POSTPRANDIAL GASTRIC, PANCREATIC, AND BILIARY RESPONSE TO HISTAMINE H2-RECEPTOR ANTAGONISTS IN ACTIVE DUODENAL ULCER

Transcription

1 GASTROENTEROLOGY 72:9-13, 1977 Copyright 1977 by The Williams & Wilkins Co. Vol. 72, No.1 Printed in U.S.A. POSTPRANDIAL GASTRIC, PANCREATIC, AND BILIARY RESPONSE TO HISTAMINE H2-RECEPTOR ANTAGONISTS IN ACTIVE DUODENAL ULCER GEORGE F. LONGSTRETH, M.D., YAY L. W. Go, M.D., AND JUAN-R. MALAGELADA, M.D. Gastroenterology Unit, Mayo Clinic and Mayo Foundation, Rochester, Minnesota Histamine H 2-receptor antagonists are potentially useful agents in duodenl!l ulcer and knowledge of their effect on postprandial digestive events will contribute to their clinical application. We studied the effect of 2- and 3-mg doses of cimetidine, an H 2-receptor antagonist, taken with an ordinary meal, on gastric, pancreatic, and biliary function. Both doses significantly reduced acid output and its delivery into the duodenum. Gastric secretory volume and pepsin output were less affected. Acid inhibition was related to blood drug levels and was less than that previously found at night in nocturnal fasting studies. As the stomach emptied the food, the gastric ph rose. The fractional gastric emptying rate, pancreatic enzyme, and bile acid outputs were unaltered. Cimetidine taken orally with meals at these doses is a potent gastric anti secretory agent without affecting other postprandial gastric, pancreatic, or biliary functions. In patients with duodenal ulcer disease, the postprandial gastric secretory response often produces pain and may be pathogenetic ally important. 1 Histamine H 2- receptor antagonists inhibit gastric acid secretion in response to multiple stimuli,2, 3 but previous studies of their postprandial effects ' 5 have only quantified gastric acid output by intragastric titration methods (artificially maintaining the ph of the stomach at 5.5) that may substantially alter gastric acid secretion and serum gastrin levels. 6, 7 Moreover, the gastric stimuli consisted of simple peptone solutions or homogenized liquid meals, 5 which may fail to elicit responses comparable to those produced by normal meals. 8 Thus, whatever effects these agents produce on the complex array of integrated digestive functions after ingestion of natural foods remain unknown. The purpose of these studies was to characterize the physiological effects of an H 2 -receptor antagonist, cimetidine, 2 on postprandial digestive function. To this end we have used methods, previously developed and validated Received June 14,1976. Accepted July 1, This work was presented in part at the Annual Meeting of the American Gastroenterological Association, Miami, Florida, May Address reprint requests to: J.-R. Malagelada, M.D., Gastroenterology Unit, Mayo Clinic, Rochester, Minnesota 559l. This investigation was supported in part by Research Grant AM-698 and Training Grant AM-5259 from the National Institutes of Health, United States Public Health Service, and a grant-in-aid from Smith Kline and French Laboratories. Dr. Longstreth is a National Institutes of Health Trainee in Gastroenterology. The authors appreciate the technical assistance of Judith Duenes, Ruth Bolton, Cathy DeVos, Jane Bailey, 'and Richard Tucker, the secretarial help of Gaurdis Grube, the statistical consultation of Dr. William F. Taylor and Alice Langworthy, and the valuable cooperation of Dr. Roger Crossley, Smith Kline and French Laboratories. 9 by US,9, 1 to quantify gastric, pancreatic, and biliary responses to oral cimetidine after an ordinary meal in patients with active duodenal ulcer. Methods Patients. Ten patients (9 males), ages 21 to 57 years, mean 45.7, were studied. All had active duodenal ulcer disease diagnosed on the basis of current typical symptoms and endoscopic (4 patients) or radiological (6 patients) evidence of duodenal ulcer. None had undergone prior gastrointestinal or biliary tract surgery or had other significant disease. Informed consent was obtained. Studies were approved by the Mayo Clinic Human Studies Committee on February 6, Design. We performed 1 studies on 5 patients, each of whom took 2 mg of cimetidine or placebo in randomized single blind order on successive days. Subsequently, we performed 12 studies on 6 patients, each of whom took 3 mg of cimetidine or placebo in randomized, double blind order on successive days. One patient participated in both sets of studies. Procedure. Methods for quantification of postprandial volume of gastric contents and its rate of emptying into the duodenum, acid, pepsin, and total secretory outputs, acid emptying rates, and pancreatic lipase, trypsin, and bile acid outputs have been previously described. 