8/14/20151 MIGRAINE DR.ABDUL LATIF MAHESAR Department of medical pharmacology KING SAUD UNIVERSITY 1March 2011

8/14/20152 Types of Migraine 1. Migraine without aura is called as common type of Migraine 80% 2. Migraine with aura is called as Classic type of Migraine 20%

8/14/20153 Triggering factors (in a persons who are prone to migraine) ► May be 1. Physical: fatigue, fasting, exercise. 2. Psyclogical: stress, anxiety, depression 3. Diseases: Hypertension, Fever, Sinus Hypertension, Fever, Sinus

8/14/20154 Triggering factors cont’d 4. Hormonal: Menstruation, Menopause, Oral contraceptive pills. Menstruation, Menopause, Oral contraceptive pills. 5. Diet Cheese, Chocolate, alcohol, Caffeine 6. Climate: Change in temperature Change in temperature

8/14/20155 Pathophsiolgy of migraine ► Pathophysiological characteristics are vague and inconsistent. ► One statement is this, that unknown events lead to abnormal dilation of carotid arteriovenous anastmosis in the head, located mainly in the cranial skin and ears, this diverts blood from capillary beds, thereby producing cerebral ischemia and hypoxia. Antimigraine drugs close this shunt and thereby restore the blood to brain. ► Other explanation is that a spreading depression of neural impulses occur from a focal point of vasoconstriction followed by vasodilatation ► vasoconstriction followed by vasodilatation or vasodilatation alone accounts for local edema and focal tenderness which is often observed in migraine patients

8/14/20156 ► 5HT- is a key mediator in the pathogenesis of migraine ► 5-HT receptors are present in carotid vasculature, stimulation of these receptors lead to vasoconstriction of carotid arteriovenous anastmosis ► Therefore 5-HT –receptor agonists have become mainstay of acute treatment of migraine

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8 ► PHASES OF VASCULAR THEORY 1. Phase one: Vasoconstriction of intra- and extracranial blood vessels may be due to the release of 5-HT from platelets or mast cells. o Plasma platelet concentration of 5-HT varies with different phases of migraine. o Urinary excretion of 5-HT and its metabolites are elevated. o Migraine attack increases with agents which cause release of biogenic amine (e.g. 5-HT) o migraine aura occurs in this phase.

8/14/ Phase two: Vasodilation of intra- and extracranial blood vessels may be due to the release of neurotransmitters such as substance P or neurokinin. 3. Phase three; Inflammatory reactions due to liberation of inflammatory mediators Inflammatory reactions due to liberation of inflammatory mediators

8/14/ Types of Migraine: according to the severity and frequency of attacks. Mild: once a month Normal daily activities are not disturbed. Moderate: More than once a month Normal daily activities may or may not be disturbed Severe: More than 3 attacks per month. Normal activities are difficult to continue patients need to be treated with both acute and prophylactic medicines.

8/14/ Drugs Used to Treat Migraine ► ► Migraine sufferers need drugs that work acutely for acute migraine attacks, are effective, and can be conveniently taken. ► Drugs Used to Abort Acute attacks of Migraine: Non-specific drugs: Non-specific medications increase patients’ tolerance to pain, nausea, and associated symptoms. 1. NSAIDs (usually in combination with caffeine) Aspirin, Ibuprofen, Naproxen, Paracetamol Note: Indomethacin is not used because it causes headache as a side effect. Note: Indomethacin is not used because it causes headache as a side effect.

8/14/  Antiemetics: Metoclopramide, Domperidone, Domperidone,Cyclizine 3.5-HT 3 receptor antagonists( present at enteric neurons of the intestine, they inhibit vomiting and increased pressure in the stomach) Ondansetron used for both acute attacks as well as for prophylaxis.

8/14/ Specific antimigraine drugs: 1. 5-HT 1 receptor agonists (-triptans) SumatriptanZolmitriptan Naratriptan and others 2. Ergot alkaloids: Ergotamine tartrate, Dihydroergotamine

8/14/ Triptans ► Sumatriptan ► Zolmitriptan ► Naratriptan ► Rizatriptan ► Elitriptan ► Almotriptan and others.

