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OTC Agents for Constipation, Diarrhea, Hemorrhoids, and Heartburn

I. CONSTIPATION A. General information 1. Definition. Constipation is the difficult or infrequent passage of stool. Normal stool frequency ranges from two to three times daily to two to three times per week. Patients may experience abdominal bloating, headaches, or a sense of rectal fullness from incomplete evacuation of feces. 2. Causes. Constipation can be caused by many factors, including: a. Insufficient dietary fiber b. Lack of exercise c. Poor bowel habits, such as failure to respond to the defecatory urge or hurried bowels (i.e., incomplete evacuation) d. Medications, such as narcotics, antacids, or anticholinergics (e.g., antidepressants, antihypertensives, antihistamines, phenothiazines, antispasmodics) e. Organic problems, such as intestinal obstruction, tumor, inflammatory bowel disease, diverticulitis, hypothyroidism, or hyperglycemia 3. Practitioners should question the patient about the following: a. Normal stool frequency b. Duration of the constipation c. Frequency of constipation episodes d. Exercise routine e. Amount of dietary fiber consumed f.Presence of other symptoms g. Medications used currently h. Medications used to relieve constipation and their effectiveness B. Treatment 1. Nonphannacologic a. Increase intake of fluids and fiber (e.g., cereals, green vegetables, fruit, potatoes) b. Increase exercise to increase and maintain bowel tone c.Bowel training to increase regularity 2. Pharmacologic. Therapeutic agents are classified according to their mechanism of action. Laxatives should not be taken if nausea, vomiting, or abdominal pain is present. a. Bulk-forming laxatives. These medications are natural or synthetic polysaccharide derivatives that adsorb water to soften the stool and increase bulk, which stimulates peristalsis. Bulk-forming laxatives work in both the small and large intestines. The onset of action of these agents is slow (12-24 hours and up to 72 hours), which is why they are best used to prevent constipation rather than to treat severe acute constipation. There are both natural and synthetic products. All bulk-forming agents must be given with at least 8 ounces of water to minimize the possible constipation experienced by some patients. Some bulkforming medications may contain sugar, so diabetics should use sugar-free products. Bulk-forming agents should not be used if patients have an obstructing bowel lesion, intestinal strictures, or Crohn's disease because they can make this situation worse and possibly result in bowel perforation. i. Natural bulk-forming laxatives i. Psyllium (e.g., Metamucil, Konsyl-D, Fiberall, Effer-Syllium). An adult dosage is 2.5-7.5 g one to three times per day. A child's dosage is half the adult dosage one to three times per day. ii. Malt soup extract (e.g., Maltsupex). An adult dosage is 16 g two to four times per day. A child's dosage is 16 g one to two times per day. ii. Synthetic bulk-forming laxatives

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Methylcellulose (e.g., Citrucel). An adult dosage is 1-2 g one to three times per day. A child's dosage is 0.5 g one to three times per day. ii. Polycarbophil (e.g., KonsyI Fiber, Fiber Con, Fiberall). An adult dosage is 1 g one to four times per day. A child's dosage is 0.5 g one to three times per day. Calcium polycarbophil may impair the absorption of tetracyclines if the drugs are taken concurrently. b. Saline and osmotic laxatives work by creating an osmotic gradient to pull water into the small and large intestine. This increased volume results in distention of the intestinal lumen, causing increased peristalsis and bowel motility. These laxatives also increase the activity of cholecystokinin-pancreozymin, which is an enzyme that increases the secretion of fluids into the gastrointestinal (Gl) tract. The onset of action varies depending on the ingredient and dosage form. Rectal formulations (e.g., enemas, suppositories) have an onset of action of 5-30 minutes, whereas oral preparations work within 3-6 hours. a. Saline laxatives include sodium and magnesium salts. As much as 20% of magnesium may be absorbed from these products, which may lead to hypermagnesemia in patients with preexisting renal impairment. Patients with hypertension or congestive heart failure should not receive saline laxatives on a prolonged basis due to fluid retention from sodium absorption. Products include: i. Magnesium citrate (Citrate of Magnesia) ii. Magnesium hydroxide (Phillips' Milk of Magnesia) iii. Magnesium sulfate (Epsom salt) iv. Sodium phosphate (Fleet Phospho-Soda) b. Osmotic laxatives i. Glycerin is available in rectal products in suppository or liquid form (e.g.. Fleet Babylax). Rectal burning may occur with glycerin products. In addition to the osmotic effect, sodium stearate in these products can produce a local irritant effect. ii. Lactulose (e.g., Chronulac) is available only by prescription and is used to decrease blood ammonia levels in hepatic encephalopathy. It may cause flatulence and cramping and should be taken with fruit juice, water, or milk to increase the palatability. iii. Sorbitol, a nonabsorbable sugar, is similar in efficacy to lactulose, which can be administered orally (70% solution) or rectally (25% solution). The adverse effects are the same and include flatulence, cramping, and abdominal pain over the first few days.
i. c. Stimulant

laxatives. These medications work in the small and large intestine to stimulate bowel motility and increase the secretion of fluids into the bowel. All stimulant laxatives can cause abdominal cramping. Also, chronic use of stimulant laxatives can lead to cathartic colon, which results in a poorly functioning colon and resembles the symptoms of ulcerative colitis. However, most cases of cathartic colon were published before 1960 when more toxic ingredients (e.g., podophyllin) were used in laxative products. The oral preparations usually have an onset of action within 6-10 hours. Rectal preparations usually have an onset of action within 30-60 minutes. i. Anthraquinone laxatives include senna, cascara sagrada, and casanthranol. Melanosis coli, which is a dark pigmentation of the colonic mucosa, can result with long-term use of anthraquinone laxatives. This usually disappears 6-12 months after discontinuing the medication. In addition, there is no indication that melanosis results in adverse consequences. Discoloration (pink/red, yellow, or brown) of the urine may occur. Cascara sagrada is excreted into breast milk. Anthraquinone products include: Senna (e.g.. Senokot, Ex-Lax, Fletcher's Castoria) is considered to be more potent than cascara products; however, senna causes more abdominal

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cramping. Cascara sagrada. Liquid preparations of cascara are more reliable than solid dosage forms. Casanthranol is considered to be a mild stimulant laxative and is present in Peri-Colace, which also contains docusate.
ii.

iii.

