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Emetics and antiemetics

Presented by:
Puja Bohora
Sudisha Maharjan
Purnima K.C
Anisha Maharjan
Rupa Rana
Ram Babu Thapa
Sunita Nakarmi
(B.Pharmacy, 3rd yr.)
Emesis
• Emesis is the forceful expulsion of the contents of the stomach and upper
intestinal tract through the mouth.

How does emesis occur?


• Vomiting occurs due to stimulation of the emetic(vomiting) centre situated
in the medulla oblongata.
• The chemoreceptor trigger zone (CTZ) located in the area postrema and
the nucleus tractus solitarius (NTS) are the most important relay areas for
afferent impulses arising in the GIT, throat, and other viscera.
• CTZ is also accessible to blood borne drugs, mediators, hormones, toxins
etc., because it is unprotected by the blood brain barrier (BBB).
• Cytotoxic drugs, radiation, and other g.i. irritants release 5-HT from
enterochromaffin cells→ acts on 5-HT3 receptors present on vagal afferents
and sends impulses to NTS and CTZ.
Contd…
• Released in large quantity, 5-HT may also spill into circulation and reach
CTZ.
• It may as well be released from platelets by inflammatory mediators.
• The CTZ and NTS express a variety of receptors e.g. histamine H1,
dopamine D2, serotonin 5-HT3, cholinergic M and opioid µ through which
the emetic signals are relayed and which could be targets of antiemetic
drug action.
• The vestibular apparatus generates impulses when body is rotated or
equilibrium is disturbed or when ototoxic drugs act, which reach the
vomiting centre mainly relayed from the cerebellum and utilize muscarinic
as well as H1 receptors.
• Various unpleasant sensory stimuli such as bad odour, ghastly sight, severe
pain as well as fear, recall of obnoxious event, anticipation of an emetic
stimulus cause nausea and vomiting through higher centres.
Emetics
The drugs that produce vomiting are called emetics. These are drugs used to
evoke vomiting.
Classification of emetics;
1. Act on CTZ i.e. centrally acting emetics
e.g. Apomorphine and Morphine
2. Peripherally acting emetics
e.g. Alum, cupper sulphate, zinc sulphate, sodium chloride
3. Act reflexly and on CTZ
e.g. Ipecacuanha
Apomorphine
• Apomorphine is semisynthetic derivatives of morphine.
• These are centrally acting emetics.
• Nausea and vomiting is due to direct stimulation of CTZ in the medulla.
• Acts as a dopaminergic agonist on CTZ .
• The drug injected i.m./s.c. in a dose of 6 mg, it promptly induces
vomiting within 5-10 minutes.it shouldn’t be used if respiration is
depressed, because it has inherent respiratory & CNS depressant
actions.
Clinical use:
• Acute cases of poisoning
• Alcohol intoxication
• For the removal of foreign body from esophagus.
Contd…
Adverse effects:
• Weakness
• Sedation
• Drowsiness
• Abdominal discomfort
• Bitter mouth
Contraindications:
• Hernia
• Severe heart diseases
• Peptic ulcer
• Hypertension
• Threatened abortion
Ipecacuanha
• The dried roots of Cephaelis ipecacuanha contains emetine and used as
a syrup ipecac 15-20 ml in adults, 10-15 ml in children, 5 ml in infants for
inducing vomiting.
MOA
It acts by irritating the gastric mucosa as well as through CTZ.
Clinical use; same as apomorphine
Adverse effects
Weakness, sedation, drowsiness, abdominal discomfort, bitter mouth
Contraindications
Hernia, peptic ulcer, severe heart diseases, HTN, threatened abortion
All emetics are contraindicated in:
• Corrosive (acid, alkali) poisoning : risk of perforation and more injury to
esophageal mucosa.
• CNS stimulant drug poisoning : convulsions may be precipitated.
• Kerosene poisoning : chances of aspiration of the liquid due to low
viscosity and chemical pneumonia are high.
• Unconscious patient : may aspirate the vomitus, because laryngeal reflex
is likely to be impaired.
• Morphine or phenothiazine poisoning : emetics are ineffective.
Anti-emetics
• These are drugs used to prevent or suppress vomiting.
• These drugs provide symptomatic relief only.
• The ultimate relief is obtained by the removal of causative factor.
Classification
• H1 antihistaminics : Promethazine, Diphenhydramine, Dimenhydrinate,
Cyclizine , Meclozine, cinnarizine
• 5-HT3 antagonists : Odansetron , Granisetron , Dolasetron
• Prokinetic drugs : Metoclopramide, Domperidone, Cisapride ,
Mosapride
• Neuroleptics : Chlorpromazine, Prochlorperazine, Halopridol etc.
• Anticholinergics :Scopolamine(Hyoscine), Dicyclomine
• Adjuvant antiemetics :

