LECTURE 3 - Pharmacology of drugs for nausea and vomiting

Vomiting center

reticular formation in the lateral medulla

types of 5-HT3R antagonists

ondansetron (Zofran)*

granisetron

palonosetron

dolasetron

D2R antagonists

prochlorperazine (Compazine)*

promethazine (Phenergan)*

chlorpromazine, olanzapine (Zyprexa)*,

droperidol,

haloperidol

trimethobenzamide

D2/5-HT3R antagonists

metoclopramide (Reglan)

Antihistamines (H1R antagonists)

dimenhydrinate (Dramamine)*

diphenhydramine (Benadryl)*

meclizine

what medication is an Antimuscarinic (mAchR antagonists) ?

scopolamine

NK1R antagonists

aprepitant, fosaprepitant (Emend)*, netupitant, rolapitant

Cannabinoids (CB1&2R agonists)

dronabinol, nabilone

Corticosteroids

dexamethasone (Decadron)*

5-HT3R antagonists uses

Uncomplicated N/V (not useful for motion sickness)

Prevention of postoperative N/V

CINV

5-HT3R antagonist

MOA

Block 5-HT3R in the vomiting center

Block peripheral 5-HT3R on afferent spinal nerves that project to Nucleus of Tractus Solitarius → main antiemetic effect

Monotherapy 5-HT3R antagonists

effective in preventing acute, not delayed phase of N/V

To augment efficacy for 5-HT3 antagonists together with

Corticosteroids for acute CINV

NK1R antagonist for delayed CINV

how many receptors does 5-HT bind to?

14

13 out of 14 5-HT are ____

G-protein coupled receptors

Ligand-gated ion channel

5-HT3 receptor

1st generation 5-HT3R antagonists

Ondansetron (Zofran) T1/2 ~ 4 hrs

Granisetron (Kitryl) T1/2 ~ 6 hrs

Dolasetron (Anzemet) T1/2 ~ 9 hrs

Palonosetron (Aloxil)

T1/2 ~ 40 hrs

highest affinity → sticks to the receptor longer

5-HT3R antagonists (“-setrons”)

SE

CNS

GI (diarrhea/constipation)

rash

muscle spasm

why avoid dolasetron?

Avoid dolasetron in patients with QT prolongation

Other setrons can also cause a small QT prolongation at high doses

Phenothiazines’ receptors

D2R, M1R, H1R, α1R antagonists

D2R antagonists

Uses

CINV

Motion sickness

Pre / post-surgery to prevent opioid-induced N/V

Vertigo

D2R antagonists

SE

Sedation/drowsiness

dizziness/fainting

dry mouth

QT prolongation

EPS

what does Butyrophenones do ?

antiemetic (D2R)

sedative (H1R) effects

Types of butyrophenones

Haloperidol (Haldol)

Droperidol (Inapsine)

Haloperidol (Haldol)

1st generation antipsychotic

Droperidol / Haloperidol

SE

sedation

EPS, QT prolongation

Examples of Thienobenzodiazepines

Olanzapine (Zyprexa)

Olanzapine (Zyprexa)

2nd generation antipsychotic with D2R antagonism

Thienobenzodiazepines - OLANZOPINE

SE

EPS

H/A

wt gain

Substituted benzamides

Metoclopramide (Reglan)

Trimethobenzamide (Tigan)

Trimethobenzamide (Tigan)

Very potent

blocks emetic impulses to the vomiting center

D2R antagonist

weak H1R effects

Substituted benzamides

SE

EPS

CNS

Antihistamines

used in prevention of motion sickness

Antihistamines

MOA

inhibit histaminergic signals from the vestibular center to the vomiting center

Dimenhydrinate (Dramamine) duration of action

4 -6 hrs

what can Dimenhydrinate (Dramamine) be combined with to reduce drowsiness?

Chlorotheophylline

Antihistamines

SE

anti-SLUDGE

Neurokinin receptor antagonists (NK1RAs)

MOA

prevent substance P from binding NK1R in the brain

types of Antihistamines meds

• Diphenhydramine (Benadryl®, ZzzQuil®)

• Dimenhydrinate (Dramamine® Original)

• Meclizine (Bonine®, Dramamine® Less Drowsy)

• Hydroxyzine (Atarax®)

NK1RAs Uses

prevention of acute / delayed CINV

what is NK1RAs used in combination with?

5-HT3R antagonists and corticosteroids

how is Aprepitant (Emend) taken?

PO

how is Fosaprepitant taken?

IV prodrug metabolized to aprepitant in 30 min

what can Netupitant be used in combination with

palonosetron (Akynzeo)

Rolapitant (Varubi)

long-acting; combo with ‘setron and dexamethasone

BETTER COMBO THAN TAKEN ALONE

Muscarinic receptor antagonist

Scopolamine

what is Scopolamine efficacy similar to?

dimenhydrinate

Scopolamine

use

motion sickness

sedating due to anticholinergic properties IV/PO; transdermal patch is tolerated better)

Cannabinoid receptor agonists

Dronabinol (Marinol; CIII)

Nabilone (Cesamet; CII)

Cannabinoid receptor agonists

uses

prevention / treatment of CINV

used with phenothiazine