Zolmitriptan

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Zolmitriptan
Zolmitriptan Structure V.1.svg
Zolmitriptan 3D BS.png
Clinical data
Trade names Zomig, others
Other namesBW-311C90; BW311C90; 311C90; BW-311-C-90; ML-004; ML004; [(4S)-2-Oxo-1,3-oxazolidin-4-yl]methyl-N,N-dimethyltryptamine
AHFS/Drugs.com Monograph
MedlinePlus a601129
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth, nasal spray
Drug class Serotonin 5-HT1B and 5-HT1D receptor agonist; Antimigraine agent; Triptan
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Oral: 40% [2]
Protein binding 25% [2]
Metabolism Liver (CYP1A2-mediated, to active metabolite; also MAO Tooltip monoamine oxidase) [2]
Metabolites • N-Desmethylzolmitriptan [2]
• Zolmitriptan N-oxide [2]
• Indole acetic acid derivative [2]
Elimination half-life Zolmitriptan: 3 hours [2]
N-Desmethylzolmitriptan: 3.5 hours [2]
Excretion Urine: ~65% [2]
Feces: ~30% [2]
Identifiers
  • (S)-4-({3-[2-(Dimethylamino)ethyl]-1H-indol-5-yl}methyl)-1,3-oxazolidin-2-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.158.186 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C16H21N3O2
Molar mass 287.363 g·mol−1
3D model (JSmol)
  • O=C1OC[C@@H](N1)Cc2ccc3c(c2)c(c[nH]3)CCN(C)C
  • InChI=1S/C16H21N3O2/c1-19(2)6-5-12-9-17-15-4-3-11(8-14(12)15)7-13-10-21-16(20)18-13/h3-4,8-9,13,17H,5-7,10H2,1-2H3,(H,18,20)/t13-/m0/s1 Yes check.svgY
  • Key:ULSDMUVEXKOYBU-ZDUSSCGKSA-N Yes check.svgY
   (verify)

Zolmitriptan, sold under the brand name Zomig among others, is a serotonergic medication which is used in the acute treatment of migraine attacks with or without aura and cluster headaches. [3] It is taken by mouth as a swallowed or disintegrating tablet or as a nasal spray. [3]

Contents

Side effects include neck/throat/jaw pain/tightness/pressure, dizziness, paresthesia, asthenia, somnolence, warm/cold sensations, nausea, heaviness sensation, and dry mouth. [3] The drug acts as a selective serotonin 5-HT1B and 5-HT1D receptor agonist. [3] Structurally, it is a triptan and a tryptamine derivative. [3] [4]

It was patented in 1990 and was approved for medical use in 1997. [5] [3]

Medical uses

Migraine

Zolmitriptan is used for the acute treatment of migraines with or without aura in adults. [3] It is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine. [3]

Off-label uses

Available forms

Zolmitriptan is available as a swallowed tablet, an orally disintegrating tablet, and as a nasal spray, in doses of 2.5 and 5 mg. People who get migraines from aspartame should not use the disintegrating tablet (Zomig ZMT) as it contains aspartame. [7]

A 2014 Cochrane review has shown that zolmitriptan 5 mg nasal spray was significantly more effective than the 5 mg oral tablet. [8]

Contraindications

Zolmitriptan is contraindicated in patients with cerebrovascular or cardiovascular disease because serotonin 5-HT1B receptors are present in coronary arteries. Such conditions include, but are not limited to, coronary artery disease, stroke, and peripheral vascular disease. [6] It is also contraindicated in hemiplegic migraine. [6]

Side effects

Side effects include neck/throat/jaw pain/tightness/pressure, dizziness, paresthesia, asthenia, somnolence, warm/cold sensations, nausea, heaviness sensation, and dry mouth. [3]

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. [6]

Zolmitriptan has a weak affinity for serotonin 5-HT1A receptors; these receptors have been implicated in the development of serotonin syndrome. [6]

Interactions

Following administration of cimetidine, the elimination half-life and total exposure of zolmitriptan and its active metabolite were approximately doubled. [6]

Pharmacology

Mechanism of action

Zolmitriptan is a selective serotonin 5-HT1B and 5-HT1D receptor agonist with weak affinity for the serotonin 5-HT1A receptor. [9] It also has affinity for other serotonin receptors, including the serotonin 5-HT1E, 5-HT1F, 5-HT2B, 5-HT5A, and 5-HT7 receptors. [9] Conversely, its affinities for the serotonin 5-HT2A, 5-HT2C, 5-HT3, 5-HT4, and 5-HT6 receptors are negligible or undetectable. [9]

Its action on serotonin 5-HT1B and 5-HT1D 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. [6]

Pharmacokinetics

Zolmitriptan has a rapid onset of action and has been detected in the brain as early as within 5 minutes of intranasal administration. On average, zolmitriptan has an oral bioavailability of 40%, a mean volume of distribution of 8.3 L/kg after oral administration, and 2.4L/kg after intravenous administration. [6] 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. [10]

