Lecture 22 - Migraine Flashcards
a primary headache disorder characterized by recurring headaches that are moderate to sever, pulsating in nature, last from 2-72 hours, sensitivity to normal sensory input (makes pain worse), and sometimes nausea/vomiting
migraines
~20% of migraines are preceded by:
aura (visual disturbances consisting of flashing lights or zigzag lines moving across the field of vision)
migraines are thought to be driven by:
cortical spreading depression
a wave of neuronal depolarization followed by desensitization/depression that propogates across the cortex
cortical spreading depression
migraine risk is likely due to:
genetic and environmental factors
do migraines affect women or men more?
women
the increased incidence in women after puberty indicates that _____ may play a role in migraines
sex hormones
migraines that involve weakness of half the body, and follow an autosomal dominant inheritance pattern
familial hemiplegic migraines
what are the three major genetic mutations associated with familial hemiplegic migraine?
- P/Q type Ca++ channel
- Na+/K+ ATPase
- Na+ channel subunit
how do genetic mutations to Ca++ channels, Na+ channels, and ATPases impact migraine prevelance?
mutations lower the threshold for cortical spreading depression
the largest cranial nerve
the trigeminal nerve (CN V)
what are the three branches of the trigeminal nerve?
- ophthalamic
- maxillary
- mandibular
- senses pain and temperature in the head region
- innervates the dura mater
- controls cerebral blood vessels
these are all functions of the:
trigeminal nerve
pain in the head is detected by the _____ of the trigeminal nerve innervating the _____ and associated _____
opthalamic branch, dura mater, blood vessels
the cause of migraine is still unkown, but they are thought to be a:
neurovascular disease
what three factors provide evidence to the idea that migraines are a neurovascular disease?
- extracerebral vessels dilate during migraine attack
- cranial blood vessel stimulation provokes headache
- vasoconstrictor drugs alleviate pain
the release of 5HT leads to:
vasoconstriction
migraineurs have low levels of _____ between attacks
5HT
true or false: 5HT is released during migraine attacks
true
a molecule located in trigeminal peripheral afferents which are released in response to pain and lead to vasodilation
calcitonin gene-related peptide (CGRP)
true or false: CGRP levels are elevated in those with migraine
true
migraine treatments that are taken daily to prevent attacks
prophylactic treatments
migraine treatments that are taken once an attack occurs
abortive treatments
what are the major non-pharmacological prophylactic treatments to migraines?
identifying and avoiding triggers (diet, exercise, consistent sleep, avoiding excessive caffeine and alcohol, minimizing stress)
what are the major pharmacological prophylactic treatments to migraines?
- beta blockers (propanolol)
- anticonvulsants (gabapentin)
- antidepressants (amitriptyline)
in what cases are pharmacological prophylactic treatments best used?
best for people with very frequent migraines (5+ a month)
why might pharmacological prophylactic treatments not be best for people with infrequent migraines?
lots of side effects associated with medications
what are the major abortive treatments to migraines?
non-specific analgesics (aspirin, acetominophen, NSAIDs, opioids)
what is the risk of using abortive migraine treatments (particularly opioids)?
risk of medication overuse headache
are aspirin, acetominophen, and NSAIDs effective at treating migraine pain?
not really (severity of pain is too much for them to handle)
caffeine is an:
adenosine receptor antagonist
adenosine receptor antagonists lead to:
vasoconstriction and increased absorption of some analgesics (like acetominophen and ergotamines)
caffeine can improve migraine treatment during an attack, but may also trigger:
headaches or result in rebound headache (withdrawl)
the first specific anti-migraine agents (no longer first line therapy due to risks)
ergot alkaloid
ergot alkaloids are agonists for ______ receptors that inhibit ______
5HT-1b/d, neurogenic inflammation
what are the major risks of using ergotamines as a migraine treatment?
off-target effects, coronary vasoconstriction (ischaemic changes and anginal pain)
the use of ergotamines to treat migraine pain is not recommended in patients with:
peripheral vascular disease, coronary heart disease, uncontrolled hypertension, stroke, etc
first line migraine therapy that acts as a selective agonist at the 5HT-1b/d agonist
triptans (sumatriptan)
what are the two mechanisms of sumatriptan?
vasoconstriction and inhibition of trigeminal nerve
what are the two major types of CGRP inhibitors?
- small molecule CGRP antagonists
- monoclonal antibodies to CGRP or CGRP receptor
why are CGRP inhibitors being developed as a migraine treatment?
people with migraines have higher levels of CGRP in their brains
monoclonal antibodies inhibit CGRP signalling leading to:
vasoconstriction
there are several small molecule antagonists to the CGRP receptor that have been approved in the last five years known as the:
gepants
why are small molecule drugs normally preferred over antibodies?
- faster and easier to manufacture
- less immunogenic risk
- better tissue permeability (antibodies are too big)
- can be given orally (antibodies must be given via IV)
what are the major advantages of developing antibody treatments?
- more selective for targets (less off target effects)
- quicker to develop a new antibody than a new small molecule drug
a CGRP inhibitor which was efficient at treating migraine, but had poor bioavailability and was abandoned at the Phase II clinical trial
olcegepant (BIBN4096)
a CGRP inhibitor which had several Phase III clinical trials supporting anti-migraine efficacy and safety, but issues associated with liver toxicity and was abandoned
telcagepant (MK-0974)
CGRP inhibitor which has been approved for market distribution that is effective at treating migraine and has little effect on liver aminotransferase levels
rimegepant (Nurtek)
