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Similar to Pharmacology of Antiemetics & Prokinetics.pptx
Pharmacology of Antiemetics & Prokinetics.pptx
- 1. Pharmacology of Antiemetics &Prokinetics Dr. Firoz M. Tadavi Associate Professor Dept. of Pharmacology
- 2. Nausea A sensationof unease and discomfort in stomach with an urge to vomit. It often, but not always precedes vomiting Vomiting It is a expulsive reflex of upper GIT with the act of expelling the contents inside. It is a protective phenomenon, seen in normal life, by consumption of irritant substances & physiological conditions like pregnancy
- 3. Causes Motion sickness GI infection Migraine Morningsickness Food poisoning Side effects of medication Fainting
- 4. Nausea and Vomitingmay be an early warning sign in case of: Small Bowel obstruction Appendicitis Brain tumor Ingestion of poison Pancreatitis Hepatitis
- 5. Some drugswhich may cause vomiting are Antimicrobials – Erythromycin, Tetracycline Anticancer drugs Apomorphine Amiodarone Chloroquine Metronidazole Ergot derivatives
- 8. APPROACH OF THE TREATMENT Treatmentof cause Treatment of symptoms Supportive therapy
- 9. CLASSIFICATION Antidopaminergic: chlorpromazine,metoclopromide, domperidone Antihistaminic: promethazine,cyclizine Anti-5 HT3: ondansetron, granisetron Antimuscarinic: scopolamine Antagonist of NK1 receptors for substance p: aprepitant Miscellaneous
- 10. PROKINETIC DRUGS Definition: Theseare drugs which promote GI transit and speed gastric emptying by enhancing co- ordinated propulsive motility Metoclopramide Domperidone
- 11. Metoclopramide D2 receptorantagonist & 5- HT4 agonist It causes forward propulsion of upper GIT contents. It is due to enhanced action of ACh at muscarinic receptor Increases resting tone of gastroesophageal sphincter. Also speeds up gastric emptying due to prokinetic action.
- 12. Preparation and dosage Availableas 10 mg tablets, as syrups and injection. Dose is 5-10 mg orally, IM or IV. Well absorbed orally Crosses blood brain barrier and placenta Half life-3 to 6 hr. Adverse effects: Sedation, dizziness, loose stools, muscle dystonia Long term use-parkinsonism and galactorrhoea Metoclopramide
- 13. Uses Antiemetic forpost operative, drug induced, chemotherapy induced or disease associated vomiting, radiation sickness, etc. Less effective in motion sickness. As a gastrokinetic May succeed in stopping hiccups. Management of gastroesophageal reflux disease (GERD). Metoclopramide
- 14. Domperidone Selective D2receptor antagonist. Acts peripherally & does not cross BBB easily. Therefore fewer central effects. Accelerates Gastric motility & emptying Lower esophageal sphincter tone is increased Esophageal peristalsis is augmented
- 15. Dosage: Effective orally& parenterally. 10-20 mg 3-4 times a day orally Well absorbed orally Bioavailability is 15% due to first pass metabolism Adverse effects: dry mouth, loose stools, headache Rashes, Galactorrhea Cardiac arrhythmias (rapid i.v.) Domperidone
- 16. Advantages Prokinetic actionnot attenuated by atropine. Lesser side effects compared to metochlopramide. Can be used along with levodopa or bromocriptine in parkinsonism Disadvantages Less efficacious gastrokinetic than metochlopramide and not useful against highly emetogenic chemotherapy. Cardiac arrhythymias have developed on rapid IV injection. Domperidone
- 17. Neuroleptics Chlorpromazine It is primarilyused to treat psychotic disorders such as schizophrenia, treatment of bipolar disorder, Nausea and vomiting due to uremia, carcinomatosis, radiation sickness, Hiccups Oral, IM, IV infusion Bioavailability 10-80% Protein binding 90-99%, Biological half-life : 30 hours
- 18. Neuroleptics Side effects movementproblems sleepiness, dry mouth, low blood pressure upon standing, and increased weight. neuroleptic malignant syndrome, and low white blood cell levels.
