ANTI-EMETICS

SUBJECT: SYSTEMIC
PHARMACOLGY
23-10-2014
MERIN BABU
M.Pharm 1st Semester
Department of Pharmacology
Amrita School Of Pharmacy,
Kochi

NAUSEA & VOMITING

ACT OF EMESIS: To get rid the stomach and intestine toxic
substances and prevent further ingestion.
VOMITING: Expulsion of gastric contents through mouth due
to mass antiperistalsis.
NAUSEA: Uneasy feeling of vomiting.
RETCHING: Series of weaker and unproductive vomiting
movements.

VOMITING

Vomiting is a complex process that consists of :

PRE-EJECTION PHASE:
Gastric relaxation and retro peristalsis.

RETCHING:
Rhythmic action of respiratory muscles preceding
vomiting and consist of abdominal & intercoastal muscles
and diaphragm against a closed glottis.

EJECTION:
Intense contraction of abdominal muscles and relaxation of
upper oesophageal sphincter.

Followed by multiple autonomic phenomena:

Salivation, Shivering, Vasomotor changes

ANTI-EMETIC MECHANISM

ANTI-EMETIC MECHANISM
Anti-emesis process is
coordinated by a central
emesis center in lateral
reticular formation of
midbrain adjacent to
both chemoreceptor
trigger zone (CTZ) in
the area postrema
(AP) at the bottom of 4th
ventricle and solitary
tract nucleus (STN).
Lack of blood-brain
barrier (BBB) allows
CTZ to monitor the blood
and CSF for toxic
substances and to relay
information to emesis

ANTI-EMETIC MECHANISM
Vestibular apparatus generates impulses during motion
sickness which reach vomiting center via cerebellum.
Vestibular apparatus is rich in M1, H1 receptors.
Emesis also receives information from gut through vagus
nerve (via STN) and splanchnic afferent nerves via
spinal cord. They are rich in 5HT3 receptors.
Irritants of GIT mucosa ( irritants, chemotherapeutic
drugs, radiation, endogenous toxins and poisons ) --- release
mucosal serotonin from entero-chromaffin like cells (ECL
cells) which activate 5HT3 receptors.
Inputs to emesis center also come from cerebral cortex
( particularly in anticipatory nausea & vomiting.
M1, H1,5HT3 and neurokinin-1 (NK1) receptors are
present in vomiting center.

CLASSIFICATION OF ANTI-EMETIC DRUGS

5HT3 ANTAGONISTS:
Ondansetron, Granisetron, Dolansetron, Palonosetron,
Ramosetron, Tropisetron.
CENTRALLY ACTING DOPAMINE RECEPTOR
ANTAGONIST:
Metoclopramide, Domperidone, Chlorpromazine,
Prochlorperazine
HISTAMINE (H1) RECEPTOR ANTAGONIST:
Cyclizine, Promethazine, Diphenhydramine, Hydroxyzine
ANTICHOLINERGIC ( MUSCARINIC RECEPTOR
ANTAGONIST):
Hyoscine (Scopolamine)
NEUROKININE RECEPTOR ANTAGONIST:
Aprepitant

OTHER ANTI-EMETIC DRUGS

CORTICOSTEROIDS:
Betamethasone, Dexamethasone

VITAMIN B6 (PYRIDOXINE):

PHOSPHATED CARBOHYDRATE
SOLUTION:

5HT-3 ANTAGONISTS
DRUG
ONDANSETR
ONprototype
drug

MOA

PK

USE

ADVERSE
EFFECTS

5-HT is
Anti-emetic
Chemother Constipation/
released from effect persists
apy
Diarrhoea
enterochroma for long time
induced
Headache
ffin cells (ECL)
even after
emesis
Lightheadnes
of small
they
s
intestine in
disappear
response to
from
chemotherapy
circulation.
agents.
These
A: well
stimulate
absorbed
vagal
from GIT.
afferents
initiating
M:
vomiting
metabolised
reflex.
by CY1A2,
CYP2D6,
Antagonism of
CYP3A4
5HT-3
followed by
receptors
glucouridinati

5HT-3 ANTAGONISTS
DRUG
GRANISETRO
N

MOA

PK

USE

ADVERSE
EFFECTS

M: liver

Chemothera
py induced
nausea
- Nausea
secondary to
upper
abdominal
irradiation
Hyperemesis
of pregnancy

Constipation/
Diarrhoea
Headache

M: CYP2D6
E: urine

Delayed
emesis- due
to long half
life

DOLANSETR
ON

PALONOSETR
ON

DOPAMINE RECPTOR ANTAGONISTS

METOCLOPRAMIDE:
Acts centrally blocking D2 receptors in CTZ.
Used in nausea and vomiting due to GI
disorders, in postoperative period and
vomiting due to cytotoxic drugs and
radiotherapy.
DOMPERIDONE:
Blocks D2 receptors in CTZ and acts as
antiemetic.
Advantage: doesnt cross BBB rare
extrapyramidal effects
SE: headache, dryness of mouth, diarrhoea,
rashes

ANTI-HISTAMINERGIC DRUGS

H1 antagonists --- useful for motion sickness and post-operative em

Act on vestibular afferents and within brainstem.

