Anti-emetics:

Therapy of
nausea and vomiting

Eurek Ranjit,
B. Pharm., M. Sc. (UK), M. Phil. (UK)
EMESIS
In emesis, stomach empties in a retrograde manner.
Pyloric sphincter is closed while esophagus relax to allow
gastric contents to be propelled by forceful, synchronous
contraction of abdominal wall muscles & diaphragm.
Closure of glottis (& elevation of soft palate) prevent entry
of vomitus into trachea & nasopharynx.
Coordination b/w these stages is done by medullary center
for emesis, which is activated by diverse stimuli.
These are conveyed via vestibular apparatus, visual,
olfactory & viscerosensory afferents from upper alimentary
tract.
Psychic experiences may also activate emetic center.
BRIEF OVERVIEW OF EMESIS/VOMITING
Nausea & Vomiting (N & V) may occur in various conditions:
 Pregnancy

 Motion sickness

 Medications

 Disease states: Hepatitis

 Administration of chemotherapy

~70-80% patients undergoing chemotherapy experience N

& V.
~40% experience vomiting in anticipation of chemotherapy
N & V can lead to rejection of potentially curative
chemotherapy
Uncontrolled vomiting: dehydration & nutrient depletion
BRIEF OVERVIEW OF EMESIS/VOMITING-2:
VOMITING CENTRE, CTZ AND NTS

Stimulation of vomiting centre, situated in medulla

oblongata, causes vomiting.
Chemoreceptor trigger zone (CTZ) & Nucleus tractus
solitarius (NTS) are most important areas relaying
afferent impulses.

CTZ
 located in area postrema, which is outside BBB.

 Responds to chemical stimuli in blood, hormones,

toxins, mediators etc.
 BRIEF OVERVIEW OF EMESIS/VOMITING-3:
VOMITING CENTRE, CTZ & NTS
Multiple pathways are involved.
CTZ & NTS expresses variety of receptors, involved in
transmitting emetic signals (targets of antiemetic therapy):
Histamine (H1)
Dopamine (D2)
Serotonin (5-HT3)
Cholinergic (Muscarinic)
Neurokinin NK1
Opioid (µ)
Cannabinoid CB1
Vomiting centre responds to impulse from: vestibular
system, periphery (pharynx & GIT), higher brainstem etc.
Cytotoxic Drugs, Radiation, other
irritants

Damage cells, irritate gut mucosa

Release mediators from mucosa

(e.g. 5HT)

Act on afferent neurones

Send emetogenic impulses to NTS,

CTZ & stimulate Emetic Centre
EMETICS
 Used to induce vomiting ONLY when undesirable
substance are ingested.

Apomorphine:

 Acts as dopaminergic agonist on CTZ.

 Should not be used if respiration is depressed as it has

respiratory depressant action (semi-synthetic derivative of
morphine)

 Has prompt response

Dose: 6mg IM/SC
 EMETICS-2
Ipecacuanha/ Ipecac syrup:
Emetine is the active ingredient present.
Acts reflexly by irritating gastric mucosa and via CTZ.

Contra-indications of emetics:
 Corrosive poisoning (acid, alkali)

 CNS stimulant poisoning (convulsions may be

precipitated)
 Kerosene poisoning (chances of aspiration)

 Unconscious patient (may aspirate the vomitus as

laryngeal reflex probably impaired)
 Morphine poisoning
ANTI-EMETICS
 Drugs used to prevent or suppress vomiting
 Should be used only when cause of vomiting is known

Classification of anti-emetics:
 Anticholinergics/antimuscarinics

[Scopolamine, Dicyclomine]
 H1 antihistamines [Promethazine, Cinnarizine]

 Neuroleptics [Prochlorperazine, Haloperidol]

 Prokinetic drugs [Metoclopramide, Domperidone, Itopride]

 5-HT3 antagonists [Ondansetron, Granisetron, Ramosetron]

 Neurokinin receptor antagonists [Aprepitant, Fosaprepitant]

 Other agents: Cannabinoids [Dronabinol, Nabilone]

 Adjuvant anti-emetics [Dexamethasone]

ANTI-EMETICS:
ANTICHOLINERGICS
Hyoscine hydrobromide (Scopolamine hydrobromide)
Muscarinic receptor antagonist, blocks cholinergic nerve
impulse across vestibular pathway-vomiting centre.
 Very useful in motion sickness

 Brief duration of action, suitable for short brisk journey.

