Ergot Alkaloids

ERGOT ALKALOIDS

Ergot is a fungus Claviceps purpurea which grows on rye, millet and some other grains. The grain is replaced by a purple, hard, curved body called ‘sclerotium’. Epidemics of ergot poisoning (ergotism), due to consumption of contaminated grains, have been recorded from the beginning of history. It still occurs in epidemic and sporadic forms. Dry gangrene of hands and feet which become black (as if burnt) is the most prominent feature. Miscarriages occur in women and cattle. A convulsive type is also described.

Ergot had been used by midwives to quicken labour since the middle ages. This use received medical sanction in the 19th century, but its dangers were recognized by the beginning of the present century and then it was advocated only after delivery. Dale and Barger (1906 onwards) isolated the ergot alkaloids and studied their pharmacology. Ergometrine was isolated in 1935.

Ergot contains a host of pharmacologically active substances—alkaloids, LSD, histamine, ACh, tyramine and other amines, sterols, etc.

Natural Ergot Alkaloids

These are tetracyclic indole containing compounds which may be considered as derivatives of lysergic acid. They are divided into—

a)     Amine alkaloid Ergometrine (Ergonovine): which is oxytocic

b)    Amino acid alkaloids Ergotamine, Ergotoxine (mixture of ergocristine + ergocornine + ergocryptine): they are vasoconstrictor and α adrenergic blocker.

Other Semisynthetic Derivatives

a)     Dihydroergotamine (DHE), Dihydroergotoxine (Codergocrine): are antiadrenergic, cerebroactive.

b)    2Bromoαergocryptine (Bromocriptine): is a dopaminergic agonist.

c)     Methysergide: it is mainly anti 5HT.

Synthetic non-lysergic acid derivatives which pharmacologically resemble ergot alkaloids are — Lisuride, Pergolide, Lergotrile and Metergoline. The ergot alkaloid related compounds have diverse pharmacological properties. They act as agonists, partial agonists and antagonists on certain subtypes of α adrenergic, serotonergic and dopaminergic receptors in a tissue specific manner.

Actions

Ergotamine

It acts as a partial agonist and antagonist at α adrenergic and all subtypes of 5HT₁ and 5HT ₂ receptors, but does not interact with 5HT₃ or dopamine receptors: produces sustained vasoconstriction, visceral smooth muscle contraction, vasomotor centre depression and antagonizes the action of NA and 5HT on smooth muscles. The overall effect of oral/rectal doses of ergotamine on BP is insignificant. It is a potent emetic (through CTZ) and moderately potent oxytocic. At high doses CNS stimulation and paresthesias may be experienced. On chronic exposure (ergot poisoning) vasoconstriction is accompanied by damage to capillary endothelium—thrombosis, vascular stasis and gangrene.

Dihydroergotamine (DHE)

Hydrogenation of ergotamine reduces serotonergic and αadrenergic agonistic actions, but enhances αreceptor blocking property. Consequently DHE is a less potent vasoconstrictor; primarily constricts capacitance vessels and causes less intimal damage. It is a weaker emetic and oxytocic, but has some antidopaminergic action as well.

Dihydroergotoxine (Codergocrine)

This hydrogenated mixture of ergotoxine group of alkaloids is a more potent α blocker and a very weak vasoconstrictor. In the brain, a variety of partial agonistic/ antagonistic actions on 5HT receptors, metabolic and vascular effects and enhancement of ACh release in cerebral cortex have been demonstrated. It has been advocated for treatment of dementia (see Article No. 35).

Bromocriptine

The 2 bromo derivative of ergocryptine is a relatively selective dopamine D2 agonist on pituitary lactotropes (inhibits prolactin

release), in striatum (antiparkinsonian) and in CTZ (emetic—but less than ergotamine). In certain brain areas weak antidopaminergic action has also been shown. It has very weak anti 5HT or α blocking actions and is not an oxytocic.

Ergometrine (Ergonovine)

This amine ergot alkaloid has very weak agonistic and practically no antagonistic action on α adrenergic receptors: vasoconstriction is not significant. Partial agonistic action on 5HT receptors has been demonstrated in uterus, placental and umbilical blood vessels and in certain brain areas. It is a moderately potent 5HT₂ antagonist in g.i. smooth muscle and a weak dopaminergic agonist on the pituitary lactotropes as well as CTZ; emetic potential is low. The most prominent action is contraction of myometrium; used exclusively in obstetrics.

Pharmacokinetics

Oral bioavailability of amino acid ergot alkaloids and their hydrogenated derivatives is poor (< 1%) due to slow and incomplete absorption as well as high firstpass metabolism. Bioavailability is better after sublingual and rectal administration, but still often erratic. They are metabolized in liver and excreted primarily in bile. Ergotamine is sequestrated in tissues—produces longer lasting actions compared to its plasma t½ of 2 hours. Ergot alkaloids effectively cross bloodbrain barrier.

Adverse Effects

Nausea, vomiting, abdominal pain, muscle cramps, weakness, paresthesias, coronary and other vascular spasm, chest pain are the frequent side effects. These drugs are contraindicated in presence of sepsis, ischaemic heart disease, peripheral vascular disease, hypertension, pregnancy, liver and kidney disease.

Preparations And Dose

Ergotamine: For migraine 1–3 mg oral/sublingual, repeat as required (max 6 mg in a day); rarely 0.25–0.5 mg i.m. or s.c.; ERGOTAMINE, GYNERGEN, INGAGEN 1 mg tab, 0.5 mg/ml and 1 mg/ml inj.

Dihydroergotamine: For migraine 2–6 mg oral (max 10 mg/ day), 0.5–1 mg i.m., s.c. repeat hourly (max 3 mg); DIHYDERGOT, DHE 1 mg tab, MIGRANIL 1 mg/ml inj. Also used for postural hypotension, herpes zoster, mumps.

Dihydroergotoxine (codergocrine) For dementia 1–1.5 mg oral or sublingual, 0.15–0.6 mg i.m., HYDERGINE 1.5 mg tab, CERELOID 1 mg tab.