книги студ / Color Atlas of Pharmacology

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 hypokalemia).

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.

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 (hypokalemia). 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 ileum (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.

2.a Small Bowel Irritant Purgative, Ricinoleic Acid

Castor oil comes from Ricinus communis (castor plants; Fig: sprig, panicle, seed); it is obtained from the first coldpressing of the seed (shown in natural size). Oral administration of 10–30 mL of castor oil is followed within 0.5 to 3 h by discharge of a watery stool. Ricinoleic acid, but not the oil itself, is active. It arises as a result of the regular processes involved in fat digestion: the duodenal mucosa releases the enterohormone cholecystokinin/pancreozymin into the blood. The hormone elicits contraction of the gallbladder and discharge of bile acids via the bile duct, as well as release of lipase from the pancreas (intestinal peristalsis is also stimulated). Because of its massive effect, castor oil is hardly suitable for the treatment of ordinary constipation. It can be employed after oral ingestion of a toxin in order to hasten elimination and to reduce absorption of toxin from the gut. Castor oil is not indicated after the ingestion of lipophilic toxins likely to depend on bile acids for their absorption.

2.b Large Bowel Irritant Purgatives (p. 177 ff)

Anthraquinone derivatives (p. 176) are of plant origin. They occur in the leaves

(folia sennae) or fruits (fructus sennae) of the senna plant, the bark of Rhamnus frangulae and Rh. purshiana, (cortex frangulae, cascara sagrada), the roots of rhubarb (rhizoma rhei), or the leaf extract from Aloe species (p. 176). The structural features of anthraquinone derivatives are illustrated by the prototype structure depicted on p. 177. Among other substituents, the anthraquinone nucleus contains hydroxyl groups, one of which is bound to a sugar (glucose, rhamnose). Following ingestion of galenical preparations or of the anthraquinone glycosides, discharge of soft stool occurs after a latency of 6 to 8 h. The anthraquinone glycosides themselves are inactive but are converted by

colon bacteria to the active free aglycones.

Diphenolmethane derivatives (p. 177) were developed from phenolphthalein, an accidentally discovered laxative, use of which had been noted to result in rare but severe allergic reactions. Bisac- odyl and sodium picosulfate are converted by gut bacteria into the active colonirritant principle. Given by the enteral route, bisacodyl is subject to hydrolysis of acetyl residues, absorption, conjugation in liver to glucuronic acid (or also to sulfate, p. 38), and biliary secretion into the duodenum. Oral administration is followed after approx. 6 to 8 h by discharge of soft formed stool. When given by suppository, bisacodyl produces its effect within 1 h.

Indications for colon-irritant purgatives are the prevention of straining at stool following surgery, myocardial infarction, or stroke; and provision of relief in painful diseases of the anus, e.g., fissure, hemorrhoids.

Purgatives must not be given in abdominal complaints of unclear origin.

3. Lubricant laxatives. Liquid paraffin

(paraffinum subliquidum) is almost nonabsorbable and makes feces softer and more easily passed. It interferes with the absorption of fat-soluble vitamins by trapping them. The few absorbed paraffin particles may induce formation of foreign-body granulomas in enteric lymph nodes (paraffinomas). Aspiration into the bronchial tract can result in lipoid pneumonia. Because of these adverse effects, its use is not advisable.

Antidiarrheal Agents

Causes of diarrhea (in red): Many bacteria (e.g., Vibrio cholerae) secrete toxins that inhibit the ability of mucosal enterocytes to absorb NaCl and water and, at the same time, stimulate mucosal secretory activity. Bacteria or viruses that invade the gut wall cause inflammation characterized by increased fluid secretion into the lumen. The enteric musculature reacts with increased peristalsis.

The aims of antidiarrheal therapy are to prevent: (1) dehydration and electrolyte depletion; and (2) excessively high stool frequency. Different therapeutic approaches (in green) listed are variously suited for these purposes.

Adsorbent powders are nonabsorbable materials with a large surface area. These bind diverse substances, including toxins, permitting them to be inactivated and eliminated. Medicinal charcoal possesses a particularly large surface because of the preserved cell structures. The recommended effective antidiarrheal dose is in the range of 4–8 g. Other adsorbents are kaolin (hydrated aluminum silicate) and chalk.

Oral rehydration solution (g/L of boiled water: NaCl 3.5, glucose 20, NaHCO3 2.5, KCl 1.5). Oral administration of glucose-containing salt solutions enables fluids to be absorbed because toxins do not impair the cotransport of Na+ and glucose (as well as of H2O) through the mucosal epithelium. In this manner, although frequent discharge of stool is not prevented, dehydration is successfully corrected.

