Академический Документы
Профессиональный Документы
Культура Документы
w 190-VAlk,
AV V
4VUL Arlik
1"
I .in
k.- ( It
RICHARD K. ROOT, MD: * It is a pleasure to introduce Dr duced and inversely proportional to the integrity of the
Bruce Scharschmidt, who will discuss peptic ulcer mucosal barrier. In this context, certain disorders, such as
disease, including current concepts ofpathophysiology and the Zollinger-Ellison syndrome, represent disorders of the
medical management. Dr Scharschmidt is Professor of numerator. On the other hand, gastric ulcer disease and
Medicine and has been recently selected as the new editor of acute gastritis represent disorders in which the integrity of
the Journal of Clinical Investigation, the responsibility for the mucosal barrier is impaired and ulceration occurs even
which was transferred to the University of California, San though the amount of acid and pepsin produced is normal or
Francisco (UCSF), campus in May 1987. He received his subnormal. Moreover, one would anticipate that agents that
MD training at Northwestern University (Chicago, Ill) and are effective in healing or preventing ulcers do so by de-
served as a house o ffcer at UCSFfrom 1970 through 1972. creasing the numerator, increasing the denominator or
He subsequently spent three years at the National Institutes both.' I will briefly discuss current concepts regarding the
of Health and returned to UCSFfor a fellowship in gastro- regulation of acid secretion and the mucosal barrier.
enterology from 1975 through 1977, following which he
was appointed to the faculty and rose rapidly to the profes- Acid Secretion
sorial level. Besides his newly assumed editorship, he has The parietal cell, which is present in oxyntic glands in
recently finished a five-year term as associate editor of the fundus and body of the stomach, is the source of gastric
Gastroenterology. acid production. The parietal cell is the clear winner among
BRUCE F. SCHARSCHMIDT, MD:t Thank you, Dr Root. all epithelial cells in its ability to generate a hydrogen ion
Given the huge literature on the topic of acid peptic disease concentration gradient. The pH in the gastric lumen is often
and the large number of controlled trials that have been as low as 1 to 2, as compared with a pH of 7.4 in blood. This
carried out in the past decade, one might assume that all of 6-log concentration difference is much greater, for ex-
the important clinical questions would have been addressed ample, than the maximum hydrogen ion concentration dif-
and answered. In fact, this is not the case, and there remains ference between urine and blood. This remarkable ability of
lively debate on a number of points. In this conference I will the parietal cell to create a steep pH gradient has attracted
not review the basic aspects of acid peptic disease, in- the attention of both basic scientists and clinical investiga-
cluding the typical symptoms and approach to diagnosis, tors, and there has been considerable recent progress in our
which are already well known to most physicians. Rather, I understanding of how the parietal cell works and what regu-
will focus on currently emerging concepts and controver- lates it.
sies regarding the pathophysiology of acid peptic disease Morphology of the parietal cell. With stimulation, the
and various approaches to management. parietal cell undergoes a rather striking morphologic trans-
formation.'2-S In the resting state, the parietal cell is charac-
Pathophysiology terized by an abundant intracellular membranous tubulo-
An acid peptic disorder occurs when the injurious ef- vesicular network. The interior of this tubulovesicular net-
fects of acid and pepsin overwhelm the mucosal barrier. It work is acidic, and certain agents such as omeprazole,
is helpful to visualize acid peptic disease in the form of a which is useful in treating ulcer disease, accumulate in
pseudoequation these highly acidic compartments, as will be discussed
acid + pepsin
later. With stimulation, this membranous tubulovesicular
acid peptic disease z barrie
mcosal barrier
mucosal network disappears and is replaced by an extensive intra-
where the likelihood of acid peptic disease developing is cellular canalicular network that is in direct communication
directly proportional to the amount of acid and pepsin pro- with the lumen of the oxyntic gland and, in effect, tremen-
dously amplifies the surface area of the apical membrane of
*Professor and Chair, Department of Medicine, UCSF School of Medicine. the cell. This morphologic transformation is evident within
tProfessor of Medicine, Department of Medicine and Liver Center, UCSF. 3 minutes of parietal cell stimulation, is complete in 30
(Scharschmidt BF: Peptic ulcer disease-Pathophysiology and current medical management [Medical Staff Conference]. West J Med 1987 Jun;
146:724-733)
Supported in part by National Institutes of Health grants No. AM-26270 and No. AM-26743.
