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Alverine
Alverine
Alverine
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Alverine
Clinical data
AHFS/Drugs.comInternational Drug Names
ATC code
Legal status
Legal status
Identifiers
  • N-Ethyl-3-phenyl-N-(3-phenylpropyl)propan-1-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.005.240 Edit this at Wikidata
Chemical and physical data
FormulaC20H27N
Molar mass281.443 g·mol−1
3D model (JSmol)
  • c1ccccc1CCCN(CC)CCCc2ccccc2
  • InChI=1S/C20H27N/c1-2-21(17-9-15-19-11-5-3-6-12-19)18-10-16-20-13-7-4-8-14-20/h3-8,11-14H,2,9-10,15-18H2,1H3 checkY
  • Key:ZPFXAOWNKLFJDN-UHFFFAOYSA-N checkY
  (verify)

Alverine is a drug used for functional gastrointestinal disorders. Alverine is a smooth muscle relaxant. Smooth muscle is a type of muscle that is not under voluntary control; it is the muscle present in places such as the gut and uterus.

Adverse effects

[edit]

The side effects of Alverine include:[1][2]

  • Difficulties in breathing or shortness of breath, wheezing, swelling of the face or other parts of the body (associated with serious allergic reaction)
  • Yellowing of the whites of the eyes and the skin, due to liver inflammation
  • A feeling of nausea or dizziness
  • Headache
  • Minor allergic reaction (skin rash/itching)

It was reported that alverine may induce toxic hepatitis.[3][4]

Mechanism of action

[edit]

Alverine acts directly on the muscle in the gut, causing it to relax. Alverine is also a 5HT1A antagonist, which reduces rectal hypersensitivity.[5] This prevents the muscle spasms which occur in the gut in conditions such as irritable bowel syndrome and diverticular disease.[6] Diverticular disease is a condition in which small pouches form in the gut lining. These pouches can trap particles of food and become inflamed and painful. In irritable bowel syndrome, the normal activity of the gut muscle is lost. The muscle spasms result in symptoms such as abdominal pain and bloating, constipation or diarrhoea. By relaxing the gut muscle, alverine citrate relieves the symptoms of this condition. Alverine also relaxes the smooth muscle in the womb (uterus). It is therefore also used to treat painful menstruation, which is caused by muscle spasms in the uterus (dysmenorrhea).

Alverine capsules[7] are now available in the market. There are two strengths of capsule - 60 mg and 120 mg. The common dosage for adults and children over 12 years is 60–120 mg taken one, two or three a day, either before or after meals. Alverine is not suitable for those aged under 12 years. Women who are pregnant or breast-feeding should follow the instruction of doctors for the drug.

Total synthesis

[edit]

One way to synthesis alverine is conducted using phenylpropanol, which is brominated using sodium bromide in concentrated sulfuric acid heated to reflux, yielding (3-bromopropyl)benzene. Then, in an ice bath, it is reacted with ethylamine, yielding N-ethyl-3-phenylpropan-1-amine. Then, it is reacted with (3-bromopropyl)benzene again in alkaline pH obtained using sodium hydroxide, finally yielding alverine.[8]

Alverine synthesis[8]

Another way uses (E)-1,3-dichloropropene as a starting substrate. It is reacted with ethylamine hydrochloride and potassium carbonate in anhydrous acetonitrile, yielding (2E)-3-chloro-N-[(2E)-3-chloroprop-2-en-1-yl]-N-ethylprop-2-en-1-amine. Then, chlorine atoms are substituted with phenyl substituents in a Gringard reaction using phenylmagnesium bromide, tris(acetylacetonato)iron(III) (Fe(acac)3) as a catalyst and tetramethylethylenediamine (TMEDA) in dry tetrahydrofuran, yielding an unsaturated analogue of alverine, which is then hydrogenated using a palladium on carbon catalyst in alkaline ethanol, yielding alverine.[9]

Alternative alverine synthesis[9]

Development and marketing

[edit]

A combination of alverine citrate and simeticone (ACS) for irritable bowel syndrome therapy were compared with placebo in a phase IV clinical trial.[10] At week 4, the alverine citrate and simeticone group had lower VAS (Visual Analogue Scale) scores for abdominal pain/discomfort (median: 40 mm vs. 50 mm, P = 0.047) and higher responder rate (46.8% vs. 34.3%, OR = 1.3; P = 0.01) as compared with the placebo group.[11]

