The document discusses various antiemetics and prokinetics used in treating nausea and vomiting, detailing their mechanisms, uses, and side effects. It covers categories such as emetics, antihistamines, anticholinergics, neuroleptics, 5-HT3 receptor antagonists, and prokinetics like metoclopramide and domperidone. It also highlights contraindications and specific drug mechanisms affecting gastrointestinal motility and symptoms associated with various conditions.

1. Antiemetics and Prokinetics
Dr. Anubhav Mandal
1st
year PGT
Department of pharmacology

2. Emesis:
 Nausea & vomiting: protective reflexes to remove toxic substances from
the gastrointestinal tract.
 Nausea: feeling of impending vomitus.
 Vomiting: forceful expulsion of contents of stomach & upper intestinal
tract through mouth.
 Retching: is the laboured rhythmic gag - precedes vomiting; involving
contraction of abdominal & intercostal muscles with diaphragm against a
closed glottis.

4. Emetics:
• Commonly used emetics:
a) Apomorphine a semi-synthetic morphine derivative - stimulates
dopamine receptors in CTZ.
1. Administered parenterally (SC or IM).
b) Ipecacuanha(syrup ipecac) produced from roots of Cephalis cuanha.
1. Stimulates CTZ and active principle- emetine.
2. Administered orally & safer than apomorphine.
c) Saline water or mustard powder - domestic emetics.

5. Contraindications:
 Hypertension.
 peptic ulcer.
 Pulmonary tuberculosis.
 Uremia.
 Pregnancy.
Should be avoided in:
 corrosive poisoning (↑ intragastric pressure –> perforation)
 petroleum product poisioning (lipoid aspiration pneumonia)

8. Antihistamines-H1 blockers:
• H1 blockers - Diphenhydramine, promethazine, doxylamine,
dimenhydrinate, cinnarizine, cyclizine, meclizine; have antiemetic
properties.
• Antiemetic effect: due to sedative, H1blockade & central anticholinergic
actions.
• Cyclizine & meclizine have less sedative effect.
• Meclizine has long duration of action (24hrs).
• Mainly used for the prevention of motion sickness.
• Effective in postoperative & other types of vomiting.

9. Anticholinergics:
• Motion sickness-symptoms: nausea, headache, vomiting, salivation,
sweating etc.
• Scopolamine (hyoscine): drug of choice to prevent motion sickness.
• Blocks afferent impulses from vestibular apparatus to vomiting
centre by its anticholinergic action.
• Administered orally, intramuscularly or as transdermal patch.

10. Neuroleptics:
• Potent antiemetic & effect due to blockade of D2 receptors in CTZ.
• Have anticholinergic & antihistaminic actions.
• Prochlorperazine is commonly used as an antiemetic & can be used
in hyperemesis gravidarum (in low doses).
• Effective in the treatment of vomiting due to drugs, uremia and
systemic infections, less effective in motion sickness.
• Used for treatment of chemotherapy & radiation induced
vomiting.
• S/E: sedation, muscle dystonia, hypotension , dryness of mouth.

11. 5-HT3 RECEPTOR ANTAGONISTS:
• Well absorbed after oral administration.
• Available for intravenous administration.
• Ondansetron: available as mouth dissolving tablets.
• Granisetron: is more potent & longer acting than ondansetron.
Transdermal patch available for prevention of chemotherapy induced
vomiting.
• Ramosetron: can be administered both orally & intravenously.
• Palonosetron: has longest duration of action, most potent & has
maximum affinity for 5-HT3 receptor.

12. Adverse effects:
 Can cause headache, dizziness, diarrhea etc.
 Most common S/E of Ondansetron is: Headache.
 QT prolongation: Palonosetron; if co-administered with
moxifloxacin/erythromycin.

13. Aprepitant:
• Neurokinin receptor antagonist (NK1 receptor antagonist).
• Administered both orally & intravenously.
• Acts as a selective substance P antagonist on NK1 receptor.
• Blocks the action of substance P in CTZ & NTS.
• Highly effective in prevention of delayed emesis following moderately or
highly emetogenic chemotherapy.
• Increases efficacy of standard antiemetic regimen (5-HT3 antagonist +
dexamethasone).
• Well tolerated, extensively bound to plasma protein (>95%) metabolized
by hepatic CYP3A4 & excreted in stool.
• Flatulence can occur.

