Ergot Alkaloids - Anti-Migraine Drugs

Ergot Alkaloids

Ergot is produced by a fungus, Claviceps purpurea, which infests certain types of grain, especially rye. The spores of the fungus are carried by insects or wind to young rye where they germinate into hyphae (filaments). The hyphae penetrate deep into the grain and harden into a purplish structure called sclerotium, which elaborates a number of ergot alkaloids, (videinfra). During wet seasons, C. purpura can infest wheat, barley,rye (most common), oats, wheatgrass, quackgrass, smooth bromegrass, wild rye and bluegrasses.

Examples of ergot alkaloids include dihydroergocornine, dihydroergocristine, dihydroergosine, dihydroergotamine, dihydroergotaxime, ergobasine, ergocornine, ergocristine, ergocryptine, ergosine, ergometrine or ergonovine, ergot-amine, ergotaxime, methylergonovine, bromocriptine, lergot-rile, lisuride, lysergol, metergoline, methylergonovine, and methysergide. All these are derivatives of 6-methylergoline, a tetracyclic compound. There have been more than 350 chemi-cals identified, but less than 10 are used therapeutically. The primary clinical uses have been to relieve the pain of migraine and to contract the post-partum uterus. Natural ergot is also the source of the potent hallucinogen lysergic acid diethylamide or LSD.

Uses

·              Treatment of migraine and cluster headaches.

·              Prophylaxis and treatment of postpartum or post-abortion bleeding.

·              Treatment of uterine atony, menorrhagia, and menopausal bleeding.

·              Bromocriptine is used in the treatment of Parkinsonism, suppression of lactation, hypogonadism, galactorrhoea, and mastalgia. It is also indicated for acromegaly.

·     Ergot derivatives (e.g. bromocriptine pergolide) have been used for the treatment of prolactin-secreting pituitary tumours and hyperprolactinaemic infertility.

·     Dihydrogenated ergot alkaloids (dihydroergocornine, dihydroergocristine and dihydroergocryptine) in combina-tion, (ergoloid mesylates) in equal amounts are available in numerous products for the relief of senility symptoms.

Toxicokinetics

·              Oral administration of ergot alkaloids is associated in general with poor absorption and extensive first-pass hepatic metabolism.

·              Ergotamine is absorbed erratically, incompletely, and slowly from the GI tract following therapeutic oral doses. Rectal doses seem to be absorbed more predictably.

·              Ergometrine is rapidly absorbed after oral and intramus-cular injection; onset of uterine contractions occur in about 5 to 15 minutes after an oral dose, and 2 or 3 minutes after an intramuscular dose.

·              Intramuscular absorption is unpredictable but is approxi- mately 10 times more when compared to oral administration.

·              Suppositories may increase bioavailability by as much as 20 times.

·              Peak plasma levels are generally achieved in 1/2 hour to 2 hours, volume of distribution is about 2 L/kg and half-life varies from 1.4 to 6.2 hours.

·              Ergotamine is metabolised by the liver by largely undefined pathways; 90% of the metabolites are excreted in the bile. Less than 10% is excreted in the urine.

Mode of Action

·              The ergot alkaloids act as partial agonists and/or antagonists at adrenergic, dopaminergic, and tryptaminergic (serotonin) receptors. The degree of activity of each alkaloid at these receptor sites varies greatly and determines the pharmaco- logical activity of the different agents.

·              The major pharmacological effects include smooth muscle stimulation, resulting in vasoconstriction, hypertension, increased uterine muscle activity, peripheral adrenergic blockade, and central sympatholytic activity, resulting in hypotension.

Adverse Effects

·              Nausea, vomiting, weakness in legs, myalgia, tingling and numbness of fingers and toes, precordial distress, tachy- or bradycardia, and localised itching and oedema.

·              Severe and sometimes fatal bronchospasm may occur following therapeutic doses of ergotamine in patients with a history of asthma.

·              A rare complication of methysergide use is pleuropulmo- nary fibrosis which resolves when the drug is discontinued.

·              Seizures may occur within a few hours of administration of ergot alkaloid uterotonics to neonates.

·              Foetal mortality and hypoxic-type anomalies along with other multiple deformities have been observed in humans and experimental animals. Foetal distress, stillbirths and abortion have also occurred.

·     Ergotamine is secreted into human milk and can exert its pharmacological effects to an infant by this route; cautious use is advised. Prolonged administration can inhibit lacta-tion.

·     The American Academy of Pediatrics considers the use of ergotamine during breastfeeding to be contraindicated based on a study in which vomiting, diarrhoea, and convul-sions were observed in most nursing infants.

Clinical (Toxic) Features

·            Excessive use of ergot preparations leads to a condition called ergotism which is characterised by burning of extremities, haemorrhagic vesiculations, pruritis, formi-cation, nausea, vomiting, bradycardia, and peripheral ischaemia of lower extremities sometimes leading to gangrene. Prolonged vasospasm and vasoconstriction are responsible for pain, pallor, coolness, paraesthesias, absence of pulse, and gangrene in the extremities.

