Sumatriptan

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Sumatriptan
Sumatriptan.svg
Sumatriptan 3D ball-and-stick.png
Clinical data
Trade names Imitrex, Imigran, others
AHFS/Drugs.com Monograph
License data
Routes of
administration 		oral, subcutaneous injection, nasal spray, transdermal electrophoresis
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 15% (oral) / 96% (by subcutaneous injection)
Protein binding 14–21%
Metabolism Monoamine oxidase (MAO)
Elimination half-life 2.5 hours
Excretion 60% urine; 40% feces
Identifiers
  • 1-[3-(2-Dimethylaminoethyl)-1H-indol-5-yl]-N-methyl-methanesulfonamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.130.518 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C14H21N3O2S
Molar mass 295.40 g·mol−1
3D model (JSmol)
  • O=S(=O)(NC)Cc1cc2c(cc1)[nH]cc2CCN(C)C
  • InChI=1S/C14H21N3O2S/c1-15-20(18,19)10-11-4-5-14-13(8-11)12(9-16-14)6-7-17(2)3/h4-5,8-9,15-16H,6-7,10H2,1-3H3 Yes check.svgY
  • Key:KQKPFRSPSRPDEB-UHFFFAOYSA-N Yes check.svgY
   (verify)

Sumatriptan, sold under the brand name Imitrex among others, is a medication used to treat migraine headaches and cluster headaches. [1] It is taken orally, intranasally, or by subcutaneous injection. [2] Therapeutic effects generally occur within three hours. [2]

Contents

Its primary effect as a serotonin 5-HT1B/5-HT1D receptor agonist [3] can create common side effects such as chest pressure, fatigue, vomiting, tingling, and vertigo. [2] Serious side effects may include serotonin syndrome, heart attacks, strokes, and seizures. [2] With excessive use, medication overuse headaches may occur. [2] It is unclear if use during pregnancy or breastfeeding is safe. [4] The mechanism of action is not entirely clear. [2] It is in the triptan class of medications. [2]

Sumatriptan was patented in 1982 and approved for medical use in 1991. [5] It is on the World Health Organization's List of Essential Medicines. [6] It is available as a generic medication. [1] In 2021, it was the 109th most commonly prescribed medication in the United States, with more than 5 million prescriptions. [7] [8] It is also available as the combination product sumatriptan/naproxen.

Medical uses

Sumatriptan is effective for ending or relieving the intensity of migraine and cluster headaches. [9] It is most effective when taken early after the start of the pain. [9] Injected sumatriptan is more effective than other formulations. [10]

Oral sumatriptan can be used also in the treatment of post-dural puncture headache. [11]

Adverse effects

Overdose of sumatriptan can cause sulfhemoglobinemia, a rare condition in which the blood changes from red to green, due to the integration of sulfur into the hemoglobin molecule. [12] If sumatriptan is discontinued, the condition reverses within a few weeks.[ citation needed ]

Serious cardiac events, including some that have been fatal, have occurred following the use of sumatriptan injection or tablets. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation. [13]

The most common side effects [14] reported by at least 2% of patients in controlled trials of sumatriptan (25-, 50-, and 100-mg tablets) for migraine are atypical sensations (paresthesias and warm/cold sensations) reported by 4% in the placebo group and 5–6% in the sumatriptan groups, pain and other pressure sensations (including chest pain) reported by 4% in the placebo group and 6–8% in the sumatriptan groups, neurological events (vertigo) reported by less than 1% in the placebo group and less than 1% to 2% in the sumatriptan groups. Malaise/fatigue occurred in less than 1% of the placebo group and 2–3% of the sumatriptan groups. Sleep disturbance occurred in less than 1% in the placebo group to 2% in the sumatriptan group.