Bisacodyl (e.g., Dulcolax) is a diphenylmelhane derivative. The tablet formulations of bisacodyl are enteric coated, so they should not be crushed or chewed. Also, bisacodyl-containing products should not be taken within 1 hour of ingesting antacids or milk. Castor oil (e.g.. Purge) has an onset of action within 2-6 hours. Castor oil works primarily at the small intestine, which can result in strong cathartic effects (e.g., excessive fluid and electrolyte loss). These cathartic effects can lead to dehydration. Castor oil should not be used in pregnant patients because it may induce premature labor.

d. Emollient

laxatives act as surfactants by allowing absorption of water into the stool, which makes the softened stool easier to pass. These medications are particularly useful in patients who must avoid straining to pass hard stools, such as those who recently had a myocardial infarction or rectal surgery. However, clinical trials evaluating emollient "stool-softening* laxatives show that these products, when compared to placebo, do not affect the weight or water content of the stool or the frequency of stool passing. Emollient laxatives have a slow onset of action (24-72 hours), which is why they are not considered the drug of choice for severe acute constipation, and they are more useful for preventing constipation. 1) Products. Emollient laxatives are salts of the surfactant docusate. These products contain insignificant amounts of calcium, sodium, or potassium, and there are no splcific guidelines for the selection of any one product. The products include: a. Docusate sodium (Colace, Doxinatc) b. Oocusate calcium (Surfak) c. Docusate potassium (Kasoft 2) Dosage information. The adult dosage is 50-300 mg per day. A child's dosage is 50-150 mg per day. Each dose must be taken with at least 8 ounces of water. Liquid preparations should be taken in fruit juice or infant formula to increase pafata-bility. Docusate products may facilitate the systemic absorption of mineral oil, so these agents should not be used concurrently. e. Lubricant laxative (mineral oil). Mineral oil works at the colon to increase water retention in the stool to soften the stool. It has an onset of action of 6-8 hours. a. Dosage information. An adult dosage is 15-45 ml per day. A child's dosage is 5-15 ml per day. b. Warnings 1. Mineral oil can decrease absorption of fat-soluble vitamins (i.e., vitamins A, D, E, K), so it should not be used on a chronic basis. 2. Elderly, young, debilitated, and dysphagic patients are at the greatest risk of lipid pneumonitis from mineral oil aspiration. 3. Emollients (e.g., docusate) may increase the systemic absorption of mineral oil, which can lead to hepatotoxicity. 4. Mineral oil products may cause anal seepage, which results in itching (i.e., pruritus ani) and perianal discomfort. Mineral oil should be taken on an empty stomach. C. Special patient issues 1. Pediatric patients. The bowel patterns of pediatric patients varies. During the

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first weeks of life, infants pass approximately four stools per day. As children get older, approximately 1-3 stools are passed per day. Constipation should be expected if there is a drastic change from a child's baseline bowel function. a. Nonpharmacologic methods, such as increasing the amount of fluid or sugar in a child's formula in younger children or increasing the bulk content of the child's diet (fruit, fiber cereals, vegetables), should be tried before the use of medications. b. If nonpharmacologic methods do not work, rectal stimulation may be useful. Pharma-cotogic agents that can be used for acute relief include glycerin suppositories and magnesium laxatives. Stimulant laxatives should be administered as a last resort, but enemas should not be used in children less than 2 years of age and with extreme caution in children between 2 and 5 years of age (see I C 4). Bulk-forming agents and stool softeners can be used if the constipation does not need immediate relief. 2. Pregnant patient*. Constipation in pregnancy is common and is often due to compression of the colon by the enlarged uterus. Pregnant patients should avoid any preparation that may be absorbed systemically (e.g., stimulant laxatives), any preparation that can interfere with vitamin absorption (e.g., mineral oil), or any preparation that can induce premature labor (e.g., castor oil). Pregnant patients should use bulk-forming agents or stool softeners.
3. Geriatric

patients tend to be at risk for constipation due to insufficient dietary (fiber) and fluid ingestion, failure to establish a regular bowel time habit, and abuse of stimulant laxatives resulting in a loss of smooth muscle tone in the bowel promoting constipation. These causes should be Investigated in addition to primary disease states (e.g., hy-pothyroidism) and medications (opiates, anticholinergics) that may lead to constipation in elderly patients. A major concern with geriatric patients is the possible loss of fluid that can be induced by aggressive laxative treatment (e.g., enemas and high-dose saline laxatives). Geriatric patients should not use stimulant laxatives on a chronic basis, and patients with renal impairment should not use magnesium products. of enemas. Enemas are useful for evacuation of the bowel before surgery, child birth, and for the treatment of acute constipation that has not responded to other medications (e.g., bisacodyl suppositories). An enema is the dosage route with the enema fluid determining the mechanism of evacuation (stimulant, osmotic). When administered correctly, an enema evacuates only the distal colon similar to a normal bowel movement. This is accomplished by having the patient lie on his/her side with the knees tucked toward the chest. While in this position, one pint (500 ml) of enema solution should be slowly squeezed into the rectum. This should be retained up to 1 hour or until definite lower abdominal cramping is felt. At this point the bowel movement is ready for expulsion. Although all enemas cause abdominal cramping, some may have more serious adverse effects than others. Soap enemas can cause much rectal irritation and have been reported to cause anaphylaxis and rectal gangrene. The popular sodium phosphate enemas (e.g., Fleet) are very effective but have resulted in hyperphosphatemia, hypocalcemia (tetany), hypokalemia, metabolic acidosis, and cardiac death usually due to conduction abnormalities in very small children. This has mainly occurred in children less than 2 years of age or between 2 and 5 years of age with predisposing factors. These factors include chronic renal disease, anorectal malformations, and/or Hirschsprung's disease, which allow phosphate blood concentrations to become abnormally high and potassium and calcium to become low predisposing these patients to cardiac arrhythmias and potentially death. Therefore, the use of enemas is highly discouraged in children under 5 years of age. abuse is a term to describe the routine, chronic use of laxatives on a

4. Use

5. Laxative

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daily basis (e.g., elderly patients) to the administration of high doses several times daily by patients with anorexia nervosa or bulimia for weight control. Excessive use of laxatives can lead to excessive diarrhea and vomiting resulting in fluid and electrolyte abnormalities. In addition to the risks to patients from hypokalemia (metabolic alkalosis, cardiac conduction problems), patients can also develop osteomalacia, liver disease, and cathartic colon. Cathartic colon results from superficial ulcerations in the colon as well as damage to the muscularis mucosa and submucosa. This results in a loss of tone of the smooth and striated muscle and causes poor bowel function.

