Introduction
The scientific definitions of constipation rely mostly on stool number. However, patients use the term constipation not only for decreased frequency, but also for difficulty in initiation or passage, passage of firm or small-volume feces, or a feeling of incomplete evacuation. Constipation occurs when a person passes less than three bowel movements a week or has difficult bowel movements.
Causes of Constipation
- Lack of dietary fiber,
- Some drugs
- Hormonal disturbances
- Neurogenic disorders and
- Systemic illnesses.
In most cases of chronic constipation, no specific cause is found. Up to 60% of patients presenting with constipation will have normal colonic transit. These patients either have irritable bowel syndrome or define constipation in terms other than stool frequency (e.g., changes in consistency, excessive straining, or a feeling of incomplete evacuation.
Treatment of Constipation
Constipation has two approaches in its treatment. These are:
- Non-pharmacological approach and
- Pharmacological approach
1. Non-pharmacological Approach
This entails
- Adherence to a fiber-rich (20 to 30 g daily) diet
- Adequate fluid intake
- Appropriate bowel habits and training and
- Avoidance of constipating drugs.
Constipation related to medications can be corrected by use of alternative drugs where possible, or adjustment of dosage.
2. Pharmacological Approach
- Laxatives
- Prokinetic agents
- Suppositories and Enemas
Laxatives
The terms laxatives, cathartics, purgatives, aperients, and evacuants often are used interchangeably. There is a distinction, however, between laxation (the evacuation of formed fecal material from the rectum) and catharsis (the evacuation of unformed, usually watery fecal material from the entire colon).
Most of the commonly used agents promote laxation, but some are actually cathartics that act as laxatives at low doses. In addition to treating constipation, laxatives frequently are employed before surgical, radiological, and endoscopic procedures where an empty colon is desirable.
Mechanism of Action of Laxatives
- It enhances retention of intraluminal fluid by hydrophilic or osmotic mechanisms
- It decreases net absorption of fluid by effects on small- and large-bowel fluid and electrolyte transport; or
- It alters motility by either inhibiting segmenting (non-propulsive) contractions or stimulating propulsive contractions
Classification of Laxatives
Classification of laxatives by the pattern of effects produced by the usual clinical dosage
1. Bulk forming Laxatives: Softening of Feces, 1 To 3 Days
- Bran
- Psyllium preparations
- Methylcellulose
- Calcium polycarbophil
- Surfactant laxatives
- Docusates
- Poloxamers
- Lactulose
2. Stimulant laxatives: Soft or Semifluid Stool, 6 To 8 Hours
- Stimulant laxatives
- Diphenylmethane derivatives
- Bisacodyl
- Anthraquinone derivatives
- Senna
- Cascara sagrada
3. Osmotic laxatives: Watery Evacuation, 1 To 3 Hours
- Sodium phosphates
- Magnesium sulfate
- Milk of magnesia
- Magnesium citrate
- Castor oil
Osmotic laxatives are employed in high dosage for rapid cathartic effect and in lower dosage for laxative effect.
Osmotically Active Agents
a. Saline Laxatives
Laxatives containing magnesium cations or phosphate anions commonly are called saline laxatives: magnesium sulfate, magnesium hydroxide, magnesium citrate, sodium phosphate.
Mechanism of Action of Saline Laxatives
- Their cathartic action is believed to result from osmotically mediated water retention, which then stimulates peristalsis.
- production of inflammatory mediators.
- Magnesium-containing laxatives may stimulate the release of cholecystokinin, which leads to intraluminal fluid and electrolyte accumulation and to increased intestinal motility.
Phosphate salts are better absorbed than magnesium-based agents and therefore need to be given in larger doses to induce catharsis.
The most frequently employed preparation of sodium phosphate is an oral solution (FLEET PHOSPHO-SODA), which contains 1.8 g of dibasic sodium phosphate and 4.8 g of monobasic sodium phosphate in 10 ml.
The usual adult dose is 20 to 30 ml taken with ample water.
A newer preparation of phosphate salts (VISICOL) is available in tablet form, containing 1.5 g total sodium phosphate per tablet.
Magnesium- and phosphate-containing preparations are tolerated reasonably well by most patients. However, they must be used with caution or avoided in patients with renal insufficiency, cardiac disease, or preexisting electrolyte abnormalities, and in patients on diuretic therapy.
b. Non digestible Sugars and Alcohols.
Lactulose is a synthetic disaccharide of galactose and fructose that resists intestinal disaccharidase activity. This and other non absorbable sugars such as sorbitol and mannitol, are hydrolyzed in the colon to short-chain fatty acids, which stimulate colonic propulsive motility by osmotically drawing water into the lumen.
Sorbitol and lactulose are equally efficacious in the treatment of constipation caused by opioids and vincristine, of constipation in the elderly, and of idiopathic chronic constipation.
