Antiemetics

Prof. Dr. Fatima Rizvi

Department of Pharmacology
Learning objectives
At the end of the lecture, students
should be able to-

Discuss the causes of emesis &

classification of anti- emetic drugs

Explain basic and clinical

pharmacokinetic and dynamic of
Antiemetic drugs

Enlist the Emetics and its clinical

indication
 Emesis

• Act of forceful expulsion of

gastric contents through the mouth
• Often preceded by nausea
 Antiemetics

• Drugs that prevents nausea and vomitng are called

antiemetics.
• Various drugs including some antihistamine and
anticholinergics have this effect.
• They are used for conditions like motion sickness,
radiation or chemotherapy induced vomiting,
migraine and vertigo.
 CAUSES OF EMESIS.

Nausea and Vomiting may be a manifestation of

 Adverse effects from Medications.
 Systemic disorders and Infections.
 Pregnancy .
 Vestibular Dysfunction .
 Raised Intracranial Pressure.
 Radiation and Chemotherapy.
 Gastrointestinal obstruction, Dysmotility or
Infection
 Pathophysiology of Emesis
Cancer chemotherapy
Cerebral cortex
Opioids Smell
Sight Anticipatory
emesis Thought
Chemoreceptor Vestibula
Vomiting Centre
Trigger Motion r
(medulla) sickness
Zone Muscarinic, 5 HT3 & nuclei
(CTZ) Histaminic H1 Muscarinic 1
(Outside BBB) Histaminic H
Dopamine D2 Chemo & radio therapy
5 HT3,, Gastroenteritis

Opioid Receptors Pharynx & GIT

5 HT3 receptors
Pathophysiology of Emesis
Neurotransmitters Involved
• Histamine via H1 receptors
• Serotonin via 5HT3 receptors
• Acetylcholine via M receptors
• Dopamine via D2 receptors
 Classification - Antiemetic drugs

H1 antihistamines

●
Meclizine, Cinnarizine, Cyclizine, Dimenhydrinate, Diphenhydramine.

Muscarinic Antagonist
●
Hyoscine (Scopolamine).

Selective 5-HT3 Antagonists

●
Ondansetron, Granisetron, Palonosetron & Dolasetron.
D2 Antagonists
• (a) Substituted Benzamides
• Metoclopramide, Trimethobenzamide
• (b) Butyrophenones
• Domperidone , Droperidol
• (c) Phenothiazines
• Prochlorperazine, Promethazine & Thiethylperazine.
Cannabinoids
• Dronabinol , Nabilone

Glucocorticoids
• Dexamethasone, Methylprednisolone

Benzodiazepines
• Diazepam , Lorazepam

Neurokinin-I Antagonist
• Aprepitant (oral formulation), Fosaprepitant (IV formulation)
 D2 Antagonists
Substituted Benzamides
●
Metoclopramide, Trimethobenzamide

Butyrophenones
●
Domperidone , Droperidol

Phenothiazines
●
Prochlorperazine, Promethazine & Thiethylperazine.
 Metoclopramide
Chemistry: Substituted Benzamide
MOA: Dopamine D2 receptors antagonist
It is potent Antiemetic & Prokinetic agent
As Antiemetic
• It has potent Antiemetic & antinausea effect.
• Blocks D2 receptors in CTZ of the medulla (area postrema)
As Prokinetic agent
• It can selectively stimulate gut motor function.
• Blocks D2 receptor in GIT & blocks the normal inhibitory
effect of Dopamine on cholinergic smooth muscle
stimulation--- ↑ motility.
The Uses - Metroclopramide

Potent antiemetic controls / reduces vomiting due to

• Uremia
• Radiation
• Viral gastro enteritis, hepatic-biliary disease
• Anticancer drugs
• Migraine
• Post operatively & pre-operatively
 Metoclopromide

• D2 receptor antagonist
• Increases the esophageal peristaltic amplitude, increase lower
esophageal sphincter pressure and enhance gastric emptying.
CLINICAL USES
A) GERD(Gasteroesophageal reflux disease)
They are used in combination with anti -secretory agents in patients
with regurgitation or refractory heart burn
B) Impaired Gastric Emptying
Metoclopramide and Domperidone are widely used in the
treatment of patients with delayed gastric emptying due to post
surgical disorders and Diabetic Garstoparesis
C) Symptomatic treatment of non ulcer dyspepsia
D) Postpartum lactation stimulation
Domperidone sometime use to promote postpartum lactation
 Metroclopramide…

