21 Migraines Flashcards
What is the leading cause of disability worldwide, particularly in those under 50?
Migraine
What is Migraine?
Primary headache disorder characterized by recurring headaches that are moderate to severe, pulsating in nature, last from 2-72 hours
- Sensitivity to normal sensory input (light, sound, head movement)
- Sometimes nausea and vomiting
What is an aura?
- Visual disturbances consisting of flashing lights or zigzag lines moving across the field of vision
Aura is thought to be driven by:
Aura is thought to be driven by: cortical spreading depression:
- wave of neuronal depolarization followed by desensitization (depression) that propagates across the cortex
What is cortical spreading depression?
Wave of activity that propogates across the cortex (less intense than seizures) but causes mild visual disturbances
- wave of neuronal depolarization followed by a period of desensitization (because of refractory period) = reduced activity
What specific type of migraine has a strong genetic contribution?
Familial hemiplegic migraine
What is familial hemiplegic migraine?
What is the genetic contribution?
Migraine that includes weakness of half of the body
- Genetic:
- Autosomal dominant inheritance
- 3 known genetic mutations:
- P/Q-type Ca2+ channel
- Na+/K+ATPase
- Na+ channel subunit
What are three known genetic mutations that cause familial hemiplegic migraine?
3 known genetic mutations:
- P/Q-type Ca2+ channel
- Na+/K+ATPase
- Na+ channel subunit
Mutations lower the threshold for cortical spreading depression
What is the largest cranial nerve?
Trigeminal nerve
What are the three branches that the peripheral processes of the trigeminal nerve divide into?
What are the 3 main purposes of these branches?
- Ophthalmic
- Maxillary
- Mandibular
The trigeminal nerve has peripheral processes that divide into three branches _______, _______ and _______.
These have 3 main purposes:
The trigeminal nerve has peripheral processes that divide into three branches opthalmic, Maxillary and Mandibular.
These have 3 main purposes:
- Sense pain and temperature in head region (as well as proprioception)
- innervates the dura mater (membrane surrounding the brain)
- Controls cerebral blood vessels (trigeminovascular system)
- responsible for bring O2 into the brain
Pain in the head is detected by the ______ branch of the trigeminal nerve innervating the ______ and associated _______
Pain in the head is detected by the ophthalmic branch of the trigeminal nerve innervating the dura mater and associated blood vessels
The cause of migraine is still unknown but is thought to be a ________ disease.
Three pieces of evidence for this:
The cause of migraine is still unknown but is thought to be a neurovascular disease.
Evidence:
- During a migraine attack, the extracerebral vessels dilate
- Cranial blood vessel stimulation provokes headache
- eg NO = vasodilation = headache
- Vasoconstrictor drugs alleviate headache pain
How is serotonin linked to migraine?
Serotonin seems to work by influencing vascular tone in the cerebral region
- Release of 5-HT (serotonin) leads to vasoconstriction
In between attacks, migraineurs have low levels of _____
In between attacks, migraineurs have low levels of 5-HT (serotonin)
During migraine attacks, ____ is released
During migraine attacks, serotonin (5-HT) is released
Serotonin (5-HT) released from trigeminal nerves can influence vaso_____; people susceptible to migraines have lower levels of _______; and ______ is released during migraine attacks
Serotonin (5-HT) released from trigeminal nerves can influence vasoconstriction; people susceptible to migraines have lower levels of serotonin (5-HT); and serotonin (5-HT) is released during migraine attacks
What is CGRP and how is it linked to migraine?
CGRP = Calcitonin gene-related peptide (CGRP) located in trigeminal peripheral afferents
- Released from afferents in response to pain (in nociceptors) = leads to vasodilation
- promotes inflammation
- CGRP elevated in those with migraine suggesting there may be increased signalling of vasodilation
Treatment strategies for migraine include both ______ and _______ strategies
Treatment strategies for migraine include both prophylactic and abortive strategies
- Prophylactic: preventative - taken daily to prevent attacks
- Abortive: Taken once an attack occurs
What are some non-pharmacological prophylactic intervention?
Identify and avoid/minimize triggers
Common triggers: Caffeine, alcohol, stress, inconsistent sleep, diet, exercise
What are three possible pharmacological prophylactic interventions?
