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Key drug. Drugs marked as key drugs are those most commonly used. Drugs are listed in general order of potency.
Laxatives are divided into five primary categories, which vary in terms of mechanism of action, potency, effect, indication, and cost. These five categories consist of bulk, stool softeners, osmotic, stimulants, and enemas.
Therapeutic Overview
The large intestine contains a mixture of the remnants of several meals ingested over 3 to 4 days. The ascending colon holds the contents of the stomach for about an hour. The transverse colon is the primary site for processing feces. The descending colon is a holding tank and conduit for feces for about 24 hours. The sigmoid colon and the rectum act as reservoirs. The nerves responsible for the activation of mass movement are located in the descending colon. Skeletal muscles that maintain continence are located in the surrounding pelvic floor. The integrity of the nervous system is necessary for coordination of the defecation process.
Contractions occur almost continuously in the large intestine and are divided into two basic types. The segmental pattern of motility occurs in the transverse colon, where most of the removal of water and electrolytes occurs and feces are moved forward very slowly. The circular muscles are responsible for segmental contractions. Ring-like contractions divide the colon into chambers called haustra. Haustrations mix and compress the feces, facilitating absorption of water while moving the feces backward and slowly forward. The second type of contraction, the mass movement (power propulsion), is a different process that occurs in the transverse and descending colon to promote bowel movements. Evacuation is aided by (1) voluntary muscles of the abdomen that contract to promote propulsion, (2) relaxation of the circular muscles, with disappearance of haustral contractions, and (3) distention of the gut caused by increased contents of the bowel. The increase in mass movements after a meal is called the gastrocolic reflex.
Pathophysiology
An abnormality anywhere in the evacuation system can cause constipation. Without enough mass, contractions are not stimulated. Disruption of the nerves that control the process prevents proper stimulation of the muscles. Weakness of the muscles of the abdominal wall, of the circular muscles (segmental contractions), or of the muscles that control mass movement also inhibits a bowel movement. Pain with stretching of the gut inhibits contractions. Any structural defect forms a physical barrier to proper transit.
Disease Process
Constipation is a very common complaint among individuals of all ages, leading to 2.5 million physician visits annually in the United States. Prevalence ranges from 2% to 27%.
Constipation means very different things to different patients. Often it is perceived as infrequent or difficult defecation. Some of these changes normally occur if a patient becomes less active or eats less food. The frequency of bowel movements in normal patients ranges from 3 to 12 a week. Changes in consistency are generally due to changes in the amount of fiber eaten. The objective definition of constipation is two or fewer bowel movements per week, or excessive difficulty and straining at defecation.
Chronic functional constipation (CC) and irritable bowel syndrome with constipation (IBS-C) are both functional GI disorders. The definitions of these conditions, which are diagnosed on the basis of symptom criteria, were updated in 2005 with the use of the Rome III criteria. This framework is particularly helpful for categorizing symptoms in difficult cases. According to Rome III, symptoms must be present over the previous 3 months and must have an onset at least 6 months prior to the time of diagnosis. For CC, symptom criteria include straining, lumpy or hard stool, and a sense of incomplete evacuation. Patients also must have insufficient criteria to be given a diagnosis of IBS.
True clinical constipation includes the diagnostic findings of a large amount of feces in the rectal ampulla on digital examination and/or excessive fecal loading of the colon, rectum, or both on abdominal radiograph. Constipation can be acute or chronic, intermittent or continuous.
Constipation has many causes, ranging from inadequate fiber to colon cancer. Medications are an important cause (Table 28-1). Systemic disease may cause constipation through neurologic gut dysfunction, myopathies, and electrolyte imbalances. Diabetic patients may have autonomic nerve dysfunction. Structural causes can be the result of a congenital defect or the structural obstruction of a mass, which may be cancerous. Any sudden change in bowel habits warrants a thorough investigation. The primary cause is a disturbance in motility; secondary causes include medications, malignancy, and non-GI disease.
TABLE 28-1
Medications and Other Agents That Contribute to Constipation
Agents | Example |
Analgesics | codeine |
morphine | |
Prostaglandin inhibitors | |
Antacids | Aluminum hydroxide |
Calcium carbonate | |
Anticholinergics | Antidepressants |
Antihistamines | |
Antiparkinson drugs | |
Antipsychotics | |
Antispasmodics | |
Anxiolytics | |
Other | Anticonvulsants |
Antihypertensives | |
Barium sulfate | |
Iron | |
Lead | |
Monoamine oxidase inhibitors | |
Polystyrene resins verapamil |
Irritable bowel syndrome (IBS) is characterized by a strong relationship between abdominal pain and defecation. Individuals with IBS have visceral hypersensitivity, or increased perception of gut-related events. In IBS, the onset of constipation generally corresponds with an onset of pain at defecation. In patients with functional constipation, some abdominal discomfort or even pain with defecation may occur if a long interval has passed since the last bowel movement, but pain is not a predominant or frequent symptom associated with defecation. Patients with IBS may report abdominal pain, even if they empty their bowels regularly. By definition, functional GI disorders are diagnosed on the basis of symptoms. For many patients, a complete history and physical examination will allow the clinician to make an accurate diagnosis.
