- Email: [email protected]
Effect of H2-receptor antagonists on gastric acid secretion and serum gastrin concentration
00165085/78/7402-0366$02.00/O GMTROENTZ~OLOGY 74:366-370,1978 Copyright0 1978by tbe AmericanGastroenterological Association
Vol. 74, No. 2, Part2 Printedin U.SA.
EFFECT OF Hz-RECEPTOR ANTAGONISTS ON GASTRIC SECRETION AND SERUM GASTRIN CONCENTRATION
ACID
A review CHARLES T. RICHARDSON, M.D. Department oflnternal Medicine, University of Texas Southwestern
Division of Gastroenterology, Veterans Administration Medical School, Dallas, Texas
Hospital and The
Cimetidine inhibits basal and nocturnal acid secretion and acid secretion stimulated by histamine, pentagastrin, caffeine, insulin, sham feeding, and food. Cimetidine (300 mg) inhibits basal acid secretion in duodenal ulcer patients by 95% for at least 5 hr. When taken at bedtime, cimetidine inhibits nocturnal acid secretion by greater than 80% for most of the night. Cimetidine markedly inhibits food-stimulated acid secretion and is more effective than anticholinergic drugs. However, to get adequate suppression of food-stimulated acid secretion throughout the day, cimetidine should be given with each meal. Cimetidine has no effect on nocturnal serum gastrin concentration, but, when stimulated bv food. serum gastrin concentration is higher after cimetidine than after placebo. ” ’ Histamine HZ-receptor antagonists markedly inhibit basal and nocturnal gastric acid secretion and acid secretion stimulated by histamine, pentagastrin, caffeine, bethanechol, 2-deoxyglycose, insulin, sham feeding, and food.‘-lo The following is a review of the effect of HZ-receptor antagonists on acid secretion and serum gastrin concentration in duodenal ulcer patients. Effect
on basal and nocturnal
acid secretion.
The
effect of cimetidine on basal acid secretion in 7 duodenal ulcer patients is shown in figure 1.2Basal acid secretion was measured for 1 hr by aspiration and ranged from 2.5 to 3.5 mEq per 30 min. Medication, either placebo or 300 mg of cimetidine, was given and the nasogastric tube was clamped to allow for emptying and absorption of medication. After 1 hr gastric aspiration was reinstituted. One and one-half hours after medication acid secretion was decreased by cimetidine to less than 0.1 mEq per 30 min. Acid secretion was still inhibited to this level 5 hr after cimetidine. Figure 2 shows the effect of cimetidine on basal gastric juice volume (top panel) and hydrogen ion concentration (bottom panel) in 7 duodenal ulcer patients2 Cimetidine decreased gastric juice volume by about 35 to 55%. Hydrogen ion concentration, on the other hand, was markedly suppressed throughout the 5-hr study and from 2V2 to 4 hr was less than 1 mEq per liter. Therefore, cimetidine inhibits basal acid secretion by moderately reducing gastric juice volume and markedly decreasing hydrogen ion concentration. The effect of cimetidine on nocturnal acid secretion Address requests for reprints to: Charles T. Richardson, M.D., Department of Internal Medicine, Division of Gastroenterology, The University of Texas Southwestern Medical School, Dallas, Texas 75235.
in 6 duodenal ulcer patients is shown in figure 3. l Acid secretion was measured for 1 hr and ranged from 8.3 to 11.8 mEq per 30 min. Placebo or 300 mg of cimetidine was given at 11 PM and the nasogastric tube was clamped to allow for emptying and absorption of medication. After 1 hr gastric aspiration was reinstituted. Cimetidine suppressed acid secretion throughout the night. From 12:30 to 6 AM cimetidine inhibited acid secretion by greater than 80%. From 1 until 6:30 AM acid secretion was less than 1 mEq per 30 min. When given at bedtime, cimetidine markedly inhibits nocturnal acid secretion. Effect on food-stimulated acid secretion. Food, especially protein, is a potent stimulus of acid secretion. Therefore, it is important that an antisecretory drug effectively suppress food-stimulated acid secretion. In the following experiments a homogenized steak meal was infused through a nasogastric tube, and acid secretion was measured by in vivo intragastric titration.‘l Dose-response experiments. The effect of increasing oral doses of cimetidine on food-stimulated acid secretion is shown in figure 4.1° On the left side of this figure, percentage of inhibition of food-stimulated acid secretion is shown for the total 3-hr period after a steak meal. By increasing the dose of cimetidine, 3-hr acid secretion was inhibited to a progressively greater extent so that, with 400 mg, 3-hr secretion was inhibited by approximately 76%. On the right side of figure 4 percentage of inhibition of food-stimulated acid secretion is shown during the 30-min period of maximal inhibition. Just as with total 3-hr secretion, increasing the dose of medication increased the inhibitory effect. Doses as low as 25 mg transiently reduced acid secretion by 50%. However, for the total 3-hr period such low doses inhibited secretion by only 30%. Therefore, in choosing
366
ACID SECRETION LmEq/30min)
PHARMACOLOGY
CLINICAL
February 1978
Z-
OF Hz-RECEPTOR
\
1
?? p‘O
300 rnP
02
,CillW+di”~
c -,I J th
1
:
TIME
BASAL
fly*
AFTER
:
B
:
MEDICATION
4E
(HR)
FIG. 1. Effect of cimetidine on basal acid secretion in 7 duodenal ulcer patients. (From Henn et al.?
r
so Medkotion I
~Plocrbo
GASTRIC JUICE VOLUME (mV30min)
6o
_/
40 ??
