Nausea & Vomiting MedChem

Define emesis

Processing of vomiting

What are the three phases of emesis?

Nausea, retching, vomiting

Define nausea

Imminent need/inclination to vomit

Define retching

Labored movement of abdominal and thoracic muscles prior to vomiting

Define vomiting

Forceful ejection of gastric contents caused by reverse peristalsis

What can cause nausea and vomiting?

GI, CV, infectious agents, neurologic, metabolic disease processes

Pregnancy

Chemotherapy/radiation induced nausea and vomiting (CINV/RINV)

Postoperative nausea and vomiting (PONV)

Stimulation of which sensory centers can stimulate the vomiting center?

Chemoreceptor trigger zone (CTZ), vestibular system, cerebral cortex, GI tract, heart

Describe the role of the vomiting center (VC)

Afferent impulses, leads to efferent impulses to salivation and respiratory centers, pharyngeal, GI, and abdominal muscles

What stimulates the CTZ?

Circulating toxins, chemotherapeutic agents, emetics, and uremia, hypoxia

Describe the CTZ

Major chemosensory region for emesis, usually associated with CINV

Where is the CTZ located?

Outside BBB = easily accessible to stimuli

Samples both CSF and blood (periphery)

What receptors are present in the CTZ?

Chemoreceptors, 5-HT3, dopamine D2, mu opioid receptors, M1 mAChR, NK1 (substance P), CB1

What stimulates the vestibular system?

Motion

Where is the vestibular system located?

Inner ear, provides positional information to CNS

Describe histamine H1R in the vestibular system

Neuron activated if mismatch between visual and vestibular systems

Describe M1 mAChR in the vestibular system

Transmits signal to VC

What can trigger nausea/vomiting through the CNS?

ANXIETY

Emotion, stress, headaches, psychiatric disorders, anticipatory nausea vomiting (ANV)

What receptors are located in the GI tracts and stimulate vagal and spinal afferent inputs to the VC and CTZ?

Serotonin receptors (5-HT3R), chemoreceptors, mechanoreceptors

What visceral signals can trigger nausea/vomiting?

Angina, chemotherapy, radiation, distention, infectious gastroenteritis

Where are 5-HT receptors located?

Present in the gut, VC, CTZ, and CNS

How is serotonin released?

Chemotherapy agents, noxious agents, and distention stimulate enterochromaffin cells in the gut lumen to release 5-HT

What does serotonin do following its release?

Binds/activates 5-HT3 receptors along the vagal afferent

Stimulates VC to trigger nausea and vomiting

What cells are responsible for the synthesis and release of 5-HT?

Enterochromaffin cells

Describe excitatory signals sent to the myentric plexus

Excitatory motor neurons release ACh and trigger contraction of smooth muscle cells

Describe inhibitory signals sent to the myenteric plexus

Inhibitory motor neurons release nitric oxide and ATP and trigger relaxation of smooth muscle cells

What drug classes are used for treatment of nausea and vomiting?

Serotonin (5-HT3R) antagonists

Antihistamines (H1R antagonists)

Antimuscarinics (M1 mAChR)

Dopamine (D2) antagonists

Neurokinin 1 Antagonists

Cannabinoids (Agonists)

Benzodiazepines

Corticosteroids

What drugs are serotonin (5-HT3R) antagonists?

Ondansetron, alosetron, dolasetron, granisetron, palonosetron

What drugs are antihistamines (H1R antagonists)?

Diphenhydramine, dimenhydrinate, meclizine, cyclizine, hydroxyzine

What drug is an antimuscarinic (M1 mAChR)?

Scopolamine

What drugs are dopamine (D2) antagonists?

Chlorpromazine, prochlorperazine, promethazine, droperidol, haloperidol, domeperidone, metoclopramide, trimethobenzamide

What drugs are neurokinin 1 antagonists?

Aprepitant, netupitant, fosaprepitant, rolapitant

What drugs are cannabinoids (agonists)?

Dronabinol, nabilone

What drugs are benzodiazepines?

Alprazolam, lorazepam, midazolam

What drugs are corticosteroids?

Dexamethasone, methylprednisone, prednisone

What is the MOA of 5-HT3R antagonists?

Blocks peripheral 5HT3R on sensory vagal fibers (nerves) along the walls of the GI tract

Block central 5HT3R in the VC and CTZ = decreased serotonergic inputs from GI tract to VC and CTZ

May also inhibit mAChR (minor)

Describe the biosynthesis of 5-HT

Tryptophan is transformed to serotonin

Know serotonin structure

What do all 5-HT3R antagonists contain and what is its function?