THE WESTERN JOURNAL OF MEDICINE o JUNE 1987 o 146 6 725
2
"standard" doses. Recent studies indicate, however, that all propriate. Sucralfate has been shown to produce minimal side
three H2-receptor antagonists are comparably effective in the effects apart from constipation, which is dose-related. It ap-
healing of duodenal ulcers when given as a single night-time pears to be effective for the treatment of duodenal ulcers and
dose in large enough amounts. Thus, this difference in po- possibly also gastric ulcers, as well as for preventing ulcer
tency and duration of action may not be critical in the initial recurrence.
therapy for duodenal or gastric ulcer disease. It may be more Bismuth preparations. Bismuth-containing preparations,
relevant, however, for preventing ulcer relapse, as will be currently available in Europe but not in the United States,
discussed below. have also been effective in healing ulcers.3031 The mechanism
Cimetidine binds to hepatic cytochrome P450 and inhibits of action of such agents is unknown, but because bismuth is
the oxidative metabolism of a variety of drugs. This effect is not known to neutralize acid or inhibit secretion, it is pre-
probably most significant for theophylline, warfarin sodium sumed to act by enhancing the mucosal barrier. Of interest is
and phenytoin, but even for these drugs, adverse clinical that two studies have shown that duodenal ulcers healed with a
consequences have only rarely been reported. There is also bismuth preparation are less likely to relapse than ulcers
preliminary evidence that a single night-time dose of cimeti- healed with an H2-receptor antagonist (see below). I am not
dine has less effect on the metabolism of these agents than aware of similar studies looking at nonprescription bismuth
does the multiple daily dosing regimen previously used. As preparations available in the United States.
compared with cimetidine, ranitidine binds weakly to hepatic Omeprazole. Omeprazole is the newest and most potent
cytochrome P450. While minor effects of ranitidine ingestion agent in terms of its ability to inhibit acid secretion.65-70 It
on the metabolism of other drugs have been reported, they are inhibits the H+, K+-ATPase that mediates the final step in acid
probably not of clinical significance. Famotidine, like raniti- secretion. Its potency is much greater than that of H2-receptor
dine, appears to have little effect on the metabolism of other antagonists, and it has a longer duration of action. A single
drugs, but postmarketing clinical experience is limited. dose can decrease acid output by more than 90% for a period
Both cimetidine and ranitidine have proved to be remark- of 24 hours or more. It accumulates and is concentrated in the
ably safe agents. Hypersensitivity reactions and adverse ef- highly acidic compartments of the parietal cell. When acti-
fects on central nervous system function have been reported vated by acid, omeprazole attacks sulfhydryl groups and irre-
with both but are exceedingly rare. Recently there have been versibly inactivates the H+, K+-ATPase, which helps to ex-
reports of an apparent association between the intravenous plain its long duration of action. The accumulation of
administration of ranitidine, particularly in doses of 100 mg omeprazole in parietal cells also explains a peculiar pharma-
or larger, and reversible abnormalities in liver function cokinetic property of this drug: namely, it is maximally effec-
tests.59 Famotidine, like cimetidine and ranitidine, appears to tive at a time when drug concentrations in the blood are no
be associated with few side effects. Again, however, post- longer detectable.
marketing experience with this agent is comparatively lim- Omeprazole has been effective for the treatment of duo-
ited. denal ulcer disease, and its high potency and long duration of
Antiandrogenic side effects including gynecomastia and action are particularly attractive for the treatment of the Zol-
impotence have been reported with the use of cimetidine, but linger-Ellison syndrome,6970 which is associated with a dra-
not with the other agents. These are dose-related and are seen matic hypersecretion of acid.
