Module 8 - Pharmacotherapy for Gastrointestinal Disorders

Geriatric Pharmacy Review

Module 8: Pharmacotherapy for Gastrointes;nal Disorders

Copyright 2011 American Society of Consultant Pharmacists

Accreditation Information

ASCP is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

This home study web activity has been assigned 3 credit hours.

ACPE UPN: 0203-0000-10-092-H01-P

Release Date: 5/19/2010

Expiration Date: 6/15/2013

To receive continuing education credit for this course, participants must complete an on-line evaluation form and pass the on-line assessment with a score of 70% or better. If you do not receive a minimum score of 70% or better on the assessment, you are permitted 4 retakes. After passing the assessment, you can print and track your continuing education statements of credit online.

Geriatric Pharmacy Review courses have not yet been approved for Florida consultant pharmacy continuing education.


Content Experts

Current Content Experts:

David P. Elliot, PharmD Department of Clinical Pharmacy West Virginia University

Jennifer L. Hardesty, PharmD, FASCP Clinical Assistant Professor University of Maryland School of Pharmacy

Legacy Content Experts:

Angela C. Cafiero, PharmD, CGP Assistant Professor of Clinical Pharmacy University of the Sciences in Philadelphia Philadelphia College of Pharmacy

William R. Garnett, PharmD Professor of Pharmacy and Pharmaceutics Virginia Commonwealth University Medical College of Virginia


Content Expert Disclosures

David Elliot, PharmD, has no relevant financial relationships to disclose.

Jennifer L. Hardesty PharmD, FASCP has no relevant financial relationships to disclose.

Angela C. Cafiero, PharmD, CGP has no relevant financial relationships to disclose.

William R. Garnett PharmD , discloses the following relationships: Speakers Bureau: Meridian, Shire, Elan and Wyeth Grants: Glaxo-Smith Kline, Ortho McNeil, Meridian, Shire, Elan


Aging and Gastrointestinal Function

Learning Objectives

By the end of this Review Concept you should be able to:

Identify major changes in the gastrointestinal tract due to aging.

List common gastrointestinal complaints of the elderly.

List major concerns of the pharmacist regarding the treatment of gastrointestinal problems in the elderly.

Describe diagnostic methods used to identify and characterize gastrointestinal disorders.

List the major gastrointestinal disorders requiring pharmacological intervention.

Review other problems that can contribute to gastrointestinal disorders.

Outline quality of life issues and the impact of treatment on the elderly patient’s life.


Age-Related Changes in Gastrointestinal Functioning

• Chewing, tasting, and salivary functions decline

• Swallowing is less efficient

• Dental carries and tooth loss impair chewing

• Esophageal motility and musculature decrease

• Delay in gastric emptying

• Gastric mucosal cytoprotective prostaglandins decrease

• Gastrin production increases, acid production decreases, gastric pH increases

• Small intestines may show impaired absorption of vitamin D, calcium, iron, electrolytes, and water, but increased

absorption of vitamins A and K

• Colon has less mucosa and musculature and an increase in collagen in the colon wall, reduction in gastric blood flow

• Anorectal area shows nerve and muscle loss, resulting in decreased perception of anorectal distention

• Phase I metabolism decrease (oxidation, reduction, hydrolysis)

• Phase II metabolism remains the same

• Bile ducts enlarge, bile synthesis decreases

• Gallstone formation increases

• Pancreas shows enlarged ducts, atrophy of acini glands

• Liver decreases in size, blood flow perfusion, and general protein synthesis

• Increased incidence of diverticulosis due to decreased tensile strength of smooth muscle in colon wall.


Age-Related Changes in Gastrointestinal Functioning

The function of the gastrointestinal system is well preserved during the aging process; however, subtle changes occur that can affect the elder. The clinical significance of these age-related changes range from a minor effect to no effect on normal physiological processes. Mastication may be affected by dental decay and tooth loss, which can result in a decrease in nutritional intake. Chewing, tasting, and salivary functions tend to decline, and swallowing is less efficient.

A decrease in neuromuscular function could affect esophageal motility which could increase development of gastroesophageal reflux. The decrease of gastric prostaglandins results in an increased susceptibility to Helicobacter pylori infections. Gastric acid decreases, thus resulting in a decreased absorption of certain vitamins and minerals such as folic acid and vitamin B-12. The small intestine may show impaired absorption of vitamin D, calcium, iron, electrolytes, and water but greater absorption of vitamins such as A and K.

The colon has less mucosa and musculature and an increase in collagen in the colon wall, which decreases the strength of the colon. This age-related change results in slower transport and increased risk of diverticulitis, colon polyps and constipation. Fecal incontinence can develop from the changes in nerve and muscle loss of the anorectal area. As the liver decreases in size, metabolic functioning decreases. This especially affects medications that undergo phase I metabolism. Bile ducts and the ducts of the pancreas become enlarged, thus increasing the risk of blockage.


Management of GI Problems in the Elderly

Common Patient Complaints:

• Heartburn or reflux • Constipation • Diarrhea • Xerostomia • Abdominal pain or discomfort • Nausea and vomiting

Major Pharmacist Concerns:

• Delays in diagnosis due to patient self-treatment • Prompt identification of life-threatening disorders • Treatment of underlying disease and

symptom management • Prevention of drug-induced disorders • Monitoring of liver function

Age-related gastrointestinal changes can impact the elder’s dietary intake and hydration status. In changing their dietary intake and hydration status, elders become more prone to development of constipation, diarrhea, heartburn or gastroesophageal reflux disease, xerostomia, abdominal pain and dyspepsia.

Along with the increased risk of age-related xerostomia, any medication that has the potential to cause xerostomia drastically increases this risk. Proper evaluation of medications will assist in minimizing the risk of xerostomia. Xerostomia also increases the risk of dental caries, due to the lack of saliva and use of hard candy to stimulate saliva. Diarrhea and constipation are among the most common complaints of older adults. Elders seek over the counter self-remedies for theses complaints and are often poorly monitored until the symptoms become difficult to manage.

Once the most life-threatening disorders have been ruled out, proper medications can control many symptoms and help to prevent relapses. For the pharmacist of geriatric patients, major areas of concern include prevention of drug-induced disorders, evaluation of the effectiveness of pharmacological therapy without adverse effects and monitoring liver function to insure maximum drug efficacy.


Diagnostic Testing and Monitoring of Gastrointestinal Disorders

Blood Screening Tests:

• CBC with differential • Liver function tests (LFTs) such as alkaline

phosphatase and transaminases (e.g., ALT, AST) • Serum chemistry panel especially creatinine (Scr),

Blood Urea Nitrogen (BUN), and albumin • Viral hepatitis tests • Bilirubin levels • Protein fractionation • Carcinoembryonic antigen (CEA) level

Other Diagnostic Techniques:

• Fecal occult and gastric fluid assessment • X-rays and contrast media • Ultrasound and CT scans • Endoscopy techniques • H. pylori antibody test • Gallstone analysis and enzymatic studies

Early detection and treatment of gastrointestinal disorders is of primary concern in order to avoid invasive and debilitating solutions. Screening and monitoring of gastrointestinal function can range from simple blood tests to complete endoscopic workups. A complete blood count with differential can assist in detection of a gastrointestinal infection. Routine measures of the patient’s hydration status are evaluated through serum creatinine and blood urea nitrogen. Serum albumin levels are necessary to assess nutritional status.

Without major complaints, the first indication of ulcers, blockages, anemia and cancer may come from a complete blood count. Fecal occult blood test or tests on other body fluids are used to detect the presence of blood. Techniques such as x-rays and contrast media may be used to pinpoint the location of ulcers and other defects. Endoscopy techniques such as the colonoscopy or flexible sigmoidoscopy provide direct evidence of ulcers, blockages and tumors. More specialized tests such as gallstone analysis and H. pylori antibody test may further help in prevention and treatment of gallstones and ulcers.

Enzymatic studies can detect pancreatitis and liver dysfunction. Carcinoembryonic antigen levels can be used for cancer detection. The use of these various tests or techniques can assist in diagnosis of gastrointestinal problems.


Major Gastrointestinal Disorders in the Elderly

• Dental caries and periodontal disease • Xerostomia • Oral Candida • Oropharyngeal dysphagia • Peptic ulcer disease (PUD), including

gastric and duodenal ulcers • Gastroesophageal reflux disease (GERD) • Constipation • Diarrhea • Atrophic gastritis • Hemorrhoids • Fecal incontinence • Inflammatory bowel disease (IBD) • Irritable bowel syndrome (IBS) • Diverticulosis • Bowel obstructions • Hepatic disease, including cirrhosis • Gall bladder disease • Pancreatic disease • Obesity and nutritional problems • Cancer of the gastrointestinal tract

Aging is associated with an increased prevalence of several gastrointestinal disorders. Each of the major gastrointestinal disorders seen in the elderly can be very debilitating if not properly treated. Prompt and accurate identification of these disorders is important.

Complete medical histories, including self-dosing of over-the counter medications and herbal products, are imperative to review before a treatment plan is devised. Pharmacotherapy must be tailored to the individual needs of each patient and monitored for effectiveness and adverse effects. Treatment of gastrointestinal disorders can vary, depending upon the setting the elder resides in or the cause of the GI disorder.

For example if a medication has induced constipation, treating the cause of the constipation by changing the medication to another effective medication would be preferred over treating the adverse effect. Increasing fluid and fiber intake is preferable to routine use of laxatives.


Problems that Can Contribute to Gastrointestinal Disorders

• Medications

• Co-morbid disease states: • Stroke • Neurological disorders • Psychiatric disorders • Diabetes mellitus

• Malnourishment

• Dehydration

• Environment, lifestyle exposures

• Low-fiber diet

Evidence is controversial as to the extent and clinical significance of the age-related changes in GI function. Changes in GI function could be due to an increase in the prevalence of certain diseases or medications that affect the GI tract. Some examples of diseases that affect the GI tract are: stroke, Parkinson’s disease, depression, dementia, and diabetes mellitus. Some examples of medications that can affect gastrointestinal motility are: antidepressants, antihistamines, antipsychotics, opioid analgesics, calcium channel blockers and antispasmodics. Lifestyle exposures to alcohol or tobacco can impact gastrointestinal function. Clinically significant abnormalities in GI function should be fully evaluated for other causes and not solely attributed to aging.


Quality of Life Issues for the Elderly

• Dietary restrictions may be difficult • GI discomfort and pain can dominate daily life • Bowel habits and symptoms may prevent social interactions • Fear of life-threatening diseases can cause elderly to try hiding symptoms and plan life around the malady • Weight lose and frailty

Quality of life becomes an issue when the elderly attempt to live with symptoms of gastrointestinal problems and ignore progressive signs of disease. Although dietary restrictions are a source of irritation for the elderly, maintaining control over digestive functions assumes much more importance. For many geriatric patients, medications can determine the extent of control and quality of their daily lives. For the geriatric pharmacist, careful consultation and monitoring can help achieve those goals. Major gastrointestinal disorders and their pharmacotherapy will be presented in the remainder of this module.


Resources

For additional information, see:

Baime MJ, et.al.(1994). “Aging of the Gastrointestinal System.”In:Hazzard WR, Bierman EL, Blass JP, Ettinger WH, & Halter JB.(Eds.).Geriatric Medicine and Gerontology, 3rd ed.New York:McGraw-Hill:665-681.

Beers MH & Berkow R.(2000).The Merck Manual of Geriatrics. 3rd edition. Section 13, “Gastrointestinal Disorders.” Whitehouse Station, NJ:Merck Research Laboratories: 1000-1154.

Blechman MB & Gelb AM.(1999).“Aging and gastrointestinal physiology.”In:Borum ML (ed.).Clinics in Geriatric Medicine.Philadelphia:W.B. Saunders:429-438.

Crotty B & Smallwood RA.“Upper gastrointestinal tract.”Med J Austral.1995;162(2):95-97.

Duthie B. (1998). Practice of Geriatrics, 3rd ed. Chapter 46:Gastrointestinal disorders. W.B . Saunders Company.

Geokas MC, et.al.“The aging gastrointestinal tract, liver, and pancreas.”Clin Geriatr Med.1985;1:177.

Greenwald, D.A. (2004) Aging, the Gastrointestinal Tract, and Risk of Acid-Related Disease. Am J Med 117(5A): 8s-13s.

Goldschmeidt M, et.al.“Effect of age on gastric acid secretion and serum gastrin concentrations in healthy men and women.”Gastroenterology.1991;101:977.

Hall KE, et al.(1999).“Age-associated changes in gastrointestinal function.”In:Hazzard WR, Blass JP, Ettinger WH, Halter JB, & Ouslander JG.(Eds).Principles of Geriatric Medicine and Gerontology, 4th ed.New York:McGraw-Hill: 835-842.


Resources

Martinez J.P. & Mattu A.M. (2006) Abdominal Pain in the Elderly. Emerg Med Clin N Am. 24:371-388.

McFadden DW & Zinner MJ.“Gastroduodenal disease in the elderly patient.”Surg Clin North Am.1994;74(1):113-126.

O’Mahony D, et al.“Aging and intestinal motility:A review of factors that affect intestinal motility in the aged.”Drugs & Aging.2002;19(7):515-527.

Online Resources:

http://digestive.niddk.nih.gov/ddiseases/a-z.asp

Lexi-Comp Online Drug Information Database

Merck Manual of Geriatrics Online


Peptic Ulcer Disease

Learning Objectives:


• Define the major features of peptic ulcer disease (PUD).

• Describe the pathogenesis of PUD.List common causes and risk factors for PUD.

• Identify important signs and symptoms of PUD.

• Describe tests and procedures used to diagnose PUD and select appropriate treatment.

• Determine the significance of relevant test results leading to a correct diagnosis.

• Outline general principles for the pharmacotherapy of PUD.

• Compare and contrast the primary medications used for treatment of PUD in terms of effect, dosing, duration of treatment and adverse reactions.

• Describe alternative treatments for PUD and their implications for the elderly.


Introduction to Peptic Ulcer Disease (PUD)

Definition: Erosion in the lining of the stomach or duodenum resulting in ulceration and organ damage

Epidemiology:

• Affects up to 10% of the general population • 500,000 new cases per year • 4 million experience recurrence each year • Incidence increases with age • Elderly experience increased complications and mortality, with 50% of patients >70 years experiencing complications. • Mortality rates are 15% for elderly > 65 years compared with 2% for younger patients


Introduction to Peptic Ulcer Disease (PUD)

Peptic ulcer disease in the elderly primarily refers to gastric and duodenal ulcers that develop in the mucosal lining. Approximately half a million new cases of peptic ulcer disease are diagnosed in the United States each year, many of which occur in individuals over the age of sixty. The elderly are especially susceptible to the complications of peptic ulcer disease and have a much higher risk of mortality than younger adults.


Pathogenesis of Peptic Ulcer Disease

Gastric and duodenal ulcers are defects in the lining of the stomach or duodenum that form when gastric acid overwhelms the normal protective mechanisms of the GI tract. Harmful conditions such as a highly acidic environment or mucosal irritation from bacteria or medications can trigger a cascade of inflammation, cytokine release, and subsequent mucosal injury and ulceration:

Mucosal irritation ↓

Imbalance between hydrochloric acid, pepsin secretions, and the natural defenses of the mucosal lining ↓

Pepsin is activated by the acidic conditions and proceeds to enzymatically digest the mucosal, muscular, and vascular layers

↓ Natural defenses of mucosal lining are further compromised via:

• Decreased mucous to lubricate and prevent acid penetration • Decreased bicarbonate secretion to neutralize acid, reduce pepsin • Decreased healing and cell replacement • Decreased blood flow • Decreased levels of prostaglandin E2, which enhances all of the above defenses

↓ Ulcer formation


Pathogenesis of Peptic Ulcer Disease

PUD-associated complications occur in about 50% of patients >70 years, and include:

• Bleeding – elderly patients with ulcers have more frequent and more severe bleeding than younger patients. • Perforation – ulcer crater burrows through the gastric or intestinal wall; occurs more frequently with duodenal ulcers • Gastric outlet obstruction- can result from acute inflammation and edema near the gastroduodenal junction • Penetration- less common form of perforation that burrows into an adjacent organ (i.e. pancreas, liver or colon)

The gastric and duodenal ulcers characteristic of peptic ulcer disease or P-U-D result from mucosal irritation and consequent imbalances between hydrochloric acid , pepsin secretions and the natural defenses of the mucosal lining. Pepsin is activated by the acidic conditions and proceeds to enzymatically digest the mucosal, muscular and vascular layers. Mucous, bicarbonate, and prostaglandin production is compromised, allowing for mucosal injury by the caustic acids and enzymes. After an ulcer crater is formed, PUD can progress to complications such as bleeding, obstruction and perforation.


Etiology of Peptic Ulcer Disease

It is estimated that over 90% of duodenal ulcers, and from 70% to 75% of gastric ulcers, are caused by H. pylori. Most of the ulcers not caused by H. pylori are believed to result from irritations and ulcerations from medications such as aspirin and non-steroidal anti-inflammatory drugs (NSAIDs). . Helicobacter pylori Bacterial Infection: H. pylori is spread through human saliva and feces, and via food and water sources.

• May create an ulcer in the mucosal layer by using its toxins, enzymes and inflammatory cytokines to cause injury in the GI mucosa. • May increase the release of gastrin which in turn increases acid production, leading to mucosal damage. • May impair endogenous protective mechanisms.

NSAIDs: The increasing and widespread use of aspirin for cardiovascular purposes and prescribed or OTC NSAIDs for pain places users at a substantially increased risk for PUD.

NSAIDs:, • Act directly on the mucosa, inhibiting prostaglandin E2. •  This results in:

• decreased protective mucous production • decreased bicarbonate secretion • decreased mucosal blood flow and platelet aggregation, which can interfere with healing processes.

• Increase leukotriene release, which adds to mucosal damage • Newer COX-2 selective inhibitors do not inhibit prostaglandin E2 in the GI tract to the extent of traditional NSAIDs, and theoretically have a decreased chance of causing ulcers.


