Emetics & Anti-

emetics

Dr. K.I
 Vomiting
• Vomiting or emesis is the forceful
expulsion of the contents of the
stomach via the mouth or sometimes
through the nose.

• Emesis occurs due to stimulation of

the emetic center situated in the
medulla oblongata
 Emesis
• Emesis is a protective mechanism
which serves to eliminate harmful
substances from the stomach and
duodenum.

• The vomiting reflex is stimulated by

two centers in the medulla
1. vomiting center
2. chemoreceptor trigger zone(CTZ)
 Emesis Contd…

• The Vomiting center initiates,

regulates and controls the act of
vomiting

• The CTZ is also accessible to blood

borne drugs, mediators, hormones,
toxins etc.
 Causes of Vomiting
• Nausea and vomiting may be
manifestations of many conditions and
may occur due to stimulation of
vomiting center that responds to
inputs from:
1. Higher cortical centers stimulation
(CNS)
2. Chemoreceptor trigger zone (CTZ)
stimulation
3. Disturbance of vestibular system
 1. Stimulation of Chemoreceptor
Trigger Zone (CTZ)
 CTZ is an area of medulla that
communicates with vomiting center
to initiate vomiting.

 CTZ is physiologically outside BBB.

 CTZ contains D2 receptors, 5HT3

receptors & opioid receptors.
 Stimulation of the CTZ Contd..
 The CTZ can be stimulated via several
ways:
a.Tactile stimulation of the back of the
throat, a reflex to get rid of something
that is too big or too irritating to be
swallowed
b.Excessive stomach distention
c. Increasing intracranial pressure by
direct stimulation
d.Stimulation of the vestibular receptors
in the inner ear
 Stimulation of the CTZ Contd..

e. Intense pain fibre stimulation

f. Direct stimulation by various
chemicals, toxins (blood, CSF), fumes,
certain drugs [emetogenic drugs
(opioids, general anesthetics, digitalis,
L-dopa)], radiation, uremia and debris
from cellular death
• The stimulation of the CTZ initiates a
complex series of responses that first
prepare the system for vomiting and
then cause a strong backward
peristalsis to rid the stomach of its
contents.
2. Stimulation of the periphery via
sensory nerves
 GIT irritation
 myocardial infarction
 renal or biliay stones

3. Higher cortical centers stimulation

 Emotional factors
 Nauseating smells or sights
 4. Disturbance of Vestibular
System
o The Vestibular nuclei, also
located in the medulla,
receives signals from the
labyrinth located in the inner
ear.

o This structure mediates nausea

and vomiting of motion
sickness
o Motion sickness will activate the
vestibular cochlea nerve which
connects the labyrinth to the
vestibular nuclei

o This then activates the muscarinic

1 and histamine 1 receptors
located on the vestibular nuclei,
which in turn stimulates the CTZ,
which in turn stimulates the VC to
Receptors Associated with Nausea and
Vomiting
 Neurotransmitters Involved

• Histamine via H1 receptors

• Serotonin via 5HT3 receptors
• Acetylcholine via M receptors
• Dopamine via D2 receptors
•Substance P (Neurokinin receptors,
NK1)
•Opioid (Opioid receptors)
 Emetics

• Drugs that produce/induce vomiting

are called emetics

• **Emetics should never be used if the

patient is not fully conscious or if a
substance is corrosive.
 Classification of Emetics
1. Stimulants of CTZ (Centrally Acting)
a. Apomorphine
b. Morphine
2. Irritants of gastric mucosa
(Peripherally acting)
a. mustard
b. sodium chloride
3. Both CTZ stimulant and irritant effect
a. ipecacuanha
b. digitalis
 Apomorphine

• It is obtained by treating morphine

with HCL
• Mechanism:
• Produce vomiting in 5-10 minutes after
admn
• Dose- 2 to 4mg
• Route- subcutaneous/IM
 Mustard

• It is a household remedy to induce

vomiting

• Dose- 1 teaspoonful with water

 Ipecacuanha
• It is obtained from the dried rhizome
and roots of Carapicheae ipecacuanha
from which it derives its name.
• Commonly available as syrup
• Dose- 15 to 20 ml
• Induces vomiting within 15 minutes
 ANTI-EMETICS
• Anti-emetics are drugs that prevent
vomiting or emesis.

