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MIGRAINEMIGRAINE

DR.ABDUL LATIF MAHESARDR.ABDUL LATIF MAHESAR

Department of medical Department of medical pharmacologypharmacology

KING SAUD UNIVERSITYKING SAUD UNIVERSITY

11 March 2011March 2011

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Types of MigraineTypes of Migraine

1.1. Migraine without aura is called as common Migraine without aura is called as common type of Migraine type of Migraine 80% 80%

2.2. Migraine with aura is called as Classic type Migraine with aura is called as Classic type of Migraine of Migraine 20%20%

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Triggering factorsTriggering factors(in a persons who are prone to migraine)(in a persons who are prone to migraine)

► May beMay be

1.1. Physical:Physical:

fatigue, fasting, exercise.fatigue, fasting, exercise.

2.2. Psyclogical:Psyclogical:

stress, anxiety, depressionstress, anxiety, depression

3.3. Diseases:Diseases: Hypertension , Fever, SinusHypertension , Fever, Sinus

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Triggering factors Triggering factors cont’dcont’d

4.4. Hormonal:Hormonal:

Menstruation, Menopause, Oral contraceptive Menstruation, Menopause, Oral contraceptive

pillspills..

5.5. DietDietCheese , Chocolate, alcohol, CaffeineCheese , Chocolate, alcohol, Caffeine

6.6. Climate:Climate: Change in temperatureChange in temperature

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Pathophsiolgy of Pathophsiolgy of migrainemigraine

► Pathophysiological characteristics are vague and inconsistent.Pathophysiological characteristics are vague and inconsistent.

► One statement is this, that unknown events lead to abnormal dilation One statement is this, that unknown events lead to abnormal dilation of carotid arteriovenous anastmosis in the head, located mainly in the of carotid arteriovenous anastmosis in the head, located mainly in the cranial skin and ears, this diverts blood from capillary beds, thereby cranial skin and ears, this diverts blood from capillary beds, thereby producing cerebral ischemia and hypoxia. Antimigraine drugs close producing cerebral ischemia and hypoxia. Antimigraine drugs close this shunt and thereby restore the blood to brain.this shunt and thereby restore the blood to brain.

► Other explanation is that a spreading depression of neural impulses Other explanation is that a spreading depression of neural impulses occur from a focal point of vasoconstriction followed by occur from a focal point of vasoconstriction followed by vasodilatationvasodilatation

► vasoconstriction followed by vasodilatation or vasodilatation alone vasoconstriction followed by vasodilatation or vasodilatation alone accounts for local edema and focal tenderness which is often accounts for local edema and focal tenderness which is often observed in migraine patientsobserved in migraine patients

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► 5HT- is a key mediator in the pathogenesis of 5HT- is a key mediator in the pathogenesis of migrainemigraine

► 5-HT receptors are present in carotid vasculature, 5-HT receptors are present in carotid vasculature, stimulation of these receptors lead to stimulation of these receptors lead to vasoconstriction of carotid arteriovenous anastmosisvasoconstriction of carotid arteriovenous anastmosis

► Therefore 5-HT –receptor agonists have become Therefore 5-HT –receptor agonists have become mainstay of acute treatment of migrainemainstay of acute treatment of migraine

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► PHASES OF VASCULAR THEORYPHASES OF VASCULAR THEORY1.1. Phase one: Vasoconstriction of intra- and extracranial blood Phase one: Vasoconstriction of intra- and extracranial blood

vessels may be due to the release of 5-HT from platelets or mast vessels may be due to the release of 5-HT from platelets or mast cells.cells.

o Plasma platelet concentration of 5-HT varies with different Plasma platelet concentration of 5-HT varies with different phases of migraine.phases of migraine.

o Urinary excretion of 5-HT and its metabolites are elevated.Urinary excretion of 5-HT and its metabolites are elevated.

o Migraine attack increases with agents which cause release of Migraine attack increases with agents which cause release of biogenic amine (e.g. 5-HT)biogenic amine (e.g. 5-HT)

o migraine aura occurs in this phase.migraine aura occurs in this phase.

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2.2. Phase two:Phase two:Vasodilation of intra- and extracranial blood Vasodilation of intra- and extracranial blood

vessels may be due to the release of neurotransmitters vessels may be due to the release of neurotransmitters such as substance P or neurokinin.such as substance P or neurokinin.

3.3. Phase three;Phase three; Inflammatory reactions due to liberation of Inflammatory reactions due to liberation of

inflammatory mediatorsinflammatory mediators

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Types of Migraine:Types of Migraine: according to the severity and according to the severity and frequency of attacks.frequency of attacks.

