Color Atlas of Pharmacology (Part 15): Drugs for the Treatment of Peptic Ulcers

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Drugs for the Treatment of Peptic Ulcers cipitated antacid or, phosphate depletion of the body with excessive intake of Al(OH)3. Na+ ions remain in solution even in the presence of HCO3–-rich pancreatic secretions and are subject to absorption, like HCO3–. Because of the uptake of Na+, use of NaHCO3 must be avoided in conditions requiring restriction of NaCl intake, such as hypertension, cardiac failure, and edema. Since food has a buffering effect, antacids are taken between meals (e.g., 1 and 3 h after meals and at bedtime). Nonabsorbable antacids are preferred. Because Mg(OH)2 produces a laxative effect (cause: osmotic action,...

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Nội dung Text: Color Atlas of Pharmacology (Part 15): Drugs for the Treatment of Peptic Ulcers

166 Drugs for the Treatment of Peptic Ulcers Drugs for Gastric and Duodenal Ulcers cipitated antacid or, phosphate deple- tion of the body with excessive intake of In the area of a gastric or duodenal pep- Al(OH)3. tic ulcer, the mucosa has been attacked Na+ ions remain in solution even in by digestive juices to such an extent as the presence of HCO3–-rich pancreatic to expose the subjacent connective tis- secretions and are subject to absorption, sue layer (submucosa). This self-diges- like HCO3–. Because of the uptake of Na+, tion occurs when the equilibrium use of NaHCO3 must be avoided in con- between the corrosive hydrochloric acid ditions requiring restriction of NaCl in- and acid-neutralizing mucus, which take, such as hypertension, cardiac fail- forms a protective cover on the mucosal ure, and edema. surface, is shifted in favor of hydro- Since food has a buffering effect, chloric acid. Mucosal damage can be antacids are taken between meals (e.g., promoted by Helicobacter pylori bacte- 1 and 3 h after meals and at bedtime). ria that colonize the gastric mucus. Nonabsorbable antacids are preferred. Drugs are employed with the fol- Because Mg(OH)2 produces a laxative lowing therapeutic aims: (1) to relieve effect (cause: osmotic action, p. 170, re- pain; (2) to accelerate healing; and (3) lease of cholecystokinin by Mg2+, or to prevent ulcer recurrence. Therapeu- both) and Al(OH)3 produces constipa- tic approaches are threefold: (a) to re- tion (cause: astringent action of Al3+, p. duce aggressive forces by lowering H+ 178), these two antacids are frequently output; (b) to increase protective forces used in combination. by means of mucoprotectants; and (c) to Ib. Inhibitors of acid production. eradicate Helicobacter pylori. Acting on their respective receptors, the transmitter acetylcholine, the hormone I. Drugs for Lowering Acid gastrin, and histamine released intra- Concentration mucosally stimulate the parietal cells of the gastric mucosa to increase output of Ia. Acid neutralization. H+-binding HCl. Histamine comes from entero- groups such as CO32–, HCO3– or OH–, to- chromaffin-like (ECL) cells; its release is gether with their counter ions, are con- stimulated by the vagus nerve (via M1 tained in antacid drugs. Neutralization receptors) and hormonally by gastrin. reactions occurring after intake of The effects of acetylcholine and hista- CaCO3 and NaHCO3, respectively, are mine can be abolished by orally applied shown in (A) at left. With nonabsorb- antagonists that reach parietal cells via able antacids, the counter ion is dis- the blood. solved in the acidic gastric juice in the The cholinoceptor antagonist pi- process of neutralization. Upon mixture renzepine, unlike atropine, prefers cho- with the alkaline pancreatic secretion in linoceptors of the M1 type, does not the duodenum, it is largely precipitated penetrate into the CNS, and thus pro- again by basic groups, e.g., as CaCO3 or duces fewer atropine-like side effects AlPO4, and excreted in feces. Therefore, (p. 104). The cholinoceptors on parietal systemic absorption of counter ions or cells probably belong to the M3 subtype. basic residues is minor. In the presence Hence, pirenzepine