CLINICAL PHARMACOLOGY OF GASTROINTESTINAL AGENTS
Drugs used in digestive disorders primarily alter GI secretion, absorption, or motility. They may act systemically or locally in the GI tract. The drug groups included in this section are drugs used for acid-peptic disorders, laxatives, antidiarrheals, and antiemetics. Other drug groups used in GI disorders include cholinergics, anticholinergics, corticosteroids, and antiinfective drugs.
Drugs used in Dyspepsia and Peptic Ulcer Disease
There are three major landmarks in the management of peptic ulcer disease. The first was the introduction of the H2 receptor antagonists (H2RA) of which the first was cimetidine. This gave effective acid suppression for the first time.
Drug Category: H2-receptor antagonists
Inhibit the action of histamine on the parietal cell, which inhibits acid secretion. The 4 drugs in this class are all equally effective and are available over the counter in half prescription strength for heartburn treatment. Although the IV administration of H2 blockers may be used to treat acute complications (eg, GI bleeding), the benefits are yet to be proven.
Drug Category: Proton pump inhibitors
Bind to the proton pump of parietal cell, inhibiting secretion of hydrogen ions into gastric lumen. Proton pump inhibitors relieve pain and heal peptic ulcers more rapidly than H2 antagonists do. Drugs in this class are equally effective. They all decrease serum concentrations of drugs that require gastric acidity for absorption, such as ketoconazole or itraconazole. Five drugs are now FDA approved in this category. Omeprazole will soon go off patent and be available as a generic.
The third was the discovery that Helicobacter pylori is associated with much peptic ulcer disease, and with this came the rationale for eradication of the organism. As a result of these innovations, the need for surgery for peptic ulcer has been dramatically reduced. H pylori infection is associated with about 95% of duodenal ulcers and 80% of gastric ulcers.
· Symptomatic management of ulcer dyspepsia and non-ulcer dyspepsia
· Healing of gastric or duodenal ulcers
· Eradication of Helicobacter pylori
· Healing of ulcers related to drugs. This is usually the NSAIDs and in some cases it may be desirable to continue the drug and to give something to heal the ulcers.
· Many of the drugs used in the management of peptic ulcer disease carry a warning that they should not be used in pregnancy or whilst breast feeding. This is usually because of lack of information about safety in pregnancy rather than evidence of adverse effects in pregnancy.
· The exception is misoprostol, a prostaglandin analogue, that should be avoided in pregnancy as it may cause abortion. Indeed, gynaecologists sometimes use it for that end.
· Beware of the possibility of failing to diagnose gastric malignancy.
· PPIs are metabolised mostly in the liver. In liver disease, do not exceed the following doses:
o 30mg daily for lansoprazole
o There are no data on the use of rabeprazole in people with severe hepatic impairment so the manufacturer advises caution.
· Omeprazole and esomeprazole may interfere with warfarin monitoring.
· If metronidazole is used, remember to warn the patient to avoid alcohol.
The article on peptic ulcer disease includes a list of warning signs that may suggest that the patient has a gastric malignancy rather than a peptic ulcer. Malignancy needs to be diagnosed and treated accordingly. Acid suppression will ease the pain of gastric carcinoma and in doing so may delay diagnosis. Acid suppression in malignancy is not contraindicated. It can give in relief in palliative care. Care is required so as not to miss the diagnosis.
Initiation of treatment
Management is not just pharmacological but should include attention to lifestyle. This may include stopping smoking, more regular meals, ceasing excessive alcohol consumption and possibly stopping drugs that may be contributing to the problem. There may be times that it is necessary to continue these drugs but treatment may be given to heal ulcers and to prevent recurrence.
Choice of treatment
· Antacids are cheap, simple and may be all that is required for relief of occasional symptoms. Most antacids contain a mixture of aluminium hydroxide that tends to cause constipation and magnesium hydroxide that tends to cause diarrhoea. The balance between the two cannot be assured and there may be disturbance of bowel function. If a large amount of antacid is being consumed, consider acid suppression. The BNF advises that complexes such as hydrotalcite confer no special advantage.
· The H2RAs provide a swift and effective means of acid suppression and can be used intermittently to achieve control of symptoms. The PPIs are more prolonged in action, produce more profound acid suppression and are more expensive. Their greater efficacy may still provide value for money.
