Acid peptic disorders include a number of conditions whose pathophysiology is believed to be the result of damage from acid and pepsin activity in the gastric secretions. This talk focuses on gastroesophagealreflux disease (GERD) and peptic ulcer disease, the two most common and well-defined disease states.
Gastroesophageal reflux diseaseDefinitionGERD is defined as chronic symptoms of heartburn, acid regurgitation, or both, or mucosal damage produced by the abnormal reflux of gastric contents into the esophagus. Reflux esophagitis occurs in a subgroup of GERD patients with histopathologically demonstrated characteristic changes in the esophageal mucosa.
PathophysiologyGERD occurs when the normal antireflux barrier between the stomach and esophagus is impaired, either transiently or permanently.Therefore, defects in the esophagogastric barrier , such as lower esophageal sphincter incompetence , transient lower esophageal sphincter relaxation , and hiatal hernia , are the primary factors involved in the development of GERD.Symptoms develop when the offensive factors in the gastroduodenal contents, such as acid, pepsin, bile acids , and trypsin , overcome several lines of esophageal defense, including esophageal acid clearance and mucosal resistance.
Signs and SymptomsClassic symptoms of GERD are heartburn , defined as a retrosternal burning discomfort, and acid regurgitation.Symptoms often occur after meals and can increase when a patient is recumbent .Other ancillary symptoms seen in typical reflux are dysphagia, odynophagia, and belching.Atypical GERD symptoms include chest pain, asthma, cough, hoarseness, sore throat, globus, and repetitive throat clearing.
DiagnosisThere is no diagnostic gold standard for this disease. Classic symptoms of acid regurgitation and heartburn are specific but not sensitive for the diagnosis of GERD, as determined by abnormal 24-hour pH monitoring .It is reasonable to consider an empirical trial of antisecretory therapy in a patient with classic symptoms of GERD in the absence of alarm signs.
Endoscopic evaluation should be performed under the following conditions : Failure to respond to an empirical course of antisecretory therapy. Alarm signs suggesting complicated reflux disease (e.g., dysphagia, odynophagia, bleeding, weight loss, anemia) Chronic symptoms (>10 years) in a patient at risk for Barretts esophagus. Patients requiring chronic antisecretory therapy.
Endoscopy is the technique of choice to evaluate the mucosa in patients with symptoms of GERD.Erosions or ulcerations at the squamocolumnar junction, as well as the findings of Barretts esophagus, are diagnostic of GERD .However, Barretts epithelium must be confirmed by a biopsy revealing intestinal metaplasia.
Treatment and Outcomes The goals of treatment in GERD are To relieve symptoms, heal esophagitis , prevent recurrence of symptoms, and prevent complications.Lifestyle Modification Various lifestyle modifications are recommended for the treatment of GERD. Which include… avoiding precipitating foods (e.g., fatty foods, alcohol, caffeine), avoiding recumbency for 3 hours postprandially, elevating the head of the bed, quitting smoking, and losing weight.
MedicationThe cornerstone of GERD therapy is the administration of agents that decrease gastric acid secretion, thereby decreasing esophageal acid exposure. An antacid , which only neutralizes acid that is already secreted, Approximately 20% of patients experience symptom relief with these therapies. Administration of histamine-2 (H2) receptor antagonists (H2RAs) in standard divided doses achieves complete symptom relief in approximately 60% of patients and heals esophagitis in about 50%. PPIs are superior to H2RAs in regard to healing erosive esophagitis and relieving symptoms, with healing rates approaching 90% and symptom relief.
Because of their superiority in healing esophagitis and maintaining symptom relief, PPIs are the treatment of choice in patients with frequent reflux symptoms. PPIs should always be given before meals ; a single dose may be given in the morning to patients with daytime symptoms and in the evening to those with nighttime symptoms. PPIs are generally well tolerated, with the most common side effects being diarrhea and headache. patients whose GERD is well controlled on PPI therapy may consider step-down therapy to an H2 receptor blocker.