9, 1 In summary, patients took no antacid or other medication during the 12 hr preceding the studies. Mter an overnight fast, they swallowed a triple lumen duodenal tube and a double lumen gastric sump tube. For the 3OO-mg dose studies a small polyvinyl perfusion tube was attached to the gastric tube with its orifice 15 cm proximal to the aspiration site. We used one lumen of the duodenal tube for continuous perfusion of normal saline (2 ml per min) containing a nonabsorbable marker, 1 J,LC of [HC jpolyethylene glycol ( [HC jpeg) per liter at the level of the papilla of Vater. We used a second lumen for continuous sampling of duodenal contents 2 cm distally to the perfusion site, at the level of the angle of Treitz. The third lumen was a duodenal air vent to facilitate suction. In the 3OO-mg studies,

2 1 LONGSTRETH ET AL. Vol. 72, No.1 we perfused the stomach with normal saline (2 ml per min) containing another marker, 1 IlC of [3H ]polyethylene glycol ([3H]PEG) per liter. For 1 hr (basal period), we continuously aspirated gastric and duodenal samples by pump (-4 mm Hg). Our previous studies 11 excluded any effect of trans pyloric intubation on gastric motor or secretory responses to a similar meal. At the end of the 1-hr base line period, we stopped gastric perfusion and aspiration, and the patients ate a meal consisting of 9 g (uncooked weight) of ground tenderloin steak seasoned with.1 g of salt, 25 g of white bread with 8 g of butter, and 6 g of vanilla ice cream with 35 g of chocolate syrup. Also, they drank one glass of water (24 ml) containing 15 g of polyethylene glycol (PEG). They swallowed the test capsules with a small amount of the drinking water as they began eating the meal. Thereafter, we sampled gastric and duodenal contents every 1 min as previously described 9 until the gastric samples no longer contained food particles. In the 3-mg studies we resumed perfusion and aspiration in the stomach and continued these procedures in the duodenum until 4 hr after the meal was eaten for continued measurement of gastric, pancreatic, and biliary secretory outputs. We obtained blood for serum gastrin determination 3 min and immediately before the meal was served and, beginning 15 min after the meal, at 3-min intervals until the end of the study. Also, we obtained blood for cimetidine concentration before and at 3-min intervals after the meal. Analytical methods and calculations. The ph of the samples was measured with a Fisher Accumet model 52 and previously described methods were used to determine concentrations of acid, 9 pepsin, 12 bile acids, 13 trypsin and lipase,,. ['3C ]peg and [BH ]peg, 15 and PEG. '8 Serum gastrin and blood cimetidine concentrations were determined by radioimmunoassay17 and high pressure gas-liquid chromatography (Biochemistry Department, Smith Kline and French Laboratories, Philadelphia, Pa.), respectively. Calculations of volumes and secretory outputs were based on concentrations of markers, acid, enzymes, and bile acids as previously described. 9 1 Postprandial gastric secretory outputs were determined at lo-min intervals and pancreatic enzyme and biliary outputs were determined at 3-min intervals. Clinical laboratory tests. The following clinical laboratory tests were carried out before the first study, within 3 days, and again within 7 days after the last study: blood count (including leukocyte and differential counts); determinations of urea, creatinine, SGOT, bilirubin, alkaline phosphatase, lactate dehydrogenase, uric acid, and urinalysis. Statistical analysis. To compare data after 2- and 3-mg doses of cimetidine with the respective placebo studies, we applied three-way analysis of variance'" to treatment, time, and patient variables. When interaction between treatment and time was significant (P <.5) or there was a significant difference over all (P <.5) with no interaction, we applied the paired t-test 18 to data from each postprandial interval. Cumulative postprandial outputs of gastric acid, pepsin, and secretory volume were compared (placebo versus cimetidine) in each subject to determine the percentage inhibition produced by the drug (table 1). Results Volume of gastric contents and gastric emptying rate. Cimetidine (3 mg) significantly decreased the volume of gastric contents after the 1st postprandial hour and consistently reduced the absolute rate of emptying into the duodenum (fig. 1). However, the fractional rate of gastric emptying (percentage volume of gastric contents emptied per unit of time) remained unchanged (fig. 1). Analysis of variance showed a significant decrease in over-all volume of gastric contents after cimetidine (P =.35), borderline significance for the reduction in absolute gastric emptying rate (P =.9), and no effect on fractional gastric emptying. The 2-mg dose had no significant effect on any