Term
| characteristics of an aura |
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Definition
20% of patients experience aura before migraine headaches
ASSOCIATED WITH WAVE OF CORTICAL SPREADING DEPRESSION (CSD) originating in the occipital lobe and then spreading toward the frontal lobe
most often described as VISUAL CHNAGES |
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Term
| characteristics of a migraine |
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Definition
A PRIMARY NEUROVASCULAR DISORDER
results from dysfunction of the TRIGEMINOVASCULAR SYSTEM
the disorder manifests as recurring attacks, usually lasting 4-72 hours
these attacks, which can interfere with normal functioning, involve unilateral throbbing headache pain of moderate to severe intensity
there is no overwhelming consensus view on the cause of migraine headache
it is best to think of migraines from a pathophysiological point of view as a neurovascular process (the leading hypothesis)
migraine attacks usually involve nausea, sometimes vomiting, photophobia, and hypersensitivity to auditory stimuli |
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Term
| role of calcitonin gene related peptide (CGRP) in migraines |
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Definition
CGRP is a POTENT VASODILATOR, new target of migraine therapy
thought to play a major role in the pathophysiology of migraines |
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Term
| used AFTER ONSET of migraine |
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Definition
migraine abortive drugs
ergot alkaloids and triptans used to treat migraine attacks after onset (as opposed to migraine prophylaxis) |
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Term
| clinical course of migraine |
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Definition
[image]
prodrome is an early, non-specific, mild sign or symptoms that a disease or attack is imminent
aura occurs in about 20% of cases
mild pain begins and progresses to moderate to severe pain
the pain gradually resolves
the process can take from 4-72 hours |
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Term
| drugs for treatment of acute migraine attack |
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Definition
NSAIDs:
aspirin, ibuprofen, naproxen
ERGOT AGENTS:
ergotamine tartrate, dihydroergotamine (DHE)
TRIPTANS (5HT1 agonists):
sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, frovatriptan, eletriptan
OTHERS:
butorphanol, prochlorperazine, acetaminophen with codeine, acetaminophen with caffeine and butalbital
abortive drugs are administered after onset of migraine symptoms |
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Term
| drugs for migraine prophylaxis |
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Definition
NSAIDs:
aspirin, ibuprofen, naproxen
ERGOT AGENTS:
methysergide
BETA RECEPTOR ANTAGONISTS:
timolol, propranolol, atenolol, nadolol
ANTIDEPRESSANTS:
amitriptyline, doxepin, imipramine, fluoxetine, phenelzine
ANTICONVULSANTS:
valproic acid, topiramate
CALCIUM CHANNEL BLOCKERS:
verapamil, nimodipine
OTHERS:
gabapentin, vitamin B2
if headaches are more severe and/or frequent then the patient may be a good candidate for prophylaxis |
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Term
| migraine pathophysiology: genetic studies |
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Definition
calcium channels:
certain familial types of migraines are associated with calcium ion channel mutations resulting in prolonged channel inactivation
glutamate transporters |
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Term
| vascular hypothesis of migraine pathophysiology |
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Definition
VASOCONTRICTION = ORIGINATING FACTOR
early phase of vasoconstriction (correlates with aura) followed by dilation of meningeal vessels
vessel dilation activates trigeminal sensory pathway (associated with head pain)
[image]
problems with this hypothesis:
changes in blood flow similar in magnitude have been observed (caused by other factors) that do not result in head pain (vasoconstriction is not sufficient to trigger migraines) |
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Term
| cortical spreading depression (CSD) hypothesis of migraine pathophysiology |
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Definition
cortical spreading depression (CSD) is a wave of depolarization followed by depression of neuronal electrical activity and reduced blood flow is associated with migraine aura; head pain follows
CSD -> decreased blood flow -> pain
this hypothesis states that the initiating factor involves neurons in the cerebral cortex (CSD)
a wave of neuron depolarization spreads over the cortex starting in the occipital lobe and proceeding toward the frontal lobe
the CSD is thought to be associated with the aura phase
in support of this hypothesis:
drugs that are effective in preventing migraine attacks also inhibit CSD
problems with this hypothesis:
CSD can be induced in animal model by application of high extracellular K concentration, but this does not activate trigeminal afferent (cause pain)
