Pharm - Migraines

Question 1

Etiology of Migraines

Answer 1

The theory of cortical spreading depression
Correlating to visual field disturbances (scotoma)
Release of pro-inflammatory neuropeptides (CGRP and substance P)
Activation and sensitization of trigeminal afferent from dural vasculature

The Serotonin theory of migraine etiology
Increased urine 5-HIAA levels and decreased plasma [5HT]
Most anti migraine drugs are either 5HT agonist or antagonist
Increased risk of an attack during reserpine or fenfluramine therapy.

Question 2

NSAIDs

Answer 2

Ibuprofen, indomethacin, aspirin, naproxen
Increase pain threshold secondary to decrease prostaglandin synthesis

Side effects: ulcers, GI bleeding, and rebound headaches may occur

Question 3

Triptans

Answer 3

Sumatriptan, zolmitriptan, naratriptan

Mechanism of action: stimulate vasoconstriction in the basilar artery and blood vessels in the dura mater secondary to 5HT1A stimulation
Block the release of pro-inflammatory neurotransmitters (CGRP, substance P) within the perivascular space in the vicinity of the trigeminal nerve

Side effects: serotonin syndrome, contraindicated in patients with coronary artery vasospasm

Question 4

Opioids

Answer 4

Codeine (Moderate opioid agonist)
Mechanism of action:  pain sensation secondary to agonist effects at , , and δ receptors
Metabolized to morphine (a much stronger analgesic)

Clinical applications: used in patients in whom triptans are not tolerated ,mild to moderate paint (codeine), severe pain (morphine)

Side effects: addiction, respirator distress

Question 5

Corticosteroids

Answer 5

dexamethasone

Mechanism of action: indirect inhibition of phospholipase A, anti inflammatory effects.
No Eicosinoids. No sensitization

Adverse effects: increase risk of steroid toxicity, should not be used frequently

Question 6

Xanthine alkaloids

Answer 6

Caffeine
Mechanism of action: Relaxation of (vascular) smooth muscles secondary to increase levels of cAMP
Clinical applications: headaches, may be combined with acetaminophen, aspirin (Excedrin migraine) for management of moderate pain in migraine
Side effects: insomnia, agitation, restlessness, cardiac arrhythmia, palpitation etc.

Question 7

OTC Analgesic

Answer 7

Acetaminophen
Acetaminophen and opioids (codeine) remain the only viable option during pregnancy
Toxicity: Metabolite (NAPQI) may be limiting in certain patients
Overdose is treated with N-acetyl-cysteine

Question 8

B-blockers

Answer 8

Propranolol: non-selective beta blocker, has membrane-stabilizing effects
Proven effective for migraine prophylaxis

Question 9

Ca2+ channel blockers

Answer 9

Verapamil: useful for migraine prophylaxis, relieves symptoms of aura

Question 10

ACE inhibitor

Answer 10

Lisinopril: reduces the duration and severity of migraines

Question 11

Tricyclic Anti Depressants

Answer 11

Amitriptyline, nortriptyline
Mechanism of action: inhibits 5HT & NE reuptake

Adverse effects: 1st AV bundle branch block, anorexia, blurred vision, dry mouth, confusion, constipation, tachycardia and urinary retention

Sedation, weight gain, orthostatic hypotension (more with the elderly), reflex tachycardia, drowsiness and dizziness
May precipitate mania in patients with bipolar affective disorders

Question 12

Adverse effects: 1st AV bundle branch block, anorexia, blurred vision, dry mouth, confusion, constipation, tachycardia and urinary retention

Sedation, weight gain, orthostatic hypotension (more with the elderly), reflex tachycardia, drowsiness and dizziness
May precipitate mania in patients with bipolar affective disorders

Answer 12

Mechanism of action: antagonist @ 5HT1, 5HT2A, and 5HT2C, moderately anti histamine and mildly anti cholinergic
Clinical uses: prophylaxis for recurrent migraine headaches, esp. useful when β-blockers are contraindicated

Side effects: weight gain, anti muscarinic effects, potentiates drowsiness associated with sedatives, tranquilizers, antidepressants

Contraindicated with use of MAO inhibitors

Question 13

Anti Seizures

Answer 13

Topiramate, Lamotrigine (migraine with aura)
Mechanism of action: Inhibits voltage-gated Na+ channels, AMPA/kainate receptors and high voltage Ca2+ channels
enhance GABA transmission
Clinical uses: generalized tonic clonic, and partial seizures, migraine prophylaxis
Adverse effects: P450 inducer (its own metabolism is induced by carbamazepine & phenytoin),
increases intra ocular pressure, poor concentration and memory, ataxia, somnolence and weight loss.

Question 14

Anti Seizures

Answer 14

Valproate
inhibits Na+ channels, T-type Ca2+ channels
Enhance GABA transmission
For generalized and absence seizures, migraine prophylaxis
drowsiness, weight gain, tremor, hair loss, fetal abnormality, liver abnormality, bone marrow depression

Gabapentin
Mechanism of action: structural analog of GABA, inhibits high voltage-activated Ca2+ channels (HVA)
for partial seizures, neuroleptic pain etc.
Adverse effects: dizziness, sedations and peripheral edema (at high doses), may have withdrawal syndrome

Question 15

Botulinum toxin

Answer 15

Type A botulinum toxin
Destroys synaptic SNAP-25→  neurotransmitter release
Approved for treatment of chronic migraine headaches in adults
Injected directly into muscles of the fore head and neck
May cause reversible paralysis

Question 16

Anti Emetic Agents

Answer 16

Chlorpromazine & prochlorperazine
Mechanism of action: anti cholinergic, anti dopaminergic, weak anti adrenergic and anti histaminergic activity

Clinical uses: antiemetic, schizophrenia, tourettes’s syndrome, Huntington’s chorea and dementia

Adverse effects: poikilothermic, blurred vision, constipation, agranulocytosis (rare but serious), phototoxicity (chlorpromazine)

Extra pyramidal effects: 
neuroleptic malignant syndrome, 
tardive dyskinesia, 
amenorrhea, 
galactorrhea, 
falls positive pregnancy in women,
 gynecomastia and decreased libido in men

Weakly diuretic
Amplifies quinidine-mediated cardio toxicity (prochlorperazine only)

Question 17

Metoclopramide

Answer 17

Anti Emetic Agents
Mechanism of action: agonist @ 5HT4, antagonist @ D2 and 5HT3 receptors

Clinical uses: alone or in combination with aspirin for migraines; gastric stasis (following diabetic gastroparesis): GI radiology (increases transit in barium studies): occasionally used to stimulate lactation

Adverse effects: galactorrhea, extrapyramidal effects, tardive dyskinesia
Contraindication: pheochromocytoma, Parkinson’s disease

Question 18

Preventive Medications

Answer 18

• B-blockers: Propranolol
• Ca2+ channel blockers: Verapamil
• ACE inhibitor: Lisinopril
• Tricyclic Anti Depressants: Amitriptyline, nortriptyline
• Pizotifen
• Anti Seizures: Topiramate, Valproate and Gabapentin
• Botulinum toxin

Question 19

Anti Emetic Agents

Answer 19

Metoclopramide, Chlorpromazine and prochlorperazine