· Attempts should be made to eradicate Helicobacter pylori whenever it is found, whether the diagnosis is duodenal ulcer, gastric ulcer, NSAID induced ulcer or even non-ulcer dyspepsia.
· Only chelated bismuth should be used. It is rather unpleasant to take but it is effective at helping to eradicate H pylori and may have a place in second line treatment after previous failure of eradication.
· Misoprostol tends to be used to heal NSAID associated ulcers. Using a prostaglandin analogue to heal ulcers caused by prostaglandin antagonism is logical but it does tend to cause diarrhoea too and may be unacceptable. Proprietary combinations of NSAID with misoprostol are available.
· Prokinetic agents have fallen from favour. NICE says that cisapride is no longer licenced whilst the evidence for metoclopramide and domperidone is limited.1
Simple antacids will usually give symptomatic
relief of fairly short duration. However, such relief is very non-specific and
should not be taken as indicative of peptic ulcer disease. Heartburn may also
occur in this condition although it is more typical of gastro-oesophageal reflux disease.
An antacid alginate mixture is
usually preferred for reflux.
More profound and prolonged acid suppression may be achieved with a H2RA or, better still, a PPI. The problem is that if the patient is due for endoscopy, the ulcer may heal before the investigation is performed. It may also interfere with the diagnosis of H pylori infection.2
Both H2RAs and PPIs are usually produced at a
standard dose and a lower (half) dose. Some may also be produced at a higher
dose that is usually reserved for gastro-oesophageal reflux disease. To a
considerable extent, the PPIs have superseded the H2RAs as they are more potent
and have a longer effect, although the H2RAs are cheaper.
Clinical Knowledge Summaries recommend that if an ulcer is proven but H pylori testing is negative, then acid suppression at full dose should be offered for 1 or 2 months. A lower maintainance dose may be continued after. The full course should be taken as there is little correlation between the relief of symptoms and the healing of ulcers and if medication is stopped too soon the ulcer will relapse.
Helicobacter pylori eradication
The article on Helicobacter pylori gives much more
detail about the diagnosis and treatment of the infection, including follow up.
If the infection is suspected or demonstrated, then eradication is the logical
course of action. NICE suggests that eradication should be offered if a test is
positive1 and they give
grade A level of evidence. Clinical Evidence suggests that even in the
absence of a history of ulceration, that the finding of the infection should
lead to eradication. It is effective in non-ulcer dyspepsia. There are several regimes that
are available. They usually consist of high dose acid suppression with a PPI
and two antibiotics, also at quite high dose. The usual recommended duration of
treatment is 7 days and it is said to give eradication in about 90% of cases. A
14 days course may produce a higher rate of eradication but the incidence of
adverse effects may make compliance poor. Diarrhoea is common with two
antibiotics at high dose. The BNF states that 2 week regimens using a proton
pump inhibitor and a single antibacterial are licensed, but produce low rates
of eradication and are not recommended.
The following is based on the recommendations of Helicobacter pylori eradication
· omeprazole 20mg
· amoxicillin 1000mg
· clarithromycin 500mg, all twice daily for 7 days.
An alternative regimen with a similar eradication rate of around 90% is:
· omeprazole 20mg
· clarithromycin 250mg
· metronidazole 400mg, again all twice daily for 7 days.
There is probably no difference between the various PPIs available, provided that they are used at equivalent dose and this is a matter of personal choice. It would be reasonable to have local protocols based upon local patterns of antibiotic resistance. Resistance to metronidazole, in particular, is highly variable.If there is failure of treatment, this is usually due to poor compliance or antibiotic resistance. The latter can even develop during treatment, especially with a single antibiotic. A further attempt at eradication may be made. The regimen should be adjusted according to the nature of the problem. If it was poor compliance, a more tolerable regimen may be required. If there is antibiotic resistance and the organism has been cultured after endoscopy, it may be possible to obtain sensitivities. It is common practice to use 4 drugs for a repeated attempt. The antibiotics can be changed and chelated bismuth may be used. A typical quadruple therapy would be:
· a PPI twice a day
· bismuth 120 mg four times a day
· metronidazole 400 mg three times a day
· oxytetracycline 500 mg four times a day, all for 7 days.