MildMild:: once a month once a month

Normal daily activities are not disturbed.Normal daily activities are not disturbed.

ModerateModerate:: More than once a month More than once a month

Normal daily activities may or may not be disturbedNormal daily activities may or may not be disturbed

Severe:Severe: More than 3 attacks per month. More than 3 attacks per month.

Normal activities are difficult to continue Normal activities are difficult to continue patients need to be treated with both acute and patients need to be treated with both acute and prophylactic medicines.prophylactic medicines.

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Drugs Used to Treat Drugs Used to Treat MigraineMigraine

► Migraine sufferers need drugs that work acutely for acute migraine attacks, are effective, and can be conveniently taken.

► Drugs Used to Drugs Used to AbortAbort Acute attacks of Acute attacks of Migraine:Migraine:

Non-specific drugs:Non-specific drugs:Non-specific medications increase patients’ tolerance to pain , Non-specific medications increase patients’ tolerance to pain , nausea, and associated symptoms.nausea, and associated symptoms.

1.1. NSAIDsNSAIDs (usually in combination with caffeine)(usually in combination with caffeine)

Aspirin, Ibuprofen, Naproxen, ParacetamolAspirin, Ibuprofen, Naproxen, Paracetamol

Note:Note: IndomethacinIndomethacin is not used because it causes is not used because it causes headache as a side effect. headache as a side effect.

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2.2. Antiemetics:Antiemetics:

Metoclopramide,Metoclopramide,

Domperidone,Domperidone,

CyclizineCyclizine

3.3. 5-HT5-HT33 receptor antagonists receptor antagonists((presentpresent at enteric neurons of the intestine, they at enteric neurons of the intestine, they inhibit vomiting and increased pressure in inhibit vomiting and increased pressure in the stomach)the stomach)

OndansetronOndansetron used for both used for both acuteacute attacks as well as for attacks as well as for prophylaxisprophylaxis..

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Specific antimigraine Specific antimigraine drugs:drugs:

1.1. 5-HT5-HT11 receptor agonists (-triptans) receptor agonists (-triptans)Sumatriptan Sumatriptan Zolmitriptan Zolmitriptan Naratriptan and othersNaratriptan and others

2.2. Ergot alkaloids:Ergot alkaloids:Ergotamine tartrate,Ergotamine tartrate,DihydroergotamineDihydroergotamine

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TriptansTriptans

► SumatriptanSumatriptan► ZolmitriptanZolmitriptan► NaratriptanNaratriptan► RizatriptanRizatriptan► ElitriptanElitriptan► Almotriptan and others.Almotriptan and others.

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Cont’dCont’d

► In contrast to ergot alkaloids, their effect is limited to 5-HT In contrast to ergot alkaloids, their effect is limited to 5-HT 1D/1B1D/1B receptors . Therefore, they are receptors . Therefore, they are more selective than ergots.selective than ergots.

► They are inactive at They are inactive at αα1, 1, αα2, 2, ββ –adrenergic , dopaminergic, or –adrenergic , dopaminergic, or muscarinic receptors. muscarinic receptors.

► They act specifically via receptor mediated binding in the CNS They act specifically via receptor mediated binding in the CNS and its vascular system.and its vascular system.

► They suppress the excitability of cells in the trigeminal nuclei of They suppress the excitability of cells in the trigeminal nuclei of 5HT5HT1D/1B1D/1B receptor within the brain stem receptor within the brain stem

► Produce vasoconstriction of meningeal, dural, cerebral vessels Produce vasoconstriction of meningeal, dural, cerebral vessels via stimulation of vascular 5HT via stimulation of vascular 5HT 1B1B receptors receptors

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SUMATRIPTANSUMATRIPTAN

► It was the 1It was the 1stst approved triptan for acute treatment of migraine approved triptan for acute treatment of migraine

► Mechanism of action:Mechanism of action:It is a selective agonist at 5-HTIt is a selective agonist at 5-HT1B/1D1B/1D receptors and a selective receptors and a selective cerebral vasoconstrictor.cerebral vasoconstrictor.

Pharmacokinetics:Pharmacokinetics:It can be administered orally, by injection , nasal spray, and It can be administered orally, by injection , nasal spray, and suppositorysuppository

Orally, it undergoes extensive 1Orally, it undergoes extensive 1stst pass hepatic metabolism pass hepatic metabolism poor poor oral bioavailabilityoral bioavailability

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► when administered subcutaneously its absorption is rapidwhen administered subcutaneously its absorption is rapid

► Peak plasma concentration is reached at 12 minutes with a Peak plasma concentration is reached at 12 minutes with a bioavailability of 97%bioavailability of 97%

► It has a shorter duration of action with a half life of 2 hours.It has a shorter duration of action with a half life of 2 hours.