Etiology of Peptic Ulcer Disease

Other Potential Causes:

• Corticosteroid use • Corrosive medications: potassium chloride, bisphosphonates • Abnormal motility in the stomach and duodenum leading to more mucosal damage • Hypersecretion of acid within affected areas (rare)

In the past, controlling peptic ulcers was based primarily on controlling the amount of stomach acid and the intake of irritating foods. It now appears that many of these ulcers are caused by a bacterium, Helicobacter pylori, which responds to treatment with antibiotics and acid suppression.

Helicobacter pylori bacteria are acid-labile spiral gram negative rods which cause ulceration of the mucosal lining by increasing the release of gastrin and acid production. Nearly all other ulcers are caused by the use of aspirin or other non-steroidal anti-inflammatory drugs. These drugs may act directly on the mucosa inhibiting prostaglandin E2, or they may increase leukotriene release which adds to mucosal damage.

Alternatives such as the COX-2 specific inhibitors, or traditional NSAIDS plus a proton-pump inhibitor confer some protection from NSAID-induced damage.. It is interesting to note that gastric ulcers appear most often with patients over age 50 having group A blood type.


Risk Factors for Peptic Ulcer Disease and Associated Complications

• H. pylori infection • NSAID use • Advanced age • Corticosteroid use • Warfarin use • Cigarette smoking • Alcohol Use • Chronic diseases such as COPD, cirrhosis,

chronic renal failure, and cystic fibrosis • Severe physiologic stress- trauma, burns, surgery • Family history

Risk factors for the development of peptic ulcer disease include H. pylori infection, use of certain medications, and alcohol use to name a few. Cigarette smoking is another important risk factor, which reduces prostaglandin E-2 production, inhibits pancreatic bicarbonate production and promotes reflux and gastric emptying.

Genetic predisposition and stress reactions can increase risk as well. Factors Increasing the risk for PUD-related complications include chronic diseases such as COPD, use of anticoagulants and advanced age. Dietary factors such as spices, milk, beer, coffee, tea and sodas may cause dyspepsia but do not, by themselves, increase the risk of peptic ulcer disease.


Signs & Symptoms of Peptic Ulcer Disease

In the elderly, the presentation of PUD is frequently atypical. Classic PUD-associated abdominal pain occurs in only approximately 35% of patients and abdominal pain is absent in 50-60% of NSAID-induced ulcers. Pain may be reported as vaguely located or as simple indigestion.

General: • Epigastric pain in clusters that may be characterized as:

• vague discomfort • abdominal fullness or cramping • burning sensation • aching or gnawing feeling

• Nausea and vomiting • Weight loss • Fatigue

Gastric Ulcers: Pain occurs 5-15 minutes after eating, and remains until the stomach empties (may be several hours) Pain is generally absent during fasting times. Vomiting blood or “coffee ground emesis” Abdominal indigestion

Duodenal Ulcers: Pain 1-3 hours after a meal, relieved by simple antacids, milk, or food Pain may awaken patient at night Pain may worsen if no food is eaten Black tarry stools may be present and may be seen with gastric ulcer


Signs & Symptoms of Peptic Ulcer Disease

In many geriatric patients, the signs and symptoms of peptic ulcer disease are not experienced until the stomach or duodenum is actually perforated or gastrointestinal bleeding is evident. Initial symptoms include epigastric pain, nausea and vomiting, weight loss and fatigue. Some elderly may self-medicate with over-the-counter products and simply hide painful symptoms. It is important to note changes in abdominal pain patterns and the ineffectiveness of antacids which signal a more serious condition.

While a detailed history of symptoms may be helpful, more testing is necessary to determine the cause and location of the problem. If a peptic ulcer is suspected, discontinuation of aspirin and other non-steroidal anti-inflammatory agents should be considered until a diagnosis is confirmed.


Diagnostic Testing for PUD

If ‘alarm’ symptoms such as evidence of GI bleeding, anemia, weight loss, difficulty swallowing, recurrent vomiting newly appear or specific symptoms have been present for a long time, invasive tests are recommended. If no “alarm” symptoms are present, then non-invasive tests followed by treatment is recommended.

Non-invasive • Analysis of stool to detect occult blood • CBC, including hemoglobin, hematocrit and other indices to detect anemia • Urea breath test for H. pylori (American College of Gastroenterology has identified this test as the noninvasive test of choice for the diagnosis of H. pylori infection) • Stool antigen testing for H. pylori • Serological blood tests to screen for H. pylori • Liver function tests (LFTs), amylase, and lipase to determine differential diagnosis • Other tests such as haptoglobin, CEA, amylase and the Schilling test to rule out other disorders

Invasive • Direct testing of gastric contents • Upper GI series with contrast media to determine type of ulcer • Esophagogastroduodenoscopy (EGD) to pinpoint the damaged area and obtain a biopsy for additional testing • Endoscopy techniques, including urease test on biopsy tissue, culture and histological studies to confirm H. pylori


Diagnostic Testing for PUD

If the elderly patient presents with ‘alarm’ symptoms such as evidence of GI bleeding, anemia, weight loss, difficulty swallowing, or has experienced specific symptoms for a long time, invasive tests are recommended. If no “alarm” symptoms are present, then non-invasive tests followed by treatment is recommended.

Non-invasive testing can help to narrow down the diagnosis and rule out other causes. Other tests such as haptoglobin, CEA, amylase and the Schilling test may help to rule out other disorders with similar symptoms. Serological blood tests can be used to initially screen for Helicobacter pylori infection, however endoscopy is the most definitive test. Invasive testing such as an upper GI series with contrast media will detect type and location of ulcer. . If test results indicate an actively bleeding ulcer, treatment should begin immediately. The site of the ulcer will help determine the most effective treatments and preventative measures for each patient.


Pharmacotherapy for Peptic Ulcer Disease

Patients with suspected or diagnosed PUD should discontinue use of offending substances such NSAIDs, alcohol and tobacco as soon as possible.

Pharmacotherapy for PUD includes using medications that neutralize or inhibit gastric acid secretion, promote healing through simulation of mucosal defense mechanisms, and eradicate H. pylori. First-line therapies for treatment of H.pylori infection are proton-pump inhibitor-based triple therapies, and bismuth-based triple therapies. Monotherapy is not recommended for H. pylori infection due to limited efficacy and potential for antimicrobial resistance. For ulcers not caused by H. pylori, acid suppression or protective therapies are most effective.

Antibiotics (double or triple therapy): • Metronidazole • Clarithromycin • Amoxicillin • Erythromycin • Tetracycline

Antisecretory Agents: • Proton pump inhibitors • Histamine2 receptor antagonists

Other Agents: • Antacids • Misoprostol • Bismuth-containing compounds • Sucralfate

Examples of Triple- and Quadruple-therapy combinations for H. Pylori:

• Clarithromycin 500mg BID + Amoxicillin 1000mg BID + Omeprazole 20mg BID for 10-14 days

• Metronidazole 500mg BID + Clarithromycin 500mg BID + Lansoprazole 30mg BID for 14 days

• Metronidazole 500mg TID + Bismuth 525mg TID + Tetracycline 500mg QID + Omeprazole 20mg QD for 14 days


Pharmacotherapy for Peptic Ulcer Disease

In recent years, treatment plans for peptic ulcer disease have shifted away from symptom reduction and surgical interventions to the elimination of primary causes and recurrence. When the presence of H. pylori is established, two or three antibiotics combined with an acid suppressing agent for 10-14 days can provide complete healing and prevent recurrence. Reducing the acid environment with acid suppressing agents can help cure the ulcer, mitigate painful symptoms, allow for healing and help to prevent recurrences.


Treatment of PUD with Proton Pump Inhibitors (PPI)

Mechanism of Action: I irreversibly inhibit enzymes in parietal cells necessary for gastric acid secretion

Agents and Dosing Range for PUD:

• Omeprazole (Prilosec®): 20- 40 mg daily • Lansoprazole (Prevacid®): 15 -60 mg daily • Rabeprazole (Aciphex®): 20-40 mg daily • Pantoprazole (Protonix®): 40mg-80 mg daily • Esomeprazole (Nexium®): 40mg daily

Duration of Therapy: 4-8 weeks; if part of a double or triple therapy regimen 14 days.

Adverse Drug Reactions: headache, abdominal pain, diarrhea, constipation, flatulence, reduced vitamin B12 absorption, pernicious anemia (with long-term use).

Drug-Drug Interactions:

In general, proton pump inhibitors can reduce the absorption of oral iron, ketoconazole, and itraconazole, and some protease inhibitors.

PPIs can increase serum concentrations of diazepam, amiodarone, phenytoin, warfarin and propranolol, to name a few. Check prescribing information for individual agents for a full review of drug-drug interactions.


Treatment of PUD with Proton Pump Inhibitors (PPI)

Acid reducing agents are an important part of the therapeutic regimen for the elderly patients with peptic ulcer disease. Proton pump inhibitors are often part of such therapies because they irreversibly inhibit enzymes in parietal cells necessary for gastric acid secretion. Agents include omeprazole, esomeprazole, lansoprazole, rabeprazole and pantoprazole.

While expensive, these agents are still cost-effective because they relieve symptoms and heal ulcers more rapidly than either histamine2 receptor antagonists or sucralfate. When used alone, treatment typically lasts four to eight weeks, with increased duration and increased dosage recommended for smokers. Side effects of proton pump inhibitors include headache and irritation of the gastrointestinal tract.

Drug interactions with narrow therapeutic medications like warfarin, phenytoin, and carbamazepine are possible, so these drugs must be monitored closely.


Treatment of PUD with Histamine2 Receptor Antagonists (H2 RA)

Mechanism of Action: reversibly bind H2 receptors on parietal cells, reducing acid production and partial inhibition of acetylcholine and gastrin-stimulated acid production.

Agents and Initial Dosing for PUD* :

• Cimetidine (Tagamet®): 800mg-1600mg daily • Nizatidine (Axid®): 150 -300mg qd • Rantidine (Zantac®): 300mg QD • Famotidine (Pepcid®): 20 mg bid or 40 mg qd

(*Note: GERD and PUD prophylactic therapy may have different dosage recommendations; H2 RA doses should be reduced if CrCL<50ml/min

Duration of Therapy: 6-8 weeks + 2-4 more weeks for smokers and older adults; if gastric ulcer is more than 1 cm, + 12 weeks for complete healing

Adverse Drug Reactions: dizziness/drowsiness, headache, GI irritation, transient confusion,, thrombocytopenia (rare). Cimetidine may also cause gynecomastia and significant inhibition of hepatic drug metabolism.

Drug-Drug Interactions: Class-wide: May hamper efficacy of ketoconazole and itraconazole, or medications that require an acidic environment for absorption. Also some H2 blockers have been reported to affect INR. Cimetidine:. inhibition of CYP450 may increase levels of benzodiazepines, beta blockers, phenytoin, calcium channel blockers, clozapine, theophylline, warfarin, and various antidepressants to name a few.


Treatment of PUD with Histamine2 Receptor Antagonists (H2 RA)

Histamine-2 receptor antagonists reversibly bind H2 receptors on parietal cells, reducing acid production and partially inhibiting acetylcholine and gastrin-stimulated acid production. Histamine2 receptor antagonists include cimetidine, nizatidine, ranitidine, and famotidine. Side effects of histamine2 receptor antagonists include drowsiness, headache, and GI irritation. Elderly patients taking cimetidine must be carefully monitored for central nervous system effects and drug-drug interactions. It is also important to note that H2-RA are now available for over-the-counter treatment of meal-induced heartburn, acid indigestion, and sour stomach at lower doses then what are available by prescription.


Treatment of PUD with Antacids

Mechanism of Action:

• Antacids form a weak base which reacts with gastric acids to form salts and water • As the pH of gastric environment rises above 4, pepsin becomes inactive and gastrin is inhibited • Antacids forming aluminum salts enhance mucosal defense mechanisms • Effects may last 15-30 minutes, or as long as 1-2 hours with food

Dosing: 100-144 mEq as needed (refer to individual product packaging)

Agents:

Sodium bicarbonate based medications (Alka-Seltzer® products,)- Rapid action and relief, but these products may cause electrolyte imbalances, and urinary or systemic alkalosis leading to edema, hypertension and heart failure. Many Alka-Seltzer® products also contain aspirin.

Aluminum hydroxide and dihydroxy forms (AlternaGel®: ,Maalox®, Mylanta®) - weaker effects but can inhibit gastric hyperacidity; . Use with caution in patients with CHF, renal failure, edema. Hypophosphatemia and aluminum intoxication may occur with prolonged administration or large doses. Constipation can result from formation of insoluble aluminum chloride. Aluminum antacids can decrease the efficacy of tetracycline and fluroquinolone antibiotics via binding interactions. Also may affect absorption of bisphosphonates, phenytoin, and antifungals.


Treatment of PUD with Antacids

Calcium carbonate (Tums®, Titralac®, Rolaids®,) - a good neutralizer, but may cause constipation and nausea; absorption of calcium chloride may cause hypercalcemia with muscle weakness, kidney stones, gastric acid rebound. May affect absorption of tetracycline, fluroquinolones, digoxin, and levothyroxine.

Many OTC antacid products contain multiple agents: Gaviscon®, Rolaids®, Di-Gel®, Maalox®, Mylanta®.

Antacids are widely used to relieve the symptoms of peptic ulcer disease and can be effective if properly managed. When ingested, antacids form a weak base which reacts with gastric acids to form salts and water. Effects may last fifteen to thirty minutes, or up to one to two hours when taken with food. Unfortunately, antacids differ in their neutralizing capacity, how quickly and how long they are effective, adverse reactions, palatability, convenience of use and cost. Some, like Alka Seltzer, may also contain aspirin and other non-steroidal anti-inflammatory drugs that cause further damage to the gastrointestinal tract. Combinations of aluminum hydroxide and magnesium hydroxide antacids may cancel out adverse bowel effects such as diarrhea and constipation, but dosage levels must be monitored to ensure concurrent medications are properly absorbed or excreted. Antacids should only be used as PRN therapy to reduce symptoms.


Treatment of PUD with Misoprostol (Cytotec®)

Mechanism of Action: reduces gastric acid production and protects mucosa

Indications: Prevention of NSAID-induced gastric ulcers; misoprostol should not be used as a first-line therapy for gastric or duodenal ulcers.

Dosing:

• 200 mcg QID or 400 mcg BID with food • Doses of 100 mcg QID or 200 mcg BID can be used if higher doses are not tolerated. • Combination product with diclofenac sodium (Arthrotec®) contains 200mcg of misoprostol per tablet to decrease NSAID-induced ulcers

Adverse Drug Reactions:

• Abdominal pain, cramping • Headache • Uterine contractions • Diarrhea (dose dependent)


Treatment of PUD with Misoprostol (Cytotec®)

Other medications may be used for the primarily for the prophylaxis of PUD, but may not be appropriate for many elderly patients. Misoprostol is a prostaglandin E1 analog that reduces gastric acid production and protects the mucos, facilitating healing. It is used to prevent aspirin and NSAID-related irritation and ulceration. Misoprostol is contained in a combination product with diclofenac sodium called Arthrotec®. The combination product is used in patients who are at risk for ulcers. Arthrotec® comes in two strengths, 50mg and 75mg, along with 200mcg of misoprostol in each tablet.


Treatment of PUD with Bismuth-Containing Compounds

Mechanism of Action: suppresses H. pylori and stimulates prostaglandins that protect mucosa

Agents and Dosing:

• Bismuth subsalicylate (Pepto Bismol®, Kaopectate® or combination therapy packs): 524mg BID or 262 mg QID x 4 weeks

• Helidac® combination pack: bismuth subsalicylate + tetracycline 500 mg QID and metronidazole 500 mg TID


• Do not use if patient has a hypersensitivity to salicylates or any component of the formulation; history of severe GI bleeding, coagulopathy , or renal failure.

• May potentiate effects of aspirin and warfarin • May cause black stools or tongue • Note: each 262.4 mg tablet of bismuth subsalicylate contains an equivalent of 130 mg aspirin.


Treatment of PUD with Bismuth-Containing Compounds

Bismuth subsalicylate suppresses H. pylori and stimulates prostaglandins that then protect mucosa. One tablet of bismuth subsalicylate taken four times a day with appropriate antibiotics has been found to be effective in eradicating Helicobacter pylori. Side effects of bismuth-containing products include increased risk for bleeding, headache, black tongue and black stools.


Treatment of PUD with Sucralfate (Carafate®)


• Combines with proteins to form a viscous paste-like barrier resistant to acid and pepsin • Binds bile salts • Stimulates prostaglandins

Dosing:

• 1-2 g QID for ulcer healing, 1 g QID for maintenance. • Because of the potential for sucralfate to alter the absorption of some drugs, separate administration (take other

medication 2 hours before sucralfate) should be considered when alterations in bioavailability are believed to be critical

Duration of Treatment: 6-8 weeks; elderly may require up to 12 weeks of therapy.


• Constipation • Nausea • Aluminum toxicity/seizures • Use with caution in patients with chronic renal failure who have an impaired excretion of absorbed aluminum.

Drug-drug interactions:

• reduces absorption of other drugs by binding them (e.g., phenytoin, digoxin, theophylline, warfarin, and quinolone antibiotics)


Treatment of PUD with Sucralfate (Carafate®)

Sucralfate is an aluminum salt of a sulfated disaccharide that combines with proteins to form a viscous barrier resistant to acid and pepsin.

It also binds bile salts and stimulates prostaglandins. Treatment is normally six to eight weeks, but may be up to 12 weeks in an older individual. Sucralfate can cause constipation, and nausea; also, aluminum can accumulate in patients with renal insufficiency, leading to seizures.

Sucralfate may bind to drugs in the GI tract, causing decreased absorption. This is particularly important for patients on narrow therapeutic medications such as phenytoin, digoxin, theophylline, warfarin, and the quinolone antibiotics.

The dose of the interacting drug should be separated from sucralfate by 2 hours. Sucralfate has no effect on H. pylori.


