Anti-

Migraine

Drugs

By: Tamara L.

Carrell

Medicinal Chemistry

Spring 2006

Dr. Buynak

Introduction to Migraines

• http://www.healthscout.com/animation/1/14/main.html

• http://www.stoppain.org/pain_medicine/content/chronicpain/headache.asp#

What is a migraine?

idiopathic, recurring headache disorder

manifesting as attacks lasting 4 to 72 hours.

•unilateral location, pulsating quality

•moderate or severe intensity

•aggravation by routine physical activity

•association with nausea, photophobia, and phonophobia.

What causes

migraines?

Genetic Component•familial hemiplegic migraine

• autosomal dominant trait

•19p3 chromosome: Missense mutations

•change in the mediation of the 5-HT and excitatory neurotransmitter release

Environmental factors •common food triggers are cheese, wine, alcohol, chocolate and caffeine

•noise and odors or behavior factors such as stress, sleep deprivation, or excess sleep

•increased migraine prevalence: parasitic diseases of the nervous system (Chagas’ disease )

Vascular vs. Brain Dysfunction

Theory: Edward Liveing proposed that migraines were due to “nerve storms evolved out the optic thalamus”

Evidence: 1983 where it was demonstrated that electrical signals resulted in blood flow changes that mimicked the vascular changes that occur during a migraine

=Neurovascular hypothesis

Theory: ‘Father of neurology,’ Thomas Willis proposed the vascular theory: dilatation of blood vessels in the head was the cause of migraines

Evidence: when pressure was applied to the superficial temporal artery, the patient improved

Moebius: migraines result from both brain dysfunction and vascular dysfunction

Four Phases of a Migraine

•Premonitory

•Aura

•Headache

•Resolution

SymptomsPremonitory symptoms

• Depression• cognitive dysfunction• bouts of food cravings• feeling tired or weary• stiff neck• hypersomnia and difficulty

concentrating

Migraine Attack

• moderate or severe pain (unilateral or throbbing)

• lasts hours to 2-3 days• aggravated by routine activity• nausea and sometimes

vomiting• photophobia and phonophobia

•“focal neurological symptoms that precede, accompany or (rarely) follow an attack” (Silberstein)

•sensory aura: example- weakness

•visual aura: example- scotomata- simple flashes and specks

History of Migraines and

Treatment

•Galen in about 200AD used the word hemicranin to identify “a painful disorder affecting approximately one-half of the head” (Villalon)

•Hippocrates’ idea that migraines were due to vapors rising from the stomach to the head; treatment involved spinning people to decrease vapors

•Result of malevolent beings that either occupied the cranium or implanted the headache within the skull by the ancient Greeks

• The oldest written evidence of migraine treatment is from the Ebers Papyrus, an Egyptian medical manuscript that dates back to 1200BC

•Blood-letting/trepanation

Non-specific Drugs

•Purpose: reduce inflammation and ease the pain of a migraine

•Barbiturate hypnotics are rarely used due to the lack of positive clinical trial results

•With the opioids addiction is a key concern

•The NSAIDs are the drug of choice due to the low cost, success rate, and oral form

•Metoclopramide

•NSAID’s

•Chlorpromazine

•Barbiturate/hypnotics

•Opioids

•Neuroleptics

•Antiemetics

5-HT1 family: 5 subtypes the 5-HT1B and the 5-HT1D were integral to the migraine pathway

Binding of a 5-HT receptor causes a signal transduction and amplification through the activation of a G-protein complex

Ergots•nonselective serotonin 5-HT1 receptor agonists

•selective vasoconstriction of blood vessels

•Discovered from a fungus (Claviceps purpurea) that grows on rye by W.H. Thomson in 1884

•purified ergot alkaloid in 1925

•serious side effects such as ergotism (gangrene of the feet, legs, hands and arms)

Triptans

•Humphrey in 1972 at Glaxo (GlaxoSmithKline) searched for a selective vasoconstrictor for only the extracranial circulation

•Sumatriptan is an agonist at the 5-HT1B/1D receptors and produces selective vasoconstriction of the carotid vascular bed

•The release of neuropeptides is decreased (calcitonin gene-regulated peptide (CGRP)) = decrease in the pain signaling sequence that is active in the trigeminal nucleus during a migraine attack

•Revolutionary in the treatment of migraines!