Reinforce the importance of compliance as it is not easy to take so many tablets so many times a day, even for just a week.
Ulcers associated with NSAIDs
If a drug is thought to be the cause of peptic ulceration, it is sensible to stop the drug or change it to another with a lower risk. There may be times when it is desirable to continue that drug. An old person may need treatment for arthritis to maintain mobility or aspirin may be required in cardiovascular disease. It is often possible to heal the ulcer without stopping the offending drug and a maintenance dose is continued to prevent relapse.
· Clinical Knowledge Summaries recommend that omeprazole 20mg daily is preferable to ranitidine 150mg twice daily as the respective rates of healing are 80% and 63%.
· H2RAs are slow to heal the ulcers if the offending drug is not stopped and so, under these conditions, a PPI is preferred.
· H pylori eradication is no more effective than omeprazole alone to heal ulcers, but if the infection is present, then eradication will reduce the rate of relapse.
· H pylori is not associated with an increased risk of ulcer with NSAIDs in the elderly but there is an increased risk of bleeding.
Drug Category: Prostaglandins
Can prevent peptic ulcers in patients taking NSAIDs and may be used with NSAIDs in patients at a high risk of complications.
Misoprostol is a prostaglandin analogue that is both an antisecretory and a protective agent for the healing of both gastric and duodenal ulcers. Its use is limited as diarrhoea is a common adverse effect and acid suppression tends to be better tolerated. Only the higher doses of misoprostol match acid suppression for efficacy.
Patients should be reviewed at the end of a course of treatment, especially H pylori eradication, to confirm a satisfactory outcome.
If simple acid suppression is given, review after 1 or 2 months is required to ascertain that the end is being achieved and there are no warning signs such as weight loss to suggest malignancy.
Complications and reasons to discontinue drug
It may be necessary to stop treatment if adverse effects become intolerable or are of a serious nature.
· During H pylori eradication, abdominal discomfort and diarrhoea are very common but the patient should be encouraged to persist to achieve eradication and to heal the ulcer permanently. Lactobacilli, usually ingested in the form of natural unpasteurised yoghurt, may be of value in replacing the natural flora of the gut and they may also have a suppressive effect on H pylori.8
· Adverse reactions to PPIs and H2RAs are usually rare and mild but severe problems can arise. Rare but not serious problems may include taste disturbance, peripheral oedema, photosensitivity, fever, arthralgia, myalgia and sweating. Serious problems include liver dysfunction, hypersensitivity reactions (including urticaria, angioedema, bronchospasm, anaphylaxis), depression, interstitial nephritis, blood disorders (including leucopenia, leucocytosis, pancytopenia, thrombocytopenia), and skin reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous eruption).
· Misoprostol often causes diarrhoea and abdominal pain, especially at higher doses.
Treatment goals are the relief of discomfort and protection of the gastric mucosal barrier to promote healing. Eradication of H pylori infection is a prolonged and complicated process requiring confirmation of the presence of the organism, which is beyond the scope of practice in the ED. Cessation of the causative agent and antacids may be sufficient outpatient therapy in mild cases. Most patients require an H2-receptor antagonist or a proton pump inhibitor, which has been proven to provide faster and more reliable healing than antacids. Either an H2-receptor blocker or a proton pump inhibitor can be used as a first-line agent. With continued symptoms, they may be used together. In refractory cases, sucralfate also may be indicated.
Drug Category: Antacids
Aluminum-containing and magnesium-containing antacids can be helpful in relieving symptoms of gastritis by neutralizing gastric acids. These agents are inexpensive and safe.
Drug Category: Gastrointestinal agents
Are effective in the treatment of peptic ulcers and in preventing relapse. Their mechanism of action is not clear. Multiple doses are required, and they are not as effective as the other options.
LAXATIVES AND CATHARTICS
Laxatives and cathartics are somewhat arbitrarily classified as bulk-forming laxatives, surfactant laxatives or stool softeners, saline cathartics, stimulant cathartics, lubricant or emollient laxatives, and miscellaneous. Individual drugs are listed in Drugs at a Glance: Laxatives and Cathartics.
