Anxiolytics - Medication for migraine
18 important questions on Anxiolytics - Medication for migraine
So the traditional medicine against migraine is ergots. What is the history?
VERY potent vasoconstrictors (people thought the problem with migraine was vasodilations)
- 1868: Use of ergot in the treatment of one-sided headache
- 1925: Identified active chemical of ergot (ergotamine)
- 1940’s: Ergotamine tartrate became the preferred treatment for acute migraine (now replaced by triptans).
- 1946: Approval of dihydroergotamine (DHE) (form of ergotamine) (more prophylactic).
- Now Migranal® (nasal spray with dihydroergotamine).
So the active ingredient of ergots is ergotamine. What is the structure of this ingredient?
- It looks similar to the amines (serotonin, noradrenaline and dopamine)
- Because looks like monoamines it binds to multiple receptors: 5GT, a1/2, D2
- You don't want to give it to patients with a cardiovascular problems
- Side effects.
- Cause vasoconstriction in vessels
What does the vascular theory say? And is it true (3 arguments)?
Mechanical excitation of sensory fibers; fibers that are innervated by the dilatated blood vessels. Ergotamine gives relief of pain.
=> you should get aura from this.
Not true because only 2/3 of the patients have aura + drugs with other working mechanisms do also work + blood flow studies do not support this theory.
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Does the vascular theory not even a little plays a role?
What is thought to be the mechanism of migraine nowadays? At which the medicines are based on.
One type of receptor can stimulate cerebral vasoconstriction = 5-HT1B/1D. (They know this because of a study with in a dog isolated saphenous vein.)
So you want a drug that is selective for this receptor.
GR-43175 (sumatriptan) was the first of different triptans. Which ones? For which receptors do this triptans have a great affinity?
Pharmacokinetics. Sumatriptan has some problems with this. Which problems?
Low oral bio-availability = 14%
You want it to stay longer in the bloodstream.
Which type of triptan has a long half-live?
Which ganglion is important and why?
Sensory ganglion responsible for sensory perception of the whole skull.
(Peripheral branches and sensory branches (to spinal cord) Drawing of the neuron. Neuron with a branch to both sides = it is very symmetrical.)
Periphery vessels terminate in the meningitis and on the blood vessels. Every activity in a specific brain region (high metabolic products) activate the terminals => Transmitted to the ganglion => brain stem => thalamus => cortex.
So it is a brain event!
So what is the physiology of migraine nowadays?
Migraine is not caused by a primary vascular event, but by the following cascade:
1. Increased excitability of CNS (e.g., due to Cortical Spreading Depression)
2. Activation of perivascular sensory trigeminal nerves
3. Peripheral (dura vessel) and central (trigeminal nucleus in brainstem) release of neuropeptides.
4. Pain impulses (trigeminal nerve to trigeminal nucleus to thalamus)
5. Meningeal blood vessel dilation follows trigeminal nerve activation
Which neuropeptides are included (3)?
- Substance P
- Calcitonin gene-related peptide (CGRP)
- Neurokinin A
What is the result of the release of the neuropeptides?
- Pain sensitivity
- Tissue and vessel swelling
- Inflammation
=> so basically the vasodilation problem.
Which receptors are where? And what does this mean for medication?
5-HT1b= on the bloodvessels => vasoconstriction
5-HT1d/f = terminals in the central nerve, upper spinal cord => inhibition of transmission to the upper spinal cord.
So you don't want to constrict the blood vessel.
1D was tried (also on the heart valves) so not a good idea.
1F was tried => didn't work out at first. Three years ago one drug was excepted. Does cross the blood-brain barrier (sedation so attention when driving)
What happens when you activate the specific receptors?
So you can make sure to inhibit the transmission with agonist for the 5-HT receptor, so there is no release neuropeptides, you can also try to find a way that the neuropeptides, when they are released doent work on their receptors. Which drug is based on this principle?
Problems:
- To big
- Liver toxicity
But then Ubrogepant.
Acute drug and prevention.
How did they use CGRP targeting for profphylaxis?
So what is the difference between acute and prophylactic treatment?
Endogenous factors: leao's cortical spreading depression. What does it mean?
Not synapticly mediated.
Massive polarisation.
- glutamate
- potassium
At the center of the CSD.
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