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II. DIARRHEA is an abnormal increase in the frequency and looseness of stools. The overall weight and volume of the stool is increased (more than 200 g or ml/day), and the water content is increased to 60%-90%. In general, diarrhea results when some factor impairs the ability of the intestine to absorb water from the stool, which causes excess water in the stool. Antidiarrheals may serve to prevent an attack of diarrhea or to relieve existing symptoms. A. Classification. Diarrhea can be classified based on mechanisms or etiology. 1. Classification by mechanism (1) Osmotic diarrhea occurs when a nonabsorbable solute pulls excess water into the intestinal tract. (a) Ingestion of large meals or certain osmotic substances (e.g., sorbitol, glycerin) can lead to diarrhea. (b) Disaccharidase deficiency, which is a lack of enzymes needed to break down disac-charides in the gut for absorption (e.g., lactase deficiency), results in an increase in osmotic sugars (i.e., lactose, sucrose) in the intestinal tract. (c) Medications that can induce osmotic diarrhea include lactulose and magnesium-containing antacids and laxatives. (2) Secretory diarrhea occurs when the intestinal wall is damaged, resulting in an increased secretion rather than absorption of electrolytes into the intestinal tract. Common sources include: (a) Bacterial endotoxins (e.g., Escherichia coli. Vibrio cholerae, Shigella, Staphylococ-cus aureus) (b) Bacterial infections (e.g., Shigella, Salmonella} (c) Viral infections (e.g., rotavirus, Norwalk virus) (d) Protozoal infections (e.g., Ciardia lamblia, Entamoeba histolytica) (e) Miscellaneous causesinflammatory bowel disease and medications (e.g., prostaglandins, antibiotics, colchicine, chemotherapeutic agents) (3) Motility disorders. Diarrhea induced by motility disorders results from decreased contact time of the fecal mass with the intestinal wall, so less water is absorbed from the feces. (a) Motility disorders include irritable bowel syndrome, scleroderma, diabetic neuropathy, gastric/intestinal resection, and vagotomy. (b) Medications that can induce motility disorders include parasympathomimetic agents that enhance the effects of acetylcholine (e.g., metoclopramide, bethanechol), digitalis, quinidine, and antibiotics. 1. Antibiotics cause diarrhea by causing intestinal irritation, increased bowel motility, and altered bowel microbial flora. 2. Most antibiotic-induced diarrhea can be minimized by taking the agent with food. 2. Classification by etiology a. Acute diarrhea (lasts less than 2 weeks) a. Infection. Most common sources include viral and bacterial, but protozoal diarrhea also occurs. Organisms include: i. Viruses that commonly cause diarrhea include rotaviruses and the Norwalk virus. 1. Rotaviruses usually affect children under 2 years of age. The virus has an onset of 1-2 days and lasts 5-8 days. Patients usually have vomiting, a mild fever, and may experience severe dehydration. There is usually no blood or pus in the stool. 2. The Norwalk virus affects older children and adults. It has an onset of 12 days and lasts 24-48 hours (the "24-hour bug"). As with rotaviruses, there is mild fever but no blood or pus in the stool. Bacteria. Most bacterial diarrhea results from consumption of

ii.

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contaminated water or food with an onset of diarrhea in 8 hours to several days. Diarrhea due to consumption of contaminated food or water that occurs in a foreign country (e.g., Mexico, third world countries) is referred to as traveler's diarrhea. 1. Toxigenic bacteria. Diarrhea caused by toxigenic E. coli, S. aureus, V. cholerae, and Shigella results from the secretory effects of enterotoxins released by these organisms in the small intestine. Patients usually experience large-volume stools that are watery or greasy. 2. Invasive bacteria. Diarrhea caused by invasive E. coli, Shigella, Salmonella, Campylobacter, and Clostrldium difficile results from mucosal invasion of the colon. This results in a dysentery-like diarrhea, which is characterized by an extreme urgency to defecate, abdominal cramping, tenesmus, fever, chills, and small-volume stools that contain blood or pus. iii. Protozoa. G. lamblia, E. histolytica, and Cryptosporidium cause explosive, foul-smelling, large-volume, watery stools. This is thought to be caused by invasion of the small intestine, which causes damage to the microvilli and, therefore, decreases absorption of fluids. This type of diarrhea can result in large fluid losses, and patients are at risk for dehydration. Although protozoan-induced diarrhea is self-limiting, it may persist for several months, so therapy should be considered to eradicate the organism. b. Diet-induced diarrhea. Diarrhea induced by foods results from food allergies, high-fiber diets, fatty or spicy foods, large amounts of caffeine, or milk intolerance. The best treatment is prevention, by avoiding troublesome foods. c. Drug-induced diarrhea
b.

Chronic diarrhea (lasts longer than 2 weeks). If a patient suffers from diarrhea for long periods of time, or from recurrent episodes of diarrhea, the following causes must be considered: protozoa) organisms, food-induced diarrhea (e.g., lactose intolerance), irritable bowel syndrome, malabsorption syndromes (e.g., cellac sprue, diverticulosis, short bowel syndrome), inflammatory bowel disease, pancreatic disease, and hyperthyroidism.