Bulk-forming laxatives (eg, polycarbophil, psyllium seed) are substances that are largely unabsorbed from the intestine. When water is added, these substances swell and become gellike. The added bulk or size of the fecal mass stimulates peristalsis and defecation. The substances also may act by pulling water into the intestinal lumen. Bulk-forming laxatives are the most physiologic laxatives because their effect is similar to that of increased intake of dietary fiber. They usually act within 12 to 24 hours, but may take as long as 2 to 3 days to exert their full effects.
Surfactant Laxatives (Stool Softeners)
Surfactant laxatives (eg, docusate calcium, potassium, or sodium) decrease the surface tension of the fecal mass to allow water to penetrate into the stool. They also act as a detergent to facilitate admixing of fat and water in the stool. As a result, stools are softer and easier to expel. These agents have little if any laxative effect. Their main value is to prevent straining while expelling stool. They usually act within 1 to 3 days and should be taken daily.
Saline laxatives (eg, magnesium citrate, milk of magnesia) are not well absorbed from the intestine. Consequently, they increase osmotic pressure in the intestinal lumen and cause water to be retained. Distention of the bowel leads to increased peristalsis and decreased intestinal transit time for the fecal mass. The resultant stool is semifluid. These laxatives are used when rapid bowel evacuation is needed. With oral magnesium preparations, effects occur within 0.5 to 6 hours; with sodium phosphate–containing rectal enemas, effects occur within 15 minutes.
Saline laxatives are generally useful and safe for shortterm treatment of constipation, cleansing the bowel prior to endoscopic examinations, and treating fecal impaction. However, they are not safe for frequent or prolonged usage or for certain patients because they may produce fluid and electrolyte imbalances. For example, patients with impaired renal function are at risk of developing hypermagnesemia with magnesium-containing laxatives because some of the magnesium is absorbed systemically. Patients with congestive heart failure are at risk of fluid retention and edema with sodium-containing laxatives.
Polyethylene glycol–electrolyte solution (eg, NuLytely) is a nonabsorbable oral solution that induces diarrhea within 30 to 60 minutes and rapidly evacuates the bowel, usually within 4 hours. It is a prescription drug used for bowel cleansing before GI examination (eg, colonoscopy) and is contraindicated with GI obstruction, gastric retention, colitis, or bowel perforation.
Polyethylene glycol solution (MiraLax) is an oral laxative that may be used to treat occasional constipation. Effects may require 2 to 4 days. It is a prescription drug and should not be taken longer than 2 weeks.
The stimulant cathartics are the strongest and most abused laxative products. These drugs act by irritating the GI mucosa and pulling water into the bowel lumen. As a result, feces are moved through the bowel too rapidly to allow colonic absorption of fecal water, so a watery stool is eliminated. These drugs should not be used frequently or longer than 1 week because they may produce serum electrolyte and acid–base imbalances (eg, hypocalcemia, hypokalemia, metabolic acidosisbor alkalosis). Oral stimulant cathartics include bisacodyl, cascara sagrada, castor oil, and senna products. These products produce laxative effects in 6 to 12 hours. As a result, a single bedtime dose usually produces a morning bowel movement. Rectal suppository products include bisacodyl, which produces effectsbwithin 15 minutes to 2 hours, and glycerin. In addition to irritant, stimulant effects, glycerin exerts hyperosmotic effects in the colon. It usually acts within 30 minutes. Glycerin is not given orally for laxative effects.
Mineral oil is the only lubricant laxative used clinically. It lubricates the fecal mass and slows colonic absorption of water from the fecal mass, but the exact mechanism of action is unknown. Effects usually occur in 6 to 8 hours. Oral mineral oil may cause several adverse effects and is not recommended for long-term use. Mineral oil enemas are sometimes used to soften fecal impactions and aid their removal.
Lactulose is a disaccharide that is not absorbed from the GI tract. It exerts laxative effects by pulling water into the intestinal lumen. It is used to treat constipation and hepatic encephalopathy. The latter condition usually results from alcoholic liver disease in which ammonia accumulates and causes stupor or coma. Ammonia is produced by metabolism of dietary protein and intestinal bacteria. Lactulose decreases production of ammonia in the intestine. The goal of treatment is usually to maintain two to three soft stools daily; effects usually occur within 24 to 48 hours. The drug should be used cautiously because it may produce electrolyte imbalances and dehydration.
