A.Mayet. Pharm.D, BCPS, BCNSP Associate Professor K S U

GERD  A condition which develops when reflux of stomach contents causes troublesome symptoms and/or complications.

 Syndromes with esophageal injury  (a) Reflux esophagitis  (b) Reflux stricture  (c) Barrett esophagus  (d) Adenocarcinoma

 Extraesophageal syndromes  i. Established association  (a) Reflux cough  (b) Reflux laryngitis  (c) Reflux asthma  (d) Reflux dental erosions

 Proposed association  (a) Sinusitis  (b) Pulmonary fibrosis  (c) Pharyngitis  (d) Recurrent otitis media

 Typical symptoms: Heartburn (pyrosis), regurgitation, acidic taste in the mouth

 Extraesophageal symptoms : Chronic cough, asthma-like symptoms, recurrent sore throat, laryngitis/hoarseness, dental enamel loss, and noncardiac chest pain; sinusitis/ pneumonia/ bronchitis/otitis media are less common atypical symptoms.

 Alarm symptoms: Dysphagia, odynophagia, bleeding, weight loss, choking, chest pain, and epigastric mass.  These symptoms warrant immediate referral for more invasive testing.

 Aggravating factors: Recumbency (gravity), increased intra-abdominal pressure, reduced gastric motility, decreased lower esophageal sphincter (LES) tone, and direct mucosal irritation

 Long-term complications: Esophageal erosion, strictures/obstruction, Barrett esophagus, and reduction in patient’s quality of life

Diagnosis (symptoms)  Patient description of classic GERD symptoms, such as pyrosis, is often enough to consider it an initial diagnosis; invasive testing is therefore not indicated in uncomplicated cases.  The AGA guidelines state that it is reasonable to assume a diagnosis of GERD in patients who respond to initial acid-suppressive therapy, particularly proton pump inhibitors (PPIs).

Diagnosis  Symptoms do not predict the degree of esophagitis or complications secondary to GERD, if present.  Patients presenting with extraesophageal symptoms should be assessed on a case-by-case basis to consider the need for referral or alternative/invasive testing.  Cardiac etiologies (ischemic) should be considered and explored before arriving at a diagnosis of reflux chest pain syndrome.

Diagnosis (endoscopy)  Considered the technique of choice to identify Barrett esophagus (with biopsy) or complications of GERD  Findings of typical symptoms in association with endoscopic mucosal changes are about 97% specific for the diagnosis of GERD

 Most patients with typical/atypical symptoms will have normal-appearing esophageal mucosa on endoscopy  Biopsies should be performed in areas of suspected metaplasia, dysplasia, or malignancy  Routine endoscopy to assess disease progression is not recommended

Manometry  Used to evaluate peristaltic function of the esophagus in patients with normal endoscopic findings  Should be used before pH testing to rule out esophageal motility disorders and to help localize the LES for subsequent pH testing (grade B)

pH Testing  The main outcome measure of esophageal pH monitoring is the percentage of time the pH value is less than 4 in a 24-hour period.

pH Testing  Ambulatory pH testing is useful in the following clinical situations:  Patients with no mucosal changes on endoscopy and normal manometry who have continued symptoms (both typical and atypical) (grade B)  Patients who are refractory to therapeutic doses of appropriate pharmacologic agents  Monitoring of reflux control in patients with continued symptoms on drug therapy

pH Testing  Sensitivity/specificity of 96% reported  The PPIs should be withheld for 7 days before pH testing, if possible, for the most accurate results.

GERD and H Pylori  Role of H. pylori testing and eradication is controversial in patients presenting with GERD  Symptoms should be assessed on the basis of patient presentation and risk factors for gastric cancer.

Treatment Strategies for GERD  A 4-week trial of a twice-daily PPI can be considered for patients thought to have reflux chest pain syndrome before manometry or pH testing (grade A).  Rule-out ACS (troponin, ECG)  Sensitivity and specificity of a short course of PPIs are 80% and 74% for diagnosing reflux chest pain syndrome.

Treatment Strategies for GERD  Nonpharmacologic interventions/lifestyle modifications are unlikely to control symptoms in most patients.  The AGA guidelines cite insufficient evidence to advocate lifestyle modifications for all patients, but rather, they advocate use in targeted populations.