B. Patient evaluation 1. Pharmacists who are consulted by patients should ask the patient for the following information before- recommending a therapy: a. Age of the patient b. Onset and duration of the diarrhea c. Description of stool (i:.e., frequency, volume, blood, pus, watery) d. Other symptoms (e.g., abdominal cramping, fever, nausea, vomiting, weight loss) e. Medications recently started or medications used to relieve the diarrhea f. Recent travel (where and how long ago) g. Medical history (history of Gl disorders) 2. Referrals to a physician should be made by the pharmacist who encounters a patient with diarrhea that meets the following criteria. a. Younger than 2 years of age or older than 60 years of age (with multiple medical problems) b. Bloody stools c. High fever (greater than 101F or 38Q d. Dehydration or weight loss greater than 5% of total body weight; signs of dehydrationdry mouth, sunken in eyes, crying without tears, dry skin that is not elastic like normal skin e. Duration ofdiairrhea longer than 5 days f. Vomiting

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C. Treatment 1. Nonpharmacologic a. Food/breast feeding. There has been much controversy regarding the decision "to feed" or "not to feed" children during acute episodes of diarrhea. Originally, parents were told that children should not receive food, milk-products, or breast feed for 6-48 hours after the onset of diarrhea. Recent information shows that children should remain on their normal diet or breast feeding during bouts of diarrhea because these do not make the diarrhea worse and may actually improve the diarrhea. b. Fluids. The most important part of treating acute diarrhea is the replacement of lost fluids. If patients experience mild to moderate fluid loss this can be done with oral rehydration solutions. If fluid loss is severe (more than 10% loss of body weight) and/or severe vomiting persists, then patients may need intravenous rehydration before oral maintenance fluids can be administered. Oral rehydration solutions can be easily made at home (Table 31-1) or purchased ready-to-use (Pedialyte, Infalyte, Rehydralyte, Resol). Because the secretory and absorptive mechanisms of the bowel function separately, this allows these oral rehydration solutions to be absorbed during acute episodes of diarrhea preventing severe dehydration and complications. 1. Fluid and electrolyte replacement. Fluid and electrolyte therapy is aimed at replacing what the body has lost. During this situation, the patient's fluid input and output as well as weight should be monitored. The World Health Organization has established guidelines for oral replacement therapy 2. Fluids to be avoided include hypertonic fruit juices and drinks (e.g., apple juice, powdered drink mixes, gelatin water) or carbonated beverages, which can make diarrhea worse and do not contain needed electrolytes (i.e., Na, K).

2. Pharmacologic. Based on the Food and Drug Administration (FDA) review of the various antidiarrheal products, three agents have been identified as Category I (i.e., safe and effective) ingredients: activated attapulgite, calcium polycarbophil, and loperamide. Antidiarrheal agents are classified in different categories on the basis of their chemical class or pharmacologic mechanism of action. a. Antiperistaltic drugs i. Mechanism of action. Antiperistaltic drugs act directly on the circular and longitudinal musculature of the small and large intestine to normalize peristaltic intestinal movements. They slow intestinal motility and affect water and electrolyte movement through the bowel. The frequency of bowel movements is decreased, and the consistency of stools is increased. ii. Contraindication. Antiperistaltic medications have always been restricted in patients with acute bacterial diarrhea because of the potential for these drugs to decrease clearance of the organism and enhance systemic invasion of the organism. Most information shows that this is not significant and probably will cause no harm. However, these medications should not be used in patients with colitis (potential for the development of toxic megacolon) or in children less than 2 years of age. iii. Prescription agents in this class include the opiate-related agent diphenoxylate/ atropine (e.g., Lomotil). iv. Nonprescription agents. Loperamide (e.g., Imodium A-D, Maalox AntiDiarrheal, Pepto Diarrhea Control) provides effective control of diarrhea as quickly as 1 hour after administration. Antiperistaltic drugs should not be used for more than 48 hours in acute diarrhea. a. Dosage information. An adult dosage is 4 mg followed by 2 mg after

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(2)

each unformed stool not to exceed 16 mg/day. A child's dosage is 1-2 mg up to three times per day, depending on weight and age. b. Side effects. At recommended doses, loperamide is generally well tolerated. Side effects are infrequent and consist primarily of abdominal pain, distention, or discomfort; drowsiness; dizziness; and dry mouth. Adsorbents. These medications adsorb toxins, bacteria, gases, and fluids. They are not absorbed systemically, so they produce few adverse effects. There are several products available; some are more effective than others, but none are very effective for severe acute diarrhea. These products are given for symptomatic relief and are usually administered in large doses immediately following a loose stool. a. Activated attapulgite (e.g., Kaopectate Advanced Formula, Donnagel, Diasorb). At-tapulgite is a naturally occurring aluminum magnesium silicate that absorbs eight times its weight in water. It is considered to be safe and effective in reducing the number of bowel movements, improving stool consistency, and relieving cramps associated with diarrhea. i. Dosage information. An adult dose is 600-1200 mg after each loose stool. A child's dose is 300-600 mg after each loose stool. ii. Side effects. Because activated attapulgite is inert and is not absorbed systemically, side effects are essentially nonexistent. Calcium polycarbophil (e.g., FiberCon, Mitrolan, Fiberall, Fiber-Lax) is a synthetic, hydrophilic polyacrylic resin that has the potential to absorb up to 60 times its weight in water. Polycarbophil has been shown to be safe and effective for the symptomatic treatment of diarrhea. i. Dosage information. An adult dosage is 1 gram one to four times daily. A child's dosage is 0.5 grams one to four times daily. ii. Side effects. As with attapulgite, calcium polycarbophil is not systemically absorbed. It is metabolically inactive and essentially does not produce systemic side effects. c. Miscellaneous agents i. Bismuth subsalicylate (e.g., Pepto-Bismol). Bismuth salts work as adsorbents but also are believed to decrease secretion of water into the bowel. Bismuth preparations have moderate effectiveness against traveler's diarrhea, but doses required for relief are large and must be administered frequently so these preparations may be inconvenient 1. Dosage information. An adult dosage is two tablets or 3060 ml (524 mg) every hour as needed to a maximum of eight doses in a 24-hour period. A child's dosage is 'A to 'A the adult dose. Bismuth subsalicylate can prevent traveler's diarrhea when two tablets are taken four times per day. 2. Side effects may include harmless grayish-black stools or tongue and ringing in the ears, if high doses are taken or if the patient is simultaneously taking other salicylate products. 3. Contraindication. Bismuth subsalicylate should not be given to children or teenagers during or after recovery from chicken pox or flu because of the possible association of salicylates with Reye's syndrome. ii. Lactobacillus (Bacid, Lactinex) products are intended to replace the normal bacterial flora that is lost during the administration of oral antibiotics. However, there is little information to show that these products are useful for antibiotic-induced diarrhea, so most clinicians do not recommend their use. iii. Lactase (e.g., LactAid, Lactrase, Dairy Ease) is indicated for individuals who have insufficient amounts of lactase in the small intestine. Lactose (a disaccharide present in dairy products) must
b.

