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Ergot definition
“petit ongle point derriere le pied du coq” (resemblance of the Ergot sclerotium to a cock’s spur)
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The life cycle of Claviceps purpurea (Ergot)
Ascospores & conidospores -> wind and insects -> lodge on pistils of plants -> germination -> hyphae -> mycellial threads penetrate deep into pistil -> sclerotium forms -> falls to ground -> ascocarps -> cycle repeats
Sclerotium -> harvest with grain -> flour -> bread -> ergotism
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The basic ring structure (chemistry) of Ergot alkaloids is:
ergoline
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medicinally useful derivatives are amide derivatives of:
(ergot chemistry)
D-(+)-lysergic acid
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D-(+)-isolysergic acid alkaloids are:
(ergot chemistry)
biologically inactive diastereoisomers
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some separation of ergot alkaloids may be achieved by differential water solubility
peptide alkaloids tend to be ______
nonpeptide alkaloids are ______
1) water insoluble
2) water soluble
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Parasitic source of ergot alkaloids:
Claviceps purpurea (grown on rye)
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Saprophytic source of ergot alkaloids:
Claviceps paspali (grown in fermentation broth)
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-These receptors are located in the brain
-mediate synaptic inhibition via increased K+ conductance
-peripheral receptors mediate both excitatory and inhibitory effects in smooth muscle
-the triptans (agonist)
5-HT1 Receptors
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-These receptors are located in the brain and peripheral tissue
-mediate synaptic excitication in the CNS; smooth muscle contraction (blood vessels, uterus, bronchi, gut); smooth muscle relaxation (blood vessels)
-Cyproheptadine (antagonist)
5-HT2 Receptors
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-These receptors are located in the CNS and periphery
-mediate excitiation via a 5-HT-gated cation channel
- Ondansetron and others (antagonist)
5-HT3 Receptors
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Ergot Alkaloids
- partial agonists at both _____ and _______
- agonist vs antagonist blance varies from alkaloid to alkaloid
- some agonism at the _____ receptor may also occur
- 1) 5-HT receptors
- 2) a-adrenoceptors
- 3) dopamine
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Site predominant effects: blood vessels
- a-adrenoceptor-mediated vasoconstriction that is both _________ & ________
- ________ & _________ may result
- 1) significant and prolonged
- 2) ischemia and gangrene
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Site predominant effects: Uterus
- direct uterine smooth muscle _________
- administration of these drugs _________ may be useful in preventing hemorrhage or blood loss
- 1) stimulation (contraction)
- 2) after the delivery of the placenta
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Site predominant effects: CNS
- __________ may occur
- Dopamine agonism at D2 inhibits prolactin secretion, permitting use in ___________ & _________
1) Hallucinations
2) hyperprolactinemic states & Parkinsonism
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this alkaloid is obtained from 3 different sources: parasitic, saprophytic, & synthesis
Ergonovine Source
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Nonpeptide alkaloid
colorless
water soluble as tertiary amine (highly unusual)
light sensitive
marketed as its water soluble maleate salt
Ergonovine Chemistry
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A semisynthetic homolog of ergonovine prepared via the condensation of (+)-lysergic acid with a-aminobutanol or the condensation of isolysergic acid azide with the same alcohol, then isomerization of the pdt.
Methylergonovine Source
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Colorless
very low water solubility
marketed as its water soluble maleate
Methylergonovine Chemistry
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Indicated for the prevention and treatment of postpartum and post abortal hemorrhage due to uterine atony or subinvolution (turning inward of edges)
Major action is one of direct uterine stimulation, with lesser contributions at other sites
Ergonovine and Methylergonovine
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A peptide alkaloid: alanine-proline-phenylalanine
Obtained by: parasitic source & synthesis
colorless
very lower water solubility
marketed as its water soluble tartrate salt
Ergotamine Source/Chemistry
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A semi-synthetic analog of ergotamine prepared by catalytic hydrogenation ofthe C-9/C-10 double bond ofergotamine
Colorless
Water insoluble
Marketed as its water soluble mesylate (methanesulfonate) salt
Dihydroergotamine Source/Chemistry
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semisynthetic alkaloid product prepared via bromination of the naturally occurring peptide alkaloid ergocriptine /ergocryptine
Colorless; Water insoluble
Marketed as its water soluble mesylate (methanesulfonate) salt
Bromocriptine Source/Chemistry
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potent dopamine receptor agonist via activation of certain dopamine D2 receptors in the brain --- net effect: a decrease in the turnover rate of dopamine without significant changes in concentration
Bromocriptine
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INHIBITS PROLACTIN RELEASE VIA STIMULATION OF DOPAMINE RECEPTORS IN THE CORPUS STRIATUM
Bromocriptine MOA
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Bromocriptine Indications
- •Hyperprolactinemia-associated dysfunctions (Amenorrhea & Prolactin-secreting adenomas)
- •Acromegaly (overproduction of growth hormone by anterior pituitary)
- •Treatment of the signs/symptoms of idiopathic or post-encephalitic Parkinson’s Disease
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Agonism at the 5-HT1B and 5-HT1D receptors
Ergotamine/Dihydroergotamine MOA
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Very active uterine stimulant - direct
– Increases force and frequency of contractions
– Gravid uterus is more sensitive
Ergotamine/Dihydroergotamine
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Peripheral and cranial blood vessels are constricted
– Reduces extracranial blood flow
– Decreases the amplitude of cranial artery pulsation
– Decreases the hyperperfusion of basilar (brain stem) artery territory
– Possible inhibition of the reuptake of norepinephrine at the sympathetic nerve endings
– No effect on cerebral hemispheric bloodflow
Ergotamine/Dihydroergotamine
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Central vasomotor centers are depressed
Potent emetic effect via stimulation ofthe chemoreceptor trigger zone (CTZ)
Ergotamine/Dihydroergotamine
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