zolmitriptan

Zolmitriptan is used for the acute treatment of migraines with or without aura in adults. It is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine.

• Acute treatment of cluster headaches—Level A recommendation from the American Academy of Neurology{{cite journal | vauthors = Abram JA, Patel P | title = Zolmitriptan | journal = Statpearls| date = 2020 | pmid = 32491581}}50px Text was copied from this source, which is available under a [https://creativecommons.org/licenses/by/4.0/ Creative Commons Attribution 4.0 International License].
• Acute treatment of menstrual migraine

Zolmitriptan is available as a swallowed tablet, an orally disintegrating tablet, and as a nasal spray, in doses of 2.5 and 5{{nbsp}}mg. People who get migraines from aspartame should not use the disintegrating tablet (Zomig ZMT) as it contains aspartame.{{cite journal | journal = Headache: The Journal of Head and Face Pain | year = 2001 | volume = 41 | issue =9 | pages = 899–901 | doi= 10.1046/j.1526-4610.2001.01164.x | title =Migraine MLT-Down: An Unusual Presentation of Migraine in Patients With Aspartame-Triggered Headaches |vauthors=Newman LC, Lipton RB | doi-broken-date = 9 December 2024 | pmid = 11703479 | type =abstract}}

A 2014 Cochrane review has shown that zolmitriptan 5{{nbsp}}mg nasal spray was significantly more effective than the 5{{nbsp}}mg oral tablet.{{cite journal |vauthors=Bird S, Derry S, Moore RA |title=Zolmitriptan for acute migraine attacks in adults |journal=Cochrane Database Syst Rev |issue=5 |pages=CD008616 |date=May 2014 |volume=2014 |pmid=24848613 |pmc=6485805 |doi=10.1002/14651858.CD008616.pub2 }}

Zolmitriptan is contraindicated in patients with cerebrovascular or cardiovascular disease because serotonin 5-HT_1B receptors are present in coronary arteries. Such conditions include, but are not limited to, coronary artery disease, stroke, and peripheral vascular disease. It is also contraindicated in hemiplegic migraine.

Side effects include neck/throat/jaw pain/tightness/pressure, dizziness, paresthesia, asthenia, somnolence, warm/cold sensations, nausea, heaviness sensation, and dry mouth.

As for cardiovascular side effects, zolmitriptan can increase systolic blood pressure in the elderly and increase diastolic blood pressure in both the elderly and young people. Additionally, there is the side effect of a dose-related increase in sedation. There is a risk for medication withdrawal headache or medication overuse headache.

Zolmitriptan has a weak affinity for serotonin 5-HT_1A receptors; these receptors have been implicated in the development of serotonin syndrome.

There is limited experience with overdose of zolmitriptan and there is no specific antidote for zolmitriptan overdose. A dose of zolmitriptan of 50{{nbsp}}mg, which is 10- to 40-fold the clinically used dose range of 1.25 to 5{{nbsp}}mg, commonly resulted in sedation in patients in a clinical study. Zolmitriptan has a relatively short elimination half-life of 3{{nbsp}}hours, and so symptoms of overdose may be expected to resolve within around 15{{nbsp}}hours post-intake.

Following administration of the non-selective cytochrome P450 inhibitor cimetidine, the elimination half-life and total exposure of zolmitriptan and its active metabolite were approximately doubled. The major metabolite of zolmitriptan, N-desmethylzolmitriptan (183C91), which is active and has several-fold greater affinity for the serotonin 5-HT_1B and 5-HT_1D receptors than zolmitriptan, is metabolized into an inactive form by monoamine oxidase A (MAO-A). The reversible inhibitor of MAO-A (RIMA) moclobemide combined with zolmitriptan has been found to increase N-desmethylzolmitriptan exposure and peak levels by 1.5- to 3-fold.

