pda 4.1: serotonin receptors and migraine

what is serotonin derived from?

tryptophan

what are the effects of serotonin in the periphery?

- induced blood platelets aggregation

- stimulates GI smooth muscle movement

- stimulates pain and itch sensory nerve endings

- induce contraction of vascular smooth muscle, except in skeletal muscle and the heart

what can serotonin be converted into?

melatonin (N-acetyl-5-methoxytryptamine)

where are cell bodies serotonin neurons found in the brain?

midbrain raphe nucleus

what is serotonin important for in the CNS?

- sleep/arousal

- mood, emotion

- appetite

- body temperature

what are the serotonin drugs are used to treat migraines?

- sumatriptan and related triptans

- lasmiditan

what are the signaling effects of serotonin drugs that treat migraine?

Gi/o and dec cAMP

what site do serotonin drugs that treat migraine act on?

the 5HT 1B/1D receptors on the nerve terminals in the brain

how do the serotonin drugs that treat migraines work?

they are agonists at the 5HT 1B/1D receptors and inhibit the synthesis and release of serotonin

migraine

recurrent headache (usually unilateral, pulsatile) often associated with nausea and sensitivity to light or sound

what is the ratio of migraines affecting men vs women?

15% of women

5% of men

when do migraines start and when do they peak?

start in teens, peak in 35-39 years

what are the duration of migraines?

4-72 hours (typically all day)

what are the potential triggers of migraines?

- stress, emotional upset

- hormonal changes

- sleep disturbances

- foods

- alcohol, smoke, allergens

- weather

- bright lights

- odors

- temperature changes

what are the two versions of migraines?

- common (w/o aura)

- classic (aura)

what are symptoms of migraines?

- confusion

- irritability

- phonophobia (sound sensitivity)

- photophobia (light sensitivity)

- vomiting, nausea

- speaks soft

- severe throbbing headache (unilateral at first, may spread to the opposite side)

what causes migraine aura?

cortical spreading depression (CSD)

what is CSD?

neuronal and glial activation followed by the depression of neuronal firing

what is CSD associated with?

commensurate changes in blood flow

what is migraine pain caused by?

activation of trigeminal system

what are trigeminovascular system modulated by?

input from dorsal raphe and locus coeruleus

what does activation of cells in the trigeminal nucleus result in?

release of vasoactive neuropeptides, particularly calcitonin gene-related peptide (likely accounts for throbbing pain)

what are the drugs for acute treatment of mild to moderate migraine?

- naproxen/APAP

- caffeine

- metoclopramide

what are the effects of naproxen and acetaminophen?

analgesic and anti inflammatory affect

what are naproxen and APAP used to prevent?

avoid rebound headaches

what are the benefits of caffeine in migraines?

- cerebral vasoconstriction

- potentiate analgesics

- adjuvant with other anti migraine drugs

what are the effects of metoclopramide?

adjunctive therapy that is an antagonist at the D2 receptors in the CNS and periphery

what is metoclopramide used for in migraines?

used as antiemetic and enhances gastric emptying due to effects of vomiting center and GI tract

what are the drugs used for the acute treatment of severe migraines?

- triptans

- ergots

- lasmiditan

- CGRP receptor blocker

what drug that is used to treat severe migraines is controlled?

lasmiditan (has euphoric effects)

egots

non selective 5HT recpetor agonists

what are examples of ergots?

- ergotamine

- dihydroergotamine (DHE)

lasmiditan

5HT 1F receptor agonist indicated for acute treatment of migraine with or without aura (not prevention)

what are the CGRP receptor blockers?

- ubrogepant

- rimegepant

how do CGRP receptor blockers work?

COME BACK

what is the first line of treatment for migraines?

triptans

what are the routes of triptans?

- PO

- IM

- subq

- sublingual

- nasal

what is the onset of action of triptans?

- 5 mins with injection

- 10-15 mins with nasal/sublingual

- 20-40 mins with oral

which form of triptans have the fastest acting response rate?

injectable sumatriptan

what triptan dosage form is effective in children?

sprays

what is the best form of combo therapy that is more effective than either drug alone?

sumatriptan + naproxen

what are the adverse effects of triptans?

minimal adverse effects but major issue is coronary artery vasoconstriction

who should avoid use of triptans?

patients with coronary artery disease

what could use of triptans induce?

serotonin syndrome

what puts a patient at the greatest risk for developing serotonin syndrome when using triptan drugs?

- MAOIs

- SSRIs/SNRIs

- herbal supplements (st. john's wort)

- other agents that increase serotonin neurotransmission

what are the symptoms of serotonin syndrome?

- agitation, hallucination coma

- autonomic instability (tachycardia, labile blood pressure, hyperthermia)

- nausea, vomiting, diarrhea

- muscle hyperreflexia, incoordination

what are side effects of lasmiditan?

- dizziness, fatigue

- paresthesia (skin tingling, itching, burning)

- sedation

- driving impairment

- serotonin syndrome

- euphoria and hallucination (1% of patients)

what is the mechanism of ergots for treating migraine?

- cerebral vasoconstrictors

- non-selective 5HT receptor agonist working at trigeminal nerves

what is the new formulation of ergots?

a nasal spray formulation of DHE

what are the side effects of ergots?

- nausea

- dizziness

- cramps

- vertigo

- prolonged vasospasm causing angina, gangrene

when can ergotamine dependence be seen in patients?

use >3/week

what are the contraindications for ergot usage?

- pregnancy

- sepsis

- vascular diseases

what are the drug interactions with ergots?

- triptans

- beta blockers

- nicotine

ergotism (st. anthtony's fire)

when grains are contaminated with ergot fungus and experience hallucination, vasospasm, and stimulation of uterine smooth muscle

what is the main reason ergots are contraindicated in pregnancy?

ergots induce smooth muscle contraction in the uterus and could induce abortion

what are the CGRP's used for acute treatment of migraines?

- ubrogepant

- rimegepant

- zavegepant

what are the CGRP's used to prevent migraines?

- atogepant

- erenumab

- galcanezumab

- fremanezumab

- eptinezumab

prophylactic migraine therapy

preventative migraine therapy

what does prophylactic migraine therapy work best with?

mild to moderate especially when predictable in classic migraine

what is the MOA of prophylactic migraine therapy?

elevate CSD threshold and suppress CSD

what are the primary prophylactic migraine therapies?

- beta blockers

- anticonvulsants

what are examples of beta blockers used to prevent migraines?

- propranolol

- timolol

what are examples of anticonvulsants used to prevent migraine?

- valproate

- topiramate

what are other preventative migraine therapies that is not a beta blocker or anticonvulsant?

- monoclonal antibodies targeting CGRP

- atogepant (CGRP receptor antagonist)

- antidepressant

- onabotulinumtoxinA (botox)

summary of acute treatment of migraine

know her well

summary of preventative treatment of migraine

know her well too