Zolmitriptan

Zolmitriptan

File:Zolmitriptan.svg
File:Zolmitriptan 3D BS.png
Clinical data
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; [(4S)-2-Oxo-1,3-oxazolidin-4-yl]methyl-DMT
AHFS/Drugs.com	Monograph
MedlinePlus	a601129
License data	US DailyMed: Zolmitriptan
Pregnancy category	AU: B3
Routes of administration	By mouth, intranasal
Drug class	Serotonin 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F receptor agonist; Antimigraine agent; Triptan
ATC code	N02CC03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) / S3 CA: ℞-only US: ℞-only
Pharmacokinetic data
Bioavailability	Oral: 40%
Protein binding	25%
Metabolism	Liver (CYP1A2-mediated, to active metabolite; also MAO-ATooltip monoamine oxidase A)
Metabolites	• N-Desmethylzolmitriptan • Zolmitriptan N-oxide • Indole acetic acid derivative
Elimination half-life	Zolmitriptan: 3 hours N-Desmethylzolmitriptan: 3.5 hours
Excretion	Urine: ~65% Feces: ~30%
Identifiers
IUPAC name (S)-4-({3-[2-(Dimethylamino)ethyl]-1H-indol-5-yl}methyl)-1,3-oxazolidin-2-one
CAS Number	139264-17-8 checkY
PubChem CID	60857
IUPHAR/BPS	60
DrugBank	DB00315 checkY
ChemSpider	54844 checkY
UNII	2FS66TH3YW
KEGG	D00415 checkY
ChEBI	CHEBI:10124 checkY
ChEMBL	ChEMBL1185 checkY
E number	{{#property:P628}}
CompTox Dashboard (EPA)	{{#property:P3117}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C16H21N3O2
Molar mass	287.363 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C1OC[C@@H](N1)Cc2ccc3c(c2)c(c[nH]3)CCN(C)C
InChI 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 checkY Key:ULSDMUVEXKOYBU-ZDUSSCGKSA-N checkY
(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. It is taken by mouth as a swallowed or disintegrating tablet or as a nasal spray.

Side effects include tightness in the neck or throat, jaw pain, dizziness, paresthesia, asthenia, somnolence, warm/cold sensations, nausea, chest pressure, and dry mouth. The drug acts as a selective serotonin 5-HT_1B and 5-HT_1D receptor agonist. Structurally, it is a triptan and a tryptamine derivative.

It was patented in 1990 and was approved for medical use in 1997.

Medical uses

Migraine

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.

Off-label uses

• Acute treatment of cluster headaches—Level A recommendation from the American Academy of Neurology
• Acute treatment of menstrual migraine

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.

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

Contraindications

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

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.

Overdose

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

Interactions

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.

Pharmacology

Pharmacodynamics

Zolmitriptan activities

Target	Affinity (Ki, nM)
5-HT1A	16–316 (Ki) 3,020–>10,000 (EC50Tooltip half-maximal effective concentration) 55% (EmaxTooltip maximal efficacy)
5-HT1B	0.47–20 (Ki) 3.8–60 (EC50) 99–102% (Emax)
5-HT1D	0.11–4 (Ki) 0.29–1.6 (EC50) 86–106% (Emax)
5-HT1E	10–>10,000 (Ki) 6.6–62 (EC50) 101% (Emax)
5-HT1F	28–617 (Ki) 10–420 (EC50) 97% (Emax)
5-HT2A	>10,000 (Ki) >10,000 (EC50)
5-HT2B	65–>10,000 (Ki) >10,000 (EC50)
5-HT2C	79,400 (Ki) (guinea pig) ND (EC50)
5-HT3	>3,160 (mouse)
5-HT4	>3,160 (guinea pig)
5-HT5A	398 (rat)
5-HT6	>3,160
5-HT7	87–96 (Ki) 525 (EC50)
α1A–α1D	ND
α2	79,000
α2A–α2C	ND
β1–β3	ND
D1, D2	>100,000
D3–D5	ND
H1–H4	ND
M1–M5	ND
I1, I2	ND
σ1, σ2	ND
TAAR1Tooltip Trace amine-associated receptor 1	ND
SERTTooltip Serotonin transporter	ND
NETTooltip Norepinephrine transporter	ND
DATTooltip Dopamine transporter	ND
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs:

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.

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.

Pharmacokinetics

Absorption

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 2.4 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.

Distribution

Zolmitriptan is a more lipophilic compound with greater central permeability than certain other triptans like sumatriptan. It has been found to cross the blood–brain barrier and enter the central nervous system both in animals and humans. 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.

Metabolism

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).

Elimination

Zolmitriptan 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.

Chemistry

Zolmitriptan, also known as [(4S)-2-oxo-1,3-oxazolidin-4-yl]methyl-N,N-dimethyltryptamine, is a tryptamine derivative and a 5-substituted derivative of the psychedelic drug dimethyltryptamine (DMT). It is specifically the derivative of 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 0.8 to 0.93. Zolmitriptan is much more lipophilic than sumatriptan.

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

History

Zolmitriptan was patented in 1990 and was first described in the scientific literature by 1994. It was first introduced for medical use in the United States in 1997.

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.

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

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).

Research

Obsessive–compulsive disorder

Zolmitriptan showed no effect on obsessive–compulsive disorder (OCD) symptoms nor on mood or anxiety in a clinical study.

Social deficits and aggression

See also: Serenic § Examples, Entactogen § Mechanism of action, and 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. The drug has been found to reduce aggression in rodents and has also been reported to decrease aggression in humans. 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.