Migraines Flashcards
(104 cards)
1
Q
what are the 2 types of warning signs for migraine?
A
- prodrome
- aura
2
Q
what are the 5 warning signs of migraine?
A
- food cravings
- tiredness
- excitability/hyperactivity
- change in mood
- yawning
3
Q
what are 2 types of symptoms of migraine, other than headache?
A
- allodynia
- nausea
4
Q
what is allodynia
A
when normally painless stimuli cause pain–> extreme sensitivities
5
Q
what are 3 types of allodynia?
A
- phonophobia –> sound
- photophobia –> light
- osmophobia –> odour
6
Q
what is a “classic” migraine?
A
migraine with aura
7
Q
what classifies someone as having classic migraine?
A
2+ headaches preceded by aura in a lifetime
8
Q
what are 3 symptoms of aura?
A
- blurred vision
- flashing lights/zig zag
- scotoma –> missing area of vision
9
Q
is aura reversible?
A
yes
10
Q
how long does it take aura to wear off?
A
within an hour
11
Q
when does an aura occur?
A
5-30 min before pain
12
Q
how long do migraine without aura last?
A
4-72 hours
13
Q
what are the 4 symptoms that ppl with migraine w/o aura usually experience at least 2 of?
A
- unilateral
- pulsating
- moderate/severe intensity
- aggravated by physical activity
14
Q
what are the 4 symptoms that ppl with migraine w/o aura usually experience at least 1 of?
A
- nausea
- vomiting
- photophobia
- phonophobia
15
Q
is migraine more common in men or women?
A
women
16
Q
what is the median migraine duration?
A
24h
17
Q
what percent of ppl w migraine have weekly attacks?
A
10% or more
18
Q
why are migraines maybe not caused by a specific trigger? (study)
A
in a study, only 3/27 patients had migraines caused by their supposed trigger
“trigger” was bc of selective memory –> were stressed and had a migraine so attributed the migraine to stress
19
Q
what are the 2 types of migraine drugs?
A
- prophylactic –> preventative
- abortive –> acute
20
Q
what are 3 examples of prophylactic drugs?
A
- propranolol (and some other B blockers)
- valproate
- TCAs
21
Q
why are all 3 prophylactic drugs successful?
A
they prevent 50% of attacks
22
Q
why are none of the prophylactic drugs the “best”?
A
all have same amount of side effects but have different side effects –> decide which side effects you can live with
23
Q
why are propranolol and valproate likely safer than TCAs?
A
bc TCAs have interactions with alcohol
24
Q
what did a study show about valproate reducing number of migraines?
A
valproate did reduce the number of migraines but did not completely stop all migraines –> common for prophylactic drugs
25
describe the use of beta-blockers for migraine
- in general, they work well
- propranolol is most common prophylactic drug
26
what is the adverse effect of B blockers?
contraindications where B block causes problems
27
describe the molecular targets of valproate?
valproate has multiple molecular targets but don't know which are anti-migraine
28
what are 2 adverse effects of valproate?
1. thinning hair
2. fetal malformations
29
what is the mechanism of TCAs?
block monoamine transporters
30
what are the 2 adverse effects of TCAs?
1. alcohol interaction
2. overdose risk
31
what are the 3 abortive drugs used for migraine?
1. NSAIDs
2. narcotics
3. 5HT agonists
32
why are NSAIDs used for migraine?
migraine involves inflammation that causes pain
33
why would you take NSAIDs with an anti-emetic or suppository?
bc of vomiting
(don't use as suppository if diarrhea)
34
what type of migraine cases is NSAID used?
for mild, moderate, and severe cases
35
why are narcotics not used very much for migraines? (5)
1. migraine is chronic --> would need a lot
2. narcotics have shorter duration of action than length of migraine
3. clinical trials never shown efficacy
4. morphine not analgesic for everything --> not guaranteed it will work
5. can develop tolerance
36
when are 5HT agonists used?
if NSAIDs don't work
for moderate to severe migraine
37
what are 2 classes of 5HT agonists?
1. ergot
2. triptan
38
why can triptans be better than ergot and other 5HT agonists? (2)
1. specifically made to target 5HT receptors
2. more effective + fewer side effects than ergot
39
why is ergot family pharmacologically rich?
has many targets, including 5HT receptors
40
what are the results of a study with sumatriptan vs ergotamine w/o placebo
sumatriptan works better than ergotamine
but since no placebo, don't know if drugs actually help
41
why was placebo not included in sumatriptan vs ergotamine study?
ergotamine was "gold-standard" for migraine treatment so we know it already works --> not fair to give patients placebo
42
why is caffeine taken with ergotamine?
caffeine is a pharmacokinetic helper for ergotamine
43
which non-headache symptoms does sumatriptan help with (2)? which does it not help with (1)?
helps with:
1. nausea
2. light/sound sensitivity
does not help:
aura
44
what are 2 adverse effects of ergot?