Treatment Strategies for GERD  Avoid aggravating foods/beverages; some may reduce LES pressure (alcohol, caffeine, chocolate, citrus juices, garlic, onions, peppermint/spearmint) or cause direct irritation (spicy foods, tomato juice, coffee).  Reduce fat intake (high-fat meals slow gastric emptying) and portion size.  Avoid eating 2–3 hours before bedtime.  Remain upright after meals.

Treatment Strategies for GERD  Weight loss for overweight or obese patients (grade B)  Reduce/discontinue nicotine use in patients who use tobacco products (affects LES).  Elevate the head of the bed (6–8 in.) if reflux is associated with recumbency (grade B).  Avoid tight-fitting clothing (decreases intra- abdominal pressure).

Treatment Strategies for GERD  Avoid medications that may reduce LES pressure, delay gastric emptying, or cause direct irritation: α-Adrenergic antagonists, anticholinergics, benzodiazepines, calcium channel blockers, estrogen, nitrates, opiates, tricyclic antidepressants, theophylline, NSAIDs, and aspirin.

Pharmacologic Therapies  “Step-down” treatment: Starting with maximal therapy, such as therapeutic doses of PPIs, is always appropriate as a first-line strategy in patients with documented esophageal erosion.  Advantages: Rapid symptom relief, avoidance of over-investigation  Disadvantages: Potential overtreatment, higher drug cost, increased potential of adverse effects

Pharmacologic Therapies  “Step-up” treatment: Starting with lower-dose OTC products.  Advantages: Avoids overtreatment, has lower initial drug cost.  Disadvantages: Potential under treatment (partial symptom relief), may take longer for symptom control, may lead to over investigation

AGA guideline recommendations  Empiric drug therapy is appropriate for patients with uncomplicated heartburn.  Use of antisecretory drugs for patients with esophageal GERD symptoms, with or without esophagitis, is strongly recommended (grade A).  PPIs are more effective than histamine2- receptor antagonists (H2RAs), which are, in turn, better than placebo for patients with esophageal GERD symptoms.

Pharmacologic Therapies  All PPIs are similar in efficacy when used for patients with esophageal GERD symptoms.  Data are weak to support using PPIs or H2RAs above standard doses. However, twice-daily dosing of PPIs is appropriate in patients who continue to have symptoms on once-daily PPI therapy (grade B).

Pharmacologic Therapies  Rapid-acting drugs should be used for patients who wish to take the drug in response to symptoms  Antacids are the fastest-acting agents available and may be combined with both PPIs and H2RAs.

Pharmacologic Therapies  Maintenance therapy is appropriate for patients with esophagitis in whom PPIs have been effective (grade A).  Titration to the lowest effective dose is recommended.

Pharmacologic Therapies  Most patients with nonerosive disease will continue on maintenance therapy if they initially respond, but it may not be possible to titrate them down to on-demand therapy.  On-demand therapy is not appropriate for patients with erosive esophagitis.

Pharmacologic Therapies  Dosing PPIs less than once daily as maintenance therapy is ineffective for patients who initially had erosive esophagitis  No evidence of improved efficacy by adding a bedtime dose of H2RA to twice-daily PPI therapy

Pharmacologic Therapies  AGA guideline recommendations for the management of extraesophageal symptoms  Chronic cough, laryngitis, and asthma all have definite associations with GERD.

Pharmacologic Therapies  Evidence is fair (grade B) for the use of once- or twice-daily PPI therapy in patients with an extraesophageal syndrome and a concomitant esophageal GERD syndrome (grade B).  A 2-month trial of twice-daily PPI therapy would be an appropriate therapy for these patients.

