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comprehessive overview of gastrointestinal
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- 2. 2 Learning Objectives • Atthe end of the chapter the students will be able to understand and describe the: Drugs used for the treatment of peptic ulcer disease to prevent nausea and vomiting for symptomatic treatment of constipation Broad classification, PKs, MOA and side effects of each group of drugs
- 3. 3 DRUGS FOR PEPTICULCER DISEASE Definition of Peptic Ulcer: • A benign lesion of gastric or duodenal mucosa occurring at a site where the mucosal epithelium is exposed to acid and pepsin Caused due to Excess acid/pepsin production Intrinsic defect in the mucosal defense barrier When the caustic effects of aggressive factors (acid, pepsin, bile) overwhelm the defensive factors of the GI mucosa (mucus and bicarbonate secretion, prostaglandins, blood flow)
- 4. 4 What Causes PepticUlcer Disease? • Over 90% of peptic ulcers are caused by infection with the bacterium Helicobacter pylori or by use of nonsteroidal anti-inflammatory drugs (NSAIDs) Helicobacter Pylori (H. pylori) • Most ulcers are the result of infection with H. pylori • Not all of those infected with H. pylori develop ulcers • H. pylori may result in a weakening of the mucosal defense systems, allowing for development of ulcer subsequent to acid/pepsin aggression
- 5. 5 Causes cont.. NSAIDs Longterm use of nonsteroidal anti-inflammatory drugs. NSAIDs block COX enzymes and decrease prostaglandins (PGs) Gastrinoma (Zollinger-Ellison Syndrome) Tumors of the duodenum or pancreas and secrete abnormally high amounts of gastrin which stimulates gastric acid secretion Stress ulcers Result of physical trauma (i.e., burn patients)
- 6. 6 Regulation of gastricacid secretion • Parietal cells in the GI tract have four receptors – Muscarinic receptors(M-3) – Histamine receptors(H-2) – Gastrin receptors(G)---(CCK-B) – Prostaglandin receptors(PG) • With the exception of prostaglandin receptor, activation of the other receptors increases acid secretion by parietal cells.
- 7. 7 Each secretagogue bindsto its own receptor and interacts with the others Gastrin Histamine Acetylcholine H+ CCK2 H2 M3 Ca+2 dep. pathway Ca+2 dep. pathway cAMP dep. pathway PP Gastric Lumen
- 8. 8 Treatment approaches • Treatmentapproaches of PUD is based on : Eradicating the H. pylori infection Reducing secretion of gastric acid with the use of H2-receptor antagonists or PPIs Providing agents that protect the gastric mucosa from damage, such as misoprostol and sucralfate • (Note: If patients are unable to tolerate the above therapies, neutralizing gastric acid with Non absorbable antacids is an option
- 9. 9 Antacids • Weak basesthat neutralize acid • Reacts with HCL to form salt and water • Because pepsin is inactive at a pH greater than 4, antacids also reduce pepsin activity • Present day antacids : Aluminum Hydroxide Magnesium Hydroxide NaHco3 Caco3
- 10. 10 Characteristics of CommonAntacids Feature Sodium Bicarbonate Calcium Carbonate Magnesium Hydroxide Aluminum Hydroxide Onset of action rapid intermediate rapid slow Duration of action short moderate moderate moderate Systemic alkalosis yes ? no no Effect on stool --- constipating laxative constipating
- 11. 11 Therapeutic uses_ antacids •Aluminum- and magnesium-containing antacids are used for symptomatic relief of peptic ulcer disease and GERD they may promote healing of duodenal ulcers, but the evidence for efficacy in the treatment of acute gastric ulcers is less compelling • Calcium carbonate preparations are also used as calcium supplements for the treatment of osteoporosis.
