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GIT-Drugs

1. DRUGS AFFECTING GASTROINTESTINAL TRACT Antiulcer Prokinetic Agents Antiemetic drugs Laxatives Antidiarrheal

2. I. Agents that inhibit Gastric Acid Production & Antiulcer Drugs

3. Physiology of Gastric Acid Secretion: Gastric Acid Secretion is Regulated by Neural (ACh Cholinergic - Muscarinic) Endocrine (Gastrin) and Paracrine (Histamine) secretory factors - Stomach. Secretory Products: HCl, Pepsin, Mucus, HCO 3 Amongst these : Aggressive Factors : HCl, pepsin, Helicobactor pylori infection Defensive/ Cyto protective factors : Mucus, HCO 3 Secretion and PGEs (PGE 1 and PGE 2 )

4. Sites/Location of Various Anti-Ulcer Agents

5. Brief Pharmacology of Antiulcer agents 1) Agents that Neutralize acid : Antacids : (NaHCO 3 , Al(OH) 2 , Ca(CO) 3 ). These are weak bases that form salts with HCl causing Chemical NEUTRALIZATION to buffer acid in the stomach. Antacids are thought to heal ulcer by protective effect particularly aluminum compounds. Advantages : Immediate Pain Relief & Less expensive. Disadvantages : i) Short Duration of Effect ii) Rebound Gastric Acid Secretion.

6. Major Constituents of some Antacids

7. Brief Pharmacology of H 2 Receptor Antagonists . 2) Agents that reduce Gastric acid secretion : a) H 2 Receptor Antagonists : ( Cimetidine, Ranitidine, Famotidine, Nizatidine) They inhibit 90% acid secretion in basal state as well as food-induced and nocturnal acid production. Thus, they are helpful in healing gastric and duodenal ulcers and prevent their recurrence. Have benefits in preventing increased gastric acid secretion in Zollinger-Ellison syndrome. Cimetidine Has several side effects, not a choice now - Under Prescription. Ranitidine low dose – OTC !

8. Problems with Cimetidine CNS : confusion, somnolesence, headache, dizziness Immunological : skin rashes, myalgia, itching Gonadal effects : Gynecomastia, loss of libido, impotence (elevates estrogens and prolactin secretion), galactorrhea, infertility Inhibits CyP 450 : Inhibits the metabolism of various drugs that are concomitantly taken: phenytoin, warfarin, theophylinne, TCA, BZD. These adverse effects are relatively least with ranitidine and /none with famotidine Ranitidine (150 mg bid) + midazolam leads to 65% increase in midazolam level = prolonged sedation (May 2009)

9. Proton Pump Inhibitors (PPI) Omeprazole Esomeprazole Lansoprazole Pantoprazole Rabeprazole

10. Proton Pump Inhibitors (PPI) Note: There is NO rationale in combining an H 2 blocker with a PPI for long term treatment. In ZES, to have rapid control, they are combined. PPI takes 12-24 hr to work. Proton Pump (H + K + ATPase Inhibitors: Omeprazole) Irreversible inhibitor of proton pump; blocks 98% of acid secretion in all forms of ulcer and hypersecretory Zollinger-Ellison syndrome. The drug is given in gelatin coated capsule to resist breakdown in stomach acid. It reaches the intestine, well absorbed, enters blood stream, reaches the parietal cell. It is activated to an ionized protonated form to irreversibly bind and inhibit proton pump.

11. Proton Pump Inhibitors (PPI) Uses Gastroesophageal reflux disease (GERD) Peptic ulcer (H Pylori, NSAIDs) Dyspepsia

12. Proton Pump Inhibitors (PPI): Safety Diarrhea, headache, abdominal pain < 5% Subnormal Vit B12 serum level Increased risk of enteric infections Drug Interaction: Ketoconazole and Digoxin absorption is decreased due to reduced acidity. Omeprazole may inhibit coumadin, diazepam and phenytoin metabolism

13. Additional Points - Omeprazole & Pharmacology of Sucralfate PPI are Effective in patients - refractory to H 2 receptor blockers. causes prolonged inhibition of acid secretion. Note: Omeprazole and H 2 blockers are most effective in acute/chronic/prophylactic management of ulcer.

14. 3) Cytoprotective Mucosal Defensive Agents: Sucralfate : Sucrose Octasulfate Aluminium Hydroxide is a Gel that gives a protective coating over the ulcerated region and prevents further erosion. Note: It also Stimulates PGE 1 production; adsorbs pepsin .

