4
0039-6109/92 $0.00
GASTRIC SURGERY
+ .20
MEDICAL THERAPY OF PEPTIC ULCER DISEASE Kenneth R. McQuaid, MD, and Jon I. Isenberg, MD
During the last decade, significant advances have been made in our understanding of the pathogenesis of gastric and duodenal ulcers. Although a variety of factors have been identified that may favor the development of peptic ulcers in some people, their precise mechanisms and relative contribution to ulcer pathogenesis remain unclear.34. 63 The expansion in our understanding of ulcer pathogenesis has been paralleled by the development of a number of therapeutic agents with various mechanisms of action. Extensive utilization of these drugs in randomized double-blind clinical trials has contributed immeasurably to our current medical treatment of peptic ulcer disease. OVERVIEW OF ULCER PATHOPHYSIOLOGY Mucosal Defense
The gastric and duodenal mucosa normally is protected from the potentially damaging effects of gastric acid and pepsin by ill-defined processes of resistance. 1. 58, 60 Surface epithelial cells secrete mucus, which provides an unstirred layer immediately adjacent to the epithelial surface and an effective barrier to pepsin. Continuous bicarbonate secretion by the gastric and duodenal surface epithelial cells into the overlying mucous layer results in a pH gradient in which the pH varies from approximately 7 at the epithelial surface to less than 2 in the gastric or duodenal lumen. In addition, gastric mucosal cells have apical From the Department of Medicine, Division of Gastroenterology, University of California, San Diego, San Diego, California
SURGICAL CLINICS OF NORTH AMERICA VOLUME 72 • NUMBER 2 • APRIL 1992
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4
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McQUAID & ISENBERG
membranes and tight junctions that are impermeable to the backdiffusion of acid into the cell. 74 Other factors that are important in the maintenance of mucosal integrity include blood flow and the ability of epithelial cells to renew themselves rapidly and to migrate along the basal membrane to areas of minor injury, a process referred to as "reconstitution."61 Furthermore, cytokines and growth factors undoubtedly playa role in mucosal defense, although their precise roles require further study. It is now clear that prostaglandins enhance the mucosal defense factors through the stimulation of mucus and bicarbonate secretion and blood flow. 50 Thus, there are a number of interacting factors that serve as defensive mechanisms for the maintenance of gastroduodenal mucosal integrity. Ulcers arise when there is an imbalance between these normal mucosal defense mechanisms and the "aggressive" factors such as the potentially noxious effects of acid and pepsin. A variety of factors may disrupt mucosal resistance, tipping the balance toward ulcer development. These are summarized briefly below, and comprehensive reviews are available. 34, 63 Nonsteroidal Anti-Inflammatory Drugs. The nonsteroidal antiinflammatory drugs (NSAIDs) may either cause gastric or duodenal ulcers de novo or exacerbate an underlying ulcer diathesis. 65 Chronic NSAID use is associated with the development of mucosal ulceration in 15% to 20% of patients. There is an estimated 40-fold increase in gastric ulcers and an 8-fold increase in duodenal ulcers in daily NSAID users. 64, 65 Of even more important clinical impact, chronic NSAID users are at least four to seven times as likely to experience serious gastrointestinal hemorrhage or perforation than are matched controIs. 24, 29 Chronic NSAID injury is hypothesized to arise from the inhibition of cyclooxygenase, resulting in decreased mucosal prostaglandin synthesis and impaired mucosal defense. Bacterial Action. Helicobacter pylori is a gram-negative, flagellated rod found in the antrum of more than 95% of duodenal ulcer patients as well as in most patients with gastric ulcers that are not associated with NSAIDs. 16, 34, 49 The organism does not appear to invade the antral mucosa directly but does initiate a histologic inflammatory response, chronic gastritis, which is found in virtually all patients with gastric or duodenal ulcers. Indeed, H. pylori appears to be the principal cause of idiopathic chronic (histologic) antral gastritis. 34 This inflammatory response to H. pylori could result in a breakdown in mucosal resistance to acid and pepsin. Helicobacter pylori-associated gastritis appears to be common in the general population, the rate approaching 50% in people over the age of 60. 17 In most of these people, this gastritis does not appear to be associated with dyspepsia or peptic ulcer disease. The high prevalence of H. pylori gastritis in peptic ulcer patients is intriguing; however, only a small proportion of all persons infected with H. pylori ever develop peptic ulcer disease. Therefore, other pathogenetic factors must be important in these patients. Traditional ulcer therapies effectively heal peptic ulcers but do not eradicate the chronic H. pylori infection. Recent therapeutic trials with bismuth, antibiotics, or both
MEDICAL THERAPY OF PEPTIC ULCER DISEASE
287
suggest that ulcer recurrences are markedly diminished in patients in whom H. pylori infection is eradicated (see below). These data lend strong support to the importance of H. pylori infection in the ulcer diathesis. Mucosal Bicarbonate Secretion. Both basal and stimulated (by luminal acidification, prostaglandin E, and sham feeding) bicarbonate secretion by the proximal duodenal mucosa is diminished in patients with duodenal ulcer disease. Of interest, bicarbonate secretion by the duodenal bulb is impaired in both patients with active and those with inactive (i.e., healed) duodenal ulcers. This fact suggests an intrinsic defect in duodenal defense in these patients. Whether this is a primary pathogenetic defect or is secondary to other factors requires further study.36 To date, no alterations in gastric mucosal bicarbonate secretion have been observed in ulcer patients. Cigarette Smoking. Smoking, which does not substantially alter gastric acid secretion, has been reported unequivocally to increase the incidence and complication rate of peptic ulcers, to retard ulcer healing, and to promote ulcer recurrences. Various pathogenetic mechanisms have been suggested; however, the exact mechanisms remain elusive. n, 34 Gastric Secretion
Gastric acid and pepsin are essential permIssIve factors in the pathogenetic process of ulcer formation. Schwarz's dictum "no acidno ulcer" still applies except in unusual circumstances. Although patients with duodenal ulcers as a group have higher mean basal or pentagastrin-stimulated acid outputs than normal subjects, acid secretion in most ulcer patients falls well within normal ranges. Therefore, an underlying impairment in mucosal resistance is implied. Nevertheless, duodenal ulcers rarely occur in patients with a pentagastrinstimulated acid output of less than 12 mmollhour, and only about one third of duodenal ulcer patients are true hypersecretors of gastric acid. 63 The possible mechanisms of increased acid secretion are reviewed elsewhere; in many, the increase is attributed to an enlarged mass of acid and pepsinogen-secreting oxyntic glands. 63 , 77 In contrast to those with duodenal ulcers, patients with gastric ulcers tend to have normal to low gastric acid secretion, suggesting that impaired mucosal defense is the principal element in ulcer development. Similarly, despite massive acid hypersecretion, about 10% of patients with Zollinger-Ellison syndrome do not develop duodenal or gastric ulcers. This illustrates the importance of mucosal resistance in the pathogenetic process. Other Factors
Additional factors appear to be important in the development of ulcers in some cases. Genetic predisposition, bile reflux, rapid gastric
288
McQUAID & ISENBERG
emptying, and underlying medical illness (cirrhosis, chronic obstructive pulmonary disease, cystic fibrosis) playa pathogenetic role in some patients. These factors are reviewed elsewhere. 34 In summary, peptic ulcers arise when the damaging effects of acid and pepsin or other noxious agents exceed the restorative processes favoring mucosal integrity and repair. Peptic ulcers have multiple, heterogeneous etiologies, and no single pathophysiologic defect applies in all cases.