The drug was firstly authorized for marketing on 03/06/2014. The marketing authorisation holder is Dr. Reddy's Laboratories (UK) Ltd.[12]

References

[edit]
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Alverine

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from Grokipedia
Alverine citrate is an medication classified as a relaxant, primarily used to relieve abdominal cramps, spasms, and associated with gastrointestinal conditions such as (IBS), , and painful periods (). It is typically administered orally in capsule form, with a standard dose of 60 to 120 mg up to three times daily, and is available under brand names like Audmonal and Spasmonal in various countries. Chemically, alverine is a tertiary with the molecular formula C₂₀H₂₇N, acting as N,N-bis(3-phenylpropyl)ethan, and its citrate salt form enhances for pharmaceutical use. The drug exerts its effects by inhibiting calcium influx into cells, thereby suppressing contractions induced by stimuli like or , while potentially enhancing spontaneous muscle activity at lower concentrations. This mechanism makes it particularly effective for managing symptoms of functional bowel disorders without significantly affecting gastrointestinal motility or secretion. Common side effects of alverine include , , and gastrointestinal upset, though it is generally well-tolerated with a low incidence of adverse reactions; allergic responses such as skin rash or itching may occur rarely. It is contraindicated in patients with paralytic and should be used cautiously during or due to limited data on fetal safety. Recent studies have also explored its adjunctive role in procedures like , where it may reduce spasms and improve patient comfort when combined with simethicone.

Medical uses

Indications

Alverine is primarily indicated for the relief of , , and cramping associated with (IBS). It is also approved for treating symptoms of and painful periods (). These uses focus on alleviating spasms in the gut to improve patient comfort in functional gastrointestinal disorders. The evidence base for alverine in IBS management is supported by clinical guidelines, including those from the National Institute for Health and Care Excellence () in the UK, which recommend it as a first-line alongside dietary and lifestyle modifications. It is typically prescribed for adults and adolescents over 12 years of age.

Dosage and administration

Alverine citrate is typically administered orally in capsule form for the symptomatic relief of (IBS). The standard dosage for adults, including the elderly, is 60 to 120 mg taken one to three times daily, depending on symptom severity, with a maximum daily dose not exceeding 360 mg. For pediatric use, alverine is not recommended for children under 12 years of age; for adolescents aged 12 years and older, the dosage is the same as for adults (60 to 120 mg one to three times daily). Capsules should be swallowed whole with a of water and may be taken before or after meals, with or without food, to minimize gastrointestinal discomfort. Treatment is generally intended for short-term use during symptom flares, lasting 1 to 2 weeks, after which therapy should be reassessed; if symptoms persist or worsen, medical consultation is advised, and long-term use for chronic IBS requires ongoing supervision by a healthcare provider. No specific dose adjustments are required for elderly patients, though caution is recommended due to potential increased sensitivity to medications in this population.

Pharmacology

Pharmacodynamics

Alverine citrate is a direct-acting relaxant that primarily exerts its effects on the gastrointestinal and uterine tracts by modulating calcium handling in cells. It decreases the sensitivity of contractile proteins to calcium ions, thereby reducing the force of muscle contractions and alleviating spasms. Additionally, alverine inhibits from the while paradoxically enhancing calcium influx during action potentials through inhibition of L-type inactivation, resulting in a net suppression of evoked phasic contractions. In terms of receptor interactions, alverine acts as a selective at the 5-hydroxytryptamine receptor 1A (5-HT1A), which contributes to its antinociceptive properties by reducing visceral in the gut. It demonstrates high affinity for 5-HT1A receptors but weak affinity for 5-HT3 and 5-HT4 subtypes. Alverine shows low affinity for muscarinic, histaminergic, and cholinergic receptors, as evidenced by its direct action on without significant effects on the , heart, blood vessels, or trachea. These mechanisms enable alverine to relax intestinal , thereby relieving cramps and pain associated with conditions like , while avoiding substantial side effects. It also exhibits minor relaxant effects on uterine , which may provide symptomatic relief in , although this is not its primary therapeutic application. Additionally, alverine citrate has been shown to promote myogenic differentiation in myoblasts and ameliorate in aged and disused mouse models, potentially via upregulation of fusion-related genes.

