1. Anti-Migraine Drugs Brian Lich April 3 rd, 2007

2. Overview Migraines: What are they? Symptoms? Causes? Migraines: What are they? Symptoms? Causes? History: What was done? History: What was done? Today: How are migraines currently treated? Today: How are migraines currently treated? –Specific Drugs and their mode of action Future: What are some drug “prospects”? Future: What are some drug “prospects”?

3. Migraines Migraine: a neurological disease characterized by attacks of headache, photophobia, phonophobia, and nausea. Migraine: a neurological disease characterized by attacks of headache, photophobia, phonophobia, and nausea. 3 times more common in women than men 3 times more common in women than men Up to 28 million people in the US are affected Up to 28 million people in the US are affected

4. The 4 phases of a migraine Prodrome Prodrome –Occurs hours to days before migraine without headache Aura Aura –Neurological phenomena such as disturbance of vision just before headache Pain phase Pain phase –Headache on one side of head with nausea, photophobia and other classic migraine symptoms Postdrome Postdrome –Exhaustion, irritability, depression

5. Headache vs. Migraine Headache Headache –Pain usually dispersed throughout head Migraine Migraine –Pain concentrated on one side of head

6. What causes these symptoms? Exact mechanism still not known Exact mechanism still not known Not initiated by blood vessel problems Not initiated by blood vessel problems –This is secondary Cortical spreading depression Cortical spreading depression –Inflammatory mediators irritate cranial nerves, especially the trigeminal nerve

7. Where does the headache come from? When a headache occurs, serotonin and magnesium levels drop When a headache occurs, serotonin and magnesium levels drop –Trigeminal nerve releases neuropeptides –Neuropeptides travel to outer covering of the brain and cause dilation and inflammation of meningeal blood vessels Dura and dura vessels disrupted but brain structure remains intact Dura and dura vessels disrupted but brain structure remains intact –No increased risk of a brain tumor

8. Causes Mechanism still debated Mechanism still debated Common triggers Common triggers –Hormonal: Estrogen and Progesterone –Foods: alcohol, chocolate, etc. –Stress, physical activity, sleep –Environmental stimulus: sight, smells –medications

9. Treatments of the Past Migraines have been have a medical history of 9000 years Migraines have been have a medical history of 9000 years –First mode of treatment: trepanation Galen of Pergamum was an ancient Greek physician in the 2 nd century AD Galen of Pergamum was an ancient Greek physician in the 2 nd century AD –Used the term “hemicrania” for which he thought the brain and stomach were connected –“Migraine” evolved from this term

10. Treatments of the Past… Up through medieval ages, treated with a hot iron to the head, blood letting Up through medieval ages, treated with a hot iron to the head, blood letting –Still very much misunderstood as in the case of other neurological disorders Today, some physicians still hesitant to prescribe specific anti-migraine drugs Today, some physicians still hesitant to prescribe specific anti-migraine drugs

11. Treatments of today Non-specific Non-specific –Aspirin, NSAIDs Ergots Ergots 5-hydroxytryptamine (5-HT) agonists 5-hydroxytryptamine (5-HT) agonists –Sumatriptan (imitrex) –Zolmitriptan –Naratriptan –Rizatriptan

12. Aspirin First choice drug to treat mild to moderate migraine attacks First choice drug to treat mild to moderate migraine attacks –As we know, aspirin inhibits COX-1, stopping prostaglandin synthesis from arachidonic acid –*aspirin also shows inhibitory effects on how the trigeminal nerve processes inputs (reduces pain)

13. Ergotamine Vasoconstrictor Vasoconstrictor –Therefore cannot be administered to patients with coronary diseases –Inhibits release of calcitonin gene-related peptide (CGRP) –Interact with many different neurotransmitter receptors  not specific

14. Ergotamine mode of action CGRP-receptor antagonists are being explored today CGRP

15. 5-hydroxytryptamine (5-HT) agonists A group of drugs known as triptans bind the serotonin 5-HT 1B receptors in the walls of blood vessels A group of drugs known as triptans bind the serotonin 5-HT 1B receptors in the walls of blood vessels –Leads to constriction of arteries, particularly at cerebral and dura arteries Triptans also inhibit inflammation of vessels of the dura matter that are stimulated by the trigeminal ganglion Triptans also inhibit inflammation of vessels of the dura matter that are stimulated by the trigeminal ganglion –Do this by acting as a 5-HT 1D receptor agonist

16. 5-HT receptor

17. Sumatriptan (imitrex) Sumatriptan Vs. Serotonin First triptan on the market and still very popular Cannot cross the intact BBB because it is too polar  requires much higher doses to be effective

18. New 5-HT agonists All designed to penetrate BBB All designed to penetrate BBB –Can better bind 5-HT receptors in brain as agonist to stimulate constriction –BUT, also should have the least possible vasoconstrictive effects on coronary arteries

19. Examples of new 5-HT agonists Naratriptan Eletriptan Zolmitriptan Rizatriptan Serotonin

20. Migraine Drugs of the Future Botox Botox –Immediate relief and migraine prophylaxis/prevention Administration of magnesium Administration of magnesium Patent foramen ovale surgery Patent foramen ovale surgery –Evidence that when hole between upper chambers of the heart is patched, migraines are relieved

21. Thank you!