Pharmacotherapy of GIT and Respiratory Disorders RPB20403 PDF

Pharmacotherapy of GIT and Respiratory Disorders RPB20403 By Dr. Omar AH Topic 2: Drugs used to inhibit or neutralize gastric acid secretion Learning Outcomes: 2.1 Pathophysiology of ulcers 2.2 Regulation of acid secretion by Parietal cells 2.3 Causes and risk factors 2.4 Signs and Symptoms/Diagnos...

Pharmacotherapy of GIT and Respiratory Disorders RPB20403 By Dr. Omar AH Topic 2: Drugs used to inhibit or neutralize gastric acid secretion Learning Outcomes: 2.1 Pathophysiology of ulcers 2.2 Regulation of acid secretion by Parietal cells 2.3 Causes and risk factors 2.4 Signs and Symptoms/Diagnosis 2.3 Antacids & dimethicone 2.4 Histamine (2) antagonist 2.5 Proton Pump Inhibitors 2.6 Prostaglandin analogues  Prevalence of Gastric Acid in Malaysia A cross-sectional quantitative study was conducted in Selangor, Malaysia from August to December, 2017. The study population was all Malaysian aged above 18 years old who attended the selected private clinics in Selangor state. Why is GERD Increasing in Asia? Current study revealed that the Malay ethnicity (which comprised half of the participants) has the highest percentage of gastritis 50.8% compared to others groups of ethnicities. This study was similar to previous studies which were conducted in Malaysia. It is found that it was approximately 56.6% of total Malaysians were affected by H. pylori induced gastritis. GIT is part of the digestive system; the nervous and endocrine system work together to control gastric secretions and motility associated with the movement of food throughout the GIT. But first, Where gastric secretion starts? A Pathophysiology memory refresh!  Protection layer ↓pH Dietary proteins and fats Regulation of gastric activity Gastric Acid Secretion Mechanism Vagus nerve (Pathophysiology) 1. Ach signal from the vagus nerve 2. Activate Parietal cell 3. Activate enterochromaffin-like cell (ECL cell) 4. Activate G-cell 5. G-cell & ECL cell further activate Parietal cell Cholecystokinin Parietal Cell Mechanism (Pathophysiology) Hormones & neurotransmitters (ACh, Parietal cell Histamine, Gastrin) attach to the receptors (M3, H2, CCK-B) and activate the proton pumps. PP: Active transport of H+ ions out of the cell in exchange for K+ ions. And Cl- ions get secreted into the lumen by simple diffusion. In the stomach, H+, Cl- and H2O combine to form HCL, highly acidic environment for digestion.  Mechanism of gastric acid secretion 1. Acetylcholine (Ach) from the vagus nerve directly activates parietal cells by (M3 cholinoceptors). 2. GRP (gastrin-releasing peptide) released by neurons stimulates gastrin secretion from G cells in the antrum. Gastrin released into the systemic circulation in turn activates the parietal cells via CCKB receptors (= gastrin receptors). 3. Stomach glands contain histamine cells or ECL cells (enterochromaffin - like cells), which are activated by gastrin (CCKB receptors) as well as by ACh and adrenergic substances. They release histamine, which has a paracrine effect on neighboring parietal cells (H2 receptor). Causes & risk factors of peptic ulcer 1. Factors that stimulate 2. Factors that cause the gastric acid secretion: breakdown of the Stress protective layer Alcohol H. Pylori infection Caffeine Medications: Smoking Steroids Spicy foods NSAIDs Oily foods 3. Inadequate mucosal defense (by some medications) Causes and risk factors that contribute to ulcer Peptic ulcers occur when acid in the digestive tract eats away at the inner surface of the stomach or small intestine. The acid can create a painful open sore that may bleed. Common causes include: 1. A bacterium. Helicobacter pylori bacteria commonly live in the mucous layer that covers and protects tissues that line the stomach and small intestine. Often, the H. pylori bacterium causes no problems, but it can cause inflammation of the stomach’s inner layer, producing an ulcer. H. pylori infection may be transmitted from person to another by close contact, such as kissing and by food & water. 