!Neuropharm Migranes Flashcards
LO
Classify pharmacological agents used in the treatment of migraine as therapeutic or preventative and select the best drug for clinical scenario
- select an appropriate triptans for use in the treatment
- infer side effects or ergot alkaloids from their mechanisms of action
- recognize appropriate drug combinations useful for te treatment of migraine
What triggers migraines
Glare, bright lights, sounds, hunger, let down forms tress, physical exertion, stormy weather or barometric pressure changes, hormonal fluctuations during menses, lack of or excess sleep, alcohol or other chemical stimulation
Classic migraine vs common
Classic has mini headache before?
What is the course of a migraine attack
Prodrome, headache, postdrome
What can be used to treat prodrome
Triptans, ergot alkaloids
What is used to treat the headache
NSAIDS
Acetaminophen
What are preventative agents used for
Limit frequency and severity of attack
Treat asymptomatic phase, before the prodrome
What are preventative agents
B blockers
Tricyclic antidepressants
Anticonvulsants
Ca channel blockers
Name ergot alkaloids
Dihydroergotamine (DHE)
Ergotamine+caffeine
Name triptans
Sumatriptan Almotriptan Naratriptan Zolmitriptan Riatriptan Electric tan Frovatriptan
Name B blockers
Propranolol
Timolol
Name tricyclic antidepressants
Amitriptyline
Imipramine
Name anticonvulsants
Topiramate
Valporate
Name Ca channel blocker
Verapamil
Botros for migraines MOA
Acts on motor neurons to reduce muscle activity by cleaving SNAP-25 in motor neurons, which inhibits acetylcholine release at the motor end plate
What is Botox prescribed for
Chronic migraine
What is a chronic migraine
Fifteen or more days each month with headache lasting 4 or more hours each day in people 18 or older
Neurovascular headache
Neural events result in the dilation of blood vessels
Results in pain and further nerve activation
Meninge sense pain?
They are innervated by trigeminal axons
When stimulated by vasodilation they generate throbbing unilateral migraine like pain
Calcitonin gene related peptide migraine CGRP
Released from trigeminal ad-fibers which increases dural vessel vasodilation
Substance P and neurokinin A migraine
Released from trigeminal C fibers and increase dural vessel permeability
Neurogenic inflammation theory of migraine
- a wave of electrical activity and H/K pass through nerve cells
- stimulates the release of neuropeptides (CGRP and Substance P) and inflammation (NO, histamine, and prostsagladins)
- leads to dilation of cranial blood vessels and sensitized nerve to pain
- sensitization spreads from periphery to the brain
CGRP and NO interact throughout the __ __ __
Trigeminal neurovascular system
At the cranial dura mater, trigeminal ganglion, and spinal trigeminal nucleus
___ ____ used to treat coronary artery disease can provoke migraine. How
Organic nitrates
At cranial dura mater, trigeminal ganglion, and spinal trigeminal nucleus
Brainstem dysfunction sparks a wave of excitation and depression in cortex-___ ___ ___
Cortical spreading depression
What does cortical spreading depression lead to
Cerebral vasoconstriction
Accompanied by H, K, and NO discharge from neurons
Dilation of cranial arteries-depolarization of perivascular trigeminal terminals
Electrolytes and NO dilate cranial arteries and depolarize perivascular trigeminal terminals
CGRP and neuropeptides release promotes neurogenic inflammation
Neurogenic inflammation irritates trigeminal nerve and transmits migraine pain
Pain is associated with inflammation and dilation of the meninges
CGRP and substance P act together to produce painful dural infalmmation
Cranial vessels and presynaptic trigeminal nerve terminals express a subset a serotonin receptors
5HT-1B on cranial vessels
5HT-1D peripheral neuron
5HT-1B/1D central neuron
Serotonin and its receptors modulate CGRP actions
5HT-1B receptor vasculature
5HT-1D receptor synaptic
Vascular 5HT-1B receptor for CGRP
Dilation bv
Synaptic 5HT-1D receptor forCGR????????????