- 12. 12 Side effects- antacids •The binding of phosphate by aluminum-containing antacids can lead to hypophosphatemia • In addition to the potential for systemic alkalosis, sodium bicarbonate liberates CO2, causing belching and flatulence • Absorption of the cations from antacids (Mg2+, Al3+, Ca2+) is usually not a problem in patients with normal renal function • but the sodium content of antacids can be an important consideration in patients with hypertension or congestive heart failure
- 13. 13 Histamine H2 ReceptorAntagonist • Reversible competitive inhibitors of H2 receptor • Highly selective, No action on H1 or H3 receptors • Very effective in inhibiting nocturnal acid secretion (as it depends largely on Histamine ) • Modest impact on meal stimulated acid secretion (as it depends on gastrin, acetyl choline as well as histamine)
- 14. 14 Histamine H2 antagonistsdecrease acid output Histamine Protein Kinase ATP cAMP K+ H+ Histamine Antagonist PP
- 15. 15 PKs properties H2-Antagonists CimetidineRanitidine Famotidine Nizatidine Bioavailability 80 50 40 >90 Relative Potency 1 4 - 10 20 - 50 4 - 10 Half life (hrs) 1.5 - 2.3 1.6 - 2.4 2.5 – 4 1.1 -1.6 Duration of action (hrs) 6 8 12 8 Inhibition of CYP 450 1 0.1 0 0 Dose mg(bid) 400 150 20 150
- 16. 16 Histamine H2 ReceptorAntagonist…. • In contrast to cimetidine, ranitidine, and famotidine, which are metabolized by the liver, nizatidine is eliminated principally by the kidney • Because little first-pass metabolism occurs with nizatidine, its bioavailability is nearly 100 percent.
- 17. 17 H2 Blockers–Side effects& Interactions • Extremely safe drugs • Cimetidine causes gynecomastia or impotence in men and galactorrhea in women (as it is antiandrogenic & increases prolactin level) • Cimetidine inhibits CYP450 & increases conc. of Warfarin, Theophylline, Phenytoin, Ethanol • All H2 antagonist except famotidine inhibit gastric first pass metabolism of ethanol and increase its bioavailability
- 18. 18 Proton Pump Inhibitors Protein Kinase H+ Protonpump Inhibitors PP H 2 M 3 CCK 2 EP 3 Ca2+ Ca2+ ATP cAMP (-) (+)
- 19. 19 • H+ / K+ -ATPase(the proton pump) is the final transport pathway for parietal cell hydrogen ion secretion • The pump requires large amounts of energy that is supplied by intracellular ATP • Inhibition of H+ , K+ -ATPase blocks both basal and stimulated acid secretion Omeprazole, Esomeprazole ,Lansoprazole Pantoprazole , Rabeprazole The Proton Pump Inhibitors include:
- 20. 20 Proton Pump Inhibitors– Kinetics • Given as enteric coated granules in capsule or enteric coated tablets • Pantoprazole also given intravenously • Half life – 1.5 hrs • Since they require acid for activation - given 1 hr before meals ( b/c they are pro drugs) • Other acid suppressing agents not co administered • Metabolites of these agents are excreted in urine and feces
- 21. 21 P.P.I. – Sideeffects & Interactions • Extremely safe drugs • Causes hypergastrinemia which leads to carcinod tumor in rats But no evidence of such tumors in man • Inhibit CYP 450 & hence ↓metabolsim of warfarin, phenytoin, etc • Pantoprazole & Rabeprazole have no significant interactions
- 22. 22 Mucosal Protective Agents •These compounds also known as cytoprotective compounds • have several actions that enhance mucosal protection mechanisms, thereby preventing mucosal injury reducing inflammation, and healing existing ulcers • The available compounds include: Sucralfate Misoprostol Colloidal Bismuth compounds