15. Pharmacology of Cytoprotectives. Sucralfate, Misoprostol, Bismuth Disadvantages of Sucralfate : Constipation, Dry mouth , decreases the bioavailability of other drugs because of adsorption. b) Misoprostol : Methyl PGE 1 analog. It mimics PGE 1 and enhances the production of mucus and HCO3. Thus it is cytoprotective, prevents ulceration. Particularly effective in drug induced peptic ulcer by NSAIDs and corticosteroids . Disadvantages : Diarrhea Contraindicated in pregnancy. c) Bismuth chelate: Gives a Protective coating. Increases mucus and PG production, Eradicates H. pylori.

16. Management of H. Pylori Infection Gram-negative rod colonizes in the gastro-duodenal area. Causes Erosion of the protective epithelial cells. Leading to inflammatory gastritis and severe peptic ulcer. Treatment with a H2 blocker or a Proton Pump inhibitor + Eradication of the Helicobacter colony is very Vital. Antimicrobials such as Metronidazole with Tetracycline or Amoxycillin/Clarithromycin . (PPI+2 or 3 antimicrobials is standard Triple pack) Alternatively, a Quadruple combination therapy with inclusion of bismuth compound seems to be much more effective in the eradication of resistance form of H. Pylori infection.

17. Consensus Guidelines for Treating H. Pylori I n <50 years old with mild symptoms, 1 st Line: Hp – pack for either 7 days or 14 days regimen a. Hp-Pack PPI + clarithromycin + amoxicillin 7-14 days b. PPI + clarithromycin + metronidazole 7-14 days c. Ranitidine+ Peptobismol + clarithromycin+ amoxicillin (Last one c. is triple therapy to eradicate H. Pylori). I f clarithromycin and metronidazole resistance, resort to: 2 nd Line: Quadruple Therapy: 7 days a and 7 days b. a. PPI+BMT ( Bismuth+Metronidazole+Tetracycline ) 7days b. PPI (lansoprozole) + amoxicillin 7 days.

18. Treatment of Zollinger-Ellison Syndrome (ZES) Gastrinoma of the duodenum - 2/3 rd are Malignant Elevated Gastrin Levels -peptic ulceration, gastric hyper secretion presence of gastrinoma, a non beta cell tumor of the pancreas with high gastrin output, a type of multiple neoplasm accompanied by neoplasm of the pituitary and parathyroid gland. Goal: High dose Proton pump inhibitor (omeprazole or lansoprazole)

19. II. Drugs that Promote Upper GIT Motility (Prokinetic agents) Prokinetic Agents : Agents that enhance coordinated contraction of the gastric antrum and the Duodenum: T he Major Goal is to : Increase Gastric Emptying, Relieve Gastric stasis, Prevent Reflux Oesophagitis, Heart burn Prevent Regurgitation of Gastric contents Decrease Nausea & Vomiting.

20. Prokinetic Agents Rapidly Promote Gastric Emptying By Selectively  Duodenal Motility Esophagus Gastroesophageal Sphincter Duodenum Fundus Mucus Pyloric Sphincter Stomach PH 2.3 HCL H + H + H + H + H + Choinomimetics will be unselective Proknetics modulate ACh release to promote opening of the Gastro-Duodenal Sphincter & Selectively  Duodenal Motility.

21. Why don’t we use Cholinomimetics and Anticholinesterases? Cholinomimetics (Bethanachol) & anticholinesterases (Neostigmine) promote gastrointestinal transit. T he effects are Nonspecific & several undesirable muscarinic effects predominate (salivation, gastric secretion & diarrhea) Therefore, we use selective Dopamine (D 2 ) Blockers, 5-HT 4 (serotonin) and Motilin Agonists as Prokinetics . Uses of Prokinetics:  Gastro-oesophageal Reflux disease, heartburn.  Oesophageal clearance, Relaxes gastro-duodenal sphincter. Rapid Passage of food - GIT.

22. What do Prokinetics Do? Prokinetic Agents : Site of Action Duodenum ↑ Duodenal Motility, ↑ Intestinal Transit, ↑ Opening of the Gastro Duodenal Sphincter, ↑ Rapid Passage of food, ↓↓↓ Heart Burn, ↓↓ Esophagitis, ↓↓↓ Nausea & Vomiting

23. Brief Comparative Pharmacology of Prokinetics and Specific Indications: Metoclopramide : D 2 selective Dopamine antagonist; crosses the blood brain barrier (BBB), CNS related side effects are its drawback: hyperprolactinemia, extrapyramidal (Parkinsonian) symptoms but have no antipsychotic effect. Central Dopamine antagonism is helpful in promoting Antiemetic effect . Domperidone : D 2 selective antagonist does not cross the blood brain barrier; therefore, CNS related symptoms are least no extrapyramidal side effects; however, it causes hyperprolactinemia (pituitary is outside the CNS and not covered by the BBB.).

