margarita morales medicinal chemistry spring 2010

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. 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.

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-migraine-sufferers/

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 movementLethargyFatigueDifficulty focusing

Also called a “zombie phase” Duration: A few hours to a

few days

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 outsideA 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 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/File:Cortical_spreading_depression.gif

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.

Ways to Treat Migraines

Avoiding Trigger Factors Simple Non-Drug Treatment Pain Medications Prophylactic Medications “Abortive Medications”

(acute, specific medications) Magnesium

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 anti-

inflammatory 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.

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.

Anticonvulsant Prophylactic Drugs:

Topiramate MOA How does Topiramate work?

Topiramate is an anticonvulsant that treats partial-onset 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

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.

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

“Abortive Medications” Triptans

Current Triptans in use:○ Sumatriptan○ Naratriptan○ Zolmitriptan○ Rizatriptan.○ Almotriptan ○ Frovatriptan ○ Eletriptan

Ergots Current ergots in use

○ DHE○ Ergotamine Tartrate○ Cafergot○ Isomethaheptane

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.

Sumatriptan Mechanism of Action

Sumatriptan is a 5HT receptor agonist. Sumatriptans were first administered

subcutaneously, then orally and now its available in nasal spray

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 TartrateCafergotIsometheptane

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.

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.

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.

Donitriptan

Has equal affinity to both 5HT 1a and 1d.

It is ten times more effective than sumatriptan, naratriptan

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.

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. .

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.

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?