Preventive Anti-Migraine Drugs•Prophylaxis aims to prevent migraines

•Used along with acute anti-migraine drugs

•Used for frequent, severe or for migraines that are non-responsive to acute treatment

First line agents of preventive anti-migraine treatment include the β-blockers, tricylic antidepressants, and divalproex sodium or valproic acid

Second-line agents include the calcium channel blockers and the non-steroidal anti-inflammatory drugs

Third-line agents are methysergide and phenelzine

Side-Effects & Contra-Indications

•Myocardial infarction

•Stroke

•Nausea

•Sleepiness

•Heart Disease

•Hyper-tension

•Liver Disease

•Obesity

•Side effects are due the lack of selectivity for 5-HT receptors

•The second-generation triptans have failed to reduce this limitation

Admission Routes:

Intranasal

SprayOrally Disintegrating

Oral Tablets

Rectal Suppositories

Sublingual

References

Mannix, Lisa and Files, Julia. (2005). “The Use of Triptans in the Management of Menstrual Migraines.” CNS Drugs 19 (11): 951-972. Silberstein, Stephen. (2004) “Migraine.” Lancet 363: 381-91. McCormack, Paul and Foster, Rachel. (2005) “Rizatriptan: A Pharmacoeconomic Review of its Use in the Acute Treatment of Migraine.” Pharmacoeconomics 23 (12): 1283-1298.Loder, Elizabeth. (2005) “Fixed Drug Combinations for the Acute Treatment of Migraine: Place in Therapy.” CNS Drugs 19 (9): 769-784. Bateman, Nicholas. (2000) “Triptans and migraine.” Lancet 355: 860-861.Goadsby, P.J. (2003)“Migraine: diagnosis and management.” Internal Medicine Journal 33: 436-442.Kelly, Anne-Maree. (2000) “Migraine: pharmacotherapy in the emergency department.” Medicine Cabinet 173: 189-193Parsekyan, Dikran. (2000) “Migraine prophylaxis in adult patients.” Medicine Cabinet 173: 341-345.Krymchantowski, Abouch. (2004) “Acute treatment of migraine. Breaking the paradigm of monotherapy.” BMC Neurology 4:4. Pryse-Phillips, William, MD et al. (1997) “Guidelines for the diagnosis and management of migraine in clinical practice.” Canadian Medical Association Journal 156: 1273-87.Steiner, TJ and Fontebasso, Manuela. (2002) “Headache.” BMJ 325: 881-886Gladstone, Jonathan and Gawel, Marek. (2003) “Newer Formulations of the Triptans: Advances in Migraine Management.” Drugs 63 (21): 2285-2305.Villalon, Carlos et al. (2003) “Migraine: Pathophysiology, Pharmacology, Treatment and Future Trends.” Current Vascular Pharmacology 1: 71-84.Poolsup, N et al. (2005) “Efficacy and tolerability of frovatriptan in acute migraine treatment: systematic review of randomized controlled trials.” Journal of Clinical Pharmacy and Therapeutics 30: 521-532.Neighbor, Martha, MD. (1993) “ Sumatriptan-A New Treatment of Migraine.” WJM 159: 597-598.Brutto, Oscar. (2002) “Commentary: Headache in South America.” BMJ 325: 886.Côté I, Jelnikar E. (1999). “Predator-induced clumping behavior in mussels (Mytilus edulis Linneaus).” Experimental Marine Biology and Ecology 235: 201-211.Ackerknecht, Erwin. ( Primitive Surgery. Fold Healers and Ethnomedicine. Graham JR. & Wolff HG. Arch Neurol Psyquiat 1938: 39: 737.Moskowitz MA. Ann Neurol 1984; 16: 157-68.Goldstein DJ, Roon KI, Offen WW, Ramadan NM, Phebus LA, Johnson KW, Schaus JM. & Ferrari MD. Lancet 2001b; 358: 1230-4