Pharmacokinetics
• Rapidly absorbed from GIT after oral administration.
• Undergoes a high degree first pass metabolism.
• It is excreted in the urine as free and as metabolites.
• It is also excreted in the breast milk.
• DOSE: 10-20mg orally or IV every 6 hrs
 Adverse Effects - Metroclopramide
• Extrapyramidal reactions with facial and skeletal
muscle spasms- Restlessness, Dystonias , Parkinsonian
symptoms.
-----More common in young and very old. Usually occur shortly
after staring treatment and subside with in 24 hours of stopping
the drug.
• Bowel upsets, Diarrhea
• Drowsiness and fatigue, dizziness, restlessness and anxiety.
• Galactorrhoea, Gynecomastia, impotence and
menstrual disorders – due to increased prolactin levels
 Phenothiazines

Phenothiazines
Prochlorperazine, Promethazine & Thiethylperazine
Phenothiazines are antipsychotics with potent antiemetic
property due to D2 antagonism and anti-muscarinic
properties
Sedative property due to anti-histaminic property

Mainly used as anti-emetic in severe N& V

Main A/E: EPS , sedation , postural hypotension
 Butyrophenones
Antipsychotic drugs , D2 antagonists

Droperidol
Central D2 antagonist
Main A/E: EPS , postural hypotension
QT prolongation may occur

Domperidone
• Does not cross BBB. Only blocks D2 in CTZ where BBB is leaky.
• May be used in N&V due to Levodopa, without affecting
its efficacy.
• No EPS.
• Used as antiemetic , prokinetic agent & for post partum lactation
stimulation.
Selective 5-HT3 Antagonists
 Selective 5-HT3 Antagonists
Ondansetron, Granisetron , Dolasetron & Palonosetron

MOA
• Act as ant-emetic by selectively blocking the central 5-HT3
receptors centrally at vomiting centre (CTZ) and blocking 5 -HT3
receptors on intestinal vagal and spinal afferent fibres.
• Antiemetic action is restricted to emesis caused by vagal
stimulation (e.g. post operative) & chemotherapy
• Palonosetron: newer with greater affinityfor 5-HT3 receptor
& comparatively longer half life
• No effect on Dopamine / muscarinic receptors
The Uses - Selective 5-HT3 Antagonists

• Chemotherapy- Induced Nausea & vomiting

• Primary Agents - prevention of acute chemotherapy induced
Nausea & vomiting
Effective alone in most of the cases. Efficacy is enhanced in
combination. Can be given I/V 1/2 hr before chemotherapy
• To prevent Delayed Nausea & vomiting occurring after 24 hrs
of Cancer chemotherapy
in combination with Dexamethasone & NK1
receptor antagonist.
• To prevent & treat post operative & post
radiation Nausea & vomiting
 Selective 5-HT3 Antagonists

Pharmacokinetics
• High first pass metabolism
• t1/2 : 4-9 hrs (Ondansetron, Granisetron & Dolasetron)
40 hrs (Palonosetron)
• Given once or twice daily – orally or intravenously
• Excreted by liver & kidney
• dose reduction needed in hepatic insufficiency for
Ondansetron
A/Es - Selective 5-HT3 Antagonists

• Excellent safety profile

• Headache, Dizziness & constipation
• All three drugs cause prolongation of QT interval, but
more pronounced with dolasetron.

DIs
Hepatic clearance may decrease by enzyme inhibitors
 H1antihistamines & Muscarinic Antagonists

H1antihistamines
Meclizine, Cinnarizine, Cyclizine & Diphenhydramine &
Dimenhydrinate.

• They have anticholinergic & H1 antagonist sedating properties

(1st generation).
• They produce specific depression of conduction
in vestibulocerebellar pathway.
MuscarinicAntagonist
Hyoscine (Scopolamine).
 Hyoscine (0.2–0.4 mg oral, i.m.) is the most effective drug for
motion sickness.

It has a brief duration of action;

Mechanism of Action:
• Acts by blocking conduction of nerve impulses across a cholinergic
link in the pathway leading from the vestibular apparatus to the
vomiting center.
• Transdermal patches containing Hyoscine , to be delivered over
3 days has been developed, applied behind the pinna.

