Antiemetics, Neuroleptics, Prokinetics used in emesis, MCQS for GPAT, NEET PG,NIPER, Drug inspector and pharmacist exam.

Antiemetics: Antiemetics are a heterogeneous group of drugs used to treat various causes of nausea and vomiting. Different antiemetics act on different receptors, and they may have a peripheral effect, a central effect, or both.

Antiemetic drugs can help when nausea and vomiting stem from, for example:

• motion sickness
• viral or bacterial infections, such as those responsible for the stomach flu
• pregnancy
• the effects of surgery
• other medications, such as chemotherapy

Classification of antiemetics:

A. Anticholinergics.

1. Hyoscine
2. Dicyclomine

a. Hyoscine: It is the most effective drug for motion sickness. Its antiemetic action is exerted by blocking conduction of nerve impulses across a cholinergic link in the pathway leading from the vestibular apparatus to the vomiting centre. Producing mild side effects.

b. Dicyclomine: Dicyclomine is an anticholinergic that acts as an antispasmodic agent. It blocks a natural chemical in your body called acetylcholine from acting on your stomach and intestines. By blocking this chemical, the medication slows down the natural movement of the gut and relaxes the muscles in the stomach and intestines.

B. Antihistaminics: Some of antihistaminics act as antiemetics, useful in motion sickness and lesser extent in morning sickness.

1. Promethazine
2. Diphenhydramine
3. Dimenhydrinate
4. Doxylamine
5. Meclozine(Meclizine)

a. Promethazine, Diphenhydramine, Dimenhydrinate: These drugs are used in motion sickness. for 4-6hrs, but produce sedation and dryness mouth. Driving is not advisable after taking these medications. They act through central cholinergic action by blocking the extrapyramidal side effects of metoclopramide. Combination of these antihistaminics with other anti emetics has been used in chemotherapy-induced nausea and vomiting (CINV).

b. Doxylamine: It is a sedative H1 antihistaminics. Doxylamine reduces nausea and vomiting by inhibiting histaminergic signaling to the vomiting center in the medulla. Oral absorption is slow and its t1/2 is of 10hrs.

Side effects: Dry mouth, drowsiness, abdominal upset and vertigo.

c. Meclozine: It is less sedative, less anticholinergic and has longer action. Protects from sea sickness for nearly 24hrs.

d. Cinnarizine: It is an antivertigo drug. having antimotion sickness property. It acts by inhibiting influx of ca++ from endolymph into vestibular sensory cells which mediates labyrinthine reflexes.

B. Neuroleptics: The older neuroleptics are potent antiemetics and sedative . They act by blocking D2 receptors in the CTZ. Antagonize apomorphine induced vomiting. They have broad spectrum antiemetic action effective in:

1. Disease induced vomiting: gastroenteritis, uraemia, liver disease, migraine etc.
2. Drug induced and post operative nausea and vomiting (PONV).
3. Malignancy associated and cancer chemotherapy (mildly emetogenic) induced vomiting.
4. Radiation sickness vomiting (less effective).
5. Morning sickness: should not be used except in hyperemesis gravidarum.

1. Chlorpromazine

2. Triflupromazine

3. Prochlorperazine

Prochlorperazine: It mainly works by depressing the chemoreceptor trigger zone and blocking D2 dopamine receptors in the brain. It was shown to also block histaminergic, cholinergic and noradrenergic receptors.

Uses: It is highly effective in when given i,v in vertigo associated vomiting and to some extent in chemotherapy induced nausea and vomiting (CINV).

Side effects: Muscle dystonia, extrapyramidal side effect are more prominent, Dystonic reactions are most common in children especially after i,m injection.

C. Prokinetic drugs: These drugs promote g.i.t transit and speed gastric emptying by enhancing coordinated propulsive motility.

1. Metoclopramide
2. Domperidone
3. Cisapride
4. Mosapride
5. Itopride
6. Levosulpiride
7. Cinitapride

a. Metoclopramide: D2 antagonism : Dopamine is inhibitory  transmitter in the g.i.t.  Metoclopramide increases gastric emptying by decreasing lower esophageal sphincter (LES) pressure. It also exerts effects on the area postrema of the brain, preventing and relieving the symptoms of nausea and vomiting. It blocks D2 receptor and has opposite effect -hastening the gastric emptying and enhancing the LES tone by augmenting ACh release. The central antidopaminergic action of this drug is clearly responsible for its antiemetic property.

5-HT4 agonism: It acts in g.i.t to enhance ACh release from myenteric motor neurons. This results from 5-HT4 receptor activation on primary afferent neurons (PAN) of the ENS, which in turn activates the excitatory neurons. The gastric emptying and LES tonic effects of metoclopramide are mainly due to this action.

Pharmacokinetics: Metoclopramide is rapidly absorbed in the gastrointestinal tract. It enters brain, crosses placenta and is secreted in milk.. It is partly conjugated in liver and excreted in urine within 24 hrs. T1/2 is of 3-6hrs. Acting for 4-6hrs.

Interactions: Absorption of aspirin, diazepam, digoxin may be altered by the gastric hurrying action of metoclopramide.

Side effects: It is generally well tolerated, sedation, dizziness, loose motion, muscle dystonias (in children). Long term use can cause parkinsonism, gynaecomastia and galactorrhoea.

Uses: Antiemetic, Gastrokinetic, Dyspepsia, GERD

b. Domperidone: The DA2-receptor antagonist domperidone antagonizes the inhibitory effect of dopamine, resulting in stimulation of gastric muscle contraction. This provides a mechanism for the gastrokinetic effect of domperidone. the antiemetic action mainly exerted through CTZ which is not protected by blood-brain barrier. Because of poor entry in CNS, it does not block the effect of levodopa in parkinson, but counteracts its dose-limiting emetic action.

Pharmacokinetic: It is absorbed orally but bioavailability is only 15% due to its first pass metabolism. Its metabolites excreted in urine. Plasma t1/2 is of 7.5hrs.

Side effects: Loose stools, dry mouth, headache, rashes and galactorrhoea.

Uses: Postoperative, drug and disease induced nausea and vomiting.

c. Cisapride:  Cisapride is a gastroprokinetic agent, a drug that increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT₄ receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous system.

d. Mosapride: It has similar gastrokinetic and LES tonic action due to 5-HT4 antagonistic action in myenteric plexus.

Side effects: Abdominal pain, loose motions, dizziness, headache and insomnia.

e. Cinitapride: It acts by inhibiting 5-HT2 and dopamine D2 receptors as well as stimulating 5-HT4 receptors in the myenteric plexus.

Uses: It is used in g.i disorders, like non-ulcer dyspepsia, delayed gastric emptying and GERD.

f. Itopride: Itopride increases acetylcholine concentrations by inhibiting dopamine D2 receptors and acetylcholinesterase. Higher acetylcholine increases GI peristalsis, increases the lower esophageal sphincter pressure, stimulates gastric motility, accelerates gastric emptying, and improves gastro-duodenal coordination.

Pharmacokinetics: It is metabolised by flavin monooxygenase and not by CYP450 isoenzymes.

Side effects: abdominal pain, diarrhoea, headache, galactorrhoea and gynaecomastia

Uses: effective in relieving symptoms of dyspepsia.

D. 5-HT3  antagonists: 

1. Ondansetrone
2. Granisetron
3. Palonosetron
4. Ramosetron

a. Ondansetron: It is prototype antiemetic drug used to control cancer chemotherapy/ radiotherapy induced vomiting and highly effective in PONV and disease/drug associated vomiting as well. It acts by blocking the depolarizing action of 5-HT exerted through 5-HT3 receptors on vagal afferents in the g.i.t as well as NTS and CTZ. It blocks the emetogenic impulses mainly at their peripheral origin in g.i.t and at their central relay.

Pharmacokinetics: Oral bioavailability of ondansetron is 60-70% due to its first pass metabolism. It is hydroxylated by CYP1A2, CYP2D6 and CYP3A, followed by glucuronide and sulfate conjugation. It is excreted in urine and faeces, mostly as metabolites. T1/2 is of 3-5hrs. Duration of action is of 8-12hrs.

Side effects: It is well tolerated. Some side effects are headache and dizziness.

b. Palonosetron: It is the longest 5-Ht3 blocker having the highest affinity for 5-HT3 receptors.

Pharmacokinetics: It is metabolised in liver as well in kidney mainly by CYP2D6.

Side effects: Headache, dizziness, fatigue, abdominal pain.

E. NK1 receptor antagonist: 

1. Aprepitant
2. Fosaprepitant

a. Aprepitant: It has high affinity NK1 receptor antagonist that blocks the emetic action of substance P, with little effect on 5-HT3 and D2 or other receptors.

F. Adjuvant antiemetics: 

1. Dexamethasone
2. Benzodiazepines
3. Dronabinol

a. Dexamethasone: It enhance efficacy against both acute and delay emesis.

b. Benzodiazepines: The weak antiemetic property of BZDs is primarily based on the sedative action. Diazepam given before chemotherapy as adjuvant to metaclopramide or ondansetron help by relieving the psychogenic component , anticipatory vomiting and produce amnesia for the unpleasant procedure.

c. Dronabinol: It can be used as an alternative antiemetic for moderately emetogenic chemotherapy in patients who can not tolerate other antiemetics.

MCQs:

1.  Drugs used to treat various causes of nausea and vomiting.

a. Antidiarrhoeal

b. Antiemetics

c. Antimanic

d. None

2. Which is not anticholinergic?

a. Hyoscine

b. Dicyclomine

c. Domperidone

d. None

3.  Which are the examples of antihistaminics used as antiemetics?

a. Promethazine

b. Diphenhydramine

c. Dimenhydrinate

d. All of above

4. Muscle dystonia is a side effect of which drug?

a. Metoclopramide

b. Domperidone

c. Prochlorperazine

d. Cisapride

5. Drugs promote g.i.t transit and speed gastric emptying by enhancing coordinated propulsive motility.

a. Prokinetic drugs

b. Antihistaminics

c. Anticholinergics

d. Corticosteroids

6. What are the side effects of Metoclopramide?

a. Muscle dystonia

b. Dizziness

c. Loose motion

d. All of above

7. Which antiemetic drug possess first pass metabolism?

a. Ondansetrone

b. Granisetron

c. Palonosetron

d. Ramosetron

8. Which one is NK1 receptor antagonist?

a. Aprepitant

b. Fosaprepitant

c. a$b

d. None

9. Example of Neuroleptics?

a. Domperidone

b. Metoclopramide

c. Cisapride

d. Chlorpromazine

10. Which drugs antagonize apomorphine induce vomiting?

a. Neuroleptics

b. Prokinetics

c. Anticholinergics

d. Antihistaminics

11. which drug is 5-HT3 antagonists?

a. Domperidone

b. Metoclopramide

c. Cisapride

d. Ondansetron

12. What are the uses of domperidone?

a. Postoperative, drug and disease induced nausea and vomiting.

b. Constipation

c. Diarrhoea

d. None

13. Which drug possess D2 antagonism and 5-HT4 agonism?

a. Metoclopramide

b. Ondansetron

c. Domperidone

d. Cisapride

14. What are the uses of Ondanserton?

a. chemotherapy/ radiotherapy induced vomiting

b. Post operative induced vomiting

c. Drug and disease induced vomiting

d. All of above

15. What are the side effects of Domperidone?

a. Galactorrhoea

b. Dry mouth

c. Headache

d. All of above

Answers:

1. b
2. c
3. d
4. c
5. a
6. d
7. a
8. c
9. d
10. a
11. d
12. a
13. a
14. d
15. d

References: 

1. ” K.D.Tripathi”, Antiemetics, page no 710-719, 8th edition, june 2018.
2. “Alan Carter”, Healthline, Sep 2018.

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