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Anticholinergics: Do They Work in Peptic Ulcer?
GASTROENTEROLOGY 68: 154-166, 1975
Vol. 68, :"10. 1 Printed in U.S.A.
Copyright © 1975 by The Williams & Wilkins Co.
CLINICAL TRENDS AND TOPICS ANTICHOLINERGICS: DO THEY WORK IN PEPTIC ULCER? KEVIN J. IVEY, M.D. (Q'ld), M.R.C.P. (LONDON)
A. W. Morrow Department of Gastroenterology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
The cost of anticholinergic drugs for gastrointestinal disorders is very high. In 1972, it was 9.4 out of a total drug bill of $177 million in Australia 1 and in 1970 amounted to $62.5 million in the United States. 2 Because of doubt about their efficacy an evaluation of anticholinergic drugs in the treatment of gastrointestinal disorders was carried out at the request of the Australian Drug Evaluation Committee. Manufacturers were requested to supply all literature supporting the use of their drugs in gastrointestinal disease. Review of the 300 papers in table 1, of other drugs not listed on the Australian Pharmaceutical Benefits Scheme (e.g., l-hyoscamine sulfate long acting) plus papers not supplied by the manufacturers related to drugs in table 1 (e.g., poldine 3 ,4) brought the total reviewed to approximately 400 papers. As manufacturers were asked only to supply studies supporting the effectiveness of their drug, not those failing to do SO,34 the studies evaluated could be biased towards the anticholinergic drug. Each paper submitted has been reviewed in detail elsewhere (Report to the Australian Drug Evaluation Committee on the effect of anticholinergic drugs on the gastrointestinal tract of man, 1973). This review summarizes the Received November 29, 1973. Accepted May 31, 1974. Address requests for reprints to: Dr. Kevin J. Ivey, Division of Gastroenterology, Department of Medi· cine, School of Medicine, University of Missouri, Columbia, Missouri 65201. This work was supported in part by the National Health and Medical Research Council and the Australian Tobacco Research Foundation. Based on a review for the Australian Drug Evaluation Committee.
findings with regard to peptic ulcer disease, particularly in regard to the following questions: (1) Do these drugs given orally have any physiological effect on the stomach, especially on gastric acid secretion? (2) Have they been shown by controlled clinical trials to be of value in the management of peptic ulcer? (3) Are they being administered in optimal doses and do thes'e correspond to manufacturer's recommendations? (4) What recommendations can be made regarding use of these drugs?
Pharmacology and Gastrointestinal Absorption of Anticholinergics Anticholinergics are competitive antagonists of acetylcholine released at the terminal ending of the parasympathetic nerve supply to the gastrointestinal tract (muscarinic activity). Cholinergic receptor antagonists are of two types: (1) Tertiary ammonium compounds with three bonds attached to the nitrogen atom. These antagonize muscarinic activity. They include naturally occurring anticholinergics, atropine, belladonna, I-hyoscyamine, and the synthetic drug, oxyphencyclimine (Daricon); (2) Quaternary ammonium compounds (these make up the majority of the synthetic anticholinergics) with four bonds attached to the nitrogen atom. This has two effects: (1) the molecule has some ganglion-blocking (nicotinic) activity, and (2) is less lipid-soluble and so less well absorbed from the gastrointestinal tract. Given parenterally, these agents may have greater anti parasympathetic activity than the tertiary ammonium compounds because of the former property; given orally they are poorly absorbed and, unless given
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CLINICAL TRENDS AND TOPICS TABLE
Approved name
1. Anticholinergic drugs reviewed
Trade name
Manufacturing company
No. of papers
reviewedO
Glycopyrrolate Oxyphenonium bromide
Robinul (Q)' Antrenyl (Q)
A. H. Robins Ciba
12 53