only in patients given large doses of the drug for a long period Recently it was noted that administering omeprazole to
of time. Thus, for practical considerations, antiandrogenic rats produced gastric carcinoid tumors, causing concern that
side effects are a concern only for patients treated for the the drug was intrinsically carcinogenic. Recent evidence,
Zollinger-Ellison syndrome. however, suggests that this is not the case. Carcinoid tumors
Sucralfate. Sucralfate is an aluminum salt of a sucrose have also been associated with the administration of high-po-
octasulfate. The mechanism ofaction is not completely under- tency H2-receptor antagonists72 and are described in associa-
stood, but unlike the other agents discussed it appears to act by tion with pernicious anemia. Thus, carcinoid tumors appear
enhancing the mucosal barrier.53-6064 It appears to physically not to be due to omeprazole per se but rather to the profound
coat ulcers and may bind bile acids and pepsin; there is also inhibition of acid secretion and accompanying hypergastri-
evidence that it increases the mucosal synthesis ofprostaglan- nemia that the drug produces. Gastrin, in turn, appears to
dins. Its use decreases the bioavailability of certain other stimulate certain endocrine-like cells in the gastric mucosa,
drugs, and, as with animals, staggered administration is ap- which may lead to the production of carcinoid tumors.
THE WESTERN JOURNAL OF MEDICINE - JUNE 1987 -
* 146
146
e
* 6
6 729
729
DR SCHARSCHMIDT: This is an interesting question in the dine and placebo in treatment of active peptic ulcers. Scand I Gastroenterol 1981;
16:593-602
sense that chloroquine is a weak base that is accumulated in 35. Goldberg MA: Medical treatmentof peptic ulcerdisease: Is it truly effective?
acidic compartments and increases their internal pH. In the Am J Med 1984; 77:589-591
doses used clinically, I am unaware of any effect of chloro- 36. Korman MG, Shaw RG, Hansky J, et al: Influence of smoking on healing rate
of duodenal ulcer in response to cimetidine or high dose antacid. Gastroenterology
quine on acid secretion. In in vitro systems, chloroquine does 1981; 80:1451-1453
not appear to affect stimulus-secretion coupling. 37. Boyd EJS, Wilson JA, Wormsley KG: Smoking impairs therapeutic gastric
inhibition. Lancet 1983; 1:95-97
38. Sontag S, Graham DY, Belsito A, et al: Cimetidine, cigarette smoking, and
REFERENCES recurrence ofduodenal ulcer. N Engl J Med 1984; 311:689-693
1. Richardson CT: Pharmacologic basis of peptic ulcer therapy. Viewpoints Dig 39. McCarthy DM: Smoking and ulcers-Time to quit. N Engl J Med 1984;
Dis 1985; 17:1-4 311:726-728
2. Olson C, Soll AH: The parietal cell and regulation of gastric acid secretion. 40. Schiller LR, Fordtran JS: Ulcer complications during short term therapy of
Viewpoints Dig Dis 1984; 16:1-4 duodenal ulcer with active agents and placebo. Gastroenterology 1985; 90:478-479
3. Forte JG,Black JA, Forte TM, et al: Ultrastructural changes related to func- 41. Reed B: Diseases of the Stomach and Intestine. Bristol, England, John
tional activity in gastric oxyntic cells. Am J Physiol 1981; 241 :G349-G358 Wright, 1905
4. Hirst BH, Forte JG: Redistribution and characterization of (H+-K+)-ATPase 42. Peterson WL, Sturdevant RAL, Frankl HD, et al: Healing of duodenal ulcer
membranes from resting and stimulated gastric parietal cells. Biochem J 1985; with an antacid regimen. N Engl J Med 1977; 297:341-345
231:641-649 43. Fordtran JS, Morawski SG, Richardson CT: In vivo and in vitro evaluation
5. Cuppoletti J,
Sachs G: Regulation of gastric acid secretion via modulation of a of liquid antacids. N Engl J Med 1973; 288:923-928
chloride conductance. J Biol Chem 1984; 259:14952-14959
44. Lauritsen K: Comparison of ranitidine and high dose antacid in the treatment
6. Wallmark B, Larsson H, Humble L: The relationship between gastric acid of prepyloric orduodenal ulcer. ScandJ Gastroenterol 1985; 20:123-131
secretion and gastric HI, K+-ATPase activity. J Biol Chem 1985; 260:13681-13684 45. Weberg R: Duodenal ulcer healing with four antacid tablets daily. Scand J
7. Flemstrom G, Turnberg LA: Gastroduodenal defense mechanisms. Clin Gas- Gastroenterol 1985; 20:1041-1045
troenterol 1984; 13:327-354 46. Rydning A, Weberg R, Lange 0, et al: Healing of benign gastric ulcer with
8. Guth PH: Pathogenesis of gastric mucosal injury. Annu Rev Med 1982; low dose antacids and fiberdiet. Gastroenterology 1986; 91:56-61