Zolmitriptan is a selective serotonin 5-HT_1B and 5-HT_1D receptor agonist with weak affinity for the serotonin 5-HT_1A receptor. It also has affinity for other serotonin receptors, including the serotonin 5-HT_1E, 5-HT_1F, 5-HT_2B, 5-HT_5A, and 5-HT₇ receptors. Conversely, its affinities for the serotonin 5-HT_2A, 5-HT_2C, 5-HT₃, 5-HT₄, and 5-HT₆ receptors are negligible or undetectable. It is likewise inactive as a serotonin 5-HT_2A receptor agonist.

Zolmitriptan's major metabolite, N-desmethylzolmitriptan (183C91), is also active and has about 2- to 6-fold the affinity of zolmitriptan for the serotonin 5-HT_1B and 5-HT_1D receptors.{{cite journal | vauthors = Yu AM | title = Indolealkylamines: biotransformations and potential drug-drug interactions | journal = AAPS J | volume = 10 | issue = 2 | pages = 242–253 | date = June 2008 | pmid = 18454322 | pmc = 2751378 | doi = 10.1208/s12248-008-9028-5 | url = | quote = [...] the N-demethylated metabolites from zolmitriptan and eletriptan are both active at the 5-HT1B/1D sites. In particular, the N-desmethyl-zolmitriptan acts on 5-HT1B/1D receptors with an affinity about two- to six-fold of that of zolmitriptan and its steady state concentration is also higher than the parent drug. Therefore, N-desmethyl-zolmitriptan may have important contribution to the overall zolmitriptan drug effects. This active metabolite undergoes selective MAO-A-mediated deamination metabolism, resulting in an inactive indole acetic acid derivative (21) (Fig. 3). Because zolmitriptan is extensively N-demethylated and N-desmethyl-zolmitriptan is primarily excreted via deamination, potent MAO-A inhibitors are anticipated to alter the pharmacokinetics of N-desmethyl-zolmitriptan in humans. Indeed, concurrent use of selective MAO-A inhibitor, moclobemide, has been shown to cause 1.5- to 3-fold increase in the systemic exposure (AUC) and peak drug concentration (Cmax) of N-desmethyl-zolmitriptan (25).}}

Its action on serotonin 5-HT_1B and 5-HT_1D receptors causes vasoconstriction in intracranial blood vessels; as well it can inhibit the release of pro-inflammatory neuropeptides from trigeminal perivascular nerve endings. It crosses the blood–brain barrier as evidenced by the presence of radiolabeled zolmitriptan within the cells of the trigeminal nucleus caudalis and nucleus tractus solitarii.

Zolmitriptan has a rapid onset of action and has been detected in the brain as early as within 5{{nbsp}}minutes of intranasal administration. On average, zolmitriptan has an oral bioavailability of 40%, a mean volume of distribution of 8.3{{Nbsp}}L/kg after oral administration, and 2.4{{nbsp}}L/kg after intravenous administration. According to a study of healthy volunteers, food intake seems to have no significant effect on the effectiveness of zolmitriptan in both men and women.{{cite journal | vauthors = Seaber EJ, Peck RW, Smith DA, Allanson J, Hefting NR, van Lier JJ, Sollie FA, Wemer J, Jonkman JH | title = The absolute bioavailability and effect of food on the pharmacokinetics of zolmitriptan in healthy volunteers | journal = British Journal of Clinical Pharmacology | volume = 46 | issue = 5 | pages = 433–439 | date = November 1998 | pmid = 9833595 | pmc = 1873688 | doi = 10.1046/j.1365-2125.1998.00809.x | type = abstract }}

