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Lecture 15

PHAR 301 Lecture Notes - Lecture 15: Sumatriptan, Ergotamine, Triptan


Department
Pharmacology and Therapeutics
Course Code
PHAR 301
Professor
Barbara Hales
Lecture
15

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March 15, 2016
Phar 301
1
Lecture 15: Drugs for Migraine
Terms:
"Migraine" is the disorder
"Migraines"/"Migraine headaches" are the individual episodes
"Migraineurs" are people who suffer from migraine
Aura
Nociceptive = pain-sensing
Prophylactic vs. abortive
Photophobia, phonophobia
Meninges, trigeminal nerve
Drugs
Caffeine, ergotamine
Sumatriptan, triptans
Reading
Brody pg. 397, 399-400, 403-404
Moskowitz MA (1992), Neurogenic vs. vascular mechanisms of sumatriptan and ergot alkaloids in migraine, Trends in
Pharmacological Sciences 13:307-311
o Although now quite old, it is a useful general review of mechanisms
o He discusses many of the experiments described in lecture
S Diamond (2001), A fresh look at migraine therapy. Postgrad. Med. 109: 49-60
o No need to read about drug classes not mentioned in lecture
Phillips H (2015) Your brain on migraine. New Scientist 7 March 2015, pg. 39-43
Introduction
People have been trying to get rid of migraines for years
Trepanning: drilling a hole through the skull to release evil spirits
The ancient Greeks would stand over piles of coffee beans and inhale the smoke
The Egyptians would take a clay crocodile with a straw in its mouth, fasten it on the head of the sufferer using a strip of fine
linen upon which have been written the names of the Gods and then pray
What is migraine?
It's a neurological disorder; a repetitive condition
The patient may have a prodromal phase (warning signs); a sign that a headache is coming
Other patients (approx. 1 in 5) get an aura, a strange sensation, followed by the headache
Then people usually go to sleep
Migraines are more common in women
It is in the top four most disabling disorders
Migraine with aura ("classic" migraine)
Less common
Two or more headaches preceded by aura (lifetime)
Aura symptoms, usually:
o Blurred vision
o Flashing lights or zig-zag
o Missing area of visual field (i.e. scotoma)
Aura symptoms
o Fully reversible
o Last < 1 hour
o Typically start 5-30 min before pain

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March 15, 2016
Phar 301
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Migraine without aura
Lasts 4-72 hours
At least two of:
o Unilateral
o Pulsating (hemikranion - one side of the head)
o Moderate or severe intensity
o Aggravated by physical activity
At least one of:
o Nausea
o Vomiting
o Photophobia - fear of light
o Phonophobia - fear of sound
Triggers for migraines:
Light
Stress
Sounds/noise
Certain foods
Aspartame/types of food, i.e. chocolate
Lack of sleep
Menstrual cycle
Coffee withdrawal
Migraine drugs fall into two classes: prophylactic (preventative) or abortive (acute treatment)
Prophylactic drugs for migraine
Aim: to protect from any attacks (do not wait until one starts, not even the aura)
Drugs:
o Propranolol
o Valproate
o Tricyclic "antidepressants"
All are successful since they prevent 50% of attacks
None is the best when adverse effects are taken into account
Safest are probably propranolol and valproate
These drugs don't work that well
o They reduce the recurrence of migraines by 50% at most
o Even after 4 weeks of treatment of valproate, patients still get 3 attacks in 4 weeks
Prophylactic drugs in more detail
Propanolol
o See anxiety lecture
o Most common prophylactic drug
Valproate
o See epilepsy lecture
o Multiple molecular targets
Tricyclic "antidepressants"
o See depression lecture
o Block monoamine transporters
Adverse effects of prophylactic drugs
Propranolol - contraindicated where beta-block causes problems (see anxiety lecture)
Valproate - thinning hair, fetal malformations (see epilepsy lecture)
TCAs - e.g. alcohol interaction, O/D risk (see depression lecture)

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March 15, 2016
Phar 301
3
Warning signs of an impending migraine attack
Prodrome
o Food cravings
o Tiredness
o Excitability/hyperactivity
o Change of mood
o Yawning
Drugs used to acutely treat migraine attacks, i.e. "abortive" drugs
Non-steroidal anti-inflammatory drugs (NSAIDs)
o e.g. aspirin, ibuprofen
o Often taken with anti-emetic
o First-line treatment for mild migraines
Narcotic analgesics
o e.g. codeine, morphine
o Abuse is not the only disadvantage
o Short duration of action
o Tolerance when taken long-term
o Although these drugs have been used for decades, there aren't any good clinical trials to show how they work
5HT agonists
o Mainstay for moderate-severe migraine
o Ergotamine, dihydroergotamine (DHE)
Older drugs with quite significant side-effects
o Triptans (e.g. sumatriptan = Imitrex)
Triptans are more effective, with fewer adverse effects
What caused the symptoms in this patient?
History
o 43 year old man
o Intense pains in his hands and feet that started one week ago
o For 20 years he's been taking ergotamine at 2 mg 1-6 pills/day
o He's had intermittent claudication in the last 2 years
Claudication is walking with a limp and getting a cramping pain in the leg
o 1 week ago, febrile disease (chills, cough) - treated with amoxycillin
o Pains started shortly after
At admission
o Intense pain
o Temperature is normal-ish: 37.6 degrees
o Extremities are cold, cyanotic (blue), no measurable pulse
o Carotid and femoral pulses detected
o Infiltration of lower right lobe of lung
What caused his symptoms?
o Too much vasoconstriction due to ergotamine
Treatment
o Stop ergotamine
o Give captopril (inhibits ACE, thus produces vasodilation)
o Within 6 hours, peripheral pulses and skin colour come back, less pain
St. Anthony's Fire
Two symptoms: unpleasant hallucinations and intense vasoconstriction in the peripheries leading to gangrene
The cure was to go to the shrine of St. Anthony's
It turns out that there is a fungus called the "Ergot fungus" that grows on wheat and rye which would cause these symptoms
This fungus was not found near St. Anthony's shrine
People may have been going crazy during Salem's witch trials because they would eat food with this fungus on it
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