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

PEPTIC ULCER DISEASE

A.Mayet. Pharm.D, BCPS, BCNSPAssociate ProfessorK 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


“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.


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).


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.


Maintenance therapy is appropriate for patients with esophagitis in whom PPIs have

been effective (grade A). Titration to the lowest effective dose

is recommended.


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.


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


AGA guideline recommendations for the management of extraesophageal symptoms

Chronic cough, laryngitis, and asthma all have definite associations with GERD.


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.

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


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


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).


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


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.


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

PEPTIC ULCER DISEASE

PATHOGENESIS OF NSAID-INDUCED GASTROPATHYunionized 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 COMPLICATIONSAIN PATIENTS RECEIVING NSAIDS

Odd ratio Risk Factor

1.5 RA (vs. OA)

1.6 Low-dose aspirin use alone (< 160 mg/day)

1.6 Corticosteroids

2.4 Age 50–59 years

4.1 Use of nonaspirin (nonselective) NSAID alone



5.6 Aspirin (75–160 mg/day)

5.9 History of uncomplicated ulcer

9.0 Use of more than nonaspirin NSAID daily

9.2 Age older than 80 years

12.7 Anticoagulation

15.4 History 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 consensuscardiology 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, 1.19-3.11) 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 2004. 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).

UPPER GI BLEEDING

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.

PROPHYLAXIS OF SRMD IN CRITICALLY ILL PATIENTS

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.


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


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

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

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