Pharmacokinetics

Alverine citrate is rapidly absorbed from the after , achieving median peak plasma concentrations (T_max) of the parent compound at approximately 0.75 hours. The primary , 4-hydroxyalverine, and its conjugate reach peak levels shortly thereafter, with a median T_max of 1.00 hour. Peak plasma concentrations of the occur between 1 and 1.5 hours post-dose, consistent with efficient oral uptake under conditions. The compound exhibits high (logP = 5.46), facilitating widespread distribution to various tissues, including the where its therapeutic effects are primarily exerted. Pharmacokinetic studies indicate extensive tissue penetration, though specific volume of distribution data remain limited. has not been extensively characterized in available literature. Alverine undergoes rapid and extensive hepatic metabolism, with the parent compound representing only about 3% of total circulating drug-related material. The primary involves to the active 4-hydroxyalverine, with minor contributions from N-desethylation to N-desethyl alverine. The enzymes mediating this are not fully characterized, though the process exhibits high inter-individual variability possibly due to genetic polymorphisms, where up to 17% of individuals may exhibit poor hydroxylator status. This is further conjugated via to form 4-hydroxyalverine , which predominates in plasma (accounting for up to 94% of moieties alongside the free ). This first-pass metabolism results in low systemic exposure to unchanged alverine, contributing to high inter-individual pharmacokinetic variability. Excretion occurs predominantly via the renal route, with high clearance rates for all metabolites suggestive of active tubular secretion. Biliary or fecal elimination pathways have not been quantified in detail. The elimination half-life of alverine is approximately 0.8 hours, while that of the primary is around 5.7 hours; however, recent single-dose studies in healthy volunteers report greater variability, with median half-lives extending to 16.5 hours for alverine and 15.4 hours for 4-hydroxyalverine in some subjects due to polymorphic .

Safety profile

Adverse effects

Alverine citrate is generally well-tolerated, with most adverse effects being mild and transient, resolving without intervention. In a of alverine with simethicone, possibly drug-related adverse events occurred in approximately 2% of patients. Frequencies of adverse effects are often not known from post-marketing data.

Common Side Effects

These affect more than 1% of patients and include gastrointestinal and neurological symptoms. , , and are reported. These effects are usually managed symptomatically, with no need for discontinuation in most instances.

Serious Side Effects

Rare adverse effects involve or hepatic reactions. Allergic responses may manifest as , , wheezing, facial or throat swelling, and severe skin reactions like widespread or urticaria. Isolated cases of acute have been documented, presenting with , elevated liver enzymes, and yellowing of the skin or eyes, typically resolving upon drug cessation. Itching and may also occur as part of allergic reactions. Patients experiencing these should discontinue alverine immediately and seek medical attention.

Contraindications and precautions

Alverine is contraindicated in patients with known to the active substance or any of the excipients, as this may lead to allergic reactions. It is also absolutely contraindicated in cases of paralytic or intestinal obstruction, where its effects could exacerbate the condition and worsen outcomes. Use of alverine during or is not recommended due to limited evidence of safety from preclinical studies, and it should only be considered if the potential benefits outweigh the risks under medical supervision. In patients over 40 years of age, or those presenting with symptoms such as blood in the stool, unexplained , severe , , , fever, abnormal , or difficulty urinating, alverine should be used with caution, and consultation with a healthcare provider is advised to rule out underlying serious conditions. If symptoms do not improve after two weeks or worsen, medical evaluation is essential. Elderly patients may require monitoring due to potential increased sensitivity to side effects like , which can affect balance and daily activities. Alverine may impair the ability to drive or operate machinery in susceptible individuals, so caution is recommended until the effects are known. No major drug interactions have been reported with alverine, but it may enhance CNS depression when combined with other sedatives or depressants. There are no significant interactions involving enzymes.