Resources


Andersson,T. (1996). Pharmacokinetics, metabolism and interactions of acid pump inhibitors. focus on omeprazole, lansoprazole and pantoprazole. Clin Pharmacokin; 31(1): 9-28.

Beers, M.H & Berkow, R. (2000). The Merck Manual of Geriatrics. 3nd edition Section 13, Gastrointestinal Disorders. Whitehouse Station, NJ: Merck Research Laboratories: 1000-1154.

Bianchi Porro, G. & Lazzaroni, M. (1993). Prescribing policy for antiulcer treatment in the elderly. Drugs Aging; 3(4): 308-19.

Bianchi, P.G. & Lazzaroni M.(1993). Prescribing policy for antiulcer treatment in the elderly. Drugs Aging, 3(4):308-19.

Buckley, M. & Martin, P, & (1992). O'Morain, C. Helicobacter pylori infection. implications for ulcer therapy in older patients. Drugs Aging; 5(1): 1-7.

Collins J., Ali-Ibrahim A., & Smoot D.T. (2006)Antibiotic Therapy for Heliobacter pylori. Med Clin N Am 90: 1125-1140.

Crotty, B. & Smallwood, R. A. (1995). Upper gastrointestinal tract . Med J Austral; 162(2): 95-7.

Cryer, B., et.al. (1992). Effect of aging on gastric and duodenal mucosal prostaglandin concentrations in humans. Gastroenterology, 102:1118.

Drug facts and comparisons. (1998). Facts and Comparisons, 1998 ed., St. Louis.


Resources

Garnett, W. R. (1992). Patient-outcome management of gastric acid-related disorders. Consult Pharm; 7(Suppl B): 15-26.

Gonzalez, E. R., et al. (1994). National antiulcer therapy surveillance study in long-term care facilities. Consult Pharm; 9(10): 1131-1140.

Graham, D. Y. (1996). Nonsteroidal anti-inflammatory drugs, Helicobacter pylori, and ulcers: where we stand. Am J Gastroenterol; 91(10): 2080-6.

Greenwald, D.A. (2004) Aging, the Gastrointestinal Tract, and Risk of Acid-Related Disease. Am J Med 117(5A): 8s-13s.

Lewis, J. H.(1994). A pharmacologic approach to gastrointestinal disorders. Baltimore:Williams & Wilkins.

McFadden, D. W. & Zinner, M. J. (1994). Gastroduodenal disease in the elderly patient. Surg Clin North Am; 74(1): 113-26.

Pitner, J. K., et al. (1994). Prevention of NSAID-induced gastropathy in the elderly. Consult Pharm; 9(5): 568-579.

Roth, S. H. (1995). From peptic ulcer disease to NSAID gastropathy. an evolving nosology. Drugs Aging; 6(5): 358-67.

Sand R.J. & Scheiman J.M. (2004) Diagnosis and Management of Peptic Ulcer Disease. Clin Fam Prac; 6(3): 569-587.

Sipponen, P. (1995).Helicobacter pylori: a cohort phenomenon. Amer J Surg Pathol; 19(Suppl 1): S30-6.


Resources

Smith, J.D. and Nguyen, B.N. (1997) Peptic ulcer disease and gastroesophageal reflux disease. Preparatory Program for the Certifciation Exam in Geriatric Pharmacy, Alexandria, VA: American Society of Consultant Pharmacists

Stucki, G., Johannesson, M., & Liang, M. H. (1996). Use of misoprostol in the elderly: is the expense justified. Drugs Aging; 8(2): 84-8.

Web Sites:

Drug Information Resources: A Guide for Pharmacists



Thomson Micromedex

NCG Helicobacter pylori in peptic ulcer disease

PharmInfo Net’s Gastrolinks – Peptic Ulcer Disease


Gastroesophageal Reflux Disease



• Define gastroesophageal reflux disease (GERD) and its prevalence among the elderly.

• Describe the pathogenesis of GERD.List factors that contribute to the development of GERD.

• List the major signs and symptoms of GERD.Identify important tools used to diagnose GERD.

• Outline therapeutic goals and suggested treatment regimens for GERD.

• Compare and contrast medications commonly used to treat GERD in terms of effectiveness, dosing, and adverse side effects.

• Describe non-pharmacological options for the treatment of GERD.


An Overview of Gastroesophageal Reflux Disease (GERD) in the Elderly

Definition: the abnormal and repetitive regurgitation of gastric contents

Epidemiology:

• Affects at least 30% of elderly • Prevalence increases with age • Accounts for much of the $2 billion expenditure for antacids, proton pump inhibitors, and other medications

Long-term Consequences of GERD:

• Heartburn • Esophagitis • Esophageal stricture • Barrett’s esophagus • Carcinoma • Decreased quality of life • Extra esophageal symptoms

• cough • wheezing • horseness • sore throat • dysphagia


An Overview of Gastroesophageal Reflux Disease (GERD) in the Elderly

Gastroesophageal reflux disease is a condition characterized by the abnormal and repetitive regurgitation of gastric contents causing inflammation. The condition affects as much as thirty percent of the elderly population. Milder cases present as occasional “heartburn” which may be managed by avoiding certain foods and environmental factors. As the lower esophageal sphincter loses its tone, recurrent reflux leads to a shortened esophagus and permanent reflux. Damage to the esophageal lining can be quite severe and lead to major bleeding, stricture, or even cancer in the esophagus. Treatment plans for the elderly rely primarily on pharmacotherapy designed to decrease acid production.


Spectrum of GERD

There is no data that GERD is progressive. The current view is that mild esophagitis tends to remain mild on follow-up, and the progression of GERD to erosive esophagitis to Barrett's esophagus occurs in a small proportion of patients.

The development of gastroesophageal reflux disease can be traced to frequent relaxation of the lower esophageal sphincter allowing gastric contents to inflame the area thus impairing sphincter function and esophageal motility. As gastric reflux volume increases, esophagitis may shorten the esophagus leading to a permanent malfunction of the gastroesophageal junction and greater inflammation or ulcers. If left untreated, columnar epithelium may develop to resist acids in the esophagus which in turn may develop into adenocarcinoma. However, this occurs in a minority of patients.


Factors that Affect the Development of GERD

Mechanism Factors

Direct esophageal irrita/on citric juices, tomato-‐based products, soda, coffee

Reduced Lower Esophageal Sphincter (LES) tone

faAy foods, alcohol, chocolate, caffeine, nico/ne, alpha-‐adrenergic blockers, an/cholinergic agents, benzodiazepines, beta-‐2 agonists, progesterone, calcium channel blockers, dopamine, nitrates, prostaglandins, theophylline, TCAs

Delayed gastric emptying an/cholinergic agents, narco/c analgesics, overea/ng

Impaired gastroesophageal pressure gradient supine body posi/on, obesity, /ght-‐fiLng clothing

Mucosal resistance NSAIDs

Anatomical changes hiatal hernia, reclining aOer ea/ng

Several factors can affect the development of gastroesophageal reflux disease, including foods, eating habits, and various medications. These factors are shown on your screen, along with the mechanisms through which they exacerbate the disorder.


Signs & Symptoms of GERD

Typical:

• Substernal burning or “heartburn” after eating certain foods • Heartburn when reclining or bending at the waist • Belching • Regurgitation • Nausea • Vomiting/bitter or sour taste in mouth

Atypical:

• Hoarseness of voice • Wheezing • Sore throat • Cough

Alarm:

• Swallowing difficulties • Unintentional weight loss • Blood in vomit or stool • Inability to eat solid food

Classical symptoms of gastroesophageal reflux disease include heartburn after eating certain foods or events, and heartburn when either lying down or bending at the waist after large meals.

Other symptoms include belching, regurgitation, and nausea. More atypical symptoms of GERD include hoarseness, sore throat, and cough.

The frequency and severity of heartburn symptoms do not correlate with the severity of erosive disease. Symptoms such as swallowing difficulties, bleeding and unintentional weight loss are cause for alarm and immediate evaluation.

Some patients- the elderly in particular- may be asymptomatic before a bleed, and have no warning signs.


Methods Used to Diagnose GERD

• GERD may mimic angina, asthma, COPD and throat infections. • Medical history and symptom analysis are important to diagnosis • 24-hour ambulatory esophageal monitoring is definitive, especially for patients with atypical symptoms:

• A drop in intra-esophageal pH to less than 4 for more than 7 % of the 24 hours or • A drop of 1 pH unit or more from a reliable baseline pH

• Factors such as a hiatal hernia, delayed gastric emptying, and a non-functional pyloric sphincter should be considered in the prognosis • If patient is unresponsive to drug therapy or has additional complications, assess esophageal damage with endoscopy • Testing vomit and stool for blood • Esophageal manometry can detect abnormal lower esophageal sphincter pressure

Although gastroesophageal reflux disease may initially mimic other disorders, a good medical history or esophageal pH monitoring is helpful in diagnosing the disease. Careful analysis of symptoms is also important. If further evidence is needed or if treatment is ineffective, endoscopy can determine the current condition of the first esophageal lining. When determining the status and progression of the disease, the clinician should consider the contribution of other pathological factors such as hiatal hernia, delayed gastric emptying, and a non-functional pyloric sphincter. If the patient does not respond to drug therapy or additional complications are suspected, endoscopy with biopsy can determine esophageal damage. Other tests check for blood in vomit or stool, and for abnormal pressure in the lower esophageal sphincter. Endoscopy would be done before pH monitoring; patients who do not respond to PPIs are not likely to have GERD and need endoscopy.


Diagnostic Classification of GERD

Differential Diagnoses:

• Reflux without esophagitis • Reflux with esophagitis • Reflux with severe esophagitis

Evaluation of Esophageal Lining:

• Grade 0 - normal • Grade I - single or isolated erosive lesions • Grade II - multiple lesions • Grade III - circumferential lesions • Grade IV - columnar epithelium (Barrett’s), ulcers or strictures

For the purposes of selecting treatment, GERD is typically classified as reflux without esophagitis, reflux with esophagitis and reflux with severe or erosive esophagitis. Diagnostic test results may also provide data for grading the extent of damage to the esophageal lining. This grading scheme is shown on your screen.


Treatment of GERD

Therapeutic Goals:

• Alleviate symptoms • Heal any ulcers • Avoid adverse reactions to medications • Prevent additional complications • Prevent recurrence

Step-Down Approach:

Treatment for gastroesophageal reflux disease relies on pharmacotherapy for symptomatic relief and long-term management. Other therapeutic goals include healing any ulcers, avoiding adverse reactions to medications, and preventing additional complications in the esophagus. For elderly patients, the step-down approach is favored because it can improve quality of life almost immediately.

This approach emphasizes the initial use of proton pump inhibitors or histamine-2 receptor antagonists to reduce gastric secretion. Promotility agents can be useful in some cases during the healing stage but caution must be taken to avoid adverse reactions and drug-interactions. Proton pump inhibitors are the most effective form of extended therapy for more severe GERD producing eighty to ninety percent remission.

Acute proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) to reduce acid secretion; promotility agents to improve acid clearance

Maintenance PPIs or H2 RAs; lifestyle modification to minimize risk factors


Treatment of GERD with Antacids

Mechanism of Action: Form a weak base which reacts with gastric acids to form salts and water; effects may last as long as 1-2 hours with food.

Dosing: One dose taken 30 minutes after meals and at bedtime x 4-8 weeks. Consult individual prescribing information for exact dosing.

Agents:

Sodium bicarbonate-based medications (e.g. Alka-Seltzer® products) - Rapid action and relief, but these products may cause electrolyte imbalances, and urinary or systemic alkalosis leading to edema, hypertension and heart failure. Many Alka-Seltzer® products also contain aspirin, which can cause GI irritation and breakdown.

Aluminum hydroxide and dihydroxy forms (AlternaGel®, Maalox®, Mylanta®) - weaker effects but can inhibit gastric hyperacidity; use with caution in patients with CHF, renal failure, edema; hypophosphatemia and aluminum intoxication may occur with prolonged administration or large doses. Constipation can result from formation of insoluble aluminum chloride .Aluminum antacids can decrease the efficacy of tetracycline and fluroquinolone antibiotics via binding interactions; also may affect absorption of bisphosphonates, phenytoin, and antifungals.

Magnesium hydroxide (Phillip's Milk of Magnesia®, Di-gel®, Maalox®, Mylanta®, Rolaids®) - longer lasting effects due to slower stomach emptying; can cause diarrhea and cramping. Use with caution in patients with severe renal impairment. May decrease absorption of tetracyclines, fluroquinolones, digoxin, or iron salts


Treatment of GERD with Antacids

Calcium carbonate (Tums®, Titralac® Rolaids®) - a good neutralizer, but may cause constipation and nausea; absorption of calcium chloride may cause hypercalcemia with muscle weakness, kidney stones, gastric acid rebound. May affect absorption of tetracycline, fluroquinolones, digoxin, and levothyroxine.

Many OTC antacid products contain multiple agents: Gaviscon®, Rolaids®, Di-Gel®, Maalox®, Mylanta®.

Patients with mild and infrequent symptoms may begin with lifestyle changes, antacids, or over-the-counter histamine-2 receptor antagonists. Antacids are effective in controlling symptoms in the majority of these patients, however, the neutralizing effects usually last only forty-five minutes to an hour when taken on an empty stomach. Some antacids, like Alka-Seltzer®, may also contain aspirin and other non-steroidal anti-inflammatory drugs that cause further damage to the gastrointestinal tract. Alginic acid-antacid combinations (Gaviscon®) form a viscous foam which floats on the surface of gastric contents acting as a mechanical barrier. The usual dose is two tablets chewed after meals and at bedtime. Over-the-counter histamine-2 receptor antagonists can be taken prophylactically and provide longer-lasting relief from the symptoms of GERD.


Treatment of GERD with Proton Pump Inhibitors (PPIs)

Mechanism of Action: Irreversibly inhibit enzymes in parietal cells necessary for gastric acid secretion.

Agents and Dosing for GERD:

• omeprazole (Prilosec®): 20-40 mg daily x 4-8 weeks • lansoprazole (Prevacid®): 15-30 mg daily x 4-8 weeks • rabeprazole (Aciphex®): 20 mg daily x 4-8weeks • pantoprazole (Protonix®): 20-40 mg daily x 4-8 weeks • esomeprazole (Nexium®): 20-40 mg daily x 4-8 weeks

Adverse Drug Reactions: Headache, abdominal pain, diarrhea, constipation, flatulence, reduced vitamin B12absorption, pernicious anemia (with long-term use).

Drug-Drug Interactions:

• In general, proton pump inhibitors can reduce the absorption of oral iron, ketoconazole, and itraconazole, and some protease inhibitors. • PPIs can increase serum concentrations of diazepam, amiodarone, phenytoin, warfarin, and propranolol, to name a few. • Check prescribing information for individual agents for a full review of drug-drug interactions


Treatment of GERD with Proton Pump Inhibitors (PPIs)

PPIs have the greatest effect on decreasing acid production. These agents allow for more rapid and complete healing. PPIs irreversibly inhibit enzymes in parietal cells necessary for gastric acid secretion. Higher doses of any of these drugs may be needed for more severe cases, including those with erosive esophagitis, or Zollinger-Ellison syndrome. Side effects of these drugs are usually limited to headaches and diarrhea. Although, reduced vitamin B12 absorption may occur with long-term therapy of greater than 3 years as intrinsic factor requires an acidic environment to absorb vitamin B12. Maintenance therapy is based on long-term administration of effective therapeutic dosages.


Treatment of GERD with Histamine-2 Receptor Antagonists (H2 RA)

Mechanism of Action: Rreversibly bind H2 receptors on parietal cells, reducing acid production and partially inhibiting acetylcholine and gastrin-stimulated acid production.


•  cimetidine (Tagamet®): 300-400 mg QID or 800 mg twice daily for 12 weeks • nizatidine (Axid®): 150 mg BID • rantidine (Zantac®): 150 mg BID • famotidine (Pepcid®): 20 mg BID

(Note: GERD and PUD prophylactic therapy may have different dosage recommendations; H2 RA doses should be reduced if CrCL<50ml/min)

Duration of Therapy: 4-8 weeks

Adverse Drug Reactions: Dizziness/drowsiness, headache, GI irritation, transient confusion, thrombocytopenia (rare); Cimetidine may also cause gynecomastia and significant inhibition of hepatic drug metabolism.

Drug-Drug Interactions: Class-wide: May hamper efficacy of ketoconazole and itraconazole, or medications that require an acidic environment for absorption. Also some H2 blockers have been reported to affect INR. Cimetidine: Inhibition of CYP450 may increase levels of benzodiazepines, beta blockers, phenytoin, calcium channel blockers, clozapine, theophylline, warfarin, and various antidepressants to name a few.)


Treatment of GERD with Histamine-2 Receptor Antagonists (H2 RA)

Although not as effective as proton pump inhibitors, patients who have more severe GERD with esophagitis can be treated with higher doses of histamine-2 receptor antagonists such as cimetidine, famotidine, ranitidine and nizatidine. These agents reversibly bind H2 receptors on parietal cells reducing acid production and partially inhibiting acetylcholine and gastrin-stimulated acid production. In doing so, they not only reduce the need for antacids, but allow healing of esophagitis.

When used to treat gastroesophageal reflux disease, histamine-2 receptor antagonists are administered in divided doses. While doubling the dosage of these agents may be more effective in relieving symptoms and healing esophagitis, the cost may be prohibitive for all but the most severe cases. Because over eighty percent of patients relapse when these agents are discontinued, maintenance therapy may be necessary. Side effects to watch for include drowsiness, headache, and GI irritation. The best use of H2 antagonists is for PRN and prophylaxis of events known to cause reflux. They are not as effective as PPIs and tolerance develops, perhaps through up-regulation of receptors. PPIs are essential for moderate to severe GERD, and for erosive disease. It is also important to note that H-RAs are now available for over-the-counter treatment of meal-induced heartburn, acid indigestion, and sour stomach at lower doses then what are available by prescription.


