phrm 3070 - serotonin agents

when was serotonin first identified?

1940s

serotonin is associated with what conditions

anxiety, depression, schizophrenia, drug abuse, sleep, dreaming, hallucinations, cardiovascular disorders, and appetite control

outside of the cell, serotonin is in it’s precursor form, which is

tryptophan

serotonin is also known as

5-hydroxytryptamine (5-HT)

the two major drug types of serotonin agents are

antiemetics, antimigraine

anti-emetic serotonin agents belong to these four pharmacological categories

5-HT3 antagonists, neurokinin antagonists, mixed receptor antagonists, and cannabinoid antagonists

anti-migranous serotonin agents are what pharmacological type

triptans (5-HT1 B/D agonists)

palonosetron is what kind of serotonin agent

antiemetic; 5-HT3 antagonist

aprepitant is what kind of serotonin agent

antiemetic; neurokinin antagonist

nabilone is what kind of serotonin agent

antiemetic; cannabinoid agonist

zolmitriptan is what kind of serotonin agent

anti-migranous; 5-HT1 B/D agonist

cocaine is what kind of serotonin agent

antiemetic; weak, nonselective 5-HT3 antagonist

bemesetron is what kind of serotonin agent

antiemetic; selective 5-HT3 antagonist

dolasetron is what kind of serotonin agent

antiemetic; selective 5-HT3 antagonist *widely used as an anti-emetic

granisetron is what kind of serotonin agent

antiemetic; selective 5-HT3 antagonist *widely used as an anti-emetic

ondansetron is what kind of serotonin agent

antiemetic; selective 5-HT3 antagonist *widely used as an anti-emetic

when is ondansetron used mostly

following chemotherapy as an antiemetic

what is the half life of ondansetron?

3-4 hours

what are the major adverse effects of ondansetron?

dizziness, headache, constipation

what metabolizes ondansetron?

CYP3A4 and 2D6

how does ondansetron work?

reduces activity of the vagus nerve, deactivating vomiting center in medulla

what is the brand name of dolasetron

anzemet

dolasetron is rapidly converted into what

hydrodolasetron

hydrodolasetron has what percent bioavailability

80

what is the half life of dolasetron?

4-9 hours

what is the brand name of granisetron

kytril

what is the half life of granisetron?

6 hours, but activity can last up to 24 hours per dose

what is sustol?

the extended release injectable of granisetron

sustol covers chemotherapy induced nausea for how long

up to 5 days

what is the bioavailability of granisetron?

60%

what increases the absorption of ondansetron?

food

what metabolizes granisetron?

CYP3A4

what are the major side effects of granisetron?

headache, constipation

what is the brand name of palonosetron

aloxi

what is the half life of palonosetron

128 hours

what drug is first in class for acute chemotherapy induced nausea

palonosetron

palonosetron is administered (before/after) chemotherapy

before

how long before chemotherapy should palonosetron be administered if given orally

1 hour

how long before chemotherapy should palonosetron be administered if given IV

30 minutes

what metabolizes palonosetron?

CYP2D6, CYP3A4, CYP1A2

what are the major 5-HT3 antagonists?

cocaine, MDL 72222, isasetron, zatosetron, dolasetron, indolyl propanone, ondansetron, palonosetron, tropisetron, granisetron

what are the major structural features shared between 5-HT3 antagonists?

1. basic amine or imidazole (terminal nitrogen, whether attached to methyl groups or in a ring/boat)

2. rigid aromatic or heteroaromatic ring (side opposite of amine, there will be a ring or a double ring with a nitrogen involved)

3. carbonyl group (may be an ester, may be a ketone, may be an amide)

what kind of receptor is neurokinin-1 (NK1)

g-protein coupled receptor

describe the endogenous ligand typically associated with NK1

substance P; 11 amino acid neuropeptide

what was the problem with the 1980s peptide NK1 antagonists

metabolically unstable, poor bioavailability

what is the molecular progression that led to the creation of aprepitant?

CP-96345 —> L 709210 —> L 733060 —> L742694 —> Aprepritant

what additions to L 742694 created aprepritant

1. a methyl to the carbon connected to the phenyl group with two CF3 subs

2. a fluorine atom attached to the other phenyl group

what did the methyl and fluorine additions cause in aprepitant that did not occur with L 742694

the prevention of oxidative metabolism

what is the brand name of aprepitant

emend

what is the bioavailability of aprepitant?

