1. Anti-Migraine Drugs

2. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
Introduction
Debilitating condition characterized by moderate to severe attacks of headaches
About 3 times more common in women than in men.
Unilateral, pulsating pain, lasting from 4 to 72 hours.
Nausea, vomiting, photophobia, phonophobia, tingling in the arms and legs
Aura—unusual visual, olfactory, or other sensory experiences that are a sign that the migraine will soon occur.
Cause unknown, disorder of the serotonergic control system
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

3. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
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.
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.
First mode of treatment: trepanation
Medical intervention in which a hole is drilled or scraped into the human skull, exposing the dura mater in order to treat health problems related to intracranial diseases
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

4. 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.
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

5. Classification of Migraine headache.
1) Migraine without Aura or common migraine
Does not give any warning signs before the onset of headache.
It occurs in about 70 to 80% of migraine patients
2) Migraine with Aura
Give some warning signs “ called aura” before the actual headache begins. Approximate, 20 to 30% migraine sufferers experience aura.
The most common aura is visual and may include both positive and negative (visual field defects) features.
3) Retinal migraine
It involves attacks of monocular scotoma or even blindness of one eye for less than an hour and associated with headache.
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

6. Classification of Migraine headache.
4) Childhood periodic syndromes
Involve cyclical vomiting (occasional intense periods of vomiting),
Abdominal migraine (abdominal pain, usually accompanied by nausea)
Benign paroxysmal vertigo of childhood (occasional attacks of vertigo).
They may be precursors or associated with migraine.
5) Complications of migraine describe migraine headaches and/or auras that are unusually long or unusually frequent, or associated with a seizure or brain lesion
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

7. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
Negative scotoma. Loss of local awareness of local structure
Zigzag structure
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
Positive Scotoma. Additional structures One side loss of perception.

8. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
“Yep!! Now have someone scream in you ear, stab a knife in one or both eyes. vomit, and wish to pass out or die. This will go on for days or months! Migraines are **** awful. I just wanna rip off my skull and let my throbbing brain out. Seriously, I just wanna die when I get them. "i get an aura where i start to see zig zagy patches of light and color which slowly moves around and changes shape over time. Then after about half an hour, the headaches comes. i get real sensitive to light and if i move around, it just makes it worse and makes be sick." Exactly what happens to me too! :(
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

9. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

10. Possible Etiology and Pathophysiology
The precise etiology and pathophysiology of migraine is unknown.
However, neuronal dysfunction theory is most acknowledged theory.
Activity in trigeminovascular system.
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

11. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
Abnormal Neuronal activity
Cerebral cortex, thalamus or hypothalamus in response to stress, emotion.
Activates nociceptive trigeminovascular system and causes prolong pain
Releases vasoactive neuropeptides e.g., Substance P, neurokinin A, calcitonin gene-related polypeptide, serotonin ‡
Boss
Initiate inflammatory response, sensitizes surrounding tissues and produce prolong headache
Activates trigeminovascular system, which in turn, stimulate pain stimulating neurons in brain stem and upper spinal cord
Promote vasodilation and plasma protein extravasations.
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

12. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
Low serotonin levels in the brain may lead to a process of constriction and dilation of the blood vessels which trigger a migraine.Serotonergic agonists like triptans, LSD or psilocin activate serotonin receptors to stop a migraine attack.
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

13. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
Headache vs. Migraine
Headache
Pain usually dispersed throughout head
Migraine
Pain concentrated on one side of head
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

14. Four phases of A migraine
Prodrome
Aura
Headache
Postdrome
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

15. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
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, Occurs hours to days before migraine without headache
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

16. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
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: minutes
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

17. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
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
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

18. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
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
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

19. Ways to Treat Migraines
Avoiding Trigger Factors
Simple Non-Drug Treatment
Pain Medications
Prophylactic Medications
“Abortive Medications”
(acute, specific medications)
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

20. 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.
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

21. Simple Non-Drug Treatments
Ice to head
Heat to head
Massages
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

22. Medicines used for migraine therapy
Medicines that block beta-adrenergic receptors
Propranolol, nadodol, timolol, atenolol, and metoprolol.
Reduce the frequency of attacks by 50% in 60 to 80% patients.
Side effects- fatugue, sleep disturbance, depression, hypotension etc
2) Tricyclic antidepressants
amitryptiline, nortryptiline, doxepin, imipramine etc
Independent of antidepressant activity.
Antagonist of 5-HT2, thus stabelize serotonin neurotransmission
3) Methysergide:-
Semisynthetic ergot alkaloid and is 5-HT2 antagonist.
Gives best result when taken with meals
Side effects- gastrointestinal intolerance, insomnia, and muscle cramps.
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

23. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
Abortive therapy
1) Simple analgesics
For mild and infrequent migraine- Aspirin and acetaminophen
Aspirin+acetaminophen+barbiturate = To induce sleep
aspirin+acetaminophen+narcotics = Fiorinal
Aspirin+ acetaminophen+caffiene = Esgic
Drawback- Continuous use fails to provide pain relief.
2) NSAIDs
Inhibit prostaglandin synthesis.
So may prevent inflammation in trigeminovascular system and alleviate migraine pain
They are effective for reducing the frequency, severity, and duration of migraine attacks. e,g. Aspirin, Ibuprofen, Naproxen etc.
3) Ergot family- Ergotamine-
Dihydroergotamine- available in inject able form.
The structure shares some similarity with neurotransmitter serotonin.
Acts as agonist, bind to 5-HT1,
More effective when given during early migraine attacks
4) Anticonvulsants
Topiramate
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

24. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
Aspirin
First choice drug to treat mild to moderate migraine attacks
aspirin inhibits COX-1, stopping prostaglandin synthesis from arachidonic acid
aspirin also shows inhibitory effects on how the trigeminal nerve processes inputs (reduces pain)
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

25. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
Ergotamines
Structural similarity with neurotransmitters such as serotonin, dopamine, and epinephrine and thus bind to several receptors acting as an agonist.
The anti-migraine effect is due to constriction of the intracranial extracerebral blood vessels through the 5-HT1B receptor, and by inhibiting trigeminal neurotransmission by 5-HT1D receptors.
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

26. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
Steroids
A single dose of intravenous dexamethasone, when added to standard treatment of a migraine attack, is associated with a 26% decrease in headache recurrence in the following 72 hours.
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

27. 5-hydroxytryptamine (5-HT) agonists
Triptans bind the serotonin 5-HT1B receptors in the walls of blood vessels
Leads to constriction of arteries, particularly at cerebral and dura arteries
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
First introduced in the 1990s
They bind to serotonin 5-HT1B and 5-HT1D receptors in cranial blood vessels and causes constriction and subsequent inhibition of pro-inflammatory neuropeptide release.
Equally effective because they act on serotonin receptors in nerve endings as well as the blood vessels.
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

28. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
Triptans
Sumatriptan- serotonin (5HT) receptor agonist.
They come in a number of different forms including oral, injection, nasal spray, and oral dissolving tablets.
Cant cross BBB.
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

29. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
Donitriptan
1-[[[3-(2-Aminoethyl)-1H-indol-5-yl]oxy]acetyl]-4-(4-cyanophenyl)-piperazinehydrochloride
Has equal affinity to both 5HT 1a and 1d.
It is ten times more effective than sumatriptan, naratriptan
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

30. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
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
Naratriptan
Zolmitriptan
Eletriptan
Rizatriptan
Noritriptan
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

31. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
Others
Antiemetics by mouth may help relieve symptoms of nausea and help prevent vomiting
aspirin with metoclopramide, paracetamol/codeine for analgesia, with buclizine as the antiemetic, paracetamol/metoclopramide
Midrin = Isometheptane+ dichlorophenazene+ acetaminophen- Used in patients who do not respond to ergot and triptan
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

32. The Future of Antimigraine Medication
Magnesium- Thought to stabilize the sodium potassium pump
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.
Botox- Immediate relief and migraine prophylaxis/prevention
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

33. Transcranial Magnetic Stimulation
The technology, called transcranial magnetic stimulation, or TMS, may interrupt cortical spreading depression and possibly prevent pain from arising or progressing.
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala

34. STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala
Research
Merck Corp is developing a new drug called Telcagepant which is intended to relieve pain without causing vasoconstriction (narrowing of blood vessels) as current medications such as triptans do. Telcagepant would be a safe therapy for migraine suffers with risk factors for cardiovascular disease.
Recently it has been found that calcitonin gene related peptides (CGRPs) play a role in the pathogenesis of the pain associated with migraine as triptans also decrease its release and action. CGRP receptor antagonists such as olcegepant and telcagepant are being investigated both in vitro and in clinical studies for the treatment of migraine.
In 2010, scientists identified a genetic defect linked to migraines which could provide a target for new drug treatments
STES, Sinhgad Institute of Pharmaceutical Sciences, Lonavala