► Metabolized in the liverMetabolized in the liver

► Its metabolites are excreted in urineIts metabolites are excreted in urine

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► Uses:Uses:►It is used for acute attacks of migraine of It is used for acute attacks of migraine of

moderate and severe nature. It can also be used moderate and severe nature. It can also be used to treat cluster headaches.to treat cluster headaches.

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Common adverse effects:Common adverse effects:

► Mild pain and burning sensation at the site of injection.Mild pain and burning sensation at the site of injection.

► Feeling of paraesthesia , tingling ,warmth, heaviness in head and Feeling of paraesthesia , tingling ,warmth, heaviness in head and other parts of the body.other parts of the body.

► FlushingFlushing

► DizzinessDizziness

► Rise in BPRise in BP

► Anginal pain due to its vasoconstrictor action. Anginal pain due to its vasoconstrictor action.

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Serious side effectsSerious side effects

RARE BUT SERIOUSRARE BUT SERIOUS►Vasospasm.Vasospasm.► MIMI► Inducing anginaInducing angina► HypertensionHypertension► Arrhythmias Arrhythmias

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Contraindications:Contraindications:► History of ischemia

► vasospastic coronary artery disease

► Cerebrovascular and peripheral arterial diseases

► Uncontrolled hypertension

► Pregnancy

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ZolmitriptanZolmitriptan

► It is a It is a 22ndnd generation generation triptantriptan

► It rapidly relieves migraine attacks.It rapidly relieves migraine attacks.► It is available in the form of oral tablets, oral disintegrating It is available in the form of oral tablets, oral disintegrating

tablets, fast acting nasal spray.tablets, fast acting nasal spray.► It has oral bioavailability of 40% with peak plasma It has oral bioavailability of 40% with peak plasma

concentration reached in about 1.5-2 hours.concentration reached in about 1.5-2 hours.► It is metabolized in the liver to active metabolites which have It is metabolized in the liver to active metabolites which have

higher affinity for 5-HThigher affinity for 5-HT1D/1B 1D/1B receptors than the parent drug.receptors than the parent drug.► both metabolites and parent drug have a half-life of 2-3 hours both metabolites and parent drug have a half-life of 2-3 hours ► Its plasma protein binding capacity is 14%Its plasma protein binding capacity is 14%

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Zolmitriptan cont’dZolmitriptan cont’d

► Adverse effects:Adverse effects:► Paraesthesia Paraesthesia ► Asthenia Asthenia ► NauseaNausea► DizzinessDizziness► Chest and neck tightness or heavinessChest and neck tightness or heaviness► SomnolenceSomnolence► Contraindicated in patients with Wolff-Parkinson-Contraindicated in patients with Wolff-Parkinson-

White syndrome.White syndrome.

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NaratriptanNaratriptan

► It is the longest acting triptan with a half-life of 6 hours.It is the longest acting triptan with a half-life of 6 hours.

► Its oral bioavailability is 70% Its oral bioavailability is 70%

► It gains peak plasma concentration in 2-3 hors when given It gains peak plasma concentration in 2-3 hors when given orally.orally.

► 50% of the dose is excreted in the urine unchanged50% of the dose is excreted in the urine unchanged

► It has 30 % plasma protein binding capacity.It has 30 % plasma protein binding capacity.

► It is contraindicated in severe renal and hepatic impairment or It is contraindicated in severe renal and hepatic impairment or peripheral vascular syndrome.peripheral vascular syndrome.

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ERGOT ALKALOIDSERGOT 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.

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►Mechanism of action:Mechanism of action:

Work as an agonist, partial agonist, or Work as an agonist, partial agonist, or antagonist on 5-HTantagonist on 5-HT11 receptors receptors

Partial agonist effect on Partial agonist effect on αα-adrenoceptors.-adrenoceptors.

Ergotamine is more effective during the Ergotamine is more effective during the prodrome of attack and less effective if delayed.prodrome of attack and less effective if delayed.

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► Ergots main pharmacological effect is Ergots main pharmacological effect is vasoconstriction either centrally or peripherally.vasoconstriction either centrally or peripherally.

► Vasoconstriction is ever more potentiated by Vasoconstriction is ever more potentiated by concomitant use of concomitant use of ββ-blockers. This causes severe -blockers. This causes severe vasocontriction which may lead to paraesthesia of the vasocontriction which may lead to paraesthesia of the hands and feet. Vasonconstriction might even lead to hands and feet. Vasonconstriction might even lead to gangrene.gangrene.