1. peripheral vasoconstriction
2. mental disturbance
45
what are 2 adverse effects of triptans?
1. chest tightness due to constriction of coronary arteries
2. myocardial ischemia
46
what is the common effect of ergots and triptans?
all are vasoconstrictive
47
when should a patient not take ergots and triptans?
if patient has cardiovascular problems
48
what was migraine pain initially believed to be caused by?
initially believed that something triggers meningeal blood vessels to dilate which causes pain
49
what are the 5 points of "evidence" for the vasodilation hypothesis for migraine?
1. pain pulsates in time with vessels
2. patients with vascular disease are prone to migraine
3. stimulating meningeal vessels is painful
4. nitroglycerin for angina causes vasoconstriction AND pain
5. balloon angioplasty causes pain
essentially trying to prove that vasodilation in meninges = pain
50
what are the 5 cracks in the evidence for the vasodilation hypothesis for migraine?
1. vessel does not pulsate, even with pulsating pain
2. vascular disease affects many tissues, not just vessels
3. vessels experiences diff changes in blood vessel tone, not just vasodilation
4. pain and vasodilation from nitroglycerin occur at diff times
5. balloon angioplasty usually doesn't cause pain, but if it does it's due to scraping
51
what is the currently accepted hypothesis for the cause of migraine?
NEUROGENIC INFLAMMATION
vasodilation and pain both occur but separately by diff mechanisms and the vasodilation DOES NOT cause the pain
52
what does neurogenic mean
originates in nerves
53
describe what's happening in the neurogenic inflammation hypothesis to cause migraines (8 steps)
1. meninges blood vessels are innervated by trigeminal nerve fibers
2. a trigger causes excitation --> neuropeptides are released
3. neuropeptides cause vasodilation
4. neuropeptides stimulate release of cytokines from inflammatory cells
5. inflammation occurs via vasodilation + increased vessel permeability
6. fluid leaks out of vessels to cause edema and plasma proteins enter tissue
7. inflammation leads to pain
8. inflammatory cells sensitize nerve terminals so a trigger will cause more pain thru trigeminal nerve
54
what is called when plasma proteins leak out from blood to tissue?
plasma extravasation
55
describe how the blood vessel physically interacts with the trigeminal nerve
trigeminal nerve surrounds blood vessel
trigeminal nerve has bulges (varicosities) that release neuropeptides adjacent to capillary, which allows mast cells to release mediators
56
does the trigeminal nerve have dendrites?
no
57
what are trigeminal nuclei?
clusters of trigeminal nerves
58
what are trigeminal ganglion?
connects periphery to brainstem and upper spinal cord
59
what is the result of electrical stimulation of the trigeminal nerve and what 2 things does this lead to?
electrical stimulation causes neuropeptides to be released
1. CGRP (a vasodilator) is released in plasma
2. mast cells release mediators
60
why does the release of CGRP upon stimulation of the trigeminal nerve imply that the trigeminal nerve is involved in migraine?
migraine sufferers have lots of CGRP in plasma during a migraine
and stimulation of the trigeminal nerve is what causes the release of CGRP
61
describe the experimental setup for looking at the response of meningeal sensory neurons to mechanical stimuli
- anaesthetize rats
- remove skull above cortex, leaving meninges exposed + intact
- stimulate meninges by lightly stroking or adding "inflammatory soup"
- record activity of electric sensors in trigeminal ganglion when pain AP travels thru
62
describe what happens when ipsilateral meninges is stroked
trigeminal neurons on one side will transmit the pain AP when they are stroked on the same side
63
describe what happens when contralateral meninges is stroked
trigeminal neurons on one side will NOT transmit pain AP when they are stroked on the opposite side
64
what can you conclude from the stroking experiment?
mechanical stimulation of IPSILATERAL trigeminal nerve can cause some pain
65
what is "inflammatory soup"
mimics the mediators released by cells
66
what happens when inflammatory soup is added to meninges?
there is an increase in pain AP thru the trigeminal nerves
67
what can you conclude from the inflammatory soup experiment?
inflammation can cause some pain
68
describe the experimental setup for looking at sensitization of trigeminal neurons to mechanical stimulation
- stimulate meninges with hairs of diff stiffness
- add inflammatory soup
- stimulate meninges with hairs of diff stiffness again, and see how sensitivity to mechanical forces changes
69
what were the results from the sensitization experiment?
trigeminal neurons become more sensitive to pain from mechanical stimulation when inflammatory soup was added (10x increase in sensitivity) so pain signal becomes worse
70
what 2 receptors does sumatriptan have high affinity to?
