Term
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Definition
indole alkaloid -> ergoline or ergot alkaloids
natural product -> parasite on rye, wheat, and other grains
ergotism:
gangrenous ergotism, tingling in fingers follow by dry gangrene
convulsive ergotism: same but with epileptic-type seizures
[image] |
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Term
| properties of ergot alkaloids and migraines |
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Definition
non selective:
5HT-1 and 5HT-2
adrenergic
dopaminergic
substance P and calcitonin |
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Term
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Definition
[image]
structure has many features that resemble the amine neurotransmitters; makes it very nonselective
can overlap DA, NE, and 5HT on the structure of ergotamine
phenyl ring and amine group are the same distance away
MOA: potent vasoconstrictor but it can also produce vasodilatory effects depending on the degree of resistance of the vasculature:
when resistance is low, vasodilation occurs, whereas ergotamine binding to serotonin receptors results in vasoconstriction effects |
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Term
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Definition
wide range of ADRs
avoid if patient has coronary disease
safety margin is small |
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Term
| drug interactions with ergotamine |
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Definition
potent CYP3A4 inhibitors: there is a potential risk for increased blood levels and serious toxicity including vasospasma when these drugs are used in combination (antifungals, protease inhibitors, macrolide antibiotics)
less potent CYP3A4 inhibitors should be administered with caution |
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Term
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Definition
erratic absorption
significant ADRs
prolonged use may lead to a cycle of drug tolerance and dependence
variable absorption from GIT
absorption increases with caffeine
metabolized by liver
90% of metabolites excreted in the bile |
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Term
properties of dihydroergotamine
[image] |
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Definition
fewer ADRs
less vasoconstrictor effects |
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Term
ADME of dihydroergotamine
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Definition
low oral bioavailability (1%)
high IM bioavailability (100%)
intranasal bioavailability ~40%
distribution:
high concentrations in liver, kidney, and lung
low in stomach, intestines, and brain
major route of elimination: feces |
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Term
properties of ergonovine and methylergonovine
ergonovine:
[image]
methylergonovine:
[image] |
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Definition
arterial vasoconstriction by stimulating the alpha adrenergic and serotonin receptors and inhibiting the release of endothelial derived relaxation factor
less potent than ergotamine
ergonovine is a strong inducer of uterine contractions |
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Term
properties of methylsergidine
[image] |
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Definition
exclusively used for migraine headache as a serotonin ANTAGONIST (5HT1/2 receptors)
oral bioavailability: 13%
extensive first pass metabolism
less induction of uterine contractions compred with other ergot alkaloids |
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Term
| availabile ergot alkaloids |
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Definition
ergotamine
dihydroergotamine
ergonovine
methylergonovine
methylsergide |
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Term
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Definition
agonist at serotonin receptor (5HT), more selective than the ergot alkaloids
[image]
common:
all have a triptan nucleus (phenyl ring with 5 member ring with N)
all have tertiary amine (or secondary amine in frovatriptan)
the amine is 2-3 carbons away
polar subtitutents
drugs should be lipophilic to cross the BBB |
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Term
properties of sumatriptan
[image] |
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Definition
short t1/2 (2H)
does not cross BBB
metabolized by MAO-A (reason for short t1/2)
it also relieves the associated symptoms
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Term
properties of naratriptan
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Definition
[image]
t1/2 = 6h
N incorporated in the ring prevents MAO metabolism
low CNS penetration
longer t1/2 b/c the metabolism by AMO is blocked
MAO is inhibited by steric hindrances |
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Term
properties of rizatriptan
[image] |
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Definition
[image]
t1/2 = 2-3h
more lipophilic than sumatriptan
MAO-A metabolism |
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Term
properties of zolmitripatn
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Definition
[image]
can cross BBB
t1/2 = 3-3.5h
N-demethylation to an active metabolite
metabolized by CYP3A4 and MAO |
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Term
properties of almotriptan
[image] |
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Definition
[image]
t1/2 = 3-4h
low CNS effects
metabolized by MAO |
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Term
properties of frovatriptan
[image] |
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Definition
[image]
t1/2 = 26h
CYP1A2 metabolism
NO MAO metabolism (steric hindrances)
restricted conformation |
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Term
properties of eletriptan
[image] |
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Definition
[image]
no MAO metabolism
CYP3A4 metabolism
t1/2 = 4-5h |
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Term
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Definition
indole ring
basic N (3>2) 2-3 C from position 3
polar group at position 5 |
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Term
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Definition
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