.495 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C5H11NO4S
Molar mass 181.21 g·mol−1
3D model (JSmol)
  • [Ca+2].O=C(NCCCS(=O)(=O)[O-])C.[O-]S(=O)(=O)CCCNC(=O)C
  • 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 Yes check.svgY
  • Key:BUVGWDNTAWHSKI-UHFFFAOYSA-L Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Acamprosate, sold under the brand name Campral, is a medication which reduces alcoholism cravings. [1] [5] It is thought to stabilize chemical signaling in the brain that would otherwise be disrupted by alcohol withdrawal. [6] When used alone, acamprosate is not an effective therapy for alcohol use disorder in most individuals, [7] as it only addresses withdrawal symptoms and not psychological dependence. Acamprosate is a medication that works in the brain to treat alcohol use disorder. Acamprosate works by decreasing cravings and urges to use alcohol. This allows people who take the medication to control urges to drink and help to continue to not use alcohol. Acamprosate does not help with symptoms of alcohol withdrawal. It facilitates a reduction in alcohol consumption as well as full abstinence when used in combination with psychosocial support or other drugs that address the addictive behavior. [5] [8] [9]

Contents

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. [10] Diarrhea is the most common side-effect. [11] It is unclear if use is safe during pregnancy. [12] [13]

It is on the World Health Organization's List of Essential Medicines. [14]

Medical uses

Acamprosate is useful when used along with counseling in the treatment of alcohol use disorder. [5] Over three to twelve months it increases the number of people who do not drink at all and the number of days without alcohol. [5] It appears to work as well as naltrexone for maintenance of abstinence from alcohol, [15] however naltrexone works slightly better for reducing alcohol cravings and heavy drinking, [16] and acamprosate tends to work more poorly outside of Europe where treatment services are less robust. [17] Difference in severity may also play a role. [18]

Compliance

Some struggle to take the full course of medication (2 tablets, 3 times a day), which makes acamprosate less effective. Standard support to help people take their medication involves monthly check-ins with addiction services or a GP. Research found that compared to standard support alone, extra telephone support by a pharmacist, plus financial incentives, increased the numbers who took medication as prescribed and was cost-effective. The same telephone support without financial incentives did not significantly increase the numbers taking their medication as prescribed and was less cost-effective. [19] [20]

Contraindications

Acamprosate is primarily removed by the kidneys. A dose reduction is suggested in those with moderately impaired kidneys (creatinine clearance between 30 mL/min and 50 mL/min). [1] [21] It is also contraindicated in those who have a strong allergic reaction to acamprosate calcium or any of its components. [21]

Adverse effects

The US label carries warnings about increases in 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]

Potential 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

Acamprosate calcium Acamprosate Calcium Structural Formulae.png
Acamprosate calcium

Pharmacodynamics

The pharmacodynamics of acamprosate are complex and not fully understood. [22] [23] [24]

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). [23] [7] In alcohol use disorder, one of the main mechanisms of tolerance is attributed to GABAA receptors becoming downregulated (i.e. these receptors become less sensitive to GABA). [7] 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 potentials occur through GABAA receptors), leading to neuronal over-excitation (i.e., more action potentials in the postsynaptic neuron). [7]

In addition, alcohol also inhibits the activity of N-methyl-D-aspartate receptors (NMDARs). [25] [26] 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 tremens and excitotoxic neuronal death. [27] Withdrawal from alcohol induces a surge in release of excitatory neurotransmitters like glutamate, which activates NMDARs. [28] Acamprosate reduces this glutamate surge. [29] The drug also protects cultured cells from excitotoxicity induced by ethanol withdrawal [30] and from glutamate exposure combined with ethanol withdrawal. [31]

Although its ability to correct an overabundance of glutamate is well-established, the actual molecular target behind this action is poorly known. Knowledge on this topic has seen several major revisions. [18]

GABA/NMDA hypothesis

It is originally believed to act as an NMDA receptor antagonist and positive allosteric modulator of GABAA receptors. [23] [24]

Its activity on those receptors is indirect, unlike that of most other agents used in this context. [32] An inhibition of the GABA-B system is believed to cause indirect enhancement of GABAA receptors. [32] The effects on the NMDA complex are dose-dependent; the product appears to enhance receptor activation at low concentrations, while inhibiting it when consumed in higher amounts, which counters the excessive activation of NMDA receptors in the context of alcohol withdrawal. [33]