‘?I/+-
20 :
q,
1(/2 0
-
t 2
21/2
3
r
I
4 3h
8ASAL
80
300 mg Cimctldlnc
4’4
,
YIdkatkn
5
*D-o.05
?? Pe0.01
367
ANTAGONISTS
in 7 duodenal ulcer patients is shown in figure 5.“’ With placebo, food-stimulated acid secretion reached a peak of 19 mEq per 30 min at l’lz hr after the meal and was stable at about 13 mEq per 30 min during the latter part of the study. By contrast, when 300 mg of cimetidine were given, acid secretion in response to food was markedly inhibited, especially from 1 to 3 hr. During the 30-min period of maximal inhibition which occurred at 2rl2 hr, acid secretion was reduced by 90%) and the secretory rate was less than 2 mEq per 30 min. All differences except during the first l/2 hr are statistically significant by paired t-test with a P value of less than 0.025. Duration of action. To determine the duration of action of cimetidine on food-stimulated acid secretion, an experiment was designed to simulate what happens during an average day. lo The question to be answered was whether a single 300-mg dose given with breakfast would be sufficient to inhibit the secretory response to a luncheon meal or whether an additional 300-mg dose should also be given with lunch. The results of this experiment are shown in figure 6. Placebo or cimetidine was given with an eaten breakfast meal at 8 AM and a homogenized luncheon meal was infused at 12 noon. Acid secretion was measured by in vivo intragastric titration for 3 hr (12 noon to 3 PM) in response to the luncheon meal. When cimetidine was given with the
HYDROGEN ION CONCENTRATIW 40 (mEq/L)
TOTAL
3 HOUR PERIOD
30’ PERIOD OF lN”lElTlON
MAXIMAL
loo 90 80 t WA
70 60 BASAL
TIME
AFTER
MEDICATION
PER CENT INHIBITION
(HR)
FIG. 2. Effect of cimetidine on basal gastric volume (top panel) and hydrogen ion concentration (bottom panel) in 7 duodenal ulcer patients. (From Henn et al.‘)
50 40
CiIWtldlW
30 20 IO E
(IO 100
200
300
400 ma 50 100 DOSE- OF MEDICATION
200
300
400
mg
FIG. 4. Percentage inhibition of placebo response for the total 3hr period during which acid secretion was measured (left) and for the 30-min period of maximal inhibition (right) in 7 patients with duodenal ulcer. Cimetidine, 25, 50, 100, 200, 300, or 400 mg, was given orally at the same time as an infused steak meal. (From Richardson et al. I”) 2016Medicotlon EASP.L
TIME
AFTER
MEDICATION
ACID SECRETION (mEq/30min
(HR)
FIG. 3. Effect of cimetidine on nocturnal acid secretion duodenal ulcer patients. (From Longstreth et al.‘)
in 6
a dose for therapeutic purposes, it is better to select a dose that effectively suppresses acid secretion for the total 3-hr period. Doses of 200 to 400 mg are required to suppress 3-hr acid secretion by 60 to 80%. Pattern of acid secretion. The pattern of food-stimulated acid secretion after placebo or 300 mg of cimetidine
l*I 8-
‘7?c?rIIt, BASAL TIME
AFTER
MEDICATION
(HR)
FIG. 5. Pattern of food-stimulated acid secretion after placebo or 300 mg of cimetidine in 7 duodenal ulcer patients. Placebo or cimetidine was given at the same time as an infused steak meal. (From Richardson et al.“‘)
368
RICHARDSON EATEN
‘7-
I
12
by 90 to 95%.‘, 2 The effect of 300 mg of cimetidine on food-stimulated acid secretion has been compared with that of a maximum tolerated dose of probanthine.2 Probanthine inhibited 3-hr food-stimulated acid secretion by only 31%, whereas 300 mg of cimetidine inhibited acid secretion by 68%.
INFUSED LU%!:oN
“YiKAST
Vol. 74, No. 2, Part 2
I
4
ACID
Interaction between Hz-receptor antagonists and anticholinergic drugs. Hz-receptor antagonists and anti-
‘3A.M: 11 0 3 TIME AFTER
lENcon 1 4 5 BREAKFAST
2 6 MEAL
3 PM. 7 1hours)
FIG. 6. Duration of action of cimetidine in 6 duodenal ulcer patients. Cimetidine (300 mg) or placebo was given with breakfast on 2 test days. On separate test days cimetidine (300 mg) or placebo was given with breakfast and luncheon meals. On each day acid secretion in response to the infused luncheon meal was measured by in vivo intragastric titration. 2018‘6Placebo ACID l2 SECRETION ‘0 mEq/30 min 8-
t
Meal FIG.