Treatment of GERD with Promotility Agents

Effects:

• Improve gastric emptying • Maintain lower esophageal sphincter tone • Improve esophageal clearance


Metoclopramide ((Reglan®)


Cholinergic activity with dopamine antagonism. Enhances the response to acetylcholine of tissue in upper GI tract, causing enhanced motility and accelerated gastric emptying without stimulating gastric, biliary, or pancreatic secretions; increases lower esophageal sphincter tone

• Dosing: 5-10 mg TID-QID, 30 minutes before meals and at bedtime.

• Adverse Reactions: Drowisiness, fatigue, dystonic reactions

• Drug-Drug Interactions: Anticholinergics may antagonize the mechanism of action; may increase risk of dystonic reactions if given concomitantly with antipsychotics.


Treatment of GERD with Promotility Agents

Bethanechol (Urecholine®)

• Mechanism of Action: Cholinergic agent with relatively selective muscarinic activity on smooth muscle in GI tract and bladder; results in increased peristalsis, increased GI and pancreatic secretions.

• Dosing: (unlabeled use for GERD): 10 mg TID-QID

• Adverse Reactions: GI irritation, hypotension, headaches, urinary urgency

• Drug-Drug Interactions: Bethanechol and ganglionic blockers may cause a critical fall in blood pressure. Cholinergic drugs or anticholinesterase agents may have additive effects


Treatment of GERD with Sucralfate (Carafate®)

Mechanism of Action: Combines with proteins to form a viscous paste-like barrier resistant to acid and pepsin

Dosing: (unlabeled use for GERD) 1 g 30 minutes before meals and bedtime x 4-8 weeks; may be more effective when given as a slurry.

Adverse Drug Reactions: • Constipation • Nausea • Aluminum toxicity/seizures • Use with caution in patients with chronic renal failure who have an impaired excretion of absorbed aluminum.

Drug-Drug Interactions: Because of the potential for sucralfate to alter the absorption of some drugs (e.g. phenytoin, digoxin, theophylline, warfarin, and quinolone antibiotics), separate administration (take other medication 2 hours before sucralfate) should be considered when alterations in bioavailability are believed to be critical.


Treatment of GERD with Sucralfate (Carafate®)

While its efficacy has not been proven, sucralfate is sometimes prescribed for treatment of GERD. Sucralfate is an aluminum salt of a sulfated disaccharide that combines with proteins to form a viscous barrier resistant to acid and pepsin.

Taken orally, therapy consists of one gram taken thirty minutes before meals and at bedtime. However, sucralfate is often more effective if given to patients as a slurry. Sucralfate causes constipation, hypophosphatemia, and nausea and reduces absorption of other drugs. Aluminum can also accumulate in elderly with renal problems and ultimately lead to seizures.

Given these side effects, sucralfate cannot compare with the more effective proton pump inhibitors for the treatment of gastroesophageal reflux disease. Because of the potential for sucralfate to alter the absorption of some drugs, separate administration of narrow therapeutic drugs by 2 hours from sucralfate dose.


Non-Pharmacological Treatments for GERD

Lifestyle and Dietary Changes:

• Avoid foods and medications known to trigger reflux (fatty or fried foods, alcohol, peppermint, garlic, onion, caffeine, nicotine)

• Eat smaller, more frequent meals • Stay upright 2-3 hours after eating • Elevate head of bed 6 inches for sleeping • Stop smoking • Lose extra weight • Reduce stress • Follow maintenance care plan

Support Groups:

• Provide strategies for successful self-care • Help monitor progress • Provide access to specialists, clinical pharmacists and current information

Surgical Interventions:

• Surgical reinforcement of the LES area: fundoplication, endoluminal gastroplication • Stretta procedure: radiofrequency energy to create scar tissue and tighten LES junction


Non-Pharmacological Treatments for GERD

While medications such as proton pump inhibitors and histamine-2 receptor antagonists are the key to maintenance therapy, lifestyle and dietary changes are often part of long-term treatment of gastroesophageal reflux disease. Common strategies include the avoidance of irritating foods and medications, changes in eating habits, and stress reduction. Geriatric patients tend to have more difficulty making and sustaining these changes. A support group may help the patient maintain a healthy lifestyle and find alternatives to foods and medications that trigger the disease. If conventional pharmacological and non-pharmacological therapies are unsuccessful, surgery is necessary to avoid life-threatening conditions.


Resources and References


Beers, M.H & Berkow, R. (2000). The Merck Manual of Geriatrics. 3rd edition Section 13, Gastrointestinal Disorders. Whitehouse Station, NJ: Merck Research Laboratories: 1000-1154.

Devault, K. R.(1996). Current management of gastroesophageal reflux disease. Gastroenterologist; 4:24-32


Elliot, D., Small, S. (1997). Gastroesophageal reflux disease (GERD). Journal of the American Society of Consultant Pharmacists, 13 (Suppl.5)

Fennerty, M. B., et.al. (1996). The diagnosis and treatment of gastroesophageal reflux disease in a managed care environment: suggested disease management guidelines. Arch Intern Med;156:477-84

Fullard M, et al. (2006) Systematic Review: Does Gastro-oesophageal Reflux Disease Progress? Aliment Pharmacol Ther;24 (1):33-45.

Garnett, W. R.(1998). Considerations for long-term use of proton-pump inhibitors. American Journal of Health-system Pharmacy; 55:2268-79.


Nelson, J. B., Castell, D. O.(1988). Esophageal motility disorders. Dis Mon, 34:299

Richter, J. E., et.al.(1998). Helicobacter pylori and gastroesophageal reflux disease: The bug may not be all bad. Am J Gastro; 93:1800-02



GERD Information Center at http://www.gerd.com

PharmInfo Net’s GERD Information Center at http://pharminfo.com/disease/gerd/gerd_info.html


Constipation in the Elderly

Learning Objectives


• Define constipation, its prevalence and impact on the elderly population.

• List the major causes of constipation, including medications.

• Identify the signs and symptoms of constipation, and the diagnostic methods used to characterize the disease.

• Describe non-drug treatment options for constipation.

• Compare and contrast different kinds of laxatives in terms of effectiveness, dosing, and adverse reactions.

• Outline general guidelines for treating and maintaining quality of life in elderly adults with chronic constipation.


Introduction to Constipation in the Elderly

Constipation: Less than three bowel movements each week (many definitions exist, however, this one is frequently used).

Types: • Slow-transit constipation • Rectal-outlet delay

Epidemiology: Affects 20 – 30% of the elderly population

Impact: If untreated, may lead to complications such as fecal impaction, anal fissures, prolapse or hemorrhoids, megacolon, volvulus, and a tendency to develop colorectal cancer.

Symptoms of constipation are extremely common, with prevalence being reported as high as 30%. Many patients seek medical care for constipation, but fortunately most do not have a life-threatening or disabling disorder, and the primary need is for control of symptoms. The impressive number of people affected and the cost of most diagnostic tests dictate that in the next century we can manage this symptom in a cost-effective manner. Constipation is defined as having less than 3 bowel movements each week and can be sub-categorized as slow-transit constipation or as rectal outlet delay. Most patients have the slow transit form and will experience additional aspects of the problem including straining, hard stools, or incomplete evacuation on more than 1 in 4 occasions. Patients with rectal outlet delay will complain of having a feeling of anal blockage or prolonged defecation for more than 10 minutes. Constipation is a common complaint of the elderly, with nearly one-third of adults over age sixty reporting symptoms and the use of laxatives. The prevalence of constipation is higher in nursing home patients, especially those with impaired mobility, compared to community dwelling patients.


Etiology of Constipation

• Dietary and lifestyle changes • Functional outlet obstruction due to striated muscle failure • Decreased internal and external anal sphincter tone • Diseases such as

• Colon cancer • Stroke • Hypothyroidism • Neurological disorders • Hypercalcemia • Scleroderma • Hyperparathyroidism • Depression • Diabetic neuropathy

• Dehydration • Medications

In the elderly, the decreased gastrointestinal motility can be related to reduced dietary fiber, decreased fluid intake, lack of activity, or common diseases including: colon cancer, stroke, hypothyroidism, diabetes, and Parkinson’s disease. Many patients with chronic symptoms have developed a pattern of suppressing the urge to defecate and waiting until a more convenient opportunity to have a bowel movement. Unfortunately, the urge may not return. A common, and, often overlooked, cause of constipation is use of certain medications.


Medications That Are Commonly Associated With Constipation

Analgesics • Narcotic analgesics • NSAIDs

Anticholinergics • Older antihistamines • Tricyclic antidepressants • Antispasmodics • Anticholinergic anti-Parkinson’s medications

Diuretics

Metallic cations • Aluminum • Calcium • Iron • Barium • Bismuth

Calcium channel blockers

Many medications are culprits in causing or contributing to constipation. Sometimes constipation is well recognized and preventive measures are taken to avoid constipation, as with narcotics. However, drug-induced constipation may go unrecognized.


Assessing Constipation

Symptoms:

• Hard stool • Painful bowel movements • Straining during defecation • Reduced frequency of bowel movements • Bloating • Malaise

Diagnosis:

• Abdominal exam • Rectal exam • Occult blood tests • Colonoscopy • Radiographic studies • Sigmoidoscopy

Major symptoms of constipation include hard stool, painful bowel movements, and straining during defecation. Bloating and malaise are also common. Diagnostic testing is sometimes appropriate and may include a rectal exam, occult blood tests, colonoscopy, radiographic studies with a barium enema, and sigmoidoscopy. These tests are done primarily to rule out other disorders. Sometimes a person with impacted stool may actually experience diarrhea as liquid stool passes the impacted stool. A careful abdominal exam is helpful in differentiating impaction from loose stools.


Non-Pharmacologic Treatment of Constipation

Primary Strategies:

• Regular exercise as tolerated • Development of regular stool schedule • Removal of unnecessary constipating medications

Dietary Adjustments:

• Increase fiber consumption up to 10+ grams / day • Vegetables, fruits, cereals

• Increase fluids up to 1500+ mL / day • Add prunes or prune juice as a source of fiber and sorbitol • Add a bulk forming product as a fiber source

Bulk-Forming Products:

• Calcium polycarbophil (Fiberall®), FiberCon®) • Psyllium (Metamucil®) • Methylcellulose (Citrucel®)


Non-Pharmacologic Treatment of Constipation

Non-drug approaches should be first line therapy tried prior to using laxatives and other medications. Regular exercise and scheduled bowel movements may help to establish and maintain regularity. Constipating medications should be substituted with non-constipating ones when possible. Increasing dietary fiber to ten grams or more each day and fluids to fifteen hundred milliliters or more is recommended. Prunes and prune juice are preferred by some patients although there is some debate on their mechanism of action. They are a source of fiber and sorbitol but may have some stimulant effects as well. Bulk-forming products, such as calcium polycarbophil, methylcellulose or psyllium, may be substituted for dietary fiber.

Adequate fluid intake is required while using these products to prevent GI obstruction or impaction. Bulk forming laxatives are primary used for chronic constipation as these agents assist in maintaining regular bowel movements and will not help to relieve acute symptoms. For the ambulatory and alert elder, these non-pharmacological treatments may be sufficient to control and prevent constipation. Non-pharmacological therapies should continue even if other interventions are necessary.


Treatment of Constipation with Emollients and Lubricants

Mineral Oil or Liquid Petroleum:

Role in Therapy • Use should be discouraged • Other therapies are as effective and are safer

Comments • Penetrates and softens stool • May impair absorption of fat-soluble vitamins • Contraindicated in patients who are bedridden or have dysphagia or GERD • Potential exists for aspiration • Typical dose:15 – 45 mL

Docusate:

Role in Therapy • Prevent constipation • Ineffective for acute or chronic management of constipation

Comments • Products: docusate sodium (Colace®), docusate calcium (Surfak®) • Promotes mixing of fatty and aqueous substances, leading to evacuation by mucosal irritation • Also promotes net intestinal secretion of water • PRN use not appropriate due to onset of action • Typical dose:50 – 360 mg QD



Most laxatives are available as over-the-counter medications, allowing anyone to self-medicate. Mineral oil is often used but its potential adverse effects outweigh its potential advantages, particularly for chronic use. Mineral oil can be aspirated and a small amount absorbed systemically resulting in acute adverse effects such as lipoid pneumonia and inflammation of intestinal mucosa, liver, and spleen. Systemic absorption may be increased when used with docusate. Long-term use may place patients at risk of fat soluble vitamin deficiency.

Docusate is a stool-softener and is usually used as either the sodium salt (e.g. Colace®) or the calcium salt (e.g. Surfak®) however, products containing the potassium salt are also available. The three salts are considered to be clinically equivalent. Products containing docusate are the most commonly prescribed “laxative” to the elderly, especially nursing home elderly. While they improve the miscibility of fatty substances and water, allowing for better mixing and eventual evacuation of the stool, they have also been show to promote the net intestinal secretion of water.

Stool softeners have slow onset of action of 1 to 3 days and thus are not beneficial for acute constipation. Controlled trials have not proven that docusate is effective in treating chronic constipation in elderly patients. Docusate is often used in combination with a stimulant laxative, however, controlled studies are not available that demonstrate that the combination is more effective than the stimulant alone.

Docusate is perhaps best reserved for prevention of constipation in patients who may be at increased risk for a limited period of time (e.g. period of bed rest due to an acute illness).



Most laxatives are available as over-the-counter medications, allowing anyone to self-medicate. Mineral oil is often used but its potential adverse effects outweigh its potential advantages, particularly for chronic use. Mineral oil can be aspirated and a small amount absorbed systemically resulting in acute adverse effects such as lipoid pneumonia and inflammation of intestinal mucosa, liver, and spleen. Systemic absorption may be increased when used with docusate. Long-term use may place patients at risk of fat soluble vitamin deficiency.

Docusate is a stool-softener and is usually used as either the sodium salt (e.g. Colace®) or the calcium salt (e.g. Surfak®) however, products containing the potassium salt are also available. The three salts are considered to be clinically equivalent. Products containing docusate are the most commonly prescribed “laxative” to the elderly, especially nursing home elderly. While they improve the miscibility of fatty substances and water, allowing for better mixing and eventual evacuation of the stool, they have also been show to promote the net intestinal secretion of water.

Stool softeners have slow onset of action of 1 to 3 days and thus are not beneficial for acute constipation. Controlled trials have not proven that docusate is effective in treating chronic constipation in elderly patients. Docusate is often used in combination with a stimulant laxative, however, controlled studies are not available that demonstrate that the combination is more effective than the stimulant alone.

Docusate is perhaps best reserved for prevention of constipation in patients who may be at increased risk for a limited period of time (e.g. period of bed rest due to an acute illness).


Treatment of Constipation with Saline Laxatives

Mechanism of Action: • Increase intra-luminal water content and net secretion of fluid into colon

Role in Therapy: • Typically used for patients with acute constipation • Can be used for chronic constipation in low doses

Contraindications: • Patients with renal failure

Adverse Reactions: • Depends on extent of renal impairment and amount of stool loss. • Low doses can be used to manage chronic constipation. • Excessive dosing will produce diarrhea and dehydration. • Specific electrolyte disturbances depend on salt.

Agents and Dosing:

• Magnesium Salts • Products • Magnesium hydroxide (Milk of Magnesia®):2.4 – 4.8 oz • Magnesium sulfate:10 – 30 g • Magnesium citrate (Citro-Mag®):18 g or 12 oz • Possible Electrolyte Disturbance • Hypermagnesemia


Treatment of Constipation with Saline Laxatives

• Sodium Phosphate Salts • Products

• Sodium phosphate and sodium biphosphate (Fleet® enema, Fleet® phospo soda) • Possible Electrolyte Disturbances • Hypocalcemia, hypernatremia, hyperphosphatemia, hypocalcemia, hypokalemia

Saline laxatives produce soft stools through their osmotic effects. The increased retention of fluid in the small intestine results promotes the release of cholecystekinin and an increase in peristalsis. The most commonly used saline laxatives contain magnesium salts such as magnesium hydroxide or magnesium citrate. Phosphate is the poorly absorbed anion in products containing sodium phosphate.

Saline laxative are often used to manage acute constipation, however, lower doses administered on a regular schedule can be used to manage chronic symptoms. However, electrolyte absorption becomes more of a concern when used chronically, particularly in patients with renal impairment. Magnesium can accumulate in patients with severe renal function. Sodium phosphate products should also be avoided in patients with renal impairment.

This belongs with osmotic agents (sorbitol, lactulose)


Treatment of Constipation with Hyperosmolar Laxatives

Role in Therapy: • Chronic constipation: low doses • Bowel evacuation: high doses of polyethylene glycol (PEG) 3350 with electrolytes (e.g. Colyte®, GoLYTELY®)

Mechanism of Action: • Poorly absorbed agents that retain water in the gut lumen

Agents and Dosing for Chronic Constipation: • Lactulose: 20 – 40 g daily in divided doses • Sorbitol 70%: 20 – 40 g daily in divided doses • Glycerin suppositories: 3 g rectally • Polyethylene glycol 3350: 17 g in 8 oz of fluid (e.g. Miralax)

Adverse Reactions: • Bloating, flatulence, cramps • High doses: diarrhea with electrolyte disturbances


Treatment of Constipation with Hyperosmolar Laxatives

Hyperosmolar laxatives are non-absorbable sugars that draw water into the lumen. They may also lower the pH of the colon and produce peristalsis. In low doses, they can be used in place of a bulk laxative to treat chronically constipated patients. Large doses of PEG 3350 are administered in electrolyte solutions (e.g. Colyte®, GoLYTELY®) as part of bowel preparation protocols.

Lactulose is a semisynthetic disaccharide that is metabolized into hydrogen and organic acids. These acids increase the osmolarity of the colon, altering electrolyte transport and colonic motility. Lactulose is usually well-tolerated but may cause bloating. Sorbitol has been shown to be as effective as lactulose, with a similar side effect profile; however, sorbitol has historically been less expensive than lactulose. Due to their sweet taste, some elderly patients prefer these agents. PEG 3350 is available in powder form for administration with fluid and can be used instead of either lactulose or sorbitol solutions.


