EMESIS AND ANTIEMETICS

PCL 304
 Emesis
• Emesis is a physical event that results in the forceful
evacuation of gastric contents through the mouth.

• Emesis can be a valuable (indeed life-saving) physiological

response to the ingestion of a toxic substance (e.g. alcohol),
but it is also an unwanted side-effect of many clinically used
drugs, notably in patients receiving cancer chemotherapy.

• Emesis also occurs in early pregnancy, in the form of

motion sickness and accompanies numerous disease states
(e.g. migraine) and also bacterial and viral infections.
 Pathophysiology of Emesis
• The central neural regulation of vomiting is vested in two
separate units in the medulla. These are the vomiting
centre and the chemoreceptor trigger zone (CTZ).

• Both are near the floor of the fourth ventricle, close to

the vital centres

• Vomiting centre is within the blood brain barrier (BBB)

• CTZ outside in the area postrema

 Pathophysiology of Emesis
Emesis occours when the vomiting centre is stimulated, the
vomiting reflex occours, which is divided into three phases:
1. Pre-ejection phase: which is characterized by a sensation of
nausea with gatric relaxation and retroperistalsis

2. Retching phase: which is characterized by a labored

movement of abdominal and respiratory muscles before
vomiting

3. Ejection Phase: which is characterized by an intense

contraction of abdominal muscles and relaxation of upper
esophageal sphincter resulting in expulsion of gastric contents
 Pathophysiology of Emesis…
• The CTZ is sensitive to chemical stimuli and is the main site of action of
many emetic and antiemetic drugs.

• The blood-brain barrier is relatively permeable in the neighborhood of the

CTZ, allowing circulating mediators to act on it directly. The CTZ is also
concerned in the mediation of motion sickness, a condition caused by
stimulation of the vestibular apparatus triggered by certain types of
movement.

• The main neurotransmitters considered to be involved in the control of

vomiting are acetylcholine, histamine, 5-HT and dopamine. It has been
hypothesized that enkephalins are also implicated in the mediation of
vomiting.
• Drugs blocking these receptors are potential targets
 Classification Antiemetic drugs
1. H1 receptor antagonist (e.g Meclizine, Cinnazarine and
Diphenhydramine, Doxylamine)
2. Muscarinic Antagonist (e.g Hyoscine, Dicyclomine)
3. Selective 5-HT3 Antagonists (e.g Ondasetron, Granisetron, Palonosetron
4. D2 Antagonists
a. Subtituted Benzamides (e.g metoclopramide, Trimethobenzamide
b. Butyrophenones (e.g Domperidone, Droperidol
c. Phenothiazines (e.g prochlorpromazine promethazine
5. Cannabinoids (e.g Dronabinol, Nabilone)
6. Glucorticoids (e.g Dexamethasone, methylprednisolone)
7. Benzodiazepines (e.g Diazepam, Lorazepam)
8. Neurokinin-1 Antagonist (e.g Aprepitant (oral formulation) Fosaprepitant)
 H1 receptor antagonist
• MOA: Acts directly on medullary chemoreceptor trigger zone and
vomiting centre by blocking histamine receptors and have sedative action

• Indications
• Motion sickness
• Morning sickness
• Postoperative vomiting
• Vomiting induced by radiation and cytotoxic drugs

• Adverse Effects: Dry mouth, Blurred vision, Dizziness and drowsiness

• Contraindications: Respiratory depression, Coma

 Muscarinic Antagonist
• MOA: Hyoscine blocks the action of acetylcholine on
muscarinic receptors in CNS and inhibits conduction of
impulse across vestibular apparatus to the vomiting center.

• Indications
• Motion sickness
• Morning sickness

• It is often administered as a transdermal patch.

• Adverse Effects : Sedation and Dry mouth
 Selective 5-HT3 Antagonists
• MOA: Ondansetron is a Selective 5-HT3-receptor antagonists. It
blocks the depolarizing action of 5HT3 (Serotonin) through 5HT3
receptor on vagal afferents in the GIT and in the brain.

• Indications
• 1st choice in chemotheraphy induced nausea and vomiting
• Radiation induced vomiting
• Postoperative nausea and vomiting
• Adverse effects: headache, abdominal discomfort, allergic
reactions, constipation or diarrhea and rashes

• They are given orally

 D2 Antagonists

• MOA: It blocks D2 receptor in the CTZ, increases tone of

lower esophageal sphincter, enhances contractions of
gastric antrum and releases pyloric sphincter.

• Indications
• Nausea and vomiting associated with gastrointestinal
disorders
• Chemotherapy induced vomiting

• Adverse Effects: loose stools, headache, gynecomastia,

galactorrhea, rashes, dry mouth.
 Metoclopramide
• MOA: Acts centrally by blocking D2 receptors in CTZ and peripherally by
enhancing the action of acetylcholine at muscarinic nerve endings in the gut.
It raises tone of lower esophageal sphincter, relaxes pyloric antrum and
duodenal cap, and increases peristalsis and emptying of the upper gut.
• D2 antagonism
• 5HT4 agonism
• 5HT3 antagonism

• Indications
• Postoperative, drug induced, disease induced, radiation and chemotherapy
induced vomiting.
• Accelerate gastric emptying
• Dyspepsia
• Gastroesophageal reflux disease (GERD)
 Antipsychotic phenothiazines
• MOA: Prochlorperazine blocks D2 in the CTZ and
suppress vomiting

• Indications
• Disease induced vomiting
• Hyperemesis gravidarum

• Adverse Effects
• Dry mouth, drowsiness, extrapyramidal
 Cannabinoids
• MOA: Nabilone is a synthetic cannabinoid and has properties
similar to tetracannabinol (the active constituent of marijuana),
which has an emetic action.

• Indicatons
• It is used to relieve nausea or vomiting caused by cytotoxic drugs.

• Adverse Effects
• Somnolence, dry mouth, decreased appetite, dizziness, euphoria,
dysphoria, postural hypotension, confusion and psychosis. These
may be reduced if proclorpromazine is given concomitantly.
 Glucocorticoids
• MOA: Possibly by suppressing peritumoral
inflammation and prostaglandin production.

• Indication
• Enhance the efficacy of 5HT3 receptor
antagonists in the treatment of chemotherapy
induced.
 Neurokinin-1 antagonists
MOA: Aprepitant is a substance P antagonist
that acts by blocking neurokinin receptors.
• Indications
• Used orally
• Used in the prevention of acute and delayed
chemotheraphy-induced nausea and vomiting
and for the prevention of postoperative
nausea and vomiting.
 Clinical use of anti-emetic drugs
• Histamine H1-receptor antagonists:
– cyclizine: motion sickness
– cinnarizine: motion sickness, vestibular disorders (e.g. Ménière's disease)
– promethazine: severe morning sickness of pregnancy (but only if absolutely essential).
• Muscarinic receptor antagonists:
– hyoscine: motion sickness
• Dopamine D2-receptor antagonists:
– phenothiazines (e.g. prochlorperazine): vomiting caused by uraemia, radiation, viral
gastroenteritis; severe morning sickness of pregnancy (but only if absolutely essential)
– metoclopramide: vomiting caused by uraemia, radiation, gastrointestinal disorders,
cytotoxic drugs.
• 5-Hydroxytryptamine 5-HT3-receptor antagonists (e.g. ondansetron): vomiting
caused by cytotoxic anticancer drugs; postoperative vomiting; radiation-induced
vomiting.
• Cannabinoids (e.g. nabilone) for vomiting caused by cytotoxic anticancer drugs.