14. Adjuvant antiemetics:
Cannabinoids:
1) Dronabinol- obtained from marijuana plant or synthesized.
2) Used to prevent cancer chemotherapy induced vomiting not
responding to other antiemetics.
3) Effective orally.
4) Side effects-
a) Sedation, Hallucination, disorientation.
b)Central sympathomimetic effects (tachycardia, palpitation,
hypotension).
c) Drug dependence.

15. Glucocorticoids-
• Dexamethasone, betamethasone, methylprednisolone.
• Used in combination with ondansetron or metoclopramide for
chemotherapy induced acute & delayed vomiting.
• Benificial effect - anti-inflammatory property.
Benzodiazepines-
• Lorazepam, diazepam and alprazolam.
• Used to control psychogenic & anticipatory vomiting.
• Benificial effect: sedative, amnesic and anxiolytic effects.

16. PROKINETICS:
• Drugs that promote GI motility & speed of gastric emptying by
enhancing peristalsis.
• Examples:
• Metoclopramide.
• Domperidone.
• Cisapride, Mosapride.
• Renzapride, Itopride,Prucalopride.
• Levosulpiride.
• Tegaserod.

17. • Acetylcholine(Ach): major neurotransmitter in the GIT responsible for
peristaltic movement.
• Secretion of Ach is affected by other neurotransmitter.
• Activation of prejunctional excitatory 5-HT4 receptors increase the release
of Acetylcholine.
• Activation of prejunctional inhibitory D2 and 5-HT3 receptors inhibits the
release of Acetylcholine.
• Prokinetic drugs act by:
• 5HT4 agonistic activity.
• D2 & 5-HT3 antagonistic activity.

19. METOCLOPRAMIDE
• A benzamide like procainamide.
• Has more prominent effect on upper GIT.
• Mechanism of action:
• 5-HT4 agonistic action - enhances the release of ACh from myenteric
plexus. (Main prokinetic action.)
• D2 antagonistic action in CTZ - mainly responsible for antiemetic
effect.
• 5-HT3 antagonistic action - At higher concentration, blocks 5-HT3
receptors in CTZ.

20. Prokinetic effect on upper GIT-
• ↑ lower esophageal sphincter (LES) tone.
• ↑ tone & amplitude of antral contractions.
• Relaxation of pyloric sphincter.
• ↑ peristalsis of small intestine & forward movement of contents of upper GIT.
• Does not have significant effect on motility of colon.
USES:
• As an anti-emetic in:
• Disease associated vomiting.
• Drug induced vomiting (not used to control levodopa-induced vomiting).
• Postoperative vomiting.
• Cancer chemotherapy-induced vomiting: is used in combination with 5HT3 antagonists
or dexamethasone or promethazine or diazepam.
• Vomiting due to radiation sickness but less effective against motion sickness.

21. • Gastroesophageal reflux disease(GERD):
• Symptomatic relief in patients with reflux esophagitis by increasing the
tone of LES.
• Reduces volume of GI contents that reflux into esophagus.
• Alleviate symptoms associated with gastric stasis in patients with
diabetes, postoperative or idiopathic gastroparesis.
• Stimulate gastric emptying before general anaesthesia in emergency
surgeries.
• Treatment of intractable hiccups.

22. • PHARMACOKINETICS:
• Rapidly absorbed after oral administration & can also be given
by IM/IV routes.
• Has short half-life of 4 hours.
• Poorly bound to plasma protein & crosses blood brain barrier.
• Partly metabolized & excreted in urine.
• DRUG INTERACTION:
• Metoclopramide & levodopa: Metoclopramide crosses BBB &
blocks D2 receptors in basal ganglia and interferes with the
anti-parkinson effect of levodopa.
• Accelerates the absorption of diazepam but reduces digoxin
absorption by its prokinetic effect.

23. ADVERSE EFFECTS:
• Drowsiness, dizziness, diarrhea etc.
• Extrapyramidal symptoms: muscle rigidity, tremor, acute dystonia
(spasm of muscles of face, tongue, neck & back) due to blockade of D2
receptor in basal ganglia(drug induced parkinsonism) – treated with
promethazine/diphenhydramine.
• On long term use: gynaecomastia, galactorrhea and menstrual
irregularities occur due to blockade of inhibitory effect of dopamine on
prolactin release.