1. 5HT1B
2. 5HT1D
71
what are 2 ways to measure drug affinity for a receptor? which is better?
1. IC50
2. Ki (eqb dissociation constant)
72
affinity of abortive drugs to 5HT1D receptor corresponds to __________
affinity of abortive drugs to 5HT1D receptor corresponds to drug effectiveness
73
what do all abortive drugs have in common? does this mean high or low Ki?
all abortive drugs have high affinity for 5HT1D receptor (ergot and triptans)
low Ki
74
what is the activity of prophylactic drugs at 5HT1D?
nearly negligible affinity --> very high Ki
75
describe the targets of triptans
all have high affinity for 5HT1D and 5HT1B only
(+ somewhat high affinity for 5HT1A)
76
describe the targets of ergot drugs
many targets --> pharmacologically rich
includes 5HT receptors
includes alpha1 receptor
77
what is the significance of ergot drugs targeting the alpha1 receptor?
explains why ppl taking ergot can experience vasoconstriction
78
what are the 3 functions of sumatriptan?
1. pain
2. inflammation
3. vasodilation
79
why does sumatriptan act in the periphery?
does not cross BBB
80
where is 5HT1D located?
at trigeminal neuron
81
what type of receptor is 5HT1D?
presynaptic receptor involved in the release of neuropeptides
82
what does sumatriptan do at 5HT1D receptor? and what does this lead to?
prevents the release of neuropeptides which prevents inflammation, release of mediators, pain etc.
83
where is 5HT1B receptor located?
at blood vessel beside trigeminal neurons
84
what is the role of 5HT1B receptor?
vasoconstriction
85
what does sumatriptan do at 5HT1B?
vasoconstriction
86
what is c-fos?
transcription factor involved in pain
87
when is there low expression of c-fos?
under basal conditions
88
when does expression of c-fos increase?
if trigeminal neurons at meninges are excited
89
what can expression of c-fos tell you?
can tell you how much trigeminal neuron activation there is i.e. how much pain signal there is
90
describe measurement of c-fos in the vehicle (untreated) control condition
lots of trigeminal nuclei are expression c-fos --> therefore lots of pain
91
describe measurement of c-fos in the sumatriptan condition
fewer trigeminal nuclei expressing c-fos --> less pain
92
what does the c-fos experiment confirm?
confirms that triptans work in the periphery to inhibit conduction of pain from trigeminal to CNS
93
describe the aura progression (5 steps)
1. trigger causes neurons a small part of the visual cortex to become overactive
2. lose vision in focal part of vision first
3. glutaminergic neurons become active and glutamine spreads to other neurons
4. causes wave of excitation at 3mm/min
5. glutaminergic activation spreads in a band until it fizzles out (doesn't affect entire cortex)
94
why is there higher [K+ and H+] in extracellular space? 2 steps
1. since neurons are hyperactive, they become so depolarized/excited that they cannot do more AP and become refractory
2. electrical gradient is lost due to depolarization so K+ and H+ that's normally retained in neuron is released
95
what is the result of higher [K+ and H+]?
stimulates trigeminal nerve fibers to fire at the meninges to cause pain, nausea, emesis, autonomic activation
96
describe the checkerboard experiment that shows cortical spreading depression
patients look at screen w checkerboard where black and white squares alternate and activity in visual cortex is tracked (functional mri)
97
what do normal ppl show with functional mri?
neuronal activity is normal as checkerboard switches btwn black and white
98
what do ppl who see aura show with functional mri?
one hemisphere has abnormal neuronal activity
99
what is fovea?
fixation point
100
how is spreading depression shown in neuronal activity?
when scotoma started to appear, there is a disturbance in foveal part of visual cortex
then as time went on, there is disturbance further and further out in visual cortex
101
what type of migraine patients have cortical spreading depression?
ppl with migraine w aura
102
describe what happens when ppl were injected with CGRP
triggered migraines in ppl who get migraines but not in normal subjects
103
describe the use of CGRP receptor antagonists as migraine treatment and the downsides
in clinical trials and seem to be effective, but not more effective than sumatriptan
but caused liver damage
104
describe the use of monoclonal antibodies against CGRP or its receptor
highly selective for their targets and specifically designed to act on the trigeminal pain pathway to prevent activity of CGRP
effective and safe
