REVIEW Phartnacotherapy of peptic ulcer disease F MOLINA, MD, MM VOi iRA, Pl ID, CN WILLIAMS, MD, FRCPC HE ETIOLCXW OF PEI"TIC ULCER DIS­ F MOLINA, MM VOHRA, CN WILLIAMS. Pharmacotherapy of peptic ulcer ease is multifoctorial (1,2), and disease. Can Gastroenterol 1991 ;5( 1):21-33. The etiology of peptic ulcer is T J factors such as environment, ethnicity, multifactorial; except for omeprazole, all drugs used for the treatment of peptic ulcer result in healing with no statistical difference at four weeks. The healing pre-existing c.liscasc cone.Ii ti on (3 ), ciga­ rare increases with time for active medication and placebo, and is lower among rette consumption (4-7) and nonster­ smokers than nonsmokers for all drugs but misoprostol. Mucosa[ protectives (or oidal anti-inflammatory drugs (3 ,8) 'cytoprotectives') as a group seem to have a lower relapse rate than the Hz have heen implicated. T he patho­ receptor antagonists at one year. Combination therapy has not yet proved to be physiological mechanisms suggest an better than single drug therapy; however, the number ofs tudies is still small, and imbalance between aggressive factors more clinical trials are necessary. Resistant ulcers have demonstrated that acid (acid, pepsin anc.l Helicobacter />ylori) is one of several etiological factors and that more research is needed to elucidate and defensive factors ( mucus, bicarbo­ the reason(s) for refractoriness. The choice of therapeutic agent is generally made nate, bloodflow, epithelial cell regen­ according to patient compliance, medication cost, side effects, effectiveness, eration, gastric emptying and pyloric relapse rate and physician experience with the drug. Long term maintenance function). therapy is effective in the prevention of ulcer relapse and is especially recom­ T he importance of acid in the de­ mended for selected patient groups, including patients with recurrent or bleeding ulcer, patients with concomitant nonsteroidal anti-inflammatory drug use, and velopment of peptic ulcers is supported elderly women. Omeprazole is the treatment of choice for moderate to severe by the fact that 80% will heal after four esophagitis and should be reserved for large and resistant ulcers. to six weeks of treatment with an acid­ rec.lucing agent (9). However, maximal Key Words: Drug therapy , Duodenal ulcer , Peptic ulcer acid output in patients with duodenal ulcer overlaps that in normals (3), and Pharmacotherapie de l'ulcere gastro,duodenal basal acid output is not generally in­ RESUME: Les causes de l'ulcere gastro-duodenal sont multifactorielles; a ['ex­ creasec.l (3). In contrast, meal-stimu­ ception de l'omeprazole, tousles medicaments utilises clans le traitement de cette lated acid and nocturnal acid secretion affection provoquent la guerison sans aucune difference statistique a quatre are increased in peptic ulcer patients semaines. Le taux de guerison augmente avec le temps sous traitement actif et (3,10). The pivotal roleofacid in peptic traitement placebo, et ii est plus bas pour les fumeurs que pour les non-fumeurs ulcers is fu rther indicated by the fact dans le cas de tous les medicaments saufle misoprostol. Le groupe des cytoprotec­ that these ulcers heal when nocturnal teurs semble donner un taux de recidive inferieur a celui des anti-H2 a un an. Le acid secretion is inhibited (I 0). Duodenal ulcer patients release Department~ of Medicine and Pharmacology, Division of Ga.moenterology, Dalhousie more gastrin in response to food th::m University, Halifax, Nova Scotia Correspondence and re/)rint1 : OT CN Williams, Professor and Head , Di11L11on of people without ulcers, with less feed ­ Gastroenterology, Dalhousie Univmity. Halifax, Nova Scotia B3H 4H7. Telephone (902) back inhibition by luminal acid , and 494-2333 greater parietal cell sensitivity to the Recei11ed for publication July 17, 1990. Acce/ned August 20, 1990 secretory effect of gastrin ( l l ). CAN] 0ASTROENTEROL VOL 5 No 1 JANUARY/FEBRUARY 1991 21 M OLINA et al 39 patients whose duodenal ulcers traitement par une association medicamenteuse n'a pas encore prouve sa su­ healed, 59% relapsed at one year. The periorite par rapport a la monotherapie; cependant, le nombre d'essais est encore bas et ii est nccessaire de multiplier les etudes cliniques. Les ulceres rebelles ont relapse rate was 27% among panenrs demontrc que la secretion acidc est l'un des nombreux facteurs etiologiques et who were H pylori culture-negative hut qu'il faut poursuivre la recherche pour decouvrir les raisons de la resistance au 79% among patients who were H /))•Ion traitement. Le choix de ['agent therapcutique est generalement determine en culture-positive (32 ). In another group fonction de ['adhesion du patient, du coCit du medicament, des effets secondaires, of patients in whom H pylori was crndi­ de l'efficacite, du taux de recidive et de ['experience du medecin avec le medi­ cared, 66% had a relapse of duodenal cament prescrit. La therapie de maintien a long terme est efficace clans la ulcer with H pylori recurrence, whi le prevention des rccidives ulcereuses ct elle est surtout recommandce pour les only I 0% with no recurrence ofH pylon groupes de patients selectionnes - les malades porteurs d'ulceres recidivants ou had duodenal ulcer relapse (32). hemorragiques, ceux qui suivent un traitement concomirant d'anti-inflamma­ Antimicrobial agents and bismuth roires non stero"idiens, et Jes femmes a.gees. L'omeprazole est le traitement de compounds reduce H J>ylori infection, choix Jans Jes OCSophagites modcrees a sevcres Ct i[ devrait Ctre reserve aux which is accompanied by heali ng rares ulceres de grandes dimensions et rebelles. comparable to those obtained with acid suppression, with the added advantage that they may also reduce the relapse Without acid, pepsi n (to which plays an important role in the defence rate of duodenal ulcer (33,34). Thus,a glycoproteins in gastric mucus, collagen system. combinatio n of tinidazole (an anti­ and elastin in the gastric and d uodenal Gast ric empty ing increases in microbi al similar to met ronidazole) mucosa are susceptible) is unable to patients with duodenal ulcer, and the with colloidal bismuth subcitrnte damage the mucosa, but in combina­ normal response of decreased emptying healed a greater proportion of patient; tion with acid it produces more severe with acidification of the duodenum is with duodenal ulcer and eradicated H damage than acid alone ( 12, 13). impaired (25). In a<ldition , retrograde pylori better than placebo or drug alone. The mucus secreted by the surface duodenal mo vements arc less frequent, It is likely that the concept of trealmg epithelium of the stomach forms an ad­ less pronounced and less effective, lead­ duodenal ulcer disease wi th an an, herent layer (14) that delays back dif­ ing to a deficiency in the transport of tibiotic will be pursued enthusiastically fu~ io n of h yd rogen io ns into t he neutra lized d uoden a l con tents and in the near future. The ideal agent, cor· epitheliu t;!_1 ( 15, 16), and pepsin diffuses bicarbonate from distal to proximal rcct dose, duratio n of therapy for poorly through the mucus (1 7). How­ duodenum, thus lowering pH in the eradication of the organism and rate of ever, the amount of mucus secreted is duodenal bulb (26). Motility abnor­ recurrence of both organism and ulcer not likely to be enough by itself co malities found in experimental ulcers are unknown at this time. mai ntain a neutral pH near the epi­ include decreased waves and mi.,xing thelial surface when the luminal pH is waves in the proximal duodenum and GOALS AND PRINCIPLES OF 2.0 (18). Stimulated by luminal acid, increased waves in the distal duodenum DRUG THERAPY FOR surface epithelial cells also secrete bi­ (27). Their interaction causes a diver­ PEPTIC ULCER carbonate (1 9). A lthough the amount sion of biliary and/or pancreatic secre­ The goals of therapy are eliminanon secreted basally is no more than 10 to tions, with increased inc id ence and of symptoms, ulcer healing, prevention 15% of basal acid production (1 8 ), and severi ty of posterio r wall ulcer induced of recurrence and prevention of com­ thus is not sufficient to protect the mu­ by cysteamine in the rat. Correction of plications (35). cosa alone, mucus and bicarbonate to­ this diversion reverses the effect (28). The ideal drug for peptic ulcer treat, gether form a barrier that produces a pH Recently H pylori has been impli­ ment would: have a 100% healing rate gradient (neutral pH near the mucosa cated in the et iology of duodenal ulcer. and no side effects; require only one and an acid pH in the lumen) (20,2 1) This microorganism has been found dose every 24 h; provide antisecretorv wh ich prevents mucosa! damage from under the gastric mucus layer, adherent effectiveness for 24 h; enhance mucosa! the acid. Another clement of defence is to epithelial cells and sometimes con­ defence; and benefit the natural history a hydrophobic lining of glycolipids over centrated over intracellular junctions of the disease (36). Unfortunately, no the epithelium, impeding proton dif­ (29). H pylori produces a large amount presently available drug fulfills all of fusion and proteolysis of the mucosa of urease, and the release of ammonia these requirements. Pat ients shou ld (22). by urcase may increase gastric pH, avoid the following: foods that provoke Mucosa[ ischemia is the most impor­ protecting H pylori from gastric acid symptoms, because although diet chan­ tant factor in acute gastric ulceration (30) and undermining gastric mucosa! ges cannot heal ulcers by themselves, (23 ), because bloodfl ow is critical m the integrity. H pylori was detected in 85% they may allevi,1 te sy mpto ms (37); maintenance of normal mucosa! energy of 232 patients with duodenal ulcers.