8/14/201515Cont’d ► In contrast to ergot alkaloids, their effect is limited to 5-HT 1D/1B receptors. Therefore, they are selective than ergots. ► In contrast to ergot alkaloids, their effect is limited to 5-HT 1D/1B receptors. Therefore, they are more selective than ergots. ► They are inactive at α1, α2, β –adrenergic, dopaminergic, or muscarinic receptors. ► They act specifically via receptor mediated binding in the CNS and its vascular system. ► They suppress the excitability of cells in the trigeminal nuclei of 5HT 1D/1B receptor within the brain stem ► Produce vasoconstriction of meningeal, dural, cerebral vessels via stimulation of vascular 5HT 1B receptors

8/14/ SUMATRIPTAN ► It was the 1 st approved triptan for acute treatment of migraine ► Mechanism of action: It is a selective agonist at 5-HT 1B/1D receptors and a selective cerebral vasoconstrictor. Pharmacokinetics: It can be administered orally, by injection, nasal spray, and suppository Orally, it undergoes extensive 1 st pass hepatic metabolism  poor oral bioavailability Orally, it undergoes extensive 1 st pass hepatic metabolism  poor oral bioavailability

8/14/ ► when administered subcutaneously its absorption is rapid ► Peak plasma concentration is reached at 12 minutes with a bioavailability of 97% ► It has a shorter duration of action with a half life of 2 hours. ► Metabolized in the liver ► Its metabolites are excreted in urine

8/14/ ► Uses: ► It is used for acute attacks of migraine of moderate and severe nature. It can also be used to treat cluster headaches.

8/14/ Common adverse effects: ► Mild pain and burning sensation at the site of injection. ► Feeling of paraesthesia, tingling,warmth, heaviness in head and other parts of the body. ► Flushing ► Dizziness ► Rise in BP ► Anginal pain due to its vasoconstrictor action.

8/14/ Serious side effects RARE BUT SERIOUS ► Vasospasm. ► MI ► Inducing angina ► Hypertension ► Arrhythmias

8/14/ Contraindications: Contraindications: ► ► History of ischemia ► ► vasospastic coronary artery disease ► ► Cerebrovascular and peripheral arterial diseases ► ► Uncontrolled hypertension ► ► Pregnancy

8/14/ Zolmitriptan ► It is a 2 nd generation triptan ► It rapidly relieves migraine attacks. ► It is available in the form of oral tablets, oral disintegrating tablets, fast acting nasal spray. ► It has oral bioavailability of 40% with peak plasma concentration reached in about hours. ► It is metabolized in the liver to active metabolites which have higher affinity for 5-HT 1D/1B receptors than the parent drug. ► both metabolites and parent drug have a half-life of 2-3 hours ► Its plasma protein binding capacity is 14%

8/14/ Zolmitriptan cont’d ► Adverse effects: ► Paraesthesia ► Asthenia ► Nausea ► Dizziness ► Chest and neck tightness or heaviness ► Somnolence ► Contraindicated in patients with Wolff-Parkinson-White syndrome.

8/14/ Naratriptan ► It is the longest acting triptan with a half-life of 6 hours. ► Its oral bioavailability is 70% ► It gains peak plasma concentration in 2-3 hors when given orally. ► 50% of the dose is excreted in the urine unchanged ► It has 30 % plasma protein binding capacity. ► It is contraindicated in severe renal and hepatic impairment or peripheral vascular syndrome.

8/14/ ERGOT ALKALOIDS ► ► ERGOTAMINE ► ► DIHYDROERGOTAMINE ► ► NOTE: The use of ergots in migraine headaches should be restricted to patients with frequent, moderate attack or infrequent but severe attacks. ► ► They are only used to abort the attack and only in limited doses.

8/14/ ► Mechanism of action: Work as an agonist, partial agonist, or antagonist on 5-HT 1 receptors Work as an agonist, partial agonist, or antagonist on 5-HT 1 receptors Partial agonist effect on α-adrenoceptors. Ergotamine is more effective during the prodrome of attack and less effective if delayed.

8/14/ ► Ergots main pharmacological effect is vasoconstriction either centrally or peripherally. ► Vasoconstriction is ever more potentiated by concomitant use of β-blockers. This causes severe vasocontriction which may lead to paraesthesia of the hands and feet. Vasonconstriction might even lead to gangrene.

8/14/201528Pharmacokinetics ► Ergotamine can be administered by any route, but its oral absorption is erratic (incomplete) very slow, it is usually administered with caffeine to facilitate its absorption. ► Orally: it undergoes extensive 1 st pass hepatic metabolism ► 90% of metabolites are excreted in the bile ► Has a plasma half life of 2 hours ► Sublingual ergotamine tartrate* has poor bioavailability. ► Rectal suppositories are the best route of absorption for ergotamine * Commercial name for sublingual ergotamine

8/14/ ► Inhalation: Dihydroergotamine mesylate, produces quick effect ► In severe cases and when prompt effect is needed, ergotamine drugs can be administered intramuscularly or intravenously. ► The parenteral route has a long duration of action about 24 hours as it has a high and long tissue binding ability, it may get accumulated in the body with repeated administration. ► Dihydroergotamine is less completely absorbed and eliminated more rapidly than ergotamine due to its rapid hepatic clearance.