of these functions. Gastric secretory outputs. Cimetidine (3 mg) markedly decreased postprandial acid output throughout the 4-hr observation period beginning 3 min after ingestion (when blood cimetidine levels started to rise) (fig. 2). The intragastric ph reflected the same effect (fig. 2), 2 patients showing anacidity (PH 7.) at the end of 4 hr. Analysis of variance showed that cimetidine significantly reduced acid output (P <.1) and total secretory volume (P =.2) and increased ph (P <.1). The 2-mg dose only decreased the acid output (P =.6). Neither dose altered pepsin concentration, but the 3-mg dose showed a borderline effect on pepsin output (P =.6), probably caused by the decrease in secretory volume. Mter the 3-mg dose, percentage inhibition of acid significantly exceeded that of volume and pepsin (table 1). After the 2-mg dose, the same trend was observed (table 1) but the differences did not reach statistical significance. The reduction in acid output after cimetidine appeared to be related to mean postprandial blood levels of the drug (fig. 3) and not to the acid output observed after placebo. Rate of delivery of acid into the duodenl,lm and distal duodenal ph. Cimetidine (3 mg) markedly reduced Meal +Drug 4 2 o 5 4 Cimetidine P<.5 FIG. 1. Effect of orally administered cimetidine (3 mg) on postprandial volume of gastric contents and gastric emptying rates in duodenal ulcer.

3 January 1977 POSTPRANDIAL RESPONSES TO CIMETIDINE IN DUODENAL ULCER 11...'!.8 IlTJ Meal '" + 1 <>" "'" "I.6 Drug "!..!> ::... r l r.2'(,. " S " ' "'I: Ii; 6 5 Meal + Drug r \ cimetidine,iirrn. 4 3 lin!. II 2 )tplocebo 1 1M.an tsem * I ****************** I I I I I 'P<.5 FIG. 2. Effect of orally administered cimetidine (3 mg) on postprandial gastric ph and acid output in duodenal ulcer. TABLE 1. Effect of cimetidine (given with meal) on postprandial gastric secretion in duodenal ulcer Secretion % inhibition of secretory output" Cimetidine (2 mg) Cimetidine (3 mg) Pancreatic enzyme and biliary output. Postprandial output of lipase, trypsin, and bile acids was not affected by cimetidine (fig. 5). Analysis of variance failed to demonstrate any effect caused by either the 3- or 2-mg dose. Serum gastrin concentration. Mter cimetidine (3 mg), postprandial serum gastrin levels tended to be higher, beginning within the 1st hour, and the differences became statistically significant in the 2nd and 3rd postprandial hours (fig. 6). A similar trend was observed with the 2-mg dose, but the differences were not statistically significant. Individual responsiveness to cimetidine. The relationship of dose to effect as determined by analysis of variance differed significantly (P <.2) from patient to patient with regard to gastric volume, volume of gastric contents emptied, gastric ph, acid and pepsin output, acid emptied, and serum gastrin. Blood cimetidine concentration. Peak cimetidine blood levels of.6 ±.9 (mean ± SEM) and 1. ±.1 ILg per ml (P <.5) occurred after doses of 2 and 3 mg, respectively. The areas under the curves calculated from 1 8 r::.'. 6 -<:: o.!:: 4 Oral cimetidine 3mg <> "t 2 o 2mg L - O L Q Acid 3S.5 ± ± 7.S Pepsin 3.3 ± ± ll.s Volume 27.4 ± ± 11.4 a Mean ± SEM. Inhibition of acid exceeded that of pepsin (P <.1) and volume (P <.5). postprandial rates of acid delivery into the duodenum (fig. 4). This effect began 4 min after ingestion of the drug (with the meal) and persisted until the stomach was empty of food and gastric perfusion and aspiration were initiated. The 2-mg dose produced a lesser, but significant, effect as confirmed by analysis of variance, which established a significant reduction in over-all gastric acid emptying rates for both the 3- and 2-mg doses (P <.2, both). Peak rates of acid delivery into the duodenum were decreased from 28.8 ± 3.8 meq per hr (placebo) to 14.8 ± 2.5 (P <.2) by the 3-mg dose, and from 33.3 ± 5.9 meq per hr (placebo) to 19. ± 3.5 (P <.2) by the 2-mg dose. The ph of duodenal contents aspirated at the angle of Treitz reflected the decrease in acid entering the duodenum produced by cimetidine. As shown by figure 4, after cimetidine (3 mg) the duodenal ph increased during the 2nd and 3rd postprandial hours but remained nearly unchanged after placebo. Mean cimetidine blood level,flg/ml FIG. 3. Relation of mean postprandial cimetidine concentration in blood to inhibition (expressed as percentage of output after placebo) of postprandial secretion of gastric acid in each patient. 5 Meal + Drug. Ii;' 4. " I i 3 ; g "'... 2 " Q l111111!111.!::.f! Cimelidine t" ********* I I *' ** I 8 7 <:; J r::. 6 rillf'r" C e l i d i n e '" 1 Placebo <::l 5-1:. I I -1 *P<O.O!l FIG. 4. Effect of orally administered cimetidine (3 mg) on postprandial acid delivery into the duodenum and duodenal ph.