2. Regular use of certain pain relievers. Taking aspirin, and some over the counter and prescription pain medications called nonsteroidal anti-inflammatory drugs (NSAIDs) can irritate or inflame the lining of the stomach and small intestine. These medications include ibuprofen (Advil), naproxen (Aleve), ketoprofen and others. They do not include acetaminophen (Tylenol). Peptic ulcers are more common in older adults who take these pain medications frequently or in people who take these medications for osteoarthritis. 3. Other medications. Taking certain medications along with NSAIDs, such as steroids, anticoagulants, low-dose aspirin, selective serotonin reuptake inhibitors (SSRIs), alendronate (Fosamax) and risedronate (Actonel), can increase the chance of developing ulcers Factors causing an increased risk of peptic ulcers: 1. Smoking may increase the risk of peptic ulcers in people who are infected with H. pylori. 2. Alcohol can irritate and erode the mucous lining of your stomach, and it increases the amount of stomach acid that’s produced. 3. Having untreated stress. 4. Eating spicy and oily foods. Factors that cause the breakdown of the protective layer 1. Helicobacter pylori Is a gram-negative, flagellated, spiral bacterium sometimes with a slightly curved rod shape Infection with H. pylori does not cause illness. Most H. pylori-positive cases are asymptomatic, but a chronic infection, can cause inflammation of the stomach, which can lead to the development of peptic ulcers! Treatment: Triple-drug therapy consisting of a proton-pump inhibitor, amoxicillin and clarithromycin given for 14–21 days H. pylori Factors that cause the breakdown of the protective layer (Cont~) 2. NSAIDs, they inhibit COX = inhibit PG = inhibit Mucus secretion = cause ulcer. Peptic Ulcers Signs and Symptoms Peptic Ulcers Signs and Symptoms The most common symptom is a burning sensation or pain in the middle of the abdomen between chest & belly button. Typically, the pain will be more intense when the stomach is empty, smoking, bending or drinking soda, and it can last for few minutes to several hours. Other common signs and symptoms of ulcers include: 1. Dull pain in the stomach 2. Weight loss 3. Not wanting to eat because of pain 4. Nausea or vomiting 5. Bloating 6. Feeling easily full 7. Burping or acid reflux 8. Heartburn, which is a burning sensation in the chest 9. Pain that may improve when you eat, drink, or take antacids 10. Anemia, whose symptoms can include tiredness, shortness of breath, or paler skin 11. Dark, tarry stools 12. Vomit that’s bloody or looks like coffee grounds Diagnosis of Peptic Ulcer Medical history Physical exam Laboratory tests for H. pylori (Urea breath test) Endoscopy & biopsy to eliminate cancer X-rays (barium swallow) Peptic Ulcer Diagnosis To detect an ulcer, the doctor may first take a medical history and perform a physical exam. Then undergo diagnostic tests, such as: 1. Laboratory tests for H. pylori. The doctor may recommend tests to determine whether the bacterium H. pylori is present in the body. The doctor may look for H. pylori using a blood, stool or breath test. The breath test is the most accurate. Blood tests are generally inaccurate and should not be routinely used. For the breath test, the patient drink or eat something that contains radioactive carbon. H. pylori breaks down the substance in the stomach. Later, the patient blows into a bag, which is then sealed. If the patient is infected with H. pylori, the breath sample will contain the radioactive carbon in the form of carbon dioxide. If the patient is taking an antacid prior to the testing for H. pylori, make sure to let the doctor know. Depending on which test is used, the doctor may recommend to discontinue the medication for a period because antacids can lead to false-negative results. 