33: 183-196
47. Freston JW: Cimetidine-I. Development, pharmacology, and efficacy; II.
9. Rees WDW, Tarnberg
LA: Mechanisms of mucosal
for the 'mucus-bicarbonate' barrier. Clin Sci 1982; 62:343-348
gastric protection: A role Adverse reactions and patterns of use. Ann Intern Med 1982; 97:573-580; 728-734
48. Zeldis JB, Friedman LS, Isselbacher KJ: Ranitidine: A new H2-receptor
10. Allen A, Garner A: Mucus and bicarbonate secretion in the stomach and their antagonist. N Engl J Med 1983; 309:1368-1373
possible role in mucosal protection. Gut 1980; 21:249-252 49. Smith JL: Clinical pharmacology of famotidine. Digestion 1985; 32:15-23
11. Ross IA, Bahari HMM, lbrnberg LA: The pH gradient across mucus ad- 50. Graham DY, Akdamar K, Dyck WP, et al: Healing of benign gastric ulcer:
herent to rat fundic mucosa in vivo and the effect of potentially damaging agents. Comparison of cimetidine and placebo in the United States. Ann Intern Med 1985;
Gastroenterology 1981; 81:713-718 102:573-576
12. Williams SE, Turnberg LA: Studies of the protective properties of gastric 51. Isenberg JI, Peterson WL, ElashoffJD, et al: Healing of benign gastric ulcer
mucus. Adv Exp Med Biol 1982; 144:184-188 with low dose antacid or citnetidine-A double blind, randomized placebo-controlled
13. LaMont JT: Structure and function of gastrointestinal mucus. Viewpoints trial. N Engl J Med 1983; 308:1319-1324
DigDis 1985; 17:1-4
52. Legerton CW: Duodenal and gastric ulcer healing rates: A review. Am J Med
14. Konturek SJ, Brzozowski T, Piastucki I, et al: Role of locally generated 1984; 77:2-7
prostaglandins in adaptive gastric cytoprotection. Dig Dis Sci 1982; 27:967-971 53. Hallerback B, Aanker-Hansen 0, Carling L, et al: Short term treatment of
15. Sharon P, Cohen F, Zefroni A, et al: Prostanoid cultured synthesis by gastric gastric ulcer: A comparison of sucralfate and cimetidine. Gut 1986; 27:778-783
and duodenal mucosa: Possible role in the pathogenesis of duodenal ulcer. Scand J 54. Gitlin N, McCullough AJ, Smith JL: A multicenter, double-blind, random-
Gastroenterol 1983; 18:1045-1049
ized, placebo-controlled comparison of nocturnal and twice-a-day famotidine in the
16. Ahlquist DA, Dozois RR, Zinsmeister AR, et al: Duodenai prostaglandin treatment ofactive duodenal ulcer disease. Gastroenterology 1987; 92:48-53
synthesis and acid load in health and in duodenal ulcer disease. Gastroenterology 55. Ireland A, Colin-Jones DG, Gear P, et al: Ranitidine 150 mg twice daily vs
1983; 85:522-528 300 mg nightly in treatment ofduodenal ulcers. Lancet 1984; 2:274-276
17. Robert A, Nezamis JE, C, et al: Mild irritants prevent gastric
Lancaster
56. Kildebo S, Aronsen 0, Bernersen B, et al: Cimetidine, 800 mg at night, in
necrosis through 'adaptive cytoprotection' mediated by prostaglandins. Am J the treatment ofduodenal ulcers. Scand J Gastroenterol 1985; 20:1147-1150
Physiol 1983; 245:G1 13-G121
57. Lee FI, Reed PI, Crowe JP, et al: Acute treatment of duodenal ulcer: A
18. Chailet N, Gallo-Torres HE, Bounameaux Y, et al: Prostaglandins and the multicentre study to compare ranitidine 150 mg twice daily with ranitidine 300 mg
protection of the gastroduodenal mucosa in humans: A critical review. J Clin Phar- once at night. Gut 1986; 27:1091-1095
macol 1985; 25:564-582
19. Leung FW, Robert A, Guth PH:
58. Ryan FP, Jorde R, Ehsanullah RSB, et al: A single night time dose of
