Editing Sumatriptan (section)

==Pharmacology==

=== Mechanism of action ===
{| class="wikitable" class="wikitable floatright sortable"
|+<small>Receptor affinities of sumatriptan</small>
!<small>Receptor</small>
!<small>pK<sub>i</sub></small>
!<small>Source</small>
|-
|<small>'''5-HT<sub>1A</sub>'''</small>
|<small>5.99-6.59</small>
|<small><ref name="Boess_1994">{{cite journal | vauthors = Boess FG, Martin IL | title = Molecular biology of 5-HT receptors | journal = Neuropharmacology | volume = 33 | issue = 3–4 | pages = 275–317 | date = March 1994 | pmid = 7984267 | doi = 10.1016/0028-3908(94)90059-0 }}</ref></small>
|-
| rowspan="2" |<small>'''5-HT<sub>1B</sub>'''</small>
|<small>8.7 (human)</small>
|<small><ref name="Boess_1994" /></small>
|-
|<small>6.33-7.35 (rat)</small>
|<small><ref>{{cite journal | vauthors = Hamblin MW, Metcalf MA, McGuffin RW, Karpells S | title = Molecular cloning and functional characterization of a human 5-HT1B serotonin receptor: a homologue of the rat 5-HT1B receptor with 5-HT1D-like pharmacological specificity | journal = Biochemical and Biophysical Research Communications | volume = 184 | issue = 2 | pages = 752–759 | date = April 1992 | pmid = 1315531 | doi = 10.1016/0006-291X(92)90654-4 }}</ref></small>
|-
|<small>'''5-HT<sub>1Dα</sub>'''</small>
|<small>8.73-8.47</small>
|<small><ref name="Boess_1994" /></small>
|-
|<small>'''5-HT<sub>1Dβ</sub>'''</small>
|<small>7.21-8.11</small>
|<small><ref name="Boess_1994" /></small>
|-
|<small>'''5-HT<sub>1E</sub>'''</small>
|<small>5.68</small>
|<small><ref name="Boess_1994" /></small>
|-
|<small>'''5-HT<sub>1F</sub>'''</small>
|<small>7.1-7.64</small>
|<small><ref name="Boess_1994" /></small>
|-
|<small>'''5-HT<sub>2B</sub>'''</small>
|<small><6</small>
|<small><ref name="Boess_1994" /></small>
|-
|<small>'''5-HT<sub>2C</sub>'''</small>
|<small><5</small>
|<small><ref>{{cite journal | vauthors = Bonhaus DW, Weinhardt KK, Taylor M, DeSouza A, McNeeley PM, Szczepanski K, Fontana DJ, Trinh J, Rocha CL, Dawson MW, Flippin LA, Eglen RM | title = RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist | journal = Neuropharmacology | volume = 36 | issue = 4–5 | pages = 621–629 | date = April 1997 | pmid = 9225287 | doi = 10.1016/S0028-3908(97)00049-X }}</ref></small>
|-
|<small>'''5-HT<sub>4</sub>'''</small>
|<small><5 (guinea pig)</small>
|<small><ref name="Boess_1994" /></small>
|-
|<small>'''5-HT<sub>5A</sub>'''</small>
|<small>4.8-6.8 (mouse)</small>
|<small><ref name="Boess_1994" /></small>
|-
| rowspan="2" |<small>'''5-HT<sub>5B</sub>'''</small>
|<small>5.1 (mouse)</small>
|<small><ref name="Boess_1994" /></small>
|-
|<small>6.09 (rat)</small>
|<small><ref name="Boess_1994" /></small>
|-
|<small>'''5-HT<sub>6</sub>'''</small>
|<small><5.59</small>
|<small><ref>{{cite journal | vauthors = Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW | title = Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor | journal = Journal of Neurochemistry | volume = 66 | issue = 1 | pages = 47–56 | date = January 1996 | pmid = 8522988 | doi = 10.1046/j.1471-4159.1996.66010047.x }}</ref><ref>{{cite journal | vauthors = Hirst WD, Abrahamsen B, Blaney FE, Calver AR, Aloj L, Price GW, Medhurst AD | title = Differences in the central nervous system distribution and pharmacology of the mouse 5-hydroxytryptamine-6 receptor compared with rat and human receptors investigated by radioligand binding, site-directed mutagenesis, and molecular modeling | journal = Molecular Pharmacology | volume = 64 | issue = 6 | pages = 1295–1308 | date = December 2003 | pmid = 14645659 | doi = 10.1124/mol.64.6.1295 }}</ref></small>
|-
|<small>'''5-HT<sub>7</sub>'''</small>
|<small>6-7</small>
|<small><ref name="Boess_1994" /></small>
|-
|<small>'''CB1'''</small>
|<small><5</small>
|<small><ref>{{cite journal | vauthors = Plassat JL, Boschert U, Amlaiky N, Hen R | title = The mouse 5HT5 receptor reveals a remarkable heterogeneity within the 5HT1D receptor family | journal = The EMBO Journal | volume = 11 | issue = 13 | pages = 4779–4786 | date = December 1992 | pmid = 1464308 | pmc = 556953 | doi = 10.1002/j.1460-2075.1992.tb05583.x }}</ref></small>
|-
| colspan="3" |<small>The bigger pK<sub>i</sub> value, the stronger receptor affinity</small>
|}
{{Further|Serotonin receptor agonist|Triptan#Mechanism_of_action}}
Sumatriptan is molecularly similar to [[serotonin]] (5-HT), and is a [[5-HT receptor]] (types [[5-HT1D|5-HT<sub>1D</sub>]] and [[5-HT1B|5-HT<sub>1B</sub>]]<ref>
{{cite journal | vauthors = Razzaque Z, Heald MA, Pickard JD, Maskell L, Beer MS, Hill RG, Longmore J | title = Vasoconstriction in human isolated middle meningeal arteries: determining the contribution of 5-HT1B- and 5-HT1F-receptor activation | journal = British Journal of Clinical Pharmacology | volume = 47 | issue = 1 | pages = 75–82 | date = January 1999 | pmid = 10073743 | pmc = 2014192 | doi = 10.1046/j.1365-2125.1999.00851.x }}</ref>) [[agonist]]. Sumatriptan's primary therapeutic effect is related in its inhibition of the release of [[calcitonin gene-related peptide]] (CGRP), likely through its 5-HT<sub>1D/1B</sub> receptor agonist action.<ref>{{cite journal | vauthors = Juhasz G, Zsombok T, Jakab B, Nemeth J, Szolcsanyi J, Bagdy G | title = Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack | journal = Cephalalgia | volume = 25 | issue = 3 | pages = 179–183 | date = March 2005 | pmid = 15689192 | doi = 10.1111/j.1468-2982.2005.00836.x | s2cid = 13007101 }}</ref> This has been substantiated by the efficacy of more recently developed CGRP targeting drugs and antibodies developed for the preventive treatment of migraine.<ref>{{cite journal | vauthors = Tso AR, Goadsby PJ | title = Anti-CGRP Monoclonal Antibodies: the Next Era of Migraine Prevention? | journal = Current Treatment Options in Neurology | volume = 19 | issue = 8 | pages = 27 | date = August 2017 | pmid = 28653227 | pmc = 5486583 | doi = 10.1007/s11940-017-0463-4 }}</ref> How agonism of the 5-HT<sub>1D/1B</sub> receptors inhibits CGRP release is not fully understood. CGRP is believed to cause sensitization of trigeminal [[Nociception|nociceptive]] neurons, contributing to the pain experienced in migraine.<ref>{{cite journal | vauthors = Giniatullin R, Nistri A, Fabbretti E | title = Molecular mechanisms of sensitization of pain-transducing P2X3 receptors by the migraine mediators CGRP and NGF | journal = Molecular Neurobiology | volume = 37 | issue = 1 | pages = 83–90 | date = February 2008 | pmid = 18459072 | doi = 10.1007/s12035-008-8020-5 | s2cid = 25689799 }}</ref>

