ANTIEMETICS Dr.

Bikram Tewari
EMESIS/VOMITING - BACKGROUND
Emetic Response: Relaxation of fundus, body of stomach and
also the oesophageal sphincter and oesophagus – but
contraction of pylorus and duodenum in retrograde manner –
then rythmic contraction of diaphragm and abdominal muscles
- expulsion of abdominal content via mouth

Vomiting Centre: Medulla Oblongata

Relay Centers: chemoreceptor trigger zone (CTZ) and nucleus

tractus solitarius (NTS)
Afferent impulses: GIT, throat and other viscera
Triggering agents: Blood borne drugs, mediators, hormones
and toxins etc. – clinically cytotoxic drugs and radiation
Transmitter: 5-HT (enterochromaffin cells) – act on 5HT3
receptor of ENS – these neurons are connected to vagal and
spinal visceral neurones ---impulse transmitted to CTZ and NTS
Spilling of 5-HT due to massive release – acts on CTZ via
vascular route
 EMESIS/VOMITING – CONTD.
Other mediators: H1, D2, 5HT3, Muscarinic M and opioid µ etc. –
expressed in CTZ and NTS
Vestibular apparatus: generates impulses
 When body is rotated
 Body equilibrium disturbed
 Ototoxic drugs
Mainly relayed by cerebellum to vomiting centre – Muscarinic and H1
receptors
Directly in higher centres: Bad smell, ghastly sight, recall of an obnoxious
event, pain, fear etc. – drug cisplatin
ANTIEMETICS
1. Anticholinergics:
Hyoscine, Dicyclomine
2. H1 antihistaminics:
Promethazine, Diphenhydramine, Dimenhydrinate, Doxylamine,
Cyclizine, Meclizine and Cinnarazine
3. Neuroleptics (D2 blockers):
Chlorpromazine, Triflupromazine, Prochlorperazine and Haloperidol
4. Prokinetics:
Metoclopramide, Domperidone, Cisapride, Mosapride ,Itopriide and
Tegaserod
5. 5HT3 antagonists:
Ondansetron, Granisetron, Palonosetron, Ramosetron
6. Newer Ones:
NK1 receptor antagonist – Aprepitant, Fosaprepitant
7. Adjuvant:
Dexamethasone, Benzodiazepines and Cannabinoids
(dronabinol, Nabilone)
ANTICHOLINERGICS
Hyoscine: Motion Sickness (0.2 to 0.4 mg IM)
 Used IM/SC, but short duration of action
 MOA: Blocking of cholinergic link of vestibular apparatus to the vomiting centre –
does not work in vomiting due to other aetiology
 ADRs: Sedation, dry mouth and other anticholinergic effects
 Transdermal delivery system (1.5 mg)
Dicyclomine: Prophylaxis of motion sickness and morning sickness
H ANTIHISTAMINICS
1

Primarily used in motion sickness, morning sickness and some other

vomiting in lesser extent –
Other actions: anticholinergic and antidopaminergic actions
Promethazine (Phenothiazine), diphenhydramine: (highly sedative)
4 – 6 Hours protection
 Combined with metoclopramide in chemotherapy induced nausea and vomiting:
additive effect plus counters extra pyramidal effects
Promethazine theoclate (Avomine) – motion sickness
Doxylamine: Sedative H1 antihistaminic – marketed in combination with
Pyridoxine – specifically for morning sickness – duration of action 10
Hours (at bed time) – drowsiness, dry mouth, vertigo

Meclizine: Long duration of action – sea sickness

Cinnarizine: anti vertigo action – inhibits Ca++ influx from endolymph
into the vestibular sensory cells—inhibits labyrinthine
reflexes
MOTION SICKNESS AND MORNING SICKNESS
Motion Sickness:
Anticholinergics are preferred – followed by H1 Antihistaminics
Antidopaminergics do not work
Administered 0.5-1hr before commencing journey
Morning Sickness:
Preferably drugs should be avoided
Reassurance and dietary modification
 Doxylamine, Dicyclomine, Promethazine or Metoclopramide are preferred at low
doses
NEUROLEPTICS
Uses:
Useful in drug induced post anaesthetic nausea and vomiting
Disease induced vomiting – Gastroenteritis, Uraemia, liver disease
Cancer chemotherapy
Radiation sickness (less)
Morning sickness
ADRs:
 Sedation, acute muscle dystonia
 Diagnose the cause first before administering
Prochlorperazine (Stemetil)
 D2 blocking agent - labyrinthine suppressant
 Antivertigo and antiemetic action.
 Effective in Chemotherapy induced nausea and vomiting with
vertigo

A/E:
EPS and muscle dystonia
PROKINETICS - METOCLOPRAMIDE
Actions on GIT: On upper GIT - Increases gastric peristalsis
 Relaxes pylorus and 1st part of duodenum – better gastric emptying
 LES tone increased – also increases Intestinal peristalsis
Actions on CNS: Acts on CNS – can counter Apomorphine induced
vomiting
 Gastrokinetic action contributes
 No antipsychotic property, but has extra pyramidal and prolactin secreting effects
(Promethazine context)
 METOCLOPRAMIDE – CONTD. - MOA
1. D2 antagonism:
Dopamine is inhibitory transmitter in GIT via D2 receptor
– delays gastric emptying
– also relaxation of LES
– nausea and vomiting
Metoclopramide causes opposite effect
 Also central antidopaminergic action causing EPS & hyperprolactinaemia
2. 5-HT4 agonism:
Enhanced Acetylcholine release in myenteric plexus – gastric
hurrying and increased LES tone
3. 5-HT3 antagonism: (antiemetic)
At high concentrations block 5HT3 receptors on myenteric
interneurons and in CTZ /NTS
Pharmacokinetics:
Onset Of Action: Oral: 0.5-1hr
I.M: 10 min
I.V: 2 min
T 1/2 = 4 – 6 Hrs.
SITES OF ACTION OF PROKINETICS
Stimuli – cause 5-HT
release