it is currently believed that CSD is associated with aura, but is not required for subsequent migraine headache (only 20% of attacks are preceded by aura) |
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Term
| neurovascular hypothesis of migraine pathophysiology |
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Definition
hypothesis states cranial nerve V (trigeminal) activation is initial event
PERIPHERAL COMPONENTS of trigeminal innervate areas of head, face, jaw, and meningeal blood vessels
3 main branches (V1, V2, V3); include primary neurons
CENTRAL COMPONENT of the trigeminal include neurons that connect the trigeminal nucleus caudalis (TNC) to the thalamus, and neurons that connect the thalamus to cortex; include secondary and tertiary neurons
most current hypothesis
according to this hypothesis migraines are caused by activation of trigeminal sensory (afferent) neurons
V1, V2, and V3 are also known as upper, middle, and lower branches of trigeminal (cranial nerve V)
[image]
trigeminal is made mostly of sensory nerve fibers (primary neurons)
secondary neurons connect the TNC to the thalamus
tertiary neurons connect the thalamus to the cortex
sequence of nerves and anatomy are as follows:
(dermatomes)-primary nerve -> (TNC)-secondary nerve -> (thalamus)-tertiary nerve -> cortex
[image]
1. trigeminal nerves are activated; environmental factors involved are foods or stress, also some evidence for genetic factors involving ion channels
2. the activated trigeminal nerves cause vasodilation
3. vasodilation causes activation of sensory trigeminal nerves
4. these nerves transmit pain to the TNC (trigeminal nucleus caudalis) and also release neuropeptides, furthering the vasodilation and causing inflammation
5. signal is transmitted from the TNC in the brainstem through the thalamus and then onto the cortex where pain is perceived; according to the neurovascular hypothesis, vasodilation is not the cause of migraine, but a consequence of trigeminal nerve activation |
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Term
| key components of the neurovascular migraine hypothesis |
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Definition
mast cells, endothelial cells, neurons, CGRP, NO, histamine, edema
[image]
initiating factor is activation of trigeminal nerves (signal)
vasodilation is caused by CGRP and substance P release from the activated trigeminal nerves
also there is some evidence that mast cells are involved in migraine headache
these cells are activated by the trigeminal nerve release of substance P
the mast cells in turn release histamine (contributes to vasodilation)
CGRP also stimulates endothelial cells to release NO, bradykinin, and VIP (vasoactive intestinal peptide) causing edema |
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Term
| anti-migraine activity of ergot alkaloids and triptans is mediated by ( ) |
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Definition
serotonin receptor
the receptor has 7 transmembrane spanning domains
there are many subtypes
nearly all are GPCRs; one is an ion channel
serotonin receptors have a broad tissue distribution and wide range of physiologic effects
located throughout the CNS, on platelets, smooth muscle, and nerve endings
serotonin can cause urterine contraction, bronchial constriction, platelet aggregation, emotional and behavioral responses
serotonin has effects on cerebral blood vessel tone and trigeminal neurotransmission |
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Term
| actions and distribution of 5HT-1A |
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Definition
distribution:
raphe nuclei, hippocampus
actions:
Gi, decreased cAMP
involved in anxiety disorder (buspirone is a selective 1A partial agonist) |
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Term
| actions and distribution of 5HT-1B |
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Definition
distribution:
CNS, cerebral vessels
actions:
Gi, decreased cAMP
activation causes vasoconstriction of cerebral vessels (mediate therapeutic action of triptans and ergot alkaloids) |
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Term
| actions and distribution of 5HT-1D |
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Definition
distribution:
CNS, cerebral vessels
actions:
Gi, decreased cAMP
activation causes vasoconstriction of cerebral vessels (mediate therapeutic action of triptans and ergot alkaloids) |
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Term
| actions and distribution of 5HT-2A |
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Definition
distribution:
platelets, smooth muscle, cerebral vessels
actions:
Gq, increased IP3
activation causes vasoconstriction of peripheral vessels, but DILATION of cerebral vessels |
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Term
| actions and distribution of 5HT-3 |
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Definition
distribution:
area postrema, sensory and enteric nerves
actions:
receptor is a Na/K ion channel
mediates CTZ (chemoreceptor trigger zone) response in the area postrema in the medulla |
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Term
| actions and distribution of 5HT-4 |