Gastric mucosal blood flow in rats after
ranitidine in the acute treatment of gastric ulcer: A European multicentre trial. Gut
administration of 16,16-dimethyl prostaglandin E2 at a cytoprotective dose. Gastro- 1986; 27:784-788
enterology 1985; 88:1948-1953
59. Souza-Lima MA: Ranitidine and hepatic injury. Ann Intern Med 1986;
20. Lacy ER: Prostaglandins and histological changes in the gastric mucosa. Dig 105:140
Dis Sci 1985; 30:835-945
21. Rathbone BJ, Wyatt
60. Richardson CT: Sucralfate (Editorial). Ann Intern Med 1982; 97:269-272
JI, Heatley RV: Campylobacter pyloridis-A new
factor in peptic ulcer disease. Gut 1986; 27:635-641 61. Miyake T, Ariyoshi J, Suzaki T, et al: Endoscopic evaluation of the effect of
sucralfate therapy and other clinical parameters on the recurrence rate of gastric
22. Marshall BJ, Armstrong JA, McGechie DB, et al: Attemnpt to fulfill Koch's ulcers. Dig Dis Sci 1980; 25:1-7
postulates for pyloric Campylobacter. Med J Aust 1985; 142:436-439
23. Ramsey EJ, Carey KV, Peterson WL, et al: Epidemic gastritis with hypo-
62. Martin F, Farley A, Gagnon M, et al: Comparison of the healing capacities
of sucralfate and cimetidine in the short-term treatment of duodenal ulcer: A double
chlorhydria. Gastroenterology 1979; 76:1449-1457 blind randomized trial. Gastroenterology 1982; 82:401-405
24. Bardham KD: Refractory duodenal ulcer. Gut 1984; 25:711-717
63. Van Deventer G, Schneidman D, Walsh JH: Sucralfate and cimetidine as
25. Lam SK, Lee NW, Koo J,
et al: Randomised crossover trial of tripotassium single agents and in combination for treatment of active duodenal ulcers: A dou-
dicitrato bismuthate versus high
dose cimetidine for duodenal ulcers resistant to ble-blind, placebo-controlled trial. Am J Med 1985; 79(2c):39-44
standard doses of cimetidine. Gut 1984; 25:703-706
64. Brandstaetter G, Kratochvil P: Comparison of two sucralfate dosages (2 g
26. Quatrini M, Basilisco G, Bianchi PA: Treatment of 'cimetidine-resistant' twice a day versus I g four times a day) in duodenal ulcer healing. Am J Med 1985;
chronic duodenal ulcers with ranitidine or cimetidine: A randomised multicentre 79(2c):36-38
study.Gut 1984;25:1113-1117 65. Londong W, Londong V, Cederberg C, et al: Dose-response study of omepra-
27. Pounder RE: Duodenal ulcers that will not heal. Gut 1984; 25 697-702 zole on meal-stimulated gastric acid secretion and gastrin release. Gastroenterology
28. Wormsley KG: Assessing the safety of drugs for the long-term treatment of 1983; 85:1373-1378
peptic ulcers. Gut 1984; 25:1416-1423 66. Gustavsson S, Adami HO, Loof L, et al: Rapid healing of duodenal ulcers
29. Sonnenberg A, Webersinke R: The costs of medical and surgical treatment of with omeprazole: Double-blind dose-comparative trial. Lancet 1983; 2:124-125
duodenal ulcer disease (Abstr). Gastroenterology 1986; 90:1643 67. Lauritsen K, Rune SJ, Bytzer P, et al: Effect of omeprazole and cimetidine on
30. Martin DF, Hollanders D, May SJ, et al: Difference in relapse rates of duodenal ulcer. N Engl J Med 1985; 312:958-961
duodenal ulcer after healing
with cimetidine or tripotassium dicitrato bismuthate. 68. Nielsen AM, Stenderup J, Wandall JH, et al: Reduction of gastric acid
Lancet 1981; 1:7-10 secretion by 10 mg and 30 mg omeprazole once daily. Scand J Gastroenterol 1985;
31. Hamilton I, O'Connor HJ, Wood NC, et al: Healing and recurrence of 20:1236-1238