• They provide symptomatic relief as

removal of causative factor leads to
ultimate relief
 Contd..
• Two centres: Vomiting Centre (VC)
and Chemoreceptor Trigger Zone
(CTZ) are involved.

• VC is within the blood brain

barrier(BBB)

• CTZ outside in the area postrema

(outside the BBB)

• They are connected together. How?

Factors Involved in Emesis
Control
 Classification
1. D2 Antagonists
a.Substituted Benzamides
Metoclopramide, Trimethobenzamide
1.Butyrophenones
Domperidone, Droperidol

a.Phenothiazines
Prochlorperazine, Promethazine &
Thiethylperazine.
 Classification (2)
2. Muscarinic Antagonist
a. Hyoscine
b. Meclozine

3. H1 Antihistamines
a.Cyclizine
b.Promethazine (phenergan)

4.Neuroleptics
a.chlorpromazine
b.prochlorpromazine
 Classification (3)

5. Selective 5-HT3 antagonists

a. Ondancetron
b. Granicetron
c. Palonosetron
d. Dolasetron.

6. Cannabinoids
Dronabinol, Nabilone
 Classification (4)

7. Glucocorticoids
Dexamethasone, Methylprednisolone

8. Benzodiazepines
Diazepam , Lorazepam
9. Neurokinin-I Antagonist
Aprepitant (oral formulation),
Fosaprepitant (IV formulation)
 D2 Antagonists
a.Substituted Benzamides
Metoclopramide, Trimethobenzamide

b.Butyrophenones
Domperidone, Droperidol

c.Phenothiazines
Prochlorperazine, Promethazine &
Thiethylperazine.
 a. Substituted Benzamides
e.g. Metoclopramide
• These drugs which promote
gastrointestinal motility and quicken
gastric emptying
• It has both central and peripheral
effects
-Central- Blocks D2 receptors in CTZ of
the medulla

-peripheral- increased gastric emptying

dose- 5- 10 mg
 Metoclopramide contd..
•Dose- 5-10 mg
•Indications
oPotent antiemetic controls / reduces
vomiting due to
oUremia, Radiation, Viral gastro
enteritis, hepatic-biliary disease,
Anticancer drugs, Migraine, Post
operatively & pre-operatively
•Side effects: restlessness, drowsiness,
dizziness and or dystonic reactions
 Contd..
Pharmacokinetic
• Rapidlysabsorbed 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: 10-20 mg orally or IV every 6
hrs
 Adverse Effects
• Extrapyramida reactions with facial
and skeletal muscle spasms-
Restlessness, Dystonias , Parkinsonian
symptoms.

• More common in the young and very

old.

• Usually occur shortly after starting

treatment and subside within 24 hours
of stopping the drug.
 Adverse Effects contd..
• Bowel upsets, Diarrhea

• Drowsiness and fatigue, dizziness,

restlessness and anxiety.

• Galactorrhoea, Gynecomastia,
impotence and menstrual disorders –
due to increased prolactin levels
 b. Butyrophenones
e.g. Domperidone
• Action- Does not cross BBB. Only
blocks D2 in CTZ.

• May be used in nausea & vomiting

due to Levodopa, without affecting its
efficacy.

• No extrapyramidal side effects.

• Dose- 10 mg, 30 mg tablets
• - 1 mg/ml syrup

• Used as an antiemetic agent & for

post partum lactation stimulation

Side effects: Headache, dizziness, dry

mouth, nervousness, flushing, or
irritability
 C. Phenothiazines
e.g. Promethazine
• Phenothiazines are antipsychotics
with potent antiemetic property due
to D2 antagonism and anti-muscarinic
properties

• Sedative property due to anti-

histaminic property
 Promethazine Contd..

• Mainly used as anti-emetic in

severe nausea & Vomiting

• Main A/E: Extrapyramidal

• S.E, sedation, postural hypotension

 Muscarinic Antagonists
• Action- Competitively inhibits action of
acetylcholine at muscarinic receptors

• Hyoscine: very effective in controlling

motion sickness

• Dose: 0.4-0.6mg po 30 min before

commencment of a journey

• It is a labrynthine sedative
 H1 Antihistamines & Muscarinic
Antagonists
H1 Antihistamines
•Meclizine, Cinnarizine, Cyclizine &
Diphenhydramine & its salt
Dimenhydrinate.
•They have anticholinergic & H1
antagonist sedating properties (1st
generation).