Zolmitriptan is a more lipophilic compound with greater central permeability than certain other triptans like sumatriptan.{{cite journal | vauthors = Martin GR | title = Pre-clinical pharmacology of zolmitriptan (Zomig; formerly 311C90), a centrally and peripherally acting 5HT1B/1D agonist for migraine | journal = Cephalalgia | volume = 17 | issue = Suppl 18 | pages = 4–14 | date = October 1997 | pmid = 9399012 | doi = 10.1177/0333102497017S1802 | url = }}{{cite journal | vauthors = Lionetto L, Casolla B, Mastropietri F, D'Alonzo L, Negro A, Simmaco M, Martelletti P | title = Pharmacokinetic evaluation of zolmitriptan for the treatment of migraines | journal = Expert Opin Drug Metab Toxicol | volume = 8 | issue = 8 | pages = 1043–1050 | date = August 2012 | pmid = 22762358 | doi = 10.1517/17425255.2012.701618 | url = }} It has been found to cross the blood–brain barrier and enter the central nervous system both in animals and humans.{{cite journal | vauthors = Deen M, Christensen CE, Hougaard A, Hansen HD, Knudsen GM, Ashina M | title = Serotonergic mechanisms in the migraine brain - a systematic review | journal = Cephalalgia | volume = 37 | issue = 3 | pages = 251–264 | date = March 2017 | pmid = 27013238 | doi = 10.1177/0333102416640501 | url = | quote = The central mechanisms of triptans are a subject of intense debate and have been investigated in several studies. Brain PET studies reported that zolmitriptan crosses the BBB and binds to central 5-HT1B receptors with relatively low occupancy (77,78). It is still unknown whether sumatriptan has a central effect.}} In a clinical pharmacokinetic study, brain concentrations were about 20% of plasma concentrations. However, in another clinical study, the drug achieved relatively low occupancy of central serotonin 5-HT_1B receptors (4–5%) as measured by positron emission tomography (PET) imaging.{{cite journal | vauthors = Varnäs K, Jučaite A, McCarthy DJ, Stenkrona P, Nord M, Halldin C, Farde L, Kanes S | title = A PET study with [11C]AZ10419369 to determine brain 5-HT1B receptor occupancy of zolmitriptan in healthy male volunteers | journal = Cephalalgia | volume = 33 | issue = 10 | pages = 853–860 | date = July 2013 | pmid = 23430984 | doi = 10.1177/0333102413476372 | url = }}{{cite journal | vauthors = Wall A, Kågedal M, Bergström M, Jacobsson E, Nilsson D, Antoni G, Frändberg P, Gustavsson SA, Långström B, Yates R | title = Distribution of zolmitriptan into the CNS in healthy volunteers: a positron emission tomography study | journal = Drugs in R&D | volume = 6 | issue = 3 | pages = 139–147 | date = 2005 | pmid = 15869317 | doi = 10.2165/00126839-200506030-00002 | url = }}

Zolmitriptan is metabolized into three major metabolites by the human hepatic cytochrome P450 enzymes—primarily CYP1A2. Two-thirds of the parent compound breaks down into the active metabolite N-desmethylzolmitriptan (183C91), while the remaining one-third separates into the other two inactive metabolites: zolmitriptan N-oxide and an indole acetic acid derivative. N-Desmethylzolmitriptan circulates at higher levels than those of zolmitriptan. This metabolite is deaminated by monoamine oxidase A (MAO-A).

Zolmitriptan has an elimination half-life of about 3{{nbsp}}hours before it undergoes renal elimination; its clearance is greater than the glomerular filtration rate suggesting that there is some renal tubular secretion of the compound.

Zolmitriptan is a triptan and a substituted tryptamine. It is specifically the derivative of N,N-dimethyltryptamine (DMT) in which the hydrogen atom at position 5 of the indole ring has been substituted with a [(4S)-2-oxo-1,3-oxazolidin-4-yl]methyl group.

The experimental log P of zolmitriptan is 1.6 to 1.8. For comparison, the experimental log P of sumatriptan is 0.93.{{cite web | title=Sumatriptan | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/5358 | access-date=27 October 2024}} It is much more lipophilic than sumatriptan.

Analogues of zolmitriptan include other triptans like sumatriptan, naratriptan, rizatriptan, eletriptan, almotriptan, and frovatriptan.

