Emergent therapies for migraine Flashcards
Where are 5HT-1F receptors found?
They are found exclusively at neural synapses, therefore do not have any effects on the vasculature. 5HT1F receptor agonists therefore do not have any circulatory contraindications
What are some examples of 5HT1F receptor agonists
Naratriptan - mixed 5-HT1B/1D/1F agonist. Approved
Lasmiditan - selective 5-HT1F agonist. Phase III
What may be the role of CGRP in migraine?
Migraine headache is thought to be associated with dilatation of cranial vessels and activation of the trigemino-vascular system. It plays a role in pain transmission. In man stimulation of the trigeminal ganglion results in the release of CGRP During a migraine attack CGRP increases.
What are some CGRP related migraine therapies?
- Small molecule antagonists ( anything ending in epants) - CGRP monoclonal antibodies either can cause removal of receptor or the peptide
What are the premonitary symptoms of migrane?
it may begin around 3 days before the onset of migraine. Changes are beginning to occur in the brain preceeding the migraine attack
Mood changes -particularly irritability
Fatigue
Cognitive changes
Food craving
Repetitive yawning
Neck stiffness
What is a migraine aura?
Fully reversible neurological changes of various severity e.g., scotoma, flashing lights, tunnel vision, sensory, motor,
Around 30% of migraine sufferers will experience an aura.
Apart from throbbing headaches, what other symptoms occur during migraine?
Severe, throbbing pain
Nausea
Photophobia
Phonophobia
Osmophobia (odours)
What are the postdromal syndromes of migraine?
Fatigue
Cognitive changes
Neck stiffness
What is the vasodilatory theory of migraine?
It was once believed that migraine was due to hypertension or dilation of the blood vessels, and this was supported by the efficacy of sumitriptan (vasodilator).
Recent neuroimaging studies (angiographs) have shown however that there is only modest vasodilation in migraine.
There is no association between throbbing pain and the arterial output for dental pain as mesaured by getting people to tap out the throbs.
What is the leading theory of migraine?
That migraine is a disorder of sensory processing due to alterations in many brain structures such as brain stem nuclei.
Light doesn’t trigger migraines, but your brain begins to process it abnormally
Wind up sensitisation of peripheral input, loss of inhibition, excitation leading up to the migraine.
One theory states that migraine is actually a resetting
What is the mechanism of medication overuse in triptans?
The precise mechanism is unknown. There is an upregulation of 5HT1D receptors, and an increase of CGRP within the brain.
Rodents with osmotic mini pumps to recieve daily sumitriptans show reduced mechanical withdrawal thresholds as measured by von frey. Removal of sumitriptan shows normalisatiion within 2 weeks.
Biggest problem: After normalisation, if rats are injected with a triptan again then they immediately become sensitised again, masking a latent sensitisation.
Define medication overuse headache
Headache on more than 15 days per month combined with the regular overuse of acute medication for more than 3 months.
triptans > 10 days per month
NSAIDs > 15 days per month
Migraine patients are sensitive to medication overuse headache.
Normally resolves with medication withdrawal (60% reduction of attacks)
What is the mechanism of action of botox?
Cleavage of SNARE proteins - preventing neurotransmitter release at NMJ.
It is unknown whether botox is taken up into the CNS to prevent signalling (botox cleaveage of SNARE is non-specific and would occur at any synapse). SNAP/SNARE cleavage byproducts have been found in the brain, but it is unknown whether this is an uptake of byproducts or of botox.
Transcranial magnetic stimulation
Single pulse transcranial stimulation of the cortex was first designed to be used on the onset of aura, however it has been found that it has prophylactic use.
It is useful for pregnant women as it has no drug side effects.
What is the mechanism of action of triptans?
• Peripheral neuronal inhibition
• Central neuronal inhibition (Variable BBB penetration)
– Trigeminocervical complex
– Brainstem (Periaqueductal gray)
– Diencephalon (Thalamus etc.)
*** need to look into precise mechanisms and investigate vasoconstriction
