Ergot Alkaloids Dr Naila Abrar LEARNING OBJECTIVES After

Ergot Alkaloids Dr. Naila Abrar

LEARNING OBJECTIVES After this session, you should be able to: • know the source and classification of ergot alkaloids; • describe pharmacological actions of ergot alkaloids; • comprehend the clinical indications of ergot alkaloids; and • describe the adverse effects & contraindications of ergot alkaloids.

SOURCE: fungus - Claviceps purpurea DISCOVERY: ERGOTISM: St. Anthony’s fire

Claviceps purpurea

CLASSIFICATION AMINE ALKALOIDS Ø 6 - Methylergoline, lysergic acid diethylamide, ergometrine (ergonovine), methysergide PEPTIDE ALKALOIDS ØErgotamine, dihydroergotamine, a - ergocryptine, bromocriptine

CHEMISTRY • Ergoline nucleus • Derivatives of tetracyclic compound 6 methylergoline • Substituent in beta configuration at position 8 and a double bond in ring D • Natural alkaloids: ergotamine, ergonovine (derivatives of d-lysergic acid) • Semisynthetic & synthetic: dihydroergotamine, bromocriptine, LSD, methysergide

PHARMACOKINETICS • Variable absorption from GIT • Ergotamine- poor oral BA • Speed of absorption and peak blood levels of ergotamine improved with caffeine • Routes: oral S/L, I/M, I/V, nasal, rectal • Extensive metabolism • Ergonovine & methylergonovine - rapidly absorbed

MECHANISM OF ACTION • Multi-receptor function • Agonist, partial agonist, and antagonist at a , serotonin • Presynaptic 5 HT receptor (5 HT 1 A/1 D) • Partial agonist at 5 HT 2 - uterus • Partial agonist at CNS dopamine • Antagonist at blood vessels dopamine

PHARMACOLOGICAL ACTIONS CNS • Hallucinogenic • LSD – drug abuse (agonist at 5 HT 2 in CNS) • Nausea, vomiting – CTZ D 2 • Decrease extrapyramidal symptoms - striatum D 2 Ø Inhibition of prolactin secretion – pituitary D 2 Ø Bromocriptine, pergolide, cabergoline

VASCULAR SMOOTH MUSCLE • • • a stimulation – VC – increase TPR & BP Also vascular 5 HT 2 Ergotamine- partial agonist Vasospasm Flow of blood to periphery decreases Slow dissociation from receptors

UTERUS • • Stimulation of a & 5 HT 2 More in uterus at term Ergonovine (ergometrine) more selective Rhythmic contractions and relaxation in small doses and prolonged contracture at higher doses

GIT • Stimulation of 5 HT 2 receptors • Increase motility, diarrhea, abdominal cramps • Dopamine receptors CTZ – anorexia, nausea, vomiting

CLINICAL USES MIGRAINE Ø Triptan drugs Ø Prodrome of attack – ergotamine tartrate Ø Increase absorption with caffeine Ø S/L 2 mg half hourly till relief - No more than 6 mg for each attack or no more than 10 mg /wk Ø 0. 25 -0. 5 mg I/V or I/M total dose of 2 -3 mg in 24 hrs Ø 0. 5 mg nasal spray- repeated after 15 mins if req. total dose of 2 mg in 24 hrs

HYPERPROLACTINEMIA Ø Bromocriptine, cabergoline, pergolide PARKINSONISM Ø Bromocriptine, decrease EP effects POST PARTUM HEMORRHAGE Ø Ergonovine maleate 0. 2 mg I/M DIAGNOSIS OF VARIANT ANGINA Ø Ergonovine to localize reactive segments of coronaries during angiography SENILE CEREBRAL INSUFFICIENCY Ø Alzheimer’s disease

ADVERSE EFFECTS GIT: NVD, abdominal cramps VASOSPASM: Severe, gangrene CNS: Hallucinations, delirium, mania, drowsiness, sedation, drugs of abuse - LSD RETROPERITONEAL FIBROSIS: Methysergide ERYTHROMELALGIA: with ergot derived dopamine agonists like pergolide BP: Raised UTERUS: Abortion

Erythromelalgia

CONTRAINDICATIONS • • • Pregnancy Renal disease Hepatic disease Psychotic illness Collagen diseases Peripheral Vascular disease