Transcript Anti-migraine Medications

Margarita Morales
Medicinal Chemistry
Spring 2010
What is a Migraine?

A migraine is a severe painful
headache that is often preceded or
accompanied by sensory warning
signs such as flashes of light, blind
spots, tingling in the arms and legs,
nausea, vomiting, and increased
sensitivity to light and sound. The
excruciating pain that migraines
bring can last for hours or even
days.
History of Migraines
Have been with us for at least 7,000 years.
 In ancient Greece, Galen attributed these painful
headaches as “ascent of vapors” or humors from the
liver to the brain. He called them Hemicranias.
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 Hemicrania Megrim Migraine
In the 17th century, the idea of rising humors was
replaced by increased blood flow.
 In the 1980s, Harold G. Wolff of New York-Presbyterian
Hospital, said that migraine pain stems from the
dilation and stretching of brain blood vessels, leading
to the activation of pain-signaling neurons.

What Actually Happens During a
Migraine?
Brain Scans suggest that Migraines
arise from an increase in blood flow of
about 300% PRECEDING the
headache.
 Circulation and blood flow appear
normal during the headache.
 Also thought to arise from a disorder in
the nervous system affecting the
brainstem.
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4 PHASES OF A MIGRAINE
 Prodrome
 Aura
 Headache
 Postdrome
Prodrome
Stage of Migraine that is characterized
by difficulty concentrating, yawning,
fatigue and/or sensitivity to light and
noise.
 Duration: A few hours to a few days

Aura
Stage of migraine that is characterized
by visual illusions of sparks and lights,
often followed by blind or dark spots in
the same place as the bright
hallucinations
 Duration: 20-60 minutes
 http://www.healthjockey.com/2007/11/20/
brain-differences-detected-in-migrainesufferers/
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Headache
Stage characterized by
excruciating or throbbing pain
along with sensitivity to light
and sound.
 May be accompanied by
nausea and vomiting
 Sometimes only half of the
head or part of the head is in
pain.
 Duration: 4 – 72 hours

Postdrome

Characterized by:
 sensitivity to light and
movement
 Lethargy
 Fatigue
 Difficulty focusing
Also called a “zombie
phase”
 Duration: A few hours to
a few days

Possible Physiology of Aura
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Neuronal activity is controlled by Na, K, and Ca flows across
nerve cells through pumps and channels.
Pumps Resting Cells: High K and Low Na and Ca
Channels open inc. Na and Ca flow (depolorizes membrane)
Cell is more pos on inside than outsideA Neuron Fires
Neurotransmitters are released.
Normally, cells then briefly hyper-polarize: they become strongly
negative on the inside relative to the outside .
Hyperpolarization closes the sodium and calcium channels and
returns the neurons to their resting state soon after firing.
But neurons can remain excessively hyperpolarized, or inhibited,
for a long time following intense stimulations.
The phases of hyperexcitability followed by inhibition that
characterize cortical spreading depression can explain the
changes in blood flow that have been documented to occur before
migraine pain sets in.
When neurons are active and firing, they require a great deal of
energy and blood—just what investigators see during brain scans
of patients experiencing aura.
But afterward, during inhibition, the quiet neurons need less
blood.
Cortical Spreading Depression
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Wave of hyperactivity
followed by a wave of
inhibition and it usually
occurs in the visual cortex.
2-6mm per wave
This is what is thought to
happen during migraines
with aura.
http://en.wikipedia.org/wiki/F
ile:Cortical_spreading_depr
ession.gif
What causes the pain??
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Thought that trigeminal nerves are the ones to
blame.
After brainstem activation and/or CSD, the
trigeminal system (TS) is activated, releasing
neuropeptides in the brainstem and in the
peripheral nerve endings at the meninges.
Actions of these neuropeptides at peripheral
sites(in the meninges) and within the brain play an
important role in the generation and maintenance
of headache pain and possibly other migraine
symptoms.
Ways to Treat Migraines
Avoiding Trigger Factors
 Simple Non-Drug Treatment
 Pain Medications
 Prophylactic Medications
 “Abortive Medications”
(acute, specific medications)
 Magnesium
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Avoiding Trigger Factors

For reasons unknown, migraines can be
set of by many factors like alcohol,
perfume, dehydration, excessive
exercise, menstruation, stress, weather
changes, seasonal changes, allergies,
lack of sleep, altitude, flickering lights
and hunger.
Simple Non-Drug Treatments
Ice to head
 Heat to head
 Massages

Pain Medications
Aspirin
 Acetaminophen
 NSAIDS- Non steroidal antiinflammatory drugs.
 Fiorinal or Fioricet
 Tylenol with Codeine
 Ultram

