Medical Pharmacology Topics   

Ergot Alkaloids

Ergot alkaloids come from a grain fungus. Lysergic acid forms their structural backbone. The levo (-) isomers of ergot alkaloids are pharmacologically active. Their pharmacology is very complex: they may be agonist or antagonists of dopamine, seratonin and/or a-adrenergic receptors. In general, they markedly vasoconstrict the carotid vasculature (blood supply to face and neck), affecting large conducting arteries more than arterioles.

The ergot alkaloids are classified as either amine alkaloides or ergopeptines. Several ergot alkalaoids are used in the treatment of migrane. Migrane is defined as recurrent headaches lasting 4-72 hrs, with our wihtout nausea or aura (visual/auditory disturbances). It is due to inflammation of the dura after trigeminal stimulation. Migranes also respond to non-steroidal antinflammatory drugs (NSAIDs) and triptan treatment. Sumatriptan is a non-ergot with potent seratonin (5-HT1D and 5-HT1B) agonist activity, wihtout any activity in toher seratonin, dopamine or adrenergic receptors. The order of clinical potency is: ergotamine = dihydroergotamine > sumatriptan.

Egots have poor oral bioavailability. Macrolide antibiotics may maskedly enhance the bioavailability of ergots by inhibiting CYP3A, and this may provoke ishemia (?, because of vasospansm?). Coadministraton of b-blockers or nicotine may provoke vasoconstriciton. D2 agonists cause emesis and migrane (?) and may alter GI physiology. Adverse effects include acroparesthesia, myochardial ischemia, and headache. Ergots are contraindicated in pregnant or fertile women due to teratogenesi, and when conditions excists that may worsen vasoconstriction.

Mixed Receptor Agonists

The ergot amine alkaloids are generally seratonin agonists and partial agonist at dopamine and a-adrenergic receptors, with some important exceptions.

Ergovine and methylergovine are seratonin agonists and partial agonists at dopamine and a-adrenergic receptors. Ergovine stresss-testing is used clinically to diagnose coronary vasopasm (arterial blood pressure can be moderately increased).

Both ergovine and methylergovine increase the frequency and force of uterine contractions. High doses (poisoning) produces sustained contractions, inappropriate for indution/facilitation of labor. Used at the appropriate dose, these agents quickly contol bleeding after delivery of the placenta. they have also been used therapeutically for delayed uterine involution (?). An adverse effect in these application is the decreased secretion of prolactin due to the partial agonist action on D2 receptors of the pituitary, thus preventing nursing.

The ergot amine alkaloid methysergide is a potent seratonin antagonist (and a partial agonist?), and has no dopamine or adrenergic activity. It is used profilactically to prevent migrane, and its active metabolite is methylergovine.

The ergopeptines are generally seratonin and dopamine agonists, with more effect on D2 than D1, and partial a-drenergic agonists, with the exception of bromocriptine.

Ergotamine and dihydroergotamine are seratonin agonists and dopamine agonists withmore effect on D2 than on D1 receptors. They are also partial agonists at a-adrenergic receptors. They are used to treat migranes, since their action on seratonin receptors may inhibit trigeminal inflamation.

Coadministration with caffeine enhances the bioavailability of ergotamine. Metoclopramide, a D2 and 5-HT5 antagonist, may enhance ergotamine therapy for migrane.

Dopamine Agonists

The ergot amine alkaloid pergolide and the ergopeptine bromocriptine are dopamine agonists. Pergolide acts on both D1 and D2 receptors, and has no seratonin nor adrenergic ectivity. Bromocriptine is a D2 agonist and seratonin antagonist, and has no adrenergic activity. As a result of their D2 agonist action, both pergolide and bromocriptine are effective in the treatment of Parkinson's disease.

These agents may induce hallucinations, confusion and nausea, and rarely cause retroperitoneal fibrosis and digital vasospasm. Anoter side effect of these agents is hypotension by stimulation of D2 receptors in the CNS, although continued bromocriptine treatment ocassionally leads to hypertension.

Both bromocriptine and pergolide stimulate D2 receptors in the pituitary, decreasing cAMP and prolactin secretion. They may be used to reat pituitary prolactinomas, which cause amenorrhea and galactorrhea in women and decreased libido in men. The space-occupiying effect of a large pituitary adenoma puts pressure on the optic chiasm. Bromocriptine is used to reduce the size of the adenoma through inhibition of pituitary cell division.

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