Zolmitriptan
Medication used in treatment of migraines From Wikipedia, the free encyclopedia
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]
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| Trade names | Zomig, others |
| Other names | BW-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 |
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| Routes of administration | By mouth, nasal spray |
| Drug class | Serotonin 5-HT1B and 5-HT1D receptor agonist; Antimigraine agent; Triptan |
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| Bioavailability | Oral: 40%[2] |
| Protein binding | 25%[2] |
| Metabolism | Liver (CYP1A2-mediated, to active metabolite; also MAO)[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] |
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| ECHA InfoCard | 100.158.186 |
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| Formula | C16H21N3O2 |
| Molar mass | 287.363 g·mol−1 |
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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
- Acute treatment of cluster headaches—Level A recommendation from the American Academy of Neurology[6]
- Acute treatment of menstrual migraine[6]
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
Summarize
Perspective
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, and 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]
Legal status
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 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.[21][22][23][24][25][26] The drug has been found to reduce aggression in rodents[27][28][29] and has also been reported to decrease aggression in humans.[30][31] 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.[21][22][23]
References
Further reading
External links
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