Isopropamide iodide
Smith Kline & French McNeil Searle
16
Hyoscine-n-butyl bromide
Tryrimide (Q) Darbid Nacton (Q) Pro-Ban thine (Q) Buscopan (Q)
11
Oxyphenycyclimine Hexocyclium methylsulfate Pipenzolate bromide
Daricon (T) Tral(Q) Piptal (Q)
Boehringer Ingelheim Beecham Abbott Lakeside
22 10 26
Mepenzolate bromide Methscopolamine bromide
Cantil (Q) Pamine (Q)
Lakeside Upjohn
15 15
Mebeverined
Duspatal d Colofac Merbentyl (T) Monodral (Q) Donnatal (T)
Philips Duphar
Pol dine methymethosulfate Propantheline bromide
Dicyclomine hydrochloride Penthienate bromide Belladona and phenobarbital Tiemonium iodide Atropine methylnitrate Tridihexethyl chloride Atropine sulfate
Merrell Winthrop A. H . Robins
Visceralgin (Q) Fawns and McAlian Eumydrin (Q) Winthrop Pathilon (Q) Lederle (T)
15 17
9 31 11 7 20 10 0 0
---
Manufacturer's recom· mended dose'
Maximum single reCOffi-
mended dose'
1 mg 3 times daily 5-10 mg several times daily 5 mg twice daily
2mg 10mg
4 mg every 6 hr 15 mg 3 times daily, 2 at night 20 mg 4 times daily
6mg 30 mg
5-10 mg twice daily 50-75 mg twice daily 5-10 mg 3 times daily and at night 25-50 mg every 6 hr 2.5 mg 3 times daily and at night 100 mg 3-4 times daily
10mg
5 mgat night
10-20 mg 3-4 times daily 5 mg 3-4 times daily 10mg 1-2 tablets 3-4 times daily 50 mg 3 times daily and at night 1 mg 25-50 mg 3-4 times daily 0.6 mg
300' Other drugs I-Hyoscyamine sulfate"
I
Egazil (T) Egacen
HassleAB Astra, Sweden
Relevant papers of studies on gastrointestinal tract in man supplied by manufacturer, "1973 Physician's Handbook of Drugs, New Ethicals Pty ., Ltd., Balgowlah, New South Wales. 'T or Q refer to tertiary or quaternary ammonium compound . d Not strictly an anticholinergic drug. 'Review of relevant papers not supplied by manufacturers brought total reviewed close to 400. I Not on Australian Pharmaceutical Benefits scheme .
o
in large doses, have less effect. 5 Beerman et al. 6 found almost 100% absorption of orally administered radioactive-labeled tertiary atropine, but only 15 to 25% absorption of quaternary ammonium methylatropine , propantheline, and methylscopolamine, and less than 5% absorption of hyoscine butyl bromide. 6 Fewer side effects after oral administration of quaternary ammonium drugs may be due to reduced gastrointestinal absorption . 5 Little is known
about the metabolism of anticholinergic agents in man apart from atropine, 50% of which appears in the urine 4 hr after an intramuscular injection. 6 The longer action of certain synthetic anticholinergics is attributed to delay in gastrointestinal absorption. 37
Physiological Basis of Use Use of anticholinergics in peptic ulcer disease is based largely on the role of the
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In the majority of these studies the mean reduction in basal acid output was about 50%. As most subjects studied were hypersecretors with duodenal ulcer, this degree of reduction in acid output resulted in an output in the normal range. Table 2 shows clearly that in the great majority of studies , for drugs to have an effect even on basal acid output, they must be given at least in the maximal dose recommended by the manufacturer, or in doses up to 10 times 21 , 22 the recommended dose. Of the apparent exceptions, hexocyclium (Tral) is a "long-acting" drug which has a recommended dose (50 mg or 75 mg) 2 or 3 times that of the short-acting drug (25 mg). The gastric secretory studies were carried out shortly after administration, which is really equivalent to using the maximum recommended dose of the short-acting drug. The oxyphenonium I'tudy was carried out in Indian patients 31 ; 5 times the recom mended dose was needed to have a similar effect on American subjects.32 The final exception was a study on both pipenzolate and propantheline,29 which measured only "free acidity" by titrating with Topfer's reagent. A second controlled study, using the same dose of pipenzolate, found no significant reduction of basal or