2. MIGRAINE

3. BY PROF, AZZA EL-MEDANY

4. MIGRAINE Recurrent attacks of headache. Unilateral, associated with migraine aura ( anorexia, nausea, vomiting, visual or auditory disturbances ). Common in young female. Pulsating or throbbing in character. Sustain for more than 2 hours. Affect about 10-20% of population

5. RISK FACTORS PHYSICAL Fatigue, Fasting,Exercise PSYCHOLOGICAL Stress, Anxiety, Depression DISEASES Hypertension,Fever

6. CONTINUE HORMONAL Menstruation, Menopause,Oral contraceptive pills. DIET Cheese, Chocolate,Alcohol CLIMATIC FACTORS Temperature changes

7. VASCULAR THEORY PHASE ( 1) :: V.C. of intra& extracranial b.v. may be due to release of 5HT from platelet or mast cells. Migraine aura occurs in this phase. PHASE (2): V.D. of intra & extracranial b.v. may be due to release of neurotransmitters as substance P,or neurokinins. PHASE (3) : Inflammatory reactions due to liberation of inflammatory mediators

8. Cassification Of Migraine Mild Moderate Severe

9. (Cont.) MILD One attack /month Normal daily activities continue. MODERATE One or two attacks / month Normal daily activities may or not continue.

10. CONTINUE SEVERE More than 3 attacks / month Normal activities cannot continue. Patients treated with both acute & prophylactic medications.

11. Drugs used in acute attack NSAIDS ANTIEMETICS ERGOT ALKALOIDS TRIPTAN CLASS

12. NSAID,s Inhibits prostaglandins synthesis centrally. Antiemetic drugs are usually added to increase their absorption. No withdrawal symptoms on sudden withdrawal. Main adverse effects Gastric Upset.

13. ANTIEMETICS e.g. Metoclopramide, Domperidone They are dopamine receptors antagonist. Given at the onset of the attack as adjunctive therapy to reduce gastric symptoms ( N.& V.). To improve oral absorption of analgesics

14. ERGOT ALKALOIDS Ergotamine Dihydroergotamine They act as partial agonists ( Agonist & Antagonist) at adrenergic, dopaminergic & serotonergic (5- HT 1 B/ 1 D)receptors.

15. N.B. Patients advised to take ergot preparations at the earliest sign of a migrain attack for the maximal benefit. Their main pharmacological effect is V.C. either centrally or peripherally.

16. PHRMACOKINETICS Ergotamine can be given by all routes. Orally undergoes extensive 1 st pass metabolism. Sublingual has a bioavailability less than 1% Rectal route best method of absorption Nasal spray I.M., SC, I.V.

17. CONTINUE Usually given in combination with caffeine to facilitate its absorption. Long acting drug Cumulative drug. High tissue binding 90% of metabolites are excreted in the bile Its effect persist up to 24 hours.

18. CLINICAL USES Acute attack of migraine ( Moderate & Severe ).

19. ADVERSE EFFECTS Nausea, vomiting( direct effect on CNS emetic centre), diarrhea, abdominal pain. Coldness, numbness of fingers & toes. Prolonged use causes paresthesias, gangrene. Coronary vasospasm. Rebound headache ( V.D after V.C) CNS (hallucination)

20. CONTRAINDICATIONS Pregnancy Peripheral & coronary vascular diseases. Hypertension Impaired hepatic or renal diseases

21. CONTINUE In concurrent use with : TRIPTANS β- BLOCKERS In prophylaxis of migraine

22. TRIPTAN CLASS Triptans have selective agonist activity at 5-HT 1D & 1B subtype receptors. Unlike ergotamine, triptans are effective when given 4 hours or longer after the onset of the attack. They are more expensive than ergot.

23. MECHANISM OF ACTION Reducing the excitability of neurons in the trigeminovascular system via stimulation of brain stem 5-HT 1B/1D receptors. Attenuating the release of neuropeptides with inflammatory & vasodilating effect as substance P via 5- HT 1D receptors.

24. Continue Vasoconstriction of cerebral & extracerebral vessels by stimulation of vascular 5HT 1B receptors. N.B. Coronary artery contains 5-HT 1B receptors so they cause coronary vasoconstriction.

25. SUMATRIPTAN Selective agonist at 5-HT 1D&1B receptors.

26. PHRMACOKINETICS Orally undergoes 1 st pass hepatic metabolism.( bioavailability 14-17% S.C ( rapid absorption, peak in 12 min). Bioavailability 97%. I.V. Not given ( risky ). Nasal spray HALF-life 2 hrs.

27. ZOLMITRIPTAN Oral bioavailability (40%). Metabolized in liver to active metabolites which have a higher affinity to 5HT 1 B & 1 D receptors than the parent drug. Half- life for both 2-3hrs. Plasma protein binding 14%.

28. NARATRIPTAN Oral bioavailability 70%. Half-life 6 hrs ( longest). 50% excreted unchanged in urine. Plasma protein binding 30%.

29. CLINICAL USES Acute attack of migraine ( moderate & severe ). Acute cluster headache.

30. ADVERSE EFFECTS Mild pain & burning sensation at the site of injection. Paresthesia, warmth, heaviness in head or other parts of the body. Dizziness Hypertension Coronary artery vasospasm (anginal pain), MI, Ventricular arrhythmias. Bitter taste ( nasal spray)

31. CONTRAINDICATIONS Coronary vascular disease. Ischemic heart disease. Hypertension Concurrent use with ergotamine Concurrent use with β- blockers. Naratriptan is contraindicated in patients with severe renal or hepatic impairment.

32. PROPHYLAXIS OF MIGRAINE INDICATIONS Two or more attacks / month Acute symptomatic treatment is required more than 2-3 times/ week. Drugs used in acute attack are ineffective, intolerable or contraindicated.

33. CONTINUE Headache is severe and associated with neurological symptoms. Drugs used in prophylactic treatment need several weeks to manifest their effects. Treatment should continue for 6 months & can be repeated after a rest period.

34. DRUGS USED IN PROPHYLAXIS Methysergide Cyproheptadine & Pizotifen β- blockers Calcium channel blockers Antidepressant drugs Ondansetron

35. METHYSERGID 5HT 2A&C receptor antagonist. Anti-inflammatory effect. Mild V.C. effect. Given orally. Used only for prophylaxis treatment. Not used for more than 6 months, repeated after a holiday of one month.

36. SIDE EFFECTS Retroperitoneal, pericardial, pleural or valvular fibrosis ( mainly after prolonged use). Nausea,Vomiting, Diarrhea. Peripheral edema. CNS manifestations

37. CONTRAINDICATIONS With β- blockers. With ergot alkaloids. Valvular diseases Pregnancy

38. CYPROHEPTADINE & PIZOTIFEN Antiserotonergic ( 5HT 2A ) receptors. Antihistaminic ( H 1 ) receptors. Anticholinergic SIDE EFFECTS Vertigo, Drowsiness Increase body weight.

39. ONDANSETRON 5-HT 3 antagonist. Effective for prophylaxis of migraine. Effective in the treatment of chemotherapy induced nausea.

40. β- BLOCKERS Act through β- blocking effect on intra or extracranial blood vessels. Antiserotonergic effect.

41. CONTRAINDICATIONS Old age Bronchial asthma A-V block CHF

42. ANTIDEPRESSANTS TCA & SSRIs prevent the release of 5HT from brain mast cells. Prevent V.C. which trigger 1 st phase.

43. CALCIUM CHANNEL BLOCKERS Decrease severity & frequency of migraine through blocking the influx of calcium.