Sorbitol is a monosaccharide that pulls water into the intestinal lumen and has laxative effects. It is often given with sodium polystyrene sulfonate (Kayexalate), a potassiumremoving resin used to treat hyperkalemia, to prevent constipation and aid expulsion of the potassium–resin complex.
Laxatives and cathartics are widely available on a nonprescription basis and are among the most frequently abused drugs. One reason for overuse is the common misconception that a daily bowel movement is necessary for health and wellbeing, even with little intake of food or fluids. This notion may lead to a vicious cycle of events in which a person fails to have a bowel movement, takes a strong laxative, again fails to have a bowel movement, and takes another laxative before the fecal column has had time to become reestablished (2 to 3 days with normal food intake). Thus, a pattern of laxative dependence and abuse is established.
Laxatives are also abused for weight control, probably most often by people with eating disorders and those who must meet strict weight requirements (eg, some athletes). This is a very dangerous practice because it may lead to lifethreatening fluid and electrolyte imbalances.
Indications for Use
Despite widespread abuse of laxatives and cathartics, there are several rational indications for use:
1. To relieve constipation in pregnant women, elderly clients whose abdominal and perineal muscles have become weak and atrophied, children with megacolon, and clients receiving drugs that decrease intestinal motility (eg, opioid analgesics, drugs with anticholinergic effects)
2. To prevent straining at stool in clients with coronary artery disease (eg, postmyocardial infarction), hypertension, cerebrovascular disease, and hemorrhoids and other rectal conditions
3. To empty the bowel in preparation for bowel surgery or diagnostic procedures (eg, colonoscopy, barium enema)
4. To accelerate elimination of potentially toxic substances from the GI tract (eg, orally ingested drugs or toxic compounds)
5. To prevent absorption of intestinal ammonia in clients with hepatic encephalopathy
6. To obtain a stool specimen for parasitologic examination
7. To accelerate excretion of parasites after anthelmintic drugs have been administered
8. To reduce serum cholesterol levels (psyllium products)
Contraindications to Use
Laxatives and cathartics should not be used in the presence of undiagnosed abdominal pain. The danger is that the drugs may cause an inflamed organ (eg, the appendix) to rupture and spill GI contents into the abdominal cavity with subsequent peritonitis, a life-threatening condition. Oral drugs also are contraindicated with intestinal obstruction and fecal impaction.
Choice of a laxative or cathartic depends on the reason for use and the client’s condition.
1. For long-term use of laxatives or cathartics in clients who are elderly, unable or unwilling to eat an adequate diet, or debilitated, bulk-forming laxatives (eg, Metamucil) usually are preferred. However, because obstruction may occur, these agents should not be given to clients with difficulty in swallowing or adhesions or strictures in the GI tract, or to those who are unable or unwilling to drink adequate fluids.
2. For clients in whom straining is potentially harmful or painful, stool softeners (eg, docusate sodium) are the agents of choice.
3. For occasional use to cleanse the bowel for endoscopic or radiologic examinations, saline or stimulant cathartics are acceptable (eg, magnesium citrate, polyethylene glycol–electrolyte solution, bisacodyl). These drugs should not be used more than once per week. Frequent use is likely to produce laxative abuse.
4. Oral use of mineral oil may cause potentially serious adverse effects (decreased absorption of fat-soluble vitamins and some drugs, lipid pneumonia if aspirated into the lungs). Thus, mineral oil is not an oral laxative of choice in any condition, although occasional use in the alert client is unlikely to be harmful. It should not be used regularly. Mineral oil is probably most useful as a retention enema to soften hard, dry feces and aid
in their expulsion.
5. In fecal impaction, a rectal suppository (eg, bisacodyl) or an enema (eg, oil retention or Fleet enema) is preferred. Oral laxatives are contraindicated when fecal impaction is present but may be given after the rectal mass is removed. Once the impaction is relieved, measures should be taken to prevent recurrence. If dietary and other nonpharmacologic measures are ineffective or contraindicated, use of a bulk-forming agent daily or another laxative once or twice weekly may be necessary.
6. Saline cathartics containing magnesium, phosphate, or potassium salts are contraindicated in clients with renal failure because hypermagnesemia, hyperphosphatemia, or hyperkalemia may occur.
7. Saline cathartics containing sodium salts are contraindicated in clients with edema or congestive heart failure because enough sodium may be absorbed to cause further fluid retention and edema. They also should not be used in clients with impaired renal function or those following a sodium-restricted diet for hypertension.