Mechanism of action

Sumatriptan is molecularly similar to serotonin (5-HT), and is a 5-HT receptor (types 5-HT1D and 5-HT1B [15] ) agonist. Sumatriptan's primary therapeutic effect is related in its inhibition of the release of Calcitonin gene-related peptide (CGRP), likely through its 5-HT1D/1B receptor-agonist action. [16] This has been substantiated by the efficacy of more recently developed CGRP targeting drugs and antibodies developed for the preventive treatment of migraine. [17] How agonism of the 5-HT1D/1B receptors inhibits CGRP release is not fully understood. CGRP is believed to cause sensitization of trigeminal nociceptive neurons, contributing to the pain experienced in migraine. [18]

Sumatriptan is also shown to decrease the activity of the trigeminal nerve, which presumably accounts for sumatriptan's efficacy in treating cluster headaches. The injectable form of the drug has been shown to abort a cluster headache within 30 minutes in 77% of cases. [19]

Pharmacokinetics

Sumatriptan is administered in several forms: tablets, subcutaneous injection, and nasal spray. Oral administration (as succinate salt) has low bioavailability, partly due to presystemic metabolism—some of it gets broken down in the stomach and bloodstream before it reaches the target arteries. A rapid-release tablet formulation with the same bioavailability but a high concentration can achieve therapeutic effects on average 10–15 minutes earlier than other oral forumulations. When injected, sumatriptan is faster-acting (usually within 10 minutes), but the effect lasts for a shorter time. Sumatriptan is metabolised primarily by monoamine oxidase A into 2-{5-[(methylsulfamoyl)methyl]-indole-3-yl}acetic acid, which is then conjugated to glucuronic acid. These metabolites are excreted in the urine and bile. Only about 3% of the active drug may be recovered unchanged.[ citation needed ]

There is no simple, direct relationship between sumatriptan concentration (pharmacokinetics) per se in the blood and its anti-migraine effect (pharmacodynamics). This paradox has, to some extent, been resolved by comparing the rates of absorption of the various sumatriptan formulations, rather than the absolute amounts of drug that they deliver. [20] [21]

History

Sumatriptan vials Sumatriptan vails 100 5509.jpg
Sumatriptan vials

In 1991, Glaxo received approval for sumatriptan, which was the first available triptan.

In July 2009, the US FDA approved a single-use jet injector formulation of sumatriptan. The device delivers a subcutaneous injection of sumatriptan, without the use of a needle. Autoinjectors with needles have been previously available in Europe and North America. [22]

Phase III studies with an iontophoretic transdermal patch (Zelrix/Zecuity) started in July 2008. [23] This patch uses low voltage controlled by a pre-programmed microchip to deliver a single dose of sumatriptan through the skin within 30 minutes. [24] [25] Zecuity was approved by the US FDA in January 2013. [26] Sales of Zecuity have been stopped following reports of skin burns and irritation. [27]

Society and culture

In the United States, it is available only by medical prescription. It is available over the counter in many states in Australia. The product requires labelling by a pharmacist and is only available in packs of two without a medical prescription. [28] However, it can be bought over the counter in the UK [29] and Sweden. [30]

In Russia versions of sumatriptan, which are not registered in the National registry of medications, may be regarded as narcotic drugs (derivatives of dimethyltryptamine). [31]

Generics

Glaxo patents for sumatriptan expired in February 2009. At that time, Imitrex sold for about $25 a pill. [32] Par Pharmaceutical then introduced generic versions of sumatriptan injection (sumatriptan succinate injection) 4- and 6-mg starter kits and 4- and 6-mg filled syringe cartridges, and 6-mg vials soon after. [33]

Mylan Laboratories Inc., Ranbaxy Laboratories, Sandoz (a subsidiary of Novartis), Dr. Reddy's Laboratories, and other companies have been producing generic versions of sumatriptan tablets in 25-, 50-, and 100-mg doses. Generic forms of the drug are available in U.S. and European markets after Glaxo's patent protections expired in the respective countries. A nasal spray form of sumatriptan known as AVP-825 has been developed by Avanir and is generically available in some countries. [34]

Controversy

According to the American Headache Society, "Patients frequently state that they have difficulty accessing triptans prescribed to them." [35] In the U.S. triptans cost from $12 to $120 each, and more than 80% of U.S. health insurance plans place a limit on the amount of pills available to a patient per month, which has been called "arbitrary and unfair." [36]

Related Research Articles

<span class="mw-page-title-main">Migraine</span> Disorder resulting in recurrent moderate-severe headaches

Migraine is a genetically influenced complex neurological disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea and light and sound sensitivity. Other characterizing symptoms may include nausea, vomiting, cognitive dysfunction, allodynia, and dizziness. Exacerbation of headache symptoms during physical activity is another distinguishing feature. Up to one-third of migraine sufferers experience aura: a premonitory period of sensory disturbance widely accepted to be caused by cortical spreading depression at the onset of a migraine attack. Although primarily considered to be a headache disorder, migraine is highly heterogenous in its clinical presentation and is better thought of as a spectrum disease rather than a distinct clinical entity. Disease burden can range from episodic discrete attacks, consisting of as little as several lifetime attacks, to chronic disease.

