Protective Drugs

gravid uterus) significantly restrict its therapeutic utility.

Carbenoxolone (B) is a derivative of glycyrrhetinic acid, which occurs in the sap of licorice root (succus liquiri-tiae). Carbenoxolone stimulates mucus production. At the same time, it has a mineralocorticoid-like action (due to inhibition of 11-p-hydroxysteroid dehy-drogenase) that promotes renal reabsorption of NaCl and water. It may, therefore, exacerbate hypertension, congestive heart failure, or edemas. It is obsolete.

III. Eradication of Helicobacter pylori C. This microorganism plays an important role in the pathogenesis of chronic gastritis and peptic ulcer disease. The combination of antibacterial drugs and omeprazole has proven effective. In case of intolerance to amoxicillin (p. 270) or clarithromycin (p. 276), metronidazole (p. 274) can be used as a substitute. Colloidal bismuth compounds are also effective; however, the problem of heavy-metal exposure compromises their long-term use.

Sucralfate (A) contains numerous aluminum hydroxide residues. However, it is not an antacid because it fails to lower the overall acidity of gastric juice. After oral intake, sucralfate molecules undergo cross-linking in gastric juice, forming a paste that adheres to mucosal defects and exposed deeper layers. Here sucral-fate intercepts H+. Protected from acid, and also from pepsin, trypsin, and bile acids, the mucosal defect can heal more rapidly. Sucralfate is taken on an empty stomach (1 h before meals and at bedtime). It is well tolerated; however, released Al3+ ions can cause constipation.

Misoprostol (B) is a semisynthetic prostaglandin derivative with greater stability than natural prostaglandin, permitting absorption after oral administration. Like locally released prosta-glandins, it promotes mucus production and inhibits acid secretion. Additional systemic effects (frequent diarrhea; risk of precipitating contractions of the Lullmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.

Consequences Frequent Diarrhea
B. Chemical structure and protective effect of misoprostol
Propulsive Movement Digestive System

Laxatives

Laxatives promote and facilitate bowel evacuation by acting locally to stimulate intestinal peristalsis, to soften bowel contents, or both.

1. Bulk laxatives. Distention of the intestinal wall by bowel contents stimulates propulsive movements of the gut musculature (peristalsis). Activation of intramural mechanoreceptors induces a neurally mediated ascending reflex contraction (red in A) and descending relaxation (blue) whereby the intralumi-nal bolus is moved in the anal direction.

Hydrophilic colloids or bulk gels (B) comprise insoluble and nonabsorb-able carbohydrate substances that expand on taking up water in the bowel. Vegetable fibers in the diet act in this manner. They consist of the indigestible plant cell walls containing homoglycans that are resistant to digestive enzymes, e.g., cellulose (1 ^ 4p-linked glucose molecules vs. 1 ^ 4a glucoside bond in starch, p. 153).

Bran, a grain milling waste product, and linseed (flaxseed) are both rich in cellulose. Other hydrophilic colloids derive from the seeds of Plantago species or karaya gum. Ingestion of hydrophilic gels for the prophylaxis of constipation usually entails a low risk of side effects. However, with low fluid intake in combination with a pathological bowel stenosis, mucilaginous viscous material could cause bowel occlusion (ileus).

Osmotically active laxatives (C)

are soluble but nonabsorbable particles that retain water in the bowel by virtue of their osmotic action. The osmotic pressure (particle concentration) of bowel contents always corresponds to that of the extracellular space. The intestinal mucosa is unable to maintain a higher or lower osmotic pressure of the luminal contents. Therefore, absorption of molecules (e.g., glucose, NaCl) occurs isoosmotically, i.e., solute molecules are followed by a corresponding amount of water. Conversely, water remains in the bowel when molecules cannot be absorbed.

With Epsom and Glauber's salts (MgSO4 and Na2SO4, respectively), the SO42- anion is nonabsorbable and retains cations to maintain electroneu-trality. Mg2+ ions are also believed to promote release from the duodenal mucosa of cholecystokinin/pancreozymin, a polypeptide that also stimulates peristalsis. These so-called saline cathartics elicit a watery bowel discharge 1-3 h after administration (preferably in isotonic solution). They are used to purge the bowel (e.g., before bowel surgery) or to hasten the elimination of ingested poisons. Glauber's salt (high Na+ content) is contraindicated in hypertension, congestive heart failure, and edema. Epsom salt is contraindicated in renal failure (risk of Mg2+ intoxication).