histaminestimulated acid secretion during prolonged administration of this drug. 30 Many of the studies listed in table 2 were not strictly controlled, and their design would not be acceptable to publishers of similar studies of acid secretion in animals. In many studies,20, 23-33, 35 basal (and/or Clinical Studies Showing Reduced Gasstimulated) acid secretion was measured tric Acid Secretion initially shortly after admission to hospiBecause of the variable absorption of tal. The ulcer patient was then treated for anticholinergic drugs, particularly the syn- several weeks with bed rest, cessation of thetic quaternary ammonium agents, stud- smoking, antacids , and anticholinergics, ies of acid secretion after oral administra- and the acid measurements repeated and tion are essential. Of the 400 papers re- compared with the initial pretreatment viewed on anticholinergic drugs , only a studies. 20, 23-33. 35Only a few workers made dozen or so reasonably well controlled any attempt to assess reproducibility of studies could be found to show any reduc- acid measurements under the conditions of tion of basal or histamine-stimulated acid their trial. 23, 28. 36 The sole well designed secretion in man by an anticholinergic drug study of acid secretion during prolonged given orally. These studies are listed in anticholinergic therapy was that of Watable 2,20-37 and manufacturers' recom- lan,36 who also determined reproducibility mended doses in table 1. of acid output during placebo therapy.
vagus nerve in the control of gastric acid secretion. The aim of therapy is to reduce acid secretion. The role of acid in the causation of pain of peptic ulcer is not as clear cut as might first appear. Antacids frequently relieve ulcer pain, but in a dose usually insufficient to neutralize intragastric contents. 7 Neither can pain in peptic ulcer always be attributed to acid alone . In studies of the gastric mucosal barrier in gastric ulcer patients large amounts of acid (32 mEq per 15 min) may be instilled consecutively without pain developing. 8-1o Although it is known that acid plays a major role in the pathogenesis of peptic ulcer12 there is no objective evidence as yet that "less acid will form less ulcer," 13 although this is possible. Neither medical vagotomy with atropine (man},14. 15 nor surgical vagotomy (animals)16. 17 has a protective effect on the gastric mucosal barrier. Surgical vagotomy (truncal or selective) does reduce acid output. In two separate series, basal acid output was reduced by a mean of approximately 65% and histamine-stimulated acid output by 70%.18, 19 In spite of incomplete inhibition of acid secretions, surgical vagotomy does reduce peptic ulcer recurrence. The rationale, therefore, of anticholinergic therapy in peptic ulcer may be reasonable if it can be supported by (1) evidence of acid reduction; (2) improvement in ulcer symptoms; or (3) increased healing and/or decreased recurrence rate.
TABLE
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2. Controlled studies showing reduced human gastric acid secretion and drug dose a Drug
Oxyphencyclimine Isopropamide Hexocyclium b Poldine Pipenzolate Oxyphenonium Glycopyrrolate Penthienate Hyoscine methobromide 1-Hyoscyamine b Atropine sulfate Propantheline
Basal acid output
Maximum'· Maximum 2l and above 2l· 22 Recommended" C Above maximum"-" Recommended" No effect recommended'· Recommended" c. e Above maximum" Above maximum'" 33 Above maximum" Above maximum 35 Above maximum'" ' •. 37 Above maximum" Recommended29
Histamine-stimulated acid output
Maximum'· Recommended" Maximum" Above'.-28 d
C
C
Above maximum"
Above maximum'" ' •.
37
C
a Studies in which doses are listed as "above maximum" used side effects to determine dose." Dose "recommended" by manufacturer for maintenance therapy; "maximum" dose recommended: "above maximum" dose recommended by manufacturer. b "Long-acting" formulation. c See text. d Sub maximal histamine stimulation. 28 e Indian subjects.