<span class="mw-page-title-main">Cluster headache</span> Neurological disorder

Cluster headache (CH) is a neurological disorder characterized by recurrent severe headaches on one side of the head, typically around the eye(s). There is often accompanying eye watering, nasal congestion, or swelling around the eye on the affected side. These symptoms typically last 15 minutes to 3 hours. Attacks often occur in clusters which typically last for weeks or months and occasionally more than a year.

<span class="mw-page-title-main">Triptan</span> Class of pharmaceutical drugs

Triptans are a family of tryptamine-based drugs used as abortive medication in the treatment of migraines and cluster headaches. This drug class was first commercially introduced in the 1990s. While effective at treating individual headaches, they do not provide preventive treatment and are not considered a cure. They are not effective for the treatment of tension–type headache, except in persons who also experience migraines. Triptans do not relieve other kinds of pain.

<span class="mw-page-title-main">Rizatriptan</span> Medication used for the treatment of migraine headaches

Rizatriptan, sold under the brand name Maxalt among others, is a medication used for the treatment of migraine headaches. It is taken by mouth. It can also be applied on the tongue. It is a serotonin (5-HT) 1B/1D receptor agonist (triptan).

<span class="mw-page-title-main">Zolmitriptan</span> Medication used in treatment of migraines

Zolmitriptan, sold under the brand name Zomig among others, is a triptan used in the acute treatment of migraine attacks with or without aura and cluster headaches. It is a selective serotonin receptor agonist of the 1B and 1D subtypes.

<span class="mw-page-title-main">Dihydroergotamine</span> An ergot alkaloid used to treat migraines

Dihydroergotamine (DHE), sold under the brand names D.H.E. 45 and Migranal among others, is an ergot alkaloid used to treat migraines. It is a derivative of ergotamine. It is administered as a nasal spray or injection and has an efficacy similar to that of sumatriptan. Nausea is a common side effect.

Caffeine/ergotamine is the proprietary name of a medication consisting of ergotamine tartrate and caffeine. This combination is used for the treatment of headaches, such as migraine headache.

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

Methysergide, sold under the brand names Deseril and Sansert, is a monoaminergic medication of the ergoline and lysergamide groups which is used in the prophylaxis and treatment of migraine and cluster headaches. It has been withdrawn from the market in the United States and Canada due to adverse effects. It is taken by mouth.

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

Almotriptan is a triptan medication discovered and developed by Almirall for the treatment of heavy migraine headache.

<span class="mw-page-title-main">Calcitonin gene-related peptide</span> Peptide hormone in animals

Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides consisting of calcitonin, amylin, adrenomedullin, adrenomedullin 2 (intermedin) and calcitonin‑receptor‑stimulating peptide. Calcitonin is mainly produced by thyroid C cells whilst CGRP is secreted and stored in the nervous system. This peptide, in humans, exists in two forms: CGRP alpha, and CGRP beta. α-CGRP is a 37-amino acid neuropeptide and is formed by alternative splicing of the calcitonin/CGRP gene located on chromosome 11. β-CGRP is less studied. In humans, β-CGRP differs from α-CGRP by three amino acids and is encoded in a separate, nearby gene. The CGRP family includes calcitonin (CT), adrenomedullin (AM), and amylin (AMY).

<span class="mw-page-title-main">Antimigraine drug</span> Medication intended to reduce the effects or intensity of migraine headache

Antimigraine drugs are medications intended to reduce the effects or intensity of migraine headache. They include drugs for the treatment of acute migraine symptoms as well as drugs for the prevention of migraine attacks.