24. DOMPERIDONE:
• Butyrophenone derivative.
• Antiemetic & prokinetic effects are due to blockade of D2 receptors.
• Less potent & less efficacious than metoclopramide.
• Poorly crosses BBB, Extrapyramidal side effects are rare.
• Atropine blocks the prokinetic effect of metoclopramide but not
domperidone.
• Administered orally but oral bioavailability is low because of
extensive first-pass metabolism.
• Metabolized in liver & metabolites are excreted in urine.
• Preferred antiemetic in children.

25. • Increases prolactin level.
• Counteracts vomiting induced by levodopa or bromocriptine
without affecting their anti-parkinsonian effect, so preferred
over metoclopramide.
• Side effects:
• Dryness of mouth
• Diarrhea
• Headache
• Skin rashes
• Galactorrhea & menstrual irregularities.

26. Cisapride:
• Dose: 10-20 mg oral TDS
• Prokinetic action: mainly due to 5-HT4 agonistic
• Has weak 5-HT3 antagonistic activity & no D2 antagonistic activity.
• Uses-GERD (primary indication), non ulcer dyspepsia, impaired
gastric emptying and constipation etc.
• Side effects: Abdominal cramps & diarrhea, dizziness, rise in serum
transaminase.

27. • Can cause QT prolongation when used with drugs which inhibits
CYP3A4 enzyme. E.g: fluconazole, ketoconazole, erythromycin,
clarithromycin, antidepressants like nefazodone.
• Due to QT prolongation & ventricular arrhythmias, it has been
withdrawn in USA but still available in India.
• Congeners: Mosapride (5mg oral TDS), Renzapride, Zacopride do
not cause QT prolongation or arrhythmias.

28. Mosapride:
• Prokinetic effect due to 5-HT4 agonistic action.
• Has weak 5-HT3 antagonistic effect.
• Does not cause Extrapyramidal symptoms, hyperprolactinemia
(no D2 blocking action).
• Has no antiemetic effect.
• Useful in dyspepsia, diabetic gastroparesis, GERD etc.
• S/E: dizziness, diarrhea, headache etc.

29. Amisulpride:
• Dopamine(D2) receptors are located in the CTZ which is involved
in emesis.
• Selective D2 & D3 receptor antagonist.
• US-FDA approved drug, for the prevention of postoperative
nausea & vomiting alone or in combination with other
antiemetics.
• Administered 5 mg as a single IV dose at time of induction of
anaesthesia.
• A/E: increased prolactin level, chills, infusion site pain,
hypotension, hypokalemia etc.

30. • Itopride:
• Prokinetic effect due to D2-antagonistic action &
anticholinesterase activity.
• Does not cause EPS & drug interactions are rare.
• Levosulpiride: blocks peripheral & central D2
receptors-has prokinetic & antiemetic effects and useful
in IBS & GERD.
• Cinitapride: blocks 5-HT2 & D2 receptors in the gut and
useful in GERD.

31. • Cholecystokinin (CCK) is a gastro-intestinal hormone that is released
from the intestine in response to meal & slows down gastric emptying.
• Loxiglumide:
• CCK1 receptor antagonist that has been developed mainly to improve & speed
up gastric emptying and GIT motility.
• Prucalopride:
• Safest analogue of cisapride.
• Highly selective 5-HT4 receptor agonist.
• Used to treat severe constipation.

32. Tegaserod:
• Selective 5-HT4 agonist with no action on 5-HT3 receptors.
• Mainly augments colonic motility along with promotion of gastric
emptying & intestinal transit.
• Has less effect on LES tone.
• Used in constipation & irritable bowel syndrome.

33. Macrolides (motilin agonists):
• Drugs- erythromycin, azithromycin, clarithromycin.
• Directly stimulate motilin receptors on GIT smooth muscle.
• Have no effect on colonic motility.
• Standard dose of erythromycin used for gastric stimulation is: 40 mg IV
or 200-250 mg orally TDS.
• Can be used to improve gastric emptying in patients with diabetic
gastroparesis and in small bowel dysmotility(seen in pseudo-
obstruction).
• Tolerance develops rapidly to its prokinetic effects.

34. Thank you