MEDICAL THERAPY OF PEPTIC ULCERS
Since the introduction of the histamine H 2-receptor antagonists in the late 1970s, the treatment of ulcer patients has undergone a number of clinically important modifications. Some examples include the observation that evening (or nocturnal) single-dose H 2-antagonist treatment is as effective as multiple daily doses; the introduction of more potent H 2-receptor antagonists; the development of the H+/K+-ATPase inhibitors, with their prolonged antisecretory effects; the recognition of H. pylori infection, its relation to antral gastritis, and the effect of its eradication in diminishing duodenal ulcer recurrences; and the development of drugs that neither neutralize gastric acid nor alter its production (i.e., sucralfate and low-dose antacids). Twenty years ago, the principal goal in ulcer treatment was to expedite ulcer healing. Today, it is quite easy, under most conditions, to heal both gastric and duodenal ulcers with anyone of a number of drugs. Therefore, the emphasis has appropriately shifted to the prevention of gastroduodenal mucosal injury (often attributable to NSAIDs), as well as to the prevention of ulcer recurrences and complications. Also, although the need for elective surgery or peptic ulcer has decreased substantially, there appears to be an increase in ulcer complications, particularly in the elderly, often associated with NSAID ingestion. In addition, as reviewed elsewhere in this issue, surgery still plays an important therapeutic role in patients who are noncompliant with medical therapy, those with nonhealing gastric ulcers, and those with frequent recurrences in spite of medical management.
Pharmacologic Therapy
Several pharmacologic agents enhance the healing of peptic ulcers. In keeping with the classification of pathogenetic factors given above, pharmacologic agents may be subsumed into two categories: those that promote ulcer healing by reducing intragastric acidity and those that enhance mucosal defense mechanisms. Of note, the precise mechanism(s) of action of some drugs is not fully understood.
MEDICAL THERAPY OF PEPTIC ULCER DISEASE
289
Reduction of Intragastric Acidity
H2 Antagonists. Pharmacology. Histamine H 2-receptor antagonists have enjoyed a favored status for the acute treatment of duodenal and gastric ulcers for the past decade because of their efficacy, patient acceptance, and excellent safety profile. A complete review of the clinical pharmacology of these agents is beyond the scope of this article, and the reader is referred to several recent reviews. 19, 20, 22, 28, 34, 39-41 Briefly, four H2 antagonists have been approved by the Food and Drug Administration (FDA) for clinical use in the US: cimetidine, ranitidine, famotidine, and nizatidine. A fifth, roxatidine, is available in Europe. These compounds share an aromatic ring system and have a flexible side chain that is affixed to a polar uncharged group (Fig, 1). These agents produce reversible, competitive inhibition of the histamine H2 receptor of the parietal cell, thereby reducing intracellular cAMP levels and acid secretion. Parietal cells also contain receptors for gastrin and acetylcholine (muscarinic type), both of which stimulate acid secretion by increasing intracellular calcium. 77 Of note, there appears to be a potentiating effect on acid secretion between the agents activating the cAMP pathway (e.g., histamine) and the calcium pathway (e.g., gastrin and acetylcholine), Hence, the histamine H 2-receptor antagonists inhibit, not only histamine-stimulated acid secretion, but also basal and sham feed-, pentagastrin-, and meal-stimulated acid secretion
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#:
290
McQUAID & ISENBERG
in a linear dose-dependent fashion. 34 The H2 antagonists may inhibit as much as 90% of gastrin- or vagal-stimulated acid secretion; however, complete inhibition has not been demonstrated. Thus, administration of cimetidine 300 mg four times daily markedly raises the nocturnal pH in a sustained manner but has a more modest impact on the gastric daytime profile, with large peaks and troughs induced by meal-stimulated acid secretion. More recently, once-daily nocturnal or evening dosing regimens of H2 antagonists have demonstrated efficacy equivalent to more frequent dosing in the healing of peptic ulcers (see below). The relative potencies and pharmacokinetic properties of the four available H2 antagonists are summarized in Table 1. On the basis of several pharmacologic studies, ranitidine and nizatidine are four to eight times as potent, and famotidine is 20 to 50 times as potent, as cimetidine on a molar basis. Thus, equipotent doses are famotidine 40 mg, ranitidine 300 mg, nizatidine 300 mg, and cimetidine 1200 to 1600 mg. However, increased potency does not necessarily confer a therapeutic advantage povided the drugs can be administered in equipotent doses without toxicity. The H2 antagonists have a remarkably low incidence of side effects, less than 3%. Central nervous system side effects occur in a few patients, particularly those receiving intravenous H2 antagonists, in whom the rate is less than 1 %.34 These symptoms have been noted Table 1. COMPARISON OF PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES OF FOUR AVAILABLE H2 -RECEPTOR ANTAGONISTS Cimetidine
Relative potency Equivalent dose (mg) Bioavailability (%) Time to peak serum con centra· tion (hr) Serum half-life (hr) Urinary excretion of oral dose (%) Oral dosage forms available (mg)
Doses Acute duodenal ulcer Acute gastric ulcer
Prevention of duodenal ulcer recurrence
Ranitidine
Nizatidine
Famotidine
1 1600 60-80 1-2
4-8 300 SO-60 1-3
4-8 300 90-100 1-3
20-S0 40 40-S0 1-3
1.S-2.S SO
2-3 30
1-2 >90
2.S-4 30
200 300 400 800 300 400 800 300 400 800 400
1S0 300
1S0 300
20 40
1S0 mg qid 300 mg hs
1S0 mg bid 300 mg hs
20 mg bid 40 mg hs
1S0 mg bid 300 mg hs
Not approved in US 1S0 mg hs
40 mg hs
mg mg mg mg mg mg mg
qid bid hs qid bid hs hs
1S0 mg hs
20 mg hs
Modified from Isenberg JI, McQuaid KM, Laine LA, et al: Acid-peptic disorders. In Yamada T, Alpers DH, Owyang C, et al (eds): Textbook of Gastroenterology. Philadelphia, JB Lippincott, 1991, pp 1241-1352; with permission.