Isopropomidc
TIME
7. Effect of a maximum
(minutes)
tolerated
dose of isopropamide,
300
mg of metiamide, and 300 mg of metiamide plus isopropamide on meal-stimulated acid secretion in 6 patients with duodenal ulcer. The difference in total 3-hr acid secretion between 300 mg of metiamide plus isopropamide and 300 mg of metiamide given alone is statistically significant by paired t-test (P < 0.025). (From Richardson et al.‘“)
breakfast meal at 8 AM but not with the luncheon meal, acid secretion was still inhibited from 4 to 7 hr later. However, the degree of inhibition during the latter part of the study was slight so that from 5l/2 to 7 hr there was only a 25 to 35% reduction in acid secretion. Therefore, one dose given with breakfast will not adequately suppress acid secretion in response to a luncheon meal. When 300 mg of cimetidine were given with the breakfast and luncheon meals, food-stimulated acid secretion was effectively suppressed throughout the 7hr period. This experiment suggests that cimetidine should be given with each meal to reduce acid secretion effectively throughout the day. Comparison with anticholinergic drugs. Anticholinergic drugs have been used as antisecretory agents for a number of years and serve as a standard by which new antisecretory drugs can be compared. These compounds reduce basal and nocturnal acid secretion by about 50 to 60%.12Histamine Hz-receptor antagonists, on the other hand, reduce basal and nocturnal secretion
cholinergic drugs are thought to inhibit acid secretion by blocking the stimulatory effect of two separate agonists: histamine and acetylcholine, respectively. Therefore, experiments have been designed to evaluate the effect of combinations of these drugs on acid secretion. Figure 7 compares the effect on food-stimulated acid secretion of 300 mg of metiamide plus a maximum tolerated dose of isopropamide with that of either metiamide or isopropamide alone.‘” Metiamide was given 30 min before the meal and isopropamide 2 hr before the meal. The drug combination was more effective in suppressing food-stimulated acid secretion than was either drug given alone. At 60, 90, and 120 min after the meal, acid secretion with the drug combination was less than 1 mEq per 30 min, and even at 180 min acid secretion was only 2.4 mEq per 30 min. All of the differences in total 3-hr acid secretion were statistically significant by paired t-test (P < 0.025). Therefore, the inhibitory effects of metiamide and isopropamide are additive and a combination of these drugs suppressed acid secretion to a greater extent than either drug given alone. The effect of a maximum tolerated dose of glycopyrrelate, an anticholinergic drug, 300 mg of metiamide, and the combination of glycopyrrolate and metiamide on basal acid secretion in a patient with ZollingerEllison syndrome is shown in figure 8.14A maximum tolerated dose of glycopyrrolate produced only a modest decrease in acid secretion. Metiamide (300 mg), on the other hand, decreased acid secretion from 25 mEq per 30 min to near 0 at 11/2 hr after medication. It remained at this level for the next hour; however, by 4 hr after medication acid secretion had returned to basal levels. When 300 mg of metiamide was combined with a maximum tolerated dose of glycopyrrolate, acid secre-
TIME
AFTER
MiDlCATlON
(hours)
FIG. 8. Effect on basal acid secretion of a maximum tolerated dose of glycopyrrolate, 300 mg of metiamide, and 300 mg of metiamide combined with a maximum tolerated dose of glycopyrrolate in a patient with Zollinger-Ellison syndrome. (From Richardson and Walsh.14)
February
other hand, when a steak meal was eaten and pH allowed to seek its natural level (right panel), serum gastrin concentration was higher after cimetidine than after placebo and the differences were statistically significant at 2 and 3 hr after medication. This increase in food-stimulated serum gastrin concentration presumably occurs because of an increase in antral pH after cimetidine.
Medcotion
1
PlOCCbo
‘?I0 k SERUM GASTRIN
~
\_ P 300
100
(pglmll
rnq
Clmetidnnc
TIME
AFTER
MEDICATION
REFERENCES
IHR)
FIG. 9. Effect of cimetidine on nocturnal serum gastrin concentration in 6 duodenal ulcer patients. (From Longstreth et al.‘)
PH 5 0
1OOr
Natural
lOOr
pH
9080-
20 10 I-
U’
TIME
369
DISCUSSION
1978
A___
I
(hours)
M’+“l
Medicotaan
FIG. 10. Effect concentration in 6 response when pH response when pH (From Richardson
2
I___
3
7
Meal t MedIcalIon
TIME
(hours)
2
3
of cimetidine on food-stimulated serum gastrin duodenal ulcer patients. The left panel shows the was maintained at 5.0. The right panel shows the was allowed to seek its own level (natural pH). et al.“Y
tion was suppressed below 5 mEq per 30 min for 4 hr and at the end of the study acid secretion was still only 8 mEq per 30 min. In this patient with Zollinger-Ellison syndrome, the inhibitory effect of metiamide was prolonged by the concomitant administration of an anticholinergic drug. Effect on serum gastrin concentration. The effect of cimetidine on nocturnal serum gastrin concentration in 6 duodenal ulcer patients is shown in figure 9.’ Serum was obtained at intervals from lo:30 PM until 7 AM. Gastrin concentration after placebo or 300 mg of cimetidine remained at premeditation levels throughout the night. Therefore, cimetidine has no effect on nocturnal serum gastrin concentration. The effect of cimetidine on meal-stimulated serum gastrin concentration in 6 duodenal ulcer patients is shown in figure lO.‘OWhen a homogenized steak meal was infused through a nasogastric tube into the stomach and pH maintained constant at 5.0 (left panel), the rise in serum gastrin concentration in response to the meal was similar after either placebo or cimetidine. On the