- 23. 23 Prostaglandins (PGE2 &PGI2 ) Inhibits: – Acid secretion – Gastrin release – Pepsin secretion Stimulates: – Mucus secretion – Bicarbonate secretion – Mucosal blood flow • Act at prostaglandin EP3 receptors on parietal cells & on epithelial cells • These compounds act by both inhibition of acid production and by increasing defense mechanisms • These compounds are also effective against direct damage produced by alcohol, aspirin and NSAIDs, and are therefore termed “cytoprotective”
- 24. 24 Misoprostol • Synthetic analogof prostaglandin E1 • Anti-acid secretory effect 0.1 to 0.2 mg results in 85% to 95% acid reduction • Prevention of NSAID induced gastric ulcers Side Effects • Diarrhea • Abortion • Exacerbate IBD and should not be given
- 25. 25 Sucralfate • This complexof aluminum hydroxide and sulfated sucrose binds to positively charged groups in proteins of both normal and necrotic mucosa • In acidic pH polymerizes to viscous gel that adheres to ulcer crater • creates a physical barrier that impairs diffusion of HCl and prevents degradation of mucus by pepsin and acid • It also stimulates PG release as well as mucus and bicarbonate output • Taken on empty stomach 1 hr. before meals • Concurrent antacids, H2 antagonist avoided (as it needs acid for activation )
- 26. 26 Colloidal Bismuth Compounds •Coats ulcer, stimulates mucus & bicarbonate secretion • Direct antimicrobial activity against H.pylori • Not used for long periods – bismuth toxicity
- 27. 27 Eradication of H.pylori TripleTherapy • Until recently, the most commonly recommended first line treatment regimen Omeprazole 20mg bid clarithromycin, 500 mg bid amoxicillin 1 g/ metronidazole 500mg bid All are given for 14 days • Due to increasing treatment failures attributable to rising clarithromycin resistance, “quadruple therapy” is now recommended as first-line treatment.
- 28. 28 Eradication …… Quadruple therapy bismuthsubsalicylate 524 mg qid + metronidazole 500 mg qid + tetracycline 500 mg qid + omeprazole 20mg bid all given for 14 days or amoxicillin 1 g bid + clarithromycin 500 mg bid + metronidazole 500 mg bid + omeprazole 20mg bid all given for 14 days. • After completion of antibiotic therapy, the PPI should be continued once daily for a total of 4–6 weeks to ensure complete ulcer healing
- 29. 29 ANTIEMETICS Antiemetics • Used toprevent nausea and vomiting – Serotonin 5 HT3 Antagonists – Dopamine D2 Antagonist – Anticholinergics – H1 Antihistaminics
- 30. 30 Vomiting Centre (medulla) Cerebral cortex Anticipatory emesis Smell Sight Thought Vestibular nuclei Motion sickness Pharynx& GIT(Vagal ) Chemo & radio therapy Gastroenteritis Chemoreceptor Trigger Zone (CTZ) (Outside BBB) Cancer chemotherapy Opioids Muscarinic, 5 HT3 & Histaminic H1 5 HT3 receptors Dopamine D2 5 HT3,,Opioid Receptors Muscarinic Histaminic H1 Patho physiology of Emesis
- 31. 31 Serotonin 5 HT3Antagonist • Potent antiemetics • Even though 5 HT3 receptors are present in vomiting centre & CTZ, the antiemetic action is restricted to emesis caused by vagal stimulation. • High first pass metabolism • Excreted by liver & kidney • Given once or twice daily – orally or intravenously
- 32. 32 Serotonin 5 HT3Antagonist……… Ondansetron 0.15 mg/kg /day Granisetron 10 μg/kg/ day Dolasetron 1.8 mg/kg/ day Indications Chemotherapy induced nausea & vomiting – given 30 min. before chemotherapy. Postoperative & post radiation nausea & vomiting Adverse Effects • Excellent safety profile • Headache & constipation • All three drugs cause prolongation of QT interval, but more pronounced with dolasetron
- 33. 33 Dopamine D2 Antagonist •Antagonise D2 receptors in CTZ • Drugs available Metoclopramide 10–20 mg PO /I.V every 6 hours Domperidone 10 mg PO three times a day • Both drugs are also prokinetic agents due to their 5 HT4 agonist activity • Metoclopramide crosses BBB but domperidone cannot Aside effects • Extrapyramidal: restlessness, dystonias, and parkinsonian symptoms – metoclopramide • Galactorrhea by blocking the inhibitory effect of dopamine on prolactin release- both drugs