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with all agents and include headaches, lethargy, confusion, depression, and hallucinations. Cimetidine may induce impotence and gynecomastia in a dose-dependent fashion because of its inhibition of estradiol metabolism and displacement of dihydrotestosterone from peripheral androgen-binding sites. 34 This reaction is uncommon with conventional doses of cimetidine and virtually never occurs with standard doses of other agents. All agents may increase prolactin secretion from the anterior pituitary. Cimetidine has also been shown in vitro to enhance cell-mediated immunity, which offers potential therapeutic advantages and disadvantages. 34 Differences in the drug interactions of the H2 antagonists are of potential clinical importance. Cimetidine binds the hepatic cytochrome P450 microsomal mixed-function oxidase system, inhibiting phase I oxidation and dealkylation in a dose-dependent fashion. Cimetidine may thereby raise the serum concentrations of drugs metabolized by this enzyme system. Ranitidine binds with 10% to 20% of the avidity of cimetidine, and nizatidine and famotidine have negligible direct P450 inhibition. For most drugs, this inhibition by cimetidine is of little clinical significance, but problems may arise with P450-metabolized medications that have a narrow therapeutic-to-toxic ratio such as theophylline, warfarin, lidocaine, and phenytoin. 34 Monitoring of drug concentrations is indicated if cimetidine is to be used in combination with these agents. It is safer, however, to choose an alternative H2 antagonist with less interactive potential. 34 All H2 antagonists may inhibit the absorption of certain drugs such as ketoconazole that require an acidic milieu for gastric absorption. Finally, it has recently been determined that all H2 antagonists except famotidine inhibit gastric alcohol dehydrogenase, an enzyme that plays an important role in the first-pass metabolism of alcohol. Increased peak blood concentrations of alcohol may thereby occur in patients taking H2 antagonists, with a greater risk of intoxication. 31 Duodenal Ulcers. All four available H2 antagonists are efficacious in the treatment of duodenal ulcer disease. Cimetidine was the first H2 antagonist clinically available. It initially was administered in doses of 200 mg three times daily with meals and 400 mg at bedtime or as 300 mg four times daily, doses calculated to suppress gastric acid secretion throughout the 24-hour period. The availability of ranitidine in 1981 precipitated double-blind multicenter trials in which either ranitidine 150 mg twice a day or cimetidine 400 mg twice a day was compared with cimetidine 1 gmJday in four doses. It became readily apparent that twice-daily regimens were equivalent in efficacy to the four times a day regimens, yielding overall ulcer healing rates of 75% after 4 weeks and 85% to 90% after 8 weeks of therapy. 34 The importance of nocturnal acid secretion in the pathogenesis of duodenal ulcers has been hypothesized for more than 50 years. More recently, a number of randomized double-blind trials have compared once-daily bedtime doses of cimetidine 800 mg or ranitidine 300 mg with the equivalent dosage administered in twice-daily regimens. 34 The healing rates were equivalent. Such a nightly schedule almost com-
ytl
292
McQUAID & ISENBERG
pletely suppresses nocturnal acid secretion but has little or no effect on daytime intragastric acidity.34 Subsequent to these studies, famotidine and nizatidine also have been tested, with the same conclusions: twicedaily regimens have no therapeutic advantage over once-daily bedtime regimens. 34 All H2 antagonists are approved and recommended or oncedaily bedtime dosing in the treatment of uncomplicated duodenal ulcer disease. Hunt et al performed an extensive meta-analysis that compared the degree of acid suppression derived from a number of pharmacologic studies of different H2 antagonist regimens with the ulcer healing rates from a number of controlled clinical trials in which these different H 2antagonist regimens were used. 37 The ulcer healing rates correlated better with the percentage suppression of nocturnal intragastric acidity than with the suppression of total or daytime acidity (Fig. 2). Taken together, this statistical analysis and the clinical trials provide compelling evidence for the importance of nocturnal acid suppression in the healing of duodenal ulcers. However, the pre-eminent role of nocturnal acid suppression in ulcer therapy is not embraced by all investigators. 7, 34 The relative importance of meal-stimulated acid secretion versus nocturnal acid secretion in the pathophysiology of duodenal ulcers merits further study, Nevertheless, H2 antagonists are much more effective in inhibiting nocturnal than meal-stimulated acid secretion, and the utilization of once-daily nocturnal dosing regimens is based on sound clinical data, Pharmacologic studies suggest that administration of famotidine or ranitidine with the evening meal rather than at bedtime provides equivalent nocturnal acid suppression but superior 24-hour acid suppression because of improved suppression in the post-supper hours. Several studies have compared early evening and bedtime doses of H2 antagonists in duodenal ulcer therapy. Although the overall 4-week 100r-------------------------------------------~
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50 40 30
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10
20
30
40
50
60
70
80
90
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Suppression of Nocturnal [H+] Activity (%) Figure 2. Correlation between suppression of nocturnal intragastric acidity and 4-week duodenal ulcer healing rates for different H2-receptor antagonist regimens, (From Jones
DB, Howden CW, Burget OW, et al: Acid suppression in duodenal ulcers: A meta-analysis to define optimal dosing with antisecretory drugs, Gut 28:1120, 1987; with permission,)
4
MEDICAL THERAPY OF PEPTIC ULCER DISEASE
293
healing rates are equivalent, there is a significant improvement in the 2-week ulcer healing rates with early evening dosing. It would appear that early evening dosing provides an effective alternative to standard bedtime dosing in duodenal ulcer therapy.34 To summarize, Hz antagonists administered in a variety of regimens yield an overall healing rate of 75% at 4 weeks and 85% to 95% at 8 weeks3 (Fig. 3). For patients with uncomplicated duodenal ulcers, oncedaily evening or nocturnal regimens offer ease of administration, improved patient compliance, lower cost, and less risk of drug interactions and is therefore recommended. Gastric Ulcers. The Hz antagonists are well established as effective agents for acute gastric ulcer therapy. In view of the fact that most patients have normal or even reduced acid secretion, it may seem paradoxical to treat them with acid-inhibitory agents. However, it is clear that further reduction of gastric acidity with Hz antagonists promotes ulcer healing. As with duodenal ulcer, healing rates for gastric ulcers increase progressively with increasing duration of treatment. However, the average time for complete ulcer healing is delayed by approximately 2 to 4 weeks for gastric ulcer compared with duodenal ulcer, such that healing rates of 55% to 65% and 80% to 90% are
100
80
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0
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Omeprazole H2 -antagonists
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0 2
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Duration of treatment (weeks) Figure 3. Duodenal ulcer healing rates over time reported for H2-receptor antagonists, omeprazole, and non-acid-inhibitory agents. Values calculated from 85 studies. (From Bauerfind P, Hoelz HR, Blum AL: Ulcer treatment regimens and duration of inhibition of acid secretion: How long to dose. Scand J Gastroenterol 23(suppl 153):23, 1988; with permission.)
294
McQUAID & ISENBERG
observed at 4 and 8 weeks, respectively3,33 (Fig. 4). The apparent delay in gastric ulcer healing may be in large part attributable to their being of greater size than duodenal ulcers. An analysis of the factors influencing gastric ulcer healing reveals some differences from duodenal ulcers. With active treatment or placebo therapy, there is a strong correlation between gastric ulcer healing and the length of observation. 33 Healing rates during placebo administration increase progressively wih time, approaching 50% to 60% at 8 weeks. In contrast, duodenal ulcer healing rates with placebo do not increase significantly beyond 4 weeks. 13 Although gastric ulcer healing rates with Hz antagonists are related to the degree of suppression of intragastric acidity, the relation is not nearly as strong as with duodenal ulcers. There is, in fact, little difference in gastric ulcer healing rates between the different drugs administered in a variety of regimens. 33 As with duodenal ulcers, nocturnal dosing is equal in efficacy to the more frequent dosing regimens in the healing of uncomplicated gastric ulcers.34 Nevertheless, studies of nocturnal dosing of H2 antagonists for gastric ulcers are limited, and their applicability to an unselected group of patients is unclear. Omeprazole. Pharmacology. Omeprazole is the first of a new line of antisecretory agents: the H+/K+-ATPase (proton pump) inhibitors.
100
80
C Q)
60
~
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CL
40
20
•
Omeprazole
•
Hrantagonists
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0 2
4
6
8
10
12
Duration of treatment (weeks) Figure 4. Gastric ulcer healing rates over time reported with H2 -receptor antagonists, omeprazole, and non-acid-inhibitory agents. Values derived from 31 studies. (From Bauer-
find P, Hoelz HR, Blum AL: Ulcer treatment regimens and duration of inhibition of acid secretion: How long to dose. Scand J Gastroenterol 23(suppl 153):23, 1988; with permission.)