Mechanism of Action of Aspirin
in Migraine Pain Relief
Aspirin is a pain reliever.
 In Migraines it is thought to
Inhibit effects of the trigeminal
nerve inputs thereby reducing pain.
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Prophylactic Medications
For those patients who experience severe and
complicated migraines more than 2 times a month.
 Three categories
 Anticonvulsants
○ Topiramate (Topamax)
 Antidepressants
○ Verapamil or Nortriptyline
 Antihypertensives
○ Propranolol or Venlafaxine
 If one doesn’t work then it is given in combination
with the others.
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Anticonvulsant Prophylactic
Drugs: Topiramate MOA
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How does Topiramate work?
 Topiramate is an anticonvulsant that treats partialonset and primary generalised seizures.
 It has multiple MOA’s
○ Blocks Sodium Channels
○ Enhancement of GABAa receptor mediated
inhibition.
○ Antagonism of glutamate
○ Inhibition of high voltage activated calcium
channels.
Antihypertensive Prophylactic
Drugs: Propranolol
Central action of propranolol mediated
by inhibition of central B-receptors
interfering with the vigilance-enhance
andrenergic pathways.
 Interacts with 5-HT receptors
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Antidepressant Prophylactic
Drugs: Nortriptyline
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It inhibits the reuptake
of norepinephrine
(noradrenaline) and, to a
lesser extent, serotonin.
5HT 2A antagonist
Side effects: dry mouth,
constipation,sedation
and increased appetite.
Hypothesis of 5 HT Receptor
One theory suggests that activation of 5HT1D receptors located on intracranial
blood vessels leads to vasoconstriction,
which correlates with the relief of
migraine headache.
 The alternative hypothesis suggests
that activation of 5-HT1D receptors on
sensory nerve endings of the trigeminal
system results in the inhibition of proinflammatory neuropeptide release
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“Abortive Medications”
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Triptans
 Current Triptans in use:
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Sumatriptan
Naratriptan
Zolmitriptan
Rizatriptan.
Almotriptan
Frovatriptan
Eletriptan
Ergots
 Current ergots in use
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DHE
Ergotamine Tartrate
Cafergot
Isomethaheptane
The Triptans
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First introduced in the 1990s
Their action is attributed to their binding to
serotonin 5-HT1B and 5-HT1D receptors in
cranial blood vessels that causes constriction
and subsequent inhibition of pro-inflammatory
neuropeptide release.
They are effective because they act on
serotonin receptors in nerve endings as well
as the blood vessels. This leads to a decrease
in the release of several peptides, including
CGRP and substance P.
Sumatriptan Mechanism of
Action
Sumatriptan is a 5HT receptor agonist.
 Sumatriptans were first administered
subcutaneously, then orally and now its
available in nasal spray
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The Ergots
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Ergots are also 5HT 1B and 1D seratonin
receptor agonists.
They are very old drugs.
Often cause more side effects than Triptans
but are longer lasting.
Ergots in use include:
 DHE (Dihydroergotamine mesylate)
 Ergotramine Tartrate
 Cafergot
 Isometheptane
Dihydroergotamine mesylate
(DHE) Mechanism of Action
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Binds to noradrenaline and dopamine receptors.
Stimulates vasoconstriction by stimulating alphaadrenergic and serotonin receptors
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Has high affinity for 5-HT 1,2 receptors.
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Activation of 5HT1  Vasoconstriction
Migraine relief.
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The Future of Antimigraine
Medication
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Magnesium
Noritriptan
Combination of antidepressants,
antihypertensive, and antiepileptic drugs.
Drugs that target trigeminal neurotransmitters
like glutamate and Nitric Oxide.
Transcranial Magnetic Stimulation: A handheld
device that transmits brief pulses of magnetic
stimulation is being evaluated for the treatment
of migraine with and without aura.
Magnesium
In clinical trials
 Thought to stabilize the sodium
potassium pump.
 Reported that Low levels of Magnesium
may be responsible for release of NMDA
receptors which leads to spontaneous
discharge and CSD.
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Donitriptan
Has equal affinity to both 5HT 1a and
1d.
 It is ten times more effective than
sumatriptan, naratriptan
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Transcranial Magnetic
Stimulation
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The premise is that this technology,
called transcranial magnetic stimulation,
or TMS, may interrupt cortical spreading
depression and possibly prevent pain
from arising or progressing.
Reading Assignment
Goodman and Gilman’s The
Pharmacological Basis of Therapeutics,
pp. 297-8 (large print only), and 305-8
(large print only)
 Kalra, Arun A.; Elliott, Debra. Acute
migraine: current treatment and
emerging therapies. Therapeutics and
Clinical Risk Management (2007), 3(3),
449-459. .
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Optional Reading/ References
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Cassuci, Gerardo. “Central Mechanism of
Action of Antimigrain Prophylactic Drugs.”
Neurological Sciences. Vol 29 May 2008
(p123-126)
Rapaport, Alan. “Intranasal Medications for the
Treatment of Migraine and Cluster Headache.”
CNS Drugs 2004; 18 (10): 671-685
Dodick, David W. “Why Migraines Strike”
Scientific American, Aug2008, Vol. 299 Issue
2, p56-63.
Waeber, Christian. Expert Opinion on
Emerging Drugs: Emerging drugs in migraine.
Homework Questions
5-HT (5-hydroxytryptamine, Serotonin)
is an important neurotransmitter, and the
triptans are important new drugs for
treatment of migraine. Draw the
structures of 5-HT and sumatriptan,
documenting their similarities and
differences.
 Which specific subtypes of 5-HT
receptors are targeted by the triptans?
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