Treatment of Constipation with Stimulant Laxatives

Role in Therapy

• Acute constipation • Used on a PRN basis

• Chronic constipation • After trial or consideration of other agents • Used on a regular schedule (e.g. 3-5 days per week)


• Directly stimulating the myenteric plexuses of the colon, increasing motility • Impair active transport mechanisms resulting in retention of water and electrolytes in gastrointestinal contents • Produces a soft stool making combination with a stool softener unnecessary

Agents and Dosing:

• Senna (e.g. Senokot®, Ex-Lax®): • Senna concentrate 374 – 748 mg • Sennosides 8.6-17.2 mg

• Bisacodyl (e.g. Dulcolax®):10 – 30 mg) • Castor Oil: 15- 60 mL


Treatment of Constipation with Stimulant Laxatives

Adverse Reactions:

• Flatulence, cramps • Diarrhea and electrolyte disturbances in higher doses • Chronic use

• Possible dependence (controversial) • Colon pigmentation (unknown significance)

Stimulant laxatives are used when constipating medications must be continued, or acute constipation is non-responsive to other drugs. Their shorter onset of action of 6 to 12 hours allows for their use in acute constipation. These agents exert their effects by directly stimulating the myenteric plexuses of the colon, thus increasing motility. The stimulant laxatives that remain on the US market contain senna or bisacodyl.

Castor oil may have multiple mechanisms of action. It may act as a surfactant, but it also is thought to induce significant water and electrolyte secretion. There is some concern that castor oil could cause destruction of intestinal epithelium. Castor oil has a quick rapid of action and is often reserved for bowel preparation before diagnostic or surgical procedures.


Other Agents Used to Treat Chronic Constipation

Role in Therapy Constipation refractory to other agents.

Examples Lubiprostone (Amitiza®): a prostaglandin E1 derivative

NOTE: Tegaserod (Zelnorm®): a selective serotonin partial agonist was approved for use in women with constipation associated with irritable bowel syndrome. However, it was withdrawn from the market in March, 2007 due to an increased risk of serious cardiovascular adverse events, including myocardial infarction, unstable angina and stroke-associated with the use of the medication.

Many other agents can be used in an attempt to normalize bowel function in patients with chronic constipation. Lubiprostone has received FDA indication for chronic constipation in selected patients. This and other less commonly used agents are most often reserved for patients who have not responded to more conventional therapy.


Guidelines for the Treatment of Constipation

Acute Constipation: • Initial: Tap water enemas, glycerin suppositories, milk of magnesia (MOM), or low dose stimulant laxatives • Follow-up: Implement preventative measures to obtain > 3 stools per week

Impaction: • Initial: Tap water enemas daily until empty with concomitant manual disimpaction

• Sodium phosphate, biphosphate enema, polyethylene glycol may be used cautiously • MOM may be used if necessary

• Follow-up: Enemas for 5-6 weeks after clear, until sensation returns • Contraindicated: Irritants such as magnesium agents, soap water enemas due to ineffectiveness, risk of rupture

Chronic constipation: • Initial: Bulk-forming laxative, hyperosmotic laxative, low dose magnesium hydroxide, or stimulant • Follow-up: Continue therapy, increase dose, or add another initial agent

Opioid-induced: • Initial: Bulk-forming laxative, hyperosmotic laxative or stimulant • Follow-up: Evaluate for impaction and treat.


Guidelines for the Treatment of Constipation

Selection of a treatment plan for constipation should be based on the underlying cause. Even when the cause is known, these treatment plans must be individualized in order to take into consideration care plans for other disorders and the ability of the patient or their caregivers to follow specific treatment requirements. Pharmacological therapies are stratified into acute, chronic, opioid-induced, and impaction. Non-pharmacological therapy should always coincide with pharmacological therapy. Remember to continuously monitor for adverse effects with laxative use.




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Harari D, Gurwitz JH, & Minaker KL.“Constipation in the elderly.” J Am Geriatr Soc.1993;41:1130-1140.

Herndon CM, Jackson KC, Hallin PA. Management of opioid-induced gastrointestinal effects in patients receiving pallitive care. Pharmacotherapy 2002;22(2):240-50.

Landers KT & Elliott DP.“Treatment strategies for the management of constipation in long-term care patients.”Consult Pharm.2000;15(7):725-733.

Locke GR, Pemberton JH, Phillips SF.“AGA technical review of constipation.”Gastroenterology.2000;119:1766-1778.

Monane M, Avorn, J, Beers MH, & Everitt DE.“Anticholinergic drug use and bowel function in nursing home patients.”Arch Intern Med.1993;153:633-638.

Norton C. Constipation in older patients: effects on quality of life. Br J Nurs 2006;15(4):188-92.

Schiller LR.“Clinical pharmacology and use of laxatives and lavage solutions.”J Clin Gastroenterology.1999;28(1):11-18.



Wald A.“Constipation in elderly patients: pathogenesis and management.”Drugs Aging.1993;3(3):220-231.

Whitehead WE, et al.“Constipation and laxative use in the elderly living at home:Prevalence and relationship to exercise and dietary fiber.”J Am Geriatr Soc.1989;37:423.


Diarrhea in the Elderly



• Define diarrhea and its impact on the elderly population.

• List the main signs, symptoms, and complications of diarrhea.

• State the principal causes of diarrhea.

• List diagnostic parameters that indicate the presence of diarrhea and its severity.

• Describe the goals of treatment of diarrhea.

• Explain the importance of oral rehydration therapy in the treatment of diarrhea.

• Compare and contrast commercially available solutions and home preparations for oral rehydration therapy.

• Compare and contrast other pharmacological agents that are commonly used to treat diarrhea, in terms of their effects, dosing requirements, and adverse reactions.

• Identify preventative measures and lifestyle considerations for the elderly.


Introduction to Diarrhea in the Elderly

Defining Characteristics:

• More than 3 bowel movements in 24 hours • Stools containing more than 200 grams • Excess fluidity and decreased consistency

Acute Diarrhea:

• Production of loose stools with excessive frequency or stool output for less than 4 weeks • Acquired through the ingestion of food or water contaminated with pathogenic microbes, or food intolerance.

Chronic Diarrhea:

• Production of loose stools with or without increased stool frequency for more than 4 weeks • Categorized as watery, bloody, or fatty

Epidemiology:

• Common among the elderly • Accounts for nearly 15 deaths per 100,000 adults > 74 years. • Scope of the problem in nursing homes is underreported • 1 of 4 most common causes of infections


Introduction to Diarrhea in the Elderly

Clinically, diarrhea is defined as having more than three bowel movements in a twenty-four hour period, and stools in excess of two hundred grams with excess fluidity and decreased consistency. Diarrhea can be subdivided into acute and chronic diarrhea. An acute episode of diarrhea usually resolves within 1-2 weeks with appropriate medication. Chronic diarrhea lasts more than 4 weeks and is commonly caused by medications or other medical conditions. Diarrhea is very common among the elderly and can be life threatening due to the effects of fluid loss and electrolyte imbalances. The disorder accounts for nearly fifteen deaths per one hundred thousand adults over age 74. The scope of the problem in nursing homes is underreported but remains among the four most common causes of infections.


Clinical Presentation of Diarrhea

Pathogenic Mechanism:

• Large volumes of fluid loss by: • Osmosis: osmotic gradient prevents absorption of water • Active secretion: net luminal secretion of water • Altered motility: rapid gastric emptying • Exudation: bloody, inflammatory

Signs & Symptoms:

• Cramping • Flatulence • Headaches • Abdominal pain • Dizziness • Thirst • Muscle weakness

Duration of Episodes:

• Usually 24 – 48 hours

Complications if Diarrhea is Left Untreated:

• Dehydration • Malnutrition • Incontinence • Secondary renal failure • Congestive heart failure • Cerebral damage

Diarrhea is characterized by large volumes of fluid loss. Osmosis, active secretion, altered motility, and exudation can all contribute to diarrhea. Initial symptoms include: cramping, headaches, abdominal pain, dizziness, and muscle weakness.

Although episodes are usually limited to a twenty-four to forty-eight hour period, the resulting dehydration and electrolyte imbalances may be life-threatening in the elderly, leading to secondary renal failure, heart failure, and cerebral damage.


Etiology of Diarrhea

Infectious:

• Bacterial (e.g., Campylobacter, Clostridium, E. coli, Salmonella, Shigella, S.aureus, C.difficile) • Viral (e.g., adenovirus, rotavirus, calicivirus, coronavirus, Norwalk virus) • Parasitic (e.g., cryptosporidium, Entamoeba histolica, Giardia)

Latrogenic:

• Dietary supplements • Tube feeding • Antibiotics • Certain antacids and acid-suppressing medications • Bulk and osmotically active laxatives (e.g., milk of magnesia (MOM), lactulose) • Other medications (e.g., digoxin, quinidine, methyldopa) • Food intolerance

Gastrointestinal:

• Obstructive lesions • Motility disorders with impaction • Inflammatory bowel disease (Crohn’s disease) • Malabsorption • Mesenteric atherosclerosis and ischemia • Portal hypertension


Etiology of Diarrhea

Systemic:

• Diabetes mellitus • Thyrotoxicosis • Uremia

Neoplastic:

• Obstructive lesions • Secretory adenomas • Hormone-secreting tumors

Common causes of diarrhea include bacterial, viral and parasitic infections, food poisoning, and digestive disorders. Medications such as antibiotics and magnesium containing antacids can also cause diarrhea. The elderly in nursing homes are especially susceptible to causative agents such as the bacterium Clostridium difficile and various viruses.


Diagnostic Indicators of Diarrhea

• Orthostatic changes in blood pressure • Fever, leukocytotsis • Total plasma protein • Plasma specific gravity • Urine tests such as timed sodium, potassium, osmolality • Blood tests to assess fluid and electrolyte abnormalities • Stool culture for enteric pathogens • Flexible sigmoidoscopy (to identify psueomebranes or ischemia) • Physical examination:

• Sunken eyes, complaints of thirst, weakness, weight loss

Diagnostic indicators for diarrhea include orthostatic changes in blood pressure, total plasma protein, and plasma specific gravity. Urine tests such as timed sodium, potassium, and osmolality may also be of value to determine significant volume loss. Utilization of blood tests is necessary to assess for dehydration or anemia. Stool cultures will identify if there is an infectious cause to the diarrhea. Diagnostic testing is often limited and may only indicate that damage has already been done. Initiating treatment early can shorten the course, severity, and recovery time from diarrhea.


Goals of Treatment of Diarrhea

• Provide symptomatic relief • Management of dietary intake • Prevent and restore excessive fluid or electrolyte loss • Treat reversible cause • Manage secondary disorders

Goals of the treatment of diarrhea start with providing symptomatic relief. It is important to identify and control the underlying cause of diarrhea. Maintaining fluid and electrolyte balance is a priority.


Non-Pharmacological Therapy

• Avoid dairy products • Avoid caffeine containing products • Oral rehydration therapy

Further, management of the patient’s dietary intake should include avoidance of dairy and caffeine containing products. As mentioned on the previous screen, it is imperative to increase fluid and electrolyte intake to restore a normal hydration level and prevent further dehydration and electrolyte loss.


Oral Rehydration Therapy (ORT) for Diarrhea

• Most effective treatment for all types of diarrhea • Therapy consists of replacing fluids lost with solutions of appropriate volume and electrolyte components • With severe losses, patients should take sips every 3 – 5 minutes until fluid levels are restored • Replacement of 200 – 400 mLs for every loose stool • Rehydration must begin early in the diarrhea cycle in order to avoid vascular complications and organ damage

Adverse effects of ORT:

• Overhydration • May cause hypernatremia, hyperkalemia, kidney failure, cardiac arrhythmias and congestive heart failure

Monitoring Parameters:

• Urine output should be monitored closely to determine the endpoint of hydration • Goal = urination every 3 – 4 hours with urine specific gravity < 1.015


Oral Rehydration Therapy (ORT) for Diarrhea

The management of diarrhea includes the elimination of symptoms and use of oral rehydration therapies. Complications of severe and moderate diarrhea in the elderly are significantly reduced if oral rehydration solutions are given early and in sufficient quantity.

Care must be taken not to introduce solutions too quickly as vomiting could result. Doses of oral rehydration solutions should be tailored to the individual based on body weight and severity of the diarrhea. Usual replacement for adults is 200-400 milliliters of oral electrolyte solution for every loose stool. Over hydration can lead to hypernatremia, hyperkalemia, kidney failure, cardiac arrhythmias and heart failure.

Urine output must be closely monitored to determine the endpoint of hydration. In general, oral rehydration therapy is adequate if the patient is passing urine every three to four hours and the specific gravity of the urine is less than one-point-zero-one-five. Watery diarrhea may not require any further treatment than oral rehydration therapy.


Contents of Oral Rehydration Solutions


Contents of Oral Rehydration Solutions

There are commercially manufactured solutions for oral rehydration therapy as well as recipes for home preparation. Although many of these preparations have been designed for use in children, they are also appropriate for use in older patients. There are 4 main constituents in these oral rehydration solutions. They include electrolytes such as sodium, potassium, and chloride, bicarbonate as either sodium bicarbonate or sodium citrate to correct or prevent metabolic acidosis, and a carbohydrate source usually given as glucose and water to replace the fluid losses. In many cases, use of these solutions precludes the need for additional medications or antibiotics.


Homemade Oral Rehydration Solutions

Glucose-based:

20 tbs. White Corn Syrup (dextrose) 4 tsp. NaCl 3 tsp. NaHCO3

Sucrose-based (adults only):

6 oz. Table sugar (sucrose) 1/2 oz. NaCl 1/3 oz. NaHCO3 1/5 oz. KCl

Rice-based:

4 oz. Rice Powder (glucose/protein) 1/2 oz. NaCl 1/3 oz. NaHCO3 1/5 oz. KCl

A selection of home preparations for oral hydration therapy is shown on your screen. Sugar or amino acid based solutions enhance sodium absorption, maintain potassium balance, and often contain sodium bicarbonate to correct acidosis. Disaccharide-based (sucrose) solutions form twice as many carbohydrate molecules upon hydrolysis, which lessens the osmotic load placed on the intestinal lumen. Rice-based solutions are as effective as sugar-based solutions and are much less expensive. The starch contained in these solutions is hydrolyzed to glucose and protein.


Treatment of Acute Diarrhea with Bismuth Salicylate (Pepto Bismol®, Kaopectate®)


• Local anti-inflammatory, anti-secretory, and bactericidal activity • Binds to toxins produced by microorganisms • Stimulates the absorption of fluid and electrolytes across intestinal walls

Indications:

• Traveler's diarrhea due to Escherichia coli • Other acute episodes of non-specific diarrhea

Dosing:

• Starting: 30 mL PO or 2 tablets / hour • Max 8 doses every 24 hours until diarrhea stops

• Maintenance: 60 mL PO QID


• Do not use if patient has a hypersensitivity to salicylates or any component of the formulation; history of severe GI bleeding, coagulopathy , or renal failure.

• May potentiate the effects of aspirin and warfarin • May cause black stools or black tongue • Note: each 262.4 mg tablet of bismuth subsalicylate contains an equivalent of 130 mg aspirin.


Treatment of Acute Diarrhea with Bismuth Salicylate (Pepto Bismol®, Kaopectate®)

Contraindications:

• Hypersensitivity to bismuth preparations, aspirin or salicylates

While oral rehydration is the first choice for treating most diarrheas, other medications may be useful in treating specific cases of acute diarrhea. One example is the use of bismuth subsalicylate for relieving traveler’s diarrhea and other non-specific acute diarrhea. Bismuth subsalicylate combines antimicrobial activity with an antisecretory function. Bismuth subsalicylate is initially dosed at thirty milliliters or 2 tablets every hour for up to eight doses in 24 hours or until diarrhea stops. Adverse reactions in the elderly involve immediate salicylate sensitivity and irritation from longer-term use. Utilize caution when patients are using bismuth subsalicylate with other medications as this agent can bind to some medications and decrease absorption of other medications such as warfarin.


Treatment of Acute Diarrhea with Opioids


• Slowing GI motility allowing for greater absorption

Indications:

• Non-specific acute diarrhea

Agents and Dosing:

• Diphenoxylate with atropine (Lomotil®):2.5 – 5 mg PO QID • Difenoxin with atropine (Motofen®):1 – 2 mg PO initially, then 1 mg after each loose stool or every 4 hours

• Max 8 mg per 24 hours • Loperamide (Imodium®):4 mg PO initially, then 2 mg after each loose stool until controlled

• Max16 mg per day • Does not cross the blood-brain barrier

• Paregoric (camphorated opium tincture):5 – 10 mLPO up to every 4 hours. • Contains morphine 0.4 mg/mL and alcohol 45%. • Do not confuse this product with opium tincture which is 25 times more potent

Adverse Drug Reactions: • Anticholinergic effects (diphenoxylate with atropine) • CNS toxicity

• Sedation, confusion • Respiratory depression


Treatment of Acute Diarrhea with Opioids

Contraindications: Patients with diarrhea caused by enteric bacteria or toxic medications

Opioids act by slowing gastrointestinal motility, allowing for greater absorption. They also decrease cramping. Four opioids used in the treatment of diarrhea include: (1) diphenoxylate with atropine; (2) difenoxin, an active metabolite of diphenoxylate, with atropine; (3) loperamide, which is used for chronic diarrhea in certain diseases; and (4) paregoric. If diarrhea is caused by enteric bacteria or toxic medications, use of opioid medications can cause more damage by delaying the elimination of those toxins. Patients purchasing OTC agents should be warned that they should not be used if the diarrhea is from enteric bacteria or toxic drugs..


Treatment of Acute Diarrhea from Clostridium difficile

Cause:

• Diarrhea and colonic inflammation that occur during or shortly after administration of antibiotics or chemotherapy. • Cytotoxin from C. difficile triggers epithelial necrosis and inflammation • Accompanied by fever, leukocytotsis • Relapse rates average 20-25%

Treatment:

• Metronidazole 250mg PO QID for 7-14 days, or • Vancomycin 125mg PO QID for 7-14 days • Cholestyramine resin and Lactobacillus acidophilus have also been used to manage diarrhea which can occur after

antibiotic therapy.