MEDICAL THERAPY OF PEPTIC ULCER DISEASE
295
This enzyme is the final common step in the acid-secretory process of the parietal cell. 77 Several recent reviews of the pharmacology of omeprazole are available. 32, 34, 42, 57 Although it resembles H2 antagonists somewhat in structure, its mechanism of action is completely different. Omeprazole is a lipophilic, weak base (pKa 4,0) that is inactive in its native form. After intestinal absorption, it distributes rapidly throughout the body. Within the acidified tubulovesicles and secretory canaliculi of the parietal cell, this weak base becomes charged (i.e., protonated and polar) and therefore highly concentrated. This protonated compound undergoes a conformational change to the active drug, a suJfenamide that binds covalently to the H+/K+-ATPase pump, inhibiting the enzyme irreversibly (Fig. 5). Restoration of acid secretion after omeprazole administration requires synthesis by the parietal cell of new H+/ K+-ATPase. Thus, the drug has a duration of action that exceeds 24 hours despite a serum half-life of only about 60 minutes. Doses of 20 to 30 mg per day inhibit more than 90% of 24-hour acid secretion in most subjects compared with 37% to 68% for standard doses of H2 antagonists. 32 The daily optimal dosage for inhibition of 24-hour acidity is 20 to 30 mg for most patients; however, 20 mg/day is clearly inadequate for some subjects. With higher doses of omeprazole, nearly complete inhibition of acid secretion may be achieved. 42 In short, omeprazole is an almost ideal drug: it is administered as an inactive compound, it is highly concentrated and activated adjacent to its site of activity, and it has a short serum half-life but a long duration of action. It is apparent from the 24-hour intragastric acidity profile that Blood
Cytosol
(pH 7.4)
(pH 7.1)
Secretory Canaliculus (PH
0039-6109/92 $0.00
GASTRIC SURGERY
+ .20
MEDICAL THERAPY OF PEPTIC ULCER DISEASE Kenneth R. McQuaid, MD, and Jon I. Isenberg, MD
During the last decade, significant advances have been made in our understanding of the pathogenesis of gastric and duodenal ulcers. Although a variety of factors have been identified that may favor the development of peptic ulcers in some people, their precise mechanisms and relative contribution to ulcer pathogenesis remain unclear.34. 63 The expansion in our understanding of ulcer pathogenesis has been paralleled by the development of a number of therapeutic agents with various mechanisms of action. Extensive utilization of these drugs in randomized double-blind clinical trials has contributed immeasurably to our current medical treatment of peptic ulcer disease. OVERVIEW OF ULCER PATHOPHYSIOLOGY Mucosal Defense
The gastric and duodenal mucosa normally is protected from the potentially damaging effects of gastric acid and pepsin by ill-defined processes of resistance. 1. 58, 60 Surface epithelial cells secrete mucus, which provides an unstirred layer immediately adjacent to the epithelial surface and an effective barrier to pepsin. Continuous bicarbonate secretion by the gastric and duodenal surface epithelial cells into the overlying mucous layer results in a pH gradient in which the pH varies from approximately 7 at the epithelial surface to less than 2 in the gastric or duodenal lumen. In addition, gastric mucosal cells have apical From the Department of Medicine, Division of Gastroenterology, University of California, San Diego, San Diego, California
SURGICAL CLINICS OF NORTH AMERICA VOLUME 72 • NUMBER 2 • APRIL 1992
285
4
286
McQUAID & ISENBERG
membranes and tight junctions that are impermeable to the backdiffusion of acid into the cell. 74 Other factors that are important in the maintenance of mucosal integrity include blood flow and the ability of epithelial cells to renew themselves rapidly and to migrate along the basal membrane to areas of minor injury, a process referred to as "reconstitution."61 Furthermore, cytokines and growth factors undoubtedly playa role in mucosal defense, although their precise roles require further study. It is now clear that prostaglandins enhance the mucosal defense factors through the stimulation of mucus and bicarbonate secretion and blood flow. 50 Thus, there are a number of interacting factors that serve as defensive mechanisms for the maintenance of gastroduodenal mucosal integrity. Ulcers arise when there is an imbalance between these normal mucosal defense mechanisms and the "aggressive" factors such as the potentially noxious effects of acid and pepsin. A variety of factors may disrupt mucosal resistance, tipping the balance toward ulcer development. These are summarized briefly below, and comprehensive reviews are available. 34, 63 Nonsteroidal Anti-Inflammatory Drugs. The nonsteroidal antiinflammatory drugs (NSAIDs) may either cause gastric or duodenal ulcers de novo or exacerbate an underlying ulcer diathesis. 65 Chronic NSAID use is associated with the development of mucosal ulceration in 15% to 20% of patients. There is an estimated 40-fold increase in gastric ulcers and an 8-fold increase in duodenal ulcers in daily NSAID users. 