24. Erythromycin: Prokinetic Effect Besides being a Macrolide antibiotic, it activates Motilin Receptors and enhances Duodenal Motility. Erythromycin does NOT exert D 2 receptor, CNS or Hyperprolactinemia Effects, It is Not an Antiemetic. Erythromycin also enhances Colonic motility (lower GIT motility) and promotes watery diarrhoea. Thus, it is useful in promoting colonic hypermotility to relieve constipation, besides being a prokinetic agent.

25. Why Cisapride is not used now? Cisapride is a 5HT4 selective serotonin agonist . It  cholinergic transmission in the Gastroduodenal region, Not an antiemetic, Has No D2 receptor blockade activity . Popular prokinetic agent until 1998. Not used now, Why? Blocks cardiac K + channels and causes ventricular arrhythmia- torsades de pointes (long QT syndrome). Cardiotoxicity  when combined with clarithromycin. Because Clarithromycin is a CYP3A4 inhibitor and  the metabolism of cisapride and  its cardiotoxicity . [Cisapride blocks the K + channels in the heart and GIT, and the blockade K+ channels  GIT Motility].

26. Antiemetic Drugs I.Vomiting : A physiological protective antiperilstatic response resulting in forceful expulsion of the GI contents as a result of a series of integrated events. II . Sequence of Events in the act of vomiting : 1. Nausea: Increased salivation, mydriasis, sweating and pallor. 2. Retching: Contraction of abdominal muscles, antiperistaltic movement. 3. Vomiting: Contraction of diaphragm and forceful expulsion of GIT contents through mouth.

27. III. Causes of Nausea and Vomiting: III. Causes of Nausea and Vomiting: 1. Drug induced (iatrogenic) Cytotoxic drugs (Cisplatin, Methotrexate, Nitrogen mustards) Opioids (morphine), Cholinomimetics Cardiac glycosides, Emetin, Apomorphine L-Dopa, Bromocriptine, High dose estrogen (ethinyl estradiol) 2. Infectious G.I. disorders Bacterial and viral toxins 3. Noninfectious G.I.T. disorders Gastric outlet obstruction Gastric irritants

28. III. Causes of Nausea and Vomiting: 4. During early pregnancy (first trimester, morning sickness due to high estradiol in circulation). 5. CNS related Motion sickness, Menier’s disease, CNS toxic agents Increased intracranial pressure, Stroke

29. ANTIEMETICS 1. Anti Histamines 2. Anticholinergics 3. Benzodiazepines 4. Dopamine antagonists 5. 5-HT3 selective Antagonist 6. Cannabinoids 7. Corticosteroids

30. ANTIEMETICS – Antihistamines (1) 1. Anti Histamines : eg. Diphenhydramine, Doxylamine, Dimenhydrinate , Cyclizine, Meclizine. H1 receptors - in the solitary tract nucleus and involved in transmission from the vestibular apparatus to the emetic center. They block H1 receptors and prevent peripheral stimulation of the emetic center. Uses: Most effective in Motion Sickness and inner ear dysfunction (Menier’s disease) Adverse effects: Drowsiness, Sedation, Blurred vision, Dry mouth (Atropine-like).

31. ANTIEMETICS 2. Anticholinergics 2. Anticholinergics : eg. Scopalamine (and not atropine) Block peripheral stimulation of the emetic center. Uses: In Motion Sickness Adverse effects: Dry mouth, Drowsiness, Blurred vision and Tachycardia

32. ANTIEMETICS 3. Benzodiazepines 3. Benzodiazepines : eg. Lorazepam, Alprazolam Prevent central cortical induced vomiting, enhance very Uses: For anxiety and Chemotherapy. Adverse effects: Drowsiness

33. 4. Dopamine antagonists : a ) Non-selective DA Antagonists : eg. Phenothiazines Act at the chemoreceptor trigger zone (CTZ) by inhibiting dopaminergic transmission and also decrease vomiting caused by gastric irritants by inhibiting the stimulation of peripheral Vagal and sympathetic afferents Adverse effects: Acute dystonic reaction, Orthostatic hypotension, Extrapyramidal side effects and blood dyscrasias. b) D2 Selective Antagonists : eg. Metoclopramide, Domperidone Selective blockade of D2 receptors in the CTZ.

