Cafergot Mechanism of Action

Pharmacotherapeutic Group: Antimigraine preparations. ATC Code: N02CA52.
Pharmacology: Pharmacodynamics: Ergotamine has a tonic action on vascular smooth muscle and has a special affinity for arterial monoaminergic receptors (NA and HT), especially in the external carotid network.
Ergotamine may lead to vasoconstriction by stimulating alpha-adrenergic and 5-HT receptors. It has a moderate to elevated affinity for several sub-types of serotoninergic receptors, but its beneficial effect on migraine is mainly linked to its action as an agonist of 5-HT1B and 5-HT1D receptors.
Ergotamine aborts attacks of migraine with or without aura by its specific vasotonic action on distended extracranial arteries. Caffeine accelerates and increases the enteral absorption of egotamine.
Pharmacokinetics: Ergotamine: Absorption: Ergotamine is rapidly absorbed following oral administration. Maximum plasma concentrations are reached 1.5 to 2 hours after administration.
Studies with tritium-labelled ergotamine have shown that approximately 62% of the oral dose is absorbed via the gastrointestinal route. Maximum plasma concentrations are reached approximately 2 hours after ingestion.
Any potential increase in plasma caffeine concentrations due to an interaction with one or more other medicinal products may lead to a rise in ergotamine absorption. Caffeine is significantly metabolised by CYP1A2 and medicinal products that increase or reduce enzyme activity may affect the metabolic clearance of caffeine.
Distribution: Oral bioavailability is 62 ± 3%.
The medicinal product has a high level of tissue affinity.
Protein binding of ergotamine is 98%. The absolute bioavailability of the parent drug is approximately 2% following oral administration and approximately 5% following rectal administration.
Biotransformation: Ergotamine is significantly metabolised in the liver and is a substrate of the CYP3A4 enzyme system. It has been suggested that the therapeutic effects of the medicinal product are partially linked to the active metabolites.
Elimination: The parent drug and metabolites are excreted mainly in the bile. Plasma elimination takes place in two stages, with alpha and beta half-lives of 2.7 and 21 hours, respectively.
Elimination in the urine is low (4.3 ± 0.4%). The drug is primarily eliminated via the biliary and faecal routes.
The addition of caffeine speeds up excretion into the blood and increases gastric absorption by at least 44%.
Caffeine: Absorption: Following oral administration, caffeine is rapidly and almost completely absorbed via the gastrointestinal route, and the maximum concentrations reached after the oral administration of 175 mg are between 5 and 10 μg/ml. Maximum plasma concentrations are reached between 15 and 120 minutes after administration.
Distribution: Plasma protein binding of caffeine is 35%. Tissue distribution of caffeine in the body is relatively uniform, including in the cerebrospinal fluid, breast milk, saliva and sperm. The volume of distribution is approximately 0.7 l/kg. Caffeine crosses the placental barrier.
Biotransformation: Caffeine is mostly metabolised by CYP1A2 into paraxanthine. Paraxanthine is metabolised in turn into uracil and uric acid derivatives by demethylation and hydroxylation. The plasma elimination half-life is approximately 3.5 hours.
Elimination: Metabolites are predominantly excreted in the urine. Caffeine clearance is increased by smoking.