64, 65 Of even more important clinical impact, chronic NSAID users are at least four to seven times as likely to experience serious gastrointestinal hemorrhage or perforation than are matched controIs. 24, 29 Chronic NSAID injury is hypothesized to arise from the inhibition of cyclooxygenase, resulting in decreased mucosal prostaglandin synthesis and impaired mucosal defense. Bacterial Action. Helicobacter pylori is a gram-negative, flagellated rod found in the antrum of more than 95% of duodenal ulcer patients as well as in most patients with gastric ulcers that are not associated with NSAIDs. 16, 34, 49 The organism does not appear to invade the antral mucosa directly but does initiate a histologic inflammatory response, chronic gastritis, which is found in virtually all patients with gastric or duodenal ulcers. Indeed, H. pylori appears to be the principal cause of idiopathic chronic (histologic) antral gastritis. 34 This inflammatory response to H. pylori could result in a breakdown in mucosal resistance to acid and pepsin. Helicobacter pylori-associated gastritis appears to be common in the general population, the rate approaching 50% in people over the age of 60. 17 In most of these people, this gastritis does not appear to be associated with dyspepsia or peptic ulcer disease. The high prevalence of H. pylori gastritis in peptic ulcer patients is intriguing; however, only a small proportion of all persons infected with H. pylori ever develop peptic ulcer disease. Therefore, other pathogenetic factors must be important in these patients. Traditional ulcer therapies effectively heal peptic ulcers but do not eradicate the chronic H. pylori infection. Recent therapeutic trials with bismuth, antibiotics, or both
MEDICAL THERAPY OF PEPTIC ULCER DISEASE
287
suggest that ulcer recurrences are markedly diminished in patients in whom H. pylori infection is eradicated (see below). These data lend strong support to the importance of H. pylori infection in the ulcer diathesis. Mucosal Bicarbonate Secretion. Both basal and stimulated (by luminal acidification, prostaglandin E, and sham feeding) bicarbonate secretion by the proximal duodenal mucosa is diminished in patients with duodenal ulcer disease. Of interest, bicarbonate secretion by the duodenal bulb is impaired in both patients with active and those with inactive (i.e., healed) duodenal ulcers. This fact suggests an intrinsic defect in duodenal defense in these patients. Whether this is a primary pathogenetic defect or is secondary to other factors requires further study.36 To date, no alterations in gastric mucosal bicarbonate secretion have been observed in ulcer patients. Cigarette Smoking. Smoking, which does not substantially alter gastric acid secretion, has been reported unequivocally to increase the incidence and complication rate of peptic ulcers, to retard ulcer healing, and to promote ulcer recurrences. Various pathogenetic mechanisms have been suggested; however, the exact mechanisms remain elusive. n, 34 Gastric Secretion
Gastric acid and pepsin are essential permIssIve factors in the pathogenetic process of ulcer formation. Schwarz's dictum "no acidno ulcer" still applies except in unusual circumstances. Although patients with duodenal ulcers as a group have higher mean basal or pentagastrin-stimulated acid outputs than normal subjects, acid secretion in most ulcer patients falls well within normal ranges. Therefore, an underlying impairment in mucosal resistance is implied. Nevertheless, duodenal ulcers rarely occur in patients with a pentagastrinstimulated acid output of less than 12 mmollhour, and only about one third of duodenal ulcer patients are true hypersecretors of gastric acid. 63 The possible mechanisms of increased acid secretion are reviewed elsewhere; in many, the increase is attributed to an enlarged mass of acid and pepsinogen-secreting oxyntic glands. 63 , 77 In contrast to those with duodenal ulcers, patients with gastric ulcers tend to have normal to low gastric acid secretion, suggesting that impaired mucosal defense is the principal element in ulcer development. Similarly, despite massive acid hypersecretion, about 10% of patients with Zollinger-Ellison syndrome do not develop duodenal or gastric ulcers. This illustrates the importance of mucosal resistance in the pathogenetic process. Other Factors
Additional factors appear to be important in the development of ulcers in some cases. Genetic predisposition, bile reflux, rapid gastric
288
McQUAID & ISENBERG
emptying, and underlying medical illness (cirrhosis, chronic obstructive pulmonary disease, cystic fibrosis) playa pathogenetic role in some patients. These factors are reviewed elsewhere. 34 In summary, peptic ulcers arise when the damaging effects of acid and pepsin or other noxious agents exceed the restorative processes favoring mucosal integrity and repair. Peptic ulcers have multiple, heterogeneous etiologies, and no single pathophysiologic defect applies in all cases.