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iv.

v.

be broken down to glucose and galactose to be fully digested. If it is not, lactose draws water into the Gl tract and diarrhea results. Lactase is the enzyme responsible for digesting lactose. The dose is one to two capsules taken with milk or dairy products or added to milk before drinking. Titration of doses to higher levels may be required in some cases. Anti-infectives. Depending on the suspected etiology of the infectious diarrhea, prescription antibiotics and antiprotozoal medications can be used to eradicate the organisms and decrease the duration of symptoms (Table 31-3). If antibiotics are used to prevent traveler's diarrhea, therapy should be started 1 day before arrival in high-incidence regions and continue until 2 days after departure. If diarrhea has occurred, antibiotic treatment should last for 3-5 days. Anticholinergics (e.g., atropine, hyoscyamine) decrease bowel motility, which results in an increase of fluid absorption from the intestinal tract and a decrease in abdominal cramping. These products are found in combination with adsorbents or opiates. However, the amount of anticholinergic found in most products is not considered to be enough to alter the course of severe acute diarrhea. Adverse effects include dry mouth, blurred vision, and tachycardia. These products should not be used in patients with narrow-angle glaucoma.

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III. HEMORRHOIDS traditionally have been defined as clusters of dilated blood vessels in the lower rectum (internal hemorrhoids) or anus (external hemorrhoids). Simply, hemorrhoids represent downward displacement of anal cushions that contain arteriovenous anastomoses. Hemorrhoids are common. Although they are considered a minor medical problem, they may cause considerable discomfort and anxiety. A proper diagnosis is important, because there are a number of conditions that may produce symptoms that mimic those of hemorrhoids (see III D), For example, colorectal cancer may cause bleeding, which is a common symptom of hemorrhoids. Fortunately, patient reassurance and the proper administration of a few simple treatments usually improve the condition. A. Types of hemorrhoids are determined by their anatomic position and vascular origin. 1. An internal hemorrhoid is an exaggerated vascular cushion with an engorged internal he-morrhoidal plexus located above the dentate line and covere<kwith a mucous membrane. 2. An external hemorrhoid is a dilated vein of the inferior hemorrhoidal plexus located below the dentate line and covered with squamous epithelium. 3. A mixed hemorrhoid appears as a baggy swelling and exhibits simultaneous characteristics of internal and external hemorrhoids. B. Causes. Although heredity may predispose a person to hemorrhoids, the exact cause is probably related to acquired factors.
1.

2.

Situations that result in increased venous pressure in the hemorrhoidal plexus (e.g., chronic straining during defecation; small, hard stools; prolonged sitting on the toilet; occupations that routinely require heavy lifting; pregnancy) can transform an asymptomatic hemorrhoid into a problem. Pregnancy is the most frequent cause of hemorrhoids in women or childbearing age. The hemorrhoidal veins are pushed downward during defecation or straining, and, with increased venous pressure, they dilate and become engorged. Over time, the fibers that anchor the hemorrhoidal veins to their underlying muscular coats stretch, which results in prolapse.

C. Signs/symptoms 1. The most common sign/symptom of hemorrhoids is painless bleeding occurring during a bowel movement. The blood is usually bright red and may be visible on the stool, on the toilet tissue, or coloring the water in the toilet. 2. Prolapse is (he second most common sign/symptom of hemorrhoids. A temporary protrusion may occur during defection, and it may need to be replaced manually. A permanently prolapsed hemorrhoid may give rise to chronic, moist soiling of the underwear. These patients may complain of a dull aching feeling. 3. Pain is unusual unless thrombosis involving external tissue is present, and then the pain can be excruciating. 4. Discomfort, soreness, pruritus, swelling, burning, and seepage may also occur with hemorrhoids. D. Other conditions that may mimic hemorrhoids include the following, which usually require a physician's intervention. 1. An anal abscess, usually a Staphylococcus infection 2. Cryptitis, which is inflammation of the crypts (small indentations at the mucocutaneous junction) 3. An anal fissure, which is a small tear in the lining of the anus 4. An anal fistula, which is an abnormal communication between the mucosa of the rectum and the skin adjacent to the anus

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5. Inflammatory bowel diseases 6. A polyp, which is a tumor of the large intestine 7. Colorectal cancer E. Internal hemorrhoids are graded and classified into one of four groups. 1. A first-degree hemorrhoid (grade 1) does not descend nor prolapse during straining when defecating. 2. A second-degree hemorrhoid (grade 2) descends but returns spontaneously with relaxation. 3. A third-degree hemorrhoid (grade 3) requires manual replacement into the rectum after prolapse. 4. A fourth-degree hemorrhoid (grade 4) is permanently prolapsed. F. Treatment. The symptoms of hemorrhoids are produced by a cycle of events: the protrusion of the vascular submucosal cushion through a tight anal canal, which becomes further congested and hypertrophic, which causes the cushion to protrude further. All treatments of hemorrhoids aim to break this cycle, and they fall into a number of broad groups. 1. For first- and second-degree internal hemorrhoids that bleed minimally, a conservative approach can usually be taken. a. To reduce straining and downward pressure on the hemorrhoids, patients should avoid straining when defecating and avoid sitting on the toilet longer than necessary. b. Correction of constipation is of paramount importance. This can be accomplished by eating a high-fiber diet and increasing water intake and physical activity. Bulk-forming laxatives, such as psyllium, and stool softeners, such as docusate, may be helpful. c. Sitz baths for 15 minutes, three to four times a day, can soothe the anal mucosa. Tepid water should be used, and prolonged bathing should be avoided. Epsom salts (magnesium sulfate) added to the bath or the application of an ice pack can help reduce the swelling of an edematous or clotted hemorrhoid. d. OTC hemorrhoidal ointments, creams, foams, and suppositories may also help relieve symptoms. 2. Higher-grade internal hemorrhoids usually require physician expertise and specialized procedures for treatment. a. Symptomatic grades 2 or 3 hemorrhoids are often best treated with hemorrhoid banding (rubber band ligation). This procedure is performed through an anoscope; a rubber band ligature is placed on the rectal mucosa above the hemorrhoid, well above the dentate line to avoid excessive discomfort. The ligated area sloughs off in a few days. b. Infrared photocoagulation can be used for grade 2 hemorrhoids; it is less effective than banding with large hemorrhoids. Infrared light is focused at the base of the hemorrhoid, thereby destroying the varicosity secondary to the formation of a white coagulum. c. Sclerotherapy (injection of a sclerosing agent into the hemorrhoid) or cryotherapy ("freezing" the hemorrhoid) are older therapies that have been used. d. Surgical hemorrhoidectomy should be undertaken only for grades 3 or 4 hemorrhoids. Whether the procedure is done traditionally or with a laser, most patients have significant discomfort and a period of postoperative disability. e. An external, thrombosed hemorrhoid can be completely excised in an office setting, clinic, or operating room. G. Nonprescription medication for hemorrhoidal and other anorectal diseases The FDA has identified several ingredients as safe and effective to alleviate burning,

