Color Atlas of Pharmacology (Part 16): Laxatives and Purgatives

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Laxatives and Purgatives 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. Bisacodyl 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...

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Nội dung Text: Color Atlas of Pharmacology (Part 16): Laxatives and Purgatives

174 Laxatives and Purgatives 2.a Small Bowel Irritant Purgative, colon bacteria to the active free agly- Ricinoleic Acid cones. Castor oil comes from Ricinus commu- Diphenolmethane derivatives (p. 177) nis (castor plants; Fig: sprig, panicle, were developed from phenolphthalein, seed); it is obtained from the first cold- an accidentally discovered laxative, use pressing of the seed (shown in natural of which had been noted to result in size). Oral administration of 10–30 mL rare but severe allergic reactions. Bisac- of castor oil is followed within 0.5 to 3 h odyl and sodium picosulfate are convert- by discharge of a watery stool. Ricinole- ed by gut bacteria into the active colon- ic acid, but not the oil itself, is active. It irritant principle. Given by the enteral arises as a result of the regular process- route, bisacodyl is subject to hydrolysis es involved in fat digestion: the duoden- of acetyl residues, absorption, conjuga- al mucosa releases the enterohormone tion in liver to glucuronic acid (or also to cholecystokinin/pancreozymin into the sulfate, p. 38), and biliary secretion into blood. The hormone elicits contraction the duodenum. Oral administration is of the gallbladder and discharge of bile followed after approx. 6 to 8 h by dis- acids via the bile duct, as well as release charge of soft formed stool. When given of lipase from the pancreas (intestinal by suppository, bisacodyl produces its peristalsis is also stimulated). Because effect within 1 h. of its massive effect, castor oil is hardly Indications for colon-irritant purga- suitable for the treatment of ordinary tives are the prevention of straining at constipation. It can be employed after stool following surgery, myocardial in- oral ingestion of a toxin in order to has- farction, or stroke; and provision of re- ten elimination and to reduce absorp- lief in painful diseases of the anus, e.g., tion of toxin from the gut. Castor oil is fissure, hemorrhoids. not indicated after the ingestion of lipo- Purgatives must not be given in ab- philic toxins likely to depend on bile ac- dominal complaints of unclear origin. ids for their absorption. 3. Lubricant laxatives. Liquid paraffin (paraffinum subliquidum) is almost non- 2.b Large Bowel Irritant Purgatives absorbable and makes feces softer and (p. 177 ff) more easily passed. It interferes with the absorption of fat-soluble vitamins Anthraquinone derivatives (p. 176) are by trapping them. The few absorbed of plant origin. They occur in the leaves paraffin particles may induce formation (folia sennae) or fruits (fructus sennae) of foreign-body granulomas in enteric of the senna plant, the bark of Rhamnus lymph nodes (paraffinomas). Aspiration frangulae and Rh. purshiana, (cortex into the bronchial tract can result in li- frangulae, cascara sagrada), the roots of poid pneumonia. Because of these ad- rhubarb (rhizoma rhei), or the leaf ex- verse effects, its use is not advisable. tract from Aloe species (p. 176). The structural features of anthraquinone de- rivatives are illustrated by the proto- type structure depicted on p. 177. Among other substituents, the anthra- quinone nucleus contains hydroxyl groups, one of which is bound to a sugar (glucose, rhamnose). Following inges- tion of galenical preparations or of the anthraquinone glycosides, discharge of soft stool occurs after a latency of 6 to 8 h. The anthraquinone glycosides them- selves are inactive but are converted by Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Laxatives and Purgatives 175 Ricinus communis Gall- bladder CK/PZ Ricinoleic acid – O – CH2 Castor oil Ricinoleic acid – O – CH Ricinoleic acid – O – CH2 Bile Peristalsis acids Lipase Pancreas Glycerol + 3 Ricinoleic acids Duodenum CK/PZ = Cholecystokinin/pancreozymin A. Small-bowel irritant laxative: ricinoleic acid Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
176 Laxatives and Purgatives Senna Frangula Rhubarb Aloe A. Plants containing anthraquinone glycosides Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Laxatives and Purgatives 177 sugar e.g., 1,8-Dihydroxy- anthraquinone glycoside 1,8-Dihydroxy- anthrone -Anthranol Reduction Sugar cleavage Bacteria Anthraquinone glycoside A. Large-bowel irritant laxatives: anthraquinone derivatives Glucuronidation Sodium Bisacodyl picosulfate Diphenol Estera se Diphenol Sulfate Glucuronide Glucu- ronate Bacteria B. Large-bowel irritant laxatives: diphenylmethane derivatives Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
178 Antidiarrheals Antidiarrheal Agents affect brain functions at normal dosage. Loperamide is, therefore, the opioid Causes of diarrhea (in red): Many bacte- antidiarrheal of first choice. The pro- ria (e.g., Vibrio cholerae) secrete toxins longed contact time of intestinal con- that inhibit the ability of mucosal ente- tents and mucosa may also improve ab- rocytes to absorb NaCl and water and, at sorption of fluid. With overdosage, the same time, stimulate mucosal secre- there is a hazard of ileus. It is contrain- tory activity. Bacteria or viruses that in- dicated in infants below age 2 y. vade the gut wall cause inflammation Antibacterial drugs. Use of these characterized by increased fluid secre- agents (e.g., cotrimoxazole, p. 272) is tion into the lumen. The enteric muscu- only rational when bacteria are the lature reacts with increased peristalsis. cause of diarrhea. This is rarely the case. The aims of antidiarrheal therapy It should be kept in mind that antibio- are to prevent: (1) dehydration and tics also damage the intestinal flora electrolyte depletion; and (2) excessive- which, in turn, can give rise to diarrhea. ly high stool frequency. Different ther- Astringents such as tannic acid apeutic approaches (in green) listed (home remedy: black tea) or metal salts are variously suited for these purposes. precipitate surface proteins and are Adsorbent powders are nonab- thought to help seal the mucosal epithe- sorbable materials with a large surface lium. Protein denaturation must not in- area. These bind diverse substances, in- clude cellular proteins, for this would cluding toxins, permitting them to be mean cell death. Although astringents inactivated and eliminated. Medicinal induce constipation (cf. Al3+ salts, charcoal possesses a particularly large p. 166), a therapeutic effect in diarrhea surface because of the preserved cell is doubtful. structures. The recommended effective Demulcents, e.g., pectin (home antidiarrheal dose is in the range of remedy: grated apples) are carbohy- 4–8 g. Other adsorbents are kaolin (hy- drates that expand on absorbing water. drated aluminum silicate) and chalk. They improve the consistency of bowel Oral rehydration solution (g/L of contents; beyond that they are devoid boiled water: NaCl 3.5, glucose 20, of any favorable effect. NaHCO3 2.5, KCl 1.5). Oral administra- tion 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 recep- tors in the enteric nerve plexus results in inhibition of propulsive motor activ- ity 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 (seda- tion, respiratory depression, physical dependence), derivatives with periph- eral actions have been developed. Whereas diphenoxylate can still produce clear CNS effects, loperamide does not Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Antidiarrheals 179 Adsorption e.g., to medicinal charcoal Toxins Toxins Na+ Cl- Oral Fluid secretion rehydration solution: Na+ salts and glucose Glucose Antibacterial Resident drugs: e.g., co-trimoxazole microflora Pathogenic bacteria Mucosal injury Opium tincture with morphine CNS Viruses Diphenoxylate Loperamide Inhibition of propulsive peristalsis Enhanced peristalsis Opioid- receptors Protein- containing mucus Astringents: e.g., tannic acid Precipitation of Fluid loss surface proteins, sealing of mucosa Diarrhea A. Antidiarrheals and their sites of action Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
180 Other Gastrointestinal Drugs Drugs for Dissolving Gallstones (A) UCDA may also be useful in primary bil- iary cirrhosis. Following its secretion from liver into Choleretics are supposed to stimu- bile, water-insoluble cholesterol is held late production and secretion of dilute in solution in the form of micellar com- bile fluid. This principle has little thera- plexes with bile acids and phospholip- peutic significance. ids. When more cholesterol is secreted Cholekinetics stimulate the gall- than can be emulsified, it precipitates bladder to contract and empty, e.g., egg and forms gallstones (cholelithiasis). yolk, the osmotic laxative MgSO4, the Precipitated cholesterol can be reincor- cholecystokinin-related ceruletide (giv- porated into micelles, provided the cho- en parenterally). Cholekinetics are em- lesterol concentration in bile is below ployed to test gallbladder function for saturation. Thus, cholesterol-contain- diagnostic purposes. ing stones can be dissolved slowly. This Pancreatic enzymes (B) from effect can be achieved by long-term oral slaughtered animals are used to relieve administration of chenodeoxycholic excretory insufficiency of the pancreas acid (CDCA) or ursodeoxycholic acid ( disrupted digestion of fats; steator- (UDCA). Both are physiologically occur- rhea, inter alia). Normally, secretion of ring, stereoisomeric bile acids (position pancreatic enzymes is activated by of the 7-hydroxy group being ! in UCDA cholecystokinin/pancreozymin, the en- and " in CDCA). Normally, they repre- terohormone that is released into blood sent a small proportion of the total from the duodenal mucosa upon con- amount of bile acid present in the body tact with chyme. With oral administra- (circle diagram in A); however, this in- tion of pancreatic enzymes, allowance creases considerably with chronic ad- must be made for their partial inactiva- ministration because of enterohepatic tion by gastric acid (the lipases, particu- cycling, p. 38). Bile acids undergo almost larly). Therefore, they are administered complete reabsorption in the ileum. in acid-resistant dosage forms. Small losses via the feces are made up Antiflatulents (carminatives) serve by de novo synthesis in the liver, keep- to alleviate meteorism (excessive accu- ing the total amount of bile acids con- mulation of gas in the gastrointestinal stant (3–5 g). Exogenous supply re- tract). Aborad propulsion of intestinal moves the need for de novo synthesis of contents is impeded when the latter are bile acids. The particular acid being sup- mixed with gas bubbles. Defoaming plied gains an increasingly larger share agents, such as dimethicone (dimethyl- of the total store. polysiloxane) and simethicone, in com- The altered composition of bile in- bination with charcoal, are given orally creases the capacity for cholesterol up- to promote separation of gaseous and take. Thus, gallstones can be dissolved semisolid contents. in the course of a 1- to 2 y treatment, provided that cholesterol stones are pure and not too large (
Other Gastrointestinal Drugs 181 CA : Cholic acid DCA : Desoxy-CA UDCA UDCA : Ursodesoxy-CA CDCA : Chenodesoxy-CA Synthesis of bile acids to maintain store Gall-stone formed by cholesterol DAA DCA CDCA CA CA CDCA UDCA UDCA Ileum Excretion in feces A. Gallstone dissolution “Pancreatin” of slaughter animals: Protease, Amylase, Lipase Stomach Duodenum CK/PZ Addition Fat- of containing Circulation dimethicone chymus Pancreatic enzyme “Defoaming” B. Release of pancreatic enzymes and C. Carminative effect of their replacement dimethicone Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.