Serotonin & Migraine Flashcards
- Synthetic precursor of serotonin
Tryptophan (hence, 5-HT, or 5-hydroxytryptamine)
Sites of synthesis & storage of Serotonin
Synthesized from tryptophan in enterochromaffin cells (aka Kulchitsky cells in the epithelia of gut and lungs)
- taken up, stored in and released from platelets
- Degraded by MAO
Serotonin pathophysiology in PNS
Hemostasis: promotes platelet aggregation & vasoconstriction; excess can cause vasospasm
GI:
- promotes GI motility
- Malignant Carcinoid tumors: usually arise from enterochromaffin cells, and they secrete excess 5-HT –> cause diarrhea, cramps, vasospasms (treat with 5-HT receptor antagonist)
- Emesis/Nausea with chemotherapy; treated with 5-HT3 receptor antagonists (receptors on sensory nerves & brainstem)
Migraine: considered PNS b/c of vascular component (“vascular headache”)
- initial increase in 5-HT due to platelet release; subsequent decrease from platelet depletion
- 5-HT can directly stimulate pain afferents
- 5-HT constricts cerebral vessels
Serotonin pathophysiology in CNS
- depression: SSRIs, TCAs, MAOIs
- Mania
- anxiety: buspirone, SSRIs
- appetite: sibutramine, SSRIs
- sleep: Melatonin
- chronic pain: TCAs, anticonvulsants
- Schizophrenia: Clozapine
Symptoms of Classic Migraine
- 20% of total incidence
preceded by aura (neurological symptom):
- photophobia
- vertigo
- transient aphasia
- pallor
- thick speech
- chills
- tremor
- unilateral numbness/weakness
Symptoms of Common Migraine
- 80%
- without aura
- symptoms are more than just pain: nausea and vomiting are the most common
Migraines generally:
- Women > men
- associated with Ca-channelopathies
- onset usually in adolescence
- onset with waking is common
- duration is 4-72 hours
- often associated with wide variety of triggers
Migraine Triggers
Mech: activate trigeminal neurons, ultimately resulting in vascular changes (extravasation, vasodilation)
Mental
- stress
- emotionally upset
Endogenous:
- hormonal changes
- fasting
- sleep disturbances/fatigue
Exogenous:
- Alcohol
- smoke
- allergens
- nitrates
- oral contraceptives
- glutamate
- tyramine
Other:
- weather
- bright light
- odors
Drug Classes for Prophylactic Therapy for Migraines
- Propranolol
- Valproic Acid/Valproate
Other:
- TCAs (dirty): Amitriptyline, Nortriptyline
- Calcium channel blockers: Verapamil
- NSAIDS: naproxen
- ACE Inhibitors/ARBs: Lisinopril, Candesartan
Indications:
- frequent occurrences (3-5 per month)
- works best with “classic” type, predictable, mild/moderate
- Need > 6 weeks for efficacy
- drug holiday indicated after 6 months
- Beta blocker (most commonly used, best established class)
- Mechanism: unknown; possibly due to 5-HT1a receptor blockade (ANTAGONIST)
- Many side effects (usually not limiting): Fatigue, exercise intolerance, GI disturbance, depression, insomnia, nightmares
- Contraindications: asthma, depression, heart failure
- Don’t take with Ca-channel blockers
- abrupt withdrawal can cause CV distress
Propranolol
- Anticonvulsant (modest efficacy)
- Mech: blocks Na channels and 5-HT release (ANTAGONIST)
- Numerous side effects: Nausea, WEIGHT GAIN, fatigue, tremor, hair loss
- Contraindicated in pregnancy: inhibits maternal folate absorption, increasing risk for NTDs
With respect to Absence Seizures:
Mech:
- blocks tetanic firing through increasing Na+ channel inactivation
- reduces transmitter release
- Reduces T-type Ca2+ channel (excitatory channel) activity, which is associated with absence seizures
- increases GABA levels by inhibiting breakdown
Use: Used against ABSENCE SEIZURES
Pharmacokinetics:
- Well absorbed, 90% protein bound – half life 9 – 18 hr
Toxicity:
- Nausea, vomiting, other GI distress
- HEPATOTOXICITY CAN BE SEVERE
Valproic Acid/Valproate
Acute Pharmacological Tx for Mild/Moderate Migraines
- Metoclopramide
- Caffeine
Other:
- NSAIDS: naproxen (analgesic, anti-inflammatory)
- Opioid analgesics: treat pain; short acting; potential for dependence and abuse
- Phenothiazines: excellent anti-emetics
- Combo drugs: vasoconstrictor + analgesic + sedative
Mech:
- ANTAGONIST at 5-HT3 and D2 receptors
- anti-emetic: by enhancing gastric emptying (which is often slower during a migraine)
- commonly used as adjuvant (esp. with ergotamine)
Metoclopramide
Mech:
- cerebral vasoconstriction is beneficial
- aids in absorption: can potentiate analgesics
- commonly used as adjuvant
Caffeine
Treatment of Moderate/Severe Migraines
- Ergots
- Triptans
Mech:
- cerebral vasoconstrictors
- NON-SELECTIVE 5-HT AGONISTS* at trigeminal nerves
Response rates vary:
- routes of admin: oral is least effective/most erratic
- must be taken EARLY IN ATTACK
Often used in combination with caffeine & sedatives (barbiturates)
Side effects: can be limiting
- common: nausea, vomiting, cramps, vertigo (mitigate with metoclopramide)
- less common: ischemia, cold extremities, gangrene; diarrhea
- dependence may occur if used > 3 weeks
- contraindication: pregnancy, sepsis, vascular disease
Drug interactions:
- triptans
- beta-blockers*
- nicotine
Ergotamine