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discomfort, inflammation, irritation, itching, pain, and swelling. These products are simply palliative; they are not meant to cure hemorrhoids or other anorectal disease. If these products do not improve symptoms within 7 days, a physician should be consulted. A physician should also be consulted if bleeding, prolapse of the hemorrhoid, seepage of feces or mucus, thrombosis, or severe pain occurs. 1. Ointments versus suppositories. Generally, the ointment or cream dosage form is believed to be superior to a suppository, which may bypass the affected area. Patients should wash the anorectal area with mild soap and warm water and pat (not wipe) the area dry before applying a product. Alternatively, patients can use an OTC anal cleansing pad (e.g.. Tucks). Some ointments come with rectal pipes (pile pipes) that allow the patient to insert and apply the medication directly in the rectum. The openings in the rectal pipe allow the ointment to cover large areas of the rectal mucosa unreachable with the finger. The rectal pipe should be lubricated by spreading ointment around the tip of the pipe before insertion. Some clinicians advise against the use of the rectal pipe because the anal canal could be traumatized if the pipe is not inserted properly. 2. Local anesthetics block nerve impulse transmission. They should be used for symptoms of pain, itching, burning, discomfort, and irritation in the perianal region or lower anal canal (not in the rectum). The rectum contains no sensory pain receptors. a. Agents deemed safe and effective include benzocaine 5%-20% (e.g., Americaine), pramoxine HCI 1% (e.g., Anusol), benzyl alcohol 1%-20% (e.g., Hydrosal), dibucaine and dibucaine HCI 0.25%-1%, dyclonine HCI 0.5%-1%, lidocaine 2%-5% (e.g., Xy-locaine), and tetracaine and tetracaine HCI 0.5%-1 %. b. Adverse effects. These agents may produce a hypersensitivity reaction with burning and itching similar to that of anorectal disease. As a result of its unique chemical structure, pramoxine exhibits little cross-sensitivity when compared to the other local anesthetics. 3. Vasoconstrictors have been shown to decrease mucosal perfusion in the anorectal area after topical application. However, because bleeding in this area may be a sign of more serious disease, vasoconstrictors are not approved for control of minor bleeding. For temporary relief of itching and swelling, these agents have a local anesthetic effect of unknown mechanism. a. Agents deemed safe and effective include ephedrine sulfate 0.1%-1.25% in aqueous solution, epinephrine HCI 0.005%-0.01 % in aqueous solution, and phenylephrine HCl 0.25% in aqueous solution These agents are present in various ointments (e.g., Pazo) and suppositories (e.g., Medicone). b. Contraindications apply to people with cardiovascular disease, high blood pressure, hyperthyroidism, diabetes, and prostate enlargement because of the possibility of systemic absorption.
4. Protectants

provide a physical barrier, forming a protective coating over skin or mucous membranes, for temporary relief of itching, irritation, discomfort, and burning. They prevent irritation of anorectal tissue and prevent water loss from the stratum corneum. Protectants are often the bases or vehicles for the other agents used for anorectal disease. Products include aluminum hydroxide gel, cocoa butter, kaolin, lanolin, hard fat, mineral oil, white petrolatum, petrolatum, glycerin (external use only), calamine, topical starch, cod liver oil, shark liver oil, and zinc oxide. When protectants are incorporated into the formulation of an OTC product, they should make up at least 50% of the dosage unit. If two to four protectants are used, their total concentration should represent at least 50% of the whole product. When calamine, cod liver oil, shark liver oil, and zinc oxide are used as protectants, they must be combined with other protectant active ingredients. a. Absorbents take up fluids that are on or secreted by skin or mucous membranes.

Page 14 of 19 b. c. d.

Adsorbents attach to substances secreted by skin or mucous membranes. Demulcents combine with water to form a colloidal solution, which protects the skin in a way similar to mucus. Emollients, which are derived from animal or vegetable fats or petroleum products, soften or protect internal or external body surfaces.

5. Astringents

lessen mucus and other secretions and protect underlying tissue through a local and limited protein coagulant effect. Action is limited to surface cells, but astringents provide temporary relief of itching, discomfort, irritation, and burning. Products considered to be safe and effective include calamine 5%25%, witch hazel 10%-50% (external use only), and zinc oxide 5%-25%. cause desquamation and debridement of the surface cells of the epidermis and provide temporary relief of discomfort and itching. Theoretically keratolytics help expose underlying tissue to other therapeutic agents. Products considered to be safe and effective include aluminum chlorhydroxyallantoinate (alcloxa) 0.2%-2.0% and resorcinol 1%-3%. anesthetics, and antipruritics provide temporary relief of burning, discomfort, itching, pain, and soreness. The FDA has redesignated several ingredients into this category that were formerly classified as counterirritants. Ingredients considered to be safe and effective for external use in the anorectal area include menthol (0.1%-1%), juniper tar (1%-5%), and camphor (0.1%-3%). agents. Live yeast cell derivative (LYCD) (skin respiratory factor], which is a water-soluble extract of brewer's yeast, was present in Preparation H in the past. LYCD was removed from the list of "safe and effective* active ingredients by the FDA as it determined that this agent was not proven effective as per the studies submitted to it. Preparation H products have been reformulated without LYCD. Preparation H Ointment now contains the protectants (petrolatum, mineral oil, shark liver oil) and the vasoconstrictor, phenylephrine. (0.25%-1%) works by causing vasoconstriction, stabilization of lysosomal membranes, and antimitotic activity. These agents have the potential to reduce itching, inflammation, and discomfort in the anorectal area. Until recently, hydrocortisone-containing hemorrhoidal products were available by prescription only.

