Ergot Alkaloids

Dr. Naila Abrar

LEARNING OBJECTIVESLEARNING 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 purpurea

DISCOVERY:DISCOVERY:

ERGOTISM: ERGOTISM:

St. Anthony’s fire

Claviceps purpurea

CLASSIFICATIONCLASSIFICATIONAMINE ALKALOIDSAMINE ALKALOIDS6- Methylergoline, lysergic acid, lysergic acid

diethylamide, ergometrine (ergonovine), methysergide

PEPTIDE ALKALOIDSPEPTIDE ALKALOIDSErgotamine, dihydroergotamine, - ergocryptine, bromocriptine

CHEMISTRYCHEMISTRY

• 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

PHARMACOKINETICSPHARMACOKINETICS

• 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 ACTIONMECHANISM OF ACTION

• Multi-receptor function• Agonist, partial agonist, and antagonist at ,

serotonin • Presynaptic 5HT receptor (5HT1A/1D)

• Partial agonist at 5HT2 - uterus

• Partial agonist at CNS dopamine• Antagonist at blood vessels dopamine

PHARMACOLOGICAL ACTIONSPHARMACOLOGICAL ACTIONS

CNS CNS • Hallucinogenic • LSD – drug abuse (agonist at 5HT2 in CNS)

• Nausea, vomiting – CTZ D2

• Decrease extrapyramidal symptoms - striatum D2

Inhibition of prolactin secretion – pituitary D2

Bromocriptine, pergolide, cabergoline

VASCULAR SMOOTH MUSCLEVASCULAR SMOOTH MUSCLE• stimulation – VC – increase TPR & BP• Also vascular 5HT2

• Ergotamine- partial agonist• Vasospasm • Flow of blood to periphery decreases• Slow dissociation from receptors

UTERUSUTERUS• Stimulation of & 5HT2

• More in uterus at term• Ergonovine (ergometrine) more selective • Rhythmic contractions and relaxation in

small doses and prolonged contracture at higher doses

GITGIT• Stimulation of 5HT2 receptors

• Increase motility, diarrhea, abdominal cramps

• Dopamine receptors CTZ – anorexia, nausea, vomiting

CLINICAL USESCLINICAL USESMIGRAINEMIGRAINETriptan drugsProdrome of attack – ergotamine tartrate Increase absorption with caffeineS/L 2 mg half hourly till relief - No more than 6mg

for each attack or no more than 10mg /wk0.25-0.5mg I/V or I/M total dose of 2 -3mg in 24hrs0.5 mg nasal spray- repeated after 15 mins if req.

total dose of 2 mg in 24hrs

HYPERPROLACTINEMIABromocriptine, cabergoline, pergolidePARKINSONISMBromocriptine, decrease EP effectsPOST PARTUM HEMORRHAGEErgonovine maleate 0.2 mg I/MDIAGNOSIS OF VARIANT ANGINAErgonovine to localize reactive segments of

coronaries during angiographySENILE CEREBRAL INSUFFICIENCYAlzheimer’s disease

ADVERSE EFFECTSADVERSE EFFECTS

GIT:GIT: NVD, abdominal crampsVASOSPASM:VASOSPASM: Severe, gangreneCNS:CNS: Hallucinations, delirium, mania, drowsiness,

sedation, drugs of abuse - LSDRETROPERITONEAL FIBROSIS: RETROPERITONEAL FIBROSIS: MethysergideERYTHROMELALGIA:ERYTHROMELALGIA: with ergot derived

dopamine agonists like pergolide BP:BP: Raised UTERUS:UTERUS: Abortion

Erythromelalgia

CONTRAINDICATIONSCONTRAINDICATIONS

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