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, 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. 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]

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] [18] It is also contraindicated in those who have a strong allergic reaction to acamprosate calcium or any of its components. [18]

Adverse effects

The US label carries warnings about increases 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]

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; [19] [20] [21] however, it is believed to act as an NMDA receptor antagonist and positive allosteric modulator of GABAA receptors. [20] [21]

Its activity on those receptors is indirect, unlike that of most other agents used in this context. [22] An inhibition of the GABA-B system is believed to cause indirect enhancement of GABAA receptors. [22] 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. [23]

The product also increases the endogenous production of taurine. [23]

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). [20] [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; [7] 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). One of acamprosate's mechanisms of action is the enhancement of GABA signaling at GABAA receptors via positive allosteric receptor modulation. [20] [21] 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). [24] [25] 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. [26] Withdrawal from alcohol induces a surge in release of excitatory neurotransmitters like glutamate, which activates NMDARs. [27] Acamprosate reduces this glutamate surge. [28] The drug also protects cultured cells from excitotoxicity induced by ethanol withdrawal [29] and from glutamate exposure combined with ethanol withdrawal. [30]

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. [23]

Pharmacokinetics

Acamprosate is not metabolized by the human body. [21] Acamprosate's absolute bioavailability from oral administration is approximately 11%, [21] and its bioavailability is decreased when taken with food. [31] Following administration and absorption of acamprosate, it is excreted unchanged (i.e., as acamprosate) via the kidneys. [21]

Its absorption and elimination are very slow, with a tmax of 6 hours and an elimination half life of over 30 hours. [22]

History

Acamprosate was developed by Lipha, a subsidiary of Merck KGaA. [32] 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. [32] [33]

It was approved by the US Food and Drug Administration (FDA) in July 2004. [34]

The first generic versions of acamprosate were launched in the US in 2013. [35]

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. [36]

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). [28] [37]

Related Research Articles

<span class="mw-page-title-main">Alcoholism</span> Problematic excessive alcohol consumption

Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World Health Organization (WHO) estimated there were 283 million people with alcohol use disorders worldwide as of 2016. The term alcoholism was first coined in 1852, but alcoholism and alcoholic are sometimes considered stigmatizing and to discourage seeking treatment, so diagnostic terms such as alcohol use disorder or alcohol dependence are often used instead in a clinical context.

<span class="mw-page-title-main">Benzodiazepine</span> Class of depressant drugs

Benzodiazepines, colloquially called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, insomnia, and seizures. The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955, and was made available in 1960 by Hoffmann–La Roche, which followed with the development of diazepam (Valium) three years later, in 1963. By 1977, benzodiazepines were the most prescribed medications globally; the introduction of selective serotonin reuptake inhibitors (SSRIs), among other factors, decreased rates of prescription, but they remain frequently used worldwide.

<span class="mw-page-title-main">Diazepam</span> Benzodiazepine sedative

Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, and restless legs syndrome. It may also be used to cause memory loss during certain medical procedures. It can be taken orally, as a suppository inserted into the rectum, intramuscularly, intravenously or used as a nasal spray. When injected intravenously, effects begin in one to five minutes and last up to an hour. When taken by mouth, effects begin after 15 to 60 minutes.

<span class="mw-page-title-main">Alprazolam</span> Benzodiazepine medication

Alprazolam, sold under the brand name Xanax and others, is a fast-acting, potent tranquilizer of moderate duration within the triazolobenzodiazepine group of chemicals called benzodiazepines. Alprazolam is most commonly prescribed in the management of anxiety disorders, especially panic disorder and generalized anxiety disorder (GAD). Other uses include the treatment of chemotherapy-induced nausea, together with other treatments. GAD improvement occurs generally within a week. Alprazolam is generally taken orally.

Colloquially known as "downers", depressants or central nervous system (CNS) depressants are drugs that lower neurotransmission levels, decrease the electrical activity of brain cells, or reduce arousal or stimulation in various areas of the brain. Some specific depressants do influence mood, either positively or negatively, but depressants often have no clear impact on mood. In contrast, stimulants, or "uppers", increase mental alertness, making stimulants the opposite drug class from depressants. Antidepressants are defined by their effect on mood, not on general brain activity, so they form an orthogonal category of drugs.

<span class="mw-page-title-main">Baclofen</span> Medication for muscle movement disorders

Baclofen, sold under the brand name Lioresal among others, is a medication used to treat muscle spasticity such as from a spinal cord injury or multiple sclerosis. It may also be used for hiccups and muscle spasms near the end of life, and off-label to treat alcohol use disorder or opioid withdrawal symptoms. It is taken orally or by intrathecal pump. It is also sometimes used transdermally in combination with gabapentin and clonidine prepared at a compounding pharmacy.

Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certain medications such as benzodiazepines, opioids, stimulants, antiepileptics and antidepressants, as well as the recreational misuse of drugs such as alcohol, opioids and benzodiazepines. The higher the dose used, the greater the duration of use, and the earlier age use began are predictive of worsened physical dependence and thus more severe withdrawal syndromes. Acute withdrawal syndromes can last days, weeks or months. Protracted withdrawal syndrome, also known as post-acute-withdrawal syndrome or "PAWS", is a low-grade continuation of some of the symptoms of acute withdrawal, typically in a remitting-relapsing pattern, often resulting in relapse and prolonged disability of a degree to preclude the possibility of lawful employment. Protracted withdrawal syndrome can last for months, years, or depending on individual factors, indefinitely. Protracted withdrawal syndrome is noted to be most often caused by benzodiazepines. To dispel the popular misassociation with addiction, physical dependence to medications is sometimes compared to dependence on insulin by persons with diabetes.

