Ergotamine

Ergotamine aborts attacks of migraine with or without aura by its specific vasotonic action on distended extracranial arteries. Ergotamine can cause vasoconstriction by stimulating alpha-adrenergic and 5-HT receptors. It displays moderate to high affinity for various serotonin receptor subtypes however its beneficial effect in migraine are primarily linked to agonist properties at 5-HT_1B and 5-HT_1D.

Regional changes to cerebral flows resulting from intracranial arterial vasodilatation accompany the migraine attack. The mechanism seems to be related to a reduction in systemic levels of serotonin which, in turn, leads to the vasomotor changes observed. Because of its direct vasoconstrictive effect on the smooth muscles of the dilated vessels, ergotamine aborts the migraine attack and vascular headaches. Ergotamine also acts on the vasomotor centres and leads to the blockage of peripheral alpha-adrenergic receptors.

Ergotamine exerts a tonic effect on the smooth vascular musculature and presents a particular affinity for arterial monoaminergic receptors (NA and HT), especially in the external carotid network.

Numerous studies performed in animals and humans have amply demonstrated that the vasoconstrictive action of ergotamine manifests itself selectively at the carotid and extracranial arteries and is due mainly to stimulation of serotonergic and alphaadrenergic receptors.

Absorption

Studies using tritium-labelled ergotamine indicate that 62% of an oral dose is absorbed from the gastrointestinal tract. Peak plasma levels are reached about 2 hours after ingestion.

Distribution

Protein binding for ergotamine amounts to 98%.

Biotransformation

Ergotamine is extensively metabolized in the liver and is a substrate for the CYP3A4 enzyme system. It has been suggested that the therapeutic effects of the drug are partially due to active metabolites.

Elimination

Parent drug and metabolites are mainly excreted in the bile. Their elimination from plasma is biphasic, with half-lives of 2.7 and 21 hours, respectively.

Chronic and subchronic toxicity

In a 26-week oral safety study in beagle dogs, ergotamine induced vomiting, salivation and decreased heart rate. In addition, superficial necrosis at the ear margin was observed, which is a common finding in lop-eared dogs and is due to the marked vasoconstrictor effect of the drug.

Carcinogenicity

There are no data about the carcinogenic potential of ergotamine.

Reproductive toxicity

Ergotamine showed no evidence for embryonal mortality or teratogenic effects in rabbits at 1, 3 and 10 mg/kg per day, and in rats at up to 3 mg/kg per day. However, in rats given 10 mg/kg per day, maternal weight increase was inhibited, fetal ossification retarded and prenatal mortality increased. High ergotamine doses constricted the uterine vessels, reduced blood supply and thus induced hypoxia which is known to be responsible for teratogenic effects in the offspring.

At high oral ergotamine doses, developmental toxicity (e.g. decreased fetal body weight, delayed skeletal ossification or increased prenatal mortality) was observed in experimental animals. This observation has been attributed to reduced uteroplacental blood flow resulting from prolonged vasoconstriction of the uterine vessels and/or increased myometrial tone induced by ergotamine. In a reproductive performance study in male rats, fertility was not impaired. In a reproductive performance study and a peri-/post-natal study in female rats, an increased number of stillbirth and/or peri-/post-natal mortality was observed.