Zolmitriptan is a more lipophilic compound with greater central permeability than certain other triptans like sumatriptan. [11] [12] It has been found to cross the blood–brain barrier and enter the central nervous system both in animals and humans. [13] In a clinical pharmacokinetic study, brain concentrations were about 20% of plasma concentrations. [14] However, in another clinical study, the drug achieved relatively low occupancy of central serotonin 5-HT1B receptors (4–5%) as measured by positron emission tomography (PET) imaging. [13] [15] [14]

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. It has an elimination half-life of about 3 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. [6]

Chemistry

Zolmitriptan is a triptan and a substituted tryptamine. [3] [4] 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. [4]

The experimental log P of zolmitriptan is 1.6 to 1.8. [4] For comparison, the experimental log P of sumatriptan is 0.93. [16] It is much more lipophilic than sumatriptan. [9]

Analogues of zolmitriptan include other triptans like sumatriptan, naratriptan, rizatriptan, eletriptan, almotriptan, and frovatriptan. [9]

Society and culture

Brand names

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

Economics

In 2008, Zomig generated nearly $154 million in sales. [17]

AstraZeneca's U.S. patent on Zomig tablets expired on November 14, 2012, and its pediatric exclusivity extension expired on May 14, 2013. [18] 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. [19]

In Russia versions of zolmitriptan, which are not registered in the National registry of medications, may be regarded as narcotic drugs (derivatives of dimethyltriptamine). [20]

Research

Social deficits and aggression

Zolmitriptan, in a modified-release formulation that is being referred to by the developmental 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. [21] [22] [23] [24] [25] [26] As of June 2023, it 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. [21] [22] [23]

Related Research Articles

<span class="mw-page-title-main">Sumatriptan</span> Medication used for migraines & cluster headaches

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

<span class="mw-page-title-main">Ergotamine</span> Chemical compound in the ergot family of alkaloids

Ergotamine, sold under the brand name Ergomar among others, is an ergopeptine and part of the ergot family of alkaloids; it is structurally and biochemically closely related to ergoline. It is structurally similar to several neurotransmitters, and it acts as a vasoconstrictor. It is used for acute migraines, sometimes with caffeine as the combination ergotamine/caffeine.

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

Frovatriptan, sold under the brand name Frova, is a triptan drug developed by Vernalis for the treatment of migraine headaches and for short term prevention of menstrual migraine. The product is licensed to Endo Pharmaceuticals in North America and Menarini in Europe.

<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">Dihydroergotamine</span> Chemical 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.

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

Methylergometrine, also known as methylergonovine and sold under the brand name Methergine, is a medication of the ergoline and lysergamide groups which is used as an oxytocic in obstetrics and as an antimigraine agent in the treatment of migraine headaches. It reportedly produces psychedelic effects similar to those of lysergic acid diethylamide (LSD) at high doses.

<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 safety concerns. 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">Serotonin receptor agonist</span> Neurotransmission-modulating substance

A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.

<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.

5-HT<sub>1B</sub> receptor Mammalian protein found in Homo sapiens

5-hydroxytryptamine receptor 1B also known as the 5-HT1B receptor is a protein that in humans is encoded by the HTR1B gene. The 5-HT1B receptor is a 5-HT receptor subtype.

5-HT<sub>1D</sub> receptor Serotonin receptor which affects locomotion and anxiety in humans

5-hydroxytryptamine (serotonin) receptor 1D, also known as HTR1D, is a 5-HT receptor, but also denotes the human gene encoding it. 5-HT1D acts on the central nervous system, and affects locomotion and anxiety. It also induces vasoconstriction in the brain.

Triptans are a family of tryptamine-based drugs used as abortive medication in the treatment of migraines and cluster headaches. They 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.

<span class="mw-page-title-main">PNU-142633</span> Chemical compound

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

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<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.

