Gastrointestinal drugs

for mbbs teaching

1. GASTROINTESTINAL DRUGS Dr. Banhisikha Adhikari MD Pharmacology I.P.G.M.E&R

2. Drugs for Peptic Ulcer and GERD Antiemetic, Prokinetic and Digestant Drugs Drugs for Constipation and Diarrhoea Pathophysioloy Class of drugs Mechanism of action Pharmaocokinetic features Uses Adverse effects

3. PEPTIC ULCER occurs in gastrointestinal tract exposed to gastric acid and pepsin - stomach and duodenum Etiology is not clearly known A variety of psychosomatic, humoral and vascular derangements Helicobacter pylori - contributor to ulcer formation and recurrence Defensive factors gastric mucus and bicarbonate secretion, prostaglandins, nitric oxide, high mucosal blood flow, innate resistance of the mucosal cells Aggressive factors acid, pepsin, bile and H. pylori I Imbalance

4. Regulation of gastric acid secretion

5. Goals of therapy Peptic ulcer is a chronic remitting and relapsing disease lasting several years. The goals of antiulcer therapy are: • Relief of pain • Ulcer healing • Prevention of complications (bleeding, perforation) • Prevention of relapse.

6. Approaches for the treatment of peptic ulcer 1. Reduction of gastric acid secretion (a) H2 antihistamines : Cimetidine,Ranitidine , Famotidine, Roxatidine (b) Proton pump inhibitors : Omeprazole, Esomeprazole , Lansoprazole , Pantoprazole , Rabeprazole , ( c) Anticholinergic drugs : Pirenzepine,Propantheline , Oxyphenonium (d) Prostaglandin analogue : Misoprostol

7. 2. Neutralization of gastric acid (Antacids) (a ) Systemic: Sodium bicarbonate,Sod . citrate (b) Nonsystemic : Magnesium hydroxide, Mag . trisilicate , Aluminium hydroxide gel , Magaldrate , Calcium carbonate 3. Ulcer protectives : Sucralfate , Colloidal bismuth subcitrate (CBS ) 4. Anti-H. pylori drugs: Amoxicillin, Clarithromycin , Metronidazole, Tinidazole,Tetracycline

8. H2 ANTAGONISTS M arked inhibition of gastric secretion (all phases) due to competitive H2 blockade Four H2 antagonists cimetidine, ranitidine, famotidine and roxatidine are available in India CIMETIDINE - first H2 blocker to be introduced. Well absorbed orally . Well tolerated . Common side effects headache, diarrhoea/constipation, dizziness Inhibitor of several Cytochrome P-450 U se has declined due to incidence of male sexual dysfunction and several drug interactions

9. Ranitidine- 5 times more potent than cimetidine Longer duration of action with greater 24 hr acid suppression No antiandrogenic action Overall incidence of side effects is lower Famotidine - binds tightly to H2 receptors and exhibits longer duration of action despite an elimination t½ of 2.5–3.5 hr 5–8 times more potent than ranitidine Roxatidine - pharmacodynamic , pharmacokinetic and side effect profile is similar to ranitidine , but twice as potent and longer acting

10. PROTON PUMP INHIBITORS (PPIs) Omeprazole, Esomeprazole , Lansoprazole , Pantoprazole , Rabeprazole have overtaken H2 blockers for acid-peptic disorders Most powerful inhibitor of gastric acid secretion. Inhibit resting as well as that stimulated by food or any of the secretagogues react covalently with H+K+ATPase enzyme inactivate it irreversibly have high degree of selectivity of action Minimal adverse effects. Nausea, loose stools, headache, abdominal pain, muscle and joint pain All PPIs are administered orally in enteric coated form

11. Omeprazole: It is the prototype member dose dependent suppression of gastric acid secretion; without anticholinergic or H2 blocking action bioavailability is reduced by food should be taken in empty stomach 1 hr before meal Esomeprazole : It is the S-enantiomer of omeprazole ; have higher oral bioavailability Pantoprazole: It is similar in potency and clinical efficacy to omeprazole, but is more acid stable and has higher oral bioavailability Rabeprazole : cause fastest acid suppression

12. USES Peptic ulcer: Gastric and duodenal- prophylaxis, treatment , relapse Bleeding peptic ulcer Stress ulcers Gastroesophageal reflux disease (GERD) Zollinger -Ellison syndrome Aspiration pneumonia

13. PROSTAGLANDIN ANALOGUE PGE2 and PGI2 serve cytoprotective role inhibit acid secretion promote mucus and HCO3¯ secretion Misoprostol ( methyl-PGE1 ester) is a longer acting synthetic PGE1 derivative inhibits acid output dose dependently . side effects and multiple daily dosing - Patient acceptability is poor primary indication - prevention and treatment of NSAID associated gastrointestinal injury and blood loss

14. ANTACIDS basic substances Neutralize gastric acid and raise pH of gastric contents Peptic activity is indirectly reduced potency of is expressed in terms of acid neutralizing capacity (ANC ): defined as number of mEq of 1N HCl that are brought to pH 3.5 in 15 min by a unit dose of the antacid preparation Systemic antacids: potent, rapidly acting but infrequently used due to systemic side effects Nonsystemic antacids : salts of magnesium and aluminium used in combination for better tolerabilty and reduced side effects.