Opioids. Activation of opioid receptors in the enteric nerve plexus results in inhibition of propulsive motor activity and enhancement of segmentation activity. This antidiarrheal effect was formerly induced by application of opi- um tincture (paregoric) containing mor- phine. Because of the CNS effects (sedation, respiratory depression, physical dependence), derivatives with peripheral actions have been developed. Whereas diphenoxylate can still produce clear CNS effects, loperamide does not

affect brain functions at normal dosage. Loperamide is, therefore, the opioid antidiarrheal of first choice. The prolonged contact time of intestinal contents and mucosa may also improve absorption of fluid. With overdosage, there is a hazard of ileus. It is contraindicated in infants below age 2 y.

Antibacterial drugs. Use of these agents (e.g., cotrimoxazole, p. 272) is only rational when bacteria are the cause of diarrhea. This is rarely the case. It should be kept in mind that antibiotics also damage the intestinal flora which, in turn, can give rise to diarrhea.

Astringents such as tannic acid (home remedy: black tea) or metal salts precipitate surface proteins and are thought to help seal the mucosal epithelium. Protein denaturation must not include cellular proteins, for this would mean cell death. Although astringents induce constipation (cf. Al3+ salts, p. 166), a therapeutic effect in diarrhea is doubtful.

Demulcents, e.g., pectin (home remedy: grated apples) are carbohydrates that expand on absorbing water. They improve the consistency of bowel contents; beyond that they are devoid of any favorable effect.

Drugs for Dissolving Gallstones (A)

Following its secretion from liver into bile, water-insoluble cholesterol is held in solution in the form of micellar complexes with bile acids and phospholipids. When more cholesterol is secreted than can be emulsified, it precipitates and forms gallstones (cholelithiasis). Precipitated cholesterol can be reincorporated into micelles, provided the cholesterol concentration in bile is below saturation. Thus, cholesterol-contain- ing stones can be dissolved slowly. This effect can be achieved by long-term oral administration of chenodeoxycholic acid (CDCA) or ursodeoxycholic acid

(UDCA). Both are physiologically occurring, stereoisomeric bile acids (position of the 7-hydroxy group being ! in UCDA and in CDCA). Normally, they represent a small proportion of the total amount of bile acid present in the body (circle diagram in A); however, this increases considerably with chronic administration because of enterohepatic cycling, p. 38). Bile acids undergo almost complete reabsorption in the ileum. Small losses via the feces are made up by de novo synthesis in the liver, keeping the total amount of bile acids constant (3–5 g). Exogenous supply removes the need for de novo synthesis of bile acids. The particular acid being supplied gains an increasingly larger share of the total store.

The altered composition of bile increases the capacity for cholesterol uptake. Thus, gallstones can be dissolved in the course of a 1- to 2 y treatment, provided that cholesterol stones are pure and not too large (<15 mm), gall bladder function is normal, liver disease is absent, and patients are of normal body weight. UCDA is more effective (daily dose, 8–10 mg) and better tolerated than is CDCA (15 mg/d; frequent diarrhea, elevation of liver enzymes in plasma). Stone formation may recur after cessation of successful therapy.

Compared with surgical treatment, drug therapy plays a subordinate role.

UCDA may also be useful in primary biliary cirrhosis.

Choleretics are supposed to stimulate production and secretion of dilute bile fluid. This principle has little therapeutic significance.

Cholekinetics stimulate the gallbladder to contract and empty, e.g., egg yolk, the osmotic laxative MgSO4, the cholecystokinin-related ceruletide (given parenterally). Cholekinetics are employed to test gallbladder function for diagnostic purposes.

Pancreatic enzymes (B) from slaughtered animals are used to relieve excretory insufficiency of the pancreas (! disrupted digestion of fats; steatorrhea, inter alia). Normally, secretion of pancreatic enzymes is activated by cholecystokinin/pancreozymin, the enterohormone that is released into blood from the duodenal mucosa upon contact with chyme. With oral administration of pancreatic enzymes, allowance must be made for their partial inactivation by gastric acid (the lipases, particularly). Therefore, they are administered in acid-resistant dosage forms.

Antiflatulents (carminatives) serve to alleviate meteorism (excessive accumulation of gas in the gastrointestinal tract). Aborad propulsion of intestinal contents is impeded when the latter are mixed with gas bubbles. Defoaming agents, such as dimethicone (dimethylpolysiloxane) and simethicone, in combination with charcoal, are given orally to promote separation of gaseous and semisolid contents.