Download THE ERGOT ALKALOIDS

THE ERGOT ALKALOIDS
Prof.Dr. Zeliha Yazıcı
 Produced by Claviceps purpuria, a fungus that infects
grain
 Affect α adrenoceptors, dopamine receptors and 5-HT
receptors
 Ergot posining (ergotism)→ dementia with florid
hallucination, prolonged vasospasm resulted in
gangrene, and stimulation of uterine smooth muscle
(resulted in abortion in pregnancy)
Chemistry & Pharmacokinetics
 Absorbed from the GI tract
 The amine alkaloids absorbed from the rectum and
the buccal cavity and aerosol inhaler
Pharmacodynamics
Mechanism of actions
 Agonist, partial agonist, and antagonist actions at αadrenoceptors and serotonin receptors (5-HT1A and 5HT1D, less for 5-HT1C, 5-HT2 and 5-HT3),
 Agonist or partial agonist actions at CNS dopamine
receptors
Drug
5-HT
receptor
Antagonist
/partial
agonist (5HT1)
Dihydroergotamine Antagonist
/partial
agonist (5HT1)
Antagonist
Ergometrine
/partial
(Ergonovine)
agonist (5HT1)
Inactive
Bromocriptine
Ergotamine
Methylsergide
LSD
Antagonist
/partial
agonist (5HT2)
Agonist /
Antagonist
(5-HT2)
αDopamine
adrenoceptor receptor
Uterin
smooth
muscle
partial agonist
Antagonist
Inactive
++
Antagonist
Inactive
+
Weak
antagonist/
partial agonist
Weak
++
Weak antagonist
-
-
Agonist /partial
agonist
-
Agonist/inactive
Agonist/inactive
+/0
-
Central nervous system
 Hallucinogens
 LSD (lysergic acid diethylamide)→ hallucinogen (5HT2 antagonist and agonist), dopamine receptor
agonist
 Bromocriptine and pergolide → suppress prolactin
secretion (dopamine agonist)
Vascular smooth muscle
 Predictable, prolonged and potent vasocontrictors
 Dual effect (partial agonist and antagonist at α
adrenoceptors)
 Partial agonist at 5-HT2 vascular receptors
 Overdosage → severe and prolonged vasospasm
which is not reversed by α antagonist and serotonin
antagonist
 Ergotamine → a strong vasoconstrictor
Uterine smooth muscle
 α agonist → more sensitive in pregnancy
 in very small doses, can evoke rhythmic contraction
and relaxation of uterus
 at higher concentrations, induce powerful and
prolonged contracture
 ergonovine more selective
Other smooth muscle
 no effect on bronchiolar smooth muscle
 GI tract sensitivity is vary (nausea, vomiting, diarrhea)
Clinical uses
Migraine
Ergotamine tartrate (Avmigran, Cafergot, Ergafein)
 Used only in the early-onset of the migraine
Dihydroergotamine mesylate (Neomigran)
Methysergide
 Prophylactic treatment of severe, recurring migraine
Sumatriptan
Propranolol and amitriptyline
Flunarizine
Verapamil
Hyperprolactinemia
Bromocriptine (Galaktomin, Gynodel, Parlodel)
 Suppresses the production of prolactin (D2-agonist)
 Reverses effects of hyperprolactemia (amenorrhea,
galactorrhea) and infertility
 Can cause tumour regression in patients with
prolactin-secreting pituitary tumours
 Used in the treatment of acromegaly suppressing
growth hormone production
Cabergoline (Cabaser, Dostinex)
 D2-agonist
 Can cause nausea, headache, dizziness
Parkinson’s disease
Bromocriptine
 D2-agonist
 Employed as an adjunct in the treatment of
Parkinson’s disease
Pergolid (Permax)
 D1,2-receptor agonist
Postpartum hemorrhage
Ergonovine maleate
Methylergonovine maleate (Methylergometrine,
methyergobasine) (Methergin, Metiler, Uterjin)
 Strong uterotonic agents
 Have preferential action on the pregnant uterus,
stimulating sustained contraction
 Have a longer duration of action than oxytocin
Diagnosis of variant angina
Ergonovine
Senile cerebral insufficiency
Dihydroergotoxine and ergoloid mesylates
Toxicity & contraindication
 GI disturbances (diarrhea, nausea and vomiting)
 Prolonged vasospasm, gangrene, bowel infarction
 Peripheral vascular vasospasm X nitroprusside or
nitroglycerin
 Chronic methysergide → fibroblastic changes in the
retroperitoneal space, the pleural cavity and the
endocardial tissue of the heart → hydronephrosis,
cardiac murmur
 Drowsiness, hallucinations
 Contraindicated in obstructive vascular diseases and
collagen diseases, induction of labor, pregnancy
 Pregnancy risk factor X
Drug interactions
Increased effect/toxicity: antifungals, CYP3A4
inhibitors, macrolide antibiotics, protease inhibitors, MAO
inhibitors, Beta blokers, vasoconstrictors
Decreased effect: antipsychotics, metaclopramide