Chemistry and physical properties

Chemical structure

Alverine is a synthetic tertiary amine with the molecular formula C20_{20}H27_{27}N for its free base form. It is most commonly administered as the citrate salt, which incorporates citric acid and has the molecular formula C26_{26}H35_{35}NO7_{7}. This salt form enhances solubility and stability for pharmaceutical applications. The systematic IUPAC name for alverine is N-ethyl-3-phenyl-N-(3-phenylpropyl)propan-1-amine. Structurally, the features a central atom substituted with one (-CH2_{2}CH3_{3}) and two identical 3-phenylpropyl chains (-CH2_{2}CH2_{2}CH2_{2}C6_{6}H5_{5}), resulting in a symmetrical tertiary scaffold. This configuration links two phenyl rings via flexible alkyl chains to the core, contributing to its lipophilic character. The citrate salt involves of the , forming an ionic bond with the tricarboxylic acid. Alverine lacks chiral centers and is thus achiral, exhibiting no optical isomers or stereoisomers under standard conditions. Its molecular weight is 281.44 g/mol for the and 473.56 g/mol for the citrate salt. The is a colorless to pale yellow oil with a below 25 °C and low solubility (approximately 0.001 mg/mL). The citrate salt appears as a white or almost white crystalline powder with a of 100–102 °C and is slightly soluble in (about 1 g/L at 20 °C), sparingly soluble in , and slightly soluble in methylene chloride.

Formulation

Alverine citrate is primarily formulated as oral hard capsules for clinical use, available in strengths of 60 mg and 120 mg per capsule. These capsules consist of a white to off-white powder enclosed in size '3' hard shells for the 60 mg strength and size '1' shells for the 120 mg strength, marked with identifiers such as 'AV 60' or 'AV 120'. The inactive ingredients in these hard capsules typically include maize starch, pregelatinised starch (such as Starch 1500), and to aid in powder flow and capsule filling. The capsule shells are composed of , (E171), and black (E172), with printing ink containing , alcohols, , , and for marking. No preservatives are required or included in these formulations. Alverine citrate is frequently combined with simeticone in soft capsule formulations, typically containing 60 mg alverine citrate and 300 mg simeticone per capsule, to enhance anti-flatulent effects, particularly for management. These soft capsules use , , and for the shell, along with soya lecithin and fractionated as lubricants. The stability of alverine citrate hard capsules supports a of 3 years, while soft capsule combinations with simeticone have a of 30 months. Both forms should be stored below 25°C in their original to protect from moisture, with additional protection from light recommended for soft capsules.

History and availability

Development

Alverine was first synthesized in as a synthetic analog of , a natural known for its smooth muscle relaxant properties, with early research targeting its potential as an agent for functional gastrointestinal disorders. Subsequent investigations confirmed its direct action on intestinal and uterine , establishing a foundation for its use in relieving spasms associated with conditions like (IBS). Clinical trials evaluating alverine for IBS have historically been limited in number and scope. A double-blind, randomized, -controlled conducted in the early assessed alverine citrate's but found it no more effective than in reducing symptom severity or frequency, including . In contrast, phase IV studies on the alverine-simeticone combination during the provided evidence of clinical benefit; for instance, a multicenter involving 412 IBS patients demonstrated that the combination significantly outperformed in alleviating and discomfort, with response rates of 82% versus 56%. Alverine received regulatory approval from the UK's Medicines and Healthcare products (MHRA) and equivalent authorities across for the of IBS, enabling its availability as an over-the-counter and prescription medication in these regions. However, it has not been approved by the Food and Drug Administration (FDA) and remains unavailable in the American market. Despite its long-standing use, alverine lacks extensive modern randomized controlled trials, highlighting research gaps in long-term and comparative against newer IBS therapies. Current interest focuses on formulations, such as with , to enhance symptom relief and address unmet needs in IBS management.

