Transcript Anti-Migraine Drugs

Anti-Migraine Drugs
Brian Lich
April 3rd, 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 2nd
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
CGRP-receptor antagonists are being
explored today
5-hydroxytryptamine (5-HT)
agonists
• A group of drugs known as triptans bind the
serotonin 5-HT1B 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-HT1D 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!