Zolmitriptan was patented in 1990 and was first described in the scientific literature by 1994.{{cite journal | vauthors = Goadsby PJ, Edvinsson L | title = Joint 1994 Wolff Award Presentation. Peripheral and central trigeminovascular activation in cat is blocked by the serotonin (5HT)-1D receptor agonist 311C90 | journal = Headache | volume = 34 | issue = 7 | pages = 394–399 | date = 1994 | pmid = 7928323 | doi = 10.1111/j.1526-4610.1994.hed3407394.x }}{{cite journal | vauthors = Martin GR | date = 1994 | title = Pre-clinical profile of the novel 5-HT 1D receptor agonist 311C90. | journal = New Advances in Headache Research | volume = 4 | pages = 3–4 }}{{cite journal | vauthors = Peck R, Dixon R, Seaber E, On N, Mercer J, Posner J, Roland PE | title = Clinical pharmacology of 311C90.| journal = New Advances in Headache Research | date = 1994 | volume = 4 | pages = 9–10 }} It was first introduced for medical use in the United States in 1997.{{cite web | title=AstraZeneca/Burroughs Wellcome | website=AdisInsight | date=5 November 2023 | url=https://adisinsight.springer.com/drugs/800002911 | access-date=20 June 2025}}

Zolmitriptan is marketed by AstraZeneca with the brand names Zomig, Zomigon (Argentina, Canada, and Greece), AscoTop (Germany) and Zomigoro (France).

In 2008, Zomig generated nearly $154 million in sales.{{cite web|url= http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard//drugtopics/192009/597083/article.pdf |archive-url= https://web.archive.org/web/20090521090922/http://drugtopics.modernmedicine.com:80/drugtopics/data/articlestandard/drugtopics/192009/597083/article.pdf |url-status= dead |archive-date= 2009-05-21 |title=2008 Top 200 generic drugs by retail dollars }}  {{small|(332 KB)}}. Drug Topics (May 26, 2009). Retrieved on August 25, 2009.

AstraZeneca's U.S. patent on Zomig tablets expired on November 14, 2012, and its pediatric exclusivity extension expired on May 14, 2013.{{Cite web|url=https://www.drugs.com/availability/generic-zomig-zmt.html|title=Generic Zomig-ZMT Availability|website=Drugs.com}} The patent in certain European countries has already expired too, and generic drug maker Actavis released a generic version in those countries, starting in March 2012.{{cite web |url=http://www.actavis.com/en/media+center/newsroom/articles/migraine_zolmitriptan_eu.htm |url-status=dead |archive-url=https://web.archive.org/web/20120323050048/http://www.actavis.com/en/media+center/newsroom/articles/migraine_zolmitriptan_eu.htm |archive-date=2012-03-23 |title=Migraine treatment Zolmitriptan launched by Actavis in Europe}}

In Russia, versions of zolmitriptan which are not registered in the National registry of medications may be regarded as narcotic drugs (derivatives of dimethyltriptamine).{{cite web|url=http://base.garant.ru/12112176/|title=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)|quote=ДМТ (диметилтриптамин) и его производные, за исключением производных, включенных в качестве самостоятельных позиций в перечень|publisher=Гарант|access-date=2019-04-29|lang=ru}}

Zolmitriptan showed no effect on obsessive–compulsive disorder (OCD) symptoms nor on mood or anxiety in a clinical study.{{cite journal | vauthors = Tiger M, Varnäs K, Okubo Y, Lundberg J | title = The 5-HT1B receptor - a potential target for antidepressant treatment | journal = Psychopharmacology (Berl) | volume = 235 | issue = 5 | pages = 1317–1334 | date = May 2018 | pmid = 29546551 | pmc = 5919989 | doi = 10.1007/s00213-018-4872-1 | url = }}{{cite journal | vauthors = Boshuisen ML, den Boer JA | title = Zolmitriptan (a 5-HT1B/1D receptor agonist with central action) does not increase symptoms in obsessive compulsive disorder | journal = Psychopharmacology (Berl) | volume = 152 | issue = 1 | pages = 74–79 | date = September 2000 | pmid = 11041318 | doi = 10.1007/s002130000529 | url = }}