This study showed enormous variations in basal acid output in subjects treated with placebo studied over periods of up to 2 years, the mean coefficient of variation in basal acid output between initial and final studies being 47%. Walan 36 concluded that basal acid output was so variable it should not be used alone as a measure of a drug effect. The remaining studies, in Table 2,21,22,34 were all short term; i.e., acid secretion was measured shortly after administration of single doses of the anticholinergic. In these studies, either no placebo was given,21 or it was always given in the first study 34 or while a placebo was given the dose of anticholinergic was such (6 times the recommended dose 22 ) that the patient could have had little trouble distinguishing drug and placebo by side effects. Studies showing negative results were not included in table 2, apart from one study with pipenzolate. 30 In addition, results of studies in which the 1st hr was taken as the basal, then the drug given, and the 3rd or 4th hr compared with the 1st hr, were excluded. 30- 3 4 Doses required to reduce histaminestimulated acid secretion were those maxi-
mally recommended by manufacturers or above (table 2). Mean percentage reduction of acid secretion ranged from 15 to 50%_ 20,23 Isopropamide was reported to produce a mean reduction of 50% of total acid output in subjects taking the recommended dose (5 mg twice daily) for 1 to 10 weeks. This reduction resulted in acid outputs in the normal range (10 to 20 mEq per hr).23 In this study, reproducibility was tested in 5 patients by repeating the study before the subject was started on anticholinergics. In 4 of the 5 subjects, basal and stimulated acid secretion were reduced in the second test. Of the six drugs shown in table 2 to reduce histamine-stimulated acid secretion, five are advertised as longacting and are recommended to be given twice daily, but acid studies were carried out mostly within 2 hr of administration. 20, 24, 26-28, 36
Effect on Non-Histamine-Stimulated Gastric Acid Secretion Several drugs were studied by means of stimulation other than histamine or pentagastrin (table 3). These include liquid test meals,40-43 food,3, 25, 34, 44, 45, 47, 50
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CLINICAL TRENDS AND TOPICS TABLE
Drug Oxyphencyclimine
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3. Controlled studies on nonhistamine-stimulated acid secretion a Dose'
Stimulus
Effect on secretion'
Above maximum Maximum-above maximum
Liquid meal'· Insulin coma ' •.
Pol dine
Maximum-above maximum Maximum-above maximum Maximum-above maximum
Food, 25 milk meal' Food' Liquid meal"
Reduction (pH) No effect (pH) No effect"
Pipenzolate
Above maximum (2 subjects)
Insulin coma"
No effect
Oxyphenonium
Above maximum Maximum and above maximum Above maximum Recommended
Food" Food" Insulin (Hollander)'· Alcohol'l
No effect (pH) Reduction in 50% (pH) No effect Reduction"' e
Glycopyrrolate
Above maximum Maximum Maximum-above maximum
Food" Food" Food + CaCO,'·
Reduction (pH) No effect (pH) No effect (pH)
Penthienate
Recommended-above maximum (3 subjects) Recommended-above maximum (3 subjects) Above maximum Maximum-above maximum
Food"
No effect
Insulin (Hollander)"
Reduction
Food,25 milk meal'· Insulin coma '., 41
Reduction (pH) Reduction
Atropine sulfate
41
No effect" Reduction
c
Piopantheline
Above maximum Above maximum
Insulin coma'., .1 Milk meal'·
Reduction Reduction (pH)
Hyoscine-N-butylbromide
Above maximum Above maximum (3 subjects)
Milk meal'· Milk meal"
No effect (pH) Reduction (pH)
a Studies in which doses are listed as "maximum" or "maximum-above maximum" used side effects to determine dose. • Dose "recommended" by manufacturer for maintenance therapy; "maximum" dose recommended; "above maximum" dose recommended. C In most food-stimulated studies, pH only was measured. Acid secretion during insulin coma studies was measured by liquid meal technique.'· No effect ~ no significant effect. "See text. e Indian subjects.