MEDICAL THERAPY OF PEPTIC ULCERS
Since the introduction of the histamine H 2-receptor antagonists in the late 1970s, the treatment of ulcer patients has undergone a number of clinically important modifications. Some examples include the observation that evening (or nocturnal) single-dose H 2-antagonist treatment is as effective as multiple daily doses; the introduction of more potent H 2-receptor antagonists; the development of the H+/K+-ATPase inhibitors, with their prolonged antisecretory effects; the recognition of H. pylori infection, its relation to antral gastritis, and the effect of its eradication in diminishing duodenal ulcer recurrences; and the development of drugs that neither neutralize gastric acid nor alter its production (i.e., sucralfate and low-dose antacids). Twenty years ago, the principal goal in ulcer treatment was to expedite ulcer healing. Today, it is quite easy, under most conditions, to heal both gastric and duodenal ulcers with anyone of a number of drugs. Therefore, the emphasis has appropriately shifted to the prevention of gastroduodenal mucosal injury (often attributable to NSAIDs), as well as to the prevention of ulcer recurrences and complications. Also, although the need for elective surgery or peptic ulcer has decreased substantially, there appears to be an increase in ulcer complications, particularly in the elderly, often associated with NSAID ingestion. In addition, as reviewed elsewhere in this issue, surgery still plays an important therapeutic role in patients who are noncompliant with medical therapy, those with nonhealing gastric ulcers, and those with frequent recurrences in spite of medical management.
Pharmacologic Therapy
Several pharmacologic agents enhance the healing of peptic ulcers. In keeping with the classification of pathogenetic factors given above, pharmacologic agents may be subsumed into two categories: those that promote ulcer healing by reducing intragastric acidity and those that enhance mucosal defense mechanisms. Of note, the precise mechanism(s) of action of some drugs is not fully understood.
MEDICAL THERAPY OF PEPTIC ULCER DISEASE
289
Reduction of Intragastric Acidity
H2 Antagonists. Pharmacology. Histamine H 2-receptor antagonists have enjoyed a favored status for the acute treatment of duodenal and gastric ulcers for the past decade because of their efficacy, patient acceptance, and excellent safety profile. A complete review of the clinical pharmacology of these agents is beyond the scope of this article, and the reader is referred to several recent reviews. 19, 20, 22, 28, 34, 39-41 Briefly, four H2 antagonists have been approved by the Food and Drug Administration (FDA) for clinical use in the US: cimetidine, ranitidine, famotidine, and nizatidine. A fifth, roxatidine, is available in Europe. These compounds share an aromatic ring system and have a flexible side chain that is affixed to a polar uncharged group (Fig, 1). These agents produce reversible, competitive inhibition of the histamine H2 receptor of the parietal cell, thereby reducing intracellular cAMP levels and acid secretion. Parietal cells also contain receptors for gastrin and acetylcholine (muscarinic type), both of which stimulate acid secretion by increasing intracellular calcium. 77 Of note, there appears to be a potentiating effect on acid secretion between the agents activating the cAMP pathway (e.g., histamine) and the calcium pathway (e.g., gastrin and acetylcholine), Hence, the histamine H 2-receptor antagonists inhibit, not only histamine-stimulated acid secretion, but also basal and sham feed-, pentagastrin-, and meal-stimulated acid secretion
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in a linear dose-dependent fashion. 34 The H2 antagonists may inhibit as much as 90% of gastrin- or vagal-stimulated acid secretion; however, complete inhibition has not been demonstrated. Thus, administration of cimetidine 300 mg four times daily markedly raises the nocturnal pH in a sustained manner but has a more modest impact on the gastric daytime profile, with large peaks and troughs induced by meal-stimulated acid secretion. More recently, once-daily nocturnal or evening dosing regimens of H2 antagonists have demonstrated efficacy equivalent to more frequent dosing in the healing of peptic ulcers (see below). The relative potencies and pharmacokinetic properties of the four available H2 antagonists are summarized in Table 1. On the basis of several pharmacologic studies, ranitidine and nizatidine are four to eight times as potent, and famotidine is 20 to 50 times as potent, as cimetidine on a molar basis. Thus, equipotent doses are famotidine 40 mg, ranitidine 300 mg, nizatidine 300 mg, and cimetidine 1200 to 1600 mg. However, increased potency does not necessarily confer a therapeutic advantage povided the drugs can be administered in equipotent doses without toxicity. The H2 antagonists have a remarkably low incidence of side effects, less than 3%. Central nervous system side effects occur in a few patients, particularly those receiving intravenous H2 antagonists, in whom the rate is less than 1 %.34 These symptoms have been noted Table 1. COMPARISON OF PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES OF FOUR AVAILABLE H2 -RECEPTOR ANTAGONISTS Cimetidine
Relative potency Equivalent dose (mg) Bioavailability (%) Time to peak serum con centra· tion (hr) Serum half-life (hr) Urinary excretion of oral dose (%) Oral dosage forms available (mg)
Doses Acute duodenal ulcer Acute gastric ulcer
Prevention of duodenal ulcer recurrence
Ranitidine
Nizatidine
Famotidine
1 1600 60-80 1-2
4-8 300 SO-60 1-3
4-8 300 90-100 1-3
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2-3 30
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2.S-4 30
200 300 400 800 300 400 800 300 400 800 400
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1S0 300
20 40
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1S0 mg bid 300 mg hs
20 mg bid 40 mg hs
1S0 mg bid 300 mg hs
Not approved in US 1S0 mg hs
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mg mg mg mg mg mg mg
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Modified from Isenberg JI, McQuaid KM, Laine LA, et al: Acid-peptic disorders. In Yamada T, Alpers DH, Owyang C, et al (eds): Textbook of Gastroenterology. Philadelphia, JB Lippincott, 1991, pp 1241-1352; with permission.