Pain
What are triptans
Selective serotonin 5HT1B/1D receptor agonists
What do tripatans stop
Pain and dilation
What happens when triptans bind 5HT1B receptors on vascular smooth muscle
Vasoconstriction of dilated meningeal, dural and pail blood vessels
What happens when triptans bind to 5HT1D receptors on presynaptic nerve terminals
Inhibits presynaptic release of CGRP and other neuropeptides from the peripheral end of the trigeminal nerve
Triptans binding to 5HT1D receptors on the trigeminal nucleus in the brainstem does what
Modulates incoming painful sensory information from the periphery
Inhibits upward transmission of painful sensory information to the thalamus and higher brain centers where pain is perceived
Sumatriptan Cmax
PO-1-2 hours
Nasal spray-30 min
SC-15 min
Sumatriptan clearance
T1/2-1-2 hours
Metabolized by monoamine oxidase A
Sumatriptan is an ____
Indoleamine
Similar structure to serotonin and melatonin
What does sumatriptan help
Persistent pain, nausea, and photophobia
What triptans have better tolerance and claims of between efficacy relative to sumatriptan
Rizatriptan
Eletritpan
Name other triptans
Almotriptan Naratriptan Zolmitriptan Rizatriptan Eletriptan Frovatriptan
Naratriptan bioavailability
70%
T1/2 is 6 hours
Zolmitriptan
Active metabolite is a 5HT1D agonist
Frovatriptan half life
24 hours
Oral oral triptans
Easy to take
Ineffective if patient vomits
Nasal spray triptans
Effective with nausea/vomiting, simple works quickly
-few triptans formulated as nasal sprays
Injection of triptans
Works quickly
Inconvenient
Delivery sumatriptan
Injectable, nasal spray, tablets
Zolmitriptan routes
Orally disintegrating tablets, nasal spray, tablets
Does clinical failure with one triptans forecast clinical failure with all triptans in a particular patient
No
Shoul a doctor prescribe a different triptans if the first one he/she tried did not relieve pain in a particular patient
Yes
Subcutaneous injection with fastest onset-for immediate relief
SQ Sumatriptan injection is fastest
Second fastest is nasal spray of sumatriptan, zolmitriptan
What triptans has longest HL is patient needs long duration of migraine
Frovatriptan has a 24 hours HL
What triptans can not be used with MAO inhibitors
Sumatriptan, rizatriptan, zolmitriptan
What medications may make a patient at risk for serotonin syndrome if taken with triptans
Selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, serotonin dopamine reuptake inhibitors, linezolid
Who are triptans contraindicated in
History or suspicion of ischemic or vasospastic coronary disease, or other significant cardiovascular disorder
Uncontrolled HTN
Why cant triptans be used with heart vascular issues
They are all vasoconstrictors of coronary and renal vessels
What are all triptans vasoconstrictors
5HT1B/D
33 yo male presents with substernal chest pain. He had headaches for 2 weeks he took 20 tablets in 5 days of cafergot (ergotamine tartate 1 mg an caffeine 100mg) which helped then he took more to make a total of 34. Within two minutes he noted tingling in his forehead and the onset of substernal pressure. He vomited, substernal pressure, increased breathing and pulse. Pupils and eye movements are ok. No increase in ICP. Inversion of T wave, ST segment elevations, biphasic T waves . Start nitroglycerin was started and the pain resolved. Had anteroseptal and inferior MI
Yikes
Central effects of ergotism
Agitation, cerebrovascular ischemia, hallucinations, headaches, miosis, nausea, seizures, twitching , vomiting
Peripheral calinical manifestations of ergotism
Bradycardia
Clinical manifestation of ergotism ischemic effects
Angina Gangrene Hemorrhagic vesiculations and bullae Mesenteric infarction Myocardial infarction Renal infarction
Duhydroergotamine MOA
Binds 5HT 1B, 1D, and 1F and adrenergic receptors, dopamine receptors
What happens when dihydroergotamine binds to peripheral a1-adrenergic receptors
Causes worse vascular vasoconstriction when compared with triptans can lead to peripheral ischemia, vascular disease, acute coronary syndrome and/or coronary vasospasm
Treating migraine during all trimesters of pregnancy
Acetaminophen with or without codeine
Treating migraine during first and second trimester of pregnancy
Aspirin and ibuprofen
__, ___, __ are contraindicated during pregnancy
Triptans
DHE and ergot alkaloids
Why are DHE and other ergot alkaloids contraindicated in pregnancy
Abortion risk
What is a useful combination useful for migraine headache treatment
Triptans+analgesic
(Sumatriptan+naproxen= treximet
Acetaminophen, ibuprofen, naproxen)
What are some drugs that are taken daily when a patient is asymptomatic in order to limit frequency and severity of migraine attacks
B blockers -propranolol, timolol
Tricyclic antidepressants-amitriptyline, imipramine
Anticonvulsants-topiramate, valproate
Ca channel blockers -verapamil
Chronic migraine ;considerations for preventative therapy
- more than 2 migraines per month with disability
- disability lasting more than 3 days per month
- rescue medication used more than 2 times per week
- uncommon migraine conditions (with aura)
- failure of , contraindication for, or adverse events from acute treatments
Valproate
Used in patients who fail triptans therapy
Effective prophylactic treatment in migrine
MOA valproate
Increases brain GABA levels
May suppress migraine related events in cortex, perivascular parasympathetic, trigeminal nucleus caudalis
Who is valproate contraindicated in
Pregnant women.. FDA warning
Why is valproate contraindicated in pregnant women
Decrease IQ scores in children born from women using the drug
Verapamil
Ca channel blocker used for migraine prevention
What is verapamil used for
1st choice for migraine prevention -not many side effects
Proposed mechanisms of action -normalizes vessel tone, lessens Ca dependent vesicle fusion
Propranolol / timolol
B blockers used for migraine prevention
Lowers frequency of migraine attacks by 50%
MOA propranolol and timolol
- Anxiolytics action
- Decreases sympathetic activity
- Blunts cortical spreading depression
Side effects propranolol
Limited
Fatigue, CNS depression Change in sexual function Reduced exercise tolerance Hypotension and bradycardia BRONCHOCONSTRICTION (contraindicated in asthma patients)
Who is propranolol and timolol contraindicated in
Asthma bc of bronchoconstriction
What are the ergot alkaloids used to treat migraines
DHE (dihydroergotamine)
Ergotamine+caffeine
How is DHE given
Sublingual, intranasal, IV, IM, SC
How is ergotamine+caffeine given
Oral tablet, rectal suppository
Ergot alkaloids are __ specific than the triptans
Less
What do triptans interact with
A-adrenergic, dopamine, and 5HT receptors
Are ergot alkaloids agonists or antagonists
Agonist, partial agonist, or antagonist