may act by blocking of renal insufficiency, however, absorp- M1 receptors on ECL cells or submucosal tion of even small amounts may cause neurons. an increase in plasma levels of counter Histamine receptors on parietal ions (e.g., magnesium intoxication with cells belong to the H2 type (p. 114) and paralysis and cardiac disturbances). Pre- are blocked by H2-antihistamines. Be- cipitation in the gut lumen is respon- cause histamine plays a pivotal role in sible for other side effects, such as re- the activation of parietal cells, H2-anti- duced absorption of other drugs due to histamines also diminish responsivity their adsorption to the surface of pre- to other stimulants, e.g., gastrin (in gas- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Drugs for the Treatment of Peptic Ulcers 167 Acid neutralization Inhibition of acid production Pirenzepine N. vagus CaCO3 CaCO3 H+ Parietal cell H2CO3 H+ ACh M3 ACh M1 H2O CO2 H+ ATPase ECL- K+ H2 Histamine cell Ca2+ Ca2+ Pancreas Gastrin 2- Proton pump- CO3 CaCO3 inhibitors H N O S Antacids absorbable N not absorbable H3CO N CaCO3 NaHCO3 H3C CH3 Mg(OH)2 Omeprazole OCH3 Al(OH)3 H2-Antihistamines N H2O+CO2 HN CH2 S Cimetidine CH3 (CH2)2 - Na+ HCO3 NH C NHCH3 H+ N C N H3 C N CH2 O CH2 S Na+ H3C (CH2)2 Pancreas NH Absorption C NHCH3 HCO- 3 - Na+ HCO3 Ranitidine CH NO2 A. Drugs used to lower gastric acid concentration or production Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
168 Drugs for the Treatment of Peptic Ulcers trin-producing pancreatic tumors, Zol- gravid uterus) significantly restrict its linger-Ellison syndrome). Cimetidine, therapeutic utility. the first H2-antihistamine used thera- Carbenoxolone (B) is a derivative peutically, only rarely produces side ef- of glycyrrhetinic acid, which occurs in fects (CNS disturbances such as confu- the sap of licorice root (succus liquiri- sion; endocrine effects in the male, such tiae). Carbenoxolone stimulates mucus as gynecomastia, decreased libido, im- production. At the same time, it has a potence). Unlike cimetidine, its newer mineralocorticoid-like action (due to in- and more potent congeners, ranitidine, hibition of 11-!-hydroxysteroid dehy- nizatidine, and famotidine, do not inter- drogenase) that promotes renal reab- fere with the hepatic biotransformation sorption of NaCl and water. It may, of other drugs. therefore, exacerbate hypertension, Omeprazole (p. 167) can cause max- congestive heart failure, or edemas. It is imal inhibition of HCl secretion. Given obsolete. orally in gastric juice-resistant capsules, it reaches parietal cells via the blood. In III. Eradication of Helicobacter py- the acidic milieu of the mucosa, an ac- lori C. This microorganism plays an im- tive metabolite is formed and binds co- portant role in the pathogenesis of valently to the ATP-driven proton pump chronic gastritis and peptic ulcer dis- (H+/K+ ATPase) that transports H+ in ex- ease. The combination of antibacterial change for K+ into the gastric juice. Lan- drugs and omeprazole has proven effec- soprazole and pantoprazole produce tive. In case of intolerance to amoxicillin analogous effects. The proton pump in- (p. 270) or clarithromycin (p. 276), met- hibitors are first-line drugs for the treat- ronidazole (p. 274) can be used as a sub- ment of gastroesophageal reflux dis- stitute. Colloidal bismuth compounds ease. are also effective; however, the problem of heavy-metal exposure compromises II. Protective Drugs their long-term use. Sucralfate (A) contains numerous alu- minum hydroxide residues. However, it is not an antacid because it fails to lower the overall acidity of gastric juice. After oral intake, sucralfate molecules under- go 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 bed- time). It is well tolerated; however, re- leased Al3+ ions can cause constipation. Misoprostol (B) is a semisynthetic prostaglandin derivative with greater stability than natural prostaglandin, permitting absorption after oral admin- istration. Like locally released prosta- glandins, it promotes mucus production and inhibits acid secretion. Additional systemic effects (frequent