1. Longstreth GF, Go VLW, Malagelada JR: Cimetidine suppression of nocturnal gastric secretion in active duodenal ulcer. N Engl J Med 294:801, 1976 2. Henn RM, Isenberg JI, Maxwell V, et al: Inhibition of gastric acid secretion by cimetidine in patients with duodenal ulcer. N Engl J Med 293:371-374, 1975 3. Grossman MI, Konturek SJ: Inhibition of acid secretion in dog by metiamide, a histamine antagonist acting on Hz-receptors. Gastroenterology 66517-521, 1974 4. Hirschowitz BI, Gibson R: Effects of burimamide and of metiamide on gastric acid and pepsin secretion in the dog. In International Symposium on Histamine H,-Receptor Antagonists. Edited by CJ Wood, MA Simkins. Welwyn Garden City, England, Smith Kline & French Laboratories, 1973, p 273-290 5. Bajaj SC, Hirschowitz BI: Inhibition of basal and stimulated gastric H+ and pepsin secretion in duodenal ulcer patients by metiamide, an Hz-histamine antagonist. Am J Dig Dis 21:557562, 1976 6. Cano R, Isenberg JI, Grossman MI: Cimetidine inhibits caffeinestimulated gastric acid secretion in man. Gastroenterology 70: 1055, 1976 7. Mainardi M, Maxwell V, Sturdevant RAL, et al: Metiamide, an H,-receptor blocker, as inhibitor of basal and meal-stimulated gastric acid secretion in patients with duodenal ulcer. N Engl J Med 291:373-376, 1974 8. Thjodleifsson B, Wormsley KG: Gastric response to metiamide. Br Med J 2:304-306, 1974 9. Pounder RE, Williams JG, Russell RCG: Inhibition of foodstimulated gastric acid secretion by cimetidine. Gut 17:161-168, 1976 10. Richardson CT, Walsh JH, Hicks MI: The effect of cimetidine, a new histamine Hz-receptor antagonist, on meal-stimulated acid secretion, serum gastrin, and gastric emptying in patients with duodenal ulcer. Gastroenterology 71:19-23, 1976 11. Fordtran JS, Walsh JH: Gastric acid secretion rate and buffer content of the stomach after eating. Results in normal subjects and in patients with duodenal ulcer. J Clin Invest 52:645-657, 1973 12. Dotevall G, Schroeder G, Walan A: Effect of poldine, glycopyrrolate and I-hyoscyamine on gastric secretion of acid in man. Acta Med Stand 177:169-174, 1965 13. 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. Comparison with an anticholinergic drug. J Clin Invest 55:536542, 1975 14. Richardson CT, Walsh JH: The value of a histamine Hz-receptor antagonist in the management of patients with the ZollingerEllison syndrome. N Engl J Med 294:133-135, 1976
DISCUSSION OF PAPER PRESENTED BY DR. RICHARDSON DR. J. E. MCGUIGAN (Gainesville, Fla.): Let me ask you a question in regard to the gastrin levels after feeding, with and without cimetidine, in the duodenal ulcer patients. If I am correct in interpreting
your slide and your words, you have higher serum gastrin levels after feeding in the patients who are on cimetidine as contrasted with those receiving placebo. Is that correct?
370
DISCUSSION
DR. RICHARDSON: Yes. DR. MCGUIGAN:In your study there is a very small gastrin increase with placebo- a much smaller gastrin increase than we see in most normal individuals and most patients with duodenal ulcer. My experience is that there is an enormous amount of heterogeneity in terms of gastrin release among duodenal ulcer patients, and I wonder whether or not these studies have been repeated. How much additional data are there that enhanced gastrin release in response to feeding with cimetidine in the duodenal ulcer patients actually occurs. DR. RICHARDSON: Dr. Malagelada also found that after food gastrin was increased by cimetidine. Juan, do you want to comment? DR. J.-R. MALAGELADA (Rochester, Minn.): No, I just want to con&m what you said. DR. FORDTRAN:But what about when you keep pH constant? DR. RICHARDSON: When you keep pH constant at 5.0, there is no difference in the serum gastrin response to a meal with or without cimetidine. DR. FORDTRAN:So gastrin goes up after cimetidine simply because it reduces acidity in the antrum and allows the meal to stimulate more gastrin release? DR. RICHARDSON: Presumably. We also have done a similar study with antacids and found essentially the same results with antacids that we did with cimetidine. DR. S. H. LORBER(Philadelphia): Could you tell us how long the elevations of serum gastrin might persist and could you also tell us whether or not the physiological aspects of this have meaning in terms of (1) the potential of rebound secretion, and (2) whether or not the so-called tolerance that apparently may develop in patients on long term therapy may be related to the influence on serum gastrin level.
Vol. 74, No. 2, Part 2
DR. RICHARDSON: In answer to the first question, we measured gastrin for only 3 hr. Dr. Malagelada measured gastrin for 4 hr and found that by 4 hr serum gastrin concentration had returned to the placebo level. With regard to the second question, in the British studies serum gastrin levels are the same at the end of 3 months of therapy, as they are at the beginning. In other words, chronic cimetidine therapy for 3 months does not increase serum gastrin concentration. Peak acid output is also unchanged after 3 months. If we can accept peak acid output as an indicator of parietal cell mass, there is no evidence that parietal cell mass increases after cimetidine treatment. DR. G. 0. BARBEZAT(Cape Town, South Africa): We have looked at blood gastrin levels before and after HZ-receptor antagonists, both in the fasting state and after meals, and corroborate the findings of Dr. Richardson. There is no change in serum gastrin concentration after cimetidine in the fasting state. After a meal there is a slight but significant rise in gastrin which returns to normal after a few hours. DR. W. J. SNAPE, JR. (Philadelphia): Have you or anyone else noted any significant disorder of peptic digestion of a meal, with the abolishment of gastric acid secretion? And, if not, do you think that in the clinical treatment of patients it would be worthwhile giving them an antacid or some other type of therapy immediately after a meal to abolish gastric acid secretion further, in the 1st hr? DR. RICHARDSON: We have not specifically evaluated peptic digestion after cimetidine. However, as far as I know, there is no evidence that it is impaired. If indeed peptic digestion is not impaired by reduction of acid secretion, I agree with you that the addition of antacids may be beneficial to reduce gastric acidity further during the 1st hr after a meal.
