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Ergot Alkaloid Pharmacology
Module 1 — Chemistry, Receptor Pharmacology, and Toxicology
Origin and Structure
Biological Source
Claviceps purpurea
- Fungus that infects rye and cereal grains
- Sclerotia (ergots) concentrate alkaloids
- Contaminated grain caused epidemic ergotism historically
Structural Key
Lysergic Acid Backbone
- Tetracyclic ring system shared by all active derivatives
- Mimics serotonin, dopamine, and norepinephrine simultaneously
- Explains broad, non-selective receptor binding
Receptor Pharmacology
Three Receptor Families
Multi-Receptor Activity
- Serotonin type 1 and type 2 receptors
- Dopamine type 2 receptor
- Alpha-adrenergic receptors
- Degree of each varies by derivative
Core Concept
Partial Agonism
- High endogenous tone: ergot acts as antagonist
- Low endogenous tone: ergot acts as agonist
- Same drug, opposite effect — depends on tissue
Vasoconstriction and Toxicology
Mechanism
Vasoconstriction
- Alpha-adrenergic + serotonin type 2 receptor activation
- Cranial vessels: therapeutic in migraine
- Peripheral vessels: ischemia risk with excess
- Coronary vasospasm: absolute contraindication if coronary artery disease
- Acute: nausea, cold extremities, diminished pulses
- Chronic: dry gangrene from sustained vasoconstriction
- Treat: discontinue ergot, vasodilators, anticoagulation
Classic Drug Interaction
Ergot alkaloid + macrolide (erythromycin, clarithromycin) or azole antifungal or protease inhibitor → cytochrome P450 3A4 inhibition → ergot plasma concentrations rise dramatically → severe ergotism. Combination is absolutely contraindicated.