6. Keratolytics

7. Analgesics,

8. Wound-healing

9. Hydrocortisone

Page 15 of 19

IV. GASTROESOPHAGEAL REFLUX DISEASE (HEARTBURN) A. General information 1. Definition. The reflux of gastric contents into the esophagus, or gastroesophageal reflux, is generally a benign physiologic process that occurs in normal individuals multiple times throughout the day. However, patients with gastroesophageal reflux disease (CERD) may experience esophageal tissue damage (reflux esophagitis) and/or symptoms of heartburn when the acidic gastric contents stay in prolonged contact with the esophagus. 2. Symptoms. Heartburn (pyrosis) typically is described as a burning sensation or pain located in the lower chest. Because the pain may radiate up into the chest, heartburn may be confused with pain associated with myocardial infarction. Symptoms usually occur soon after meals and when lying down at bedtime. Pain on swallowing (odynophagia) may suggest severe mucosal damage in the esophagus. 3. Complications. Patients with severe, uncontrolled GERD may suffer bleeding from esophageal ulcers and pulmonary complications resulting from the aspiration of refluxed material into the upper airways and lungs. Patients who describe difficulty swallowing (i.e., dysphagia) may have an esophageal stricture, cancer, or a motility disorder. 4. Causes. There is an imbalance of aggressive and protective forces. Aggressive forces include acid and pepsin. The most important protective force is probably the lower esophageal sphincter (LES). Many patients with GERD have a weak lower esophageal sphincter. As a result, the high pressure in the stomach creates enough force to overcome the weak squeeze of the LES and allows reflux to occur. Other protective forces include esophageal clearance, gastric emptying rate, and esophageal mucosal defense. Drugs that reduce LES tone include; a. Calcium channel antagonists (e.g., nifedipine, verapamil, diltiazem) b. Nitrates c. Anticholinergic agents (e.g., tricyclic antidepressants, antihistamines) d. Oral contraceptives and estrogen 5. Pharmacists who are consulted by patients should ask for the following information before recommending a therapy. a. Duration and frequency of symptoms b. Severity of the pain and symptoms c. Timing of the symptoms (especially in relation to meals and at bedtime) d. Presence of other symptoms (nausea, vomiting, bloody stools, weight loss) e. Use of alcohol or tobacco f. Amount of high-fat foods, caffeine-containing products, chocolate, and tomato-based foods consumed g. Medications used currently, including nonprescription medications h. Medications used to relieve heartburn and their effectiveness 6. Patients with the following symptoms or conditions should be referred to a physician for evaluation rather than treated with nonprescription agents. a. Severe abdominal or back pain b. Unexplained weight loss c.Chest pain that is indistinguishable from ischemic pain d. Difficulty or pain on swallowing e. Presence or history of vomiting blood f. Black tarry bowel movements (if not taking iron or bismuth subsalicylate) g. Children younger than 12 years of age h. Possibility of being pregnant h. Symptoms not responding to antacids or nonprescription histaminereceptor antagonists (H2RAs) within 2 weeks or recurring soon after stopping B. Treatment 1. Nonpharmacologic interventions for GERD attempt to reduce or eliminate dietary and

Page 16 of 19

Life style factors that promote reflux. Specific recommendations include: a. Elevate the head of the bed about 6 inches with blocks. This position improves esophageal clearance and reduces the duration of reflux. Try to avoid just propping a patient's head up with pillows because this may worsen symptoms by increasing abdominal pressure. b. Eat evening meals at least 3 hours before going to bed to allow adequate time for gastric emptying. c.Avoid foods that reduce LES tone. 1. Chocolate 2. Mints 3. High-fat foods d. Avoid foods that irritate the esophagus. 1. Tomato-based products 2. Coffee 3. Citrus juices e. Reduce the size of meals. f. Avoid lying down after meals. g. Stop smoking. h. Limit alcohol intake. i. Limit caffeine-containing beverages j. Lose weight if appropriate. k. Avoid wearing tight-fitting clothing. 2. Pharmacologic. The management of GERD may be viewed as a stepped-care approach, with antacids, nonprescription H2RAs, and nondrug measures forming the basis for the first step. These measures may help to alleviate symptoms in patients with mild to moderate GERD but cannot be expected to heal damaged esophageal mucosa or prevent complications. Steps 2 and higher utilize prescription strength H^RAs and other prescription medications. 1) Antacids. Antacids neutralize gastric acid, which increases the pH of refluxed gastric contents and LES pressure. As a result, the refluxed contents are not as damaging to the esophageal mucosa. Antacids generally relieve heartburn within 515 minutes of administration. Antacid suspensions generally dissolve more easily in gastric acid and thereby work quicker. The duration of relief ranges from 1-3 hours. Because of their short duration, patients may need to take 4-5 doses throughout the day for adequate symptom relief. Antacids will not provide sustained neutralization of acid throughout the night. An adult dose is 40-80 mEq acid neutralizing capacity (ANQ taken as needed for symptoms. If necessary, these doses may be titrated to a scheduled regimen, such as 40-80 mEq after meals and at bedtime. a. Sodium bicarbonate (e.g., Alka-Seltzer, Bromo-Seltzer) should be used only for short-term relief of symptoms. Because each gram of sodium bicarbonate contains 12 mEq of sodium, it is contraindicated in patients with edema, congestive heart failure, renal failure, cirrhosis, and patients on low-salt diets. It is the only systemic antacid available and can thus alter systemic pH. b. Calcium carbonate (e.g., Turns) is useful for GERD but may cause constipation or less likely diarrhea. A good source of elemental calcium c. Aluminum hydroxide (e.g., Amphojel, Alternagel) often causes constipation and should be avoided in patients with hemorrhoids or constipation, which is common in the elderly. d. Magnesium hydroxide (e.g.. Milk of Magnesia) rarely is used alone for heartburn because it frequently causes diarrhea. e. Magnesium-aluminum combination antacids (e.g., Maalox, Mylanta) provide the highest ANC per volume of antacid and are used most frequently. The predominant adverse effect of these combinations is diarrhea. f. Patient information i. Patients with renal failure should avoid the use of all antacids. Potassium and magnesium content of antacids should be considered