8/14/ ► Adverse Effects: ► Nausea, vomiting, abdominal pain, and diarrhea ► Feeling of cold and numbness of limbs, tingling ► Pericardial distress, it may precipitate heart disease like anginal pain, tachycardia/bradycardia, or coronary spasm. ► Prolonged use may also give rise to rebound headache by vasodilatation followed by vasoconstriction. ► Hallucination.

8/14/ ► Contraindications: Pregnancy, fever Peripheral and coronary vascular diseases Hypertension Liver and kidney diseases In concurrent use with triptans (at least 6 hours from last dose of triptans or 24 hrs from stopping ergotamine) In concurrent use with β-blockers In concurrent use with β-blockers

8/14/ NSAIDs Inhibits Prostaglandin synthesis centrally Inhibits Prostaglandin synthesis centrally ► Usually taken with antiemetic (eg, metoclopramide) to increase their absorption and oral bioavailability ► They don’t cause withdrawal symptoms as opioids or rebound headache with ergotamine, ► Side Effects: Gastric upset, GIT ulceration or bleeding.

8/14/ Antiemetics ► Metoclopramide ► Domperidone ► Cyclizine ► These are dopamine receptor antagonists ► These are given at the onset of attack as adjunctive therapy to reduce gastric symptoms such as nausea and vomiting and improve absorption of analgesics and increase gastric motility.

8/14/ ► Domperidone can not cross blood brain barrier, can be given as a suppository. ► Side effects: ► Due to dopamine antagonist activity, they may cause sedation, diarrhea, and extrapyramidal effects.

8/14/ Drugs used for prophylaxis of Migraine ► Prophylactic treatment is indicated in conditions: ► When there is two or more attacks per month ► When acute symptomatic treatment is required for more than 2-3 times/week ► Drugs used in acute attack are ineffective, intolerable, or contraindicated. ► Headache is severe and associated with neurological symptoms ► Drugs used need several weeks for the onset of action. ► Treatment continues for six months and can be repeated

8/14/ Drugs used for prophylaxis in migraine ► Methysergide ► Cyproheptadine and pizotifen ► β-blockers ► calcium channel blockers ► Antidepressants ► Ondansetron

8/14/ METHYSERGIDE ► 5-HT2 receptor antagonist ► Anti-inflammatory ► Administered orally ► Only used for prophylaxis. Not effective in acute attacks. ► Should not be used for more than 6 months. If to be repeated, there should be a-one-month free period in between.

8/14/ Side effects Prolonged use may give rise to retroperitoneal, pericardial, pleural, or valvular fibrosis (serious side effects).

8/14/ Contraindications ► Not to be administered concurrently with β- blockers or Ergot alkaloids. ► Valvular diseases (ECG must be monitored during therapy)

8/14/ CYPROHEPTADINE AND PIZOTIFEN ► They have: Antiserotonergic (5-HT 2 ), Antaihistaminic (H-1) and Anticholinergic effects. Antiserotonergic (5-HT 2 ), Antaihistaminic (H-1) and Anticholinergic effects. Side effects: Vertigo, drowsiness Pizotifen increases appetite so there might be an increase in body weight. Pizotifen increases appetite so there might be an increase in body weight.

8/14/ ONDANSETRONE ► Is the prototypic 5-HT 3 antagonist ► It is effective for treatment of acute attack and prophylaxis for its antiemetic effect. ► Also, is preferably used for nausea and vomiting after surgery or with chemotherapeutic agents.

8/14/ β-Blockers ► Is commonly used for prophylaxis against migraine attacks. Acts mainly through blocking β-induced vasodilating effect on intra or extra cranial blood vessels. Side effects: ► Fatigue, Drowsiness, Dizziness, Depression ► Impotence ► Bradycardia Contraindications: ► Old age ► Asthma ► AV block ► CHF

8/14/ ANTIDEPRESSANTS ► Amitriptyline, SSRI (Fluoxetine) ► They prevent the release of plasma peritoneal fluid 5-HT from brain mast cells ► Prevent vasoconstriction which triggers 1 st phase ► like all prophylactic drugs, they have delayed onset of action, about 6-8 weeks. Side effects: Dry mouth, Blurred vision, Constipation

8/14/ Calcium channel blockers ► Verapamil, Nifedipine, Diltiazem, Nimodipine, Flunarizine ► They decrease the severity and frequency of migraine through inhibition of Ca ++ influx ► Side effects: ► Constipation ► Ankle edema ► Change in heart rate.