duodenal ulcer after treatment with tripotassium dicitrato bismuthate tablets (TDB) 69. Lamers CBHW, Lind T, Moberg S, et al: Omeprazole in Zollinger-Ellison
or cimetidine. Gut 1985; 27:106-1 10 syndrome. N Engl I Med 1984; 310:758-761
32. Ippoliti A, Elashoff J,
Valenzuela J, et al: Recurrent ulcer after successful 70. McArthur KE, Collen MJ, Maton PH, et al: Omeprazole: Effective, conve-
treatment with cimetidine or antacid. Gastroenterology 1983; 85:875-880 nient therapy for Zollinger-Ellison syndrome. Gastroenterology 1985; 88:939-944
33. Marks IN, Wright JP, Lucke W, et al: Relapse rates following initial ulcer 71. ElderlB: Inhibition of acid and gastric carcinoids. Gut 1985; 26:1279-1283
healing with sucralfate and cimetidine. Scand J Gastroenterol 1983; 18(suppl 72. Poynter D, Pick CR, Harcourt RA, et al: Association of long lasting insur-
83):53-56
mountable histamine H2 blockade and gastric tumors in the rat. Gut 1985; 26:1284-
34. Strom M, Gotthard R, Bodeman G, et al: Antacid/anticholinergic, cimeti- 1295
THE WESTERN JOURNAL OF MEDICINE * JUNE 1987 * 146 * 6 733
73. Vantrappen G, Janssens J, Popiela T: Effect of 15, 15-dimethyl prostaglandin 81. Gough KR, Korman MG, Bardhan KD, et al: Ranitidine and cimetidine in
E2 on the healing of duodenal ulcer. Gastroenterology 1982; 83:357-363 prevention of duodenal ulcer relapse-A double blind, randomised, multicentre com-
74. Fick A, Arber N, Sestieri M, et al: Effect of misoprostel and cimetidine on parative trial. Lancet 1984; 2:659-662
gastric cell labelling index. Gastroenterology 1985; 89:57-61 82. Kleveland PM, Larsen S, Sandvick L, et al: The effect of cimetidine on
75. Brooks FP, Watkinson G, Davies HC (Eds): Prostaglandins in gastroenter- nonulcerdyspepsia. Scand J Gastroenterol 1985; 20:19-24
ology-Focus on misoprostel. Dig Dis Sci 1985; 30:1 S-205S 83. Nesland AA, Berstad A: Effect of cimetidine in patients with non-ulcer
76. Adami HO, Bjorklund 0, Enandes L-K, et al: Cimetidine or propantheline dyspepsia and erosive prepyloric changes. Scand J Gastroenterol 1985; 20:629-635
combined with antacid therapy for short-term treatment of duodenal ulcer. Dig Dis 84. Nyren 0, Adami HO, Bates S, et al: Absence of therapeutic benefit from
Sci 1982; 27:388-393 antacids or cimetidine in non-ulcer dyspepsia. N Engl J Med 1986; 314:339-343
77. Van Deventer GM: Approaches to the long-term treatment of duodenal ulcer
disease. Am J Med 1984; 77:15-22 85. Talley NJ, McNeil D, Hayden A, et al: Randomized double-blind, placebo-
controlled crossover trial of cimetidine and pirenzipine in nonulcer dyspepsia. Gas-
78. Robinson M: Review of the peptic ulcer maintenance trials. Am J Med 1984; troenterology 1986; 91:149-156
77:23-29
86. Conn HO, Blitzer BL: Nonassociation of adrenocorticosteroid therapy and
79. Marks IN, Wright JP, Girdwood AH, et al: Maintenance therapy with su- peptic ulcer. N Engl J Med 1976; 294:473-479
cralfate reduces rate of gastric ulcer recurrence. Am J Med 1985; 79(2c): 14-17
80. Silves SE: Final report on the United States multicenter trial comparing 87. Messer J, Reitman D, Sacks HS, et al: Association of adrenocorticosteroid
ranitidine to cimetidine as a maintenance therapy following healing of duodenal therapy and peptic-ulcerdisease. N Engl J Med 1983; 309:21-24
ulcer. J Clin Gastroenterol 1985; 7:482-487 88. Spiro HM: Isthe steroid ulcer a myth? N Engl J Med 1983; 309:45-47