Vol. 74, No. 2, Part2 Printedin U.SA.
EFFECT OF Hz-RECEPTOR ANTAGONISTS ON GASTRIC SECRETION AND SERUM GASTRIN CONCENTRATION
ACID
A review CHARLES T. RICHARDSON, M.D. Department oflnternal Medicine, University of Texas Southwestern
Division of Gastroenterology, Veterans Administration Medical School, Dallas, Texas
Hospital and The
Cimetidine inhibits basal and nocturnal acid secretion and acid secretion stimulated by histamine, pentagastrin, caffeine, insulin, sham feeding, and food. Cimetidine (300 mg) inhibits basal acid secretion in duodenal ulcer patients by 95% for at least 5 hr. When taken at bedtime, cimetidine inhibits nocturnal acid secretion by greater than 80% for most of the night. Cimetidine markedly inhibits food-stimulated acid secretion and is more effective than anticholinergic drugs. However, to get adequate suppression of food-stimulated acid secretion throughout the day, cimetidine should be given with each meal. Cimetidine has no effect on nocturnal serum gastrin concentration, but, when stimulated bv food. serum gastrin concentration is higher after cimetidine than after placebo. ” ’ Histamine HZ-receptor antagonists markedly inhibit basal and nocturnal gastric acid secretion and acid secretion stimulated by histamine, pentagastrin, caffeine, bethanechol, 2-deoxyglycose, insulin, sham feeding, and food.‘-lo The following is a review of the effect of HZ-receptor antagonists on acid secretion and serum gastrin concentration in duodenal ulcer patients. Effect
on basal and nocturnal
acid secretion.
The
effect of cimetidine on basal acid secretion in 7 duodenal ulcer patients is shown in figure 1.2Basal acid secretion was measured for 1 hr by aspiration and ranged from 2.5 to 3.5 mEq per 30 min. Medication, either placebo or 300 mg of cimetidine, was given and the nasogastric tube was clamped to allow for emptying and absorption of medication. After 1 hr gastric aspiration was reinstituted. One and one-half hours after medication acid secretion was decreased by cimetidine to less than 0.1 mEq per 30 min. Acid secretion was still inhibited to this level 5 hr after cimetidine. Figure 2 shows the effect of cimetidine on basal gastric juice volume (top panel) and hydrogen ion concentration (bottom panel) in 7 duodenal ulcer patients2 Cimetidine decreased gastric juice volume by about 35 to 55%. Hydrogen ion concentration, on the other hand, was markedly suppressed throughout the 5-hr study and from 2V2 to 4 hr was less than 1 mEq per liter. Therefore, cimetidine inhibits basal acid secretion by moderately reducing gastric juice volume and markedly decreasing hydrogen ion concentration. The effect of cimetidine on nocturnal acid secretion Address requests for reprints to: Charles T. Richardson, M.D., Department of Internal Medicine, Division of Gastroenterology, The University of Texas Southwestern Medical School, Dallas, Texas 75235.
in 6 duodenal ulcer patients is shown in figure 3. l Acid secretion was measured for 1 hr and ranged from 8.3 to 11.8 mEq per 30 min. Placebo or 300 mg of cimetidine was given at 11 PM and the nasogastric tube was clamped to allow for emptying and absorption of medication. After 1 hr gastric aspiration was reinstituted. Cimetidine suppressed acid secretion throughout the night. From 12:30 to 6 AM cimetidine inhibited acid secretion by greater than 80%. From 1 until 6:30 AM acid secretion was less than 1 mEq per 30 min. When given at bedtime, cimetidine markedly inhibits nocturnal acid secretion. Effect on food-stimulated acid secretion. Food, especially protein, is a potent stimulus of acid secretion. Therefore, it is important that an antisecretory drug effectively suppress food-stimulated acid secretion. In the following experiments a homogenized steak meal was infused through a nasogastric tube, and acid secretion was measured by in vivo intragastric titration.‘l Dose-response experiments. The effect of increasing oral doses of cimetidine on food-stimulated acid secretion is shown in figure 4.1° On the left side of this figure, percentage of inhibition of food-stimulated acid secretion is shown for the total 3-hr period after a steak meal. By increasing the dose of cimetidine, 3-hr acid secretion was inhibited to a progressively greater extent so that, with 400 mg, 3-hr secretion was inhibited by approximately 76%. On the right side of figure 4 percentage of inhibition of food-stimulated acid secretion is shown during the 30-min period of maximal inhibition. Just as with total 3-hr secretion, increasing the dose of medication increased the inhibitory effect. Doses as low as 25 mg transiently reduced acid secretion by 50%. However, for the total 3-hr period such low doses inhibited secretion by only 30%. Therefore, in choosing
366
ACID SECRETION LmEq/30min)
PHARMACOLOGY
CLINICAL
February 1978
Z-
OF Hz-RECEPTOR
\
1
?? p‘O
300 rnP
02
,CillW+di”~
c -,I J th
1
:
TIME
BASAL
fly*
AFTER
:
B
:
MEDICATION
4E
(HR)
FIG. 1. Effect of cimetidine on basal acid secretion in 7 duodenal ulcer patients. (From Henn et al.?
r
so Medkotion I
~Plocrbo
GASTRIC JUICE VOLUME (mV30min)
6o
_/
40 ??