Treatment of Acute Diarrhea with Other Medications

• Polycarbophil, attapulgite and charcoal preparations act as adsorbents of noxious compounds

• Antimotility medications (Hyoscamine sulfate-Levsin®) can decrease the duration of diarrhea, but do not affect the amount of fluid loss

• The use of antibiotics is controversial due to ADRs such as frequent reinfection, “antibiotic diarrhea”, destruction of normal protective gut flora and toxicity of the antibiotics themselves

Polycarbophil, attapulgite and charcoal preparations act as adsorbents of noxious compounds, but because they can interfere with drugs necessary to treat other disorders, they are not widely recommended. Kaopectate formerly contained attapulgite, but recently was reformulated to contain bismuth subsalicylate. Antimotility medications can decrease the duration of diarrhea, but do not affect the amount of fluid loss. The use of antibiotics to treat elderly patients with diarrhea remains controversial. Even when there is clear evidence of invasive processes and specific organisms, the benefits of antibiotics must be weighed against their side effects. Adverse reactions to antibiotic use include frequent reinfection, the so-called “antibiotic diarrhea”, and destruction of normal protective gut flora. It is this kind of disruption of the normal gut flora that can lead to the overgrowth of Clostridium difficile and more serious conditions such as pseudomembranous enterocolitis.


Treatment of Chronic Diarrhea

Agents:

• Bile acid sequestrants: used for diarrhea associated with excess fecal bile acids and pseudomembranous colitis. • Adverse Drug Reactions: GI obstruction

• Opioids: slow down motility of GI tract • Adverse Drug Reactions: sedation, confusion, respiratory depression

• Octreotide: Mimics natural somatostatin by inhibiting serotonin release • Adverse Drug Reactions: bradycardia, fatigue, headache, dizziness, hyperglycemia, GI upset, cholelithiasis.

Treatment of chronic diarrhea is dependent upon controlling the underlying cause. As with acute diarrhea, use of oral hydration therapy is important to keep the patient hydrated. In patients with pseudomembranous colitis or bile acid-induced diarrhea, use of bile acid sequestrants such as cholestyramine, can assist in controlling the diarrhea. Monitor other medications used with bile acid sequestrants as there is the possibility of drug-drug binding thus decreasing absorption. Opioids are the most effective, nonspecific agents. Octreotide should be reserved as a second line agent or in patients with intestinal peptide secreting tumors. Parenteral nutrition is reserved for patients who can not maintain adequate nutritional status with the diarrhea.


When to Seek a Referral

• Unexplained diarrhea >2 weeks • Bloody diarrhea • Fecal incontinence • Secretory diarrhea with dehydration • Fever • Weight loss • Recurrent bouts of diarrhea

Seeking a referral for medical care is dependent upon the elders nutritional and hydration status and other co-morbid conditions. General guidelines include unexplained diarrhea lasting for over 2 weeks, the presence of blood in the stool, high unresolved fever, and increased weight loss. Further medical work-up is necessary in these individuals in order to identify the underlying cause of the diarrhea.


Prevention and Lifestyle Considerations

• Avoid contaminated water and food supplies through proper refrigeration, food preparation, and sanitary practices

• Monitor the use of laxatives, other drugs that may cause diarrhea, and current antibiotics

• Monitor infection control programs within the long term care facility (LTCF)

• Modify diet to increase hydration, maintain normal gut flora, and enhance immune system

• Educate healthcare professionals and the elderly concerning the benefits of oral rehydration therapy

Preventive measures can be taken to avoid outbreaks and recurrence of diarrhea for the elderly living in the community and in the nursing home environment. Proper hand washing techniques, proper food and water preparation, and a healthy diet can help prevent diarrheal infections. The consulting pharmacist can facilitate this process by monitoring for medications that have been implicated in causing diarrhea in the elderly. This includes monitoring the use of laxatives and other medications that can cause diarrhea and current antibiotic therapy.


Resources


American Gastroenterological Association Medical Position Statement:“Guidelines for the evaluation and management of chronic diarrhea.”Gastroenterology.1999;116:1461-1463.

Aranda-Michel J, Giannella RA.“Acute diarrhea: a practice review.”Am J Med.1999;106(6):670-676.

Beers MH & Berkow R.(2000).The Merck Manual of Geriatrics. 3nd edition. Section 13, “Gastrointestinal Disorders.” Whitehouse Station, NJ:Merck Research Laboratories:1000-1154.

Bennett RG & Greenough WB.(1994).“Diarrhea.” In:Hazzard WR, Bierman EL, Blass JP, Ettinger WH, & Halter JB. (Eds.).Geriatric Medicine and Gerontology, 3rd ed.New York:McGraw-Hill:1275-1284.

Duthie EA.(Ed).(1998).Modell’s drugs in current use and new drugs, 44th ed.New York:McGraw-Hill.

Greenough WB, et al.“Causes of diarrhea in the elderly:Impact on intestinal function and treatment by oral rehydration therapy.”Clin Res.1992;40:438.

Holt PR.”Gastrointestinal diseases in the elderly. “Curr Opin Clin Nutr Metab Care.2003;6:41-48.

Lewis JH.(1994).A pharmacologic approach to gastrointestinal disorders.Baltimore:Williams & Wilkins.

Lichtblau L.(1998).Drugs affecting the gastrointestinal tract, lecture from ISAP.


Resources

Margolis S.(Ed.).(1993).The Johns Hopkins handbook of drugs for the 100 major medical disorders of people over the Age of 50. New York:McGraw-Hill. Pizarro D, Posada G, Sandi L, & Moran JR.“Rice-based oral electrolyte solutions for the management of infantile diarrhea.”NEJM.1991;374(8):517-521.

Spruill WJ and Wade WE.“Diarrhea, constipation, and irritable bowel syndrome.” In:Pharmacotherapy: a pathophysiologic approach, 5th ed.Dipiro JT, Talbert RL, Yee GC, et al., eds.New York:McGraw-Hill.2002:655-669.

Online resources: Diarrhea information at: http://www.acg.gi.org/

Lexicomp Online, Lexi-Comp, Inc (2006) http://www.crlonline.com/crlonline

Merck Manual of Geriatrics (2006) http://www.merck.com/mrkshared/mmg/home.jsp


Disorders of the Colon



• Define the major disorders of the colon seen in the elderly and their impact on geriatric health.

• Describe the incidence, common signs and symptoms and causes of diverticular disease.

• List the types of colitis commonly found in the elderly.

• Describe the incidence, common signs and symptoms, and causes of irritable bowel syndrome and inflammatory bowel disease.

• Identify relevant diagnostic tools for identifying colonic disorders seen in the elderly.

• Outline treatment priorities and protocols for elderly patients with diverticular disease and colitis.

• Compare and contrast pharmacological agents used in the treatment of irritable bowel syndrome and inflammatory bowel disease in terms of effectiveness, administration and adverse reactions.


Introduction to Colonic Disorders in the Elderly

Types of Colonic Disorders:

Irritable bowel syndrome (with constipation, accounts for half of elderly GI complaints) Diverticulitis Fecal incontinence Inflammatory bowel disease Ischemic colitis Colorectal cancer

Clinical Presentation and Progression:

Many colonic disorders begin in early adulthood and worsen as aging occurs Symptoms may be treated but recur often with abdominal pain Diverticular disease and forms of colitis may lead to life-threatening conditions such as large GI bleeding and widespread infection Colorectal cancer may metastasize, leading to death


Introduction to Colonic Disorders in the Elderly

Nearly half of all gastrointestinal complaints that bring elderly people to their physician involve constipation or irritable bowel syndrome. Other common colonic disorders in the elderly include diverticulitis, fecal incontinence, inflammatory bowel disease, ischemic colitis, and colorectal cancer. Many of these disorders begin in early adulthood, display a pattern of chronic symptoms, and worsen as aging occurs. Symptoms may be treated but recur often accompanied by abdominal pains.

Diverticular disease and forms of colitis may lead to life-threatening conditions such as large GI bleeding and widespread infection. Colorectal cancer, if left untreated, will likely metastasize and lead to death. A correct diagnosis will allow for care and treatment specific for each patient and to determine if surgical intervention is necessary to avoid more damage to the colon.


Diverticular Disease

Definition: Disease associated with sac-like outpouchings of the gastrointestinal tract, which can trap feces and become infected, bleed, or rupture.

Incidence: Occurs in approximately 30% of the population >45 years old, and 65% of the population over 85 years of age.

Principal Cause: Low intake of dietary fiber leads to formation of abnormal loops and out-pouchings of tissues in the colon; also an inherent weakening of the colonic wall as the GI tract ages.

Signs & Symptoms:

• May be asymptomatic or very painful (only 15-30% of patients experience complications). • Painful diverticular disease presents with tender left lower colon and colicky attacks • Often associated with constipation or diarrhea, and symptoms increase after eating. • Diverticulitis, or infection arising in the diverticula, is mainly found in the sigmoid colon and is indicated by fever,

leukocytotsis, and rebound tenderness. • Bleeding diverticula occurs primarily in the right colon

Diagnosis:

• CT scans to pinpoint acute diverticular problems • Anemia testing to detect large bleeding diverticula • Tests for blood in stool • Flexible sigmoidoscopy • Radiographic barium enema


Diverticular Disease

Diverticular disease describes a range of conditions caused by the formation of abnormal loops and pockets of tissues in the colon. In industrialized countries, at least fifty percent of adults over 70 develop diverticula primarily due to a lack of dietary fiber. The disease may be asymptomatic or very painful. Painful diverticular disease is seen with tender left lower colon and colicky attacks.

Diverticulitis, the inflammation of diverticula, develops in 15-25% of persons with diverticulosis, and occurs mainly in the sigmoid colon . It is caused by an infection and abscess in the diverticula. Bleeding diverticula occurs in the right colon two-thirds of the time and is caused by thinning of the inflamed diverticular walls. CT scans can pinpoint acute diverticular problems while anemia testing can detect large bleeding diverticula. Other diagnostic tools include flexible sigmoidoscopy and radiographic barium enema.


Treatment of Diverticular Disease

Painful Diverticular Disease: usually treated with a high fiber, low irritating diet, and removal of offending medications. Antispasmodics such as dicyclomine or hyoscyamine and NSAID anaglesics may sometimes be used

Acute Diverticulitis: treated with broad spectrum antibiotics such as ampicillin, amoxicillin + clauvulanate, metronidazole, and gentamicin. Oral intake is reduced to clear liquids or eliminated entirely, and analgesics (NSAIDs preferably) can be used for pain

Bleeding Diverticula: conservatively treated unless large and rapid blood loss necessitates surgery

Emergency surgery: required for peritonitis, persistent high-grade bowel obstruction, or rapid GI bleeding.

Diverticular disease is treated conservatively if possible and surgically only as a last resort. Painful diverticular disease without inflammation is mainly treated non-pharmacologically; instituting a high fiber, low irritating diet, and removing drugs with adverse effects can be very effective. Treatment for diverticulitis, when acute, consists of broad spectrum antibiotics such as ampicillin, metronidazole and gentamicin. The patient must be monitored closely for signs of peritonitis and potential need for surgery. Bleeding diverticula should be conservatively treated unless large and rapid blood loss necessitates surgery.


Inflammation of the Colon

Types of Colitis:

• Irritable bowel syndrome (IBS) • Inflammatory bowel disease (ulcerative colitis, Crohn’s disease) • Ischemic colitis • Pseudomembraneous colitis • Necrotizing and cryptosporidium enterocolitis

Presentation and Progression:

• May occur at any age • Causes a wide range of painful and distressing symptoms • Chronic conditions may worsen with age or as a result of certain medications • Treatment must begin when painful symptoms first appear

Inflammation of the colon or colitis describes a variety of disorders in the elderly that include irritable bowel syndrome, inflammatory bowel disease, and various other forms of colitis. Colitis may occur at any age and cause a wide range of painful and distressing symptoms. For the elderly, chronic conditions may worsen simply with age or as a result of medications that irritate the colon. Inflammatory bowel disease and irritable bowel syndrome are disorders that must be treated when painful symptoms appear.


Irritable Bowel Syndrome (IBS)

Definition: Abdominal pain and discomfort with altered bowel habits in the absence of any other mechanical, inflammatory, or biochemical explanation for the symptoms.

Causes: Abnormal increases in spontaneous movement of large and small intestine, caused by:

• Colon muscular disturbances • Enhanced visceral sensitivity • Diet (triggers may include caffeine, corn, citrus, lactose, wheat) • Stress • Depression • Use of laxatives

Progression: Age of onset is bimodal, the first peak occurs during the 20s or 30s, and the second occurs between 50 and 80 years of age. Incidence of problems increase as patients live longer.

Signs & Symptoms:

• Abdominal tenderness, discomfort, or pain for at least 12 weeks in the preceding 12 months • Abnormal stool frequency (greater than three bowel movements per day and less than three bowel movements per

week) • Abnormal stool form (lumpy/hard or loose/watery stool) • Abnormal stool passage (straining, urgency, or feeling of incomplete evacuation) • Flatulence , bloating and distension • Intermittent pain following meals, relieved by bowel movements • Nausea and loss of appetite


Irritable Bowel Syndrome (IBS)

Diagnosis: Dependent on symptoms, medical history, and ruling out other problems.

Irritable bowel syndrome, known also as functional colitis or spastic colon, is defined as abnormal increases in spontaneous movement of the large and small intestine. These movements may be caused by colon muscular disturbances, enhanced visceral sensitivity, and factors such as diet, stress, depression, and laxative use. Irritable bowel syndrome is seen more frequently in females, and may begin around the ages of twenty or thirty.

Symptoms can be either constipation-predominant, diarrhea- predominant, or alternating diarrhea-constipation. The main symptoms include persistent abdominal discomfort, abnormal stool frequency and consistency, flatulence, bloating, distension, and intermittent pain following meals but relieved by bowel movements.

Definitive diagnosis depends on symptoms, medical history, and the exclusion of any other mechanical, inflammatory, or biochemical explanations..


Treatment of Irritable Bowel Syndrome

Non-pharmacological Treatment:

• Increase dietary fiber (most beneficial for constipation-predominant IBS) • Remove stimulants, irritants and dietary triggers from diet • Use stress reduction, psychotherapy, and relaxation techniques

Pharmacological Treatment: Treatment is dependent on the type of IBS - either diarrhea-predominant or constipation-predominant or diarrhea alternating with constipation symptoms.

Diarrhea-predominant: • Antispasmodic/anticholinergic medications: • Alosetron: Selective 5-HT3 Receptor Antagonist

• Treatment of women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have failed to respond to conventional therapy • Do not start treatment in patients who are constipated • Safety and efficacy have not been established in males • Only physicians enrolled in GlaxoSmithKline's Prescribing Program for Lotronex® may prescribe this medication

• Loperamide: maintenance dose should be slowly titrated downward to minimum required to control symptoms (typically, 4-8 mg/day in divided doses) • Tricyclic antidepressants: slow intestinal transit time, relief of pain and discomfort.

• Use with caution in the elderly- may cause drowsiness, dizziness, blurred vision, dry mouth, difficult urination


Treatment of Irritable Bowel Syndrome

Constipation-predominant:

• Serotonin 5-HT4 Receptor Agonist: tegaserod (Zelnorm®), • Withdrawn from the market March, 2007 due to an increased risk of serious cardiovascular adverse events,

including myocardial infarction, unstable angina and stroke-associated with the use of the medication. • Fiber supplements

Irritable bowel syndrome is treated by reducing symptoms. Non-pharmacologic treatment includes dietary changes such as increasing fiber, eliminating stimulants like caffeine, and removing irritants such as spices and sweets. Also, stress reduction such as meditation, exercise, or counseling can help reduce triggers such as anxiety and depression which may aggravate symptoms.

Pharmacological plans involve monitoring and removal of irritating medications, including those that cause constipation and/or diarrhea. Anticholinergic medications are sometimes effective in reducing smooth muscle contractility or hyperreactivity although these drugs have potentially dangerous side effects.. Alosetron, a selective and potent inhibitor of serotonin 5-H-T-3 receptors is indicated for the use of diarrhea predominant IBS and is only indicated for use in women.. Only physicians entered into an industry sponsored program can prescribe alosetron, and patients must understand and comply with a “Patient-Physician” agreement .


Treatment of IBS with Anticholinergic Medications

Agents:

• Quaternary Ammonium Compounds: • Methscopolamine (Pamine®) • Methantheline (Banthine®) • Propantheline (Pro-Banthine®) • Anisotropine methyl (Valpin®) • Clidinium (Quarzan®) • Glycopyrrolate (Robinul®) • Isopropamide (Darbid®) • Mepenzolate (Cantil®) • Tridihexethyl (Pathilon®)

• Tertiary Amine Compounds: dicyclomine (Bentyl®) • Other Agents: hyoscyamine (Levsin®)

Administration Guidelines:

• Start low and go slow • Administer before mealtime • Use with caution in elderly patients, due to increased sensitivity to adverse effects.

Adverse Drug Reactions: May cause confusion, drowsiness, dizziness, blurred vision, dry mouth, difficult urination. With larger doses: pupillary dilation , tachycardia sweating.


Treatment of IBS with Anticholinergic Medications

Anticholinergic medications used in the treatment of irritable bowel syndrome differ in structure and properties. Quaternary ammonium structures have prolonged action and greater effect on gastrointestinal activity. Recommended doses are more readily tolerated than other agents of this type. Tertiary amine antimuscarinic compounds such as dicyclomine hydrochloride tend to have greater antispasmodic properties.

Newer anticholinergic agents such as hyoscyamine sulfate have been found to reduce abdominal pain, bloating, and diarrhea episodes. Anticholinergic medications should be administered cautiously at the lowest effective doses before meals. The elderly are particularly susceptible to anticholinergic medications, including CNS sedation, constipation, urinary retention, and dry mouth.