Osmotic laxative effects are also produced by the polyhydric alcohols, mannitol and sorbitol, which unlike glucose cannot be transported through the intestinal mucosa, as well as by the non-hydrolyzable disaccharide, lactulose. Fermentation of lactulose by colon bacteria results in acidification of bowel contents and microfloral damage. Lac-tulose is used in hepatic failure in order to prevent bacterial production of ammonia and its subsequent absorption (absorbable NH3 ^ nonabsorbable NH4+), so as to forestall hepatic coma.

2. Irritant laxatives—purgatives cathartics. Laxatives in this group exert an irritant action on the enteric mucosa (A). Consequently, less fluid is absorbed than is secreted. The increased filling of the bowel promotes peristalsis; excitation of sensory nerve endings elicits enteral hypermotility. According to the site of irritation, one distinguishes the small bowel irritant castor oil from the large bowel irritants anthraquinone and diphenolmethane derivatives (for details see p. 174).

Misuse of laxatives. It is a widely held belief that at least one bowel movement per day is essential for health; yet three bowel evacuations per week are quite normal. The desire for frequent bowel emptying probably stems from the time-honored, albeit

A. Stimulation of peristalsis by an intraluminal bolus
Meal Bolus Viscosity

C. Osmotically active laxatives

C. Osmotically active laxatives

124), which stimulates their reabsorption in the kidney. The action of aldosterone is, however, associated with increased renal excretion of KCl. The enteral and renal K+ loss add up to a K+ depletion of the body, evidenced by a fall in serum K+ concentration (hypokale-mia). This condition is accompanied by a reduction in intestinal peristalsis (bowel atonia). The affected individual infers "constipation," again partakes of the purgative, and the vicious circle is closed (2).

Chologenic diarrhea results when bile acids fail to be absorbed in the ile-um (e.g., after ileal resection) and enter the colon, where they cause enhanced secretion of electrolytes and water, leading to the discharge of fluid stools.

mistaken, notion that absorption of colon contents is harmful. Thus, purging has long been part of standard therapeutic practice. Nowadays, it is known that intoxication from intestinal substances is impossible as long as the liver functions normally. Nonetheless, purgatives continue to be sold as remedies to "cleanse the blood" or to rid the body of "corrupt humors."

There can be no objection to the ingestion of bulk substances for the purpose of supplementing low-residue "modern diets." However, use of irritant purgatives or cathartics is not without hazards. Specifically, there is a risk of laxative dependence, i.e., the inability to do without them. Chronic intake of irritant purgatives disrupts the water and electrolyte balance of the body and can thus cause symptoms of illness (e.g., cardiac arrhythmias secondary to hypo-kalemia).

Causes of purgative dependence (B). The defecation reflex is triggered when the sigmoid colon and rectum are filled. A natural defecation empties the large bowel up to and including the descending colon. The interval between natural stool evacuations depends on the speed with which these colon segments are refilled. A large bowel irritant purgative clears out the entire colon. Accordingly, a longer period is needed until the next natural defecation can occur. Fearing constipation, the user becomes impatient and again resorts to the laxative, which then produces the desired effect as a result of emptying out the upper colonic segments. Therefore, a "compensatory pause" following cessation of laxative use must not give cause for concern (1).

In the colon, semifluid material entering from the small bowel is thickened by absorption of water and salts (from about 1000 to 150 mL/d). If, due to the action of an irritant purgative, the colon empties prematurely, an enteral loss of NaCl, KCl and water will be incurred. To forestall depletion of NaCl and water, the body responds with an increased release of aldosterone (p. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.

Anthraquinone Pharmacology
A. Stimulation of peristalsis by mucosal irritation

Interval needed to refill colon

Interval needed to refill colon

Normal filling After normal

—* defecation reflex evacuation of colon

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