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

Naratriptan (trade names include Amerge) is a triptan drug marketed by GlaxoSmithKline and is used for the treatment of migraine headaches. It is a selective 5-HT1 receptor subtype agonist.

Triptans is a word commonly used for a class of anti-migraine drugs that are selective 5-hydroxytryptamine/serotonin1B/1D (5-HT1B/1D) agonists. Migraine is a complex disease which affects about 15% of the population and can be highly disabling. Triptans have advantages over ergotamine and dihydroergotamine, such as selective pharmacology, well established safety record and evidence-based prescribing instructions. Triptans are therefore often preferred treatment in migraine.

The trigeminovascular system (TVS) refers to neurons and their axonal projections within the trigeminal nerve that project to the cranial meninges and meningeal blood vessels residing on the brain's surface. The term, introduced in 1983 denotes also the neuropeptides contained within axons that are released into the meninges to target vessels and surrounding cells.

Migraine treatment may be either prophylactic (preventive) or abortive (rescue). Prevention is better than cure, so the ideal treatment goal is to prevent migraine attacks. Because migraine is an exceedingly complex condition, there are various preventive treatments which have their effect by disrupting different links in the chain of events that occur during a migraine attack. As rescue treatments also target and disrupt different processes occurring during migraine, these are summarized, with their relative merits and demerits.

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

Donitriptan (INN) is a triptan drug which was investigated as an antimigraine agent but ultimately was never marketed. It acts as a high-affinity, high-efficacy/near-full agonist of the 5-HT1B and 5-HT1D receptors, and is among the most potent of the triptan series of drugs. Donitriptan was being developed in France by bioMérieux-Pierre Fabre and made it to phase II clinical trials in Europe before development was discontinued.

<span class="mw-page-title-main">CP-122,288</span> Chemical compound

CP-122,288 is a drug which acts as a potent and selective agonist for the 5-HT1B, 5-HT1D and 5-HT1F serotonin receptor subtypes. It is a derivative of the migraine medication sumatriptan, but while CP-122,288 is 40,000 times more potent than sumatriptan as an inhibitor of neurogenic inflammation and plasma protein extravasation, it is only twice as potent as a constrictor of blood vessels. In human trials, CP-122,288 was not found to be effective as a treatment for migraine, but its selectivity for neurogenic anti-inflammatory action over vasoconstriction has made it useful for research into the underlying causes of migraine.

<span class="mw-page-title-main">Ditan</span> Drug class

Ditans are a class of abortive medication for the treatment of migraines. The first ditan, Eli Lilly's lasmiditan, was approved by the FDA in 2019.

Fremanezumab, sold under the brand name Ajovy, is a medication used to prevent migraines in adults. It is given by injection under the skin.

Professor Patrick Humphrey OBE DSc PhD HonFBPhS is a South African-born British pharmacologist. He was instrumental in the discovery of the triptans, a group of 5-HT1B and 5-HT1D agonists used to stop single instances of cluster headache or migraine.