MEDICAL THERAPY OF PEPTIC ULCER DISEASE
291
with all agents and include headaches, lethargy, confusion, depression, and hallucinations. Cimetidine may induce impotence and gynecomastia in a dose-dependent fashion because of its inhibition of estradiol metabolism and displacement of dihydrotestosterone from peripheral androgen-binding sites. 34 This reaction is uncommon with conventional doses of cimetidine and virtually never occurs with standard doses of other agents. All agents may increase prolactin secretion from the anterior pituitary. Cimetidine has also been shown in vitro to enhance cell-mediated immunity, which offers potential therapeutic advantages and disadvantages. 34 Differences in the drug interactions of the H2 antagonists are of potential clinical importance. Cimetidine binds the hepatic cytochrome P450 microsomal mixed-function oxidase system, inhibiting phase I oxidation and dealkylation in a dose-dependent fashion. Cimetidine may thereby raise the serum concentrations of drugs metabolized by this enzyme system. Ranitidine binds with 10% to 20% of the avidity of cimetidine, and nizatidine and famotidine have negligible direct P450 inhibition. For most drugs, this inhibition by cimetidine is of little clinical significance, but problems may arise with P450-metabolized medications that have a narrow therapeutic-to-toxic ratio such as theophylline, warfarin, lidocaine, and phenytoin. 34 Monitoring of drug concentrations is indicated if cimetidine is to be used in combination with these agents. It is safer, however, to choose an alternative H2 antagonist with less interactive potential. 34 All H2 antagonists may inhibit the absorption of certain drugs such as ketoconazole that require an acidic milieu for gastric absorption. Finally, it has recently been determined that all H2 antagonists except famotidine inhibit gastric alcohol dehydrogenase, an enzyme that plays an important role in the first-pass metabolism of alcohol. Increased peak blood concentrations of alcohol may thereby occur in patients taking H2 antagonists, with a greater risk of intoxication. 31 Duodenal Ulcers. All four available H2 antagonists are efficacious in the treatment of duodenal ulcer disease. Cimetidine was the first H2 antagonist clinically available. It initially was administered in doses of 200 mg three times daily with meals and 400 mg at bedtime or as 300 mg four times daily, doses calculated to suppress gastric acid secretion throughout the 24-hour period. The availability of ranitidine in 1981 precipitated double-blind multicenter trials in which either ranitidine 150 mg twice a day or cimetidine 400 mg twice a day was compared with cimetidine 1 gmJday in four doses. It became readily apparent that twice-daily regimens were equivalent in efficacy to the four times a day regimens, yielding overall ulcer healing rates of 75% after 4 weeks and 85% to 90% after 8 weeks of therapy. 34 The importance of nocturnal acid secretion in the pathogenesis of duodenal ulcers has been hypothesized for more than 50 years. More recently, a number of randomized double-blind trials have compared once-daily bedtime doses of cimetidine 800 mg or ranitidine 300 mg with the equivalent dosage administered in twice-daily regimens. 34 The healing rates were equivalent. Such a nightly schedule almost com-
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292
McQUAID & ISENBERG
pletely suppresses nocturnal acid secretion but has little or no effect on daytime intragastric acidity.34 Subsequent to these studies, famotidine and nizatidine also have been tested, with the same conclusions: twicedaily regimens have no therapeutic advantage over once-daily bedtime regimens. 34 All H2 antagonists are approved and recommended or oncedaily bedtime dosing in the treatment of uncomplicated duodenal ulcer disease. Hunt et al performed an extensive meta-analysis that compared the degree of acid suppression derived from a number of pharmacologic studies of different H2 antagonist regimens with the ulcer healing rates from a number of controlled clinical trials in which these different H 2antagonist regimens were used. 37 The ulcer healing rates correlated better with the percentage suppression of nocturnal intragastric acidity than with the suppression of total or daytime acidity (Fig. 2). Taken together, this statistical analysis and the clinical trials provide compelling evidence for the importance of nocturnal acid suppression in the healing of duodenal ulcers. However, the pre-eminent role of nocturnal acid suppression in ulcer therapy is not embraced by all investigators. 7, 34 The relative importance of meal-stimulated acid secretion versus nocturnal acid secretion in the pathophysiology of duodenal ulcers merits further study, Nevertheless, H2 antagonists are much more effective in inhibiting nocturnal than meal-stimulated acid secretion, and the utilization of once-daily nocturnal dosing regimens is based on sound clinical data, Pharmacologic studies suggest that administration of famotidine or ranitidine with the evening meal rather than at bedtime provides equivalent nocturnal acid suppression but superior 24-hour acid suppression because of improved suppression in the post-supper hours. Several studies have compared early evening and bedtime doses of H2 antagonists in duodenal ulcer therapy. Although the overall 4-week 100r-------------------------------------------~
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Suppression of Nocturnal [H+] Activity (%) Figure 2. Correlation between suppression of nocturnal intragastric acidity and 4-week duodenal ulcer healing rates for different H2-receptor antagonist regimens, (From Jones