Surgery(laproscopic fundoplication)sssAntireflux surgery, now performed primarily by the laparoscopic approach, remains an option for carefully selected patients with well-documented GERD Patients with predominant regurgitation symptoms, which are often nocturnal, evidence of ongoing acid exposure or esophageal damage while PPIs are being used.
Cancer PreventionBarretts esophagus is a potentially serious complication of chronic GERD. It is present when the normal stratified squamous epithelium of the distal esophagus is replaced by intestinal columnar metaplasia. It is the most significant histologic outcome of long-standing GERD; the odds of developing Barretts epithelium increase by about sixfold after 10 years of symptoms . The most dreaded complication of Barretts epithelium is esophageal adenocarcinoma . However, the incidence rate for developing esophageal carcinoma is still low, these patients require not only acid suppression with PPIs to control symptoms but also continued endoscopic surveillance to detect the development of dysplasia and adenocarcinoma.
Peptic ulcer diseaseDefinitionPeptic ulcers (gastric and duodenal) are defects in the GI mucosa that extend through the muscularis mucosa.PathophysiologyPeptic ulcers are defects in the gastric or duodenal mucosa that extend through the muscularis mucosa.
Phases of gastric secretion Phase Stimuli PathwayCephalic (stimulate) Sight, smell, taste or 1) Vagus (M3 receptors) thought of food 2) Histamine (H2 receptor) 3) GastrinGastric (stimulate) Food in the stomach 1) Stretch: local reflex (M3 receptors) 2) Chemical substances in food (gastrin) 3) Increase pH: Inhibition of somatostatin (GHIH) releaseIntestinal (inhibit) Chyme in the duodenum
Mechanism of ulcer formation High [H+] in the gastric lumen Require defense mechanisms to protect oesophagus and stomach Oesophagus – LES Stomach: a number of mechanisms Mucus secretion: slows ion diffusion Prostaglandins: I2 and E2 (alcohol, aspirin, and other drugs) Bicabonate ions High Blood Flow (nitric oxide)
Under normal conditions, a physiologic balance exists between peptic acid secretion and gastroduodenal mucosal defense. thus, peptic ulcer occur when the balance between the aggressive factors and the defensive mechanisms is disrupted.Aggressive factors, such as NSAIDs, H pylori , alcohol, bile salts, acid, and pepsin, can alter the mucosal defense by allowing back diffusion of hydrogen ions and subsequent epithelial cell injury.The defensive mechanisms include tight intercellular junctions , mucus, mucosal blood flow, cellular restitution, and epithelial renewal.
Imbalance Imbalance primarily between Aggressive factors and Defensive factors: e nsiv g. Defe s, e. r facto s, u muc , PG 3 HCO e essivAggr , e,g, sf actor psin, pe acid, . tc bile e
Major Etiologies Helicobacter pylori: gram negative bacteria, can live in stomach and duodenum, May breakdown mucus layer → inflammatory response to presence of the bacteria also leads to ulcer Gastric Acid: needs to be present for ulcer to form → activates pepsin and injures mucosa Decreased blood flow: causes decrease in mucus production and bicarbonate synthesis, promote gastric acid secretion NSAIDS: inhibit the production of prostaglandins Smoking: nicotine stimulates gastric acid production
H. pylori Gram (-) rod with flagella H pylori is most common cause of PUD Transmission route fecal-oral Secretes urease → convert urea to ammonia Produces alkaline environment enabling survival in stomach Almost all duodenal and 2/3 gastric ulcer pt’s infected with HP Considered class 1 carcinogen → gastric cancer
Gastric Ulcers Common in late middle age incidence increases with age Male to female ratio — 2:1 Use of NSAIDs - associated with a three- to four-fold increase in risk of gastric ulcer Less related to H. pylori than duodenal ulcers 10 - 20% of patients with a gastric ulcer have a concomitant duodenal ulcer
Duodenal Ulcers Most common in middle age peak 30-50 years Male to female ratio — 4:1 Genetic link: 3x more common in 1st degree relatives H. pylori infection common up to 95%
Signs and symptomsHistory Epigastric pain (the most common symptom) Gnawing or burning sensation Relieved by food or antacids Patient awakens with pain at night. May radiate to the back (consider penetration) Duodenal ulcers : occurs 1-3 hours after a meal and may awaken patient from sleep. Pain is relieved by food, antacids, or vomiting. Gastric ulcers : food may increase the pain while vomiting relieves it. Nausea,Vomiting, which might be related to partial or complete gastric outlet obstruction Dyspepsia, including belching, bloating, distention, and fatty food intolerance Heartburn,Chest discomfort,Anorexia, weight loss Hematemesis or melena resulting from gastrointestinal bleeding Dyspeptic symptoms that might suggest PUD are not specific because only 20-25% of patients with symptoms suggestive of peptic ulceration are found on investigation to have a peptic ulcer.