Inflammatory Bowel Disease – Crohn’s Disease

Definition: A chronic process most often affecting the terminal ileum or colon characterized by inflammation, ulceration, and granulomas.

Cause: An autoimmune response thought to be due to hereditary factors; results in the thickening and ulceration of colon walls, primarily at the junction of the small and large intestine

Signs & Symptoms:

• Abdominal pain, often in lower right quadrant; although left-sided colitis appears to be prevalent in elderly women. • Bowel sounds (borborygmus) • Fever • Diarrhea • Weight loss • GI bleeding • Painful and foul smelling stools • Fecal Incontinence

Diagnosis:

• Colonoscopy techniques with biopsy • Upper and lower GI contrast radiography • CT and ultrasound • Enteroclysis (contrast image of small intestine) • CBC for anemia, leukocytosis; ESR, albumin • Stool guaiac tests and cultures to rule out other infections


Inflammatory Bowel Disease – Crohn’s Disease

Inflammatory bowel disease includes Crohn’s disease and ulcerative colitis. Crohn’s disease may be seen at any age and can worsen as the GI tract ages. It can occur anywhere along the GI tract between the mouth and the anus as patches of inflammation and ulcerations. Frequently found at the junction of the small and large intestine, the colon walls become thick and contain deep ulcerations. The disorder appears to be genetic in origin with family history of Crohn’s and Jewish ancestry as factors.

Symptoms include abdominal pain, mass and bowel sounds, fever, diarrhea, and weight loss. GI bleeding and fecal incontinence are also common. In later years, the disease becomes difficult to manage. Diagnosis of Crohn’s disease can be aided by endoscopic techniques with biopsy, upper and lower contrast radiography and enteroclysis. Also helpful are complete blood cell counts for anemia and infection, stool guaiac tests, and stool cultures to rule out other infections.


Treatment of Crohn’s Disease

Therapeutic Goals:

• Control inflammation • Correct nutritional deficiencies • Alleviate symptoms

Nutritional Interventions:

• Ensure adequate calories, vitamins, and protein • Avoid foods and substances that aggravate diarrhea and other symptoms • Avoid blockages by eliminating raw fruits and vegetables and hard to digest foods such as milk products.

Pharmacological Interventions:

• Monitoring and removal of irritating medications • Anti-inflammatory agents to control flare-ups • Use of antibiotics if abscesses are present • Use of other pharmacological options such as immunopsuppressants and monoclonal antibodies .

Surgical Interventions: Crohn’s disease is not cured by surgery, but it may be necessary if the patient is unresponsive to other treatments.


Treatment of Crohn’s Disease

Most treatment plans for Crohn’s disease seek to control inflammation, correct nutritional deficiencies, and alleviate symptoms. Dietary intake must ensure adequate calories, vitamins, and protein but not enhance symptoms like diarrhea. Blockages may be avoided by eliminating raw fruits and vegetables and hard to digest foods such as milk products.

Irritating medications should be avoided or removed. Pharmacological treatment is based on the severity of symptoms, bleeding, and infection. Patients that do not respond to pharmacological treatment may also require surgical intervention; but surgery does not cure the patient of Crohn’s disease.

Removal of blockages, diverticula, and non-functional portions of the intestines are difficult procedures for elderly patients and demand close post-operative monitoring to avoid infections and nutritional deficiencies.


Pharmacological Treatment of Crohn’s Disease with Aminosalicylates (5-ASA)

Sulfasalazine (Azulfidine®):

• Dosage: titrate dose slowly up to 2-4g per day in divided doses with food; dose should be reduced for renal insufficiency.

• ADRs: allergic skin reactions, headache, diarrhea, nausea and vomiting, agranulocytosis, anemia, folate deficiency.

Mesalamine (Asacol®, Pentasa®, Rowasa®):

• Dosage: • Asacol®:1.6 – 4.8g/day in divided doses • Pentasa®:2-4g/day in divided doses • Rowasa®:1 suppository BID; 60 ml enema QHS

• ADRs: • nausea/vomiting, headache, rash, abdominal pain, colitis flare. •  Postmarketing reports suggest an increased incidence of blood •  dyscrasias in patients >65 years of age

Olsalazine (Dipentum®):

• Dosage: slowly titrate to 1-3g/day in divided doses with food • ADRs: profuse watery diarrhea, nausea/vomiting, blood dyscrasias.


Pharmacological Treatment of Crohn’s Disease with Aminosalicylates (5-ASA)

Aminosalicylates are considered first line treatment for Crohn’s disease. Choosing the appropriate 5-ASA depends on the location of the inflammation, since each product’s site of action on the colon is different. Oral administration of mesalamine, sulfasalazine, and osalazine has been shown to help patients with mild to moderate symptoms.

In studies of patients on sulfasalazine therapy, success rates were higher with six grams than with four grams per day, however, side effects such as skin reactions, headache and diarrhea also increased. Five hundred milligrams twice daily is recommended, gradually increased to two to four grams in divided doses per day with food. Patients with hypersensitivity to sulfa drugs should not take sulfasalazine, and all patients should be asked about salicylate allergies before therapy is initiated.


Pharmacological Treatment of Crohn’s Disease with Prednisone, Immunosuppressants and Infliximab (Remicade®)

Prednisone: • Dosage: 20-30mg BID , tapered down by 5-10 mg/week as symptoms subside. • ADRs: Hyperglycemia, skin atrophy, mood swings, insomnia, edema, osteoporosis

Azathioprine (Imuran®): • Dosage (unlabeled use): 50 mg daily; may increase by 25 mg/day every 1-2 weeks as tolerated to target dose

of 2-3 mg/kg/day; reduced dose for renal insufficiency. •  ADRs: blood dyscrasias, liver abnormalities, nausea/vomiting/diarrhea, neurological disturbances, emotional

and metabolic disturbances. • Black Box Warning: Chronic immunosuppression increases the risk of neoplasia and serious infections.

Other agents: cyclosporine (Sandimmune®), budesonide (Entocort EC®), mercaptopurine(Purinethol®)

Infliximab (Remicade®): • Mechanism of Action: blocks intestinal inflammation by binding to and neutralizing tumor necrosis factor alpha (TNF-alpha) and TNF-alpha-producing cells

• Dosage: 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 8 weeks thereafter. If no response by week 14, consider discontinuing therapy.


Pharmacological Treatment of Crohn’s Disease with Prednisone, Immunosuppressants and Infliximab (Remicade®)

ADRs/ Black Box Warnings: Infections: Serious and potentially fatal infections (including sepsis, pneumonia, and invasive fungal and other opportunist infections) have been reported in patients receiving TNF-blocking agents. T-cell lymphoma has been reported (rarely) in adolescent and young adults with Crohn’s disease treated with infliximab and azathioprine or 6-mercaptopurine. Reactivation of latent infections have been associated with infliximab therapy. Blood dyscrasias, liver toxicities, anaphylactic reactions

Azathioprine has been found to be beneficial in the treatment of Crohn’s disease through its steroid sparing and anti-inflammatory activity. Other immunosuppressants such as cyclosporine and budenoside may also be considered for treatment of more severe cases of Crohn’s disease; however, the patient must be carefully monitored for neurological and metabolic side effects. In patients with treatment-resistant disease, a newer drug, infliximab, was shown to relieve symptoms in fifty to eighty-nine percent of patients.

Patients showed signs of relapse eight to twelve weeks after a single infusion but responded to additional infusions of the drug. Infliximab is believed to block intestinal inflammation by binding to and neutralizing TNF-alpha on the cell membrane and in serum and by destroying the TNF-alpha-producing cells. Many of these immunomodulating medications can cause blood dyscrasias and hepatotoxiciy,, so appropriate monitoring should be maintained.


Inflammatory Bowel Disease – Ulcerative Colitis

Definition: A chronic inflammatory process that causes ulcers and irritation in the inner lining of the colon and rectum. The inflammation may extend to varying degrees into the upper parts of the colon. When the entire colon is involved, the terms pancolitis or universal colitis are used. When the inflammation is limited to the rectum, it is called ulcerative proctitis.

Cause: Thought to be an autoimmune response, resulting in inflammation and ulceration in the top layers of the mucosal lining of the colon

Signs & Symptoms:

• Abdominal pain, often in lower right quadrant • Diarrhea, with or without blood in the stool • Fatigue • Loss of appetite • Weight loss • Rectal bleeding • Fever

Diagnosis:

• CBC for anemia • Stool tests to check for bleeding in colon or rectum • Stool cultures (to rule out infectious agents) • Endoscopic techniques with biopsy • Barium enema x-ray


Inflammatory Bowel Disease – Ulcerative Colitis

Like Crohn’s disease, ulcerative colitis is an autoimmune disorder that causes inflammation in the upper layers of the intestinal mucosa. Although it usually occurs in the lower part of the colon and rectum, ulcerative colitis may affect the entire colon. The most common symptoms of ulcerative colitis are abdominal pain and bloody diarrhea. Patients with mild cases may complain of fatigue, weight loss, and rectal bleeding, while patients with more severe disease may experience frequent fever and nausea.

As the immune response triggers inflammation in other parts of the body, complications such as arthritis, liver disease, and kidney stones arise. Blood tests may be done to check for anemia, which could indicate bleeding in the colon or rectum. Stool samples should also be checked for blood. Toxic megacolon, a serious complication of ulcerative colitis, occurs more often in elderly patients; symptoms include abdominal distention, high fever, and overall deterioration of condition.


Treatment of Mild to Moderate Ulcerative Colitis

Nutritional Interventions:

• Ensure adequate calories, vitamins, and protein • Avoid foods that aggravate diarrhea and other symptoms • Avoid blockages by eliminating hard-to-digest foods


• Monitoring and removal of irritating medications • Use of aminosalicylates for mild to moderate disease • Balsalazide (Colazal®)

• MOA: non-sulfa 5-aminosalicylic acid prodrug of mesalamine; releases the anti-inflammatory mesalamine in the colonic lumen; useful in patients with sulfasalazine intolerance

• Dosage: acute – 2.25g TID; maintenance – 3 or 4g/day (twice-daily dosing) • ADRs: less adverse effects than sulfasalazine; headache, nausea, diarrhea, abdominal pain, rash


Treatment of Mild to Moderate Ulcerative Colitis

Like Crohn’s disease, treatment for ulcerative colitis depends on the seriousness of the disease. Dietary interventions include the avoidance of irritating foods and medications. Pharmacotherapy typically involves the initial use of aminosalicylates such as sulfasalazine or the newest approved drug, balsalazide . Balsalazide is a non-sulfa prodrug and has been shown to be better tolerated than sulfasalzine for patients with mild to moderate disease.


Treatment of Severe Ulcerative Colitis


Corticosteroids: (oral or rectal) • Dosage:

• Prednisone 20-30mg BID orally , tapered down by 5-10 mg/week as symptoms subside. • Hydrocortisone: 10-100 mg 1-2 times/day for 2-3 weeks • Toxic megacolon: hospitalization + IV corticosteroids

• ADRs: Hyperglycemia, skin atrophy, mood swings, insomnia, edema, osteoporosis.

Azathioprine (Imuran®): • Dosage (unlabeled use): 50 mg daily; may increase by 25 mg/day

• every 1-2 weeks as tolerated to target dose of 2-3 mg/kg/day; • reduced dose for renal insufficiency.

• ADRs: blood dyscrasias, liver abnormalities, nausea/vomiting/diarrhea, neurological disturbances, emotional and metabolic disturbances. • Black Box Warning: Chronic immunosuppression increases the risk of neoplasia and serious infections.


• The only cure • Required in 25-40% of cases • Proctocolectomy with ileostomy is most common


Treatment of Severe Ulcerative Colitis

Patients with more severe disease who do not respond to aminosalicylates or balsalazine may be treated with corticosteroids such as prednisone and hydrocortisone. These drugs may be administered orally or rectally for short-term therapy; however, patients must be closely monitored for side effects such as weight gain, hypertension, mood swings and infection. About twenty-five to forty percent of patients with ulcerative colitis require a proctocolectomy or other surgical interventions due to massive bleeding, ruptured colon, or risk of cancer.




Barrett, J. A.(1992). ABCs of colorectal diseases: colorectal disorders in the elderly. Brit Med J; 305(6856): 764-6.


Cheskin, L.J. & Schuster M. M.(1994). Colonic Disorders, In Hazzard, W. R., Bierman, E.L., Blass, J. P., Ettinger, W. H. & Halter, J. B. (Eds.). Geriatric Medicine and Gerontology, 3rd ed.New York:McGraw-Hill::723-32

Dominguez E.P. & Sweeney J.F. (2006) Diagnosis and management of diverticulitis and appendicitis. Gastroenterol Clin N Am; 35:367-391.

Ehrenpreis E.D. (2005) Irritable bowel syndrome:10-20% of older adults have symptoms consistent with diagnosis. Geriatrics. 60(1): 25-28.

Hadley S.K & Gaarder S.M. (2005). Treatment of irritable bowel syndrome. Am Fam Physician; 72:2501-2506.


Rockey, D. C., et.al.(1998). Relative frequency of upper gastrointestinal and colonic lesions in patients with positive fecal occult-blood tests. N Engl J Med; 339:153-9.

Shaker R. (1998). Duthie: Practice of Geriatrics, 3rd ed. Chapter 46: Gastroenterologic Disorders. W. B. Saunders Company. .



Web Sites:

Diverticulosis and Diverticulitis

Lexicomp Online, Lexi-Comp, Inc (2006)

Merck Manual of Geriatraics (2006)

PharmInfo Net’s Gastrolinks – Listing By Disease

The Merck Manual of Geriatrics Online (2006)


Hepatobiliary Disorders in the Elderly

Learning Objectives


• Define and list the most common hepatobiliary disorders seen in the elderly.

• Describe clinical presentation and progression ofliver cirrhosis.

• Describe diagnostic indicators and treatment options used to diagnose and manage elderly patients with cirrhosis.

• Describe the clinical presentation and progression of biliary obstructions and gallbladder disease.

• Describe diagnostic indicators and treatment options used to diagnose and manage elderly patients with biliary obstruction or gallbladder disease.

• Describe clinical presentation and progression of pancreatitis.

• Describe diagnostic indicators and treatment options used to diagnose and manage elderly patients with pancreatitis.


An Overview of Major Hepatobiliary Disorders

Incidence and Impact:

• Hepatobiliary disorders are common among the elderly • Cirrhosis is 5th leading cause of death in men, 6th in women • Most common surgery in the elderly is cholecystectomy, with > 500,000 performed annually in the U.S.

Progression and Presentation:

• Many disorders develop slowly, becoming symptomatic only later in life • Liver function tests (LFTs) may be normal until threshold of damage is reached

Major Disorders That Affect the Elderly:

• Cirrhosis of the liver (alcoholic liver disease and primary biliary cirrhosis) • Biliary obstructions • Gallbladder disease (e.g., cholecystitis, cholelithiasis and choledocholithiasis) • Pancreatitis • Bacterial and viral liver infections • Drug-induced liver disease • Cancer of liver and surrounding areas


An Overview of Major Hepatobiliary Disorders

Etiological Factors:

Bacterial or viral exposure Drug toxicity from prescribed and OTC medications Alcohol and drug abuse Dietary intake related to toxicity and stone formation

In the geriatric population, hepatobiliary disorders are commonplace. For those between the ages of fifty-five and seventy-four, cirrhosis is the fifth leading cause of death in men and the sixth leading cause in women. The most common surgery in the elderly is cholecystectomy, performed at least a half a million times annually in the United States alone.

Slow to develop, hepatobiliary disease is often undetected until symptoms begin making their appearance in late adulthood. Because of the built-in redundancy and capacity of the liver, liver function tests often remain normal until a threshold of damage is reached. This damage results in major disorders such as cirrhosis, biliary obstructions and cholecystitis. Medication-induced injury to the liver and other tissues are a major etiological factor in these disorders, as well as bacterial or viral exposure, alcohol abuse and dietary intake.


Cirrhosis of the Liver

Definition: A chronic disease leading to liver tissue damage, reduced function, scarring and portal hypertension

Causes:

• Excessive alcohol or drug use • Biliary disease (autoimmune in origin, more common in women) • Viral and non-viral hepatitis • Obstructions and stenosis • Drug-induced damage • Heart and other circulatory failure • Liver abscess and sepsis • Cancer related problems • Nutritional deficiency

Cirrhosis of the liver is a chronic disease leading to liver tissue damage, reduced function, scarring, and portal hypertension. The disorder is seen frequently in the geriatric population, most often associated with the long-term abuse of alcohol and drugs. However, there are numerous causes for liver cirrhosis; the type of cirrhosis depends on the underlying causes of the liver damage. The most common causes are listed above.


Hepatotoxic Medications

Decreased hepatic volume and decreased blood flow with increased age may predispose the elderly to more frequent drug-related liver problems. Medications may cause damage to the liver in different ways:

• Damaging the liver cells directly (hepatotoxicity) • Causing cholestasis, or impairment /lack of bile flow) • Through a combination of both hepatoxicity and cholestasis. • Through immume-mediated hypersensitivity.

Commonly Used Hepatotoxic Drugs:

• Acetaminophen • ACE inhibitors • Allopurinol • Amoxicillin and clavulanic acid • Amiodarone • Anesthetic agents • Androgenic steroids • Azathioprine • Carbamazepine • Dantrolene • Erythromycin • Estrogens and oral contraceptives • Isoniazid • Ketoconazole

• Methyldopa • Nevirapine • Nitrofurantoin • NSAIDs • Oral hypoglycemic agents • Penicillins • Phenothiazines • Phenytoin • Prochlorperazine • Propylthiouracil • Sulfonamides • Tamoxifen • Tricyclic antidepressants • Valproic Acid

Commonly used medications can potentially have toxic effects on liver function, leading to injury and liver disease. Many of these medications are listed on your screen. Careful dosing and monitoring should be implemented when these drugs are used in the elderly.