- 19. Neuroleptics Prochlorperazine • Oral, IM,IV • Protein binding: 91–99% • Biological half-life: 4–8 hours, differs with the method of administration • Excretion: Biliary, inactive metabolites in urine • Uses: treatment of psychosis, manic phase of bipolar disorder, antiemetic/ antivertiginoic
- 20. 5-HT agonists 5-HT4receptors are present in neurons of the myenteric plexus. They have a prokinetic action. Cisapride Prokinetic drug:5-HT4 receptor agonist Acts on motor neurons in myenteric plexus facilitating motility throughout the GIT including colon. No direct antiemetic action. Withdrawn due to cardiotoxicity
- 21. Mosapride Congener ofcisapride Shows 5-HT4 agonism but lacks D2 antagonism. used as a prokinetic but it is not a very effective antiemetic. Studies have shown that incidences of arrhythmias may be less with mosapride. Itopride Shows D2 antagonism unlikely to cause cardiac arrhthymias 5-HT agonists
- 22. Erythromycin Macrolide antibiotic Activates motilin receptors. Used in patients with diabetic gastroparesis - is a medical condition consisting of a paresis of the stomach, resulting in food remaining in the stomach for a longer time than normal.
- 23. Antihistaminics They arecommonly used in the prevention and treatment of motion sickness. These medicines seem to prevent and treat the nausea, vomiting, and dizziness caused by motion sickness by calming the stimulation of the inner ear. Administered orally, 30 minutes before the journey.
- 24. H1 Antihistaminics Promethazine- Doseis 10-25 mg Diphenhydramine Dose is 25-50 mg Dimenhydrinate Dose is 50 mg Meclizine Dose is 25-50 mg Cinnarizine Dose is 25-50 mg
- 25. Anticholinergics Scopolamine isthe most effective drug against motion sickness when used prophylactically. A transdermal patch containing 1.5 mg of hyoscine to be delivered over 3 days has been developed. Dicyclomine (10-20mg oral) has been used for prophylaxis of motion sickness.
- 26. Anticholinergics Contraindications: Pregnancy (crossesplacenta and has teratogenic effects on foetus) Enters breast milk Elderly patients - more likely to experience adverse effects especially if they are currently using several other medications
- 27. 5-HT3 receptor antagonists Ondansetron Developed to control chemotherapy emesis blocks impulses, both at their peripheral origin and central relay Bioavailability =60 % due to first pass metabolism Duration of action= 8- 12 hr Dose - 4-8 mg IV and repeated every 8 hours
- 28. 5-HT3 receptor antagonists Granisetron 10 times more potent than ondansetron High affinity and selectivity for 5HT3 binding site Widely distributed and rapidly eliminated by hepatic metabolites, t1/2 = 8-12 hrs Tropinsetrone Rapidly absorbed through oral route Bioavalibilty = 52 % Large volume of distribution, t1/2 = 8 hrs
- 29. 5-HT3 receptor antagonists Adverse drug effect: headache dizziness chest pain hypotension Constipation’
- 30. NK1 receptor antagonist Aprepitant,Fosaprepitant Substance p released during chemotherapy Activates neurokinin receptors in chemoreceptor trigger zone and nucleus tractus solitarius Vomiting
- 31. NK1 receptor antagonist Inhibit both the acute and delayed emesis induced by cytotoxic chemotherapeutic drugs Inhibits post operative nausea and vomiting Has no effect on gastrointestinal motility Aprepitant Post operative nausea and vomiting- single dose of 40mg orally Chemotherapy induced vomiting- (125 mg + 80 mg + 80 mg) along with ondansetron and dexamethasone
- 32. NK1 receptor antagonist Adverseeffects Tolerability of the drug is good Few side effects include: 1.Weakness 2.Fatigue 3.Flatulence 4.Rise in liver enzymes
- 33. Adjuvant antiemetics Corticosteroids (e.g.Dexamethasone 8-20mg i.v.) Augment the efficacy of other primary antiemetic drugs like metoclopramide & ondansetron for highly emitogenic regimans. Also reduces certain side effects of the primary antiemetic.
