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

Claviceps purpurea

CLASSIFICATION AMINE ALKALOIDS  6- Methylergoline, lysergic acid, lysergic acid diethylamide, ergometrine (ergonovine), methysergide PEPTIDE ALKALOIDS  Ergotamine, dihydroergotamine,  - 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 , serotonin Presynaptic 5HT receptor (5HT 1A/1D ) Partial agonist at 5HT 2 - uterus Partial agonist at CNS dopamine Antagonist at blood vessels dopamine

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

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

UTERUS Stimulation of  & 5HT 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 5HT 2 receptors Increase motility, diarrhea, abdominal cramps Dopamine receptors CTZ – anorexia, nausea, vomiting

CLINICAL USES MIGRAINE  Triptan drugs  Prodrome of attack – ergotamine tartrate  Increase absorption with caffeine  S/L 2 mg half hourly till relief - No more than 6mg for each attack or no more than 10mg /wk  mg I/V or I/M total dose of 2 -3mg in 24hrs  0.5 mg nasal spray- repeated after 15 mins if req. total dose of 2 mg in 24hrs

HYPERPROLACTINEMIA  Bromocriptine, cabergoline, pergolide PARKINSONISM  Bromocriptine, decrease EP effects POST PARTUM HEMORRHAGE  Ergonovine maleate 0.2 mg I/M DIAGNOSIS OF VARIANT ANGINA  Ergonovine to localize reactive segments of coronaries during angiography SENILE CEREBRAL INSUFFICIENCY  Alzheimer’s disease

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

Erythromelalgia

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