diarrhea; risk of precipitating contractions of the Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Drugs for the Treatment of Peptic Ulcers 169 R R Sucralfate R R R R R R R = – SO3[Al2(OH)5] Conversion H+ in acidic en- vironment - – SO3 R = – SO3[Al2(OH)4]+ pH < 4 Cross-linking and formation of paste Coating of mucosal defects A. Chemical structure and protective effect of sucralfate Mucus HCl ATPase H+ K+ Parietal cell Prostaglandin receptor Induction of labor Misoprostol B. Chemical structure and protective effect of misoprostol Helicobacter Eradication pylori e.g., short-term triple therapy Gastritis Peptic ulcer Amoxicillin (2 x 1000 mg) 7 days Clarithromycin (2 x 500 mg) 7 days Omeprazole (2 x 20 mg) 7 days C. Helicobacter eradication Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
170 Laxatives Laxatives With Epsom and Glauber’s salts (MgSO4 and Na2SO4, respectively), the Laxatives promote and facilitate bowel SO42– anion is nonabsorbable and re- evacuation by acting locally to stimulate tains cations to maintain electroneu- intestinal peristalsis, to soften bowel trality. Mg2+ ions are also believed to contents, or both. promote release from the duodenal mu- 1. Bulk laxatives. Distention of the cosa of cholecystokinin/pancreozymin, intestinal wall by bowel contents stimu- a polypeptide that also stimulates peris- lates propulsive movements of the gut talsis. These so-called saline cathartics musculature (peristalsis). Activation of elicit a watery bowel discharge 1–3 h af- intramural mechanoreceptors induces a ter administration (preferably in isoton- neurally mediated ascending reflex con- ic solution). They are used to purge the traction (red in A) and descending re- bowel (e.g., before bowel surgery) or to laxation (blue) whereby the intralumi- hasten the elimination of ingested poi- nal bolus is moved in the anal direction. sons. Glauber’s salt (high Na+ content) is Hydrophilic colloids or bulk gels contraindicated in hypertension, con- (B) comprise insoluble and nonabsorb- gestive heart failure, and edema. Epsom able carbohydrate substances that ex- salt is contraindicated in renal failure pand on taking up water in the bowel. (risk of Mg2+ intoxication). Vegetable fibers in the diet act in this Osmotic laxative effects are also manner. They consist of the indigestible produced by the polyhydric alcohols, plant cell walls containing homoglycans mannitol and sorbitol, which unlike glu- that are resistant to digestive enzymes, cose cannot be transported through the e.g., cellulose (1 4!-linked glucose mo- intestinal mucosa, as well as by the non- lecules vs. 1 4" glucoside bond in hydrolyzable disaccharide, lactulose. starch, p. 153). Fermentation of lactulose by colon bac- Bran, a grain milling waste product, teria results in acidification of bowel and linseed (flaxseed) are both rich in contents and microfloral damage. Lac- cellulose. Other hydrophilic colloids de- tulose is used in hepatic failure in order rive from the seeds of Plantago species to prevent bacterial production of am- or karaya gum. Ingestion of hydrophilic monia and its subsequent absorption gels for the prophylaxis of constipation (absorbable NH3 nonabsorbable usually entails a low risk of side effects. NH4+), so as to forestall hepatic coma. However, with low fluid intake in com- 2. Irritant laxatives—purgatives bination with a pathological bowel cathartics. Laxatives in this group exert stenosis, mucilaginous viscous material an irritant action on the enteric mucosa could cause bowel occlusion (ileus). (A). Consequently, less fluid is absorbed Osmotically active laxatives (C) than is secreted. The increased filling of are soluble but nonabsorbable particles the bowel promotes peristalsis; excita- that retain water in the bowel by virtue tion of sensory nerve endings elicits en- of their osmotic action. The osmotic teral hypermotility. According to the pressure (particle concentration) of site of irritation, one distinguishes the bowel contents always corresponds to small bowel irritant castor oil from the that of the extracellular space. The in- large bowel irritants