2. Endoscopy. The doctor may use a scope to examine the upper digestive system (endoscopy). During endoscopy, the doctor passes a hollow tube equipped with a lens (endoscope) down the throat and into the esophagus, stomach, and small intestine. Using the endoscope, the doctor looks for ulcers. If the doctor detects an ulcer, small tissue samples (biopsy) may be removed for examination in a lab. A biopsy can also identify whether H. pylori is in the stomach lining. The doctor is more likely to recommend endoscopy if the patient are older, have signs of bleeding, or have experienced recent weight loss or difficulty eating and swallowing. If the endoscopy shows an ulcer in the stomach, a follow-up endoscopy should be performed after treatment to show that it has healed, even if the symptoms improve. 3. Upper gastrointestinal series. Sometimes called a barium swallow, this series of X-rays of the upper digestive system creates images of the esophagus, stomach, and small intestine. During the X-ray, the patient swallow a white liquid (containing barium) that coats the digestive tract and makes an ulcer more visible. Peptic ulcer revealed by endoscopy Helicobacter pylori infection revealed by endoscopy (nodular gastropathy)  Eating – Eating - worsen gastric ulcer improve duodenal ulcer Peptic Ulcer Management 1. Pharmacological 2. Non-pharmacological Non-pharmacological treatment of peptic ulcer 1. Avoid spicy foods 2. Avoid oily foods 3. Avoid xanthin containing beverges 4. Avoid alcohol 5. Avoid smoking 6. Avoid heavy and big meals 7. Encourage small frequent low caloric meals 8. Encourage eating healthy and green vegetables and fruits 9. Avoid ulcerating drugs e.g. NSAIDs, corticosteroids, xanthins and parasympathomimetics nasi goreng sup sayur Pharmacological treatment of Ulcer & GERD 1. Systemic (Goes to the blood circulation) (absorbable) 2. Non-systemic (local instant effect) (non-absorbable) MOA: Non-systemic anti-acids (Antacids) (for immediate relief) Used for gastroesophageal reflux disease (GERD) relieve heartburn, peptic ulcer They act directly by Aluminium hydroxide Al(OH)3 neutralizing Hydrochloric Magnesium hydroxide Mg(OH)2 Calcium carbonate CaCO3 Acid. They do not decrease Magnesium trisilicate Mg₂O₈Si₃ Sodium alginate acid secretion! Potassium bicarbonate MOA: 1.5 Metal ion combine + with gastric acid to form = salt & water. Rise stomach pH and cause rapid relief of hyperacidity! What is gastroesophageal reflux disease (GERD) ? GERD is a digestive disorder in which stomach acids, food and fluids flow back into the esophagus. It can occur at any age and may be temporary or a long- term issue. The danger of untreated GERD is that it can cause health problems such as inflammation of the esophagus, which is a risk factor for esophageal cancer. It also may lead to respiratory problems such as asthma, fluid in the lungs, chest congestion, as well as damaging teeth. E.g. of Non-systemic anti-acids Maalox® + (Simethicone): Aluminium hydroxide + Magnesium hydroxide + (Simeticone) = Anti-foaming agent used to reduce bloating, burping, discomfort or pain caused by excessive gas. Gaviscon® Sodium alginate + Sodium bicarbonate + Calcium carbonate + Potassium bicarbonate Form raft to prevent reflux MTT Mixture Magnesium Trisilicate Widely used in hospitals Dimethicone (Simethicone) Is a silicone polymer with a wide variety of uses, from cosmetics to industrial lubrication Used as an anti-foaming agent, to reduce bloating, discomfort or pain caused by excessive gas. Simethicone is a mixture of dimethicone and silicon dioxide Simethicone is a non-systemic surfactant which decreases the surface tension of gas bubbles in the GI tract. This allows gas bubbles to leave the GI tract as flatulence or belching. How about peptic ulcer long-term treatment? How to reduce gastric acid secretion? How to protect the mucosa? Acid peptic disease: i.e., peptic ulcer (gastric & duodenal), GERD, and pathological hypersecretory states i.e. Zollinger-Ellison syndrome induced by gastrin secreting tumour. MOA: Systemic anti-acids Reduce gastric acid secretion (prevent stimulation of parietal cell) Anticholinergics Prostaglandin analogue Misoprostol PG-E1 receptor Prokinetics Anticholinergics Propantheline Antiacid classes For gastroesophageal reflux disease (GERD), heartburn, peptic ulcer A. Systemic by reduction of gastric acid secretion (prevent stimulation of parietal cell) 1. Histamine-2 (H2) receptor antagonists (H2 blockers): Cimetidine, Famotidine, Ranitidine. 2. Proton pump inhibitors (PPIs): Omeprazole, Pantoprazole. 3. Prostaglandin analogue (mucus protection): Misoprostol. 4. Adjunct therapy: - Bismuth chelate, Sucralfate (Aluminum hydroxide-sulfate sucrose) - Anticholinergics : Pirenzepine, Propantheline. - Prokinetics: improve the movement (motility) of food through the digestive system, reducing the risk of acid reflux: Metoclopramide B. Non-Systemic by neutralization of gastric acid Sodium bicarbonate, Calcium carbonate, Magnesium hydroxide C. Surgery In severe ulcer, surgery may be necessary Antibiotic medications to kill H. pylori Amoxicillin (β-lactam antibiotic, aminopenicillin) Clarithromycin (Macrolide) Metronidazole (nitroimidazole antimicrobials) Histamine-2 (H2) receptor antagonists (H2 blockers): Cimetidine Famotidine Ranitidine (This drug has been withdrawn from the US market due to problems with safety) Withdra wn Proton pump inhibitors (PPIs): Omeprazole Pantoprazole Delayed-release Dexlansoprazole  Mucosal Protective Agents Sucralfate is a local acting substance that in an acidic environment (pH < 4) reacts with hydrochloric acid in the stomach to form a viscous, paste-like material capable of acting as an acid buffer for as long as 6 to 8 hours after a single dose. It also attaches to proteins on the surface of ulcers, such as albumin and fibrinogen, to form stable insoluble complexes. Aluminum hydroxide - sulfate sucrose Bismuth subsalicylate Misoprostol is a synthetic prostaglandin E1 analogue, it protect the GI mucosa by inhibiting acid secretion & reducing its volume and increasing bicarbonate & mucus secretion. Contraindicated in pregnancy (used as self-induced abortion in the black market) Treatment and drugs action in ulcer 1. Antibiotics for H. pylori. If H. pylori is found in the digestive tract, the doctor may recommend a combination of antibiotics to kill the bacterium. These may include amoxicillin, clarithromycin, metronidazole (Flagyl), tetracycline and levofloxacin. 2. Medications that block acid production & promote healing. Proton pump inhibitors (PPIs), reduce stomach acid by blocking the action of the parts of cells that produce acid. These drugs include prescription and over-the-counter medications, omeprazole, lansoprazole, rabeprazole, esomeprazole and pantoprazole. 3. Medications to reduce acid production. Called Histamine (H-2) blockers, they reduce the amount of stomach acid released into the digestive tract, which relieves ulcer pain and encourages healing. 4. Antacids that neutralize stomach acid. Antacids neutralize existing stomach acid and can provide rapid relief. Side effects can include constipation or diarrhea, depending on the main ingredients. 5. Medications that protect the lining of stomach & small intestine. In some cases, the doctor may prescribe medications called Cytoprotective agents that help protect the tissues that line the stomach and small intestine. Options include the prescription medications sucralfate and misoprostol.  Complications of untreated ulcers Perforation Scar and stricture Hole in stomach Narrowing of pylorus Peritonitis Upper abdomen pain Need urgent repair and reflux Bleeding Anaemia Haemorrhage "Education is not preparation for life; education is life itself."