An indole (or indole analog) that mimics 5-HT

Describe the metabolism of 5-HT3R antagonists

ALL ARE CYP3A4 SUBSTRATES

O, D = CYP2D6 substrates

P = CYP2D6 and CYP1A2 substrates

Describe the elimination of ondansetron

P-gp substrate

Which 5HT3R antagonist is an active drug with an active metabolite?

Dolasetron

Parent is still active, but not as active as the metabolite (hydrodolasetron)

What are adverse effects of 5HT3R antagonists?

Half-life of ondansetron increases in hepatic impairment

Decreased elimination in renal/hepatic impairment

O, D, P = risk of dose-related QTc prolongation

What is the MOA of antihistamines (H1R antagonists)?

Inverse agonist of H1 receptors in VC and vestibular system

Used for treatment of vertigo or motion sickness

Define inverse agonist

Drug that binds H1 receptor, but induces opposite pharmacological response as the agonist

What do H1RAs contain?

Ethanolamine or piperazine

Mimics ethylamine of histamine

Describe the metabolism of H1RAs

ALL are CYP2D6 substrates

Diphenhydramine and dimenhydrinate = CYP2D6 inhibitors

What are adverse effects of H1RAs?

Anticholinergic effects = CNS depressant, sedation, dry mouth, blurry vision, tachycardia

Which H1RA displays the least anticholinergic properties?

Meclizine

What is the MOA of antimuscarinics (muscarinic antagonists)?

Inhibition of M1 muscarinic acetylcholine receptors (mAChR) in the VC, CTZ, and vestibular system

Treatment of vertigo or motion sickness

What do antimuscarinics contain?

Tropane core, acylated alcohol, and tertiary amine

Mimics ACh, the endogenous ligand of mAChRs

Describe the metabolism of scopolamine

CYP3A4 aryl hydroxylation

Phase II glucuronidation/sulfation

What are adverse effects of scopolamine?

Anticholinergic effects = CNS depressant, sedation, dry mouth, blurry vision, tachycardia

Constipation, urinary retention, glaucoma, (pre)eclampsia

Skin burns in MRI from transdermal patch

What is the MOA of dopamine antagonists?

Inhibition of dopamine D2 receptors to the CTZ reduces N/V

Also effects mood/mental state in CNS = impacts anxiety, emotion-related N/V

What are ADEs of dopamine antagonists?

Haloperidol and droperidol can cause long QTc (Torsades de Pointe)

What is the MOA of neurokinin 1/substance P antagonists?

CNS inhibition of NK1 receptors in CTZ and VC

More selective than other anti-emetic receptor blockers

Define substance P

Neuromodulary peptide associated with pain, neuronal inflammation, neurodegeneration, infection

High affinity for NK1R

Which NK1/substance P antagonists are IV formulations?

Fosaprepitant and aprepitant

Co-dosed with emetogenic chemotherapy

What do all NK1RAs contain?

A benzene ring with 2F3Cs attached to the left side of the ring

Which NK1RA is a prodrug?

Fosaprepitant

Describe the metabolism of NK1RAs

ALL are CYP3A4 substrates

A, F = CYP3A4 inhibitor, CYP2C9 inducer

R = CYP2D6 inhibitor

Describe the elimination of rolapitant

P-gp inhibitor

ABCB1 inhibitor

Describe the activation of fosaprepirant

Prodrug that is dephosphorylated to aprepitant

Describe the activity of rolapitant

Is hydroxylated to form a long-acting active metabolite

Both parent drug and active metabolite are active = NOT considered a prodrug

Active metabolite has long half-life = for delayed N/V

What is the MOA of cannabinoids?

Non-selective cannabinoid receptor (CB1) agonists in CNS and PNS/periphery

Describe the effect of cannabinoids in the CNS

CB1R agonism in VC and CTZ (anti-emetic effect)

Describe the effect of cannabinoids in the PNS/periphery

CB1R agonism = decrease in GI motility

How does CB1R activation decrease N/V?

Either inhibits 5-HT release or inhibits 5-HT3R

What are adverse effects of cannabinoids?

GI = N/V, pain

CNS = mood (euphoria), sensory (increased perception to stimuli), somatic (floating), cognitive (memory, concentration)

Cardio = tachycardia, hypotension, flushing

Describe the metabolism of dronabinol

CYP3A4 and CYP2C9 substrate = hydroxylation