Side effects sedation, dry mouth and other anticholinergic side

effects; suitable only for short brisk journies.
 Dicyclomine (10–20 mg oral) has been used
for prophylaxis of motion sickness and for
morning sickness.
 H1antihistamines & Muscarinic Antagonists…

Therapeutic Uses
• Vestibular system is important in motion sickness via cranial
nerve VIII - rich in Cholinergic M1 & Histamine H1receptors
• Most effective drugs for motion sickness
• Effective for nausea & vomiting associated with
motion sickness.
• Vestibular disorders ( Meniere’s disease)
• (hyoscine) – used as transdermal patch for motion sickness
• Meclozine is long acting so useful in sea sickness
• Cinnarizine also has antivertigo effect. Act by inhibiting
influx of calcium to vestibular sensory cells from
endolymph
 Now answer this question???

 A physician prescribed Tab. Ondansetron for

prophylaxis of motion sickness. Even though
Ondansetron is a potent antiemetic it didn’t produce
any effect in this patient. Can you explain why ?
Explanation :
Vestibular nuclei has only Muscarinic and H1
histaminic receptors.
 Cannabinoids (Dronabinol)

Dronabinol ( delta-9-tetrahydrocannabinol)
• Synthesized chemically or extracted from
the marijuana plant
MOA:
• Exact mechanism – unknown
• Probably acts by stimulation of
canabinoid receptors (CB1 subtype) on
neurons in and around the vomiting
Centre
Use:
• Chemotherapy – induced nausea and
vomiting (generally in combination with
other agents
• Appetite stimulant – Anorexia
Adverse effects
Autonomic effects (sympathetic effects)

 Tachycardia, Palpitation, blood shot eyes (red eye)

 Euphoria,
 Sedation,
 Dry Mouth
 Increase Appetite,
 Hallucination
 Glucocorticoids
Dexamethasone , Methylprednisolone

• Antiemetic MOA not clear

• Enhance action of 5HT3 antagonists in
Cancer chemotherapy induced Nausea & vomiting
 Glucocorticoids
Antiemetic mechanism
• Mechanism of action is not known but probably due
to blockade of prostaglandins
• Possibly by suppressing peri-tumoral inflammation
and prostaglandin production.
Use:
• To enhance efficacy of 5HT3 receptor antagonists in
the treatment of chemotherapy-induced vomiting.
• Effective against mildly and moderately emetogenic
chemotherapy .
 Benzodiazepines
Diazepam, Lorazepam

• Used prior to Cancer chemotherapy to reduce

anticipatory vomiting
• Vomiting caused by anxiety
 Neurokinin-1 (NK1 )Antagonists
Aprepitant, Fosaprepitant

Given orally BA = 65% , Crosses BBB.

t ½ : 11 hrs, Metabolized by hepatic CYP3A4.

MOA
Act as Antiemetic: Selectively block NK1 receptor in area
postrema (substance P system)
No effect on Serotonin , Dopamine or Corticoid receptors
Augment the antiemetic activity of 5HT3 receptor
antagonists and dexamethasone
 Neurokinin-1 (NK1 )Antagonists
Uses
Used in combination with 5HT3 antagonists & Corticosteroids
for prevention of acute & chronic nausea and vomiting from
Cancer chemotherapy
A/E
• Fatigue, dizziness & diarrhea.
• Enzyme inhibition
• Metabolized by CYP3A4 & may inhibit metabolism of many anticancer drugs
(Docetaxel, Paclitaxel, Etoposide, Vinblastine, Imatinib) ---- ↑ levels --- toxicity.
 Therapeutic Uses of Anti-emetics

• Motion sickness: Hyoscine

• Vestibular disorders( Menieres, disease): Cinnerazine
• Vomiting due to Uremia, Radiation, Viral gastro enteritis,
Liver disease, Migraine, Prochlorperazine ,
Metroclopramide
• Vomiting due to pregnancy ( hyperemesis gravidarum),
Meclizine with vit. B6 (Navidoxine)
• Vomiting due to Cytotoxic Anticancer drugs: 5HT3
Antagonists Metroclopramide, Cannabinoids,
corticosteroids , Aprepitant
• Anticipatory Vomiting due to Cytotoxic Anticancer
drugs. Benzodiazepines (Diazepam)
• Post Operative Vomiting: Metoclopramide ,
Prochlorperazine , Dimenhydrinate, 5HT3 Antagonists
(Ondensetron)
 EMETICS

These are drugs used to evoke vomiting.

Ipecac syrup
• It is used to treat childhood poison ingestions at home .
• Ipecac acts as an emetic because of its local irritant effect on
the enteric tract and on the CTZ (chemoreceptor triggering
zone )

Apomorphine
• It stimulates the CTZ and causes emesis
 Indications
 Poisoning
 Acute cases of poisoning (except in corrosive
substances poisoning or if patient is not fully
conscious)
 Alcoholic intoxication

Removal of foreign bodies from the
oesophagus