They are available as 70% solutions, which are given in doses of 15 to 30 ml at night, with increases as needed up to 60 ml per day in divided doses. Effects may not be seen for 24 to 48 hours after dosing is begun.
Abdominal discomfort or distention and flatulence are relatively common in the first few days of treatment but usually subside with continued administration.
A few patients dislike the sweet taste of the preparations; dilution with water or administering the preparation with fruit juice can mask the taste.
Polyethylene Glycol-Electrolyte Solutions.
Long-chain polyethylene glycols (PEGs; molecular weight ~3350 daltons) are poorly absorbed, and PEG solutions are retained in the lumen by virtue of their high osmotic nature. When used in high volume, aqueous solutions of PEGs (COLYTE, GOLYTELY, others) produce an effective catharsis and are used widely for colonic cleansing for radiological, surgical, and endoscopic procedures (4 liters of this solution taken over 3 hours, beginning at least 4 hours before the procedure). To avoid net transfer of ions across the intestinal wall, these preparations contain an isotonic mixture of sodium sulfate, sodium bicarbonate, sodium chloride, and potassium chloride. The osmotic activity of the PEG molecules retains the added water and the electrolyte concentration assures little or no net ionic shifts.
PEGs are also increasingly being used in smaller doses (250 to 500 ml daily) for the treatment of constipation in difficult cases. A powder form of polyethylene glycol 3350 (MIRALAX) is now available for the short-term treatment (2 weeks or less) of occasional constipation, although the agent has been prescribed safely for longer periods in clinical practice. The usual dose is 17 g of powder per day in 8 ounces of water. This preparation does not contain electrolytes, so larger volumes may represent a risk for ionic shifts. As with other laxatives, prolonged, frequent, or excessive use may result in dependence or electrolyte imbalance.
Stimulant (Irritant) Laxatives
Stimulant laxatives have direct effects on enterocytes, enteric neurons, and GI smooth muscle.
Mechanism of Action of Stimulant Laxatives
- These agents probably induce a limited low-grade inflammation in the small and large bowel to promote accumulation of water and electrolytes and stimulate intestinal motility.
Other mechanisms include:
- activation of prostaglandin-cyclic AMP and NO-cyclic GMP pathways, platelet-activating factor production , and perhaps inhibition of Na+,K+-ATPase.
Examples of Stimulant Laxatives
Examples are
- Diphenylmethane derivatives
- Anthraquinones, and
- Ricinoleic acid.
a. Diphenylmethane Derivatives
Sodium picosulfate is a diphenylmethane derivative widely available. It is hydrolyzed by colonic bacteria to its active form, and hence acts locally only in the colon.
Bisacodyl is the most popular diphenylmethane derivative available. It is marketed as an enteric-coated preparation (DULCOLAX, CORRECTOL, others) and as a suppository for rectal administration.
The usual oral daily dose of bisacodyl is 10 to 15 mg for adults and 5 to 10 mg for children ages 6 to 12 years old.
The drug requires hydrolysis by endogenous esterases in the bowel for activation, and so the laxative effects after an oral dose usually are not produced in less than 6 hours; taken at bedtime, it will produce its effect the next morning.
Suppositories work much more rapidly, within 30 to 60 minutes. Due to the possibility of developing an atonic nonfunctioning colon, bisacodyl should not be used for more than 10 consecutive days.
Bisacodyl is mainly excreted in the stool; about 5% is absorbed and excreted in the urine as a glucuronide.
Overdosage can lead to catharsis and fluid and electrolyte deficits.
The diphenylmethanes can damage the mucosa and initiate an inflammatory response in the small bowel and colon. To avoid drug activation in the stomach with consequent gastric irritation and cramping, patients should swallow tablets without chewing or crushing and avoid milk or antacid medications within 1 hour of the ingestion of bisacodyl.
b. Anthraquinone Laxatives
These derivatives of plants such as aloe, cascara, and senna share a tricyclic anthracene nucleus modified with hydroxyl, methyl, or carboxyl groups to form monoanthrones, such as rhein and frangula.
Monoanthrones are irritating to the oral mucosa; however, the process of aging or drying converts them to more innocuous dimeric (dianthrones) or glycoside forms. This process is reversed by bacterial action in the colon to generate the active forms.
Anthraquinone laxatives can produce giant migrating colonic contractions and induce water and electrolyte secretion. They are poorly absorbed in the small bowel, but because they require activation in the colon, the laxative effect is not noted until 6 to 12 hours after ingestion. Active compounds are absorbed to a variable degree from the colon and excreted in the bile, saliva, milk, and urine. Their use is limited due to adverse effects such as melatonic pigmentation of the mucosa and abuse
c. Ricinoleic acid.