Pharmacologic agents  Antacids  Calcium-, aluminum-, and magnesium-based products are available OTC in a wide variety of formulations  Neutralizing acid and raising intragastric pH results in decreased activation of pepsinogen and increased LES pressure; rapid onset of action but short duration, necessitating frequent dosing

Pharmacologic Agents  Used as first-line therapy for intermittent (less than 2 times/week) symptoms or as breakthrough therapy for those on PPI/H2RA therapy; not appropriate for healing established esophageal erosions

Adverse reactions  Constipation (aluminum), diarrhea (magnesium), accumulation of aluminum/magnesium in renal disease with repeated dosing  Drug interactions: Chelation (fluoroquinolones, tetracyclines), reduced absorption because of increases in pH (ketoconazole, itraconazole, iron, atazanavir, delavirdine, indinavir, nelfinavir) or increases in absorption leading to potential toxicity (raltegravir, saquinavir)

Histamine2-receptor antagonists  Reversibly inhibit histamine2-receptors on the parietal cell  All agents available as prescription and OTC products; a variety of formulations available; generics exist for all prescription products

 Therapy with H2RAs is less efficacious than therapy with PPIs in healing erosive esophagitis

Adverse effects  Most are well tolerated. Central nervous system (CNS) effects, such as headache, dizziness, fatigue, somnolence, and confusion, are the most common.  Elderly patients and those with reduced renal function are more at risk.  Prolonged cimetidine use is associated with rare development of gynecomastia.

Drug interactions  May affect absorption of drugs dependent on lower gastric pH, such as ketoconazole, itraconazole, iron, atazanavir, delavirdine, indinavir, and nelfinavir, or increases in absorption leading to potential toxicity (raltegravir, saquinavir).

Drug interactions  Cimetidine also inhibits cytochrome P450 (CYP) enzymes 1A2, 2C9, 2D6, and 3A4. Warfarin, theophylline, and other agents metabolized by these enzymes may be affected.  Cimetidine may also compete with medications and creatinine for tubular secretion in the kidney.

Proton pump inhibitors  Irreversibly inhibit the final step in gastric acid secretion; greater degree of acid suppression achieved and typically longer duration of action than H2RAs  Most effective agents for short- and long- term management of GERD, as well as for management of erosive disease  Pantoprazole, lansoprazole, and esomeprazole are available in intravenous formulations.

Proton pump inhibitors

Adverse reactions  Overall, well tolerated; possible adverse effects include headache, dizziness, nausea, diarrhea, and constipation. Long-term use is not associated with significant increases in endocrine neoplasia or symptomatic vitamin B12 deficiency

Proton pump inhibitors  Both PPIs and H2RAs found an elevated risk of community-acquired pneumonia with these agents.  The adjusted relative risk of pneumonia was 1.89 (95% confidence interval [CI], 1.36–2.62) with PPI use and 1.63 (95% CI, 1.07–2.48) for H2RA use

Proton pump inhibitors  A recent large prospective cohort study of hospitalized patients revealed an increased risk of hospital-acquired pneumonia in nonventilated patients who were prescribed PPIs (OR = 1.3; 95% CI, 1.1–1.4) (JAMA 2009;301:2120–8).

Proton pump inhibitors  Another recent study revealed a higher incidence of fracture in patients receiving higher doses of PPIs for longer durations (OR = 1.44; 95% CI, 1.3–1.59) (JAMA 2006;296:2947–53).  New FDA labeling for PPIs as of May 2010 stating that PPIs may increase the risk of hip and spine fracture

Proton pump inhibitors  The 2008 AGA guidelines cite insufficient evidence to recommend bone density screening or calcium supplementation because of PPI use  Screening for osteoporosis in populations at risk, such as the elderly, is recommended regardless of PPI use.

Proton pump inhibitors  Studies have revealed an association of overgrowth of Clostridium difficile in patients receiving PPIs, particularly in the hospital setting. Odds ratios were reported as 2.1 (95% CI, 1.33–2.25) J Hosp Infect 2003;54:243–5 CMAJ 2004;171:33–8

Drug interactions  Drugs with pH-dependent absorption (ketoconazole, itraconazole, protease inhibitors, etc.); omeprazole inhibits the metabolism of diazepam through CYP2C19.  Recent data suggest a reduced effectiveness of clopidogrel through CYP2C19-mediated inhibition of conversion to active metabolite by omeprazole and esomeprazole.

Promotility agents  Guidelines recommend against the use of metoclopramide as adjunctive therapy or monotherapy in patients with both esophageal and extraesophageal symptoms because the risk of adverse effects (extrapyramidal symptoms [EPS]) or tardive dyskinesia) outweighs the benefit (grade D).

