Serotonin and Migraines

Examples of anti-migraine agents

Triptans 5-HT1b/d agonists

examples of anti-emetic agents

5-HT3 antagonists

Neurokinin Antagonist

Mixed Receptor Antagonists

Cannabinoids

Physiological cause of migraines

May be due to local crainial vasodilation and release of pro-inflammatory peptides from sensory nerve endings

5HT1B

Cranial blood vessels

5HT1B/D

Trigeminal pain pathway

Triptans MOA

vessel constriction

inhibit release of proinflammatory neuropeptides

Reduced transmission in trigeminal pain pathway

Order of first 3 triptan discovery

Sumatriptan

Zolmitriptan

Naratriptan

Sumatriptan

First triptan

Reduces vascular inflammation

• Metabolized by MAO-A!

Lowest oral bioavailability

Zolmitriptan

metabolized by 1a2

more potent metabolite than sumatriptan n

naratriptan

one of the most lipophilic

Favorable CNS side effect profile due to its metabolic stability

Lacks active metabolite

*remember when nara made her own sunscreen

Rizatriptan

fast acting

MAO-A (similar to Sumatriptan) ; partially by CYP2D6

Propanolol considerations!

What drug has considerations for dosing when taken with propanolol

Rizatriptan

What drug has the highest oral bioavailability amongst all the triptan

Almotriptan

almotriptan

highest oral bioavailability

Metabolized by MAO-A and CYP3A4

More favorable side effect profile

Frovatriptan

3-alkylamino side chain!

NOT a substrate for MAO-A or CYP3A4

Longest duration

Most water soluble; metabolite is eliminated in the feces

eletriptan

highest affinity for 5-HT 1b/d

metabolized via CYP3A4

Substrate for P-gp efflux pumps

general considerations with anti-migraine agents

Do not give to pts with angina, Mi, or silent ischemia due to vasoconstrictive properties

In pts taking MAOIs, other 5HT1 agonists

Preventative medication examples

Cardiovascular drugs, antidepressants, anti-seizure drugs, cyproheptadine, botox injections

Which of the following is primarily metabolized by CYP 1A2:

A. Rizatriptan (Maxalt)

B. Almotriptan (Axert)

C. Sumatriptan (Imitrex)

D. Zolmatriptan (Zomig)

Zolmitriptan

Which of the following is primarily metabolized by MAO-A?

A. Rizatriptan (Maxalt)

B. Almotriptan (Axert)

C. Sumatriptan (Imitrex)

D. Zolmatriptan (Zomig)

Sumatriptan and almotriptan and rizatriptan

Lasmiditan

5-HT1F receptor; does not cause vessel constriction

Anti-CGRP inhibitors

Aimovig

Ajovy

Emgality

Aimovig

binds to CGRP receptor

ajovy

binds to cgrp

emgality

binds CGRP, used for cluster headaches

small molecule anti-cgrp

Ubrelvy

Nurtec ODT

Qulipta

ubrelvy

binds to receptor; 3A4 metabolism

Substrate for P-gp and BCRP

nurtec oft

binds to receptor; 3A4 and 2C9;

Substrate for P-gp and BCRP

quliota

Binds to receptor

3A4, substrate for P-gp and BCRP

3 phases of vomiting

Nausea

Retching

Expulsion

Mechanism of emesis

§ Afferent inputs relay emetic signal to CNS

§ Signal is received and processed, forming efferent signals from CNS

§ Motor and chemical efferent pathways relay signals that cause physical actions of emesis

two medullary centers in brain for emesis

Chemoreceptor trigger zone

Central emesis center

5-HT3 antagonists

-trons

ondansetron

reduces activity of vagus nerve and blocks serotonin

receptors in CTZ; metabolized mostly by 3A4, partly by 2D6

dolsaetron

converted to hydrodolasetron; metabolite active with high

bioavailability and half-life

emesis following chemo

granisetron

food increases absorption; metabolized by 3A4

alosetron

used to treat diarrhea predominant IBS only in women; ADR

NOT for nausea

Palonosetron

used for CINV that appears less than 24 hr after chemo;

administered before chemo; long half-life (40 h); metabolized mostly by 2D6, also by

3A4 and 1A2

neurokinin antagonist

aprepitant

• blocks neurokinin NK receptor in CNS and peripheral nervous

  system

• metabolized mostly by 3A4, also 1A2 and 2C19

mixed receptor antagonist

metoclopramide

Antagonist to dopamine D2 receptor and 5-HT3 receptor; agonist to 5-HT-4 receptors; antiemetic activity due to D2 inhibition in CTZ;

increases transit in stomach, small intestine; adverse effects (drug-induced movement disorder)

cannabinoid agonist

Dronabinol

Nabilone

Dronabinol

Isomer of D9 THC; used for CINV, anorexia in AIDS

patients and possibly Tourette’s; peak effect=2-4h; psychoactive=4-6h; side effects;

highly insoluble; 20% bioavailability due to 1st pass effect; active metabolite; long

terminal half-life (up to 36 h)

Nabilone

Synthetic analog of D9 THC; used for CINV in patients that

fail conventional therapy; racemic mixture; extensively metabolized; moderately inhibits 2C8 and 2C9, weakly inhibits 3A4 and 2E1; multiple adverse effects

Alosetron is used for women having diarrhea-predominant IBS

Palonosetron

Metoclopramide