ANTIMIGRAINE MEDICATIONS

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ANTIMIGRAINE MEDICATIONS

• Margarita Morales
• Medicinal Chemistry
• Spring 2010

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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.

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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.
• 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.

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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

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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

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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-diffe
  rences-detected-in-migraine-sufferers/

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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

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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

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Possible Physiology of Aura

• 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 bloodjust what
  investigators see during brain scans of patients
  experiencing aura.
• But afterward, during inhibition, the quiet
  neurons need less blood.

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Cortical Spreading Depression

• 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/FileCortical_spreadi
  ng_depression.gif

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What causes the pain??

• 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.

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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.

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Simple Non-Drug Treatments

• Ice to head
• Heat to head
• Massages

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Pain Medications

• Aspirin
• Acetaminophen
• NSAIDS- Non steroidal anti-inflammatory drugs.
• Fiorinal or Fioricet
• Tylenol with Codeine
• Ultram

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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 doesnt work then it is given in
  combination with the others.

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Anticonvulsant Prophylactic Drugs Topiramate MOA

• How does Topiramate work?
• Topiramate is an anticonvulsant that treats
  partial-onset and primary generalised seizures.
• It has multiple MOAs
• Blocks Sodium Channels
• Enhancement of GABAa receptor mediated
  inhibition.
• Antagonism of glutamate
• Inhibition of high voltage activated calcium
  channels.

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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

• 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.

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Hypothesis of 5 HT Receptor

• One theory suggests that activation of 5-HT1D
  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 pro-inflammatory neuropeptide
  release

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Abortive Medications

• Triptans
• Current Triptans in use
• Sumatriptan
• Naratriptan
• Zolmitriptan
• Rizatriptan.
• Almotriptan
• Frovatriptan
• Eletriptan
• Ergots
• Current ergots in use
• DHE
• Ergotamine Tartrate
• Cafergot
• Isomethaheptane

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The Triptans

• 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.

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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

• 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

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Dihydroergotamine mesylate (DHE) Mechanism of
Action

• Binds to noradrenaline and dopamine receptors.
• Stimulates vasoconstriction by stimulating
  alpha-adrenergic and serotonin receptors
• Has high affinity for 5-HT 1,2 receptors.
• Activation of 5HT1 ? Vasoconstriction? Migraine
  relief.

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The Future of Antimigraine Medication

• 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.

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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

• 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.

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Reading Assignment

• Goodman and Gilmans 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

• 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.

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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?