Surgical therapy  PPI therapy should be tried before surgical intervention because of better safety (grade A).  Antireflux surgery such as fundoplication remains a viable option for maintenance therapy of GERD; typically used in patients unresponsive to or intolerant of medical therapy (grade A)

 Antireflux surgery is not recommended for patients who are well controlled on medical therapy or for prevention of Barrett esophagus

PATHOGENESIS OF NSAID-INDUCED GASTROPATHY unionized forms diffusion across the GI epithelial cells ionized form ion trapping cell lysis Pharmacotherapy Self Assessment program, 5th Edition NSAID-induced Gastropathy

NSAIDs  Some NSAIDs such as ibuprofen, diclofenac, and nabumetone are intrinsically less toxic to the GI tract  Naproxen, which is considered moderate risk  Piroxicam or Ketorolac, are considered high- risk drugs

RISK FACTORS FOR UPPER GI COMPLICATIONSA IN PATIENTS RECEIVING NSAIDS Odd ratioRisk Factor 1.5RA (vs. OA) 1.6Low-dose aspirin use alone (< 160 mg/day) 1.6Corticosteroids 2.4Age 50–59 years 4.1Use of nonaspirin (nonselective) NSAID alone 3.1Age 60–69 years 4.5Age 70–80 years 5.6Aspirin (75–160 mg/day) 5.9History of uncomplicated ulcer 9.0Use of more than nonaspirin NSAID daily 9.2Age older than 80 years 12.7Anticoagulation 15.4History of complicated ulcer Pharmacotherapy Self Assessment program, 5th Edition NSAID-induced Gastropathy

NSAIDs  Duration of NSAID use higher risk in first 3 months  Presence of chronic debilitating disorders such rheumatoid arthritis or CV disease may also contribute to the increased GI toxicity of NSAIDs, but these are not generally considered independent risk factors.  H. pylori infection is likely additive risk of GI toxicity in NSAID users

Diagnosis If symptom presence  Testing for H. pylori infection: Practitioners must be willing to treat if testing is positive because H. pylori is a known carcinogen  Testing is indicated for patients with active ulcer disease, history of PUD, or gastric mucosa–associated lymphoid tissue lymphoma

Primary prevention of NSAID- induced ulcers  Test and treat for H. pylori if patient is beginning long-term NSAID therapy.  Determine level of GI-related risk (low, medium, high) using (see table)  Based on association of increased risk of CV events with NSAID use, patient’s CV risk should be determined as well.  The ACG guidelines define high CV risk as patients who require low-dose aspirin for prevention of cardiac events.

Recent guidelines from a consensus cardiology and GI group (ACCF/ACG/AHQ) (Circulation 2008  Test and treat for H. pylori in patients with a history of a nonbleeding ulcer and in those with a history of an ulcer-related complication  Eradicating H. pylori before beginning chronic antiplatelet therapy is optimal  PPIs should be prescribed for patients receiving concomitant aspirin and anticoagulant therapy (unfractionated heparin, low-molecular-weight heparin, and warfarin).

Recent guidelines  A target INR of 2.0–2.5 should be used in patients for whom warfarin is added to concomitant aspirin and clopidogrel therapy  Clopidogrel is not recommended as a substitute for patients with recurrent ulcer bleeding.  Aspirin plus a PPI is superior to clopidogrel.

Recent guidelines  The health care provider who decides to discontinue aspirin therapy in patients with acute bleeding episodes should weigh the risks of subsequent GI or cardiac events.

Recent guidelines  For patients receiving dual antiplatelet therapy (aspirin plus clopidogrel) who require elective endoscopy (particularly colonoscopy and polypectomy), consider deferring if patient is at high risk of cardiac events.  Elective endoscopy should be deferred for 1 year after the placement of drug-eluting stents.

Treatment/secondary prevention of NSAID-induced ulcers  Risk factor modification  Discontinue/lower dose of NSAID if possible.  Ulcers will heal with appropriate treatment, but it may take longer with continued NSAID use.  Test for H. pylori and treat if present.