60-65%

what metabolizes aprepitant?

CYP3A4; also partly CYP1A2 and CYP2C19

what is the brand name for metoclopramide

reglan

what was the best initial treatment for CINV

metoclopramide and dexamethasone combination

what kind of agent is metoclopramide

antidopaminergic

what kind of agent is dexamethasone

anti-inflammatory steroid

what dopamine receptor does metoclopramide target

D2

metoclopramide, along with it’s antidopaminergic activity, is also a weak ______

antagonist of 5-HT3 receptors

metoclopramide is recommended for (short term/long term) use

short term

what are the common adverse effects of metoclopramide?

restlessness, drowsiness, dizziness, hypertension, hypotension, extrapyramidal effects (involuntary motor side effects)

cannabinoids are the _______ components in cannabis

psychoactive

______ is the principle psychoactive component of cannibis

THC

what does THC stand for

tetrahydrocannabinol

how do cannabinoid agonists work (think receptor binding)

bind to cannabinoid receptors CB1 and CB2 as agonists, which inhibits neurotransmission and thus demonstrating antiemetic effect (among other effects)

cannabinoid compounds must be highly (lipophilic/hydrophilic) and why?

lipophilic, so they can cross the BBB

what kind of receptors are CB1 and CB2, and where are they located

g-protein coupled receptors; present in high amounts in the brain and other body regions

what are the three major antiemetic cannabinoid agonists?

Dronabinol, Nabilone, Cannabidiol

what two cannabinoid agonists are naturally occuring

tetrahydrocannabinol (THC- but also dronabinol, pharmaceutically) and cannabidiol (CBD)

which cannabinoid agonist is synthetic and produced in the 1970s

nabilone

which sex has a higher prevalence of migraines?

women

what does a classical migraine look like?

migraine with aura (series of sensory changes that may be a sign of a migraine attack- like flashing lights, tingling, numbness)

what does a common migraine look like?

migraine without aura

what does an episodic migraine look like?

14 or fewer headache days per month, at least 5 of which are migraine days

what does a chronic migraine look like?

15 or more headache days per month, at least 8 of which are migraine days

what is a migraine

intense pulsating and throbbing headache lasting from 4 hours to 3 days- may include nausea, vomiting, sensitivity to light, sound, and movement

when were tryptamine based drugs introduced?

1990s

when are tryptamine based drugs effective?

early stages of a migraine attack

what do tryptamine based drugs do at 5-HT1B receptors?

reduce pain by causing cranial blood vessels to constrict

what do tryptamine based drugs do at 5-HT1D receptors?

block the release of neuropeptides that trigger inflammation

what is the first triptan introduced?

sumatriptan

what is the brand name of sumatriptan?

imitrex

what are the two most effective forms of sumatriptan

subcutaneous injection and nasal spray

sumatriptan reduces migraine pain and severity by reducing what?

vascular inflammation of cranial arteries and veins

what is the half life of sumatriptan?

2.5 hours

what metabolizes triptan drugs?

initially metabolized by CYP, then by monoamine oxidase (MAO-A)

what structural change differentiates sumatriptan from tryptamine?

1. the addition of two methyls on the terminal nitrogen

2. the addition of a sulfonamide onto the phenyl (SOO-NH-CH2)

what drug has the lowest oral bioavailability of all triptans

sumatriptan

what dosage forms is sumatriptan available in?

tablets, nasal solution, nasal powder, injection

what is the time of onset for a subq or nasal admin of sumatriptan?

10-15mins

what are the short term adverse effects of a subq sumatriptan injection?

dizziness, sensory disturbances, chest and throat tightness, shortness of breath

what is the structural difference between sumatriptan and zolmitriptan?

instead of the sulfonamide group, zolmitriptan has a amide group in a 5 member ring

what is zolmitriptan metabolized to?

desmethylzolmitriptan

what metabolizes zolmitriptan

CYP1A2

desmethylzolmitriptan is _____fold (more/less) potent than zolmitriptan

2-6, more

how soon is zolmitriptan’s metabolite detectable in the body after administration?

5 min

what metabolizes desmethylzolmitriptan and what does that cause

MAO-A, inactivation of the drug’s action

how much of zolmitriptan’s plasma drug concentration is it’s metabolite?

2/3

what is the brand name for zolmitriptan?

zomig

what is the brand name for naratriptan?

amerge

what is the third approved triptan drug?

naratriptan