‘?I/+-
20 :
q,
1(/2 0
-
t 2
21/2
3
r
I
4 3h
8ASAL
80
300 mg Cimctldlnc
4’4
,
YIdkatkn
5
*D-o.05
?? Pe0.01
367
ANTAGONISTS
in 7 duodenal ulcer patients is shown in figure 5.“’ With placebo, food-stimulated acid secretion reached a peak of 19 mEq per 30 min at l’lz hr after the meal and was stable at about 13 mEq per 30 min during the latter part of the study. By contrast, when 300 mg of cimetidine were given, acid secretion in response to food was markedly inhibited, especially from 1 to 3 hr. During the 30-min period of maximal inhibition which occurred at 2rl2 hr, acid secretion was reduced by 90%) and the secretory rate was less than 2 mEq per 30 min. All differences except during the first l/2 hr are statistically significant by paired t-test with a P value of less than 0.025. Duration of action. To determine the duration of action of cimetidine on food-stimulated acid secretion, an experiment was designed to simulate what happens during an average day. lo The question to be answered was whether a single 300-mg dose given with breakfast would be sufficient to inhibit the secretory response to a luncheon meal or whether an additional 300-mg dose should also be given with lunch. The results of this experiment are shown in figure 6. Placebo or cimetidine was given with an eaten breakfast meal at 8 AM and a homogenized luncheon meal was infused at 12 noon. Acid secretion was measured by in vivo intragastric titration for 3 hr (12 noon to 3 PM) in response to the luncheon meal. When cimetidine was given with the
HYDROGEN ION CONCENTRATIW 40 (mEq/L)
TOTAL
3 HOUR PERIOD
30’ PERIOD OF lN”lElTlON
MAXIMAL
loo 90 80 t WA
70 60 BASAL
TIME
AFTER
MEDICATION
PER CENT INHIBITION
(HR)
FIG. 2. Effect of cimetidine on basal gastric volume (top panel) and hydrogen ion concentration (bottom panel) in 7 duodenal ulcer patients. (From Henn et al.‘)
50 40
CiIWtldlW
30 20 IO E
(IO 100
200
300
400 ma 50 100 DOSE- OF MEDICATION
200
300
400
mg
FIG. 4. Percentage inhibition of placebo response for the total 3hr period during which acid secretion was measured (left) and for the 30-min period of maximal inhibition (right) in 7 patients with duodenal ulcer. Cimetidine, 25, 50, 100, 200, 300, or 400 mg, was given orally at the same time as an infused steak meal. (From Richardson et al. I”) 2016Medicotlon EASP.L
TIME
AFTER
MEDICATION
ACID SECRETION (mEq/30min
(HR)
FIG. 3. Effect of cimetidine on nocturnal acid secretion duodenal ulcer patients. (From Longstreth et al.‘)
in 6
a dose for therapeutic purposes, it is better to select a dose that effectively suppresses acid secretion for the total 3-hr period. Doses of 200 to 400 mg are required to suppress 3-hr acid secretion by 60 to 80%. Pattern of acid secretion. The pattern of food-stimulated acid secretion after placebo or 300 mg of cimetidine
l*I 8-
‘7?c?rIIt, BASAL TIME
AFTER
MEDICATION
(HR)
FIG. 5. Pattern of food-stimulated acid secretion after placebo or 300 mg of cimetidine in 7 duodenal ulcer patients. Placebo or cimetidine was given at the same time as an infused steak meal. (From Richardson et al.“‘)
368
RICHARDSON EATEN
‘7-
I
12
by 90 to 95%.‘, 2 The effect of 300 mg of cimetidine on food-stimulated acid secretion has been compared with that of a maximum tolerated dose of probanthine.2 Probanthine inhibited 3-hr food-stimulated acid secretion by only 31%, whereas 300 mg of cimetidine inhibited acid secretion by 68%.
INFUSED LU%!:oN
“YiKAST
Vol. 74, No. 2, Part 2
I
4
ACID
Interaction between Hz-receptor antagonists and anticholinergic drugs. Hz-receptor antagonists and anti-
‘3A.M: 11 0 3 TIME AFTER
lENcon 1 4 5 BREAKFAST
2 6 MEAL
3 PM. 7 1hours)
FIG. 6. Duration of action of cimetidine in 6 duodenal ulcer patients. Cimetidine (300 mg) or placebo was given with breakfast on 2 test days. On separate test days cimetidine (300 mg) or placebo was given with breakfast and luncheon meals. On each day acid secretion in response to the infused luncheon meal was measured by in vivo intragastric titration. 2018‘6Placebo ACID l2 SECRETION ‘0 mEq/30 min 8-
t
Meal FIG.
