Migraine: Treatment And Prevention (Fitz) Flashcards Preview

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Flashcards in Migraine: Treatment And Prevention (Fitz) Deck (35):
1

What is migraine?

Primary disorder of pain
Special form of neurovascular headache
Neural events provoke dilation of cranial blood vessels, which result in pain, further sensory and central nerve activation

2

Describe the migraine time course

Prodrome: Premonition 12-36 hrs before headache: yawning, depression, lethargy, excitability, craving, distaste

Aura: classic
None: common

Headache: Mostly unilateral ~4-72 hrs
Photophobia
Phonophobia
Nausea
Vomiting

Postdrome
Exhaustion
Fatigue

3

Describe therapeutic agents for migraine

Goal: rescue from/halt migraine attack

Frontline agents: triptans: 5HT1B/1D receptor agonists in prodrome phase

Ergot alkaloids in prodrome phase

Headache phase: NSAIDS, acetaminophen

4

Describe preventative agents for migraine

Goal: limit frequency and severity of attacks
In asymptomatic phase
Beta-blockers: propranolol, timolol
Tricyclic antidepresseants: amitriptylene, imipramine
Anticonvulsants: topirimate, valproate
Ca2+ channel blockers: verapamil

5

Describe neurogenic inflammation theory of migraine: cortical spreading depression

Wave of electrical activity and H+, K+ passing through nerve cells stimulates release of neuropeptides (CGRP, substance P) and inflammatory mediators (NO, histamine, prostaglandins) that dilate cranial blood vessels and sensitize nerves to pain
Sensitization of nerves progresses from periphery to brain

6

What are the elements of a migraine attack?

Vascular: cerebral and cranial vessels. Meningeal and dural arteries
Sensory nerves: trigeminal nerves and ganglion and trigeminal nucleus caudalis
Brain: cortical spreading wave
Brainstem: distorted sensory input
Neurogenic inflammation: neuropeptides (CGRP), nitric oxide (NO)
Serotonin receptors: 5HT1B/1D

7

Describe the mech of a migraine attack

1. Brainstem dysfunction sparks a wave of excitation/depression in cortex (CSD)
-Cerebral vasoconstriction accompanied by H+, K+, NO discharge from neurons

2. Electrolytes and NO diffuse and dilate cranial arteries and depolarize perivascular trigeminal terminals
-CGRP and neuropeptides promote neurogenic inflammation

3. Neurogenic inflammation irritates TG nerve and transmits migraine pain

8

What are the two key mediators in migraine?

CGRP and NO
They interact throughout trigeminal neurovascular system
-at crainial artery, ganglion, nucleus caudalis

9

What drug used to treat coronary artery disease provokes migraine?

Organic nitrates (NO)

10

Cranial vessels and presynaptic TG nerve terminals express a distinct subset of what receptors?

Serotonin 5HT-1 receptors:
5HT-1D peripheal neuron
5HT-1B cranial vessels
5HT-1B/1D central neuron

Therefore, serotonin and its receptors modulate CGRP actions

11

Triptans are selective serotonin 5HT-1D/1B receptor agonists. What does triptan binding to 5HT-1B receptor do?

Lowers cAMP
Stimulates vasoconstriction (opposes vasodilation)

12

What does triptan binding to 5HT-1D receptor do?

Lowers cAMP
Inhibitos presynaptic release of CGRP

13

Describe the peripheral actions of triptans

Triptans cause vasoconstriction of dilated meningeal, dural, and pial blood vessels by stimulating 5HT-1B receptors located on vascular smooth muscle

Triptans inhibit release of CGRP and other neuropeptides from peripheral end of trigeminal nerve by stimulating 5HT-1D receptors on presynaptic nerve terminals

14

What are the brainstem actions of triptans?

Triptans also have high affinity for 5HT-1D receptors located centrally in region of trigeminal nucleus caudalis in brainstem
This modulates incoming painful sensory information from periphery and inhibits its upward transmission to thalamus and higher brain centers where pain is perceived

15

Triptans are 5HT-1B/1D agonists. Do not confuse them with what other serotonin receptor (ant)agonists?

5HT-1A agonists: anxiolytic, antidepression (buspirone)
5HT-2 (serotonin): aggregates blood platelets
5HT-3 antagonists: anti-emesis (ondansetron)
5HT-4 agonists: GI disorders (cisapride)

16

What is the prototype triptan?

Sumatriptan (Imitrex)
When taken PO, its Cmax ~1-2 hrs
~15% bioavailability made it unreliable in some pts

Other delivery options:
SC: Cmax ~15 min
Nasal spray: ~30 min

Clearance:
Half-life: 1-2 hrs
Metabolized by monoamine oxidase-A
(Sumatriptan is an indoleamine)

17

What triptans besides sumatriptan are effective and tolerated with few adverse effects?

Almotriptan (Axert)
Naratriptan (Amerge): ~70% bioavailability. Half-life~ 6 hrs
Zolmitriptan (Zomig): active metabolite

Rizatriptan (Maxalt) and eletriptan (relpax):
Relative to sumatriptan, some evidence of better tolerance and better eficacy

Frovatriptan (Frova): half-life 24 hrs

18

Migraine symptoms influence choice of delivery route.
Pros/cons of medication type?

