Flashcards in Migraine: Treatment And Prevention (Fitz) Deck (35):
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
Describe the migraine time course
Prodrome: Premonition 12-36 hrs before headache: yawning, depression, lethargy, excitability, craving, distaste
Headache: Mostly unilateral ~4-72 hrs
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
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
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
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
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
What are the two key mediators in migraine?
CGRP and NO
They interact throughout trigeminal neurovascular system
-at crainial artery, ganglion, nucleus caudalis
What drug used to treat coronary artery disease provokes migraine?
Organic nitrates (NO)
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
Triptans are selective serotonin 5HT-1D/1B receptor agonists. What does triptan binding to 5HT-1B receptor do?
Stimulates vasoconstriction (opposes vasodilation)
What does triptan binding to 5HT-1D receptor do?
Inhibitos presynaptic release of CGRP
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
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
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)
What is the prototype triptan?
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
Half-life: 1-2 hrs
Metabolized by monoamine oxidase-A
(Sumatriptan is an indoleamine)
What triptans besides sumatriptan are effective and tolerated with few adverse effects?
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
Migraine symptoms influence choice of delivery route.
Pros/cons of medication type?
Pro: easy to take
Con: ineffective if pt vomits
Pro: effective with nausea/vomiting, simple, works quickly
Con: few triptans formulated as nasal sprays
Pro: works quickly
Which triptans have the most delivery options?
Orally disintegrating tablets
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
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
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?
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
Describe zolmitriptan breakdown
Zolmitriptan->CYP1A2-> N-desmethyl-zolmitriptan (active metabolite)->MAO-A->ALDH->indole acetic acid metabolite
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)
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
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
Describe migraine treatment in pregnancy. Contraindicated?
Acetampniphen +/- codeine
Aspirin: 1st, 2nd trimesters only
Ibuprofen: 1st, 2nd trimesters only
Other ergot alkaloids (abortion risk)
Describe drug combinations useful for migraine treatment
Triptans can be taken with analgesics (acetminophen, ibuprofen, naproxen)
Sumatriptan+naproxen combination = Treximet, clinically effective
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
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)
Describe Ca2+ channel blockers for migraine prevention
Verapamil often first choice because of good side effect profile
-normalizes vessel tone
-lessens Ca2+dependent vesicle fusion
Describe beta adrenergic receptor blockers for migraine prevention
Propranolol or timolol (FDA approved)
-decreases sympathetic activity
-blunts cortical spreading depression
Clinically effective in ~60-80% of pts
Lower frequency of attacks by 50%
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)*