Glucocorticoids; Dexamethasone, Methylprednisolone, Betamethasone


Benzodiazepines ; Lorazepam and Alprazolam
• Cannabinoids : Dronabinol
Antihistamines(H1-blockers)

Dimenhydrinate, Diphenhydramine, Promethazine, Cyclizine


and Meclizine.
• H1-blockers are mainly useful for the prevention of motion sickness and also used
in morning sickness, postoperative and drug induced vomiting.
MOA;
• Their antiemetic effect is due to central anticholinergic effect.
Promethazine also blocks the postsynaptic dopaminergic
receptor in the brain and has a strong adrenergic blocking
effect.
• They probably act on the vestibular apparatus or cortex.
• Sedative effect also contributesto their beneficial effect.
Contd…
Pharmakokinetics; H1- antihistamines are well absorbed after
oral and parenteral administration. They are widely distributed
throughout the body, metabolized extensively in liver and excreted in
urine.
Continued...
• Clinical uses; prophylaxis of motion sickness, drug induced and
postoperative vomiting, common cold, preanesthetic medication(
promethazine), allergic reactions, short term management of insomnia,
vertigo etc.
• Side effects; CNS depression, sedation, drowsiness, headache,
fatigue, weakness, lassitude, paradoxical excitation in children, dryness
of mouth, blurring of vision, constipation and urinary retention,
glaucoma, tachycardia, hypotension (promethazine).
Continued. .
Dose
Promethazine: 12.5-25 mg 6-8 hourly, maximum 100 mg daily,
Diphenhydramine: 25-50 mg 6-8 hourly
Maximum 300 mg daily
Contraindications :
• Hypersensitivity, coma, cardiac diseases, pregnancy, lactation,
hypokalemia, intra-arterial or SC inj. and must be administered
carefully and slowly; incorrect administration can lead to severe tissue
injury.
5-HT3 antagonists
Ondansetron, Granisetron , Dolasetron
• Ondansetron is a prototype drug.
• Granisetron is more potent, more efficacious and have longer duration
of action than that of ondansetron.
MOA
• 5-HT3 receptor depolarizes neurones by opening cation channels; elicits
reflex effects of 5-HT3 →emesis, gut peristalsis, bradycardia, transient
hypotension, apnoea, pain, itch.
• 5-HT3 antagonists blocks the depolarizing action of 5-HT through 5-HT3
receptors on vagal afferents in GIT as well as in NTS and CTZ.
Continued…
• Cytotoxic drugs/ radiation produce nausea and vomiting by causing
cellular damage → release of mediators including 5-HT from
intestinal mucosa → activation of vagal afferents in the gut →
emetogenic impulses to the NTS and CTZ.
• Ondansetron blocks emetogenic impulses both at the peripheral
origin and their central relay.
• It does not block dopaminergic receptors and apomormine or motion
sickness induced vomiting.
Contd…
Pharmacokinetics
5-HT3 antagonists are well absorbed after oral administration,
Ondansetron undergoes extensive first pass metabolism. The
metabolites are excreted in urine and faeces. These agents are also
available for intravenous administration.
Uses :
Postoperative nausea and vomiting , prevention as well as treatment of
nausea and vomiting associated with cancer chemotherapy and
radiotherapy, morning sickness.
Adverse effect
Headache, dizziness, diarrhea, fatigue, anxiety, urinary retention,
pruritus, rashes.
Contd…
Doses
Ondansetron : for Cisplatin and other highly emetogenic drugs- 8 mg
i.v. by slow injection over 15 min, 30 min before chemotherapeutic
infusion , followed by 2 similar doses 4 hour apart .
For postoperative nausea/vomiting 4-8 mg 8 hourly.
Granisetron : PO nausea and vomiting associated with cancer
chemotherapy 1-2 mg within 1 hr. before start of chemotherapy , then
2 mg /day.
I.v. nausea & vomiting associated with cancer chemotherapy 3 mg
before start of chemotherapy.
Contraindications:
• Use with Apomorphine causes profound hypotension
Prokinetic drugs
• These are the drugs that promote coordinated movement of upper
GIT and hasten gastric emptying.
• Also called as gastroprokinetic agent or gastrokinetic.
• Used to relieve gastrointestinal symptoms such as abdominal
discomfort , bloating ,constipation , heart burn, nausea, and vomiting.
• Examples : metoclopramide, domperidone , cisapride .
Metoclopramide
• Is rapidly absorbed after oral administration.
• Can also be given intra-muscularly or intra-venously .
• Onset of action: half an hour on oral and few minutes on parenteral
administration.
• Half life : 4 hours
• Poorly bound to plasma protein and crosses BBB.
MOA
• Metoclopramide shows antiemetic effect by blocking D2 receptor
in CTZ and in basal ganglia and stops signaling stimuli to vomiting
centre.
• At higher concentration, it also blocks 5-HT3 receptor in CTZ .
Prokinetic effects on upper GIT
• Metoclopramide enhance release of ACh from myenteric neurons.
• The prokinetic effect on upper GIT is mediated by muscarinic
activity, D2 receptor antagonist activity and 5-HT4 receptor agonist as
well as 5-HT3 antagonist activity.
• The prokinetic effect on GIT are:
1. Increase in tone of lower oesophageal sphincter (LES).
2. Relaxation of pyloric sphincter.
3. Increase in peristalsis movement of small intestine.
Thus, it promotes forward movement of content in the upper GIT.
Contd…
Metoclopramide