Oral (tablets):
Pro: easy to take
Con: ineffective if pt vomits

Nasal spray:
Pro: effective with nausea/vomiting, simple, works quickly
Con: few triptans formulated as nasal sprays

Injection:
Pro: works quickly
Con: inconvenient

19

Which triptans have the most delivery options?

Sumatriptan (Imitrex):
Injectable subcuntaneous
Nasal spray
Tablets

Zolmitriptan (Zomig)
Tablets
Orally disintegrating tablets
Nasal spray

20

What are the different aspects of pain relief?

Speed, degree, duration, reliability, consistency of pain relief
Freedom from recurrence
Nature of relief (headache, nausea, phonophonia, photophobia, etc)
Relative tolerability vs pain relief

21

When choosing migraine medication, how quickly does it begin working? How long does it keep working? Is pt taking other medications?

Nasal spray = fast onset of migraine relief
Subcutaneous = sumatriptan fastest

Repeated dosing confers risk of overuse

Serotonin syndrome: MAO interactions

22

1. Does clinically failure with one triptan forecast clinical failure with all triptans in a particular patient?
2. Should a doctor prescribe a different triptan if first one tried did not relieve pain in a particular patient?

1. No
2. Yes

23

Describe triptan contraindications and cautions

All triptans are modest vasoconstrictors of coronary, renal vessels, (5HT1 receptors)

Contraindicated in pts with history or suspicion of ischemic or vasospastic coronary disease, or other significant cardiovascular disorder and in pts with uncontrolled hypertension

Sumatriptan, rizatriptan, and zolmitriptan are contraindicated in pts taking MAO inhibitors because they are metabolized by MAO

24

Describe zolmitriptan breakdown

Zolmitriptan->CYP1A2->zolmitriptan N-oxide

Zolmitriptan->CYP1A2-> N-desmethyl-zolmitriptan (active metabolite)->MAO-A->ALDH->indole acetic acid metabolite

25

Describe ergot alkaloids use for migraine

Ergot alkaloids poisons/drugs of antiquity still used for severe or refractory migraine
Dihydroergotamine: sub-lingual, intranasal, IV, IM, SC
Ergotamine and caffeine (Cafergot): oral tablet, rectal suppository
Less specific: interact with alpha-receptors, dopamine receptors, various 5HT receptors and exhibit mixed action at different receptors (agonist, partial agonist, antagonist)

26

Describe fast relief vs long-lasting relief of DHE and triptan. Use together?

Injectable triptans work faster than injectable DHE
DHE worked longer. Fewer pts had return of headaches

NEVER use triptan and DHE together

27

What are side effects of ergot alkaloids?

Strong emetic action is major side effect
Vasoconstriction is worse than that seen with triptans
-St Anthony's Fire

28

Describe migraine treatment in pregnancy. Contraindicated?

Acetampniphen +/- codeine
Aspirin: 1st, 2nd trimesters only
Ibuprofen: 1st, 2nd trimesters only
Triptans: cautiously

Contraindicated:
Dihydroergotamine
Other ergot alkaloids (abortion risk)

29

Describe drug combinations useful for migraine treatment

Triptans can be taken with analgesics (acetminophen, ibuprofen, naproxen)

Sumatriptan+naproxen combination = Treximet, clinically effective

Triptan+anti-nausea
Dihydroergotamien+anti-nausea (IV)

30

Describe BOTOX as prevention of migraine

BOTOX neurotoxin directly acts on motor neurons to reduce muscle activity
BOTOX cleaves SNAP-25 in motor neurons, which inhibits *acetylcholine* release at motor endplate

31

What are considerations for preventative therapy?

>2 migraines per month with disability
Disability lasting >3 days per month
Failure of, contraindication for, or adverse events from acute treatmetns
Rescue medication used >2x per week
Uncommon migraine conditions (migraine with prolonged aura)

32

Describe Ca2+ channel blockers for migraine prevention

Verapamil often first choice because of good side effect profile

Mechanisms proposed:
-normalizes vessel tone
-lessens Ca2+dependent vesicle fusion

33

Describe beta adrenergic receptor blockers for migraine prevention

Propranolol or timolol (FDA approved)

Mechanisms proposed:
-Anxiolytic action
-decreases sympathetic activity
-blunts cortical spreading depression

Clinically effective in ~60-80% of pts
Lower frequency of attacks by 50%

34

What are cautions for beta adrenergic receptor blockers for migraine prevention?

Normally well tolerated

fatigue, CNS depression
change in sexual function
Reduced exercise tolerance
Hypotension and bradycardia

*Bronchoconstriction (contraindicated in asthmatic pts)*

35

Describe anti-epilepsy drugs in migraine prevention

Brain imaging studies show epileptic-like phenomenon that spreads over cortex
Concurrence of migraine and epilepsy in families and pts
Topirimate and valproate are approved for and effective in migraine prevention in adults

But potential suicide events