Recent guidelines  Cyclooxygenase inhibitors: Celecoxib was recently shown to have rates of ulcer recurrence and bleeding comparable with a diclofenac plus omeprazole combination  Use of celecoxib may be limited by its recent association with CV effects  Use of celecoxib is uncertain in combination with low-dose aspirin for secondary prevention of GI events.

Recent guidelines  Combination of a COX-2 inhibitor and a PPI is not well studied  May considered in high-risk patients such as the elderly, especially if they are receiving aspirin plus steroids or warfarin or have a history of a recent complicated GI event and require continued NSAID or aspirin use.

CV safety of COX-2 inhibitors and NSAIDs  Reducing COX-2–mediated prostacyclin production, the prothrombic prostaglandin thromboxane A2 continues to be produced by COX-1, leading to the development of a prothrombic state.  The degree of development of these events does not appear to be equal across the class of COX-2 inhibitors

COX-2 inhibitors  Rofecoxib 50 mg/day was first associated with a significant increase in myocardial infarction in the VIGOR trial  In the recent APPROVE trial, 25 mg/day used for preventing colonic polyps was associated with a 2-fold increase (relative risk = 1.92, 95% CI, ) in stroke and myocardial infarction during an 18-month period.

COX-2 inhibitors  Celecoxib was not associated with increases in CV events until the APC trial for cancer prevention was halted in December Daily doses of 400 and 800 mg of celecoxib conferred a 2.5- and 3.4-fold higher risk of fatal and nonfatal myocardial infarction, which suggests a dose-related response for this toxicity (N Engl J Med 2005;352:1071−80).

COX-2 inhibitors  Valdecoxib has also been associated with the development of excess thrombotic events after use in patients undergoing coronary artery bypass surgery. This agent was voluntarily withdrawn from the market in 2005

COX-2 inhibitors  Routinely monitor BP, renal function, and signs of edema or GI bleeding  Methods to reduce CV risk such as tobacco cessation, BP and lipid control, and glucose control are recommended for NSAID users but have not been proved to reduce NSAID- associated CV risk

COX-2 inhibitors  In patients for whom the risk of GI bleeding outweighs the CV risk, lower-risk NSAIDs such as ibuprofen, etodolac, diclofenac, or celecoxib should be used.  In patients for whom the CV risk outweighs the risk of GI bleeding, COX-2 inhibitors should be avoided. Limit the dose and therapy duration if possible (Clin Gastroenterol Hepatol 2006;4:1082–9).

GI Bleeding  Prevalence is 170 cases/100,000 adults; associated annual costs are about $750 million, and mortality is 6%–10%.

Causes of Upper GI Bleeding  1. Peptic ulcer disease (40%–70%)  a. NSAIDs and low-dose aspirin use  b. H. pylori  2. Esophagitis  3. Erosive disease  4. Esophageal varices  5. Mallory-Weiss tear  6. Neoplasm  7. Stress ulcers (critically ill patients)

Clinical Symptoms and Presentation  1. Hematemesis or “coffee-ground” emesis  2. Hematochezia  3. Nausea, vomiting  4. Melena  5. Shock (tachycardia, clammy skin)  6. Hypotension  7. Associated organ dysfunction (renal/hepatic/cardiac/cerebral hypoperfusion)

Management of Nonvariceal Upper GI Bleeding  Volume resuscitation and hemodynamic stabilization  Placement of one or two large-bore intravenous catheters  Replacement with crystalloid such as 0.9% normal saline is preferred; colloids, such as blood, can be given after initial resuscitation in patients with hemoglobin of less than 7 g/ dL to maintain a hemoglobin concentration of 8–10 g/dL.

Risk stratification  Clinical signs/symptoms  Use of clinical scoring scales, such as Blatchford or Rockall scores to determine risk of early rebleeding and need for urgent versus nonemergency intervention. Patients with low risk of rebleeding may be discharged after endoscopy.

Risk stratification  Placement of NG tube for aspiration  Endoscopy (within 24 hours if possible)  Assessment of comorbid illnesses (liver disease, coagulopathies, cardiac status)

Endoscopic therapy  Endoscopic therapy associated with reductions in rebleeding, need for surgery, and mortality.  Perform within 24 hours of presentation.  Observation of low-risk stigmata (a clean- based ulcer or a nonprotuberant-pigmented dot in an ulcer bed) is not an indication for hemostatic therapy.