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. ↑ "Product monograph brand safety updates". Health Canada . 6 June 2024. Retrieved 8 June 2024.
  2. 1 2 3 4 5 6 7 8 9 10 "Zolmitriptan: Uses, Interactions, Mechanism of Action". DrugBank Online. 25 November 1997. Retrieved 27 October 2024.
  3. 1 2 3 4 5 6 7 8 9 10 https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020768s023,021231s014,021450s010lbl.pdf
  4. 1 2 3 4 "Zolmitriptan". PubChem. Retrieved 27 October 2024.
  5. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 531. ISBN   9783527607495.
  6. 1 2 3 4 5 6 7 8 9 10 Abram JA, Patel P (2020). "Zolmitriptan". Statpearls. PMID   32491581. CC-BY icon.svg Text was copied from this source, which is available under a Creative Commons Attribution 4.0 International License.
  7. ↑ Newman LC, Lipton RB (2001). "Migraine MLT-Down: An Unusual Presentation of Migraine in Patients With Aspartame-Triggered Headaches". Headache: The Journal of Head and Face Pain (abstract). 41 (9): 899–901. doi:10.1046/j.1526-4610.2001.01164.x (inactive 9 December 2024). PMID   11703479.{{cite journal}}: CS1 maint: DOI inactive as of December 2024 (link)
  8. ↑ Bird S, Derry S, Moore RA (May 2014). "Zolmitriptan for acute migraine attacks in adults". Cochrane Database Syst Rev. 2014 (5): CD008616. doi:10.1002/14651858.CD008616.pub2. PMC   6485805 . PMID   24848613.
  9. 1 2 3 4 5 Tfelt-Hansen P, De Vries P, Saxena PR (December 2000). "Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy". Drugs. 60 (6): 1259–1287. doi:10.2165/00003495-200060060-00003. PMID   11152011.
  10. ↑ Seaber EJ, Peck RW, Smith DA, Allanson J, Hefting NR, van Lier JJ, et al. (November 1998). "The absolute bioavailability and effect of food on the pharmacokinetics of zolmitriptan in healthy volunteers". British Journal of Clinical Pharmacology (abstract). 46 (5): 433–439. doi:10.1046/j.1365-2125.1998.00809.x. PMC   1873688 . PMID   9833595.
  11. ↑ Martin GR (October 1997). "Pre-clinical pharmacology of zolmitriptan (Zomig; formerly 311C90), a centrally and peripherally acting 5HT1B/1D agonist for migraine". Cephalalgia. 17 Suppl 18: 4–14. doi:10.1177/0333102497017S1802. PMID   9399012.
  12. ↑ Lionetto L, Casolla B, Mastropietri F, D'Alonzo L, Negro A, Simmaco M, Martelletti P (August 2012). "Pharmacokinetic evaluation of zolmitriptan for the treatment of migraines". Expert Opin Drug Metab Toxicol. 8 (8): 1043–1050. doi:10.1517/17425255.2012.701618. PMID   22762358.
  13. 1 2 Deen M, Christensen CE, Hougaard A, Hansen HD, Knudsen GM, Ashina M (March 2017). "Serotonergic mechanisms in the migraine brain - a systematic review". Cephalalgia. 37 (3): 251–264. doi:10.1177/0333102416640501. PMID   27013238. 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.
  14. 1 2 Wall A, Kågedal M, Bergström M, Jacobsson E, Nilsson D, Antoni G, Frändberg P, Gustavsson SA, Långström B, Yates R (2005). "Distribution of zolmitriptan into the CNS in healthy volunteers: a positron emission tomography study". Drugs R D. 6 (3): 139–147. doi:10.2165/00126839-200506030-00002. PMID   15869317.
  15. ↑ Varnäs K, Jučaite A, McCarthy DJ, Stenkrona P, Nord M, Halldin C, Farde L, Kanes S (July 2013). "A PET study with [11C]AZ10419369 to determine brain 5-HT1B receptor occupancy of zolmitriptan in healthy male volunteers". Cephalalgia. 33 (10): 853–860. doi:10.1177/0333102413476372. PMID   23430984.
  16. ↑ "Sumatriptan". PubChem. Retrieved 27 October 2024.
  17. ↑ "2008 Top 200 generic drugs by retail dollars" (PDF). Archived from the original (PDF) on 2009-05-21. (332 KB). Drug Topics (May 26, 2009). Retrieved on August 25, 2009.
  18. ↑ "Generic Zomig-ZMT Availability".
  19. ↑ "Migraine treatment Zolmitriptan launched by Actavis in Europe". Archived from the original on 2012-03-23.
  20. ↑ "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 2019-04-29. ДМТ (диметилтриптамин) и его производные, за исключением производных, включенных в качестве самостоятельных позиций в перечень
  21. 1 2 "ML 004". AdisInsight. 8 June 2023. Retrieved 27 October 2024.
  22. 1 2 "Delving into the Latest Updates on ML-004 with Synapse". Synapse. 28 September 2024. Retrieved 27 October 2024.
  23. 1 2 Hess P (28 April 2023). "Going on Trial: Serotonin drug; psilocybin phase 2; placebo response data". The Transmitter: Neuroscience News and Perspectives. Retrieved 27 October 2024.
  24. ↑ Wang L, Clark EA, Hanratty L, Koblan KS, Foley A, Dedic N, Bristow LJ (August 2024). "TAAR1 and 5-HT1B receptor agonists attenuate autism-like irritability and aggression in rats prenatally exposed to valproic acid". Pharmacol Biochem Behav. 245: 173862. doi:10.1016/j.pbb.2024.173862. PMID   39197535. 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).
  25. ↑ "Maplight Autism Study". Cortica. Retrieved 27 October 2024. 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.
  26. ↑ "Zolmitriptan by MapLight therapeutics for Autism Spectrum Disorder (ASD): Likelihood of Approval". Archived from the original on 22 May 2024.

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