- 34. Adjuvant antiemetics Cannabinoids Δ9Tetrahydrocannabinol is antiemetic against moderately emetogenic chemotherapy. Acts through CB1 receptors on neurons in CTZ and vomiting centre Dronabinol Pure Δ9 THC. Given to those patients receiving chemotherapy who have stopped responding to other antiemetics.
- 35. Adjuvant antiemetics Benzodiazepines MOA- Sedative action. Relieve psychogenic component, anticipatory vomiting and produce amnesia for unpleasant procedure. Adjuvant to metoclopramide, ondansetron, diazepam/lorazepam. Suppresses dystonic side effects of metoclopramide
- 36. Vomiting in pregnancy Etiology Decrease in blood sugar level during pregnancy Increase in circulating levels of hormone Increase in HCG
- 37. Vomiting in pregnancy Frequent small meals & more fluids Psychotherapy including reassurance Placebo therapy Chewing ginger Naps during day (but not after eating) Enough sleep at night Avoid greasy & oily food
- 38. Vomiting in pregnancy Doxylamine 10 mg + pyridoxin 10mg bd Dimenhydrinate (50-100mg) used as suppository Prochlorperazine 5-10 mg IV in severe cases Metoclopramide- only if other drugs fail
- 39. Chemotherapy-induced nausea and vomiting Common most feared cancer treatment-related side effects There are several subtypes of CINV. Acute: occurring within 24 hours of chemotherapy Delayed: occurring between 24 hours and 5 days after treatment
- 40. Summary Cause of vomitingDrugs used GIT irritation Anticholinergics; in severe cases, a phenothiazine (promethazine) Motion sickness Scopolamine; Dimenhydrinate; Meclizine Pregnancy Doxylamine, Pyridoxine, Dimenhydrinate Cancer, radiation sickness, anticancer chemotherapy, Uremia Phenothiazine; Metoclopramide; Ondansetron; Nabilone; Dexamethasone Gastroperesis Prokinetic drugs Post operative Prokinetic drugs, antihistaminics
- 41.
Editor's Notes
- #3 but can be a sign of severe diseases. The act of emesis and the sensation of nausea that accompanies it are viewed as protective reflexes that serve to rid the stomach and intestine of toxic substance and prevent further ingestion. It also occurs in physiological situations like pregnancy but often it is an indication of ill health and needs to be treated. Morning sickness- affects more than 50% pregnant women in the first trimester. Many proposed etiologies. Could be a defense mechanism to protect the foetus against toxins ingested by the mother.
- #4 Conditions in which vomiting occurs GI infections, obstructions, inflammatory diseases, biliary colic. Cardiopulmonary diseases MI, CMP. Labrynthine diseases motion sickness. Intracerebral disorders like malignancy hemorrhage, hydrocephalous. Psychiatric disorders like depression. Radiation induced vomiting. Drug induced eg. Cancer chemotherapy, antibiotics. Digoxin, antiarrhythmics, oral hypoglycemics. endocrine/metabolic diseases like uremia, thyroid diseases, adrenal insufficiency, lactoacidosis. Toxins like ethanol.
- #5 Intracerebral disorders like malignancy hemorrhage, hydrocephalous.
- #6 Drug induced eg. Cancer chemotherapy, antibiotics. Digoxin, antiarrhythmics, oral hypoglycemics
- #7 Disturbances in body equilibrium - VESTIBULAR NUCLEUS (M1,H1) Blood borne drugs, mediators, toxins, hormones – CTZ D2, M1,5HT3, CB1, NK, H1 Cytotoxic drugs, radiation, GIT irritants - PAN 5HT3 – (Vagus afferent) NTS (D2,M1,5HT3, CB1, NK, H1) Bad odor, ghastly sight, fear, pain, stress,etc. -- HIGHER CENTRES VOMITING CENTRE
- #8 Phases of vomiting Pre-ejection phase: gastric relaxation and retroperistalsis. Retching: rhythmic action of respiratory muscles – contraction of abdominal and intercostals and diaphragm against a closed glottis. Ejection. Vomiting is accompanied by multiple autonomic phenomena including salivation, sweating, shivering and vasomotor changes.