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Definition
distribution:
CNS, and myenteric neurons, GI motility
actions:
Gs, increased cAMP
involved in GI motility |
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Term
| anti-migraine activity mediated through 5HT-1B and 5HT-1D |
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Definition
increased vasocontriction
decreased vasoactive peptide release
decreased pain pathway
[image]
ergot alkaloids and triptan drugs terminate the pain by activating serotonin 5HT-1B/1D receptors at three sites:
1. receptors on pial and dural vessels and thereby cause VASOCONTRICTION
2. presynaptic receptors to INHIBIT VASOACTIVE PEPTIDE RELEASE
3. receptors in the brainstem, which is believed to BLOCK PAIN transmission (specifically in the TNC) |
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Term
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Definition
ergotamine (approved for migraines)
dihydroergotamine (approved for migraines)
methysergide (5HT2 antagonist; withdrawn in U.S.)
bromocriptine |
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Term
| actions of ergot alkaloids |
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Definition
less selective than triptans
agonist at 5HT1 and other 5HT subtypes = anti-migraine therapeutic effects
agoninst on ALHPA ADRENERGIC (peripheral vasoconstriction) and dopamine (bromocriptine) receptors
as a group, ergot alkaloids have variable oral bioavailability
cause of ergotism
symptoms include: hallucinations, gangrene (caused by vasoconstriction), uterine contraction (can cause miscarriage, mediated through alpha adrenergic receptor), and GI symptoms (5HT4 activation) and emesis (5HT3 and dopamine receptor activation)
methysergide (5HT2 antagonist) can cause retroperitoneal (surrounding kidneys, bladder, aorta) fibrosis |
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Term
| receptor interaction and effects of ergotamine |
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Definition
agonist at 5HT-1B: constriction of cranial vessels (reduce edema and inflammation)
agonist activity at presynaptic 5HT-1D: inhibits release of CGRP
some central action: pain transmission blockage
partial agonist at ALPHA ADRENERGIC
this drug can antagonize the effects of EPI (epi reversal) b/c it occupies the alpha receptor (high affinity) but does not activate the receptor (lower receptor efficacy)
inactive at the dopamine receptor |
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Term
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Definition
| treatment of acute moderate to severe migraine |
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Term
| pharmacokinetics of ergotamine |
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Definition
ORAL BIOAVAILABILITY IS LOW (extensive first pass metabolism)
vasoconstriction activity of long duration |
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Term
| side effects, toxicity, and interactions of ergotamine |
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Definition
activation of chemoreceptor trigger zone (CTZ) located in the area postrema of meddula and mediates the vomiting reflex (probably mediated through 5HT3)
severe peripheral vasoconstriction caused by alpha 1 receptor activation; can also be used to constrict vessel in postpartum uterus to stop bleeding
rebound headache
EPI REVERSAL
CYP3A4 INTERACTION
vasoconstriction (avoid in peripheral vascular disease)
avoid in pregnancy |
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Term
| receptor interaction and effects of dihydroergotamine |
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Definition
agonist at 5HT-1B: constriction of cranial vessels (reduce edema and inflammation)
agonist activity at presynaptic 5HT-1D: inhibits release of CGRP
some central action: pain transmission blockage
partial agonist at ALPHA ADRENERGIC
this drug can antagonize the effects of EPI (epi reversal) b/c it occupies the alpha receptor (high affinity) but does not activate the receptor (lower receptor efficacy)
inactive at the dopamine receptor |
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Term
| uses of dihydroergotamine |
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Definition
| NASAL and injection formulations for acute migraine attack |
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Term
| pharmacokinetics of dihydroergotamine |
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Definition
good nasal absorption (35%)
1% oral bioavailability |
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Term
| side effects, toxicity, and interactions of dihydroergotamine |
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Definition
similar to ergotamine, but much less severe
less potent uterine contraction compared to ergotamine, less activation of CTZ (less emesis)
INHIBITORS OF CYP3A4 (protease inhibitors, macrolides, antibiotics, anti-fungals) INCREASE SERUM DIHYDROERGOTAMINE which increases risk of severe peripheral and cerebral ischemia
same warning applicable to ergotamine |
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Term
[image]
what has the greatest efficacy?
