Anti-Migraine DrugsAnti-Migraine Drugs

Brian LichBrian Lich

April 3April 3rdrd, 2007, 2007

OverviewOverview

• Migraines: What are they? Migraines: What are they? Symptoms? Causes?Symptoms? Causes?

• History: What was done?History: What was done?

• Today: How are migraines currently Today: How are migraines currently treated?treated?– Specific Drugs and their mode of actionSpecific Drugs and their mode of action

• Future: What are some drug Future: What are some drug “prospects”?“prospects”?

MigrainesMigraines

•MigraineMigraine: a neurological disease : a neurological disease characterized by attacks of characterized by attacks of headache, photophobia, headache, photophobia, phonophobia, and nausea.phonophobia, and nausea.

• 3 times more common in women 3 times more common in women than menthan men

• Up to 28 million people in the US are Up to 28 million people in the US are affectedaffected

The 4 phases of a migraineThe 4 phases of a migraine

• ProdromeProdrome– Occurs hours to days before Occurs hours to days before

migraine without headachemigraine without headache• AuraAura

– Neurological phenomena Neurological phenomena such as disturbance of such as disturbance of vision just before headachevision just before headache

• Pain phasePain phase– Headache on one side of Headache on one side of

head with nausea, head with nausea, photophobia and other photophobia and other classic migraine symptomsclassic migraine symptoms

• PostdromePostdrome– Exhaustion, irritability, Exhaustion, irritability,

depressiondepression

Headache vs. MigraineHeadache vs. Migraine

• HeadacheHeadache– Pain usually dispersed throughout headPain usually dispersed throughout head

• MigraineMigraine– Pain concentrated on one side of headPain concentrated on one side of head

What causes these What causes these symptoms?symptoms?

• Exact mechanism still not Exact mechanism still not knownknown

• Not initiated by blood Not initiated by blood vessel problemsvessel problems– This is secondaryThis is secondary

• Cortical spreading Cortical spreading depressiondepression– Inflammatory mediators Inflammatory mediators

irritate cranial nerves, irritate cranial nerves, especially the especially the trigeminal nervetrigeminal nerve

Where does the headache Where does the headache come from?come from? • When a headache When a headache

occurs, serotonin and occurs, serotonin and magnesium levels dropmagnesium levels drop– Trigeminal nerve Trigeminal nerve

releases releases neuropeptidesneuropeptides

– Neuropeptides Neuropeptides travel to outer travel to outer covering of the covering of the brain and cause brain and cause dilation and dilation and inflammation of inflammation of meningeal blood meningeal blood vesselsvessels

• Dura and dura vessels Dura and dura vessels disrupted but brain disrupted but brain structure remains structure remains intactintact– No increased risk of No increased risk of

a brain tumora brain tumor

CausesCauses• Mechanism still debatedMechanism still debated

• Common triggersCommon triggers– Hormonal: Estrogen and Hormonal: Estrogen and

ProgesteroneProgesterone– Foods: alcohol, Foods: alcohol,

chocolate, etc.chocolate, etc.– Stress, physical activity, Stress, physical activity,

sleepsleep– Environmental stimulus: Environmental stimulus:

sight, smellssight, smells– medicationsmedications

Treatments of the PastTreatments of the Past• Migraines have been Migraines have been

have a medical history of have a medical history of 9000 years9000 years– First mode of First mode of

treatment: treatment: trepanationtrepanation

• Galen of Pergamum Galen of Pergamum was an ancient was an ancient Greek physician in Greek physician in the 2the 2ndnd century AD century AD– Used the term Used the term

“hemicrania” for “hemicrania” for which he thought the which he thought the brain and stomach brain and stomach were connectedwere connected

– ““Migraine” evolved Migraine” evolved from this termfrom this term

Treatments of the Past…Treatments of the Past…

• Up through medieval ages, treated Up through medieval ages, treated with a hot iron to the head, blood with a hot iron to the head, blood lettingletting– Still very much misunderstood as in the Still very much misunderstood as in the

case of other neurological disorderscase of other neurological disorders

• Today, some physicians still hesitant Today, some physicians still hesitant to prescribe specific anti-migraine to prescribe specific anti-migraine drugsdrugs

Treatments of todayTreatments of today

• Non-specificNon-specific– Aspirin, NSAIDsAspirin, NSAIDs

• ErgotsErgots

• 5-hydroxytryptamine (5-HT) agonists 5-hydroxytryptamine (5-HT) agonists – Sumatriptan (imitrex)Sumatriptan (imitrex)– ZolmitriptanZolmitriptan– NaratriptanNaratriptan– RizatriptanRizatriptan

AspirinAspirin

• First choice drug to treat mild to First choice drug to treat mild to moderate migraine attacksmoderate migraine attacks– As we know, aspirin inhibits COX-1, As we know, aspirin inhibits COX-1,

stopping prostaglandin synthesis from stopping prostaglandin synthesis from arachidonic acidarachidonic acid

– *aspirin also shows inhibitory effects on *aspirin also shows inhibitory effects on how the trigeminal nerve processes how the trigeminal nerve processes inputs (reduces pain)inputs (reduces pain)

ErgotamineErgotamine

• VasoconstrictorVasoconstrictor– Therefore cannot be Therefore cannot be

administered to administered to patients with coronary patients with coronary diseasesdiseases

– Inhibits release of Inhibits release of calcitonin gene-related calcitonin gene-related peptide (CGRP)peptide (CGRP)

– Interact with many Interact with many different different neurotransmitter neurotransmitter receptorsreceptors not specific not specific

Ergotamine mode of actionErgotamine mode of action

CGRP-receptor antagonists are being explored today

CGRP

5-hydroxytryptamine (5-HT) 5-hydroxytryptamine (5-HT) agonistsagonists

• A group of drugs known as triptans bind A group of drugs known as triptans bind the serotonin 5-HTthe serotonin 5-HT1B 1B receptors in the walls receptors in the walls of blood vesselsof blood vessels– Leads to constriction of arteries, particularly at Leads to constriction of arteries, particularly at

cerebral and dura arteries cerebral and dura arteries

• Triptans also inhibit inflammation of Triptans also inhibit inflammation of vessels of the dura matter that are vessels of the dura matter that are stimulated by the trigeminal ganglionstimulated by the trigeminal ganglion– Do this by acting as a 5-HTDo this by acting as a 5-HT1D1D receptor agonist receptor agonist

5-HT receptor5-HT receptor

Sumatriptan (imitrex)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

New 5-HT agonistsNew 5-HT agonists

• All designed to penetrate BBBAll designed to penetrate BBB– Can better bind 5-HT receptors in brain Can better bind 5-HT receptors in brain

as agonist to stimulate constrictionas agonist to stimulate constriction– BUT, also should have the least possible BUT, also should have the least possible

vasoconstrictive effects on coronary vasoconstrictive effects on coronary arteriesarteries

Examples of new 5-HT Examples of new 5-HT agonistsagonists

Naratriptan

EletriptanZolmitriptan

RizatriptanSerotonin

Migraine Drugs of the Migraine Drugs of the FutureFuture• BotoxBotox

– Immediate relief and migraine Immediate relief and migraine prophylaxis/preventionprophylaxis/prevention

• Administration of magnesiumAdministration of magnesium

• Patent foramen ovale surgeryPatent foramen ovale surgery– Evidence that when hole Evidence that when hole

between upper chambers of the between upper chambers of the heart is patched, migraines are heart is patched, migraines are relievedrelieved

Thank Thank you!you!