At high concentrations, well above those that occur clinically (1 μM to 3 μM), reports of inhibition of glutamate receptor-activated responses (1 mM), enhancement of NMDA receptor function (300 μM), weak antagonization of the NMDA receptor, and partial agonism of the polyamine site of the NMDA receptor. [34] However, no direct action of acamprosate at clinically relevant concentrations has yet been reported. [34] At clinical levels, any inhibiton of the NMDA receptor probably occurs in a allosteric way. [35]

One of acamprosate's purported mechanisms of action is the enhancement of GABA signaling at GABAA receptors via positive allosteric receptor modulation. [23] [24] 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 ]

mGluR hypothesis

Two later hypothesized targets are mGluR1 and mGluR5 (10 μM). The idea originated from the fact that acamprosate blocked the neurotoxicity of an agonist of mGluR1 and mGluR5. [18] However, a subsequent study found no action of acamprosate on the mGluR1 or mGluR5 at concentrations as high as 100 μM, nor at GABAA or glycine receptors or voltage-gated sodium channels. In addition, even if the 10 μM figure is correct, it would still be clinically irrelevant. [34]

Calcium hypothesis

Spanagel et al. (2014) show that the effects of acamprosate calcium can mostly be attributed to the calcium component. Replacing calcium with sodium produces an inactive drug. Calcium chloride has a similar effect on glutamate neurotransmission. [36] [18] Moreover, calcium carbonate has a similar craving-reducing effect on human alcoholics. [37]

Synergy hypothesis

Ademar et al. (2023) report that acamprosate sodium does, in fact, enhance the effect of calcium chloride in an animal alcoholism model, and hence is not a fully inactive molecule. They also show a role of increased dopamine levels in the nucleus accumbe downstream of the glycine receptor, partly mimicking ethanol. [38]

Other effects

The product also increases the endogenous production of taurine. [33]

The substance also helps re-establish a standard sleep architecture by normalizing stage 3 and REM sleep phases, which is believed to be an important aspect of its pharmacological activity. [33]

Pharmacokinetics

Acamprosate is not metabolized by the human body. [24] Acamprosate's absolute bioavailability from oral administration is approximately 11%, [24] and its bioavailability is decreased when taken with food. [39] Following administration and absorption of acamprosate, it is excreted unchanged (i.e., as acamprosate) via the kidneys. [24] Co-administration with naltrexone increases plasma levels. [35]

Its absorption and elimination are very slow, with a tmax of 6 hours and an elimination half life of over 30 hours. [32] Steady-state levels are reached by day 5 of oral treatment. [35]

History

Acamprosate was developed by Lipha, a subsidiary of Merck KGaA. [40] 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. [40] [41]

It was approved by the US Food and Drug Administration (FDA) in July 2004. [42]

The first generic versions of acamprosate were launched in the US in 2013. [43]

As of 2015, acamprosate was in development by Confluence Pharmaceuticals as a potential treatment for fragile X syndrome. The drug was granted orphan drug designation for this use by the FDA in 2013, and by the European Medicines Agency (EMA) in 2014. [44]

Society and culture

Names

Acamprosate is the International Nonproprietary Name (INN) and the British Approved Name (BAN). Acamprosate calcium is the United States Adopted Name (USAN) and the Japanese Accepted Name (JAN). It is also technically known as N-acetylhomotaurine or as calcium acetylhomotaurinate.[ citation needed ]

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

Research

In addition to its apparent ability to help people 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). [29] [45]

It has been tried for autism, both ideopathic and fragile X syndrome-linked. [46] It appears to reduce amyloid-beta precursor protein levels. [47]

