EMETICS AND ANTIEMETICS and classificationppt
- 1. EMETICS & ANTIEMETICS © 2008 Chettinad Hospital & Research Institute
- 2. EMETICS AND ANTIEMETICS Nausea and vomiting are thought to be protective reflexes that serve to rid the gastrointestinal tract (GIT) of toxic substances. They are the symptoms of altered functions but are not diseases.
- 3. EMETICS AND ANTIEMETICS (Contd..) Nausea denotes the feeling of impending vomiting, whereas vomiting refers to the forceful expulsion of the contents of the stomach and upper intestinal tract through the mouth. Retching is the laboured rhythmic respiratory activity which usually precedes vomiting.
- 4. MECHANISM OF VOMITING The act of vomiting is a complex reflex action which is controlled by the vomiting centre in the medulla. Stimuli are relayed to this centre from peripheral areas, i.e. gastric mucosa and other parts of GIT. Sensory stimuli also arise within the central nervous system (CNS) itself (i.e. cerebral cortex and vestibular apparatus), and the impulses are transmitted to the vomiting centre
- 5. MECHANISM OF VOMITING (Contd..) The lack of a blood-brain barrier at the chemoreceptor trigger zone (CTZ) allows it to be directly stimulated by blood-borne drugs and toxic substances. Nausea and vomiting may be the symptoms of pregnancy or serious organic disturbances of almost any of the viscera or may be produced by infections, drugs, radiation, painful stimuli, metabolic and emotional disturbances, or due to travel sickness.
- 6. MECHANISM OF VOMITING (Contd..) The main neurotransmitters involved in the control of vomiting are acetylcholine (ACh), histamine, 5-hydroxytryptamine (5-HT) and dopamine.
- 7. EMETICS The drugs that produce vomiting are called emetics. Mustard and common salt act peripherally by irritating the stomach and are used as household emetics. Morphine and apomorphine are centrally acting emetics. They induce vomiting by stimulating CTZ. Syrup ipecac is a safe emetic.
- 8. EMETICS (Contd..) It has both central and peripheral actions. Emetics are indicated in certain cases of poisoning. Contraindications for the use of emetics are: 1. Children 2. Comatose patients 3. Corrosive and caustic poisoning 4. CNS stimulant drug poisoning 5. Kerosene poisoning.
- 10. ANTIEMETICS The drugs that are used to prevent or control vomiting are called antiemetics
- 11. CLASSIFICATION 1. Anticholinergics: Scopolamine (hyoscine). 2. Antihistamines (H1-blockers): Dimenhydrinate, diphenhydramine, cyclizine, meclizine, hydroxyzine and promethazine. 3. 5-HT3-receptor antagonists: Ondansetron, granisetron and dolasetron.
- 12. CLASSIFICATION (Contd..) 4. Prokinetic drugs: Metoclopramide, domperidone, cisapride and mosapride. 5. Neuroleptics: Chlorpromazine, fluphenazine, prochlorperazine and haloperidol
- 13. CLASSIFICATION (Contd..) 4. Prokinetic drugs: Metoclopramide, domperidone, cisapride and mosapride. 5. Neuroleptics: Chlorpromazine, fluphenazine, prochlorperazine and haloperidol 6. Cannabinoids: Dronabinol.
- 14. CLASSIFICATION (Contd..) 7. Adjuvant antiemetics. a. Glucocorticoids: Betamethasone, dexamethasone and methylprednisolone b. Benzodiazepines: Lorazepam and alprazolam.
- 16. ANTICHOLINERGICS Scopolamine (hyoscine) is the drug of choice used to prevent motion sickness . It blocks the afferent impulses to the vomiting centre by its anticholinergic action. Its sedative effect also contributes to its antiemetic effect. Scopolamine is not effective for other types of vomiting.
- 17. ANTIHISTAMINES (H1-BLOCKERS) H1-blockers are mainly useful for the prevention of motion sickness. They are also effective in morning sickness, postoperative and other types of vomiting. Dimenhydrinate, diphenhydramine, promethazine, cyclizine and meclizine are some of the H1- blockers that have antiemetic properties.
- 18. ANTIHISTAMINES (H1-BLOCKERS) (Contd..) Their antiemetic effect is due to sedative and central anticholinergic properties. Cyclizine and meclizine have less sedative effect. Among the antihistamines, cyclizine has the shortest duration of action (8 hours), and meclizine has the longest duration of action (24 hours).