- #10 ANTIEMETIC AGENTS - Are drugs used specifically to PREVENT or RELIEVE nausea and vomitting These are the drugs that prevent or suppress vomiting. They are classified as: Anticholinergics H1 antihistaminics Neuroleptics Prokinetic drugs 5-HT3 receptor antagonists NK1 receptor antagonists Adjuvant antiemetics
- #11 Excludes traditional cholinomimetics and anti-ChEs which produce tonic and largely uncoordinated contractions Prokinetic drugs : Promote coordinated movement of GIT. Increase strength of contraction without affecting the rhythm. Dopamine antagonists: eg Domperidone , Metoclopramide 5HT4 agonists: eg Cisapride Some prokinetic drugs that are used include : Domperidone, Metoclopramide, Mosapride, Cisapride, Itopride Erythromycin Benzimide
- #12 . Also has some amount of 5-HT4 agonist activity. Mechanism of action Blockade of D2 dopaminergic receptors in GIT and CTZ. 5-HT4 serotonergic receptor activation which ??? Enhances ACh release from myenteric motor neurons. 5-HT3 antagonism at high concentration Actions on GIT Speeds gastric emptying. Lower esophageal sphincter tone is increased and gastroesophageal reflux is opposed. Increases intestinal peristalsis. No significant action on colonic motility and gastric secretion.
- #13 Pharmacokinetics Metoclopramide is rapidly absorbed orally, enters brain, crosses placenta and is secreted in milk. Partially conjugated in liver and excreted in urine within 24 hrs. t½ is 3-6hrs. When given orally, it acts in ½ -1 hr. 10 mins IM and 2 mins after IV infusion. Action lasts for 4-6 hrs. Interactions Hastens absorption of many drugs like aspirin, diazepam by facilitating gastric emptying. Absorption of digoxin reduced. Bioavailability of cimetidine reduced. A. Pharmacokinetic: Increases absorption of – aspirin, diazepam. Decreases absorption of – digoxin. B. Pharmacodynamic: Blocks theraputic effect of levodopa by blocking D2 in basal ganglia.
- #14 Adverse effects Sedation, dizziness, loose stools, muscle dystonia (especially in children). Long term use can cause parkinsonism, galactorrhoea, gynaecomastia. Safe in pregnancy May aggravate Na retention and hypokalemia in patients with edema
- #15 Gastrokinetic Some action over the CTZ is also present Dopamine present peripherally in the upper GIT has inhibitory effect on GI motility & intragastric pressure. This is due to suppression of Ach release from neurons of myenteric plexus. Dopamine antagonists also act as central antiemetics due to Dopaminergic neurons in the brain. Domperidone Chemically related to haloperidol (antipsychotic) but pharmacologically related to metoclopramide. Pharmacokinetics Domperidone is absorbed orally but bio availability is only around 15% due to first pass metabolism. Plasma t½ is 7.5 hrs. Penetration into blood drain barrier is poor. Metabolites are excreted in urine.
- #16 Caution: should not be used in pregnant women as it appears in breast milk and reports on safety of drug in infants is not avaliable
- #17 Can be used along with levodopa or bromocriptine to counteract dose-limiting emetic action without affecting the therapeutic effect in parkinsonism.
- #18 The typical neuroleptics are potent antiemetics. They control a wide range of drug and disease induced vomiting at doses much lower than those needed in psychosis. However they should not be given unless the cause of vomiting has been identified. Antipsychotic Drugs Chlorpromazine, Prochlorperazine, Triflupromazine, Thioridazine, Trifluoperazine etc They selectively depress CTZ but have no action on vomiting centre. Hence they are ineffective in motion sickness. DOC- in nausea & vomiting due to uremia, carcinomatosis, radiation sickness etc Medicinal uses: treatment of psychosis, manic phase of bipolar disorder, antiemetic/antivertiginoic Side effects Extrapyramidal side effects such as acutedystonic reactions, pseudoparkinsonism, orakathisia. neuroleptic malignant syndrome.
- #20 Side effects Extrapyramidal side effects such as acutedystonic reactions, pseudoparkinsonism, orakathisia. neuroleptic malignant syndrome.
