Lecture 22: Migraines Flashcards
What are Migraines characterized by?
Recurring headaches that are moderate to severe, pulsating in nature, last from 2-72 hours
What is the Aura in migraines thought to be driven by?
Cortical spreading depression
What is cortical spreading depression?
A wave of neuronal depolarization followed by desensitization (depression) that propagates across the cortex. Vasodilation followed by Vasoconstriction
What causes Migraines?
A mix of genetic and environmental factors
Which sex does migraine effect more?
It affects women more than men
What is the genetic portion of migrains?
Familial hemiplegic migraines
What are Familial Hemiplegic Migraines?
A specific type of migraines that is driven by a genetic mutation
What are the additional symptoms of familial hemiplegic migraines?
It includes weakness of half of the body
What is the inheritance of Familial Hemiplegic Migraine?
It is autosomal dominant
What three genetic mutations are associated with FHM?
- P/Q-type calcium channel
- Na+/K+ ATPase
- Na+ channel subunit
What do the FMH mutations do?
Lower the threshold for cortical spreading depression
What is the largest cranial nerve?
The Trigeminal nerve
What are the three branches of the Trigeminal Nerve?
- Ophthalmic
- Maxillary
- Mandibular
What are the three purposes of the Trigeminal nerve?
- Sense pain and temperature in the head region
- Innervate the dura mater (membrane that surrounds the brain)
- Controls cerebral blood vessels (trigeminovascular system)
What is pain in the head detected by?
The opthalmic branch of the trigeminal nerve innervating the dura mater and associated blood vessels
What are the three reasons why migraines are thought to be neurovascular?
- Extracerebral vessels dilate during migraine attack
- Cranial blood vessel stimulation provokes headache
- Vasoconstrictor drugs alleviate pain
How does 5-HT affect blood vessels?
It causes vasoconstriction
What are the levels of 5-HT in people who experience migraines?
They have low levels of 5-HT between attacks
What neurotransmitter is released in the brain during migraines?
5-HT
What is the consequence of migraineurs having low levels of 5-HT between attacks?
Their blood vessels are already more dilated making them more susceptible to migraines
Why is 5-HT released during migraine attacks?
It is a reaction to mitigate the migraine effects
Where is CGRP located?
In the trigeminal peripheral afferents that innervate the vasculature of the dura mater
What happens when Trigeminal afferents are activated?
They can release the CGRP peptide which binds to receptors on the vasculature and leads to vasodilation
What does CGRP released by trigeminal afferents bind to and what does it do?
It binds to CGRP afferents and leads to vasodilation
What are the levels of CGRP in those with migraine?
They are elevated in those with migraines
What is neurogenic inflammation?
Activation of trigeminal nerve pain afferents causes surrounding inflammation through CGRP causing vasodilation
Which receptor does serotonin released during migraines bind to?
5-HT1D receptors
What does serotonin binding 5-HT1D on vasculature do during a migraine?
It blocks the activity of the Trigeminal nerve, so it blocks the vasodilatory effect
What type of receptor is a 5-HT1D coupled receptor?
An inhibitory G-protein receptor
What type of receptor is the 5HT2a receptor that LSD binds to?
A G-protein coupled receptor. It is Gq
What type of receptor is the 5HT2a receptor that LSD binds to?
A G-protein coupled receptor. It is Gq
What type of receptor is the 5HT2a receptor that LSD binds to?
A G-protein coupled receptor. It is Gq
What are the two types of migraine treatment strategies?
Prophylactic and abortive strategies
What does Prophylactic mean?
Treatments are taken daily to prevent attacks
When are abortive treatments taken?
Once an attack occurs
What are the Non-pharmacological Prophylactic Interventions?
Identify triggers
What are the Prophylactic Pharmacological Interventions?
- Beta Blockers (Propranolol)
- Anticonvulsants (Gabapentin)
- Antidepressants (Amitriptyline)
What kind of drug is Propranolol?
A beta blocker
What kind of drug is Gabapentin?
An anticonvulsant
What kind of drug is Amitriptyline?
An antidepressant
How does Beta Blockers like Propranolol affect migraines?
The decrease blood pressure
How do Anticonvulsants like gabapentin affect migraines?
They block pain transmission
How do Antidepressants like amitriptyline affect migraines?
They block SERT to inhibit serotonin reuptake which helps with vasoconstriction
What are the non-specific analgesics that can help with migraines?
Aspirin, acetaminophen, NSAIDs, opioids
What is the downside to using non-specific analgesics for migraines?
There is the risk of medication overuse headache
What receptor does caffeine act at and what does it do?
It is an adenosine receptor antagonist
Where are adenosine receptors located?
On vasculature
What does caffeine being an antagonist at the adenosine receptors do?
It causes vasoconstriction
How does Caffeine affect other analgesics?
It increases absorption of other analgesics
What is an example of a migraine medication with caffeine?
Excedrin
How are Ergotamine similar to LSD?
They are both ergot alkaloids
Which receptors do Ergotamines act at?
5HT-1b/d receptors
What does Ergotamines binding to 5HT-1b/d receptors do?
Inhibits neurogenic inflammation
What kind of G-protein coupled receptors are 5HT-1b/d receptors that ergotamines bind to?
They are Gi because they inhibit neurogenic inflammation
What is the issue with Ergotamines?
They have a low degree of receptor selectivity causing side effects like coronary vasoconstriction
What does a low Ki mean?
A high binding affinity
What does a high pKi mean?
High binding affinity
Which populations should not take Ergotamines?
Those with any heart conditions because of its low selectivity that causes side effects
What is the Absorption and Distribution characteristics of ergotamines?
It has large first pass metabolism via oral administration causing low bioavailability
What can extend to rate and extent of absorption of Ergotamines?
Caffeine
What are Ergotamines metabolized by?
The liver
What are ergotamines excreted in?
Bile
What is an example of a Triptan?
Sumatriptan
What receptors do Triptans target and what do they do?
They are selective 5-HT1b/d agonists
What are the effects of Triptans being agonists at 5-HT1b/d agonists?
They cause Vasoconstriction and inhibition of the trigeminal nerve
What kind of G-protein coupled receptors are 5-HT1b/d receptors?
The are Gi coupled receptors
Why are Triptans better than Ergotamines?
Because they avoid the side effects by being more selective
Why is the bioavailability of Triptans better when given subcutaneously?
Because of first pass metabolism
What is sumatriptan metabolized by?
Monoamine oxidase in the liver to indoleacetic acid and found in urine
What does a Phase 2 clinical trial check for?
Efficacy
What does Phase 1 check for?
Safety
What is Rimegepant (Nurtek)?
A small molecule CGRP receptor antagonist
What are CGRP antibodies?
Monoclonal antibodies to either CGRP receptor or CGRP itself that inhibits CGRP signalling leading to vasoconstriction