- 19. 5-HT3-RECEPTOR ANTAGONISTS Ondansetron is the prototype drug. Other drugs are granisetron and dolasetron. Their antiemetic effect is mainly due to the blockade of 5-HT3- receptors on vagal afferents in the gut. In addition, they also block 5-HT3-receptors in the CTZ and solitary tract nucleus (STN).
- 20. 5-HT3-RECEPTOR ANTAGONISTS (Contd..) Ondansetron and other 5-HT3 antagonists block emetogenic impulses in the gut and their central relay (CTZ and STN).
- 22. PHARMACOKINETICS 5-HT3 antagonists are well absorbed after oral administration, Ondansetron undergoes extensive first-pass metabolism. The metabolites are excreted in the urine and faeces. These agents are also available for intravenous administration.
- 23. USES 1. 5-HT3 antagonists are the most effective agents for the prevention as well as the treatment of anticancer drug-induced nausea and vomiting. 2. They are also effective in postoperative and postradiation vomiting, but they are ineffective against motion sickness.
- 24. USES (Contd..) 3. They are the preferred drugs to control vomiting in children with cyclic vomiting syndrome.
- 25. SIDE EFFECTS 5-HT3 antagonists are well tolerated. They may cause headache, dizziness and diarrhoea.
- 26. GRANISETRON Granisetron is more potent, more efficacious and longer acting than ondansetron.
- 27. PROKINETIC DRUGS Metoclopramide Metoclopramide is a D2-receptor antagonist. It has two important actions-central and peripheral.
- 28. CENTRAL ACTIONS Metoclopramide blocks D2-receptors in CTZ. At high concentrations, it also blocks 5-HT3-receptors
- 29. PROKINETIC EFFECT ON UPPER GIT Metoclopramide causes release of ACh from myenteric neurons. Thus, peripherally, it has prokinetic effect on upper GIT and enhances the rate of gastric and duodenal emptying. These effects may be due to cholinergic (cholinomimetic effect), serotonergic (5-HT4 agonism), antidopaminergic effects, and it also has direct action on the smooth muscles of upper GIT.
- 30. PROKINETIC EFFECT ON UPPER GIT Metoclopramide accelerates gastric emptying by: 1. Increasing the tone of the lower oesophageal sphincter (LES). 2. Increasing the tone and amplitude of antral contractions. 3. Relaxing the pyloric sphincter and duodenal bulb.
- 31. PROKINETIC EFFECT ON UPPER GIT (Contd..) 4. Increasing the peristalsis of small intestine. Thus, it decreases the intestinal transit time from duodenum to the ileocaecal valve (i.e. promotes the forward movement of the upper GIT). Both the central and peripheral actions contribute to its antiemetic effect.
- 32. PHARMACOKINETICS Metoclopramide is rapidly absorbed after oral administration. It can also be administered by i.m. or i.v. routes. Onset of action is within half an hour after oral dose, a few minutes after parenteral administration.
- 33. PHARMACOKINETICS (Contd..) It has a short half life of 4 hours; poorly bound to plasma proteins; crosses BBB and most of the drug is excreted unchanged in urine. In renal diseases, the dose of metoclopramide should be reduced to half the usual dose.
- 34. USES 1. As an antiemetic: Metoclopramide is effective for the prevention and treatment of: a. Vomiting due to gastrointestinal disorders b. Drug-induced vomiting c. Postoperative vomiting © 2008 Chettinad Hospital & Research Institute
- 35. USES (Contd..) d. Vomiting of migraine e. Cancer chemotherapy-induced vomiting f. Vomiting due to radiation sickness.
- 36. P.K It is ineffective against motion sickness and vomiting due to labyrinthine disorders. 2. Gastroesophageal reflux disease (GERD): Metoclopramide produces symptomatic relief in patients with reflux oesophagitis by increasing the tone of LES. By prokinetic effect, it also reduces the volume of gastroduodenal contents that reflux into oesophagus.
- 37. (Contd..) 3. To alleviate symptoms associated with gastric stasis in patients with diabetes, post- operative or idiopathic gastroparesis: Gastric stasis is characterized by upper abdominal discomfort, distension, bloating, nausea, vomiting, etc. By prokinetic effect, it controls the above symptoms.