References

  1. 1 2 British National Formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 474. ISBN   9780857113382.
  2. 1 2 3 4 5 6 7 "Sumatriptan Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 3 March 2019.
  3. ↑ Syed YY (January 2016). "Sumatriptan/Naproxen Sodium: A Review in Migraine". Drugs. 76 (1): 111–121. doi:10.1007/s40265-015-0521-8. PMID   26628293. S2CID   25060147.
  4. ↑ "Sumatriptan Use During Pregnancy". Drugs.com. Retrieved 3 March 2019.
  5. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 531. ISBN   9783527607495.
  6. ↑ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl: 10665/345533 . WHO/MHP/HPS/EML/2021.02.
  7. ↑ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  8. ↑ "Sumatriptan - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
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  11. ↑ Shaat AM, Abdalgaleil MM (1 January 2021). "Is theophylline more effective than sumatriptan in the treatment of post-dural puncture headache? A randomized clinical trial". Egyptian Journal of Anaesthesia. 37 (1): 310–316. doi: 10.1080/11101849.2021.1949195 . ISSN   1110-1849.
  12. ↑ "Patient bleeds dark green blood". BBC News. 8 June 2007. Archived from the original on 5 August 2010. Retrieved 6 March 2010.
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  14. ↑ "Tablets". fda.gov. Retrieved 19 February 2018.
  15. ↑ Razzaque Z, Heald MA, Pickard JD, Maskell L, Beer MS, Hill RG, et al. (January 1999). "Vasoconstriction in human isolated middle meningeal arteries: determining the contribution of 5-HT1B- and 5-HT1F-receptor activation". British Journal of Clinical Pharmacology. 47 (1): 75–82. doi:10.1046/j.1365-2125.1999.00851.x. PMC   2014192 . PMID   10073743.
  16. ↑ Juhasz G, Zsombok T, Jakab B, Nemeth J, Szolcsanyi J, Bagdy G (March 2005). "Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack". Cephalalgia. 25 (3): 179–183. doi:10.1111/j.1468-2982.2005.00836.x. PMID   15689192. S2CID   13007101.
  17. ↑ Tso AR, Goadsby PJ (August 2017). "Anti-CGRP Monoclonal Antibodies: the Next Era of Migraine Prevention?". Current Treatment Options in Neurology. 19 (8): 27. doi:10.1007/s11940-017-0463-4. PMC   5486583 . PMID   28653227.
  18. ↑ Giniatullin R, Nistri A, Fabbretti E (February 2008). "Molecular mechanisms of sensitization of pain-transducing P2X3 receptors by the migraine mediators CGRP and NGF". Molecular Neurobiology. 37 (1): 83–90. doi:10.1007/s12035-008-8020-5. PMID   18459072. S2CID   25689799.
  19. ↑ Ekbom K, Waldenlind E, Richard L, Andersson B, Boivie J, Dizdar N, et al. (Sumatriptan Cluster Headache Study Group) (August 1991). "Treatment of acute cluster headache with sumatriptan". The New England Journal of Medicine. 325 (5): 322–326. doi: 10.1056/NEJM199108013250505 . PMID   1647496.
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  22. ↑ Brandes JL, Cady RK, Freitag FG, Smith TR, Chandler P, Fox AW, et al. (2009). "Needle-free subcutaneous sumatriptan (Sumavel DosePro): bioequivalence and ease of use". Headache. 49 (10): 1435–1444. doi:10.1111/j.1526-4610.2009.01530.x. PMID   19849720. S2CID   25696109.
  23. ↑ Clinical trial number NCT00724815 for "The Efficacy and Tolerability of NP101 Patch in the Treatment of Acute Migraine (NP101-007)" at ClinicalTrials.gov
  24. ↑ "SmartRelief -electronically assisted drug delivery (iontophoresis)". nupathe.com. Archived from the original on 7 January 2016. Retrieved 19 February 2018.
  25. ↑ Pierce M, Marbury T, O'Neill C, Siegel S, Du W, Sebree T (June 2009). "Zelrix: a novel transdermal formulation of sumatriptan". Headache. 49 (6): 817–825. doi: 10.1111/j.1526-4610.2009.01437.x . PMID   19438727. S2CID   205683188.
  26. ↑ "Zecuity Approved by the FDA for the Acute Treatment of Migraine". nupathe.com. Archived from the original on 7 January 2016. Retrieved 19 February 2018.
  27. ↑ "Teva pulls migraine patch Zecuity on reports of burning, scarring". FiercePharma. 13 June 2016. Archived from the original on 21 March 2017. Retrieved 10 April 2017.
  28. ↑ "Poisons Standard June 2017". 18 May 2017. Archived from the original on 31 July 2017. Retrieved 22 July 2017.
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  31. ↑ "Постановление Правительства РФ от 30 июня 1998 г. N 681 "Об утверждении перечня наркотических средств, психотропных веществ и их прекурсоров, подлежащих контролю в Российской Федерации" (с изменениями и дополнениями)" (in Russian). Гарант . Retrieved 28 April 2019. ДМТ (диметилтриптамин) и его производные, за исключением производных, включенных в качестве самостоятельных позиций в перечень
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  35. ↑ Minen, M. T., Lindberg, K., Langford, A., Loder, E. (2017), "Variation in Prescription Drug Coverage for Triptans: Analysis of Insurance Formularies", Headache: The Journal of Head and Face Pain, Wiley, 57 (8): 1243–1251, doi:10.1111/head.13134, PMID   28691382, S2CID   42239120
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