8. Polyethylene glycol–electrolyte solution is formulated for rapid and effective bowel cleansing without significant changes in water or electrolyte balance.
Antidiarrheal drugs are used to treat diarrhea, defined as the frequent expulsion of liquid or semiliquid stools. Diarrhea is a symptom of numerous conditions that increase bowel motility, cause secretion or retention of fluids in the intestinal lumen, and cause inflammation or irritation of the gastrointestinal (GI) tract. As a result, bowel contents are rapidly propelled toward the rectum, and absorption of fluids and electrolytes is limited.
Some causes of diarrhea include the following:
1. Excessive use of laxatives
2. Intestinal infections with viruses, bacteria, or protozoa. A common source of infection is ingestion of food or fluid contaminated by Salmonella, Shigella, or Staphylococcus microorganisms. So-called travelers’ diarrhea is usually caused by an enteropathogenic
strain of Escherichia coli.
3. Undigested, coarse, or highly spiced food in the GI tract. The food acts as an irritant and attracts fluids in a defensive attempt to dilute the irritating agent. This may result from inadequate chewing of food or lack of digestive enzymes.
4. Lack of digestive enzymes. Deficiency of pancreatic enzymes inhibits digestion and absorption of carbohydrates, proteins, and fats. Deficiency of lactase, which breaks down lactose to simple sugars (ie, glucose and galactose) that can be absorbed by GI mucosa, inhibits digestion of milk and milk products. Lactase deficiency commonly occurs among people of African and Asian descent.
5. Inflammatory bowel disorders, such as gastroenteritis, diverticulitis, ulcerative colitis, and Crohn’s disease. In these disorders, the inflamed mucous membrane secretes large amounts of fluids into the intestinal lumen, along with mucus, proteins, and blood, and absorption of water and electrolytes is impaired. In addition, when the ileum is diseased or a portion is surgically excised, large amounts of bile salts reach the colon, where they act as cathartics and cause diarrhea. Bile salts are normally reabsorbed from the ileum.
6. Drug therapy. Many oral drugs irritate the GI tract and may cause diarrhea, including acarbose, antacids that contain magnesium, antibacterials, antineoplastic agents, colchicine, laxatives, metformin, metoclopramide, misoprostol, serotonin reuptake inhibitors, tacrine, and tacrolimus. Antibacterial drugs are commonly used offenders that also may cause diarrhea by altering the normal bacterial flora in the intestine. Antibiotic-associated colitis (also called pseudomembranous colitis and Clostridium difficile colitis) is a serious condition that results from oral or parenteral antibiotic therapy. By suppressing normal flora, antibiotics allow gram-positive, anaerobic C. difficile organisms to proliferate. The organisms produce a toxin that causes fever, abdominal pain, inflammatory lesions of the colon, and severe diarrhea with stools containing mucus, pus, and sometimes blood. Symptoms may develop within a few days or several weeks after the causative antibiotic is discontinued. Antibiotic-associated colitis is more often associated with ampicillin, cephalosporins, and clindamycin, but may occur with any antibiotic or combination of antibiotics that alters intestinal microbial flora.
7. Intestinal neoplasms. Tumors may increase intestinal motility by occupying space and stretching the intestinal wall. Diarrhea sometimes alternates with constipation in colon cancer.
8. Functional disorders. Diarrhea may be a symptom of stress or anxiety in some clients. No organic disease process can be found in such circumstances.
9. Hyperthyroidism. This condition increases bowel motility.
10. Surgical excision of portions of the intestine, especially the small intestine. Such procedures decrease the absorptive area and increase fluidity of stools.
11. Human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS). Diarrhea occurs in most clients with HIV infection, often as a chronic condition that contributes to malnutrition and weight loss. It may be caused by drug therapy, infection with a variety of microorganisms, or other factors. Diarrhea may be acute or chronic and mild or severe. Most episodes of acute diarrhea are defensive mechanisms by which the body tries to rid itself of irritants, toxins, and infectious agents. These are usually self-limiting and subside within 24 to 48 hours without serious consequences. If severe or prolonged, acute diarrhea may lead to serious fluid and electrolyte depletion, especially in young children and older adults. Chronic diarrhea may cause malnutrition and anemia and is often characterized by remissions and exacerbations.