34. Antiemetics- D2 [4] & 5-HT3 Sel. Antagonists [5]  Adverse effects: Metoclopramide precipitates extrapyramidal side effects, domperidone does not,  Uses: Both Selective and non-selective antagonists are effective anti-emetic agents in controlling nausea and vomiting encountered during cancer chemotherapy.

35. 5. 5-HT3 selective Antagonist 5. 5-HT3 selective Antagonist : eg. Ondansetron, Granisetron  They inhibit serotonin mediated responses by blocking 5HT3 receptors that are involved in the initiation of vomiting reflex. Most Effective.  Uses: Vomiting encountered in Cancer chemotherapy.

36. 6. Cannabinoids : 6. Cannabinoids : eg. Tetrahydrocannabinol, Nabilone Uses: Control of emesis when all other agents fail. Adverse effects: Hallucination, Bulemia

37. 7. Corticosteroids 7. Corticosteroids : eg. Dexamethasone Mechanism unknown. Uses: Controls Emesis in Motion Sickness, Mountaineering Effective when combined with D2 and 5HT3 Antagonists. Adverse effects: Osteoporosis, Cushingoid features, hyperglycemia, Peptic ulcer, Psychosis, pituitary, adrenal suppression and susceptibility to infection.

38. Laxatives: • Laxative – production of a soft formed stool over a period of 1 or more days • Catharsis – prompt, fluid evacuation of the bowel, more intense Indications for laxative use: • Pain associated with bowel movements • To decrease amount of strain under certain conditions • Evacuate bowel prior to procedures or examinations • Remove poisons • To relieve constipation caused by pregnancy or drugs Contraindications: • Inflammatory bowel diseases • Acute surgical abdomen • Chronic use and abuse

39. Laxatives: • Stimulate peristalsis • Soften bowel contect Classification: • Bulk laxatives – Non-absorbable carbohydrates – Osmotically active laxatives • Irritant laxatives = purgatives – Small bowel irritants – Large bowel irritants • Lubricant laxatives – Paraffin – Glycerol

40. Laxatives: Bulk laxatives: Increase in bowel content volume triggers stretch receptors in the intestinal wall => causes reflex contraction (peristalsis) that propels the bowel content forward Carbohydrate-based laxatives – Insoluble and non-absorbable – Non digestable; take several days for effect – Expand upon taking up water in the bowel – Must be taken with lots of water • Vegetable fibers (e.g. Psyllium, lineseed) • Bran (husks = milling waste product) Osmotically active laxatives – Partially soluble, but not absorbable – Saline-based (mostly sulfates) – Effect in 1-3 hrs => used to purge intestine (e.g. surgery, poisoning) • MgSO4 (= Epsom salt) • Na2SO4 (= Glauber’s salt)

41. Laxatives: Irritant laxatives: Cause irriatation of the enteric mucose => more water is secreted than absorbed => softer bowel content and increased peristaltic due to increase volume Small bowel irritants • Ricinoleic acid (Castor oil) – Active ingredient of Ricinus communis – The oil (triglyceride) is inactive – Ricinoleic acid released from oil through lipase activity

42. Laxatives: Irritant laxatives: Large bowel irritants Anthraquinones Active ingredient of Senna sp. (Folia and fructus sennae), Rhamnus frangulae (cortex frangulae) and Rheum sp. (rhizoma rhei): contain inactive glycosides => active anthraquinones released in colon take 6-10 hours to act

43. Laxatives: Irritant laxatives: Large bowel irritants Diphenolmethanes – Derivatives of phenolphtalein • Bisacodyl – Oral administration: effect in 6-8 hrs – Rectal administration: effect in 1 hr – Often used to prepare for intestinal surgery • Sodium picosulfate

44. Antidiarrheal drugs Antidiarrheal drugs: treat only symptoms! – Diarrhea is usually caused by infection (Salmonella, shigella, campylobacter, clostridium, E. coli), toxins, anxiety, drugs… – In healthy adults mostly discomfort and inconvenience – In children (particularly mal-nourished) a principal cause of death due to excessive loss of water and minerals.

45. Antidiarrheal drugs Antimotility agents: – Muscarinic receptor antagonists (not useful due to side effects) and opiates: • Morphine • Codeine • Diphenoxylate – All have CNS effects - NOT useful for diarrhea treatment • Loperamide – Selective action on the GI tract – Does not produce CNS effects – First choice antidiarrheal opoid – Combined with Dimethicone (Silicon-based gas-absorbent)