Castor Oil. An age-old home remedy, castor oil (PURGE, NEOLOID, others) is derived from the bean of the castor plant, Ricinus communis, and contains two well-known noxious ingredients: an extremely toxic protein, ricin, and an oil composed chiefly of the triglyceride of ricinoleic acid. The triglyceride is hydrolyzed in the small bowel by the action of lipases into glycerol and the active agent, ricinoleic acid, which acts primarily in the small intestine to stimulate secretion of fluid and electrolytes and speed intestinal transit. When taken on an empty stomach, as little as 4 ml of castor oil may produce a laxative effect within 1 to 3 hours; however, the usual dose for a cathartic effect is 15 to 60 ml for adults. Because of its unpleasant taste and its potential toxic effects on intestinal epithelium and enteric neurons, castor oil is seldom recommended now.
Prokinetic and Other Agents for Constipation
Prokinetic generally is reserved for agents that enhance GI transit via interaction with specific receptors involved in the regulation of motility. Currently available prokinetic agents are not very useful in the treatment of constipation. However, newer agents, particularly the more potent 5-HT4-receptor agonists such as tegaserod, may be useful for the treatment of chronic constipation.
Another potentially useful agent is misoprostol, a synthetic prostaglandin analog. Prostaglandins can stimulate colonic contractions, particularly in the descending colon, and this may account for the diarrhea that limits the usefulness of misoprostol as a gastro-protectant. On the other hand, this property may be utilized for therapeutic gain in patients with intractable constipation.
Colchicine, a microtubule formation inhibitor used for gout , also has been shown to be effective in constipation (mechanism unknown), but its toxicity has limited widespread use.
A novel biological agent, neurotrophin-3 (NT-3), recently was shown to be effective in improving frequency and stool consistency and decreasing straining, again by an unknown mechanism of action.
Enemas and Suppositories
Enemas commonly are employed, either by themselves or as adjuncts to bowel preparation regimens, to empty the distal colon or rectum of retained solid material. Bowel distention by any means will produce an evacuation reflex in most people, and almost any form of enema, including normal saline solution, can achieve this. Specialized enemas contain additional substances that either are osmotically active or irritant; however, their safety and efficacy have not been studied in a rigorous manner. Repeated enemas with tap water or other hypotonic solutions can cause hyponatremia; repeated enemas with sodium phosphate-containing solution can cause hypocalcemia. Phosphate-containing enemas also are known to alter the appearance of rectal mucosa.
Glycerin is a trihydroxy alcohol that is absorbed orally, but acts as a hygroscopic agent and lubricant when given rectally. The resultant water retention stimulates peristalsis and usually produces a bowel movement in less than an hour. Glycerin is for rectal use only and is given in a single daily dose as a 2- or 3-g rectal suppository or as 5 to 15 ml of an 80% solution in enema form. Rectal glycerin may cause local discomfort, burning, or hyperemia and (minimal) bleeding. Some glycerin suppositories contain sodium stearate, which can cause local irritation.
Dietary Fiber and Supplements
Under normal circumstances, the bulk, softness, and hydration of feces depend on the fiber content of the diet. Fiber is defined as that part of food that resists enzymatic digestion and reaches the colon largely unchanged. Colonic bacteria ferment fiber to varying degrees, depending on its chemical nature and water solubility.
Fermentation of fiber has two important effects:
- it produces short-chain fatty acids that are trophic for colonic epithelium, and
- it increases bacterial mass. Although fermentation of fiber generally decreases stool water, short-chain fatty acids also may have a prokinetic effect, and increased bacterial mass may contribute to increased stool volume.
On the other hand, fiber that is not fermented can attract water and increase stool bulk. In general, insoluble, poorly fermentable fibers, such as lignin, are most effective in increasing stool bulk and transit. Bran, the residue left when flour is made from cereals, contains more than 40% dietary fiber. Wheat bran, with its high lignin content, is most effective at increasing stool weight. Fruits and vegetables contain more pectins and hemicelluloses, which are more readily fermentable and produce less effect on stool transit. Psyllium husk, derived from the seed of the plantago herb (Plantago ovata; known as ispaghula or isabgol , is a component of many commercial products for constipation.
Conclusion
Although many choices exist for this condition, most therapies are empirical and nonspecific. Constipation often can be addressed by simple measures such as increasing fiber intake, avoiding constipating medications, and the judicious use of osmotic laxatives on an as-needed basis. For more persistent symptoms, a specific prokinetic 5-HT4-receptor agonist, tegaserod, may be used with modest efficacy in women who also have irritable bowel syndrome. Stimulant laxatives, although effective, should be avoided for long-term use. Patients with chronic constipation who do not respond to simple measures should undergo further testing to discover uncommon but specific disorders of colonic or anorectal motility.