PhysicalIn uncomplicated PUD, clinical findings are few and nonspecific. Epigastric tenderness Guaiac-positive stool resulting from occult blood loss Melena resulting from acute or subacute gastrointestinal bleeding Succussion splash resulting from partial or complete gastric outlet obstruction
Differential Diagnosis Neoplasm of the stomach Pancreatitis Pancreatic cancer Diverticulitis Nonulcer dyspepsia (also called functional dyspepsia) Cholecystitis Gastritis GERD MI—not to be missed if having chest pain
Investigations Invasive Endoscopic biopsy – demonstration of H-pylori in gastric mucosa RIPID UREASE TEST Non invasive SEROLOGIC TESTS – IgG antibody response can be quantified by ELISA Urea breath test
Management The management of patients with PUD needs to be adapted to • the specific clinical situation, • etiology, and • anticipated natural history. The first steps in management are to identify Helicobacter pylori (H. pylori) infection and users of nonsteroidal antiinflammatory drugs (NSAIDs). Both of these steps can be surprisingly difficult.
Markers of increased risk A prior history of complications A prior refractory or protracted course Giant ulcers (>2 cm) Presence of considerable depth or dense fibrosis, as suggested by a deformed ulcer bed. Medium-sized ulcers (1 to 2 cm) also deserve more caution than ulcers less than 1 cm.
H. pylori-positive ulcers Antibiotic therapy is clearly indicated if H. pylori is present in the setting of any history of ulcer disease. The goal of treatment in ulcers associated with H. pylori is to "treat once successfully". It is important to remember H. pylori ulcers recur within six months in up to 20 percent of patients after apparently successful antibiotic treatment.
Patients with a known ulcer historyThe following are general principles to consider in patientswith prior or active ulcer disease, especially if complicated:•NSAIDs should be avoided whenever possible in a patient with anulcer history.•If NSAID use is unavoidable, they should be used at the lowestpossible dose and duration.•Depending upon the timing and severity of the ulcer history,misoprostsol or PPI cotherapy should be added if NSAIDs must beused.•Active ulcers should be treated with PPI and NSAIDs should bestopped whenever possible.•H. pylori should be sought and cured if present.•Even when H. pylori has been successfully treated, PPI or misoprostolcotherapy should be used in patients with prior ulcers if NSAID usemust be continued.
H. pylori-negative ulcers H. pylori negative ulcers require special attention to ensure that H. pylori infection has been excluded and to detect NSAID use. In confirmed non-H. pylori, non-NSAID ulcers, the first consideration is excluding acid hypersecretory states, such as Zollinger-Ellison syndrome and idiopathic non-H. pylori hypersecretory DU (This is critical, especially if the ulcers are recurrent, complicated, multiple, or in the distal duodenum)
Refractory ulcers It is important to remember that many refractory cases, even after prior failed surgery, are due to occult consumption of aspirin and NSAIDs. The more problematic the ulcer, the more critical the search for surreptitious aspirin or NSAID use.
Peptic UlcersTherapy Purpose Therapy is directed at enhancing host defense or eliminating aggressive factors; i.e., H. pylori
Antacids Weak bases that neutralize acid Also inhibit formation of pepsin(As pepsinogen converted to pepsin at acidic pH) Acid Neutralizing Capacity: Potency of Antacids Expressed in terms of Number of mEq of 1N HCl that are brought down to pH 3.5 in 15 minutes by unit dose of a preparation (1 gm)
Antacids - The Oldest Remedy Systemic-Sodium Bicarbonate: Potent neutralizing capacity and acts instantly ANC: 1 gm = 12 mEq NOT USED ANYMORE FOR ITS DEMERITS: Systemic alkalosis Distension, discomfort and belching – CO2 Rebound acidity Sodium overload
Antacids Present day antacids : Buffer Type Aluminium Hydroxide (ANC 1-2.5mEq/g) Magnesium Hydroxide (ANC 30 mEq) – milk of magnesia Magnesium trisilicate (ANC 1mEq/g) Magaldrate –hydrated hydroxy magnesiun aluminate • Non Buffer Type - Calcium Carbonate
Duration of action : 30 min when taken in empty stomach and 2 hrs when taken after a meal Side effects : Aluminium antacids – constipation (As they relax gastric smooth muscle ,delay gastric emptying & have astringent action) – also cause hypophosphatemia and osteomalacia Mg2+ antacids – Osmotic diarrhoea In renal failure Al3+ antacid – Aluminium toxicity & Encephalopathy
Antacids – contd. Simethicone: Decrease surface tension thereby reduce bubble formation - added to prevent reflux Alginates: Form a layer of foam on top of gastric contents & reduce reflux Oxethazaine: Surface anaesthetic
Sucralfate – ulcer protective Salt of sucrose complexed to sulfated aluminium hydroxide (basic aluminium salt) MOA: In acidic pH polymerises to viscous gel that adheres to ulcer crater - more on duodenal ulcer Precipitates protein on surface proteins and acts as physical barrier Dietary proteins get deposited on this layer forming another coat Delays gastric emptying and causes gastric PG synthesis – protective action
Sucralfate Taken on empty stomach 1 hr. before meals Concurrent antacids, H2 antagonist avoided (as it needs acid for activation) Uses: NSAID induced ulcers Patients with continued smoking ICU Topically – burn, bedsore ulcers, excoriated skins Dose: 1 gm 1 Hr before meals ADRs: Constipation, hypophosphatemia ,inhibit absorption of phenytoin,ketoconazole,cimetidine
H2 Antagonists Cimetidine, Ranitidine, Famotidine, Roxatidine, Nizatidine and Lafutidine MOA: Reversible competitive inhibitors of H2 receptor Highly selective, no action on H1 or H3 receptors All phases of gastric acid secretion Very effective in inhibiting nocturnal(basal) acid secretion (as it depends largely on Histamine ) Modest impact on meal stimulated acid secretion (as it depends on gastrin, acetylcholine and histamine) Volume of pepsin content and IF are also reduced Volume reduced by 60 – 70% - anti ulcerogenic effect No effect on motility
H2 antagonists Kinetics: All drugs are absorbed orally adequately Bioavailability upto 80 % Absorption is not interfered by presence of food Can cross placental barrier and reaches milk Poor CNS penetration 2/3rd of the drugs are excreted unchanged in bile and urine Preparations: available as tablets, injections
H2 antagonists - ADRs Extremely safe drugs and well tolerated Main ADRs are related to Cimetidine: Antiandrogenic effects Increases prolactin secretion and inhibits degradation of estradiol by liver Cytochrome P450 inhibition – theophylline, metronidazole, phenytoin, imipramine etc. Antacids Others: Headache, dizziness, bowel upset, dry mouth Bolus IV – release histamine – bradycardia, arrhythmia, cardiac arrest Elderly - precaution
H2 antagonists - UsesPromote the healing of gastric and duodenal ulcers Duodenal ulcer – 70 to 90% Gastric Ulcer – 50 to 75% (NSAID ulcers)) Stress ulcer and gastritis GERD Zollinger-Ellison syndrome(Famotidine) Prophylaxis of aspiration pneumonia UrticariaDoses: • 300 mg/40 mg/150 mg at bed time of R, F, Rox respectively for healing • Maintenance: 150/20/150 mg BD of R, F, Rox