Practitioners should ask specifically about any OTC laxatives that the patient has taken. Evaluate for laxative abuse. Prolonged and habitual use of laxatives can result in cathartic colon, thereby causing reliance on laxatives for a regular bowel movement. Laxative abuse syndrome (LAS) is difficult to diagnose; it often is seen in women with depression, personality disorder, or anorexia nervosa. Clinical features of laxative abuse include factitious diarrhea, electrolyte imbalance, osteomalacia, protein-energy malnutrition, cathartic colon, liver disease, and steatorrhea. Many agents can be detected in urine or stool samples.
Mechanism of Action
All laxatives work by increasing fluid retention in the colon, resulting in bulkier and softer stools; by decreasing absorption of luminal water through actions on the colonic mucosa; or by increasing intestinal motility. Expected results may take from 5 minutes to several days.
Bulk Laxatives
Bulk laxatives are nondigestible and nonabsorbable. They swell in water to form a viscous solution or gel that absorbs water and expands, increasing both bulk and moisture content of the stool. Increased bulk stimulates peristalsis, and the absorbed water softens the stool. Bulk laxatives also stimulate colonic bacterial growth that increases the weight of the stool and stretches the intestinal wall, further stimulating peristalsis.
Stool Softeners
Stool softeners act to soften stool by lowering surface tension, allowing the fecal mass to be penetrated by intestinal fluids. They also inhibit fluid and electrolyte reabsorption by the intestine.
Docusate sodium is an anionic surfactant that lowers the surface tension of stool to allow mixing of aqueous and fatty substances, which softens the stool and permits easier defecation.
Osmotic Laxatives
Osmotic laxatives are largely nonabsorbable sugars, although small amounts may be absorbed. Bacteria metabolize these agents into lactic acid, formic acid, acetic acid, and carbon dioxide, which act via osmosis. This means that they are present in solution in higher concentration in the bowel, causing water to move from the tissue into the bowel to equalize osmotic pressure. The increased bulk increases colonic peristalsis. Most are disaccharides. Lactulose is a semisynthetic disaccharide of fructose and galactose. Sorbitol is a nonabsorbable sugar. However, glycerin is a naturally occurring trivalent alcohol suppository that acts via hyperosmotic action and through local irritation and lubrication. The American College of Gastroenterology (ACG) Task Force has named osmotic laxatives as among the most effective types.
Stimulants
Stimulant or irritant laxatives increase peristalsis via several mechanisms, depending on the subclass. Stimulants have a direct action on intestinal mucosa or on the nerve plexus. Diphenylmethane (bisacodyl) stimulates sensory nerves in the intestinal mucosa and increase intestinal chloride secretion. Anthraquinonenone derivatives (i.e., cascara sagrada, senna, and casanthranol) primarily stimulate colonic intramural nerve plexuses.
Senna is protected from small intestinal absorption by its glucose molecules. Colonic bacteria cleave the glucose molecules, releasing active rheinanthrones and producing an action that is specific to the colon. Senna alters the permeability of colon cell walls, resulting in increased fluid accumulation in the colon.
Saline Laxatives
Saline laxatives attract and retain water in the bowel, thereby increasing intraluminal pressure. Saline laxatives produce an osmotic effect, drawing water into the intestinal lumen of the small intestine and the colon and inducing contractions. Magnesium hydroxide also stimulates the release of cholecystokinin, which increases intestinal secretion and stimulates peristalsis and transit.
Enemas
Enemas work primarily by inducing evacuation as a response to colonic distention and via lavage. They create a barrier between the feces and the colon wall that prevents colonic reabsorption of fecal fluid, thus softening the stool. The lubricant effect also eases the passage of feces through the intestine. Oil retention–mineral enemas also work by lubricating the rectum and the colon. Soap suds enemas provide an irritant action.
Treatment Principles
Evidence-Based Recommendations
Three drugs—polyethylene glycol, lactulose, and tegaserod—are rated as signifying benefit, as demonstrated by two or more randomized controlled trials conducted with appropriate methodology.
Cardinal Points of Treatment
TABLE 28-2
Drugs of Choice in the Treatment of Constipation
Short Term | Long Term | |
First line | Mild: bulk | Bulk |
Second line | Severe: enema | Osmotic (saline class) |
Third line | Stimulants | Stimulants |
Nonpharmacologic Treatment
Nonpharmacologic measures are cost-effective and do not produce the complications associated with laxative use. These measures should be used in all patients with constipation, regardless of whether a medication is prescribed. No medication is an adequate replacement for these measures. Nonpharmacologic management of chronic constipation is encouraged for all ages, especially the young and the old. In the absence of disease, adequate colonic movements can be achieved by a regimen based on four basic components: