Antiemetics: Classification and Examples

Definition of  Emesis and Antiemetics

Emesis encompasses the forceful expulsion of the contents of stomach through the mouth or sometimes the nose. It is clearly associated with gastrointestinal motor activity. The act of emesis is controlled by the vomiting centre in the medulla which receives input from the vestibular system, the chemoreceptor trigger zone (CTZ), the cortex and the gut.
Antiemetics: These are drugs that antagonize the action of emetics or prevent emesis (Vomiting).

Causes of Emesis

Nausea  and vomiting may be manifestations of many conditions and may occur due to stimulation of vomiting center that respond to inputs from:

• Chemoreceptor trigger zone (CTZ) stimulation
• Disturbance of vestibular system
• Higher cortical centers stimulation (CNS)
• The periphery (Pharynx, GIT) via sensory nerves

Classification of antiemetic drugs

1. Serotonin 5-HT3 antagonists
2. D2 receptor antagonists
3. NK1 antagonists
4. H1-receptor antagonists
5. Muscarinic receptor antagonists
6. Cannabinoids
7. Glucocorticoids

1. Serotonin 5-HT3 antagonists

Examples of 5-HT3 antagonists include Ondansetron, Granisetron

Mechanism of Action

They block 5-HT3 receptor in vomiting center, CTZ and 5HT3 receptors on intestinal vagal afferents.

Pharmacokinetics of Ondansetron

 

• Ondansetron is completely and rapidly absorbed when orally administered
• Bioavailability is only approximately 60%
• It has a plasma proteins binding of (70 to 76%) with a terminal elimination half-life of 2.5 to 5.4 hours.
• It is metabolized in the liver and excreted in urine

Dose

4 mg IV, slowly over 2 minutes (Adult)
Paediatric: 0.1 mg/kg IV, slowly over 2 minutes. 

Adverse effects of ondansetron

• Headache
• Dizziness
• Diarrhoea
• Transient visual disturbances.

Precautions

• Not recommended in pregnancy

Uses 

• It is used in chemotherapy-induced nausea and vomiting especially.
• It also used in post-radiation Nausea and vomiting
• It equally used in post-operative nausea and vomiting

2. D2 receptor antagonists

Dopamine 2 receptor antagonists block D2 dopamine receptors in the chemoreceptor trigger zone. Drugs in this class is divided into prokinetics and Neuroleptics drugs.
Prokinetics drugs
Prokinetic drugs differ from the neuroleptics due to their agonist effects on  5 HT4 receptor. Examples of the Prokinetics drugs include:

• Metoclopramide
• Domperidone

Both metoclopramide and domperidone are prokinetic agents due to their 5 HT4 agonistic activity. They are used in GERD (gastroesophageal reflux disease), gastroparesis. and in antiemetics due to blocking D2 receptors.
Dose of metoclopramide (Adult) 

• Postoperative nausea and vomiting: 10 to 20 mg at the of surgery
• Chemotherapy-induced vomiting: Initial dose: 1 to 2 mg/kg/dose 15-30 min before chemotherapy
• Gastroesophageal Reflux Disease: dose: 10 to 15 mg orally up to 4 times a day 30 minutes before meals and at bedtime

Side effects of metoclopramide
Side effects of metoclopramide include the following:

• Dyskinesia
• Galactorrhea
• menstrual disorders
• impotence
• Sedation
• postural hypotension.

Neuroleptics (Antipsychotics)
Drugs under this subclass of antiemetic drugs include the following:

• Chlorpromazine (CPZ) and
• Droperidol

Chlorpromazine is widely distributed to the body tissues, crosses BBB and highly protein-bound (90 – 99%). It is metabolised in the liver and excreted in urine.
Dose of chlorpromazine

• Oral adult dose:10 – 25 mg every 4 – 6 hours.
• 1-12 Years: 0.5 mg/kg every 4 – 6 hours.

Side effects
The side effects of chlorpromazine include the following

• extrapyramidal symptoms
• sedation
• postural hypotension

Uses

1. Postoperative vomiting
2. Chemotherapy-induced nausea & vomiting.

3. Neurokinin1 (NK1) receptor antagonists

Eg. Aprepitant

• Is a substance P antagonists that acts by blocking neurokinin 1 receptors.
• It is given orally
• Used in prevention of acute and delayed chemotherapy-induced nausea and vomiting and for prevention of postoperative nausea and vomiting.
• Usually combined with 5-HT3 antagonists and corticosteroids.

4. H1-receptor antagonists

• Eg: Diphenhydramine, meclizine , cyclizine, Promethazine.
• They act on vomiting centre rather than on CTZ
• Most drugs in this class have sedative and antihistaminic effects.

Promethazine
Pharmacokinetics

• Oral dose is well absorbed from the GIT.
• It has a half-life of 9-16 hours (IV), a VD of 171L and a protein binding of 93%.
• It is metabolized in the liver to a variety of compounds and excreted in the urine.

Adverse effects

• Erythema, sedation, hypotension, dry mouth, constipation, urinary retention

Dose
Adult dose : 12.5mg – 25mg IM or IV no more than every 4 hours.

• Children 5 to 10 years 6.25-12.5 IM
• Less than 2 years safety has not been established

Contraindications

• Pediatric patients less than 2 years of age due to the potential for fatal respiratory depression
• Patients suffering from CNS depression or coma
• Avoid in patients taking monoamine oxidase inhibitors.

5. Muscarinic receptor antagonists

• Eg: Hyoscine (scopolamine)
• Orally, injection, patches
• Used as transdermal patches in motion sickness (applied behind the external ear).
• Not in chemotherapy-induced vomiting

Side effects

• tachycardia
• blurred vision
• dry mouth
• constipation
• urinary retention (atropine-like actions).

6. Cannabinoids

• Eg. Nabilone, dronabinol
• Mechanism of action not understood.
• Act at central cannabinoid receptors.
• Used in vomiting due to cytotoxic anticancer drugs (adjuvant therapy).
• Cannabinoids are not commonly used.

Side effects

• Euphoria
• dysphoria
• sedation
• hallucination.