Lafutidine-a novel histamine H2 receptor antagonist Lafutidine is a novel histamine H2 antagonist with gastroprotective activity. Lafutidine exhibited potent and long-lasting H2 antagonism and prolonged antisecretion. In addition, lafutidine showed a gastroprotective effect against noxious agents-induced gastric mucosal damage through capsaicin-sensitive afferent nerves. lafutidine is equal or superior to conventional H2 antagonists in antiulcer potency, and it may be useful for the prevention of ulcer relapse and or treatment of NSAIDs-induced gastroduodenal damage
Proton Pump Inhibitors Omeprazole Most effective drugs in antiulcer therapy Prodrugs requiring activation in acid environment Block enzymes responsible for secreting HCl - binds irreversibly to H+K+ATPase Prototype: Omeprazole Examples: Lansoprazole Pantoprazole Rabeprazole Esomeprazole
Omeprazole - MOA Substituted Benzimidazole derivative Its a Prodrug Diffuses into G. canaliculi = accumulation pH < 5 (proton catalyzed )= tetracyclic sulfenamide + sulphenic acid Covalent binding with sulfhydryl cysteines ofH⁺K⁺ ATPase Irreversible inactivation of the pump molecule(The charged forms cannot diffuse back across the canaliculi)Lansoprazole partially reversible Acid suppressants regardless of stimulating factors(80%- 90%)
Pharmacokinetics - PPI Oral forms are prepared as acid resistant formulations that release the drug in the intestine (because they are degraded in acid media) After absorption, they are distributed by blood to parietal cell canaliculi They irreversibly inactivate the proton pump molecule – but half life is very short and only 1-2 Hrs Still action persists for 24 Hrs to 48 hrs after a single dose – irreversible inhibition of PPI and new PP synthesis takes time (24 to 48 hour suppression of acid secretion, despite the much shorter plasma half-lives of the parent compounds) Platue state is attained after 4-5 days of dosing Action lasts for 4-5 days even after stoppage of the drug
Pharmacokinetics - PPI Given on an empty stomach because food affects absorption They should be given 30 minutes to 1 hour before food intake because an acidic pH in the parietal cell acid canaliculi is required for drug activation, and food stimulates acid production Concomitant use of other antisecretory drugs - H2 receptor antagonists – reduces action Highly protein bound and rapidly Metabolized by the liver by CYP2C19 and CYP3A4 – dose reduction necessary in severe hepatic failure Excreted in Kidneys minimally (no dose reduction needed in renal failure and elderly)
Adverse Effects The most common are GIT troubles in the form of nausea, abdominal pain, constipation, flatulence, and diarrhea Subacute myopathy, arthralgias, headaches, and skin rashes Prolonged use: Gynaecomastia, erectile dysfunction Leucopenia and hepatic dysfunction Vitamin B12 deficiency Hypergastrinemia which may predispose to rebound hypersecretion of gastric acid upon discontinuation of therapy and may promote the growth of gastrointestinal tumors (carcinoid tumors )
PPI – contd. Drug Interaction: Inhibits metabolism of Warfarin, Diazepam Therapeutic uses: 1. Gastroesophageal reflux disease (GERD) 2. Peptic Ulcer - Gastric and duodenal ulcers 3. Bleeding peptic Ulcer 4. Zollinger ellison Syndrome 5. Prevention of recurrence of nonsteroidal antiinflammatory drug (NSAID) - associated gastric ulcers in patients who continue NSAID use. 6. Reducing the risk of duodenal ulcer recurrence associated with H. pylori infections 7. Aspiration Pneumonia
Muscarinic antagonistsAtropine: Block the M1 class receptors Reduce acid production Abolish gastrointestinal spasmPirenzepine and TelenzepineMechanism of action: • Reduce meal stimulated HCl secretion by reversible blockade of muscarinic (M1) receptors on the cell bodies of the intramural cholinergic ganglia (receptors on parietal cells are M3). Unpopular as a first choice because of high incidence of anticholinergic side effects (dry mouth and blurred vision)
