AntiMigraine Drugs Brian Lich April 3 rd 2007

Anti-Migraine Drugs Brian Lich April 3 rd, 2007

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

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

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

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

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

Where does the headache come from? • 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 – No increased risk of a brain tumor

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

Treatments of the Past • 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 – Used the term “hemicrania” for which he thought the brain and stomach were connected – “Migraine” evolved from this term

Treatments of the Past… • 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

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

Aspirin • 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)

Ergotamine • 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

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

5 -hydroxytryptamine (5 -HT) agonists • A group of drugs known as triptans bind the serotonin 5 -HT 1 B 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 – Do this by acting as a 5 -HT 1 D receptor agonist

5 -HT receptor

Sumatriptan (imitrex) Sumatriptan Serotonin Vs. 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

New 5 -HT agonists • 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

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

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

Thank you!