•They produce specific depression of

conduction in vestibulocerebellar
pathway.
 H1 Antihistamines

• They act by sedating the vomiting

centre
• They are safer for long term use
• Effective in motion sickness and
vomiting due to labrynthine disoders
• E.G. Cyclizine, meclozine
• dose- 50 mg/ml inj
• 50 mg tab
 Selective 5-HT3 Antagonists
Ondansetron, Granisetron, Dolasetron &
Palonosetron
MOA
•Act as anti-emetics by selectively blocking
central 5HT3 receptors in Vomiting center &
CTZ & Mainly by blocking Peripheral 5HT3 r
eceptors on intestinal vagal and spinal affe
rent fibers.

•Antiemetic action is restricted to emesis c

aused by vagal stimulation (e.g. post oper
ative) & chemotherapy
 Contd..

*Palonosetron: newer with greater

affinity for 5-HT3 receptor &
comparatively longer half life

•No effect on Dopamine/muscarinic

receptors
 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

• No dose reduction in renal insufficiency
but needed in hepatic insufficiency
(Ondansetron)
 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
 Uses contd..

• 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
 Adverse Effects
• Excellent safety profile
• Headache, dizziness & constipation
• All three drugs cause prolongation of
QT interval, but more pronounced with
dolasetron.

Drug Interactions
Hepatic clearance may decrease by
enzyme inhibitors
 Cannabinoids (Dronabinol,
Dronabinol: Nabilone)
Tetrahydrocannabinol (THC) main
psychoactive chemical in marijuana

Pharmacokinetics:
Complete absorption on oral
administration, significant 1st pass effect,
metabolites excreted slowly over days to
weeks in faeces & urine
• MOA: Act as antiemetic & appetite
stimulant in addition to psychoactive
action. MOA not clear.
• Cancer chemotherapy induced
Nausea & vomiting with
Phenothiazines
• – synergistic effect but AEs are added
• – not used as better drugs are
available
 Glucocorticoids

Dexamethasone, Methylprednis
olone

•Antiemetic MOA not clear

•Enhance action of 5HT3 antagonists

in Cancer chemotherapy induced N
ausea & vomiting
 Benzodiazepines
e.g. Diazepam, Lorazepam

•Used prior to Cancer chemotherapy to

reduce anticipatory vomiting

•Vomiting caused by anxiety

 Neurokinin-1 (NK1 )Antagonists
e.g. Aprepitant, Fosaprepitant
• Given orally, Bioavailability=65%,
Crosses BBB.
• t½: 11 hrs; metabolized by hepatic
CYP3A4.

MOA
• Act as Antiemetic: Selectively block
NK1 receptor in area postrema.
• No effect on Serotonin, Dopamine or
Corticoid receptors
 Aprepitant
• Non peptide, selective, Neurokinin
type 1 (NK 1) receptors antagonist

• Blocks substance P from binding to

NK1 receptor

• Broader spectrum and activity in

delayed emesis (In Preclinical studies)

• 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
 Adverse Effects
• Fatigue, dizziness & diarrhoea.

• Enzyme inhibition
• Metabolized by CYP3A4 & may inhibit
metabolism of many anticancer drugs
(Docetaxel, Paclitaxel, Etoposide,
Vinblastine, Imatinib) ---- ↑ levels ---
toxicity.

• Metabolism of Aprepitant may be inhibited

by Ketoconazole, Ciprofloxacin,
Clarithromycin, Nafazodone, Ritonavir,
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, Metoclopramide
•Vomiting due to pregnancy ( hyperemesis
gravidarum), Meclizine with Vitamin B 6
(Navidoxine)
• Vomiting due to Cytotoxic Anticancer drugs:
5HT3 Antagonists, Metoclopramide,
Cannabinoids, corticosteroids , Aprepitant

• Anticipatory Vomiting due to Cytotoxic

Anticancer drugs. Benzodiazepines
(Diazepam)

• Post Operative Vomiting: Metoclopramide ,

Prochlorperazine , Dimenhydrinate, 5HT3
Antagonists (Ondensetron)