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 "Campral (acamprosate calcium) Delayed-Release Tablets Initial U.S. Approval: 2004". DailyMed. Retrieved 24 June 2024.
  2. ↑ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
  3. ↑ "Acamprosate calcium tablet, delayed release". DailyMed. 6 November 2023. Retrieved 24 June 2024.
  4. ↑ "Acamprosate calcium tablet, delayed release". DailyMed. 6 November 2023. Retrieved 24 June 2024.
  5. 1 2 3 4 Plosker GL (July 2015). "Acamprosate: A Review of Its Use in Alcohol Dependence". Drugs. 75 (11): 1255–1268. doi:10.1007/s40265-015-0423-9. PMID   26084940. S2CID   19119078.
  6. ↑ Williams SH (November 2005). "Medications for treating alcohol dependence". American Family Physician. 72 (9): 1775–1780. PMID   16300039. Archived from the original on 29 September 2007. Retrieved 29 November 2006.
  7. 1 2 3 4 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   978-0-07-182770-6. 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.
  8. ↑ Mason BJ (2001). "Treatment of alcohol-dependent outpatients with acamprosate: a clinical review". The Journal of Clinical Psychiatry. 62 (Suppl 20): 42–48. PMID   11584875.
  9. ↑ Nutt DJ, Rehm J (January 2014). "Doing it by numbers: a simple approach to reducing the harms of alcohol". Journal of Psychopharmacology. 28 (1): 3–7. doi:10.1177/0269881113512038. PMID   24399337. S2CID   36860967.
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  12. ↑ "Acamprosate (Campral) Use During Pregnancy". Drugs.com.
  13. ↑ Haber P, Lintzeris N, Proude E, Lopatko O. "Guidelines for the Treatment of Alcohol Problems" (PDF). Australian Government Department of Health and Ageing. Retrieved 20 February 2023.
  14. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
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  19. ↑ Donoghue K, Boniface S, Brobbin E, Byford S, Coleman R, Coulton S, et al. (October 2023). "Adjunctive Medication Management and Contingency Management to enhance adherence to acamprosate for alcohol dependence: the ADAM trial RCT". Health Technology Assessment. 27 (22): 1–88. doi:10.3310/DQKL6124. PMC   10641712 . PMID   37924307.
  20. ↑ "Alcohol dependence: telephone support plus financial incentives helped people take acamprosate". NIHR Evidence. 20 February 2024. doi:10.3310/nihrevidence_62108.
  21. 1 2 Saivin S, Hulot T, Chabac S, Potgieter A, Durbin P, Houin G (November 1998). "Clinical pharmacokinetics of acamprosate". Clinical Pharmacokinetics. 35 (5): 331–345. doi:10.2165/00003088-199835050-00001. PMID   9839087. S2CID   34047050.
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  23. 1 2 3 4 "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
  24. 1 2 3 4 5 6 "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 the 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 vivo studies 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.
  25. ↑ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 372. ISBN   978-0-07-148127-4.
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  35. 1 2 3 Kalk NJ, Lingford-Hughes AR (February 2014). "The clinical pharmacology of acamprosate". British Journal of Clinical Pharmacology. 77 (2): 315–323. doi:10.1111/bcp.12070. PMC   4014018 . PMID   23278595.
  36. ↑ Spanagel R, Vengeliene V, Kiefer F (2016). "Reply to: Does acamprosate really produce its anti-relapse effects via calcium? No support from the PREDICT study in human alcoholics". Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 41 (3): 661–662. doi:10.1038/npp.2015.263. PMC   4707840 . PMID   26742861.
  37. ↑ Schuster R, Winkler M, Koopmann A, Bach P, Hoffmann S, Reinhard I, et al. (2021). "Calcium Carbonate Attenuates Withdrawal and Reduces Craving: A Randomized Controlled Trial in Alcohol-Dependent Patients". European Addiction Research. 27 (5): 332–340. doi:10.1159/000512763. PMID   33567423.
  38. ↑ Ademar K, Loftén A, Nilsson M, Domi A, Adermark L, Söderpalm B, et al. (2023). "Acamprosate reduces ethanol intake in the rat by a combined action of different drug components". Scientific Reports. 13 (1): 17863. Bibcode:2023NatSR..1317863A. doi:10.1038/s41598-023-45167-3. PMC   10587117 . PMID   37857829.
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  46. ↑ Erickson CA, Wink LK, Early MC, Stiegelmeyer E, Mathieu-Frasier L, Patrick V, et al. (April 2014). "Brief report: Pilot single-blind placebo lead-in study of acamprosate in youth with autistic disorder". Journal of Autism and Developmental Disorders. 44 (4): 981–987. doi:10.1007/s10803-013-1943-3. PMID   24052275.
  47. ↑ Erickson CA, Ray B, Maloney B, Wink LK, Bowers K, Schaefer TL, et al. (December 2014). "Impact of acamprosate on plasma amyloid-β precursor protein in youth: a pilot analysis in fragile X syndrome-associated and idiopathic autism spectrum disorder suggests a pharmacodynamic protein marker". Journal of Psychiatric Research. 59: 220–228. doi:10.1016/j.jpsychires.2014.07.011. hdl:1805/11429. PMID   25300441.
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