DB, Howden CW, Burget OW, et al: Acid suppression in duodenal ulcers: A meta-analysis to define optimal dosing with antisecretory drugs, Gut 28:1120, 1987; with permission,)
4
MEDICAL THERAPY OF PEPTIC ULCER DISEASE
293
healing rates are equivalent, there is a significant improvement in the 2-week ulcer healing rates with early evening dosing. It would appear that early evening dosing provides an effective alternative to standard bedtime dosing in duodenal ulcer therapy.34 To summarize, Hz antagonists administered in a variety of regimens yield an overall healing rate of 75% at 4 weeks and 85% to 95% at 8 weeks3 (Fig. 3). For patients with uncomplicated duodenal ulcers, oncedaily evening or nocturnal regimens offer ease of administration, improved patient compliance, lower cost, and less risk of drug interactions and is therefore recommended. Gastric Ulcers. The Hz antagonists are well established as effective agents for acute gastric ulcer therapy. In view of the fact that most patients have normal or even reduced acid secretion, it may seem paradoxical to treat them with acid-inhibitory agents. However, it is clear that further reduction of gastric acidity with Hz antagonists promotes ulcer healing. As with duodenal ulcer, healing rates for gastric ulcers increase progressively with increasing duration of treatment. However, the average time for complete ulcer healing is delayed by approximately 2 to 4 weeks for gastric ulcer compared with duodenal ulcer, such that healing rates of 55% to 65% and 80% to 90% are
100
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Omeprazole H2 -antagonists
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Duration of treatment (weeks) Figure 3. Duodenal ulcer healing rates over time reported for H2-receptor antagonists, omeprazole, and non-acid-inhibitory agents. Values calculated from 85 studies. (From Bauerfind P, Hoelz HR, Blum AL: Ulcer treatment regimens and duration of inhibition of acid secretion: How long to dose. Scand J Gastroenterol 23(suppl 153):23, 1988; with permission.)
294
McQUAID & ISENBERG
observed at 4 and 8 weeks, respectively3,33 (Fig. 4). The apparent delay in gastric ulcer healing may be in large part attributable to their being of greater size than duodenal ulcers. An analysis of the factors influencing gastric ulcer healing reveals some differences from duodenal ulcers. With active treatment or placebo therapy, there is a strong correlation between gastric ulcer healing and the length of observation. 33 Healing rates during placebo administration increase progressively wih time, approaching 50% to 60% at 8 weeks. In contrast, duodenal ulcer healing rates with placebo do not increase significantly beyond 4 weeks. 13 Although gastric ulcer healing rates with Hz antagonists are related to the degree of suppression of intragastric acidity, the relation is not nearly as strong as with duodenal ulcers. There is, in fact, little difference in gastric ulcer healing rates between the different drugs administered in a variety of regimens. 33 As with duodenal ulcers, nocturnal dosing is equal in efficacy to the more frequent dosing regimens in the healing of uncomplicated gastric ulcers.34 Nevertheless, studies of nocturnal dosing of H2 antagonists for gastric ulcers are limited, and their applicability to an unselected group of patients is unclear. Omeprazole. Pharmacology. Omeprazole is the first of a new line of antisecretory agents: the H+/K+-ATPase (proton pump) inhibitors.
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Duration of treatment (weeks) Figure 4. Gastric ulcer healing rates over time reported with H2 -receptor antagonists, omeprazole, and non-acid-inhibitory agents. Values derived from 31 studies. (From Bauer-
find P, Hoelz HR, Blum AL: Ulcer treatment regimens and duration of inhibition of acid secretion: How long to dose. Scand J Gastroenterol 23(suppl 153):23, 1988; with permission.)
MEDICAL THERAPY OF PEPTIC ULCER DISEASE
295
This enzyme is the final common step in the acid-secretory process of the parietal cell. 77 Several recent reviews of the pharmacology of omeprazole are available. 32, 34, 42, 57 Although it resembles H2 antagonists somewhat in structure, its mechanism of action is completely different. Omeprazole is a lipophilic, weak base (pKa 4,0) that is inactive in its native form. After intestinal absorption, it distributes rapidly throughout the body. Within the acidified tubulovesicles and secretory canaliculi of the parietal cell, this weak base becomes charged (i.e., protonated and polar) and therefore highly concentrated. This protonated compound undergoes a conformational change to the active drug, a suJfenamide that binds covalently to the H+/K+-ATPase pump, inhibiting the enzyme irreversibly (Fig. 5). Restoration of acid secretion after omeprazole administration requires synthesis by the parietal cell of new H+/ K+-ATPase. Thus, the drug has a duration of action that exceeds 24 hours despite a serum half-life of only about 60 minutes. Doses of 20 to 30 mg per day inhibit more than 90% of 24-hour acid secretion in most subjects compared with 37% to 68% for standard doses of H2 antagonists. 32 The daily optimal dosage for inhibition of 24-hour acidity is 20 to 30 mg for most patients; however, 20 mg/day is clearly inadequate for some subjects. With higher doses of omeprazole, nearly complete inhibition of acid secretion may be achieved. 42 In short, omeprazole is an almost ideal drug: it is administered as an inactive compound, it is highly concentrated and activated adjacent to its site of activity, and it has a short serum half-life but a long duration of action. It is apparent from the 24-hour intragastric acidity profile that Blood
Cytosol
(pH 7.4)
(pH 7.1)
Secretory Canaliculus (PH