what has the highest potency? |
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Definition
greatest efficacy:
NE and 5HT
highest potency:
DHE and ERG (significant activity at lower doses than the others) |
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Term
| receptor activity of methysergidine |
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Definition
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Term
general properties of triptans
sumatriptan, naratriptan, zolmitriptan, rizatripan, frovatriptan, almotriptan, betriptan |
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Definition
MORE SELECTIVE receptor interaction compared to ergot agents
agonist activity at 5HT-1B (increased vasoconstriction) and 5HT-1D (decreased CGRP release)
5HT-1D activity IN THE TRIGEMINAL NUCLEUS CAUDALIS blocks pain transmission to cerebral cortex (must CROSS BBB TO REACH THIS RECEPTOR)
no activity at adrenergic or dopaminergic receptors
HIGHER ORAL BIOAVAILABILITY compared to ergot agents
MAO metabolism
no significant affinity for 5HT2 subtypes |
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Term
| receptor interaction and effects of sumatriptan |
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Definition
5HT-1B agonist: constriction of intracranial blood vessels
5HT-1D agonist: inhibition of vasoactive peptide release from trigeminal nerves
does not cross the BBB and therefor will NOT block pain signaling from the TNC to the cortex |
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Term
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Definition
triptan prototype
for treatment of acute migraine attacks |
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Term
| pharmacokinetics of sumatriptan |
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Definition
does not cross BBB
MAO-A METABOLISM
contraindicated in patients taking MAO inhibitors since sumatriptan is metabolized by MAO |
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Term
| side effects, toxicity, and interactions of sumatriptan |
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Definition
CORONARY ARTERY CONSTRICTION
causing chest discomfort commonly experienced by patients
contraindicated in patients with coronary artery disease |
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Term
| newer/second generation triptans |
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Definition
naratriptan
rizatriptan
zolmitriptan
almotriptan
eletriptan
frovatriptan |
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Term
| receptor interactions and effects of newer triptans |
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Definition
5HT-1B agonist: constriction of intracranial blood vessels
5HT-1D agonist: inhibition of vasoactive peptide release from trigeminal nerves
ADDITIONAL ACTION on central 5HT-1D receptors (crosses BBB)
newer triptans are more lipophilic so they can act on the central 5HT-1D receptors that are located in the trigeminal nucleus caudalis and block transmission of pain signals to thalamus |
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Term
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Definition
treatment of acute migraine
10-20% GREATER CLINICAL EFFICACY over sumatriptan |
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Term
| pharmacokinetics of newer triptans |
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Definition
higher oral bioavailability over sumatriptan
frovatriptan has longer t1/2 (27h)
some metabolized by MAO-A and CYP3A4 |
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Term
| side effects, toxicity, and interactions of newer triptans |
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Definition
most frequent effects are mild (tingling, sensation of warmth, nausea)
like sumatriptan, can cause coronary artery constriction (5HT-1B mediated)
triptans are contraindicated in patients with ischemic heart disease for this reason |
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Term
| triptans metabolized by MAO-A |
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Definition
almomtriptan
rizatriptan
sumatriptan
zolmitriptan |
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Term
| triptans metabolized by CYP3A4 |
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Definition
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