anti emetics and prokinetics_pharma.pptx

presentation about Anti emetic and prokinetic Drugs in common practice

1. Antiemetics and Prokinetics Dr. Anubhav Mandal 1 st 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.

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

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

5. Antihistamines-H 1 blockers : H 1 blockers - Diphenhydramine, promethazine, doxylamine , dimenhydrinate , cinnarizine , cyclizine , meclizine; have antiemetic properties. Antiemetic effect: due to sedative, H 1 blockade & 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.

6. 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.

7. Neuroleptics: Potent antiemetic & effect due to blockade of D 2 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.

8. 5-HT 3 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-HT 3 receptor.

9. 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.

10. Aprepitant : Neurokinin receptor antagonist (NK 1 receptor antagonist). Administered both orally & intravenously. Acts as a selective substance P antagonist on NK 1 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-HT 3 antagonist + dexamethasone). Well tolerated, extensively bound to plasma protein (>95%) metabolized by hepatic CYP3A4 & excreted in stool. Flatulence can occur.

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

12. 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.

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

14. Acetylcholine(Ach): major neurotransmitter in the GIT responsible for peristaltic movement. Secretion of Ach is affected by other neurotransmitter. Activation of prejunctional excitatory 5-HT 4 receptors increase the release of Acetylcholine. Activation of prejunctional inhibitory D 2 and 5-HT 3 receptors inhibits the release of Acetylcholine. Prokinetic drugs act by: 5HT 4 agonistic activity. D 2 & 5-HT 3 antagonistic activity.

15. METOCLOPRAMIDE A benzamide like procainamide. Has more prominent effect on upper GIT. Mechanism of action: 5-HT 4 agonistic action - enhances the release of ACh from myenteric plexus. (Main prokinetic action.) D 2 antagonistic action in CTZ - mainly responsible for antiemetic effect. 5-HT 3 antagonistic action - At higher concentration, blocks 5-HT 3 receptors in CTZ.

16. 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 5HT 3 antagonists or dexamethasone or promethazine or diazepam. Vomiting due to radiation sickness but less effective against motion sickness.

17. 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.

18. 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 D 2 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.

19. 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 D 2 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.

20. DOMPERIDONE: Butyrophenone derivative. Antiemetic & prokinetic effects are due to blockade of D 2 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.

21. 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.

22. Cisapride : Dose: 10-20 mg oral TDS Prokinetic action: mainly due to 5-HT 4 agonistic Has weak 5-HT 3 antagonistic activity & no D 2 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.

23. 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 , Z acopride do not cause QT prolongation or arrhythmias.

24. Mosapride : Prokinetic effect due to 5-HT 4 agonistic action. Has weak 5-HT3 antagonistic effect. Does not cause Extrapyramidal symptoms, hyperprolactinemia (no D 2 blocking action). Has no antiemetic effect. Useful in dyspepsia, diabetic gastroparesis , GERD etc. S/E: dizziness, diarrhea, headache etc.

25. Amisulpride : Dopamine(D 2 ) receptors are located in the CTZ which is involved in emesis. Selective D 2 & D 3 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.

26. Itopride : Prokinetic effect due to D 2 -antagonistic action & anticholinesterase activity. Does not cause EPS & drug interactions are rare . Levosulpiride : blocks peripheral & central D 2 receptors-has prokinetic & antiemetic effects and useful in IBS & GERD . Cinitapride : blocks 5-HT 2 & D 2 receptors in the gut and useful in GERD.

27. Cholecystokinin (CCK) is a gastro-intestinal hormone that is released from the intestine in response to meal & slows down gastric emptying. Loxiglumide : CCK 1 receptor antagonist that has been developed mainly to improve & speed up gastric emptying and GIT motility. Prucalopride : Safest analogue of cisapride . Highly selective 5-HT 4 receptor agonist. Used to treat severe constipation.

28. Tegaserod : Selective 5-HT 4 agonist with no action on 5-HT 3 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.

29. 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.

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