 Clots visible in an ulcer bed should be irrigated with treatment of underlying lesions.  The use of endoscopic intervention in patients with an adherent clot is controversial. This may be treated just as well with PPI therapy.

Endoscopic strategies  The combination of injection and coaptive therapy is the most efficacious approach.  The use of either technique plus pharmacotherapy is superior to monotherapy

Injection  i.Epinephrine with or without ethanolamine is inferior by itself. Combine with another endoscopic therapy.  ii. Cyanoacrylate  iii. Thrombin  iv. Sodium tetradecyl sulfate  v. Polidocanol

Thermal coaptive therapy  i. Heater probe thermocoagulation  ii. Multipolar electrocoagulation  iii. Laser coagulation (not often used because of cost)  iv. Argon plasma coagulation

Pharmacotherapeutic management of nonvariceal upper GI bleeding  Remove medications that are contributing to bleeding (NSAIDs, etc.)  PPI therapy  Use of a pre-endoscopic dose of PPI may be considered. This does not result in reduced mortality, surgery, or rate of rebleeding, but it may reduce the lesion size, the possibility of finding a high-risk lesion, and the need for endoscopic therapy.

Pharmacotherapeutic management of nonvariceal upper GI bleeding  Bolus 80 mg plus a continuous infusion of 8 mg/hour for 72 hours after endoscopic therapy. Intravenous pantoprazole, lansoprazole, or esomeprazole can be used; most data are with intravenous omeprazole

Management of nonvariceal upper GI bleeding  Use of H2RAs or somatostatin-octreotide is NOT recommended.  Test for H. pylori, and treat if results are positive. If negative, retest.  Assess the need for continued secondary prevention with PPI therapy. If needed, a single daily oral dose of a PPI is recommended.

SRMD in Critically Ill Patients  Stress-related injury: Superficial diffuse upper GI ulceration  Stress ulcer: Deeper mucosal ulceration; may lead to bleeding and hemodynamic compromise

Contributing factors to the development of SRMD  Hypoperfusion of the GI tract  Altered susceptibility to gastric acid  Loss of defense mechanisms: Mucous/bicarbonate layer, prostaglandins, cellular renewal  Alterations in gastric motility; may affect absorption of drugs

Pharmacologic prevention  Not routinely recommended in non–intensive care unit settings  Recommended in patients in an intensive care unit setting with the following risk factors: see below

Preventive treatment options  Antacids: Effectively raise pH and prevent bleeding; require several oral doses per day or administration by NG tube; possibility of diarrhea, constipation, and electrolyte abnormalities  (Am J Health Syst Pharm 1999;56:347–79)

Sucralfate:  Works by providing a direct mucosal barrier; also modulates pepsin, mucus activity, bicarbonate secretion, and tissue growth repair  Use has fallen out of favor. Requires many oral doses or administration by NG tube.  May lead to aluminum accumulation and constipation.

Sucralfate:  Is associated with lower rates of development of pneumonia. Possibility of binding to other drugs in GI tract  General efficacy regarding bleeding considered similar to H2RAs  (some data do suggest inferiority to H2RAs; N Engl J Med 1998;338:791–7)

Histamine2-receptor antagonists  Considered efficacious in the prevention of clinically significant bleeding; oral, intravenous intermittent dosing, and continuous infusion are all possible options;  High-dose intravenous (ranitidine, cimetidine, or famotidine) use can be considered first-line therapy.

Proton pump inhibitors  PPIs are commonly used for the prevention of SRMD  Recent meta analysis suggests that PPIs are similar in safety and efficacy to H2RAs  (Crit Care Med 2010;38:1197–205).  Oral or intravenous routes may be used. Alternative formulations exist for patients with difficulty swallowing or with feeding tubes

Proton pump inhibitors  Oral PPIs also as efficacious as intravenous PPI therapy for maintaining equivalent pH (Am J Gastroenterol 2001;96:2058–65)  Intravenous PPI therapy is generally considered equivalent to high-dose intravenous H2RA therapy.  Recent associations with C. difficile infections in hospitalized patients