AntiEmetics

Question 1

How many classes of antiemetics

Answer 1

7

Question 2

Name the classes

Answer 2

Anticholinergics
H1 antihistamines
D2 blockers/neuroleptics
Prokinetic drugs
5-HT3 antagonist
NK1 receptor antagonist
Adjuvant antiemetics

Question 3

Examples

Answer 3

Anticholinergic- Hyoscine

D2 blockers- chlorpromazine, triflupromazine

H1 antihistamines- Promethazine, diphenhydramine

NK1 antagonist: aprepitant

5-HT3 antagonist: Ondansetron, Ramosetron

Prokinetic: metaclopramide, Domperidon, cisapride, mosapride

Adjuvant: Dexamethasone, Benzodiazepines

Question 4

Actions of metoclopramide

Answer 4

It is a substituted benzamide called gastric hurrying agent. It acts on:-
1. GIT: effect on upper GIT, increases gastric peristalsis by relaxing pylorus and first part of duodenum which speeds up gastric emptying. LES tone is increased and Gastroesophageal reflux is opposed.

2.CNS: acts on CTZ and blocks vomiting

Question 5

MOA of metoclopramide

Answer 5

Two mechanisms

1. Dopaminergic/ D2 antagonism
   Dopamine is an inhibitory neurotransmitter, it delay gastric emptying, causes LES relaxation. Metoclopramide blocks D2 receptors, hence hastens gastric emptying, enhance LES tone.
   Central antidopaminergic action on CTZ responsible for antiemetic property
2. Serotonergic/ 5-HT4 agonism
3. 5-HT3 antagonism

It acts on GIT to enhance aCH release from myentric motor neurons. This results in 5HT4 receptor activation of ENS which activates excitatory interneurons.

Question 6

Pharmacokinetics of metoclopramide

Answer 6

Rapidly absorbed orally
Enters brain
Crossed placenta

Rate of absorption of some drugs:- Aspirin, Diazepam. Lorezapam altered due to gastric emptying

Question 7

ADR of Metoclopramide

Answer 7

Well tolerated generally
Sedation, dizziness, loose stools, muscle dystonia

Long term side effects include parkinsonism, galactorrhea, gynaecomastia

Question 8

Uses of metoclopramide

Answer 8

1. Anti emetic
2. Gastrokinetic
3. Dyspepsia
4. GERD

Question 9

Cisapride

Answer 9

Benzamide derivative
Lacks D2 antagonism
Effects on gastric motility same as metoclopramide: Emptying hastened, LES tone increased
Facilitates mobility throughout GIT including colon (no colon for metoclopramide/domperidone)
Action through 5-HT4 agonism and weak 5-HT3 antagonism

5-HT4 agonism also promotes cl- secretion into colon which together with increased motility causes loose stools

Question 10

Safety of cisapride

Answer 10

Serious ventricular arrhythmia and death among patients who took CYP3A4 inhibitors like anti fungals, macrolide. Antidepressants

At high concentrations, cisapride blocks rectifying K+ channels in heart and causes torsades de pointes/ ventricular fibrillation

Hence suspended from market

Question 11

Ondansetron uses

Answer 11

Chemotherapy/radiotherapy induced vomiting
PONV
Disease/Drug associated vomiting

Question 12

MOA Ondansetron

Answer 12

Blocks the depolarizing action of 5-HT exerted through 5-HT3 receptors on vagal afferents in git as well as NTS and CTZ

Cytotoxic drugs/radiation produce nausea and vomiting by causing cellular damage which releases mediators including 5-HT from intestinal mucosa —> activation of vagal afferents in gut resulting in transmission of emetogenic impulses to the NTS and CTZ.

No action on D2 hence no use in motion sickness and apomorphine induced CTZ

Question 13

Aprepitant

Answer 13

It is a NK1 receptor antagonist. NK is neurokinin receptor in the CTZ and NTS which is activated by substance P. No effect on 5-HT or D2. Hence no effect on motility

Oral Aprepitant with standard iv ondansetron + dexamethasone = 90% efficacy

Useful in patients ongoing multiple cycles of chemotherapy.