Isopropomidc
TIME
7. Effect of a maximum
(minutes)
tolerated
dose of isopropamide,
300
mg of metiamide, and 300 mg of metiamide plus isopropamide on meal-stimulated acid secretion in 6 patients with duodenal ulcer. The difference in total 3-hr acid secretion between 300 mg of metiamide plus isopropamide and 300 mg of metiamide given alone is statistically significant by paired t-test (P < 0.025). (From Richardson et al.‘“)
breakfast meal at 8 AM but not with the luncheon meal, acid secretion was still inhibited from 4 to 7 hr later. However, the degree of inhibition during the latter part of the study was slight so that from 5l/2 to 7 hr there was only a 25 to 35% reduction in acid secretion. Therefore, one dose given with breakfast will not adequately suppress acid secretion in response to a luncheon meal. When 300 mg of cimetidine were given with the breakfast and luncheon meals, food-stimulated acid secretion was effectively suppressed throughout the 7hr period. This experiment suggests that cimetidine should be given with each meal to reduce acid secretion effectively throughout the day. Comparison with anticholinergic drugs. Anticholinergic drugs have been used as antisecretory agents for a number of years and serve as a standard by which new antisecretory drugs can be compared. These compounds reduce basal and nocturnal acid secretion by about 50 to 60%.12Histamine Hz-receptor antagonists, on the other hand, reduce basal and nocturnal secretion
cholinergic drugs are thought to inhibit acid secretion by blocking the stimulatory effect of two separate agonists: histamine and acetylcholine, respectively. Therefore, experiments have been designed to evaluate the effect of combinations of these drugs on acid secretion. Figure 7 compares the effect on food-stimulated acid secretion of 300 mg of metiamide plus a maximum tolerated dose of isopropamide with that of either metiamide or isopropamide alone.‘” Metiamide was given 30 min before the meal and isopropamide 2 hr before the meal. The drug combination was more effective in suppressing food-stimulated acid secretion than was either drug given alone. At 60, 90, and 120 min after the meal, acid secretion with the drug combination was less than 1 mEq per 30 min, and even at 180 min acid secretion was only 2.4 mEq per 30 min. All of the differences in total 3-hr acid secretion were statistically significant by paired t-test (P < 0.025). Therefore, the inhibitory effects of metiamide and isopropamide are additive and a combination of these drugs suppressed acid secretion to a greater extent than either drug given alone. The effect of a maximum tolerated dose of glycopyrrelate, an anticholinergic drug, 300 mg of metiamide, and the combination of glycopyrrolate and metiamide on basal acid secretion in a patient with ZollingerEllison syndrome is shown in figure 8.14A maximum tolerated dose of glycopyrrolate produced only a modest decrease in acid secretion. Metiamide (300 mg), on the other hand, decreased acid secretion from 25 mEq per 30 min to near 0 at 11/2 hr after medication. It remained at this level for the next hour; however, by 4 hr after medication acid secretion had returned to basal levels. When 300 mg of metiamide was combined with a maximum tolerated dose of glycopyrrolate, acid secre-
TIME
AFTER
MiDlCATlON
(hours)
FIG. 8. Effect on basal acid secretion of a maximum tolerated dose of glycopyrrolate, 300 mg of metiamide, and 300 mg of metiamide combined with a maximum tolerated dose of glycopyrrolate in a patient with Zollinger-Ellison syndrome. (From Richardson and Walsh.14)
February
other hand, when a steak meal was eaten and pH allowed to seek its natural level (right panel), serum gastrin concentration was higher after cimetidine than after placebo and the differences were statistically significant at 2 and 3 hr after medication. This increase in food-stimulated serum gastrin concentration presumably occurs because of an increase in antral pH after cimetidine.
Medcotion
1
PlOCCbo
‘?I0 k SERUM GASTRIN
~
\_ P 300
100
(pglmll
rnq
Clmetidnnc
TIME
AFTER
MEDICATION
REFERENCES
IHR)
FIG. 9. Effect of cimetidine on nocturnal serum gastrin concentration in 6 duodenal ulcer patients. (From Longstreth et al.‘)
PH 5 0
1OOr
Natural
lOOr
pH
9080-
20 10 I-
U’
TIME
369
DISCUSSION
1978
A___
I
(hours)
M’+“l
Medicotaan
FIG. 10. Effect concentration in 6 response when pH response when pH (From Richardson
2
I___
3
7
Meal t MedIcalIon
TIME
(hours)
2
3
of cimetidine on food-stimulated serum gastrin duodenal ulcer patients. The left panel shows the was maintained at 5.0. The right panel shows the was allowed to seek its own level (natural pH). et al.“Y
tion was suppressed below 5 mEq per 30 min for 4 hr and at the end of the study acid secretion was still only 8 mEq per 30 min. In this patient with Zollinger-Ellison syndrome, the inhibitory effect of metiamide was prolonged by the concomitant administration of an anticholinergic drug. Effect on serum gastrin concentration. The effect of cimetidine on nocturnal serum gastrin concentration in 6 duodenal ulcer patients is shown in figure 9.’ Serum was obtained at intervals from lo:30 PM until 7 AM. Gastrin concentration after placebo or 300 mg of cimetidine remained at premeditation levels throughout the night. Therefore, cimetidine has no effect on nocturnal serum gastrin concentration. The effect of cimetidine on meal-stimulated serum gastrin concentration in 6 duodenal ulcer patients is shown in figure lO.‘OWhen a homogenized steak meal was infused through a nasogastric tube into the stomach and pH maintained constant at 5.0 (left panel), the rise in serum gastrin concentration in response to the meal was similar after either placebo or cimetidine. On the