Neuropharmacology is the study of how drugs affect function in the nervous system, and the neural mechanisms through which they influence behavior. There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior (neuropsychopharmacology), including the study of how drug dependence and addiction affect the human brain. Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, with the overall goal of developing drugs that have beneficial effects on neurological function. Both of these fields are closely connected, since both are concerned with the interactions of neurotransmitters, neuropeptides, neurohormones, neuromodulators, enzymes, second messengers, co-transporters, ion channels, and receptor proteins in the central and peripheral nervous systems. Studying these interactions, researchers are developing drugs to treat many different neurological disorders, including pain, neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, psychological disorders, addiction, and many others.

<span class="mw-page-title-main">Clobazam</span> Benzodiazepine class medication

Clobazam, sold under the brand names Frisium, Onfi and others, is a benzodiazepine class medication that was patented in 1968. Clobazam was first synthesized in 1966 and first published in 1969. Clobazam was originally marketed as an anxioselective anxiolytic since 1970, and an anticonvulsant since 1984. The primary drug-development goal was to provide greater anxiolytic, anti-obsessive efficacy with fewer benzodiazepine-related side effects.

<span class="mw-page-title-main">Clorazepate</span> Benzodiazepine medication

Clorazepate, sold under the brand name Tranxene among others, is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. Clorazepate is an unusually long-lasting benzodiazepine and serves as a prodrug for the equally long-lasting desmethyldiazepam, which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.

<span class="mw-page-title-main">Bretazenil</span> Chemical compound

Bretazenil (Ro16-6028) is an imidazopyrrolobenzodiazepine anxiolytic drug which is derived from the benzodiazepine family, and was invented in 1988. It is most closely related in structure to the GABA antagonist flumazenil, although its effects are somewhat different. It is classified as a high-potency benzodiazepine due to its high affinity binding to benzodiazepine binding sites where it acts as a partial agonist. Its profile as a partial agonist and preclinical trial data suggests that it may have a reduced adverse effect profile. In particular bretazenil has been proposed to cause a less strong development of tolerance and withdrawal syndrome. Bretazenil differs from traditional 1,4-benzodiazepines by being a partial agonist and because it binds to α1, α2, α3, α4, α5 and α6 subunit containing GABAA receptor benzodiazepine receptor complexes. 1,4-benzodiazepines bind only to α1, α2, α3 and α5GABAA benzodiazepine receptor complexes.

<span class="mw-page-title-main">Chlordiazepoxide</span> Benzodiazepine class sedative and hypnotic medication

Chlordiazepoxide, trade name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol, benzodiazepines, and other drugs.

<span class="mw-page-title-main">Benzodiazepine withdrawal syndrome</span> Signs and symptoms due to benzodiazepine discontinuation in physically dependent persons

Benzodiazepine withdrawal syndrome is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines as prescribed develops a physical dependence on them and then reduces the dose or stops taking them without a safe taper schedule.

<span class="mw-page-title-main">Abecarnil</span> Chemical compound

Abecarnil (ZK-112,119) is an anxiolytic drug from the β-Carboline family. It is one of a relatively recently developed class of medicines known as the nonbenzodiazepines, which have similar effects to the older benzodiazepine group, but with quite different chemical structures. It is a partial agonist acting selectively at the benzodiazepine site of the GABAA receptor.

<span class="mw-page-title-main">GABRA2</span> Protein in humans

Gamma-aminobutyric acid receptor subunit alpha-2 is a protein in humans that is encoded by the GABRA2 gene.

<span class="mw-page-title-main">Alcohol withdrawal syndrome</span> Medical condition

Alcohol withdrawal syndrome (AWS) is a set of symptoms that can occur following a reduction in alcohol use after a period of excessive use. Symptoms typically include anxiety, shakiness, sweating, vomiting, fast heart rate, and a mild fever. More severe symptoms may include seizures, and delirium tremens (DTs); which can be fatal in untreated patients. Symptoms start at around 6 hours after last drink. Peak incidence of seizures occurs at 24-36 hours and peak incidence of delirium tremens is at 48-72 hours.

<span class="mw-page-title-main">Short-term effects of alcohol consumption</span> Overview of the short-term effects of the consumption of alcoholic beverages

The short-term effects of alcohol consumption range from a decrease in anxiety and motor skills and euphoria at lower doses to intoxication (drunkenness), to stupor, unconsciousness, anterograde amnesia, and central nervous system depression at higher doses. Cell membranes are highly permeable to alcohol, so once it is in the bloodstream, it can diffuse into nearly every cell in the body.

<span class="mw-page-title-main">Benzodiazepine dependence</span> Medical condition

Benzodiazepine dependence defines a situation in which one has developed one or more of either tolerance, withdrawal symptoms, drug seeking behaviors, such as continued use despite harmful effects, and maladaptive pattern of substance use, according to the DSM-IV. In the case of benzodiazepine dependence, the continued use seems to be typically associated with the avoidance of unpleasant withdrawal reaction rather than with the pleasurable effects of the drug. Benzodiazepine dependence develops with long-term use, even at low therapeutic doses, often without the described drug seeking behavior and tolerance.

Kindling due to substance withdrawal is the neurological condition which results from repeated withdrawal episodes from sedative–hypnotic drugs such as alcohol and benzodiazepines.

Iomazenil Chemical compound

Iomazenil is an antagonist and partial inverse agonist of benzodiazepine and a potential treatment for alcohol use disorder. The compound was introduced in 1989 by pharmaceutical company Hoffmann-La Roche as an Iodine-123-labelled SPECT tracer for imaging benzodiazepine receptors in the brain. Iomazenil is an analogue of flumazenil (Ro15-1788).

References

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    Marketed formulations contain acamprosate calcium
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