serotonin agents

serotonin general characteristics

first identified in the 40s, found to be associated with a variety of issues

includes anti-migraine agents, antiemetics,

migraines general characteristics

affects 12% of worldwide populations with a higher prevalence in women

intense pulsing and throbbing headache lasting 4hrs to 3 days

n/v, sensitivity to light, sound, movement

common migraine lacks aura while classical migraine has aura

triggers: fluctuations in estrogen, meds, foods, stress, etc.

triptans general characteristics

first introduced in the 90s

used for typical migraines only

5HT1B and D agonists (cranial blood vessels and trigeminal pain pathway)

MOA: causes vasoconstriction on the receptors of dilated cranial blood vessels and reduces transmission in trigeminal pain pathway

sumatriptan/imitrex ADME

can be used SC or nasal spray with a 10-15min onset

• max dose: SC 12mg/24hrs, oral 200mg/24hrs, nasal 40mg/24hrs

lowest bioavailability of all the triptans - low lipophilicity

½ life 2.5hrs, metabolized by MAO-A

metabolite glucoronidated, undergoes renal excretion

sumatriptan/imitrex general characteristics and structure

the first triptan

can’t be given iwht MAO-A inhibitors

available in several dosage forms - used for acute treatment

Onzetra/Xsail - nasal powder with 11mg dose, 3hr ½ life, low bioavailability

has the sulfur with 2 oxygens and the secondary amine hanging off the benzene ring

zolmitriptan/zomig ADME

rapidly absorbed orally and nasally

½ life 3-4hrs

bioavailability 40-50%

metabolized by 1A2 to a more potent metabolite that accounts for 2/3 of plasma concentration

metabolite degraded by MAO-A

renal excretion

zolmitriptan/zomig general characteristics and structure

second triptan

available as tablet and ODT (2.5 and 5mg) or nasal spray (5mg)

has a 5 membered ring with an amide and an ester on it

naratriptan/amerge ADME

bioavailability 63-74%

high receptor affinity

half life 5-6hrs

metabolically stable - metabolized by multiple CYP450s to inactive metabolite

70% renally excreted unchanged

naratriptan/amerge general characteristics and structure

third triptan

highly lipophilic

looks similar to sumatriptan, but has a 6 membered nitrogen ring hanging off of the main 5 membered ring

rizatriptan/maxalt ADME

slightly faster onset than sumatriptan and available as ODT

½ life 2-3hrs

metabolized to active metabolite by MAO-A and 2D6

renal excretion

rizatriptan/maxalt general characteristics and structure

moderate lipophilicity

available in tablets and ODT (5 and 10mg)

dosing: 5-10mg, repeat after 2hr, max 30mg/24hrs

but if on propranolol max dose is 5mg or 15mg/24hrs

structure has a 5 membered ring with 3 nitrogens hanging off of the main benzene ring

almotriptan/axert ADME

metabolized by MAO-A and 3A4

½ life 3-4hrs

40% excreted renally unchanged

almotriptan/axert general characteristics and structure

highest oral bioavailability of all triptans - 70-80%

tablet doses 6.25 and 12.5mg

favorable ADR profile

frovatriptan/frova general characteristics and structure

contains 3-alkylamino side chain

longest DOA (1/2 life 26hrs)

60% bioavailable

2.5mg tabs, repeat after 2hrs, max 7.5mg/24hrs

frovatriptan/frova ADME

onset of action 2-3hrs, higher water solublility than other triptans

highest affinity for 5HT1b receptors

metabolized to active metabolite by 1A2, where it is eliminated in feces

eletriptan/relpax ADME

50% bioavailability

½ life 3.6-5.5hrs

metabolized by 3A4 to active metabolite

also a substrate for P-gp efflux pumps

eletriptan/relpax general characteristics and structure

highest affinity for 5HT1B and D

well tolerated across 20-80mg dosing range, max 80/day

structure is the bulkiest one

general contraindications for anti-migraine agents

not given to pts with angina, PMH of MI, or silent ischemia due to vasoconstrictive properties

not used with other 5HT1 agonists

not used with MAOIs

not used in hemiplegic or basilar migraines

warnings: risk of cerebrovascular event and MIs

general anti-migraine ADRs

n/v, dizziness, drowsiness, dry mouth, pain or tightness in throat, chest, neck, abnormal sensations, muscle weakness

preventative medications to use with antimigraine agents

CV drugs: beta blockers, Ca channel blockers, antihypertensives

antidepressants: TCAs

AEDs: gabapentin, topiramate, valproate

cyproheptadine (antihistamine)

botox injections in forehead and neck

lasmiditan/reyvow general characteristics and structure

high affinity for 5HT1F (located on nerves, not blood vessels → no vasocons

ADR: dizziness, sleepiness, can cross BBB

CGRP (calcitonin gene-related peptide) disruption in migraines

pro-inflammatory peptide that binds to CGRP receptor and causes vasodilation and inflammation