- #21 Lacks D2 receptor antagonism therefore is not a very effective antiemetic. It exerts prokinetic action through 5-HT4 agonism, restoring and facilitating motility throughout the GIT including colon. Reports show chances of serious ventricular arrhythmias and death due to the use of cisapride Taken along with CYP3A4 inhibitors --- Ventricular arrhythmias and death High concentrations--- Prolongation of Q-Tc interval and predisposition to Torsades de pointes and Ventricular Fibrillations
- #22 Itopride Shows D2 antagonism and has low affinity for 5-HT4 receptors. Therefore it has prokinetic and antiemetic properties. It was found unlikely to cause cardiac arrhthymias in healthy individuals and is a safe prokinetic like mosapride.
- #23 Gastroparesis, or delayed gastric emptying, is a medical condition consisting of a paresis (partial paralysis) of the stomach, resulting in food remaining in the stomach for a longer time than normal. Normally, the stomach contracts to move food down into the small intestine for digestion. The vagus nerve controls these contractions. Gastroparesis may occur when the vagus nerve is damaged and the muscles of the stomach and intestines do not work normally. Food then moves slowly or stops moving through the digestive tract. Signs & Symptoms: Diarrhea , nausea , vomiting , early satiety. Transient Gastroparesis may arise due to any acute illness. Type 1 or Type 2 Diabetes Mellitus Autonomic neuropathy Damage to Vagus nerve Anorexia nervosa & bulimia nervosa Others: Parkinson’s disease , connective tissue disorders ,
- #24 H1 receptors are located in smooth muscles, endothelium and brain. They are present in the vestibular nucleus but not in CTZ. Therefore these drugs are used mostly for motion sickness and are less effective for other forms of emesis. There are 2 generations of H1 antihistaminics, divided on the basis of their sedative effects. Some generation 1 drugs are antiemetics promethazine diphenhydramine dimenhydrinate doxylamine meclizine cinnarizine MOA is reversible competitive antagonism Motion is sensed by the brain through the pathways that send signals coming from inner ear (sensing motion, acceleration, and gravity), eyes (vision) and deeper tissues (proprioceptors). It is hypothesized that conflict among inputs is responsible for motion sickness. Without the motion-sensing organs of inner ear, motion sickness does not occur Motion sickness is a very common disturbance of the inner ear that is caused by repeated motion such as from the swell of the sea, the movement of a car, the motion of a plane in turbulent air, etc. In the inner ear, motion sickness affects the sense of balance and equilibrium and, hence, the sense of spatial orientation. The symptoms of motion sickness include: nausea, Vomiting Paleness of the skin Cold sweats Dizziness Headache Increased salivation Fatigue Other common signs are sweating and a general feeling of discomfort and not feeling well. Cognitive Behavioral Therapy The goal of cognitive behavioral therapy is to lessen the anxiety that some people have just thinking about movement or motion sickness. Breathing Techniques Slow, deliberate breathing helps reduce anxiety associated with motion sickness. The susceptibility to motion sickness is determined by balance of activation between Ach and NA sensitive neurons in RAS adjacent to vestibular nuclei. Hence drugs that block Ach in CNS e.g Scopolamine and which activate the central sympathetic areas e.g d-amphetamine are highly effective in the treatment.
