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Antiemetics

Prof. Hanan Hagar


Pharmacology Department
College of Medicine

Learning objectives

Classify the main different classes of antiemetic drugs


according to their mechanism of action.
Know the characteristic pharmacokinetics & dynamics of
different classes of antiemetic drugs.
Identify the selective drugs that can be used according to
the cause of vomiting.
Learn the Adjuvant antiemetics.
Describe the major side effects for the different classes of
antiemetics.

Causes of Vomiting
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

1. Chemoreceptor trigger zone stimulation

CTZ is an area of medulla that communicate


with vomiting center to initiate vomiting.
CTZ is physiologically outside BBB.
CTZ Contains opioid receptors, D2
receptors & 5 HT3 receptors, Substance P
stimulated by:
Drugs (opioids, general anesthetics),
Chemicals and toxins in blood, CSF.
Radiation.

2. The periphery via sensory nerves


GIT irritation, myocardial infarction, renal or
biliay stones.
3. Disturbance of vestibular system
by motion sickness
4. Higher cortical centers stimulation :
emotional factors, nauseating smells or sights.

Receptors Associated with Nausea and Vomiting

Pathophysiology of Emesis
chemotherapy
Opioids
Anesthetics

Chemoreceptor
Trigger Zone
(CTZ)
(Outside BBB)
5 HT3
Dopamine D2
Opioid receptors
Substance p

Cerebral cortex
Smell
Sight
Thought

Anticipatory emesis

Vomiting Centre
(medulla)
Muscarinic, 5 HT3 &
Histaminic H1

Motion
sickness

Chemo & radio therapy


Gastroenteritis

Pharynx & GIT


5 HT3 receptors

Vestibular
nuclei
Muscarinic
Histaminic H1

Chemical transmitters & receptors


involved in vomiting include:

Ach (Muscarinic receptors)


Dopamine (D2)
Histamine (Histaminergic receptors H1)
Serotonin (5 -HT3)
Substance P (Neurokinin receptors, NK1)
Opioid (Opioid receptors)

Classification of Antiemetic Drugs


1.
2.
3.
4.
5.
6.
7.

5-HT3 antagonists
D2 receptor antagonists
NK1 antagonists
H1-receptor antagonists
Muscarinic receptor antagonists
Cannabinoids
Glucocorticoids

5-HT3 antagonists

Drugs as Ondansetron, Granisetron


Orally or parenterally
Potent antiemetic effects
Block 5-HT3 receptor in vomiting center, CTZ
and 5HT3 receptors on intestinal vagal
afferents.

Uses of 5-HT3 antagonists

First choice for prevention of:


Chemotherapy-induced nausea and vomiting
(CINV) especially cisplatin.
Post-radiation NV& Post-operative NV
Their effects is increased by combination
with corticosteroids and NK1 antagonists.

Side effects

o Well tolerated
o mild headache, dizziness and constipation
o minor ECG abnormalities (QT prolongation)

D2 receptor antagonists

block D2 dopamine receptors in the CTZ


Two types exist:
1) Prokinetics drugs
2)

Neuroleptics (antipsychotics)

Uses of D2 receptor antagonists

are among the most commonly used drug for


nausea and vomiting of non-specific causes.

Effective against vomiting due to drugs,

gastroenteritis, post-operative, toxins,


uremia, radiation.

D2 receptor antagonists
1) Prokinetics drugs

Drugs as metoclopramide, domperidone


Both are prokinetic agents due to their 5 HT4
agonistic activity.
used in GERD (gastroesophageal reflux
disease), gastroparesis.
Used as antiemetics (blocking D2 receptors)
Metoclopramide crosses BBB but
domperidone cannot (both have antiemetic
effects as CTZ is outside BBB).

Side effects (only for metoclopramide):


Dyskinesia (extra-pyramidal side effects),
Galactorrhea, menstrual disorders,
impotence.
Sedation, postural hypotension.

D2 receptor antagonists
Neuroleptics (Antipsychotics)

Chlorpromazine (CPZ), droperidol


used for postoperative vomiting and
chemotherapy-induced nausea & vomiting.
Side effects: extrapyramidal symptoms
sedation, postural hypotension

Neurokinin1 (NK1) receptor antagonists


Aprepitant

Is a substance P antagonists that acts by


blocking neurokinin 1 receptors.
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.

H1-receptor antagonists

Effective for motion sickness, morning


sickness in pregnancy
Drugs as
Diphenhydramine
Meclizine - Cyclizine
Promethazine: severe morning sickness of
pregnancy (if only essential).
Side effects:
prominent sedation, hypotension,
anticholinergic effects (dry mouth, dilated
pupils, urinary retention, constipation.

Muscarinic receptor antagonists

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).

Cannabinoids
Nabilone, dronabinol
mechanism of action not understood.
act at central cannabinoid receptors.
Used in vomiting due to cytotoxic
anticancer drugs (adjuvant therapy).
Not commonly used.
Side effects: euphoria, dysphoria, sedation,
hallucination.

Glucocorticoids

Dexamethasone - methylprednisolone
Used in chemotherapy-induced vomiting
combined with 5-HT3 antagonists or NK1
receptor antagonists.

Glucocorticoids

Side effects:
Hyperglycemia
Hypertension
Cataract
Osteoporosis
Increased intraocular pressure
Increased susceptibility to infection
Increased appetite & obesity

Summary
The choice of antiemetic depends on the etiology
Motion sickness
Muscarinic antagonists
Antihistaminics
Vomiting with pregnancy (morning sickness)
avoid all drugs in the first trimester
Pyridoxine (B6)
.Promethazine ( late pregnancy)

Drug- induced vomiting (CTZ)


Dopamine antagonists
Post operative nausea & vomiting
Dopamine antagonists
HT3 antagonists-5
NK1 antagonists
.Vomiting due to cytotoxic drugs
HT3 antagonists-5
NK1 antagonists
D2- antagonists
Glucocorticoids
Cannabinoids

Thank you

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