Side effects: sedation & anticholinergic side effects

 Not effective against substances directly acting on CTZ,
thus not useful for vomiting of other aetiologies.

Dose: 200-400 micrograms IM.

Transdermal patch.
Patch to be applied in hairless area behind ear.
ANTI-EMETICS:
ANTICHOLINERGICS-2
Dicyclomine
(Available as Dicyclomine HCl or Dicycloverine HCl)
Uses:
 Prophylaxis of motion sickness

 Morning sickness

 Cleared of teratogenic potential

Adult Dose: Oral:10-20 mg three times daily

 ANTI-EMETICS: H1 ANTIHISTAMINES
Useful in motion sickness & postoperative vomiting.
Mode of action: Via anti-cholinergic, anti-histaminic
actions & through sedative properties.
 To prevent motion sickness, give 1/2-1hr before journey

 Antihistamines suspected to have teratogenic potential.

Avoid in pregnancy (exceptions exist).
Promethazine, diphenhydramine, dimenhydrinate
Sedative, protection of 4-6 hours (motion sickness)
Cyclizine (50mg): less sedative, less anticholinergic
Meclozine (12.5 mg): less sedative, long lasting (24 hrs)
Promethazine theoclate (Avomine) vs P. HCl.
Doxylamine (Sedative with prominent anticholinergic activity)
NEUROLEPTICS
 Block D2 receptor in CTZ.
 Produce sedation and extra-pyriamidal symptoms

 Anti-emetic dose lower than antipsychotic dose

Uses:
 Drug induced & post-anaesthetic N&V

 Disease induced vomiting: gastroenteritis, uraemia,

liver disease, migraine
 Radiation sickness

 Morning sickness: Only hyperemesis gravidarum

 Not useful for motion sickness

NEUROLEPTICS-2
Prochlorperazine
 Labrynthine supressant

 Anti-vertigo and anti-emetic effect

Side effect: Muscle dystonia

Stemetil® 5 mg tabs, 12.5mg/ml ampoule
[Dose: N & V: acute attack, 20 mg initially then 10 mg after
2hrs; prevention 5-10 mg 2-3 times daily]

Another anti-psychotic chlorpromazine is indicated for

N&V of terminal illness.
PROKINETIC DRUGS
Drugs that promote gastrointestinal transit & speed
gastric emptying.
Examples: Metoclopramide, Domperidone (& Cisapride).
Metoclopramide:
Acts via dopaminergic & serotonergic receptors
D2 antagonism:
Dopamine, inhibitory neurotransmitter via D2 receptors
delays gastric emptying, causes gastric dilatation & LES
relaxation, leading to N & V.

Metoclopramide blocks D2 receptors, in both GIT &

CNS (CTZ) causing opposite effect & antiemetic effect.
 PROKINETIC DRUGS-2
Metoclopramide (Cont’d from last slide)
Effect of metoclopramide is independent of vagal innervation.
Effect more prominent in upper GIT.
5-HT4 agonism:
5HT4 activation by Metoclopramide enhances Ach release,
enhancing gastric transit & increasing LES tone.

5-HT3 antagonism:
Blocks 5-HT3 receptors in NTS/CTZ at higher dose.
Mechanism used to control chemo induced vomiting.
 PROKINETIC DRUGS-3
Metoclopramide (Cont’d from last slide)
Drug Interaction: With various drugs. Digoxin absorption
reduced. Levodopa effect blocked.
Side effects: Sedation, diarrhoea, Dopamine receptor blockade
results in gynaecomatsia & extrapyrimidal symptoms with
dystonia. On long term use symptom of parkinsonism can
occur.
Uses: Postoperative, drug induced, disease associated, radiation
sickness induced vomiting.
Chemothreapy induced emesis (Cisplatin, cyclophosphamide)
Gastrokinetic effect: to give emergency general anasethesia
when patient has taken food, facilitate duodenal intubation.
Other uses: Dyspepsia, prevention of hiccups, GERD, as pre
anaesthetic medication
PROKINETIC DRUGS-4
Drugs such as promethazine, diphenhydramine,
diazepam, dexamethasone given IV increases effect of
metoclopramide. (Cancer chemo-induced vomiting)
Domperidone:
D2 antagonist
Antiemetic activity lower than metoclopramide