- #25 Shows greatest effectiveness against motion sickness. Piperazine has prolonged action single dose provides relief for 6-12 hrs Meclizine is long acting protects against sea sickness for nearly 24 hrs Cinnarizine is also used Meclizine Protects against motion sickness for 24 hrs. Causes less sedation Cinnarizine Antivertigo drug also used as antiemetic. Probably acts by inhibiting influx of Ca ions from endolymph into vestibular sensory cells
- #26 Definition : The term anticholinergic drugs refers to the drugs that block actions of ACh on autonomic receptors and in the CNS exerted through muscarinic receptors. Muscarinic receptors are of 5 types : M1 M2 M3 M4 and M5 First three are major subtypes Competitive antagonists Hyoscine (scopolamine) Most effective antiemetic, alkaloid drug with muscarinic antagonist effects. Relatively specific for M1 receptors. On WHO list of essential medicines. Blocks conduction of nerve impulses across a cholinergic link in pathway leading from vestibular apparatus to vomiting center Poor efficacy in vomiting of other etiologies Absorption : rapidly from GIT, can cross BBB and placenta Metabolism : completely in liver Half life : 4.5 hours Medical uses Motion sickness Sea sickness Postoperative Nausea Adverse effects: Uncommon adverse effects (0.1 - 1 %) - Dry mouth Reduced sweating Tachycardia followed bradycardia (at higher doses) Urticaria Pruritus Very rare adverse effects ( less than 0.1%) - Constipation Urinary retention Hallucinations seizures Anaphylatic shock Mydriasis Dizziness Somnolence
- #28 Cytotoxic drugs/ radiation cause cellular damage Enterochromaffin cells Release of Mediators, including 5HT, from Intestinal mucosa Activates vagal afferents in the gut Emetogenic impulse to NTS and CTZ Monoamine neurotransmitter receptor Location – GIT ,NT,AP,HIPPOCAMPUS Involve in chemotherapy induced vomiting 5 HT3 antagonist prevent emesis Ondansetrone Developed to control chemotherapy emesis Antagonis 5HT3 receptor Bioavalibilty =60 % due to first pass metabolism Duration of action= 8- 12 hr T half = 3 hrs Elimination = urine and feces Hydroxylated by CYP1A2 ,2D6 And 3A
- #29 Mechanism of action same as ondansetron
- #31 Role of NK1 Receptor Antagonist Has high affinity for NK1 receptors Blocks action of substance p Prevention of vomiting Fosaprepitant It is a parenterally administered prodrug of aprepitant
- #32 PONV - As effective as Ondensetron Over 3 days enhances antiemetic effects considerably
- #33 Contraindications Astemizole Cisapride Birth control pills Warfarin Interactions Inducers and inhibitors of CYP3A4 Cisapride Warfarin Dexamethasone Astemizole Poisoning Overdose causes Drowsiness Headache
- #34 Adjuvant antiemetics These drugs have few or no pharmacological effects, they increase the efficacy of other drugs when given at the same time. E.g. corticosteroids, benzodiazepines, cannabinoids.
- #35 Dose is 5-10 mg/sq. m BSA. It is hallucinogenic, produces disorientation and sympathomimetic effect therefore has limited use. Appetite stimulant is cachectic/AIDS patients. Given to those patients receiving chemotherapy who have stopped responding to other antiemetics. Cannabinoids (Nebilone) Antiemetic activity against moderately emetogenic chemotherapy.
- #38 IMP pts to be noted:- Patient advised to take frequent small meals and more fluids. Psychotherapy and placebo therapy are often beneficial. Ideally, avoid all drugs during first trimester. Drugs given only if nausea severe.
- #39 Promethazine- Can be used except near delivery time & during labour Inhibition of dopamine & muscarine receptor
- #40 Chemotherapy-induced nausea and vomiting (CINV) is a common side-effect of many cancer treatments Acute: occurring within 24 hours of chemotherapy Delayed: occurring between 24 hours and 5 days after treatment In acute CINV, free radicals generated by toxic chemotherapeutic agents stimulate enterochromaffin cells in the gastrointestinal tract, causing the release of serotonin. Subsequently, serotonin binds to intestinal vagal afferent nerves via 5-HT3 receptors, which trigger the vomiting reflex via the nucleus of the solitary tract (NTS) and chemoreceptor trigger zone (CTZ) . Ondansetron, dolasetron, and granisetron are most commonly used in acute CINV. Substance P is considered to be the principal neurotransmitter involved in delayed CINV. Chemotherapy drugs trigger the release of substance P from neurons in the central and peripheral nervous systems, which then binds to neurokinin-1 (NK1) receptors mainly in the NTS to induce vomiting.10, Aprepitant may also be used in delayed CINV.1 Dexamethasone is the corticosteroid of choice for CINV, and it is often used in combination with other agents to increase antiemetic efficacy in acute and delayed CINV