1. Longstreth GF, Go VLW, Malagelada JR: Cimetidine suppression of nocturnal gastric secretion in active duodenal ulcer. N Engl J Med 294:801, 1976 2. Henn RM, Isenberg JI, Maxwell V, et al: Inhibition of gastric acid secretion by cimetidine in patients with duodenal ulcer. N Engl J Med 293:371-374, 1975 3. Grossman MI, Konturek SJ: Inhibition of acid secretion in dog by metiamide, a histamine antagonist acting on Hz-receptors. Gastroenterology 66517-521, 1974 4. Hirschowitz BI, Gibson R: Effects of burimamide and of metiamide on gastric acid and pepsin secretion in the dog. In International Symposium on Histamine H,-Receptor Antagonists. Edited by CJ Wood, MA Simkins. Welwyn Garden City, England, Smith Kline & French Laboratories, 1973, p 273-290 5. Bajaj SC, Hirschowitz BI: Inhibition of basal and stimulated gastric H+ and pepsin secretion in duodenal ulcer patients by metiamide, an Hz-histamine antagonist. Am J Dig Dis 21:557562, 1976 6. Cano R, Isenberg JI, Grossman MI: Cimetidine inhibits caffeinestimulated gastric acid secretion in man. Gastroenterology 70: 1055, 1976 7. Mainardi M, Maxwell V, Sturdevant RAL, et al: Metiamide, an H,-receptor blocker, as inhibitor of basal and meal-stimulated gastric acid secretion in patients with duodenal ulcer. N Engl J Med 291:373-376, 1974 8. Thjodleifsson B, Wormsley KG: Gastric response to metiamide. Br Med J 2:304-306, 1974 9. Pounder RE, Williams JG, Russell RCG: Inhibition of foodstimulated gastric acid secretion by cimetidine. Gut 17:161-168, 1976 10. Richardson CT, Walsh JH, Hicks MI: The effect of cimetidine, a new histamine Hz-receptor antagonist, on meal-stimulated acid secretion, serum gastrin, and gastric emptying in patients with duodenal ulcer. Gastroenterology 71:19-23, 1976 11. Fordtran JS, Walsh JH: Gastric acid secretion rate and buffer content of the stomach after eating. Results in normal subjects and in patients with duodenal ulcer. J Clin Invest 52:645-657, 1973 12. Dotevall G, Schroeder G, Walan A: Effect of poldine, glycopyrrolate and I-hyoscyamine on gastric secretion of acid in man. Acta Med Stand 177:169-174, 1965 13. 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. Comparison with an anticholinergic drug. J Clin Invest 55:536542, 1975 14. Richardson CT, Walsh JH: The value of a histamine Hz-receptor antagonist in the management of patients with the ZollingerEllison syndrome. N Engl J Med 294:133-135, 1976
DISCUSSION OF PAPER PRESENTED BY DR. RICHARDSON DR. J. E. MCGUIGAN (Gainesville, Fla.): Let me ask you a question in regard to the gastrin levels after feeding, with and without cimetidine, in the duodenal ulcer patients. If I am correct in interpreting
your slide and your words, you have higher serum gastrin levels after feeding in the patients who are on cimetidine as contrasted with those receiving placebo. Is that correct?
370
DISCUSSION
DR. RICHARDSON: Yes. DR. MCGUIGAN:In your study there is a very small gastrin increase with placebo- a much smaller gastrin increase than we see in most normal individuals and most patients with duodenal ulcer. My experience is that there is an enormous amount of heterogeneity in terms of gastrin release among duodenal ulcer patients, and I wonder whether or not these studies have been repeated. How much additional data are there that enhanced gastrin release in response to feeding with cimetidine in the duodenal ulcer patients actually occurs. DR. RICHARDSON: Dr. Malagelada also found that after food gastrin was increased by cimetidine. Juan, do you want to comment? DR. J.-R. MALAGELADA (Rochester, Minn.): No, I just want to con&m what you said. DR. FORDTRAN:But what about when you keep pH constant? DR. RICHARDSON: When you keep pH constant at 5.0, there is no difference in the serum gastrin response to a meal with or without cimetidine. DR. FORDTRAN:So gastrin goes up after cimetidine simply because it reduces acidity in the antrum and allows the meal to stimulate more gastrin release? DR. RICHARDSON: Presumably. We also have done a similar study with antacids and found essentially the same results with antacids that we did with cimetidine. DR. S. H. LORBER(Philadelphia): Could you tell us how long the elevations of serum gastrin might persist and could you also tell us whether or not the physiological aspects of this have meaning in terms of (1) the potential of rebound secretion, and (2) whether or not the so-called tolerance that apparently may develop in patients on long term therapy may be related to the influence on serum gastrin level.
Vol. 74, No. 2, Part 2
DR. RICHARDSON: In answer to the first question, we measured gastrin for only 3 hr. Dr. Malagelada measured gastrin for 4 hr and found that by 4 hr serum gastrin concentration had returned to the placebo level. With regard to the second question, in the British studies serum gastrin levels are the same at the end of 3 months of therapy, as they are at the beginning. In other words, chronic cimetidine therapy for 3 months does not increase serum gastrin concentration. Peak acid output is also unchanged after 3 months. If we can accept peak acid output as an indicator of parietal cell mass, there is no evidence that parietal cell mass increases after cimetidine treatment. DR. G. 0. BARBEZAT(Cape Town, South Africa): We have looked at blood gastrin levels before and after HZ-receptor antagonists, both in the fasting state and after meals, and corroborate the findings of Dr. Richardson. There is no change in serum gastrin concentration after cimetidine in the fasting state. After a meal there is a slight but significant rise in gastrin which returns to normal after a few hours. DR. W. J. SNAPE, JR. (Philadelphia): Have you or anyone else noted any significant disorder of peptic digestion of a meal, with the abolishment of gastric acid secretion? And, if not, do you think that in the clinical treatment of patients it would be worthwhile giving them an antacid or some other type of therapy immediately after a meal to abolish gastric acid secretion further, in the 1st hr? DR. RICHARDSON: We have not specifically evaluated peptic digestion after cimetidine. However, as far as I know, there is no evidence that it is impaired. If indeed peptic digestion is not impaired by reduction of acid secretion, I agree with you that the addition of antacids may be beneficial to reduce gastric acidity further during the 1st hr after a meal.