Prostaglandin analogues(PGE2,PGI2) Inhibit gastric acid secretion Exhibit ‘cytoprotective’ activity Enhance local production of mucus or bicarbonate(PGE2) Promote local cell regeneration Help to maintain mucosal blood flow
Prostaglandin analogues - Misoprostol Actions: Inhibit histamine-stimulated gastric acid secretion Stimulation of mucin and bicarbonate secretion Increase mucosal blood flow(Reinforcing of mucous layer buffered by HCO3 secretion from epithelial cells) Therapeutic uses:Prevent ion of NSAID-induced mucosal injury (rarely used because it needs frequent administration – 4 times daily)
Misoprostol Doses: 200 mcg 4 times a day (Misoprost) ADRs: Diarrhoea and abdominal cramps Uterine bleeding Abortion Exacerbations of inflammatory bowel disease and should be avoided in patients with this disorderContraindications:1. Inflammatory bowel disease2. Pregnancy (may cause abortion)Newer- Rioprostadil and Enprostil
Omeprazole Amoxicillin Clarithromycin MetronidazoleEradication of H.pylori
Triple Therapy The BEST among all the Triple therapy regimen is:Omeprazole / Lansoprazole - 20 / 30 mg bdClarithromycin - 500 mg bdAmoxycillin / Metronidazole - 1gm / 500 mg bdGiven for 14 days followed by P.P.I for 4 – 6 weeksShort regimens for 7 – 10 days not very effective
Colloidal Bismuth SubcitratePharmacological actions:• Undergoes rapid dissolution in the stomach into bismuth oxychloride and citrate• Bismuth coats ulcers and erosions protecting them from acid and pepsin and increases prostaglandin and bicarbonate production• Uses:• Part of triple regimen • Treatment of dyspepsia and traveller’s diarrhoea
NSAIDS Related Ulcer Active Ulcer NSAID discontinued-H2 antagonists/PPI NSAID continued-PPIProphylaxis Misoprostol/PPI
IR – OME(INSTANT RELEASE OMEPRAZOLE SACHET) IR-OME is unique among PPI formulations in that it has no enteric coating Peak plasma concentration within 30 min Rapid absorption of OME and rapid onset of antisecretory effect Single daily doses of IR-OME produce prolonged acid suppression, including postprandial periods Achieves intragastric pH>4 for 18.6 hours The favorable pK and pD profiles seen with IR-OME do not appear to be achievable by using an antacid with a DR-PPI, because this is not associated with improvement or acceleration of PPI absorption
Mechanism of action of IR – OME NaHCO 3 buffers the acid NaHCO 3 buffers the acid NaHCO3 In gastric lumen –– raises In gastric lumen raises OME Intra-gastric pH Intra-gastric pH Increase in gastrin Increase in gastrin release releaseIncreased Activation of more Proton Activation of more ProtonGastrin pumps pumpssecretion With rapid absorption, most of newly With rapid absorption, most of newly activated Proton pumps are blocked activated Proton pumps are blocked Quick & prompt acid inhibition Quick & prompt acid inhibition
Potential Advantages of IR – OME• Buffer protects the PPI from acid degradation in stomach no need for an enteric coating absorption more rapid & predictable• Immediate therapeutic effect due to acid buffering•Rapid rise in pH (>6 in 1 min) may stimulate gastrin release temporary stimulation of proton pumps - > improves uptake of OME by parietal cells•Independent of food intake•More rapid & long lasting control of acid secretion
Conclusion•Compared to IV H2RAs and IR – OME given by NGtube is as effective in treating erosive gastritis.•IR-OME provides more rapid, effective & sustained pHcontrol.•IR – OME is the only PPI that is US FDA approvedfor the reduction of risk of UGI bleeding.
Future Prospects Reversible inhibitors of proton pump-AKU 517 Antagonists at CCK2, gastrin receptor Cytoprotective agents-REBAMIPIDE H.Pylori vaccination