Sumatriptan

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Sumatriptan
Sumatriptan molecule
Clinical data
Trade namesImitrex, Imigran, others
AHFS/Drugs.comMonograph
License data
Antimigraine agent; Triptan; Serotonin 5-HT1B and 5-HT1D receptor agonist
ATC code
Legal status
Legal status
subcutaneous)
Protein binding14–21%
MetabolismMonoamine oxidase (MAO)
Elimination half-life2.5 hours
Excretion60% urine; 40% feces
Identifiers
  • 1-[3-(2-Dimethylaminoethyl)-1H-indol-5-yl]-N-methyl-methanesulfonamide
JSmol)
SMILES
  • 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 checkY
  • Key:KQKPFRSPSRPDEB-UHFFFAOYSA-N checkY
  (verify)

Sumatriptan, sold under the brand name Imitrex among others, is a

injection.[2] Therapeutic effects generally occur within three hours.[2]

Its

heart attack, stroke, and seizures. 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. It is in the triptan class of medications.[2]

Sumatriptan was patented in 1982 and approved for medical use in 1991.

generic medication.[1] In 2022, it was the 95th most commonly prescribed medication in the United States, with more than 6 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. If sumatriptan is discontinued, the condition reverses within a few weeks.[12]

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] There are reports of Takotsubo cardiomyopathy and transient amnesia after sumatriptan use.[14]

The most common side effects

paresthesia 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.

Sumatriptan has a low

abuse potential;[16] however overuse is associated with medication overuse headache.[17] Moreover, prolonged sumatriptan use is associated with pronociceptive effects, resulting in allodynia. This effect's association with medication overuse headache, however, is controversial, due to the fact that animal-model studies are not consistent with typical presentation of this disorder.[18]

Interactions

Concurrent use with other triptans or ergot-containing medications (e.g., ergotamine, dihydroergotamine) within 24 hours can result in additive vasoconstriction.[19][20] Increased systemic exposure to sumatriptan can occur if used within 2 weeks after a monoamine oxidase inhibitor (MAOI).[20] Cases of serotonin syndrome have been reported with co-administration of triptans and serotonin reuptake inhibitors.[19]

Pharmacology

Mechanism of action

Further information: Serotonin receptor agonist and Triptan § Mechanism of action
Sumatriptan activities
Target
Affinity
(pKi) 		Species Ref
5-HT1A 5.99–6.59 ? [21]
5-HT1B 8.7 Human [21]
6.33–7.35 Rat [22]
5-HT1Dα 8.47–8.73 ? [21]
5-HT1Dβ 7.21–8.11 ? [21]
5-HT1E 5.68 ? [21]
5-HT1F 7.1–7.64 ? [21]
5-HT2B <6 ? [21]
5-HT2C <5 ? [23]
5-HT4 <5 Guinea pig [21]
5-HT5A 4.8–6.8 Mouse [21]
5-HT5B 5.1 Mouse [21]
6.09 Rat [21]
5-HT6 <5.59 ? [24][25]
5-HT7 6–7 ? [21]
CB1
 <5 ? [26]
Notes: The higher the pKi value, the more avidly the drug binds to the site.

Sumatriptan is molecularly similar to

5-HT1B[27]) 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.[28] This has been substantiated by the efficacy of more recently developed CGRP targeting drugs and antibodies developed for the preventive treatment of migraine.[29] 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.[30]

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.[31]

Pharmacokinetics

Sumatriptan is administered in several forms: tablets,

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 formulations.[32] When injected, sumatriptan is faster-acting (usually within 10 minutes), but the effect lasts for a shorter time.[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.[33][34]

Metabolism

Sumatriptan is metabolised primarily by monoamine oxidase A into indol-3-yl-acetaldehyde and then into corresponding carboxylic acid. It is further modified by UDP-glucuronosyltransferase into a conjugate with glucuronic acid. Other pathways are mediated by cytochrome P450 isoenzymes, which give an N-oxide derivative, and N-desmethyl and N,N-didesmethyl forms (the latter can be converted into the aldehyde by monoamine oxidase A). N-desmethyl derivative can also undergo a reaction with D-cysteine.[35]

These metabolites are excreted in the urine and bile. Only about 3% of the active drug may be recovered unchanged.[2]

Sumatriptan metabolic pathways (MAO-A – monoamine oxidase A, CYP - cytochrome P450 isoenzymes)[35]

Chemistry

The experimental

log P of sumatriptan is 0.8 to 0.93 and its predicted log P is 0.46 to 1.17.[36][37][38]

History

Sumatriptan vials

In 1991, Glaxo received approval for sumatriptan, which was the first available triptan.[citation needed]

In July 2009, the US Food and Drug Administration (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.[39]

Phase III studies with an

iontophoretic transdermal patch (Zelrix/Zecuity) started in July 2008.[40] This patch uses low voltage controlled by a pre-programmed microchip to deliver a single dose of sumatriptan through the skin within 30 minutes.[41][42] Zecuity was approved by the FDA in January 2013.[43] Sales of Zecuity have been stopped following reports of skin burns and irritation.[44]

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.[45] However, it can be bought over the counter in the UK[46] and Sweden.[47]

In Russia, versions of sumatriptan which are not registered in the State Register of Medicines may be regarded as narcotic drugs (derivatives of

dimethyltryptamine).[48]

Generics

Glaxo patents for sumatriptan expired in February 2009. At that time, Imitrex sold for about $25 a pill.

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.[50]

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.[51]

Controversy

According to the

American Headache Society, "Patients frequently state that they have difficulty accessing triptans prescribed to them."[52] 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."[53]

References

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