GIT Mujahid Gastrointestinal Drugs PDF

Gastrointestinal Drugs Gastroesophageal Reflux Disease (GERD) GERD is when acid and pepsin from the stomach flows backward up into the esophagus often called heartburn; What Causes GERD? 1) Overproduction of acid/pepsin 2) Over relaxation of the Lower Esophageal Sphincter (LES); Wha...

Gastrointestinal Drugs Gastroesophageal Reflux Disease (GERD) GERD is when acid and pepsin from the stomach flows backward up into the esophagus often called heartburn; What Causes GERD? 1) Overproduction of acid/pepsin 2) Over relaxation of the Lower Esophageal Sphincter (LES); What is Peptic Ulcer Disease A benign lesion of gastric or duodenal mucosa 1) Excess acid production 2) Intrinsic defect in the mucosal defense barrier What Causes Peptic Ulcer Disease 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; What Causes Peptic Ulcer Disease NSAIDs Long term 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. Stress ulcers Result of physical trauma (i.e., burn patients). Strategies for Protecting the Gastric Mucosa from Acid Exposure Mechanisms Example Cimetidine Inhibit Omeprazole H+ secretion Prostaglandins Muscarinic antagonists Prevent H+ Sucralfate contact Neutralize Antacids H+ acid  Multiple Mechanisms Regulate Gastric Acid CCK2 Hormonal Gastrin H2 Paracrine cAMP dep. pathway PP H+ Histamine Gastric M3 Lumen Neural Acetylcholine Strategies for Inhibiting Parietal Cell Acid Secretion Gastrin Antagonists H2 Histamine ↓cAMP PP H+ Antagonists M3 Gastric Muscarinic Lumen Antagonists Strategies for Inhibiting Parietal Cell Acid Secretion Basolateral Apical cAMP H2 (+) Histamine (+) Protein Kinase PP H+ K+ ATP EP3 (-) (-) cAMP PGI2 Parietal Cell PGE2 EP3 Mucus M? HCO3- Superficial Epithelial Cell pH 6.7 pH 2 Strategies for Inhibiting Parietal Cell Acid Secretion CCK2 Ca2+ Proton pump Inhibitors (-) EP3 cAMP Protein H+ H2 PP (+) Kinase ATP M3 Ca2+  H+, K+-ATPase (the proton pump) is the final transport pathway for parietal cell hydrogen ion secretion  H+, K+-ATPase is located in the apical membrane of the Parietal cell along the secretory canaliculi; 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 (Prilosec)  Prototype H+, K+-ATPase inhibitor; A prodrug that needs a low pH to be active; Irreversible (forms a covalent bond with the proton pump) - long lasting inhibition of acid production; Profound reduction of gastric acid - elevates gastric pH significantly (20mg/day for 7days will decrease acid by 95%); Highly protein bound; Metabolized by CYP2C & CYP3A; plasma half life of 1 to2 hours but long duration of action; Should be taken just prior to a meal and should NOT be taken with other acid-suppressing agents. Esomeprazole Simply the S-isomer of omeprazole; H+, K+-ATPase inhibitor; Given orally. Rabeprazole Lansoprazole Pantoprazole H+, K+-ATPase inhibitor; An acid-stable form and can be given by i.v.  Proton Pump Inhibitors (PPI) Well Tolerated Hypergastrinemia (can lead to tumor growth in the GI) Nausea Headaches, skin rashes Histamine H2 Antagonists Cimetidine Ranitidine Famotidine  Nizatidine  Drugs for Acid-Peptic Disorders - Cimetidine  Competitive H2 receptor Antagonist; Markedly inhibits basal acid secretion including nocturnal secretion; Readily absorbed after oral administration; Relatively brief duration of action (4-8 hr) – Given on a multiple dosing schedule; – (300-400 mg, 2-4 times daily); – Typical therapy is for 4-8 weeks.  Drugs for Acid-Peptic Disorders – Ranitidine ,Famotidine,Nizatidine  Same mechanism of action as Cimetidine but a longer duration of action (8 to 12 hrs);  Can be given less frequently; 150 or 300 mg, 1-2 times daily  Less interactions at P450 than Cimetidine.  Drugs for Acid-Peptic Disorders - Anticholinergics Blockade of acetylcholine at muscarinic (M3) receptors Pirenzepine Telenzepine Effectively blocks acid secretion (30 to 40%) Limited by side-effects  Drugs for Acid-Peptic Disorders – Prostaglandins (PGE2 & PGI2 ) Act at prostaglandin EP3 receptors on parietal cells & on epithelial cells Inhibits: Stimulates:  Acid secretion  Mucus secretion  Gastrin release  Bicarbonate secretion  Pepsin secretion  Mucosal blood flow 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”  Drugs for Acid-Peptic Disorders - Prostaglandins Misoprostol (Cytotec):  Synthetic Analog of Prostaglandin E1  Anti-acid secretory  0.1 to 0.2 mg results in 85% to 95% acid reduction  Prevention of NSAID gastric ulcers Side Effects Diarrhea Abortion Drugs for Acid-Peptic Disorders - Antacids  Antacids are weak bases that neutralize HCl in the stomach;  They raised Gastric PH;  Magnesium hydroxide  Magnesium trisilicate  Magnesium-aluminum mixtures  Calcium carbonate  Sodium bicarbonate  Characteristics of Common Antacids Feature Sodium Calcium Magnesium Aluminum Bicarbonate Hydroxide Onset of rapid intermediate rapid slow action Duration of short moderate moderate moderate action Systemic yes ? no no alkalosis Effect on --- constipating diarrhea constipating stool Drugs for Acid-Peptic Disorders – Sucralfate  Sucralfate is a basic aluminum salt of sucrose octasulfate;  In the presence of acid (pH < 3-4) some of the aluminum ions dissociate and the resulting negatively charged molecule polymerizes to form a viscous paste-like substance;  This substance adheres strongly to gastric and duodenum mucosa and adheres even more strongly to partially denatured proteins such as those found at the base of the ulcer.  