Selective 5HT1B/1D Agonists

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Chapter: Essential pharmacology : 5Hydroxytryptamine, Its Antagonists And Drug Therapy Of Migraine

These are a new class of antimigraine drugs that selectively activate 5HT1B/1D receptors, and are called ‘triptans’. Currently, they are the preferred drugs for patients who fail to respond to analgesics.


SELECTIVE 5HT1B/1D  AGONISTS

 

These are a new class of antimigraine drugs that selectively activate 5HT1B/1D receptors, and are called ‘triptans’. Currently, they are the preferred drugs for patients who fail to respond to analgesics. Ergot alkaloids are now required only in few cases. Because these drugs have been designed to act on the same subtype of 5HT receptor, pharmacodynamic differences among them are minor, but there are significant pharmacokinetic differences. All have higher oral bioavailability than sumatriptan. Fewer headache recurrences in an attack are reported with naratriptan and frovatriptan due to their longer t½, but may be slower in affording initial pain relief.

 

Sumatriptan

 

It is the first selective 5HT1B/1D receptor agonist; activates other subtypes of 5HT1 receptors only at very high concentrations, and does not interact with 5HT2, 5HT3, 5HT47, or β adrenergic, dopaminergic, cholinergic or GABA receptors. Administered at the onset of an attack of migraine, sumatriptan is as effective and better tolerated than ergotamine. About 3/4 patients obtain complete/significant relief within 2–3 hours. However, recurrence of headache within 24 hr has been noted in 20–40% patients, probably due to short t½ of sumatriptan. It tends to suppress nausea and vomiting of migraine, while ergotamine accentuates these symptoms.

 

The antimigraine activity of sumatriptan has been ascribed to 5HT1B/1D receptor mediated constriction of dilated cranial extracerebral blood vessels, especially the arteriovenous shunts in the carotid artery, which express 5HT1B/1D receptors. Dilatation of these shunt vessels during migraine attack is believed to divert blood flow away from brain parenchyma. In addition it can reduce 5HT and inflammatory neuropeptide release around the affected vessels as well as extravasation of plasma proteins across dural vessels. Like ergotamine, the triptans have been found to suppress neurogenic inflammation of cranial vessels. Suppression of impulse transmission in the trigeminovascular system has also been implicated.

 

 

Pharmacokinetics:

 

Sumatriptan is absorbed rapidly and completely after s.c. injection. Oral bioavailability averages 15%. It is rapidly metabolized by MAOA isoenzyme and metabolites are excreted in urine; elimination t½ is ~2 hours.

 

Side Effects: to sumatriptan are usually mild. Tightness in head and chest, feeling of heat and other paresthesias in limbs, dizziness, weakness are short lasting, but dose related side effects.

 

These are more common after s.c. injection, which is painful. Slight rise in BP occurs, but has little clinical relevance, because sumatriptan is not a drug for regular use. Bradycardia, coronary vasospasm and risk of myocardial infarction are the serious, but infrequent adverse effects. Few cases of sudden death have been ascribed to sumatriptan. Seizures and hypersensitivity reactions are rare.

 

Contraindications: are in patients with ischaemic heart disease, hypertension, epilepsy, hepatic or renal impairment and during pregnancy. Patients should be cautioned not to drive.

 

Sumatriptan and ergotamine should not be administered within 24 hours of each other. Interaction with 5HT uptake inhibitors, MAO inhibitors and lithium has been reported.

 

Dose: 50–100 mg oral at the onset of migraine attack, may be repeated once within 24 hours if required. Those not responding to the first dose should not be given the second dose. It is the only triptan available for parenteral use; 6 mg s.c. may be given to patients who cannot take the drug orally or in whom the pain develops very rapidly; acts in 10–20 min and is more consistently effective.

 

MIGRATAN, 50, 100 mg tabs, SUMINAT 25, 50, 100 mg tab, 60 mg/5 ml inj; SUMITREX 25, 50, 100 mg tab, 6 mg/0.5 ml inj.

 

Rizatriptan: This congener of sumatriptan is more potent, has higher oral bioavailability with slightly faster onset of action.

 

Dose: 10 mg; repeat once after 2 hr (if required).

 

RIZACT 5, 10 mg tab.

 

Naratriptan,       Zolmitriptan,     Almotriptan,     Frovatriptan         and Eletriptan  are  other  triptans  used  in  some  countries.

 

Features of some triptans are compared in the box.

 


 

* Tmax: Time to peak plasma concentration after oral dosing.


 

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