- 34. 34 H1 Antihistaminics • Mosteffective drugs for motion sickness • Drugs available Meclizine, Cyclizine Dimenhydrinate, Diphenydramine Promethazine – used in pregnancy for motion sickness Side effects dizziness, sedation, confusion, dry mouth,
- 35. 35 DRUGS FOR THETREATMENT OF CONSTIPATION PURGATIVES (LAXATIVES) • Drugs used for treatment of acute constipation (drugs accelerating the passage of food through the intestine) • A symptomatic therapy which should not be used chronically. • Constipation is defined as a decreased stool frequency and is usually associated with changes in stool consistency, difficulty of defecation and abdominal discomfort. – Living habit factors: diet (lack of fibber content, ↓fluid intake), ↓regular exercise… – Higher frequency in pregnancy – constipation – may be a symptom of the disease (e.g. GIT obstruction due to malignancies! Laxatives may mask the disease and induce complications!)----not used
- 36. 36 Classification of purgatives •Based on their mechanisms of action laxatives can be classified in to Bulk laxatives Osmotic laxatives Stimulant laxatives Emollient laxatives
- 37. 37 Bulk laxatives • drugs/naturalmaterials rich with indigestible polysaccharides • Bulk laxatives retain water, increase the volume of faeces and stimulate natural peristalsis • Remind patient of adequate fluid intake necessity! – Methylcellulose and etulose (semi-synthetic) – Agar, Psyllium, Sterculia and other natural products • Adverse reactions are weak and infrequent (safe) • Bulk laxatives can be recommended for longer treatment in contrast to most of other drugs in this group
- 38. 38 Osmotic laxatives • Themechanism of action is based on administration of poorly absorbed osmotically active agents. • It results in increased volume of fluid in the lumen of the bowel due to the osmosis it accelerates the transfer of the gut content and induce purgation • Inorganic salts: magnesium sulphate, magnesium hydroxide - Mg absorption is usually very low, however it can be a problem in small children or in patients with decreased renal functions
- 39. 39 Osmotic laxatives….. • Lactulose– semisynthetic disaccharide which is converted into fructose and galactose These are poorly absorbed and fermented to the lactic and acetic acids which acts as an osmotic laxative • Glycerine – suppositories working osmotically in the rectum is used as a safe laxative recalling natural defecation reflex • Sorbitol – rectally as suppositories is given before endoscopyic examination
- 40. 40 Stimulant purgatives • Themechanism of action is based on stimulation of intestinal motility and mucosal electrolyte secretion (stimulation of enteric nerves!) • Natural plants: Senna (Cassia senna), Aloe sp. active compounds – antraquinones (e.g. emodin). These are formed in the gut due to the activity of bacterial flora and are supposed to have direct stimulant effects in the myenteric plexus The active compounds are found in mother's milk (caution!) • Synthetic compound: bisacodyl, sodium picosulfate • Adverse reactions: abdominal cramps, pain, electrolyte imbalances, Contraindication: pregnancy, lactation, appendicitis.
- 41. 41 Emollient laxatives • Agentswhich make the stool more soft and allow its easier passage • Docusate sodium – surface active compound (oral or rectal administration) • Mineral oils (liquid paraffin) – coating stool, increasing stool weight and decreasing transit time. • It may be administered both orally or rectally. Adverse reactions: decreased absorption of fat-soluble vitamins (A,D, E, K) hypovitaminosis
Editor's Notes
- #6 CCK, cholecystokinin