{{See also|Serenic#Examples|Empathogen#Mechanism of action|List of investigational aggression drugs}}

Zolmitriptan, in a modified-release formulation with code name ML-004 (or ML004), is under development by MapLight Therapeutics for the treatment of pervasive developmental disorders (e.g., autism), agitation, and aggression.{{cite web | title=ML 004 | website=AdisInsight | date=8 June 2023 | url=https://adisinsight.springer.com/drugs/800061291 | access-date=27 October 2024}}{{cite web | title=Delving into the Latest Updates on ML-004 with Synapse | website=Synapse | date=28 September 2024 | url=https://synapse.patsnap.com/drug/64e037a51d55415f8f4919a04aef3082 | access-date=27 October 2024}}{{cite web | vauthors = Hess P | title=Going on Trial: Serotonin drug; psilocybin phase 2; placebo response data | website=The Transmitter: Neuroscience News and Perspectives | date=28 April 2023 | url=https://www.thetransmitter.org/spectrum/going-on-trial-serotonin-drug-psilocybin-phase-2-placebo-response-data/ | access-date=27 October 2024}}{{cite journal | vauthors = Wang L, Clark EA, Hanratty L, Koblan KS, Foley A, Dedic N, Bristow LJ | title = TAAR1 and 5-HT1B receptor agonists attenuate autism-like irritability and aggression in rats prenatally exposed to valproic acid | journal = Pharmacol Biochem Behav | volume = 245 | issue = | pages = 173862 | date = August 2024 | pmid = 39197535 | doi = 10.1016/j.pbb.2024.173862 | url = | quote = Interest in 5-HT1B as a target for ASD is further evidenced by the ongoing Phase 2 clinical trial of ML-004, a modified release form of the 5-HT1B/1D agonist zolmitriptan, which is being evaluated for the treatment of social communication deficits in adolescent and adult subjects with ASD (NCT05081245).}}{{cite web | title=Maplight Autism Study | website=Cortica | url=https://www.corticacare.com/research/maplight | access-date=27 October 2024 | quote=Purpose: The purpose of this study is to find out whether ML-004, an extended-release version of zolmitriptan, can support with sociability and emotional regulation in adults with ASD.}}{{cite web | url=https://www.pharmaceutical-technology.com/data-insights/zolmitriptan-maplight-therapeutics-autism-spectrum-disorder-asd-likelihood-of-approval/ | archive-url=https://web.archive.org/web/20240522133617/https://www.pharmaceutical-technology.com/data-insights/zolmitriptan-maplight-therapeutics-autism-spectrum-disorder-asd-likelihood-of-approval/ | archive-date=22 May 2024 | title=Zolmitriptan by MapLight therapeutics for Autism Spectrum Disorder (ASD): Likelihood of Approval }} The drug has been found to reduce aggression in rodents{{cite journal | vauthors = Rasia-Filho AA, Giovenardi M, de Almeida RM | title = Drugs and aggression | journal = Recent Pat CNS Drug Discov | volume = 3 | issue = 1 | pages = 40–49 | date = January 2008 | pmid = 18221240 | doi = 10.2174/157488908783421456 | url = | quote = In addition, the 5-HT1B receptors are of potential importance as target for treatment of different disorders such as depression, schizophrenia, Parkinson’s disease, and impulsive disorders [133]. Drugs acting as agonists at 5- HT1B receptors, when administered systemically, potently and efficaciously inhibit several types of aggressive behavior in mice [17,135; and for review see 63]. Systemically administered 5-HT1B receptor agonists such as CP-94,253, ampirtoline and zolmitriptan exert anti-aggressive effects in mice with moderate or high levels of aggression, without impairing non-aggressive activities [17, 23, 129,135]. Further support for the significant role of this receptor subtype derives from the finding of increased aggression in mutant 129Sv mice lacking the 5-HT1B receptor gene [136, and see 137].