aimovig, ajovy, emgality, nurtec, and ubrelvy all act on this mechanism

ADRs: hypersensitivity, immunogenicity

aimovig/erenumab

binds CGRP receptor and blocks ligand binding

½ life of 28 days = once monthly injection

ajovy/fremanezumab

binds CGRP and prevents CGRP receptor activation

½ life 31 days = once monthly 225mg or quarterly 675mg injection

emgality/galcanezumab

binds CGRP and prevents CGRP receptor activation

also approved for cluster headaches

½ life 25-30 days = monthly injections

ubrely/ubrogepant

binds CGRP receptor and blocks ligand binding

small molecule, taken orally

½ life 5-7hrs

metabolized by 3A4

substrate of P-gp and BCRP efflux transporters

nurtec ODT/rimegepant

binds CGRP receptor and blocks ligand binding

small molecule, taken orally

½ life 8-12hrs

metabolized by 3A4 and partly by 2C9

substrate of P-gp and BCRP efflux transporters

3 phases of 5HT3 activation

nausea: sensation of wanting to vomit, cold sweat, pallor, salivation, reflux of intestinal contents into stomach

retching: coordinated contraction of abdominal muscles, diaphragm, intercostals

expulsion: strong pressure in stomach due to shifts in diaphragm and abdominal muscles, triggers upper esophageal sphincter to relax to allow for expulsion of gastric contents

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 action of emesis

medullary centers: CTZ and central emesis center

ondanestron/zofran ADME

½ life 3-4hrs

metabolized by 3A4 and 2D6

ondanestron/zofran general characteristics and structure

used mostly as an antiemetic following chemo

reduces activity of vagus nerve, deactivating vomiting center in medulla

blocks 5HT receptors in CTZ

ADRs: dizziness, headache, constipation

dolasteron/anzemet ADME

metabolite has 80% bioavailability and 4-9hr ½ life

60% of metabolite excreted unchanged

dolasteron/anzemet general characteristics and structure

used to treat emesis following chemo

ADRs: headache, dizziness, constipation

granisetron/kytril ADME

½ life 6hrs, but activity can last up to 24hrs

60% bioavailability, food increases absorption

metabolized by 3A4

excreted in urine and feces

granisetron/kytril general characteristics and structure

used to treat emesis after chemo

sustol: extended released injectible form that covers acute and delayed CINV for up to 5 days

ADR: headache, constipation

alosetron/lotronex general characteristics and structure

similar structure to zofran

5HT3 antagonist, but not used for nausea - used to treat IBS-D in women only

ADRs: ischemic colitis, constipation

palonosteron/aloxi ADME

½ life 30-40hrs

metabolized by 2D6, 3A4, 1A2

palonosetron/aloxi general characteristics and structure

used for treatment of CINV in the first 24hrs after chemo - first in class for acute CINV

administered 30min before chemo via IV or 60min before via oral capsule

aprepitant/emend ADME

bioavailability 60-65%

metabolized by 3A4, 1A2, and 2C19

aprepitant/emend general characteristics and structure

used for CINV and post-op nausea

blocks the NK receptor in the CNS and PNS, with little-no affinity for other receptors

metoclopramide/reglan general characteristics and structure

D2 antagonist, 5HT3 antagonist, and 5HT4 agonist

enhances GI transit in stomach/small intestine

used to treat persistent heartburn and poor gastric emptying

ADR: restlessness, drowsiness, dizziness, changes in BP, extrapyramidal effects, most common cause of drug-induced movement disorders

dronabinol/marinol ADME

onset after 1hr

peak effect after 2-4hrs

psychoactive effects last 4-6hrs

highly insoluble in water, 95% absorbed but 20% bioavailability

highly protein bound

metabolized by hydroxylation to 11-OH

excreted in urine and feces

dronabinol/marinol general characteristics and structure

pure isomer of delta 9 THC

used for anorexia in AIDS pts and CINV, may also be useful for pts with Tourette’s

ADR: seizures, paranoia, fast heart rate, light-headedness, cannabinoid effect

syndros: dronabinol oral solution that was FDA approved in 2016

nabilone/cesamet ADME

well absorbed and distributed

extensively metabolized with some active and some inactive metabolites

moderate inhibitor of 2C8 and 2C9

weak inhibitor of 2E1 and 3A4

nabilone/cesamet general characteristics and structure

synthetic analog of delta 9 THC

used as an antiemetic for CINV and analgesic

used for those who don’t respond to conventional therapy

racemic mix of isomers

ADR: hallucinations, paranoia, elevated heart rate, lightheadedness, dizziness, vertigo, dry mouth, euphoria, ataxia headache, poor concentration