4 12 LONGSTRETH ET AL. Vol. 72, No '". 2. '" l::."' J 1. -;;-.8 :;,.s: 1.6 '" l::.s: R....4 S '" 4. " ' 3 '" l:: 2 '" ::t. 1-1 y. 1 y FIG. 5. Effect of orally administered cimetidine (3 mg) on postprandial pancreatic enzyme and bile acid outputs in duodenal ulcer \:l, 26 <:\.. ' l:: ' -4 Meal + Drug l I, T ' o Placeba I 1 :9- ' - : r C i m e t i d i n e "l 'l '-I " I " " "P<.5 FIG. 6. Effect of orally administered cimetidine (3 mg) on postprandial serum gastrin in duodenal ulcer. these studies were 1.4 ±.1 and 2.5 ±.3 f.lg per ml per 4 hr (P <.2), respectively. Four patients who took cimetidine (3 mg) with the meal had been studied previously after they took the same dose at bedtime. 19 Cimetidine blood levels in these 4 patients 1 hr after ingestion were similar:.9 ±.2 f.lg per ml (meal) and 1.1 ±.3 (nocturnal). However, at 4 hr they were lower postprandially (.5 ±.1) than during nocturnal fasting (1. ±.2) (P <.5). Patient tolerance to cimetidine. No patient manifested symptoms or signs attributable to the drug. Clinical laboratory screening revealed no abnormalities. Discussion Cimetidine taken with an ordinary meal had a profound gastric antisecretory effect in patients with active duodenal ulcer. Both 3- and 2-mg single doses significantly reduced postprandial gastric acid output and acid delivery into the duodenum. To a lesser extent, the higher dose also significantly decreased total secretory volume output and had a borderline effect on pepsin output. As was found previously in nocturnal studies, 19 acid inhibition was related to blood cimetidine concentration, which tended to be higher after the larger dose (3 mg), explaining its greater action. We found no correlation between the acid output after placebo and the degree of inhibition caused by cimetidine, suggesting that the secretory response to the meal may not be used to predict the efficacy of the drug in an individual patient. The acid-suppressing effect of cimetidine appears most remarkable when its effect on postprandial gastric ph (fig. 2) is examined. While food remained in the stomach (1 to 3 hr postprandially), cimetidine (3 mg) reduced, but did not prevent the decline in gastric ph that occurred after placebo (to a mean ph of 2.9 versus 1.6). In contrast, as the stomach became empty of food, the ph rose again after cimetidine (despite falling blood drug levels), but it remained essentially unchanged after placebo. At 4 hr (when the stomach contained no food), the mean gastric ph, 6. ± 1.3 (mean ± SEM), was similar to that (6.3 ±.8) found in another group of 6 duodenal ulcer patients (4 of whom were included in both studies) 4 hr after they took 3 mg of cimetidine at bedtime. 19 In the 4 patients whom we studied both after a meal and at night, blood cimetidine concentrations decreased faster postprandially although peak levels (at 1 hr) were similar. For any cimetidine blood level, acid inhibition was less after taking of the drug with the meal (fig. 3) than was previously found during nocturnal fasting. 19 Thus, the antisecretory effect of cimetidine is less potent during the gastric phase of secretion than during the late postprandial or nocturnal fasting phases. This may be attributable to the stronger stimulatory action during the gastric phase and to mechanisms bypassing H 2 - receptor blockade such as direct stimulation of parietal cells by food. 2 The therapeutic implication is that gastric emptying enhances acid inhibition by cimetidine, in contrast to hampering the effects of neutralizing antacids, which act only as long as they remain in the stomach. 21 Cimetidine also inhibited total gastric secretory output, reducing the volume of gastric contents delivered into the duodenum. However, the fractional rate of gastric emptying remained unchanged, suggesting that the effect of cimetidine was primarily antisecretory. As previously noted, 19 pepsin concentration was unaffected and the reduction in pepsin output paralleled the reduction in volume output. Pancreatic enzyme and bile acid outputs were not affected, suggesting that H 2 -receptor antagonists at the doses used do not block the stimulatory action of meals on pancreas and gallbladder. Postprandial serum gastrin levels increased after cimetidine, whereas in previous nocturnal studies 19 no change was found. Further, during intragastric titration (PH