}}{{cite journal | vauthors = de Boer SF, Koolhaas JM | title = 5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis | journal = Eur J Pharmacol | volume = 526 | issue = 1-3 | pages = 125–139 | date = December 2005 | pmid = 16310183 | doi = 10.1016/j.ejphar.2005.09.065 | url = | quote = Using such an ethopharmacological approach in either rats or mice, it has recently been claimed that only certain specific 5-HT1A receptor agonists (i.e., alnespirone and S-15535; de Boer et al., 1999, 2000), a mixed 5-HT1A/1B receptor agonist (i.e., eltoprazine; Olivier et al., 1995) and several specific 5-HT1B receptor agonists (i.e., CGS12066b, CP-94,253, anpirtoline, zolmitriptan, sumatriptan; Bell and Hobson, 1994; Fish et al., 1999; De Almeida et al., 2001; Miczek et al., 2004) exert behavioral specific anti-aggressive effects. In particular, it was claimed that agonists acting on the 5-HT1B receptors have more selective anti-aggressive effects in mice than those acting on 5-HT1A receptors (Miczek et al., 2004; Olivier, 2004).}}{{cite journal | vauthors = de Almeida RM, Nikulina EM, Faccidomo S, Fish EW, Miczek KA | title = Zolmitriptan--a 5-HT1B/D agonist, alcohol, and aggression in mice | journal = Psychopharmacology (Berl) | volume = 157 | issue = 2 | pages = 131–141 | date = September 2001 | pmid = 11594437 | doi = 10.1007/s002130100778 | url = }} and has also been reported to decrease aggression in humans.{{cite journal | vauthors = Tricklebank MD, Robbins TW, Simmons C, Wong EH | title = Time to re-engage psychiatric drug discovery by strengthening confidence in preclinical psychopharmacology | journal = Psychopharmacology (Berl) | volume = 238 | issue = 6 | pages = 1417–1436 | date = June 2021 | pmid = 33694032 | pmc = 7945970 | doi = 10.1007/s00213-021-05787-x | url = | quote = A high proportion of violent acts are committed under the influence of alcohol. Aggressive behaviour can also be primed in the mouse by exposure to alcohol (De Almeida et al. 2001). In findings that are consistent with our knowledge of the relationship between serotonin and aggression (Pihl and Lemarquand 1998), this impact of alcohol can be ameliorated by treatment with the 5-HT1B/1D receptor agonist zolmitriptan, an approved anti-migraine drug. However, these findings have seemingly been overlooked despite the consistency of rodent and human data (Gowin et al. 2010).}}{{cite journal | vauthors = Gowin JL, Swann AC, Moeller FG, Lane SD | title = Zolmitriptan and human aggression: interaction with alcohol | journal = Psychopharmacology (Berl) | volume = 210 | issue = 4 | pages = 521–531 | date = July 2010 | pmid = 20407761 | pmc = 9150756 | doi = 10.1007/s00213-010-1851-6 | url = }} As of June 2023, zolmitriptan is in phase 2 clinical trials for pervasive developmental disorders, phase 1 clinical trials for agitation, and is in the preclinical stage of development for aggression.

{{Reflist}}

• {{cite journal | journal = Drugs Today | year = 1998 | volume = 34 | issue = 12 | pages = 1027–1033 | doi = 10.1358/dot.1998.34.12.487488 | title = Zolmitriptan clinical studies | vauthors = MacGregor EA | pmid = 14743270}}

• {{cite web | title=Zolmitriptan Nasal Spray | website=MedlinePlus | url=https://medlineplus.gov/druginfo/meds/a605046.html }}

{{Antimigraine preparations}}

{{Serotonin receptor modulators}}

{{Tryptamines}}

{{AstraZeneca}}

{{Portal bar | Medicine}}

Category:2-Oxazolidinones

Category:5-HT1B agonists

Category:5-HT1D agonists

Category:5-HT1E agonists

Category:5-HT1F agonists

Category:Dimethylamino compounds

Category:Drugs developed by AstraZeneca

Category:Experimental psychiatric drugs

Category:N,N-Dialkyltryptamines

Category:Triptans