MIGRAINE

BY

PROF, AZZA EL-MEDANY

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

RISK FACTORS

PHYSICAL

Fatigue, Fasting ,Exercise

PSYCHOLOGICAL

Stress , Anxiety , Depression

DISEASES

Hypertension ,Fever

CONTINUE

HORMONAL

Menstruation, Menopause ,Oral contraceptive pills.

DIET

Cheese , Chocolate ,Alcohol

CLIMATIC FACTORS

Temperature changes

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

Cassification Of MigraineMild

Moderate

Severe

(Cont.)

MILD

One attack /month

Normal daily activities continue.

MODERATE

One or two attacks / month

Normal daily activities may or not continue.

CONTINUE

SEVERE

More than 3 attacks / month

Normal activities cannot continue.

Patients treated with both acute & prophylactic medications.

Drugs used in acute attack

NSAIDS

ANTIEMETICS

ERGOT ALKALOIDS

TRIPTAN CLASS

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.

ANTIEMETICS

e.g. Metoclopramide , DomperidoneThey 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

ERGOT ALKALOIDS

Ergotamine

Dihydroergotamine

They act as partial agonists ( Agonist & Antagonist) at adrenergic , dopaminergic & serotonergic (5-HT1B/1D)receptors.

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.

PHRMACOKINETICS

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

CONTINUE

Usually given in combination with caffeine to facilitate its absorption.Long acting drug Cumulative drug.High tissue binding90% of metabolites are excreted in the bileIts effect persist up to 24 hours.

CLINICAL USES

Acute attack of migraine ( Moderate & Severe ).

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)

CONTRAINDICATIONS

Pregnancy

Peripheral & coronary vascular diseases.

Hypertension

Impaired hepatic or renal diseases

CONTINUE

In concurrent use with :

TRIPTANS

β- BLOCKERS

In prophylaxis of migraine

TRIPTAN CLASS

Triptans have selective agonist activity at 5-HT1D &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.

MECHANISM OF ACTION

Reducing the excitability of neurons in the trigeminovascular system via stimulation of brain stem 5-HT1B/1D receptors.

Attenuating the release of neuropeptides with inflammatory & vasodilating effect as substance P via 5-HT1D receptors.

Continue

Vasoconstriction of cerebral & extracerebral vessels by stimulation of vascular 5HT1B receptors.

N.B.

Coronary artery contains 5-HT1B

receptors so they cause coronary vasoconstriction.

SUMATRIPTAN

Selective agonist at 5-HT1D&1B receptors.

PHRMACOKINETICS

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

ZOLMITRIPTAN

Oral bioavailability (40%) .

Metabolized in liver to active metabolites which have a higher affinity to 5HT1B & 1D receptors than the parent drug.

Half- life for both 2-3hrs.

Plasma protein binding 14%.

NARATRIPTAN

Oral bioavailability 70%.

Half-life 6 hrs ( longest).

50% excreted unchanged in urine.

Plasma protein binding 30%.

CLINICAL USES

Acute attack of migraine ( moderate & severe ).

Acute cluster headache.

ADVERSE EFFECTS

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

CONTRAINDICATIONS

Coronary vascular disease. Ischemic heart disease . HypertensionConcurrent use with ergotamine Concurrent use with β- blockers.

Naratriptan is contraindicated in patients with severe renal or hepatic impairment.

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.

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 .

DRUGS USED IN PROPHYLAXIS

Methysergide

Cyproheptadine & Pizotifen

β- blockers

Calcium channel blockers

Antidepressant drugs

Ondansetron

METHYSERGID

5HT2A&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.

SIDE EFFECTS

Retroperitoneal , pericardial , pleural or valvular fibrosis ( mainly after prolonged use).

Nausea,Vomiting, Diarrhea.

Peripheral edema.

CNS manifestations

CONTRAINDICATIONS

With β- blockers.

With ergot alkaloids.

Valvular diseases

Pregnancy

CYPROHEPTADINE & PIZOTIFEN

Antiserotonergic ( 5HT2A) receptors.

Antihistaminic ( H1) receptors.

Anticholinergic

SIDE EFFECTS

Vertigo, Drowsiness

Increase body weight.

ONDANSETRON

5-HT3 antagonist.

Effective for prophylaxis of migraine.

Effective in the treatment of chemotherapy induced nausea.

β- BLOCKERS

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

Antiserotonergic effect.

CONTRAINDICATIONS

Old age

Bronchial asthma

A-V block

CHF

ANTIDEPRESSANTS

TCA & SSRIs prevent the release of 5HT from brain mast cells.

Prevent V.C. which trigger 1st phase.

CALCIUM CHANNEL BLOCKERS

Decrease severity & frequency of migraine through blocking the influx of calcium.