Role of H. pylori in Peptic Ulcer Disease Treatment If H. pylori detected, eradication of the bacteria, along with inhibition of acid. Combination therapy with Omeprazole and Amoxycillin  Functional Disorders of the GI loss of normal” pattern of bowel movement  Primary infection, inflammation, congenital defects (disorders of the neuronal/muscular activity);  Secondary metabolic disorders (hypo- or hyper- parathyroidism, hypercalcemia), neurologic (diabetes mellitus - damage to vagal and sympathetic extrinsic nerves, intrinsic nerves; MS, heavy metal toxicity, carcinoma);  Prokinetic Drugs Substances which enhance transit of materials through the GI tract(enhance GI motility); Increase neuromuscular transmission  Prokinetic Drugs are Often Used for:  Gastroesophageal reflux disease (GERD)  Gastroparesis  Nighttime heartburn  Severerefractory constipation (sometimes caused by irritable bowel syndrome (IBS))  Prokinetic Drugs Act on Enteric Nerves to Increase Cholinergic Stimulation Muscarinic M2 (stimulated by Bethanechol)) Dopamine D2 (Blocked by Metoclopramide and Domperidone) Dopaminergic Neuron 5HT4 Stimulated by Metoclopramide Smooth (-) (+) Ach Ach (+) (+) Muscle (+) Cholinergic Cell Neuron Motilin (+) Stimulated by Erythromycin Motilin Indirect effects are mediated by M2 muscarinic receptors Metoclopramide crosses the blood-brain barrier  Prokinetic Drugs – Metoclopramide (Reglan) Metoclopramide is an antiemetic and improves gastric emptying – indirectly releases acetylcholine  Actions  Dopamine D2 receptor antagonist  Pharmacokinetics  Oral bioavailability  Crosses blood-brain barrier  Adverse Side-effects  Sedation  Dystonic reactions  Anxiety reactions  Gynecomastia  Galactorrhea Prokinetic Drugs – Domperidone (Motilium) Domperidone is an antiemetic and improves gastric emptying – Not very effective for GERD  Actions Dopamine receptor antagonist Ganglionic stimulant  Pharmacokinetics Low oral bioavailability Does not cross blood- brain barrier  Adverse Side-effects Headaches Gynecomastia Anti-emetic Classification of antiemetic drugs:  Prokinetics: Metoclopramide, domperidone  5-HT3 antagonist: ondansetron, granisetron  Antimuscarinics: Hyoscine,  H1 antihistaminic like cyclazine,promethazine.  Neuroleptics: chlorpromazine, haloperidol Preferred drugs for vomiting due to various conditions: Conditions Drugs Motion sickness Hyoscine, cyclazine, promethazine. Vomiting due to Ondansetron, anticancer drugs metoclopramide. Post operative Ondansetron, vomiting metoclopramide. Drugs used in constipation Constipation: A condition in which there is difficulty in emptying the bowels, usually associated with hardened feces. Purgatives: Purgatives are drugs are drugs that promote defecation or passage of stools. They are also called passage of laxatives and cathartics. Laxatives are milder action while cathartics and purgatives are more powerful drugs. Purgatives drugs: Bisacodyl, castor oil, lactulose, Magnesium sulfate. Some drugs causes’ constipation: Anti- cholinergic drugs like atropine, opioids, iron, calcium channel blocker. Laxatives relieve constipation and promote evacuation of th e bowel via the following:  enhancing retention of intraluminal fluid by hydrophilic or osmotic mechanisms;  decreasing net absorption of fluid by effects on small- and large bowel fluid and electrolyte transport;  altering motility by inhibiting segmenting (nonpropulsive) contractions or stimulating propulsive contractions.  Diarrhea Diarrhea: It is the condition of having at least three loose stools or liquid bowel movements each day. Most common cause is an infection of the intestines due to a virus, bacteria, or parasite; a condition known as gastroenteritis. These infections are often acquired from food or water that has been contaminated by stool, or directly from another person who is infected. Bacteria that causes diarrhea: Campylobactor, Salmonella OR E.coli  Treatment of diarrhea:  Replacement of fluid and electrolytes ORS (oral rehydration salts): Composition of ORS is NaCl, KCl, Sodium citrate and glucose mix in water.  Treatment of the cause: like antibiotic if needed.  Antidiarrheal agents: adsorbent like kaolin, pectin and charcoal. kaolin is natural compound containing magnesium and aluminium silicate while pectin is the sugar obtained from apple.  Antimotility drugs: codeine, diphenoxylate and loperamide.  Antidiarrheal Drugs Act By a Variety of Mechanisms Drugs Inhibit Stimulate Decrease Enhance Bind propulsive nonpropulsive fluid fluid luminal contractions contractions secretion* absorption secretagogues Opioids +++ +++ +++ ++ a2 agonists +++ + Anticholinergics +++ ++ Somatostatin + +++ (Octreotide) Bismuth +++ subsalicylate +++ Cholestyramine * Stimulated by secretagogues