5 January 1977 POSTPRANDIAL RESPONSES TO CIMETIDINE IN DUODENAL ULCER ) after a peptone meal, serum gastrin was similar after cimetidine and after placebo. 4 These findings suggest that cimetidine has no direct effect on gastrin release but enhances the stimulatory action of food by raising the intragastric ph.6, 7 Cimetidine (3 mg), taken orally with an ordinary meal, markedly inhibited gastric secretion without affecting gastric emptying and pancreatic or biliary function. The 2-mg dose was effective, but to a lesser extent. Cimetidine should, therefore, prove useful in the management of acid-peptic disease, by achieving a postprandial gastric antisecretory effect without interfering with other digestive functions. However, cimetidine appears to be less potent postprandially than during nocturnal fasting; thus, a higher dose or adjuvant therapy may be needed when the drug is given with meals. REFERENCES 1. Bonney GLW, Pickering GW: Observations on the mechanism of pain in ulcer of the stomach and duodenum. Clin Sci 6:63-89, Burland WL, Duncan WAM, Hesselbo T, et al: Pharmacological evaluation of cimetidine, a new histamine H.-receptor antagonist, in healthy man. Br J Clin Pharmacol 2: , Grossman MI, Konturek SJ: Inhibition of acid secretion in dog by metiamide, a histamine antagonist acting on H. receptors. Gastroenterology 66: , Henn RM, Isenberg JI, Maxwell V, et al: Inhibition of gastric acid secretion by cimetidine in patients with duodenal ulcer. N Engl J Med 293: , Richardson CT, Bailey BA, Walsh JH, et al: The effect of an H.-receptor antagonist on food-stimulated acid secretion, serum gastrin, and gastric emptying in patients with duodenal ulcers. J Clin Invest 55: , Walsh JH, Richardson CT, Fordtran JS: ph dependence of acid secretion and gastrin release in normal and ulcer patients. J Clin Invest 55: , Konturek SJ, Biernat J, Oleksy J: Serum gastrin and gastric acid responses to meals at various ph levels in man. Gut 15:526-53, Malagelada JR, Go VLW, Summerskill WHJ: Gastric functions in response to solid and homogenized meals. Clin Res 23:253A, Malagelada JR, Longstreth GF, Summerskill WHJ, et al: Measurement of gastric functions during digestion of ordinary solid meals in man. Gastroenterology 7:23-21, Brunner H, Northfield TC, Hofmann AF, et al: Gastric emptying and secretion of bile acids, cholesterol and pancreatic enzymes during digestion. Mayo Clin Proc 49:851-86, Longstreth GF, Malagelada JR, Go VLW: The gastric response to a transpyloric duodenal tube. Gut 16:777-78, Berstad A: A modified hemoglobin substrate method for the estimation of pepsin in gastric juice. Scand J Gastroenterol 5: , Rhodes J, Barnardo DE, Phillips SF, et al: Increased reflux of bile into the stomach in patients with gastric ulcer. Gastroenterology 57: , DiMagno EP, Go VLW, Summerskill WHJ: Relations between pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiency. N Engl J Med 288: , Wingate D, Sandberg RJ, Phillips SF: A comparison of stable and "C-labelled polyethylene glycol as volume indicators in the human jejunum. Gut 13: , Hyden S: A turbidimetric method for the determination of high polyethylene glycols in biological materials. K Lantbrukshogsk Ann 22: , Sizemore GW, Go VLW, Kaplan EL, et al: Relations of calcitonin and gastrin in the Zollinger-Ellison syndrome and medullary carcinoma of the thyroid. N Engl J Med 288: , Dixon WJ, Massey FJ Jr: Introduction to Statistical Analysis. Third edition. eyork, w McGraw-Hill, Longstreth GF, Go VLW, Malagelada JR: Cimetidine suppresses nocturnal gastric secretion in active duodenal ulcer. N Engl J Med 294:81-84, Debas HT, Grossman MI: Chemicals bathing the oxyntic gland area stimulate acid secretion in dog. Gastroenterology 69: , Morrissey JF, Berreras RF: Antacid therapy. N Engl J Med 29:55-554, 1974