anthraquinone and testinal mucosa is unable to maintain a diphenolmethane derivatives (for de- higher or lower osmotic pressure of the tails see p. 174). luminal contents. Therefore, absorption Misuse of laxatives. It is a widely of molecules (e.g., glucose, NaCl) occurs held belief that at least one bowel isoosmotically, i.e., solute molecules are movement per day is essential for followed by a corresponding amount of health; yet three bowel evacuations per water. Conversely, water remains in the week are quite normal. The desire for bowel when molecules cannot be ab- frequent bowel emptying probably sorbed. stems from the time-honored, albeit Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Laxatives 171 Stretch receptors Contraction Relaxation A. Stimulation of peristalsis by an intraluminal bolus H2O H2O Cellulose, agar-agar, bran, linseed B. Bulk laxatives H2O Na+, Cl- H2O H2O H2O Na+, Cl- Na+, Cl- G H2O H2O H2O H2O Na+, Cl- H2O G H2O H2O H2O Na+, Cl- Na+, Cl- H2O H2O H2O G H2O Na+, Cl- Isoosmotic H2O absorption G = Glucose H2O H2O Na+, Cl- H2O Na+, Cl- H2O Na+, Cl- H2O H2O H2O Na+, Cl- H2O H2O G H2O H2O G G Na+, Cl- H2O Na+, Cl- H2O H2O H2O Na+, Cl- H2O H2O H2O + 2- Mannitol 2 Na SO4 H2O H2O H2O H2O C. Osmotically active laxatives Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
172 Laxatives mistaken, notion that absorption of co- 124), which stimulates their reabsorp- lon contents is harmful. Thus, purging tion in the kidney. The action of aldoste- has long been part of standard thera- rone is, however, associated with in- peutic practice. Nowadays, it is known creased renal excretion of KCl. The en- that intoxication from intestinal sub- teral and renal K+ loss add up to a K+ de- stances is impossible as long as the liver pletion of the body, evidenced by a fall functions normally. Nonetheless, purga- in serum K+ concentration (hypokale- tives continue to be sold as remedies to mia). This condition is accompanied by “cleanse the blood” or to rid the body of a reduction in intestinal peristalsis “corrupt humors.” (bowel atonia). The affected individual There can be no objection to the in- infers “constipation,” again partakes of gestion of bulk substances for the pur- the purgative, and the vicious circle is pose of supplementing low-residue closed (2). “modern diets.” However, use of irritant Chologenic diarrhea results when purgatives or cathartics is not without bile acids fail to be absorbed in the ile- hazards. Specifically, there is a risk of um (e.g., after ileal resection) and enter laxative dependence, i.e., the inability to the colon, where they cause enhanced do without them. Chronic intake of irri- secretion of electrolytes and water, tant purgatives disrupts the water and leading to the discharge of fluid stools. 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 de- scending colon. The interval between natural stool evacuations depends on the speed with which these colon seg- ments are refilled. A large bowel irritant purgative clears out the entire colon. Accordingly, a longer period is needed until the next natural defecation can oc- cur. Fearing constipation, the user be- comes impatient and again resorts to the laxative, which then produces the desired effect as a result of emptying out the upper colonic segments. There- fore, a “compensatory pause” following cessation of laxative use must not give cause for concern (1). In the colon, semifluid material en- tering from the small bowel is thick- ened 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 in- curred. 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.
Laxatives 173 Reflex Irritation Peristalsis of mucosa Filling Absorption Secretion of fluid A. Stimulation of peristalsis by mucosal irritation Interval needed to refill colon Normal filling After normal defecation reflex evacuation of colon Longer interval needed to refill rectum 1 Laxative “Constipation” Renal retention of Na+, H2O Laxative Bowel inertia Aldosterone Hypokalemia Renal Enteral loss loss of K+ of K+ 2 Na+, H2O B. Causes of laxative habituation Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.