- Beta blockers (propanolol)
- decrease blood pressure = less pressure on cerebral blood vessels
- Anticonvulsants (gabapentin - inhibits Ca2+ channels that can reduce activity to prevent seizures)
- block pain transmission
- Antidepressants (amitriptyline)
- serotonin reuptake inhibitor SSRI (seen in depression lecture) by blocking SERT
What are the most common abortive strategies
Non-specific analgesics:
- aspirin
- acetaminophen
- NSAID
- opioids
Risk of medication overuse headache
What is medication overuse headache disorder? Which non-specific analgesic is it mainly associated with?
Mainly associated with Opioids (chronic use of opioids can make headaches worse)
- Headache present on >15 days/month
- regular overuse for >3 months of one or more drugs that can be taken for acute and/or symptomatic treatment of headache
- Headache has developed or markedly worsened during medication overuse
How does caffeine interact with adenosine receptors?
Caffeine is an adenosine receptor antagonist
- leads to vasoconstriction
- increases absorption of some analgesics (acetaminophen, ergotamines)
- Improves migraine treatment during attack
- may also trigger headaches or result in rebound headache (withdrawal)
What is the relationship between caffeine and migraine?
- Caffeine is an adenosine receptor antagonist
- leads to vasoconstriction
- increases absorption of some analgesics (acetaminophen, ergotamines)
- improves migraine treatment during attack
- may also cause rebound headache (withdrawal) - trigger migraine in those susceptible
What were the first developed specific anti-migraine agents?
Ergotamines (ergot alkaloids)
How do ergotamines work?
Agonists for 5HT-1b/d receptors that inhibit neurogenic inflammation (by blocking vasodilation)
- low degree of receptor selectivity which increases the risk of experiencing drug-induced side effect
- pKi = -logKi | high pki = high affinity
Ergotamine can produce ________, (not only vasoconstriction in brain) often with associated ______ changes and _____ pain in patients with coronary artery disease
Ergotamine can produce coronary vasoconstriction, (not only vasoconstriction in brain) often with associated ischaemic changes and anginal pain in patients with coronary artery disease
Use of ergotamines is contraindicated in patients with ________, _______, _________, _______
Use of ergotamines is contraindicated in patients with peripheral vascular disease, coronary heart disease, uncontrolled hypertension, stroke
What is the first line migraine therapy?
Triptans (eg sumatriptan)
- selective 5-HT1b/d agonist
- two mechanisms
- vasoconstriction
- inhibition of trigeminal nerve
- avoids side effects of ergotamine
How do triptans work and provide an example
- Triptans (eg sumatriptan)
- selective 5-HT1b/d agonist
- two mechanisms
- vasoconstriction
- inhibition of trigeminal nerve
- avoids side effects of ergotamine
- neglible binding at alpha 1 and alpha 2 receptors
What are the pharmacokinetics of Sumatriptan?
- Absorption and Distribution
- Bioavailability?
- Metabolism
- metabolized by _________ in the liver to __________
- Half-life around _______
- Excretion
- cleared in the ______
- Absorption and Distribution
- Bioavailability around 14% when taken orally, 96% when given subcutaneously (b/c first pass metabolism)
- Metabolism
- metabolized by monoamine oxidase in the liver to indoleacetic acid
- Half-life around 2 hours
- Excretion
- cleared in the urine
What enzyme degrades both serotonin and sumatriptan?
Monoamine oxidase
CGRP peptide is released from the ____________.
What is the goal of CGRP antagonists?
CGRP peptide is released from the trigeminal pain afferents and leads to vasodilation
- CGRP antagonists are meant to reverse the vasodilation implicated in migraine
What are two types of migraine treatments that target CGRP peptides?
- small molecule CGRP antagonists
- monoclonal antibodies to CGRP or CGRP receptor
- basically acts by blocking ability of CGRP to bind to receptor or
- antibodies bind to receptor and block the agonist from binding
What is rimegepant?
Rimegepant (nurtek) is a small molecule CGRP receptor antagonist in clinical development
Effective migraine treatment
Less effect on liver aminotransferase levels (safer for longterm use)
What are the CGRP antibodies and how do they treat migraines?
- Monoclonal antibodies to either the CGRP receptor or CGRP itself
- Inhibits CGRP signaling leading to vasoconstriction
What are two reasons why drugs might not be approved?
- Poor bioavailability
- side-effects (eg increased aminotransferase in liver indicating liver damage)