Stimulates extrinsic and

intrinsic pathway via
peripheral 5-HT3 receptors
Extrinsic pathway – via
vagus and dorsal root
ganglia – CNS - vomiting –
blocked by ondansetron
Intrinsic pathway – excitatory and
inhibitory interneurones co-ordinates
peristalsis
 Contraction of proximal and relaxation of
distal gut muscles
 Ach/CGRP and NANC (NO)
 Prokinetics (Meto and Csprd) – activates
prejunctional 5-HT4 – promote release of
Ach/CGRP – contractile activity
 Also weak 5-HT3 blocking action (inhibitory
neurones)
 Meto and Csprd also inhibits D2 action
normally D2 inhibits release of ACh – hence
increase release of Ach- Peristalsis
METOCLOPRAMIDE – CONTD.
ADRs: Sedation, dizziness, loose stool and muscle dystonia
Prolonged use: Parkinsonism, galactorrhoea, gynaecomastia
Safe in pregnancy but in lactating mother children may have loose stool,
dystonia etc.
DI – abolishes levodopa action
Uses:
Antiemetic: Postoperative, drug induced, disease associated,
radiation induced etc. but not effective in motion sickness. Still
preferred in vomiting due to anticancer drug – in combination with
Promethazine
Gastrokinetic: To accelerate gastric emptying – Emergency GA,
gastroparesis (post vagotomy), duodenal intubation etc.
Dyspepsia: stops hiccup
GERD: Does not aid in healing, PPIs are preferred – used as
adjuvant
DOMPERIDONE
Chemically related to haloperidol but action like Metoclopramide
D2 antagonist – in upper GIT
Rarely EP side effect – does not cross BBB, but hyperprolactinemia occurs
Acts mainly through CTZ – outside BBB
Does not abolish action of levodopa
ADRs: Less than Metoclopramide – dry mouth, loose stool, headache,
galactorrhoea etc. Arrhythmia on injection
Uses: Similar as Metoclopramide but milder spectrum of action – not
effective in chemotherapy
Read yourself (Prokinetics) – Cisapride, mosapride, Itopride etc.
5-HT3 ANTAGONIST - ONDANSETRON
Developed for Chemotherapy/radiotherapy induced vomiting
– also effective in others (PONV)
MOA: Acts peripherally as well as centrally - Blocks
depolarizing action of 5-HT3 receptors in vagus at GIT and
CTZ/NTS
No action on Dopamine receptor – does not block Apomorphine
induced vomiting and mild gastrokinetic effect
Kinetics: T1/2 life 5-7 Hrs
Dose: 8 mg slow IV for 15 minutes ½ hr before
chemotherapy.
Followed by 2 such doses 4 hours apart.
Then 8 mg orally twice daily for 1 week.
For other conditions: 4 – 8 mg IV followed by every 8
hourly.
80% success – better/equal to Metoclopramide – no
dystonia or sedation.
Adjuvants improve response.
ONDANSETRON – CONTD.
ADRs: Headache and dizziness. Mild constipation and abdominal
discomfort, Hypotension, allergic reactions, chest pain and
bradycardia etc.
Other Drugs:
Granisetron-10 times more potent than ondansetron
Palonosetron-longest duration of action
-effective in delayed onset vomiting (2nd-5th day)
Ramosetron
NK1 RECEPTOR ANTAGONIST
Aprepitant: Newer antiemetic
MOA: Emetogenic chemotherapy releases Substance P –
stimulates CTZ and NTS by acting on NK1
Blockade of NK1 receptors causes antiemetic action
Little effect on 5-HT3 or D2 receptor
GIT motility not affected
Uses: 125 mg + 80 mg + 80 mg oral for 3 days with IV
Ondansetron and Dexamethasone – for cisplatin induced
vomiting
Useful in multiple cycle patients – Orally 40 mg can be
used for PONV
Kinetics: Well absorbed orally
T 1/2 10 – 13 Hrs
ADRs: Weakness, fatigue, flatulence etc.
ADJUVANT ANTIEMETIC
Corticosteroids, Benzodiazepines and cannabinoides
THANK YOU
EMETICS
Drugs which induce vomiting
Apomorphine: Morphine derivative – semi-synthetic –
Dopaminergic agonist in CTZ
6 mg IM/SC – acts within 5 minutes
Respiratory depression
Orally – not recommended (large dose – slow inconsistent)
Parkinsonism
Ipecacuanha: Cephaelais ipecacuanha
Syrup ipecac – 15 to 30 ml (10 to 15 in child)
Action takes 15 minutes
MOA: Irritation of Gastric mucosa and directly on CTZ
 HOUSEHOLD EMETICS ?
Salt water
•Warm water – mild emetic
2 spoonful of common salt in 1 pint (~0.5 L) of warm water
Mustard seed
1 table spoonful ground mustard seeds in half-pint of warm
water
Strong coffee is one of the best domestic stimulants, especially
after a narcotic poison
NEVER GIVE EMETICS !

In Corrosive poisoning – acid and alkali (why?)

In CNS stimulant poisoning
To unconscious patients
In Morphine and Phenothiazine poisoning