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PharmacokineticsPharmacokinetics► Ergotamine can be administered by any route, but its oral Ergotamine can be administered by any route, but its oral

absorption is erratic (incomplete) very slow, it is usually absorption is erratic (incomplete) very slow, it is usually administered with caffeine to facilitate its absorption.administered with caffeine to facilitate its absorption.

► Orally: it undergoes extensive 1Orally: it undergoes extensive 1stst pass hepatic metabolism pass hepatic metabolism

► 90% of metabolites are excreted in the bile90% of metabolites are excreted in the bile

► Has a plasma half life of 2 hoursHas a plasma half life of 2 hours

► Sublingual ergotamine tartrate* has poor bioavailability.Sublingual ergotamine tartrate* has poor bioavailability.

► Rectal suppositories are the best route of absorption for Rectal suppositories are the best route of absorption for ergotamineergotamine

* Commercial name for sublingual ergotamine

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► InhalationInhalation: Dihydroergotamine mesylate, produces quick effect: Dihydroergotamine mesylate, produces quick effect

► In severe cases and when prompt effect is needed, ergotamine In severe cases and when prompt effect is needed, ergotamine drugs can be administered intramuscularly or intravenously.drugs can be administered intramuscularly or intravenously.

► The parenteral route has a long duration of action about 24 hours 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 as it has a high and long tissue binding ability, it may get accumulated in the body with repeated administration.accumulated in the body with repeated administration.

► DihydroergotamineDihydroergotamine is less completely absorbed and eliminated is less completely absorbed and eliminated more rapidly than ergotamine due to its rapid hepatic clearance.more rapidly than ergotamine due to its rapid hepatic clearance.

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► Adverse Effects:Adverse Effects:► Nausea, vomiting, abdominal pain, and diarrheaNausea, vomiting, abdominal pain, and diarrhea

► Feeling of cold and numbness of limbs, tinglingFeeling of cold and numbness of limbs, tingling

► Pericardial distress, it may precipitate heart disease like Pericardial distress, it may precipitate heart disease like anginal pain, tachycardia/bradycardia, or coronary spasm.anginal pain, tachycardia/bradycardia, or coronary spasm.

► Prolonged use may also give rise to rebound headache Prolonged use may also give rise to rebound headache by by vasodilatation followed by vasoconstriction.vasodilatation followed by vasoconstriction.

► Hallucination.Hallucination.

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► Contraindications:Contraindications:

Pregnancy, feverPregnancy, fever

Peripheral and coronary vascular diseasesPeripheral and coronary vascular diseases

HypertensionHypertension

Liver and kidney diseasesLiver and kidney diseases

In concurrent use with triptans (at least 6 hours from last dose of In concurrent use with triptans (at least 6 hours from last dose of triptans or 24 hrs from stopping ergotamine)triptans or 24 hrs from stopping ergotamine)

In concurrent use with In concurrent use with ββ-blockers-blockers

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NSAIDsNSAIDs

Inhibits Prostaglandin synthesis centrallyInhibits Prostaglandin synthesis centrally

► Usually taken with antiemetic (eg, metoclopramide) to Usually taken with antiemetic (eg, metoclopramide) to increase their absorption and oral bioavailabilityincrease their absorption and oral bioavailability

► They don’t cause withdrawal symptoms as opioids or They don’t cause withdrawal symptoms as opioids or rebound headache with ergotamine,rebound headache with ergotamine,

► Side Effects: Side Effects: Gastric upset, GIT ulceration or bleeding Gastric upset, GIT ulceration or bleeding ..

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AntiemeticsAntiemetics

► MetoclopramideMetoclopramide► DomperidoneDomperidone► CyclizineCyclizine

► These are dopamine receptor antagonistsThese are dopamine receptor antagonists

► These are given at the onset of attack as adjunctive These are given at the onset of attack as adjunctive therapy to reduce gastric symptoms such as nausea and therapy to reduce gastric symptoms such as nausea and vomiting and improve absorption of analgesics and vomiting and improve absorption of analgesics and increase gastric motility.increase gastric motility.

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►Domperidone can not cross blood brain barrier, Domperidone can not cross blood brain barrier, can be given as a suppository.can be given as a suppository.

►Side effects:Side effects: ►Due to dopamine antagonist activity, they may Due to dopamine antagonist activity, they may

cause sedation, diarrhea, and extrapyramidal cause sedation, diarrhea, and extrapyramidal effects.effects.