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.<ref>{{cite journal | vauthors =  Ekbom K, Waldenlind E, Richard L, Andersson B, Boivie J, Dizdar N, etal | title = Treatment of acute cluster headache with sumatriptan | journal = The New England Journal of Medicine | volume = 325 | issue = 5 | pages = 322–326 | date = August 1991 | pmid = 1647496 | doi = 10.1056/NEJM199108013250505 | collaboration = Sumatriptan Cluster Headache Study Group | doi-access = free }}</ref>

=== 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 formulations.<ref>{{Cite web |title=Sumatriptan |url=https://go.drugbank.com/drugs/DB00669 |access-date=2025-03-04 |website=go.drugbank.com |language=en}}</ref> When injected, sumatriptan is faster-acting (usually within 10 minutes), but the effect lasts for a shorter time.{{Citation needed|date=March 2025}}

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.<ref>{{cite journal |vauthors=Fox AW |date=February 2004 |title=Onset of effect of 5-HT1B/1D agonists: a model with pharmacokinetic validation |journal=Headache |volume=44 |issue=2 |pages=142–147 |doi=10.1111/j.1526-4610.2004.04030.x |pmid=14756852 |s2cid=25587940}}</ref><ref>{{cite journal |vauthors=Freidank-Mueschenborn E, Fox AW |date=June 2005 |title=Resolution of concentration-response differences in onset of effect between subcutaneous and oral sumatriptan |journal=Headache |volume=45 |issue=6 |pages=632–637 |doi=10.1111/j.1526-4610.2005.05129a.x |pmid=15953294 |s2cid=20755695}}</ref>

==== Metabolism ====
Sumatriptan is metabolised primarily by [[Monoamine oxidase|monoamine oxidase A]] into indol-3-yl-acetaldehyde and then into corresponding carboxylic acid. It is further modified by [[Glucuronosyltransferase|UDP-glucuronosyltransferase]] into a conjugate with [[glucuronic acid]]. Other pathways are mediated by [[Cytochrome P450 (individual enzymes)|cytochrome P450 isoenzymes]], which give an [[Amine oxide|''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 [[Cysteine|<small>D</small>-cysteine]].<ref name="Pöstges_2023">{{cite journal | vauthors = Pöstges T, Lehr M | title = Metabolism of sumatriptan revisited | journal = Pharmacology Research & Perspectives | volume = 11 | issue = 1 | pages = e01051 | date = February 2023 | pmid = 36655303 | pmc = 9849828 | doi = 10.1002/prp2.1051 }}</ref>

These metabolites are excreted in the urine and bile. Only about 3% of the active drug may be recovered unchanged.<ref name="AHFS2019" />
[[File:Sumatriptan metabolism pathway.png|center|thumb|881x881px|Sumatriptan metabolic pathways (MAO-A – monoamine oxidase A, CYP - cytochrome P450 isoenzymes)<ref name="Pöstges_2023" />]]