·            Other features of toxicity due to ergot include headache, miosis, delirium, hallucinations, and convulsions.

·            Vomiting, diarrhoea, and abdominal cramps may occur.

·            Ischaemic pancreatitis and hepatitis have been reported following acute ergotamine poisoning.

·            Ischaemia of cerebral, mesenteric, coronary, and renal vasculature have also been reported.

·            Renal failure may develop in patients with renal arterial spasm or prolonged hypotension.

·            There are some studies indicating the predisposition to mitral and/or aortic valve disease (regurgitant as well as stenotic) in patients administered ergot alkaloids for prolonged periods.

·            Hypertension, hypotension, peripheral cyanosis, tachy-cardia, bradycardia, and myocardial infarction have occurred with both therapeutic doses and overdose.

·            Cerebral, coronary, mesenteric, ophthalmic and renal artery vasospasm may produce ischaemia or infarction in the corresponding end organ.

·            Toxicity of bromocriptine is dealt with in detail under Antiparkinsonian Drugs.

Drug Interactions

·     Serious, life-threatening peripheral ischaemia has been associated with the coadministration of ergotamine with potent CYP 3A4 inhibitors. The latter include protease inhibitors (ritonavir, nelfinavir, indinavir) and macrolide antibiotics (erythromycin, clarithromycin, and trolean-domycin).

·     Based on an increased risk for ergotism and other serious vasospastic adverse events, ergotamine use is contraindi-cated with these agents.

Treatment

Acute Poisoning:

·              Since even a small dose can lead to toxicity in hyper-sensitive individuals, all unintentional or intentional ingestions should be considered potentially toxic. Therapeutic doses may be fatal in those with underlying cardiovascular disease or other predisposing conditions. Toxicity has occurred following as little as 0.5 mg (IM, IV, or SC) of ergotamine, 0.2 mg of IV ergonovine or methylergonovine, less than 5 mg SL ergotamine, and 2 mg of rectal ergotamine. Conditions known to increase susceptibility to ergot toxicity include febrile states, sepsis, malnutrition, thyrotoxicosis, pregnancy, hepatic disease, renal disease, hypertension, coronary artery disease, and peripheral vascular disease.

·      Decontamination is usually not necessary because of spontaneous vomiting.

·      Activated charcoal is beneficial.

·      Hypertension or cerebral/mesenteric/cardiac ischaemia: IV nitroglycerine (10 to 20 mcg/min and increased by 5 or 10 mcg/min every 5 to 10 min) or nitroprusside (1 to 5 mcg/kg/min intravenously) titrated to adequate blood pressure and perfusion. Phentolamine has also been suggested for treatment of severe hypertension or cerebral, myocardial or mesenteric ischaemia. In less severe cases, oral prazosin (1 to 3 mg/day), or captopril (50 mg three times a day), or nifedipine (10 mg three times a day) may be used as an alternative to parenteral agents. Diazoxide, niacin, papaverine, phenoxyben-zamine, reserpine, and tolazoline have been used in the past but are no longer recommended.

·      Peripheral ischaemia: oral prazosin, captopril, or nifedi-pine titrated to adequate perfusion. Administration of sodium nitroprusside in doses of 1 to 5 mcg/kg/min intravenously has been shown to dramatically reduce systemic vascular resistance with accompanying improvement of ischaemia. Doppler ultrasound studies and plethysmography may support the diagnosis of peripheral vascular ischaemia and be useful in assessing the efficacy of treatment. Angiography is often used when the history and clinical features are inadequate to confirm diagnosis of vascular insuf-ficiency. It will also differentiate vascular spasm from thrombosis.

·      Anticoagulant (heparin in combination with sodium nitroprusside or nitroglycerin) therapy should be insti-tuted in all patients with evidence of vascular insuf-ficiency.

·      Hyperbaric oxygen treatment has been successful in reversing ergotamine-induced peripheral ischaemia when other measures (including nitroprusside) had failed.

·      For hypotension: Infuse 10 to 20 ml/kg of isotonic fluid and place in Trendelenburg position. If hypoten-sion persists, administer dopamine or noradrenaline. Consider central venous pressure monitoring to guide further fluid therapy.

·      Bradycardia: Give atropine (0.5 mg to 1 mg IV, repeated every five minutes if bradycardia persists).

·      Convulsions and hallucinations: diazepam or lorazepam titrated until these manifestations cease.

·              Hypercoagulable states: heparin or dextran titrated until anticoagulated.

Chronic Poisoning:

·              Withdraw drug.

·              Surgery (if gangrene is advanced).

·              Sympathetic block, epidural block, or sympathec-tomy which were all advocated in the past are no more recommended today. These methods mayrelieve vasoconstriction mediated via the CNS, but do not antagonise the direct action of ergot on arteriolar smooth muscle.

Forensic Issues

·              A relationship between puerperal psychosis and ergot adminis-tration (especially ergonovine) has been postulated.