Sumatriptan

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Sumatriptan
Sumatriptan Structural Formula V.1.svg
Sumatriptan molecule
Systematic (IUPAC) name
1-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]- N-methyl-methanesulfonamide
Clinical data
Trade names Imitrex, Imigran,Treximet
AHFS/Drugs.com monograph
Licence data US FDA:link
Pregnancy cat. C
Legal status -only (US)
Routes tablet, subcutaneous injection, nasal spray
Pharmacokinetic data
Bioavailability 15% (oral)/ 96% (s.c)
Protein binding 14–21%
Metabolism MAO
Half-life 2.5 hours
Excretion 60% urine; 40% feces
Identifiers
CAS number 103628-46-2 YesY
ATC code N02CC01
PubChem CID 5358
IUPHAR ligand 54
DrugBank DB00669
ChemSpider 5165 YesY
UNII 8R78F6L9VO YesY
KEGG D00451 YesY
ChEBI CHEBI:10650 YesY
ChEMBL CHEMBL128 YesY
Chemical data
Formula C14H21N3O2S 
Mol. mass 295.402 g/mol
 YesY (what is this?)  (verify)

Sumatriptan is a synthetic drug belonging to the triptan class, used for the treatment of migraine headaches. Structurally, it is an analog of the naturally occurring neuro-active alkaloids dimethyltryptamine (DMT), bufotenine, and 5-methoxy-dimethyltryptamine, with an N-methyl sulfonamidomethyl- group at position C-5 on the indole ring.[1]

Sumatriptan is produced and marketed by various drug manufacturers with many different trade names such as Sumatriptan, Imitrex, Treximet, Imigran, Imigran recovery.

Adverse effects[edit]

Large doses of sumatriptan can cause sulfhemoglobinemia, a rare condition in which the blood changes from red to greenish-black, due to the integration of sulfur into the hemoglobin molecule.[2] If sumatriptan is discontinued, the condition reverses within a few weeks.

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.[citation needed]

The most common side-effects[3] 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[edit]

Sumatriptan is structurally similar to serotonin (5HT), and is a 5-HT (types 5-HT1D and 5-HT1B[4]) agonist. The specific receptor subtypes it activates are present on the cranial arteries and veins. Acting as an agonist at these receptors, sumatriptan reduces the vascular inflammation associated with migraines.

The specific receptor subtype it activates is present in the cranial and basilar arteries. Activation of these receptors causes vasoconstriction of those dilated arteries. Sumatriptan is also shown to decrease the activity of the trigeminal nerve, which, it is presumed, accounts for sumatriptan's efficacy in treating cluster headaches. The injectable form of the drug has been shown to abort a cluster headache within fifteen minutes in 96% of cases.[5]

Pharmacokinetics[edit]

Sumatriptan is administered in several forms; tablets, subcutaneous injection, and nasal spray. Oral administration (as succinate) suffers from poor bioavailability, partly due to presystemic metabolism—some of it gets broken down in the stomach and bloodstream before it reaches the target arteries. A new rapid-release tablet formulation has the same bioavailability, but the maximum concentration is achieved on average 10–15 minutes earlier. 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 an indole acetic acid analogue, part of which is further conjugated with glucuronic acid. These metabolites are excreted in the urine and bile. Only about 3% of the active drug may be recovered unchanged.

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.[6][7]

Approval[edit]

Sumatriptan was the first clinically available triptan (in 1991). In the United States, it is available only by medical prescription. However, it can be bought over the counter in the UK and Sweden in 50 mg dosage. Several dosage forms for sumatriptan have been approved, including tablets, solution for injection, and nasal inhalers.

