- Overview:
- Ergot alkaloids --
produced by Claviceps purpurea, a grain (rye,
especially) fungus
- This fungus
synthesizes many biologically active
agents including:
- acetylcholine
- histamine
- tyramine
and
- many
unique ergot alkaloids -- which
effect:
- alpha-adrenergic
receptors
- dopamine
receptors
- serotonin
receptors
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-
Ergot poisoning (ergotism, St. Anthony's
fire)-- symptoms:
- dementia
- florid hallucinations
- persistent
vasospasm (gangrene may develop)
- uterine muscle
stimulation (may cause abortion
in pregnancy)
- Ergot poisoning
specific manifestations depend on
the alkaloids mixture
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- Chemistry and
pharmacokinetics:
- Two Major Families:
- Tetracyclic
Ergoline Nucleus: Examples --
- lysergic
acid diethylamide (LSD)
- ergonovine
- methysergide (Sansert)
- 6-methylergoline
- lysergic
acid
- Peptide
alkaloids: Examples --
- ergotamine
- alpha-ergocryptine
- bromocriptine (Parlodel)
- Ergot alkaloids -variably
absorbed from
the GI tract
- Absorption following oral
administration: improved by caffeine
- Bromocriptine
(Parlodel): well absorbed
from the GI tract
- Metabolism:
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Ergot
Alkaloids
|
Alpha-adrenergic
receptor
|
Dopamine
receptor
|
Serotonin
receptor
(5 HT2)
|
Uterine
smooth muscle stimulation
|
Bromocryptine
|
-
|
+++
|
-
|
0
|
Ergonovine
|
+
|
+
|
-
(partial agonist)
|
+++
|
Ergonovine
|
--
(partial agonist)
|
0
|
+
(partial agonist)
|
+++
|
LSD
|
0
|
+++
|
--
|
+
|
Methysergide
|
+/0
|
+/0
|
---
(partial agonist)
|
+/0
|
-- {based on
Table 16-6,Burkhalter, A, Julius,
D.J. and Katzung, B. Histamine, Serotonin and the Ergot
Alkaloids (Section IV. Drugs with Important Actions on
Smooth Muscle), in Basic and Clinical Pharmacology,
(Katzung, B. G., ed) Appleton-Lange, 1998, p 279.}
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- Organ Systems:
- CNS:
-
hallucinogenic-- LSD:
- peripheral (5
HT2)
serotonin receptor
peripheral antagonist
- behavioral
effects: agonist
presynaptic or
postsynaptic 5 HT2
effects.
-
Dopamine
Receptor Interactions:
- Extrapyramidal
system
- Prolactin
release regulation:
- bromocriptine (Parlodel)
and pergolide (Permax)}specificity
for pituitary dopamine
receptors
- suppression
of pituitary prolactin
secretion: by activating
regulatory dopamine
receptors
- Bromocriptine (Parlodel)
and pergolide (Permax) are
competitive with dopamine
and other dopamine
agonists (apomorphine)
before the these binding
sites
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- Vascular Smooth Muscle:
- Ergotamine
(unrelated compounds) are mainly
vasoconstricting.
- Vasoconstriction:
partially blocked by
alpha adrenergic receptor
blocking drugs--
- suggesting
vasoconstriction by ergot
alkaloids may be due to
partial agonist effects
at alpha adrenergic
receptors
- Vasoconstriction:
long-lasting--
- alpha
adrenergic receptor
effects
- 5
HT receptor-mediated
effects
- Vasoconstriction:
differential vascular
sensitivity to ergot
alkaloids
- Most-common
drugs used for migraine
treatment:
- ergotamine
- ergonovine
- methysergide (Sansert)
- Overdosage
(ergotamine and related
agents)
- Severe,
long-lasting vasospasm --
- not
reversible by
alpha-antagonists
- not
reversible by serotonin
antagonists
- Uterine Smooth Muscle
- Stimulant
action:
involves serotonergic,
alpha-adrenergic, and other
effects
- Uterine sensitivity
changes during pregnancy (possibly due to
progressively increasing numbers
of alpha1
receptors
- Small
doses: rhythmic
uterine contraction and
relaxation
- Larger
doses: substantial, prolonged
contractions
- Ergonovine:
more uterine selective (agent
of choice for obstetric uses)
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- Other Smooth Muscle:
- Bronchiolar smooth
muscle: no effect
- Gastrointestinal smooth
muscle:
variable sensitivity {nausea,
diarrhea, and vomiting -- occurs
with variability in required
dosage probation impatient}
- Mechanism
of Action:
- activation
of gastrointestinal
serotonin receptors
- CNS
emetic centers
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