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Drugs used for prophylaxis of Drugs used for prophylaxis of MigraineMigraine

► Prophylactic treatment is indicated in conditions:Prophylactic treatment is indicated in conditions:

► When there is two or more attacks per monthWhen there is two or more attacks per month

► When acute symptomatic treatment is required for more than 2-3 When acute symptomatic treatment is required for more than 2-3 times/weektimes/week

► Drugs used in acute attack are ineffective, intolerable, or Drugs used in acute attack are ineffective, intolerable, or contraindicated.contraindicated.

► Headache is severe and associated with neurological symptomsHeadache is severe and associated with neurological symptoms

► Drugs used need several weeks for the onset of action.Drugs used need several weeks for the onset of action.

► Treatment continues for six months and can be repeatedTreatment continues for six months and can be repeated

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Drugs used for prophylaxis in migraineDrugs used for prophylaxis in migraine

► MethysergideMethysergide► Cyproheptadine and pizotifenCyproheptadine and pizotifen► ββ-blockers -blockers ► calcium channel blockerscalcium channel blockers► AntidepressantsAntidepressants► OndansetronOndansetron

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METHYSERGIDEMETHYSERGIDE

► 5-HT2 receptor antagonist5-HT2 receptor antagonist

► Anti-inflammatoryAnti-inflammatory

► Administered orallyAdministered orally

► Only used for prophylaxis. Not effective in acute attacks.Only used for prophylaxis. Not effective in acute attacks.

► Should not be used for more than 6 months. If to be repeated, Should not be used for more than 6 months. If to be repeated, there should be a-one-month free period in between.there should be a-one-month free period in between.

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Side effectsSide effects

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

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ContraindicationsContraindications

► Not to be administered concurrently with Not to be administered concurrently with ββ--blockers or Ergot alkaloids.blockers or Ergot alkaloids.

► Valvular diseases (ECG must be monitored Valvular diseases (ECG must be monitored during therapy)during therapy)

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CYPROHEPTADINE AND CYPROHEPTADINE AND PIZOTIFENPIZOTIFEN

► They have: They have:

Antiserotonergic (5-HTAntiserotonergic (5-HT22), ), Antaihistaminic Antaihistaminic (H-1) and (H-1) and Anticholinergic effects.Anticholinergic effects.

Side effects:Side effects:

Vertigo, drowsinessVertigo, drowsiness

Pizotifen increases appetite so there might be an increase Pizotifen increases appetite so there might be an increase in body weight.in body weight.

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ONDANSETRONEONDANSETRONE

► Is the prototypic 5-HTIs the prototypic 5-HT33 antagonist antagonist

► It is effective for treatment of acute attack and It is effective for treatment of acute attack and prophylaxis for its antiemetic effect.prophylaxis for its antiemetic effect.

►Also, is preferably used for nausea and vomiting Also, is preferably used for nausea and vomiting after surgery or with chemotherapeutic agents.after surgery or with chemotherapeutic agents.

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ββ-Blockers-Blockers

► Is commonly used for prophylaxis against migraine attacks. Acts Is commonly used for prophylaxis against migraine attacks. Acts mainly through blocking mainly through blocking ββ-induced vasodilating effect on intra or -induced vasodilating effect on intra or extra cranial blood vessels.extra cranial blood vessels.

Side effects:Side effects:► Fatigue, Drowsiness, Dizziness, DepressionFatigue, Drowsiness, Dizziness, Depression► Impotence Impotence ► BradycardiaBradycardia

Contraindications:Contraindications: ► Old ageOld age► AsthmaAsthma► AV blockAV block► CHFCHF

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ANTIDEPRESSANTSANTIDEPRESSANTS

► Amitriptyline, SSRI (Fluoxetine)Amitriptyline, SSRI (Fluoxetine)

► They prevent the release of plasma peritoneal fluid 5-HT from They prevent the release of plasma peritoneal fluid 5-HT from brain mast cellsbrain mast cells

► Prevent vasoconstriction which triggers 1Prevent vasoconstriction which triggers 1stst phase phase

► like all prophylactic drugs, they have delayed onset of action, like all prophylactic drugs, they have delayed onset of action, about 6-8 weeksabout 6-8 weeks..

Side effects:Side effects:Dry mouth, Blurred vision , ConstipationDry mouth, Blurred vision , Constipation

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Calcium channel blockersCalcium channel blockers

► Verapamil, Nifedipine, Diltiazem, Nimodipine, Verapamil, Nifedipine, Diltiazem, Nimodipine, FlunarizineFlunarizine

► They decrease the severity and frequency of migraine They decrease the severity and frequency of migraine through inhibition of Cathrough inhibition of Ca++++ influx influx

► Side effects:Side effects:► ConstipationConstipation► Ankle edema Ankle edema ► Change in heart rate.Change in heart rate.