Page 17 of 19

for patients with cardiac disease. ii. Patients should not take more than 500-600 mEq ANC of antacid per day. g. Antacids can interfere with the absorption of many drugs. In general, antacids should be spaced at least two hours apart from the administration of interacting drugs. This is often quite difficult to accomplish. Important clinical interactions with antacids may occur with the following drugs. i. Tetracycline antibiotics ii. Quinolone antibiotics (e.g., ciprofloxacin, levofloxacin) iii. Iron supplements iv. Digoxin b. Alginic acid (1) Mechanism of action. Alginic acid works by reacting with sodium bicarbonate and saliva to form a viscous solution of sodium alginate. This viscous solution floats on the surface of gastric contents so that, when reflux occurs, sodium alginate rather than acid is refluxed, and irritation is minimized. (2) Patient information a. Alginic-acid tablets must be chewed to be effective and should be followed by a full glass of water so that the viscous foam can float on it in the stomach. b. Alginic-acid products work best when patients are in the upright position. Thus, these products should not be taken at bedtime or just before lying down. c. Nonprescription H^RAs. These medications inhibit gastric acid secretion by competitively blocking H2-receptors on the parietal cell. By decreasing gastric acid secretion, the refluxed material is less damaging to the esophagus. The onset of symptom relief with H2RAs is approximately 1-2 hours, which is considerably longer than antacids; however, the duration of action can last up to 10 hours. (1)Cimetidine (Tagamet-HB) a. The adult dosage of nonprescription cimetidine is 200 mg as needed for symptoms, up to twice daily. Cimetidine 200 mg suppresses gastric acid for approximately 6 hours. b. Nonprescription doses of cimetidine may impair the hepatic metabolism and thus increase serum concentrations and the pharmacologic effects of: i. Warfarin ii. Phenytoin iii. Theophylline
(2)

Famotidine (Pepcid-AC). The adult dosage of nonprescription famotidine is 10 mg as needed for symptoms, up to twice daily. Patients who anticipate heartburn or indigestion may take one famotidine 10 mg tablet 1 hour before eating, with a maximum of two tablets within a 24-hour period. Famotidine 10 mg suppresses acid secretion for 8-10 hours. Unlike cimetidine, famotidine does not impair hepatic metabolism of other drugs. Ranitidine (Zantac75). The adult dosage of nonprescription ranitidine is 75 mg as needed for symptoms, up to twice daily. Ranitidine inhibits hepatic metabolism five to ten times less than cimetidine; therefore, the potential for drug interactions is very small. Nizatidine (Axid-AR). The adult dosage of nizatidine is 75 mg as needed for symptoms up to twice daily. Nizatidine does not impair hepatic metabolism of other drugs. Adverse effects. These agents are extremely well tolerated. The most common

(3)

(4)

(5)

Page 18 of 19

adverse effects reported with nonprescription doses are headache, diarrhea, dizziness, and nausea. d. Prescription H2RAs. Patients with moderate to severe symptoms and/or esophageal mucosal lesions require higher doses of H2RAs than are available over the counter. Unlike patients with peptic ulcer disease, patients with GERD respond best to multiple daily doses of H;RAs rather than to single bedtime doses. e. Prokinetic agents. Patients with moderate to severe GERD may benefit from the addition of these medications, which stimulate esophageal motility and increase LES tone. Prokinetic agents are available only by prescription. (1) Metoclopramide (Reglan, generic). Advene effects limit the usefulness of this agent for many patients. Such effects include sedation, depression, and extrapyramidal effects. (2) Cisapride (Propulsid) may relieve GERD symptoms and heal esophageal damage. Drugs that inhibit certain isoenzymes of the cytochrome p450 system can increase cisapride levels and cause serious cardiac arrhythmias and even death. Concomitant administration of cisapride with the following drugs is contraindicated. (a) Ketoconazole (Nizoral) (b) Itraconazole (Sporanox) (c) Miconazole (Monistat) intravenous (d) Fluconazole (Diflucan) (e) Erythromycin (various) (f) Clarithromycin (Biaxin) (g) Troleandomycin (TAO) f. Proton pump inhibitors. These prescription-only agents provide complete acid suppression by inhibiting the hydrogen-potassium ATPase pump on the surface of the parietal cell. The duration of acid suppression with these agents is about 3 days. Proton pump inhibitors are the most potent and effective agents available for relieving severe GERD symptoms and healing esophageal lesions. (1) Omeprazole (Prilosec) may inhibit hepatic metabolism and thus increase serum concentration/pharmacologic effects of the following drugs. (a) Phenytoin (b) Warfarin (c) Diazepam (2) Lansoprazole (Prevacid) has no clinically significant drug interactions C. Special patient populations 1. Pediatric patients. Gastroesophageal reflux occurs commonly in infants and children. Signs and symptoms in pediatric patients include vomiting, chest pain, irritability, feeding refusal, belching, and apnea. Serious complications (e.g., failure to thrive, esophageal strictures) can occur in infants and children. a. Antacids, with or without alginic acid, have been widely used in infants and children, but their safety has not been clearly established. b. H2RAs have been used safely in children under the supervision of health care providers. c. However, the nonprescription H;RAs are not approved for use in children younger than d. 12 years of age unless directed by a physician. 2. Pregnant patients. Heartburn occurs commonly during pregnancy because of increased abdominal pressure due to the expanding uterus as well as reduced LES pressure resulting from high concentrations of estrogen and progesterone. Nearly half of pregnant women experience GERD, especially during the third trimester. a. Antacids are generally considered safe in pregnancy as long as chronic high doses are avoided. It is best to avoid sodium bicarbonate because of the risks of systemic alkalosis and the sodium load leading to edema and weight gain. b. Data regarding the safety of alginic acid during pregnancy are not available.

Page 19 of 19

data regarding the safety of H2RAs in pregnancy are limited. Pregnant women seeking a nonprescription H;RA for GERD should be directed to use antacids, unless a physician has instructed her otherwise. 3. Elderly patients. Antacids and nonprescription H,RAs may be safely used in elderly patients without any dosage adjustments. a. Dosage reduction of prescription H,RAs may be necessary in elderly patients with reduced renal function. b. Elderly patients are more likely to be taking drugs that interact with antacids, H^RAs, omeprazole, and/or cisapride. c. Elderly patients are also more likely to have symptoms or conditions that require referral to a physician before beginning nonprescription therapy.

c. Controlled