5-HT4 agonism D2 antagonism 5-HT3 antagonism

Increases ACh secretion from the myenteric motor


neurons
Uses
• As antiemetic in:
Disease associated vomiting.
Drug induced vomiting(not in levodopa induced vomiting).
Postoperative vomiting
Cancer chemotherapy induced vomiting.
Radiation sickness
• Symptomatic relief in GERD.
• To alleviate symptoms associated with gastric stasis ( upper abdominal
discomfort, distension, bloating, nausea etc.).
• To stimulate gastric emptying during GI radiological procedures.
• In the treatment of intractable hiccups.
• Used in post surgical and diabetic hyperemesis.
Dose
Adult : 10mg tid PO
10 mg tid IM/IV
Child : Less than 10 kg – 1 mg 12 hourly
10-14 kg : 1mg bid/tid
15-19 kg : 2mg bid/tid
20-29 kg : 2.5 mg tid
More than 30 kg: 5mg tid
Adverse effects
• Drowsiness, dizziness and diarrhea.
• Extrapyramidal symptoms(EPS) like tremor, rigidity, etc. can be seen.
• Acute dystonias can occur.
• Long term use can lead to gynaecomastia, galactorrhoea and
menstrual irregularities due to blockade of inhibitory effect of
dopamine on prolactin release.
Contraindicated
• Seizure disorder
• GI disorder eg. diarrhea
• Phaeochromacytoma , breast cancer
Domperidone
• Effect almost similar to metoclopramide but less potent and less
efficacious.
• Usually given orally.
• Poorly crosses BBB, hence EPS are rare so, preffered as antimetic in
children.
• It is preffered over metoclopramide to treat vomiting induced by
levodopa or bromocriptine without affecting their anti-parkinsonian
effect as it poorly crosses BBB.
MOA
It shows antiemetic and prokinetic effect by blocking D2 receptor in
CTZ and GI respectively.
Adverse effects
• Dryness of mouth, diarrhoea, headache.
• Skin rashes
• Galactorrhoea and menstrual irregularities.
Dose
• Adult : 10-20 mg tid or qid
• Child : 0.2 mg- 0.4 mg/kg tid or qid
(Note : children are not usually recommended)
Neuroleptics
• Are potent antiemetics.
• Effective in the treatment of vomiting due to drugs, uraemia and
systemic infections.
• Not used for morning sickness.
• Less effective in motion sickness.
• Not as effective as ondansetron and metoclopramide in cytotoxic
drug induced vomiting and radiation sickness.
• Eg. : prochlorperazine, chlorpromazine, fluphenazine, haloperidol.
MOA
They show antiemetic effect by blocking D2 receptor in CTZ.
Adverse effects
• Sedation
• EPS like rigidity, tremor, etc.
• Dryness of mouth, constipation
• Hypotension
• Acute dystonias
Anticholinergics
Examples :Scopolamine (hyoscine), dicyclomine
• Scopolamine is the drug of choice to prevent motion sickness.
• It can be administered orally(0.2 mg) half an hour before journey or
as transdermal patch at least 4-5 hours before journey.
• Effect of transdermal patch last for 72 hours.
• Not effective for other types of vomiting.
MOA
By it’s anticholinergic action on muscarinic receptor present on
vestibular apparatus, suppresses vestibular disturbances and blocks
afferent impulses to vomiting centre. Hence, shows antiemetic effect.
Adverse effects
• Dryness of mouth, constipation
• Blurring of vision, headache
• Tachycardia, palpitation,hypotension
• Sedation and amnesia

Cannabinoids
Examples: dronabinol
• It is principal psychoactive component of marijuana.
• Used to prevent chemotherapy induced vomiting not responding to other
antiemetics.
• Because of it’s serious side effects like sedation, hallucination,
disorientation, tachycardia, palpitation, increased appetite and drug
dependence, kept as reserve antiemetic.
Adjuvant anti-emetics
Glucocorticoids
• Examples : dexamethasone, betamethasone, methylprednisolone
• They are commonly used corticoids in combination with ondansetron
or metoclopramide in the treatment of anti-cancer drug induced
vomiting.
• They increase antiemetic activity.

Benzodiazepines
• Examples : lorazepam, alprazolam
• Used to control psychogenic and anticipatory vomiting.
• Their beneficial effect is mainly due to their sedative , amnesic and
antianxiety effects.