Antidiarrheal drugs include a variety of agents, most of which are discussed in other chapters. When used for treatment of diarrhea, the drugs may be given to relieve the symptom (nonspecific therapy) or the underlying cause of the symptom (specific therapy). Individual drugs are listed in Drugs at a Glance: Antidiarrheal Drugs.
A major element of nonspecific therapy is adequate fluid and electrolyte replacement. When drug therapy is required, nonprescription antidiarrheal drugs (eg, loperamide) may be effective. Loperamide (Imodium) is a synthetic derivative of meperidine that decreases GI motility by its effect on intestinal muscles. Because loperamide does not penetrate the central nervous system (CNS) well, it does not cause the CNS effects associated with opioid use and lacks potential for abuse. Although adverse effects are generally few and mild, loperamide can cause abdominal pain, constipation, drowsiness, fatigue, nausea, and vomiting. For nonprescription use, dosages for adults should not exceed 8 mg/day; with supervision by a health care provider, maximum daily dosage is 16 mg/day. In general, loperamide should be discontinued after 48 hours if clinical improvement has not occurred. Overall, opiates and opiate derivatives are the most effective agents for symptomatic treatment of diarrhea. These drugs decrease diarrhea by slowing propulsive movements in the small and large intestines. Morphine, codeine, and
related drugs are effective in relieving diarrhea but are rarely used for this purpose because of their adverse effects. Opiates have largely been replaced by the synthetic drugs diphenoxylate, loperamide, and difenoxin, which are used only for treatment of diarrhea and do not cause morphine-like adverse effects in recommended doses. Diphenoxylate and difenoxin require a prescription.
Bismuth salts have antibacterial and antiviral activity; bismuth subsalicylate (Pepto-Bismol, a commonly used overthe- counter drug) also has antisecretory and possibly antiinflammatory effects because of its salicylate component.
Octreotide acetate is a synthetic form of somatostatin, a hormone produced in the anterior pituitary gland and in the pancreas. The drug may be effective in diarrhea because it decreases GI secretion and motility. It is used for diarrhea associated with carcinoid syndrome, intestinal tumors, HIV/AIDS, and diarrhea that does not respond to other antidiarrheal drugs.
Other nonspecific agents sometimes used in diarrhea areanticholinergics and polycarbophil and psyllium preparations. Anticholinergic drugs, of which atropine is the prototype, are infrequently used because doses large enough to decrease intestinal motility and secretions cause intolerable adverse effects. The drugs are occasionally used to decrease abdominal cramping and pain (antispasmodic effects) associated with acute nonspecific diarrhea and chronic diarrhea associated with inflammatory bowel disease. Polycarbophil (eg, FiberCon) and psyllium preparations (eg, Metamucil) are most often used as bulk-forming laxatives. They are occasionally used in diarrhea to decrease fluidity of stools. The preparations absorb large amounts of water and produce stools of gelatin-like consistency. They may cause abdominal discomfort and bloating.
Indications for Use
Despite the limitations of drug therapy in prevention and treatment of diarrhea, antidiarrheal drugs are indicated in the following circumstances:
1. Severe or prolonged diarrhea (>2 to 3 days), to prevent severe fluid and electrolyte loss
2. Relatively severe diarrhea in young children and older adults. These groups are less able to adapt to fluid and electrolyte losses.
3. In chronic inflammatory diseases of the bowel (ulcerative colitis and Crohn’s disease), to allow a more nearly normal lifestyle
4. In ileostomies or surgical excision of portions of the ileum, to decrease fluidity and volume of stool
5. HIV/AIDS-associated diarrhea
6. When specific causes of diarrhea have been determined
Contraindications to Use
Contraindications to the use of antidiarrheal drugs include diarrhea caused by toxic materials, microorganisms that penetrate intestinal mucosa (eg, pathogenic E. coli, Salmonella, Shigella), or antibiotic-associated colitis. In these circumstances, antidiarrheal agents that slow peristalsis may aggravate and prolong diarrhea. Opiates (morphine, codeine) usually are contraindicated in chronic diarrhea because of possible opiate dependence. Difenoxin, diphenoxylate, and loperamide are contraindicated in children younger than 2 years of age.