On April 15, 2008, the US FDA approved Treximet, a combination of sumatriptan and naproxen, an NSAID.[8] This combination has shown a benefit over either medicine used separately.[9]

In July 2009, the US FDA approved a single-use jet injector formulation of sumatriptan. The device delivers a subcutaneous injection of 6 mg sumatriptan, without the use of a needle. Autoinjectors with needles have been previously available in Europe and North America for several years.[10]

Phase III studies with a iontophoretic transdermal patch (Zelrix/Zecuity) started in July 2008.[11] This patch uses low voltage controlled by a pre-programmed microchip to deliver a single dose of sumatriptan through the skin within 30 minutes.[12][13]Zecuity was approved by the US FDA in January 2013.[14]

Generics[edit]

Sumatriptan vials 100 5509

On November 6, 2008, Par Pharmaceutical announced that it would begin shipping generic versions of sumatriptan injection (sumatriptan succinate injection) 4 mg and 6 mg starter kits and 4 mg and 6 mg pre-filled syringe cartridges to the trade immediately. In addition, Par anticipates launching the 6 mg vials early in 2009.[15]

Mylan Laboratories Inc., Ranbaxy, Sandoz, Dr. Reddy's Pharmaceuticals and other companies have received FDA approval for generic versions of Imitrex tablets in 25-, 50-, and 100-milligram doses since 2009. The drug is available in U.S. and European markets, since Glaxo's patent protections have expired in those jurisdictions. However, sales of a generic delivered via nasal spray are still restricted in the United States.

See also Sumavel DosePro (above).[10]

Chemistry[edit]

Sumatriptan synth.png

U.S. Patent 4,785,016

References[edit]

  1. ^ The presence of the sulfonamide group in the molecule does not make sumatriptan a "sulfa drug", since it does not have any anti-microbial properties.
  2. ^ "Patient bleeds dark green blood". BBC News. 8 June 2007. Retrieved 6 March 2010. 
  3. ^ Tablets
  4. ^ Razzaque Z, Heald MA, Pickard JD, et al. (1999). "Vasoconstriction in human isolated middle meningeal arteries: determining the contribution of 5-HT1B- and 5-HT1F-receptor activation". Br J Clin Pharmacol 47 (1): 75–82. doi:10.1046/j.1365-2125.1999.00851.x. PMC 2014192. PMID 10073743. 
  5. ^ Treatment of acute cluster headache with sumatriptan. The Sumatriptan Cluster Headache Study Group. N Engl J Med 1991;325:322-6.
  6. ^ Fox, A. W. (2004). "Onset of effect of 5-HT1B/1D agonists: a model with pharmacokinetic validation". Headache 44 (2): 142–147. doi:10.1111/j.1526-4610.2004.04030.x. PMID 14756852.  edit
  7. ^ Freidank-Mueschenborn, E.; Fox, A. (2005). "Resolution of concentration-response differences in onset of effect between subcutaneous and oral sumatriptan". Headache 45 (6): 632–637. doi:10.1111/j.1526-4610.2005.05129a.x. PMID 15953294.  edit
  8. ^ GSK press release – Treximet (sumatriptan and naproxen sodium) tablets approved by FDA for acute treatment of migraine
  9. ^ Brandes JL, Kudrow D, Stark SR, et al. (April 2007). "Sumatriptan-naproxen for acute treatment of migraine: a randomized trial". JAMA 297 (13): 1443–54. doi:10.1001/jama.297.13.1443. PMID 17405970. 
  10. ^ a b Brandes, J.; Cady, R.; Freitag, F.; Smith, T.; Chandler, P.; Fox, A.; Linn, L.; Farr, S. (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.  edit
  11. ^ ClinicalTrials.gov NCT00724815 The Efficacy and Tolerability of NP101 Patch in the Treatment of Acute Migraine (NP101-007)
  12. ^ SmartRelief -electronically assisted drug delivery (iontophoresis)
  13. ^ Pierce, M; Marbury, T; O'Neill, C; Siegel, S; Du, W; Sebree, T (2009). "Zelrix: a novel transdermal formulation of sumatriptan". Headache 49 (6): 817–25. doi:10.1111/j.1526-4610.2009.01437.x. PMID 19438727. 
  14. ^ Zecuity Approved by the FDA for the Acute Treatment of Migraine
  15. ^ "PAR PHARMACEUTICAL BEGINS SHIPMENT OF SUMATRIPTAN INJECTION". Par Pharmaceutical. 2008-11-06. Retrieved 2008-11-25. [dead link]