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Ergot Alkaloids

Ergot alkaloids are the group of agents or different alkaloid preparations having specific affects on different receptors.

Classification

Derivatives &constituents of ergot

1. Amine alkaloids
  • 6-methyl ergoline
  •  lysergic acid
  •  lysergic acid diethylamide (LSD)‏
  • Ergometrine
  • methysergide
2. Peptide alkaloids
3. Non-specific constituents
  • Acetylcholine
  •  histamine
  • tyramine

Source

Natural in a fungus claviceps purpurea (infects grains specially rye).

History

History of ergot alkaloids is 2000 years old. It is usually found on weeds and grains especially in damp and moist storage conditions.

In ancient times, effects of ergot alkaloids were seen and included ergotism, which is poisoning by ergot alkaloids. Another was Saint Anthony’s fire. People used to visit shrine of Anthony because of burning sensation (due to vasoconstriction) and were relieved there. This was due to the fact that they were served uncontaminated weeds and cereals.

This was still reported in 1950s as contaminated grains and cereals were ingested in some parts of the worls. Ergots are also found on the pastures on which animals feed.

If poisoning occurs, it leads to vasoconstriction and gangrenous effects are seen. Acetyl choline, tyramine and histamine may be released.

Receptors

  1. alpha receptors
  2. dopamine receptors
  3. 5-hydroxy tryptophan/serotonin receptors

Chemistry

Derivative of compound 6-methyl ergoline and containing a tetracyclic nucleus.

Pharmacokinetics

Absorption

Absorption is variable. Oral dose of ergotamine is ten times greater than I/M dose Oral absorption is increased with caffeine. 100 mg of caffeine is sufficient for absorption of 1 mg of ergotine.

Oral absorption of ergot alkaloids can be improved with caffeine.

Bioavailability

Less than 1 % after oral administration. Bioavailability is greater after rectal suppositories. It can be given parentally (IV or IM) as well.

Route of Administration

Oral, per rectum, buccal cavity, aerosol inhaler, I/M.

Metabolism

Metabolism occurs in the liver. Ergot alkaloids undergo extensive first pass metabolism, thus rectal route may be used. 90 % metabolites are excreted in bile only traces of unmetabolized drug found in urine & faeces.

Pharmacological   Actions

1. CNS
a. Hallucinogenic

LSD and methysergide act on central serotonin receptors having agonist effect.

 b. Parkinsonism

Ergot alkaloids have extra-pyramidal effects especially motor effects e.g. Parkinsonism. Act as agonists on dopamine receptors present in nigrostriatal pathway of basal ganglia to increase motor activity.

 c. Nausea & Vomiting

By affecting the chemoreceptor trigger zone ergot alkaloids act on the dopamine receptors to produce nausea and vomiting.

d. Prolactin secretion

Any tumor or dopamine antagonists when administered can cause hyper-prolactemia resulting in infertility and gynecomastia. Ergot alkaloids acting as dopamine agonists bring about improvement and suppress release of prolactin. Bromocriptine is very effective having high affinity, and

  1. inhibits release.
  2.  causes regression of tumor size.
2. Vascular smooth muscle

Ergotamine and methysergide act as potent vasoconstrictors increasing TPR and B.P. Blood flow to periphery is decreased. Apart from vasospasm, gangrene also takes place. Red, swollen and severe painful condition occurs. If it is severe, it becomes difficult to revert the condition even with antagonists like alpha and serotonin antagonists. (as effects produced by alpha and serotonin receptors)

3. Uterus

Ergometrine has powerful stimulant effects on uterus. Serotonin and alpha receptors are found in uterine smooth muscles. When given in small doses, contraction and relaxation of smooth muscles is seen. In high doses, sustained contraction occurs which may lead to spontaneous abortion. Thus, the dose needs to be monitored.

Alpha receptors are upregulated with progressing pregnancy, thus during later period, uterus is more sensitive to ergot alkaloids effects.

4. GIT

Serotonin and dopamine receptors produce effects. Serotonin receptors cause an increase in intestinal movement leading to diarrhea and abdominal cramps. Dopamine acts on chemoreceptor trigger zone to cause nausea and vomiting.

5. Eye

Alpha receptors may have agonist and antagonists effects. Ergotamine has alpha antagonist effect, producing miosis (constriction). Ergometrine has alpha agonist effect producing mydriasis (dilatation).

Ergot alkaloids have no role in glaucoma.

6. Metabolic Effects

Metabolic effects are not very much established. They may inhibit hyperglycemia, as seen in administration of adrenaline. This is not understood very well.

Therapeutic Uses

1.      Migraine

Ergot alkaloids are effectively used. During severe attacks, a person may see aura, visual scotoma, hemianopia and even loss of vision, speech abnormality, nausea and vomiting.

Pathophysiology involves the trigeminal division, vasodilator substances are released including calcitonin gene related peptides and substance P. Extravasation within perivascular spaces cause the stimulation of nerves, which leads to classical headache.

Mechanism of action involves agents having vasoconstrictor activity. These include:

  1. Serotonin and ergot preparations
  2. NSAIDS
  3. Beta blockers
  4. Anti epileptics
  5. Calcium channel blockers

Ergotamine is effective during acute phase of migraine and is not used in prophylaxis. They may be given orally, buccal, inhaler, aerosol, IM, IV or in the form of suppository.

The oral absorption is increased by combining with caffeine. 1 mg ergotamine is used with 50 mg of caffeine. Ergotamine dose is 0.25-0.5 mg given intravenously. Dihydroergotamine is given 0.5-1 mg intravenously.

Dose of ergotamine must never exceed beyond 6 mg per attack or 10 mg /week. This is because of cumulative effects and toxicity might occur.

For prophylaxis, methysergide does not have uncumulative effects. (effect connective tissue, used subendocardial fibrosis and retroperitoneal fibroplasias)

2.      Hyperprolactinemia

Increased prolactin may cause enhanced gynecomastia and infertility. Because of dopamine effect regression of tumour size occurs

3. Parkinsonism

Acting through nigrostiatal dopaminergic pathway, improvement in extra pyramidal signs occurs, helpful with dopamine agonists.

4. Post partum hemorrhage

Ergotamine when given after delivery or during delivery of placenta or severe uterine bleeding 2 mg IM dose is effective within 5 minutes. It is not administered before delivery as may cause spontaneous abortion.

5. Diagnosis of variant angina

During angiography administered for vasoconstrictor effects for diagnosis of angina.

6. Senile cerebral insufficiency

Ergot alkaloids have some role. Research is also going on for Alzheimer disease.

7.      Acromegaly

Bromocryptine, by dopamine action, causes decrease in growth hormone in acromegaly. It increases GH in normal person.

Adverse Effects

  1. GIT disturbances: (Nausea, Vomiting, Diarrhoea & abdominal cramps.
  2. Spontaneous Abortion.
  3. Methysergide – central stimulation & hallucination.
  4. Drowsiness.
  5. Convulsions.
  6. Over dosage with ergotamine and ergometrine causes vasospasm ——- gangrene.
  7. Bowel infarction —- mesenteric artery vasospasm.
  8. Connective tissue proliferation in the retroperitoneal space, pleural cavity and endocardial tissue of heart with chronic therapy of methysergide, leading to:
    a. Hydronephrosis (compression of uterus, urine remains in kidneys)
    b. Heart murmurs

Contraindications

  • Obstructive vascular diseases.
  • Collagen diseases.
  • Early pregnancy
  • Renal/liver disease
  • Diarrhoea
  • Sepsis/infection (delays healing)

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