Cisapride (withdrawn in many countries):

Previously used for GERD. Safety issues with reports
of ventricular arrhythmia (prolonged Q-T interval)
when taken with CYP3A4 inhibitors (azole antifungals,
macrolides)
 5-HT3 ANTAGONISTS/
5-HT3 SEROTONIN RECEPTOR BLOCKERS
Ondansetron, granisetron, dolasetron
 They selectively block 5-HT3 receptors in periphery

(GIT) & in the brain (CTZ)

 Important role in treating chemotherapy associated emesis.

 Long duration of action

 Administered as a single dose prior to chemotherapy

Dose of ondansetron: Oral/ IM 8 mg 1-2 hrs before

chemotherapy, followed by 2 further doses of 8mg at
interval of 2-4 hours (if necessary)

Caution: ECG changes (prolongation of QT interval)

ONDANSETRON: SIDE EFFECTS
Headache, lightheadedness, dizziness, drowsiness,
tiredness, or constipation may occur.
Serious side effects: stomach pain, muscle
spasm/stiffness, vision changes (e.g., temporary loss of
vision, blurred vision).
Rare but very serious side effects: chest pain,
slow/fast/irregular heartbeat, severe dizziness, fainting.

[Note: This medication may increase serotonin & rarely cause a very serious
condition called serotonin syndrome/toxicity. The risk increases if patient is also
taking other drugs that increase serotonin, thus it is vital to take drug history of
the patient ]
NEUROKININ RECEPTOR ANTAGONISTS
Receptor activated by Substance P
Drugs bind to neurokinin (NK1) receptor in area postrema.
Aprepitant is given orally, blocks substance P and its
emetic effect, has little effect on 5HT3 and D2 receptors.
Fosaprepitant is given IV

NK1 antagonists may be used for chemotherapy induced

vomiting in combination with 5HT3 antagonists.
Side effects: Tiredness or hiccups may occur.
Rarely allergic reaction [rash, itching/swelling (especially of
face/tongue/throat), severe dizziness, trouble breathing.]
OTHER ANTI-EMETICS
Pyridoxine is used in prevention of vomiting in pregnancy.
It probably serves as cofactor in GABA synthesis (GABA
is inhibitory neurotransmitter at CTZ & may suppress
vomiting)
Benzodiazepines & Barbiturates may act by raising the
threshold for vomiting by depressing the CNS.
Cannabinoids: Dronabinol may act by stimulation of
cannabinoid receptors in the vomiting centre. Synthetic
cannabinoids dronabinol & nabilone have
antinauseant/antiemetic effects that may benefit AIDS &
cancer patients.
Motilin receptor agonist: Erythromycin
SPECIFIC TYPES OF VOMITING
Pregnancy vomiting occurs in 1st trimester; thus any drug
given can coincide with period of maximal fetal
vulnerability.
Drug should be used only when continuous vomiting
threatens to disturb electrolyte & water balance to a
degree that places fetus at risk.

Drug-induced vomiting.
To prevent vomiting during cancer chemotherapy,
5-HT3-receptor antagonists (ondansetron, granisetron etc)
can be used alone or in combination with glucocorticoids
(methylprednisolone, dexamethasone).
 SPECIFIC TYPES OF VOMITING
Anticipatory N&V in chemotherapy can be attenuated by a
benzodiazepine (as lorazepam)
Dopamine agonist-induced nausea in parkinsonism can be
countered by D2-antagonists that penetrate poorly into
CNS (e.g., domperidone, sulpiride).
Metoclopramide is effective in N&V of GI origin (5-HT4-
agonism) & at high dosage in chemotherapy- &
radiation(low potency antagonism at 5-HT3- & D2).
Phenothiazines (e.g., levomepromazine, perphenazine) may
suppress N&V after certain surgery, or is due to opioid
analgesics, GI irritation, uraemia, & diseases
accompanied by elevated intracranial pressure.
Thank you