Clinical Presentation and Progression of Cirrhosis

Signs and Symptoms:

• Weight loss and anorexia • Nausea • Vomiting • Weakness and fatigue • Jaundice (yellowing of the skin) • Edema • Abdominal pain • Indigestion • Ascites • Spider angiomas • Pale or clay-colored stools • Impotence • Confusion and sleep disturbances (hepatic encephalopathy)

Complications:

• Bleeding disorders (e.g., coagulopathy, esophageal ) • Fluid accumulation/ascites • Osteoporosis • Encephalopathy • Liver failure • Death

Typical symptoms of cirrhosis include weight loss, nausea, vomiting, and weakness. Ascites, edema, and abdominal pain are also common. If left untreated, cirrhosis of the liver can lead to vitamin deficiencies, bleeding disorders, encephalopathy, liver failure and death. Prognosis is poor in advanced cirrhosis, with a fifty-percent survival rate after two years. Survival in alcohol related cirrhosis depends on severity of the disease prior to stopping the use of alcohol.


Diagnostic Indicators of Cirrhosis

• Anemia on a complete blood cell count (CBC) • Elevated liver enzymes (may be low with advanced chronic disease) • Elevated bilirubin fractions • Prolonged coagulation tests • Low serum albumin • Elevated IgM and IgG • Presence of antimitochondrial antibody • Blood ammonia – associated with hepatic encephalopathy • Liver biopsy indicating cirrhosis

Cirrhotic damage may not be detected until routine tests of liver enzymes show elevated values. Diagnostic examination and X-rays may reveal an enlarged liver, with additional test results showing anemia, abnormal coagulation, low serum albumin, and elevated immunoglobulins. Other blood, urine and body fluid tests can refine the diagnosis and rule out other conditions. After long standing disease the LFTs may be low or normal. This is a bad prognostic sign.


Treatment of Chronic Cirrhosis

Goals:

• Inhibit progress of disease • Minimize damage to liver cells • Reduce complications

Interventions:

• Stop the use of alcohol or hepatotoxic drugs • Avoid excessive use of acetaminophen • Vitamin supplements (including Vitamin K) • Diet modification • Observation for fluid accumulation, peritontits, and encephalopathy

Treatment of cirrhosis is aimed at inhibiting its progress, minimizing damage to liver cells, and reducing complications. For many drug-induced cases, removing the offensive agent will allow for healing and a return of full liver functioning. Treatment plans for chronic cirrhosis focus on the prevention of fluid imbalances, encephalopathy, and coma. They involve vitamin therapy, sodium-restricted-low protein diet and rest. Patients must be watched for spontaneous peritonitis, which can occur with ascites.


Treatment of Acute Cirrhosis

Nutritional/Pharmacological Interventions

Liver disease can affect the body in a variety of ways, including bleeding disorders, fluid imbalances, and acute mental status changes from encephalopathy. Consequently, treatments will depend on which symptoms are present.

Bleeding disorders (e.g., coagulopathy, esophageal varices): • Vitamin K supplementation • Beta-blocker or isosorbide mononitrate to reduce portal hypertension and risk for esophageal varices

Fluid accumulation/Ascites: • Diet modifications to improve nutrition • Low sodium (<2000mg/day) • Low protein (20 to 40 g/day) • Fluid restriction • Diuretic use (spironolactone 100-300 mg/day in divided doses to reduce ascites without decreasing potassium; hydrochlorothiazide or furosemide may be added) • Antibiotic use for prevention or treatment of bacterial peritonitis

Encephalopathy: • Lactulose 30-45ml PO TID to QID (enough to produce 2 or 3 loose stools per day • Neomycin 4-12g PO per day in divided doses


Treatment of Acute Cirrhosis

Viral Hepatitis: Interferon therapy • Treatment of chronic hepatitis B or C, alone or in combination with ribavirin. • Interferon Alfa, Peginterferon Alfa, Ribavirin


• Liver resection • Transjugular intrahepatic portalsystemic shunt (TIPS) to relieve esophageal varices due to portal hypertension

Patients with acute disease and serious complications require pharmacotherapy, surgery and/or blood transfusions. For example, oral neomycin is often given in divided doses to reduce bacterial toxins, while thirty to forty-five grams of lactulose helps reduce serum ammonia buildup.Beta blockers may be prescribed to reduce portal hypertension and the risk of varices. Potassium-sparing diuretics such as spironolactone can be used to reduce ascites and edema without decreasing potassium.

For viral cases, interferon therapy can be used to prevent further disease progression. Although sometimes used to treat acute alcohol-induced liver damage, corticosteroids such as prednisone and methylprednisolone are generally avoided in the elderly due to their side effects.


Biliary Obstruction and Choledocholithiasis

Definition: Choledocholithiasis is the general term for blockage of any ducts that carry bile from the liver to the gallbladder, or from gallbladder to the small intestine

Causes:

• Gallstones • Tumors • Cysts • Inflammation • Enlarged nodes in the porta hepatis • Pancreatitis • Trauma (e.g., surgery, accident)

Obstruction of the ducts leading to and from the gallbladder is usually caused by gallstones. Tumors, cysts, and enlarged nodes in the porta hepatis may also play a role. While these kinds of obstructions can usually be resolved, delays in treatment can lead to complications such as liver disease, cirrhosis and cancer, which are often difficult to treat.


Presentation and Diagnosis of Choledocholithiasis

Signs and Symptoms:

• Jaundice • Dark urine • Pale stools • Constant itching • Upper right quadrant abdominal pain • In a minority of patients, pain can be reported in the epigastrum, chest or upper abdomen

Diagnostic Tests and Indicators:

• Increased bilirubin fractions • Increased liver enzymes • Increased alkaline phosphatase and isoenzymes • Increased urine bilirubin • Endoscopic retrograde cholangiopancreatography (ERCP) ultrasound, and percutaneous transhepatic cholangiograms will confirm diagnosis • ERCP (endoscopic retrograde cholangiopancreatography) is the gold standard test.

Symptoms of choledocholithiasis include jaundice, dark urine, pale stools, constant itching and upper right quadrant abdominal pain. Test results may show elevated bilirubin fractions, liver enzymes, alkaline phosphatase and isoenzymes, and urine bilirubin. Tests such as endoscopic retrograde cholangiopancreatography, ultrasound, and percutaneous transhepatic cholangiograms can be used to confirm diagnosis.


Treatment of Choledocholithiasis

• Endoscopic sphincterotomy • Extracorporeal shock wave lithotripsy • Direct laser lithotripsy • Electrohydraulic lithotripsy

For the elderly with choledocholithiasis or stones in the bile duct, endoscopic sphincterotomy can avoid major surgery and is successful at least seventy-four percent of the time. Although the procedures take some time, older patients can also use extracorporeal shock wave lithotripsy and direct laser or electrohydraulic lithotripsy. Once the obstruction is cleared, underlying causes such as gallbladder disease must be addressed.


Cholelithiasis

Pathogenesis: Gallstones containing cholesterol, calcium, bile salts and protein in varying amounts impair gallbladder function and produce obstructions in ducts. The chance of having gallstones increases with age; 10-15% of men and 25% - 30% of women will eventually develop gallstones.

Risk Factors Associated with Formation of Gallstones:

• Diabetes mellitus • Female gender • Cystic fibrosis • High fat, low fiber diet • Obesity • Prolonged fasting • Total parenteral nutrition • Rapid voluntary weight loss • Oral contraceptive use • Hyperlipidemia

Signs and Symptoms:

• Severe right upper or upper middle abdominal pain following meals and taking deep breaths • Nausea • Vomiting • Heartburn, chills and shaking


Cholelithiasis

Diagnostic Methods:

• Ultrasound (effective in 93% of cases) • Oral cholecystography (effective in 65% of cases) • CT scan showing stones or common bile duct dilatation (present in 75% of patients, but not a definitive diagnosis) • Laboratory abnormalities- In patients with simple acute cholelithiasis there may not be marked laboratory

abnormalities. However, if an infection ensues (cholangitis), pain, fever, and lab abnormalities will be present in a majority of cases.

• Other radiographic techniques

Cholelithiasis or the presence of gallstones is the source of most gallbladder disease in the elderly. While many patients are initially asymptomatic, the onset of symptoms can be quite severe, especially after a meal containing fatty foods. These symptoms include nausea, vomiting, heartburn, chills and shaking. Abdominal ultrasound is successful in detecting gallstones ninety-three percent of the time while oral cholecystograms will detect them sixty-five percent of the time.


Treatment of Cholelithiasis

Surgical: Cholecystectomy remains the most consistently effective treatment

Pharmacological: Oral bile acid acids may be used to dissolve gallstones but have limited effectiveness; agents include:

ursodiol (Actigall®): 8-10 mg/kg; headache, dizziness, and constipation possible.

Elderly patients with stones but no symptoms are usually not treated. Non-surgical treatment of symptomatic cholelithiasis includes dissolution with the oral bile acid solutions ursodiol. Unfortunately, this therapy is not typically used since it is time-consuming and successful in only twenty-nine percent of cases after one year. Instead, cholecystectomy remains the medical standard for dealing with the problem.


Cholecystitis

Definition: An infection of the gallbladder initiated by an obstruction of the cystic duct

Primary Cause: Calculi in the cystic duct

Signs and Symptoms:

• Abdominal tenderness and pressure • Disorientation • Toxic appearance • Low-grade temperature • Leukocytosis

Complications:

• Empyema, perforation, gangrene (40%) • Subphrenic, subhepatic or liver abscesses (15%)

Cholecystitis develops after calculi or inflammation blocks the cystic duct, resulting in infection. The cause of the blockage is usually calculi in the cystic duct itself, producing a lack of drainage and resulting pressure. The presentation of cholecystitis may be subtle in elderly patients; abdominal tenderness and pressure present in only half of the patients. Disorientation and a toxic appearance may be accompanied by a low-grade fever despite acute underlying infection. About forty percent of acute cases show empyema, perforation or evidence of gangrene, and fifteen percent have subphrenic, subhepatic or liver abscesses.


Diagnosis and Treatment of Cholecystitis

Diagnostic Methods and Indicators:

• Tests for elevated white cell count and anemia • Abdominal CT scan • Radiography • Ultrasound • Oral cholecystogram • Anaerobic and aerobic blood cultures

Surgical Treatment:

• Surgery is the only effective way to remove infection • 10% mortality rate in patients > 65 years

Pharmacological Treatment:

• Antibiotic therapy must account for a wide variety of organisms and target areas • Infections such E. coli and Klebsiella sp. may be treated by specific antibiotic therapy • Anaerobes are more difficult to treat

Diagnostic methods for detecting cholecystitis include tests for elevated white cell count and anemia. Abdominal CT scan, radiography, ultrasound and oral cholecystogram are also useful. Cholecystitis is difficult to diagnose, and the only effective way to remove infected tissue is surgery. Combinations of antibiotics have proven effective when matched to common organisms such as E. coli and Klebsiella sp. However, anaerobes are also frequently found, making treatment more difficult. In general, antibiotic therapy must account for a wide variety of organisms and target areas in cases of cholecystitis.


Pancreatitis

Definition: An infection, inflammation or irritation of the pancreas

Incidence: More common in elderly men

Causes: • Gallstones • Alcohol abuse • Viral infections • Surgery or trauma ( i.e. steering wheel injury) • Medications

• Acetaminophen • Azathioprine • Corticosteroids • Didanosine • Estrogens • Furosemide • Metronidazole • Pentamidine • Salicylates • Sulfonamides • Tamoxifen • Tetracycline • Thiazide diuretics • Valproic acid

Pancreatitis is an infection, inflammation or irritation of the pancreas which presents as either a chronic or acute disease, or as a pancreatic abscess. The disease is commonly seen in the elderly, especially elderly men. The most common causes of pancreatitis in the elderly are gallstones, alcohol abuse, , surgery and medications. Several medications implicated in the acute pancreatitis can be found above.


Presentation and Diagnosis of Pancreatitis

Signs & Symptoms:

• Pain similar to gallbladder disease • Sudden onset of severe epigastric pain that may radiate to back or entire abdomen; persistent epgastric tenderness may follow. • Vomiting • Diarrhea • Weight loss (with chronic disease)

Diagnostic Tests and Indicators (acute disease):

• Low blood pressure and heart rate above 90/min • Elevated serum amylase, lipase and urine amylase • Elevated white blood cell count and serum glucose or decreased serum calcium may be seen • Inflammation can be shown by abdominal ultrasound and CT scan


Presentation and Diagnosis of Pancreatitis

Pancreatitis may present as a chronic or acute disease, as a chronic disease with acute flare-ups, or as a pancreatic abscess. Acute pancreatitis often presents with painful symptoms very similar to gallbladder disease. Panniculitis or inflammation of the fatty skin layer on the front of the abdomen may be seen due to release of pancreatic enzymes.

Chronic pancreatitis presents as a recurring and persistent inflammation with similar but less urgent symptoms. There is often a series of acute attacks. Because pancreatitis can mimic other disorders, including gallbladder disease, differential diagnosis is often difficult.

Diagnostic indicators for acute pancreatitis include low blood pressure and heart rate above ninety beats per minute, elevated serum amylase, lipase and urine amylase, elevated white blood cell count and serum glucose, and decreased serum calcium. The site of inflammation can usually be located by abdominal ultrasound and CT scan. Ultrasound and CT scan are also helpful in detecting abscesses caused by inadequate drainage of a pseudocyst.


Treatment of Acute and Chronic Pancreatitis

Acute Pancreatitis:

• Analgesic pain relief (avoid meperidine) • Withholding oral intake of food and water • Supportive measures- nasogastric suction, IV fluid replacement • Endoscopic removal of gallstones blocking pancreatic drainage • Surgical removal of the pancreas • Nutritional support

Chronic Pancreatitis:

• Low-fat diet (< 40-50 g/day) (diet may be supplemented with fat, especially medium chain triglycerides) • Removal of alcohol and caffeine • Control of blood glucose and pancreatic enzymes • Fat-soluble vitamins and calcium supplementation • Pain medications as needed

Pancreatic Abscesses:

• Percutaneous methods • Laparotomy


Treatment of Acute and Chronic Pancreatitis

For the pharmacist treating elderly patients with pancreatitis, a review of medications with the potential for causing pancreatitis is essential. Acute cases and those presenting with abscesses must be treated immediately. Treatment involves analgesic pain relief, withholding oral intake of food and nutritional support, and other supportive measures. It is a myth that meperidine causes less spasm of the sphincter of Oddi and is the only opiate that should be used in acute pancreatitis.

To the contrary, use of meperidine should be avoided in the elderly. Endoscopic removal of gallstones blocking pancreatic drainage may be necessary. Surgery, including removal of the pancreas, may be necessary to avoid further complications. Chronic pancreatitis must be managed from both a pharmacological and nutritional perspective with close monitoring of pain relief medications. Pancreatic abscess seen in acute or chronic pancreatitis are treated by percutaneous methods or by laparotomy. Without treatment, mortality among the elderly is high.


Pharmacological Treatment of Pancreatitis

Acute Pancreatitis:

• Broad-spectrum antibiotics (e.g., imipenem): may help in reducing pancreatic sepsis secondary to acute pancreatitis

• Analgesics: to alleviate pain • Nutritional Support

Chronic Pancreatitis:

• Pancrelipase (pancreatin, pancrelipase): doses are individualized, but typically given before each meal/snack. • H2 receptor antagonists (e.g., cimetidine, famotidine): to increase gastric pH and improve absorption of

pancreatic enzymes • Vitamin supplements: to correct for vitamin malabsorption secondary to pancreatic insufficiency

Although no specific pharmacological agents have been shown to affect the course of severe pancreatitis, some agents may provide supportive therapy. The use of antibiotics such as imipenem, for example, may be helpful in reducing the pancreatic sepsis that often results from necrotizing pancreatitis and pancreatic abscesses.

Patients with chronic pancreatitis who do not respond to low fat diets may be given oral pancreatic enzyme supplements at mealtime to correct for malabsorption. PPIs, which increase gastric pH and improve the absorption of pancreatic enzymes, may be used with these patients to improve absorption of fat nutrients. Vitamin B-12 supplementation and fat soluble vitamins may be needed to correct for malabsorption due to pancreatic insufficiency.


Resources



Drug Information for the Health Care Professional. (1992). USP DI, 12th ed., Rockville, MD: The US Pharmacopeial Convention 1992.


Gilliam, J. .H. (1994). Hepatobiliary disorders In Hazzard, W. R., Bierman, E.L., Blass, J. P., Ettinger, W. H. & Halter, J. B. (Eds.). Geriatric Medicine and Gerontology, 3rd ed.New York:McGraw-Hill: 707-15.

Heidelbauch J.J. & Sherbondy MA. (2006) Cirrhosis and Chronic Liver Failure: Part II. Complications and Treatment. Am Fam Phys.75(5): 767-776.

Kaplan, A., et.al. (1995). The Liver and Tests of Hepatic Function.In Harris, J. M., et.al. (Eds). Clinical Chemistry Interpretation and Techniques, 4th ed:31 3-45.


Lichtblau, L.(1998). Factors that modify drug effects and drug interactions, lecture from ISAP, online, http://www.university.com/ISAP, update 9/11/98.

Nathwanti, RA (2006). Drug Hepatotoxicity. Clin Liver Dis 10:207-217.


Resources

Rybacki, J. J., Long J. W. (1997). Guidelines for the use of drugs by the elderly. In The Essential Guide to Prescription Drugs, 1997 ed. 16-18.

Sherman S. & Lehman G. Opioids and the sphincter of Oddi.(1994) Gastrointest Endosc 40:105–6.

Warren, K. W. et. al.(1987). Diseases of the gallbladder and bile ducts, in Schiff, L., Schiff, E. R. (Eds.). Diseases of the Liver, 6th ed. Philadelphia: Lippincott, p.1289.

Web Sites:

Diseases of the liver and common laboratory tests

Liver disease resources at

Surgical guidelines and treatment

Pancreatic disorders information

PharmInfo Net’s Gastrolinks – Liver



Documents

Module 8 - Pharmacotherapy for Gastrointestinal Disorders