15. ULCER PROTECTIVES Sucralfate : basic aluminium salt of sulfated sucrose polymerizes at pH < 4 by cross linking of molecules, assuming a sticky gel-like consistency. strongly adheres to ulcer base acts as a physical barrier preventing acid, pepsin and bile from coming in contact with the ulcer base Colloidal bismuth subcitrate : a colloidal bismuth compound; water soluble but precipitates at pH < 5 mechanism of action is not clear: probably increase gastric mucosal PGE2, mucus and HCO3¯ production. detach and inhibit H.pylori directly

16. ANTI-HELICOBACTER PYLORI DRUGS is a gram negative bacillus attaches to surface epithelium beneath the mucus maintains a neutral microenvironment around the bacteria promotes back diffusion of H+ ions causation of chronic gastritis, dyspepsia , peptic ulcer, gastric lymphoma and gastric carcinoma

17. Antimicrobials against H. pylori are: amoxicillin, clarithromycin , tetracycline and metronidazole / tinidazole Eradication of H. pylori concurrently with PPI therapy of peptic ulcer: faster ulcer healing, prevents ulcer relapse

18. US-FDA approved regimen is: Lansoprazole 30 mg + Amoxicillin 1000 mg+ clarithromycin 500 mg, all given twice daily for 2 weeks . National Formulary of India (NFI, 2010): 1 week consisting of: Omeprazole 40 mg OD + Metronidazole 400 mg TDS + Amoxicillin 500 mg TDS . Quadruple therapy: CBS 120 mg QID +tetracycline 500 mg QID + metronidazole 400mg TDS + omeprazole 20 mg BD for failure cases.

19. GERD Reflux of acid gastric contents into lower 1/3rd of esophagus Functional disorder: relaxation of lower esophageal sphincter (LES) in the absence of swallowing causes esophagitis, erosions, ulcers, pain on swallowing , dysphagia, strictures, and increases the risk of esophageal carcinoma . Treatment : Proton pump inhibitors (PPIs ) H2 blockers Antacids Sodium alginate Prokinetic drugs: Metoclopramide, cisapride

20. Antiemetic Drugs

21. Physiology of Emesis stimulation of the emetic centre situated in the medulla oblongata- Vomiting Multiple pathways are involved chemoreceptor trigger zone ( CTZ ) and nucleus tractus solitarius ( NTS) - relay areas for afferent impulses arising in the g.i.t, throat and other viscera CTZ is also accessible to blood borne drugs , mediators , hormones , toxins

22. Emetics like Apomorphine , Ipecacuanha are used when a poison has been ingested CTZ and NTS express a variety of receptors: histamine H1, dopamine D2, serotonin 5-HT3, cholinergic M, neurokinin NK1 , cannabinoid CB1 and opioid μ receptors through which the emetic signals are relayed and are targets of antiemetic drug action.

23. CLASSIFICATION 1. Anticholinergics : Hyoscine , Dicyclomine 2. H1 antihistaminics: Promethazine, Diphenhydramine, Dimenhydrinate, Cinnarizine . 3. Neuroleptics: Chlorpromazine(D2 blockers), Triflupromazine 4.Prokinetic drugs: Metoclopramide, Domperidone , Cisapride , Mosapride , Itopride 5. 5-HT3 antagonists: Ondansetron, Granisetron , Palonosetron , Ramosetron 6. NK1 receptor antagonists : Aprepitant , Fosaprepitant 7. Adjuvant antiemetics: Dexamethasone, Benzodiazepines, Dronabinol

24. ANTICHOLINERGICS : Hyoscine - most effective drug for motion sickness. by blocking conduction of nerve impulses across a cholinergic link in the pathway leading from the vestibular apparatus to the vomiting centre H1 ANTIHISTAMINICS: useful mainly in motion sickness and to a lesser extent in morning sickness, postoperative and some other forms of vomiting NEUROLEPTICS: act by blocking D2 receptors in the CTZ useful in d rug induced and postoperative nausea and vomiting ( PONV ). Disease induced vomiting: gastroenteritis, uraemia , liver disease, migraine

25. PROKINETIC DRUGS promote gastrointestinal transit and speed gastric emptying by enhancing coordinated propulsive motility Metoclopramide Introduced as a ‘gastric hurrying’ agent , a commonly used antiemetic MOA involves- a) D2 antagonism b) 5-HT4 agonism c) 5-HT3 antagonism generally well tolerated but Long-term use can cause parkinsonism , galactorrhoea and gynaecomastia Effective and popular drug for many types of vomiting— postoperative , drug induced, disease associated (especially migraine) Also used as a gastrokinetic , in Dyspepsia and other functional g.i . disorders, GERD

26. Domperidone : D2 receptor antagonist antiemetic and prokinetic actions have a lower ceiling extrapyramidal side effects are rare Side effects Are much less than metoclopramide Cisapride : prokinetic with little antiemetic property restores and facilitates motility throughout the g.i.t ., including colon however predisposes to torsades de pointes/ ventricular fibrillation. Subsequently withdrawn from the market

27. 5-HT3 ANTAGONISTS Ondansetron, Granisetron , Palonosetron , Ramosetron Distinct class - developed to control cancer chemotherapy /radiotherapy induced vomiting effective in PONV and disease/drug associated vomiting Blocks 5-HT3 receptors on vagal afferents in the g.i.t. as well as in NTS and CTZ generally well tolerated except headache and dizziness superiority in terms of efficacy as well as lack of side effects and drug interactions has been demonstrated over metoclopramide and phenothiazines

28. NK1 RECEPTOR ANTAGONISTS Aprepitant , Fosaprepitant high affinity NK1 receptor antagonist blocks the emetic action of substance P at CTZ Oral aprepitant combined with standard i.v. ondansetron+ dexamethasone regimen significantly enhanced the antiemetic efficacy against high emetogenic cisplatin based chemotherapy Effective against acute as well as delayed phase of vomiting Particularly useful in patients undergoing multiple cycles of chemotherapy

29. Important topics Regulation of gastric acid secretion Anti ulcer drug classification H2 blockers Proton pump inhibitors Anti H pylori regimens Rationale behind antacid combination Antiemetic classification Prokinetic agents 5HT3 antagonists