Marketing and regulation

Alverine is marketed under several brand names worldwide, including Spasmonal and Audmonal for the standalone formulation, as well as generics in various regions. The drug is also available in combination with simeticone, containing alverine citrate 60 mg and simeticone 300 mg per capsule, marketed as Meteospasmyl or Simalvia, to address both spasms and gas-related symptoms in gastrointestinal disorders. Alverine is widely available in the , , and parts of , where it can be obtained over-the-counter from under supervision or by prescription, particularly for patients with a prior diagnosis of . In the UK, it is classified as a (P), allowing purchase without a prescription if symptoms have been previously assessed by a healthcare professional. Availability in is supported through nationally authorized products via the framework, while in Asian markets such as and , it is distributed through local pharmaceutical companies under generic and branded forms. In the United States, alverine is not approved by the and remains limited to import options or alternative markets, with no routine commercial distribution. The market for alverine has seen growing demand, primarily driven by the increasing prevalence of and related functional gastrointestinal disorders globally. Regulatory oversight of alverine emphasizes its classification as a prescription or medicine in most jurisdictions to ensure appropriate use for symptomatic relief. In the UK, it falls under the Medicines and Healthcare products Regulatory Agency (MHRA) guidelines as a pharmacy-only product, with ongoing monitoring through pharmacovigilance programs such as the Yellow Card Scheme, which collects reports of suspected adverse reactions to support post-marketing safety assessments. Similar surveillance mechanisms exist in via the European Medicines Agency's system, ensuring continuous evaluation of benefit-risk profiles across authorized formulations.

References

  1. https://go.drugbank.com/drugs/DB01616
  2. https://patient.info/medicine/alverine-capsules-audmonal-spasmonal
  3. https://www.medicines.org.uk/emc/product/11542/pil
  4. https://pubchem.ncbi.nlm.nih.gov/compound/Alverine
  5. https://www.caymanchem.com/product/26892
  6. https://www.nature.com/articles/s41598-024-62922-2
  7. https://www.medicines.org.uk/emc/product/11541/pil
  8. https://bnf.nice.org.uk/treatment-summaries/irritable-bowel-syndrome/
  9. https://www.nice.org.uk/guidance/cg61/chapter/1-recommendations
  10. https://www.medicines.org.uk/emc/product/11541/smpc
  11. https://www.mims.com/singapore/drug/info/alverine?mtype=generic
  12. https://assets.hpra.ie/products/Human/26851/LicenseSPC_PA1352-010-001_04052018162127.pdf
  13. https://pmc.ncbi.nlm.nih.gov/articles/PMC2190002/
  14. https://www.wjgnet.com/1007-9327/full/v20/i20/6031.htm
  15. https://onlinelibrary.wiley.com/doi/abs/10.1211/0022357011777783
  16. https://www.mims.com/malaysia/drug/info/alverine
  17. https://pubmed.ncbi.nlm.nih.gov/34847441/
  18. https://pmc.ncbi.nlm.nih.gov/articles/PMC7855969/
  19. https://www.medicines.org.uk/emc/product/11542/smpc
  20. https://onlinelibrary.wiley.com/doi/10.1111/ijcp.12333
  21. https://www.medicines.org.uk/emc/files/pil.11541.pdf
  22. https://www.scirp.org/journal/paperinformation?paperid=42394
  23. https://www.e-lactancia.org/media/papers/Alverine-DS-LTTph2012.pdf
  24. https://pmc.ncbi.nlm.nih.gov/articles/PMC4724969/
  25. https://pubchem.ncbi.nlm.nih.gov/compound/Alverine-Citrate
  26. https://assets.hpra.ie/products/Human/26852/LicenseSPC_PA1352-010-002_04052018162122.pdf
  27. https://mhraproducts4853.blob.core.windows.net/docs/95feaaa686f5f903adb45730a11a161563ab4417
  28. https://pmc.ncbi.nlm.nih.gov/articles/PMC3922238/
  29. https://pubmed.ncbi.nlm.nih.gov/12030962/
  30. https://pubmed.ncbi.nlm.nih.gov/20003095/
  31. https://pmc.ncbi.nlm.nih.gov/articles/PMC4033443/
  32. https://www.drugs.com/international/alverine.html
  33. https://medtigo.com/drug/alverine-citrate-simeticone/
  34. https://www.ema.europa.eu/en/documents/psusa/alverine-simeticone-list-nationally-authorised-medicinal-products-psusa00000125202202_en.pdf
  35. https://medex.com.bd/generics/49/alverine-citrate/brand-names
  36. https://www.gov.uk/guidance/the-yellow-card-scheme-guidance-for-healthcare-professionals
  37. https://yellowcard.mhra.gov.uk/idaps/ALVERINE
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