- 38. (Contd..) 4. To stimulate gastric emptying during gastrointestinal radiological procedures and also before general anaesthesia in emergency surgeries. 5. Metoclopramide has been used in the treatment of intractable hiccups. © 2008 Chettinad Hospital & Research Institute
- 39. (Contd..) 4. To stimulate gastric emptying during gastrointestinal radiological procedures and also before general anaesthesia in emergency surgeries. 5. Metoclopramide has been used in the treatment of intractable hiccups.
- 40. ADVERSE EFFECTS They are drowsiness, dizziness and diarrhoea. Extrapyramidal symptoms (EPS: tremor, rigidity), etc. are due to blockade of D2-receptors in basal ganglia (drug-induced parkinsonism). They are the most important side effects. Dystonic reactions are rarely seen, and they disappear after withdrawal of the drug. They respond readily to benztropine, benzhexol or promethazine.
- 41. ADVERSE EFFECTS (Contd..) Long-term use may lead to gynaecomastia, galactorrhoea and menstrual irregularities by blocking the inhibitory effect of dopamine on prolactin release.
- 42. DRUG INTERACTIONS Metoclopramide accelerates the absorption of diazepam and reduces digoxin absorption by its prokinetic effect.
- 43. METOCLOPRAMIDE AND L-DOPA Metoclopramide is effective to control L-Dopa-induced vomiting, but it interferes with the antiparkinsonian effect of L- Dopa as it crosses the BBB and blocks the D2-receptors in basal ganglia.
- 44. DOMPERIDONE It is a butyrophenone derivative and has effects almost similar to metoclopramide. Its antiemetic and prokinetic effects are due to blockade of dopamine (D2)-receptors It is less potent and less efficacious than metoclopramide. It does not cross the BBB and hence extrapyramidal side effects are rare, but it increases the prolactin level.
- 45. DOMPERIDONE (Contd..) Domperidone is usually administered orally, but its oral bioavailability is low because of extensive first-pass effect; metabolized in the liver and metabolites are excreted in urine. Domperidone is a preferred antiemetic in children, as it rarely produces EPS.
- 46. DOMPERIDONE (Contd..) Domperidone counteracts vomiting induced by L-Dopa or bromocriptine without affecting their antiparkinsonian effect as it does not cross the BBB. Hence, it is preferred over metoclopramide to treat vomiting induced due to these drugs. The important side effects are dry mouth, diarrhoea, headache, skin rashes, galactorrhoea and menstrual irregularities.
- 47. NEUROLEPTICS They are potent antiemetics. Their antiemetic effect is due to blockade of D2-receptors in the CTZ. In addition, they have anticholinergic and antihistaminic actions.
- 48. NEUROLEPTICS (Contd..) Among these, prochlorperazine is commonly used as an antiemetic. They are effective in the treatment of vomiting due to drugs, uraemia and systemic infections. These drugs are not used for morning sickness.
- 49. NEUROLEPTICS (Contd..) Neuroleptics are not as effective as ondansetron and metoclopramide in cytotoxic drug-induced vomiting and radiation sickness. They are ineffective in motion sickness. The common side effects are sedation, extrapyramidal symptoms, dryness of mouth, hypotension
- 51. ADJUVANT ANTIEMETICS Glucocorticoids Glucocorticoids such as dexamethasone, betamethasone and methylprednisolone are used as adjuvant antiemetics. These agents are commonly used in combination with ondansetron or metoclopramide in the treatment of anticancer drug-induced vomiting.
- 52. ADJUVANT ANTIEMETICS (Contd. .) Glucocorticoids The beneficial effect of steroids is due to their anti-inflammatory property and also inhibition of prostaglandin (PG) synthesis.
- 53. BENZODIAZEPINES Lorazepam and alprazolam are used to control psychogenic and anticipatory vomiting. The beneficial effect is mainly due to their sedative, amnesic and antianxiety effects.
- 54. CANNABINOIDS Dronabinol It is the principal psychoactive component of marijuana and is used to prevent cancer chemotherapy-induced vomiting in patients refractory to other antiemetics. It is effective orally. It produces serious side effects such as sedation, hallucinations, disorientation, increased appetite and drug dependence, hence kept as a reserve drug.
- 55. © 2008 Chettinad Hospital & Research Institute Thank you