CYCLIZINE, HYDROXYCYZINE, PROMETHAZINE, DIPHENHYDRA

PROMETHAZINE:
Most potent and effective.
Drug must be taken 1 hr before the motion.
Useful for chemotherapy/ radiation therapy for malignancies.

ANTI-CHOLINERGIC DRUGS
HYOSCINE (SCOPOLAMINE):
Labyrinthine sedative.
Very effective in motion sickness.
Motion sickness is due to over stimulation of
vestibular apparatus along with psychological
and environmental factors.
Given as transdermal patch.
Useful for post-operative nausea & vomiting.

SUBSTANCE P ANTAGONISTS
Nausea and vomiting associated with
Cisplatin have 2 components:
Acute Phase: within 24hrs after
chemotherapy
Delayed Phase: affects only some
patients ( only days 2-5)
Antagonists for NK1 receptors for
substance P
-- APREPITANT
Have anti-emetic effects in delayed
nausea and improve the efficiency of
standard anti-emetic regimen.
Aprepitant given along with highly
emetogenic chemotherapy in combination
with 5HT3 ANTAGONIST +

CANNABINOIDS
DRONABINOL- naturally occurring
cannabinoid.
Stimulates CB1 subtype of
cannabinoid receptors on neuron in and
around vomiting center in brain stem.

PHARMACOKINETICS:
Highly lipid soluble drug.
Onset of action within 1 hr. Peak levels
within 2-4hrs.
USE:
E: urine.
Useful prophylactic agent in chemo patients when others are not effec
ADVERSE EFFECTS:
Complex effects on CNS-central sympathomimetic effect.
Palpitation, tachycardia, vasodilation, hypotension.
Abrupt withdrawal --- abstinence syndrome.

OTHER ANTI-EMETICS
GLUCOCORTICOIDS:
DEXAMETHASONE:

Useful for treatment in nausea in

patients with widespread cancer.
Suppress peritumoural inflammation &
PG production.
PHOSPHATED CARBOHYDRATE
SOLUTION:
Aqueous solution of glucose, fructose
and phosphoric acid- relieve nausea.
It is taken for a short period of time.

TYPES OF EMESIS
MOTION SICKNESS
MORNING SICKNESS
(VOMITING DURING
PREGNANCY)
CHEMOTHERAPY/ RADIATION
INDUCED NAUSEA AND
EMESIS (CIE)
POST OPERATIVE EMESIS
VOMITING OF VARIED
ORIGIN & ADJUVANT ANTIEMETIC

TYPES OF EMESIS-MOTION SICKNESS

Result during space flights, taking
off and landing of an aeroplane etc.
It is a labyrinthine vomiting via
stimulation of
vestibular nuclei.
Drugs used:
H1 ANTAGONIST/ CENTRAL
ACTING
ANTICHOLINERGIC.
Hyoscine.
Side effects of hyoscine:
anticholinergic
Blurred vision, dryness of
mouth, cyclopelgia, sedation and
sleepiness.
DIPHENHYDRAMINE, CYCLIZINE,

CINNARAZINE-Anti
vertigo drug.
Used in prevention of
motion sickness.
Acts as antihistaminic,
anticholinergic,
antiserotonin & Ca2+
channel blocker.
Inhibits influx of Ca2+
from endolymph into

TYPES OF EMESIS-MORNING SICKNESS

Morning sickness ( Vomiting
during pregnancy).
During 1st trimester of pregnancy
due to effect of increased
oestrogen levels on CTZ.
DOXYLAMINE- safest drug.
CYCLIZINE, MECLIZINE
VITAMIN B6 (PYRIDOXINE):
High doses (60mg/d) acts as
cofactor for enzyme glutamate
decarboxylase and increases
GABA.
Inhibits neurotransmitter at
CTZ.

TYPES OF EMESIS- CIE

Anti-cancer drugs induce emesis by

direct activation of 5HT3 receptors in
CTZ / may activate vagal and splanchnic
5HT3 receptors to send emetogenic
signals to vomiting center through
neurotransmitters.

ONDANSETRON
GRANISETRON
DOLASETRON
TROPISETRON
PALONOSETRON
RAMOSETRON

TYPES OF EMESIS-POST OPERATIVE

VOMITING

Complications in patients receiving

general anaesthesia.

5HT3 ANTAGONIST- preferred

PROCHLORAZINE- blocks Dopamine 2

and muscarinic receptors.

PROMETHAZINE- potent
anticholinergic and antihistaminic.

TYPES OF EMESIS-VOMITING OF VARIED

ORIGIN
Drug induced vomiting.
Increased intra-cranial pressure induces emesis.
Vomiting in patients due to brain injury, cerebral tumour,
hydrocephalous- increases CSF pressure.
- Activates receptors on CTZ.
NABILONE, DRONABINOL.

REFERENCE
i. Laurence L.B, Bruce A C, Bjorn C K. Goodman and
Gilmans The Pharmacological Basis of Therapeutics.2011.
12th edition. China: Mc Graw Hill books; pp: 1341-6.
ii. Padmaja Udayakumar. Textbook of medical
pharmacology.2nd edition. New Delhi: CBS Publishers and
distributors; pp: 326-9.
iii. Sharma HL , Sharma KK. Principles of pharmacology.2nd
edition. Hyderabad: Paras publisher; pp: 395-9.