alcohol,31 insulin (Hollander test), 34, 46 and insulin coma. 40 , 41, 43 The results of these tests were more variable and more difficult to interpret, For example, the majority of studies of food-stimulated acid secretion measured only pH in timed samples from the stomach, It is possible that studies which measure only pH may miss an effect of the drug on volume, and therefore on total gastric acid output. 57, 60 In general, as for basal and histamine-stimulated acid output, reduction in acid output occurred with doses of anticholinergics above those maximally recommended, but not with
routine recommended doses. Some of the inherent difficulties and the need for adequate controls are exemplified by the studies of Hunt and Wales,.2 Douthwaite and Hunt,51 and Douthwaite et al. 52 with poldine. Liquid test meals of 750-ml volume containing 50 g per liter of glucose and nonabsorbable indicator were used. Acid secretion was calculated on the basis of Hollander's two-component hypothesis. 5 3, 54 The drug was given in "optimal effective dose," 55 i.e., the dose of ~rug was increased until side effects occurred, and then was reduced by one or two tablets
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per day. Most patients studied had duodenal ulcer and were inpatients initially. A test meal was done on admission and again after placebo every 6 hr for 3 to 4 days. From then on, poldine was given and the patient was studied from time to time. Results of these studies showed a reduction in calculated acid secretion in the majority of patients, compared to the initial study. Studies repeated in the subjects as outpatients showed a similar reduction in acid secretion. In 9 of the 14 patients, gastric secretion of acid after stopping treatment in the hospital was less than in the control studies before treatment. 51 These patients were then followed up as outpatients on poldine for periods of up to 3 years, and acid secretion continued to be "inhibited." 5 2 The problems of interpreting this study are as follows: 1. No control studies were done with placebo given throughout the duration of therapy. Studies were only compared with an initial two studies within the first 3 days of admission. Thus, allowance for the effect of therapy or getting used to the procedure was not made. This is especially relevant since 9 of the 14 subjects showed acid secretion lower than initial "control" studies after cessation of therapy. 2. Measurements of acid secretion based on the Hunt test meal are dependent on the acid concentration of the fluid emptying through the pylorus. Acid concentration is calculated on the assumption that gastric emptying is linear, whereas, in fact, it is exponential. 56 When the volume of fluid leaving the pylorus is small, this may not be so important, but where large volumes of gastric emptying such as 250 to 450 ml are concerned, as in this study, the errors in estimating the H+ ion concentration may be large, giving rise to errors in calculation of H+ ion secretion. 3. H + ion secretion was not directly measured , but was calculated from Hollander's two-component hypothesis. 53. 5. The assumptions inherent in this hypothesis have been discussed elsewhere, 14 but , in particular, no allowance is made for movement of H+ or Na+ ions by diffusion. 8 In support of these objections when these
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patients were subsequently studied in a double blind manner with poldine, no significant difference in gastric acid secretion between control and drug-treated groups was found. 42 Although the authors suggested that gastric secretion was reduced long term in both groups, compared to initial control studies, the reasons are more likely to be found in the above objections than to any prolonged effect of poldine for over 2 years after stopping the drug.
Long Term Treatment and Gastric Acid Secretion The studies of Hunt and Wales!2 Douthwaite and Hunt,51 and Douthwaite et al. 52 have often been quoted as indicating that long term treatment with anticholinergics will reduce gastric secretion for long periods after cessation of the drug, but the evidence does not support this conclusion. In 1962, Lawrie et aI., 64 using the test meal technique,56 reported reduction in acid secretion in a patient with the ZollingerEllison syndrome which continued for 5 months after the drug was discontinued. These authors subsequently reported 65 that acid secretion began to rise 3 months later, and in the following year the patient was operated on for a complicated duodenal ulcer. Although it is possible that pol dine did in fact reduce acid secretion for a prolonged period in this patient, it is equally possible that this represented a spontaneous temporary remission. 66 -7o Walan 36 found no significant difference between initial values for basal and maximal acid outputs after histamine and values 3 weeks after stopping therapy for 2-year duration with l-hyoscyamine in sustained release tablets. Kaye and associates 63 repeated studies of basal and maximal acid outputs 1 year after treatment with l-hyoscyamine in sustained release tablets, glycopyrrolate, and placebo. No significant changes occurred in maximal acid output, but basal acid output was significantly increased compared to initial values after glycopyrrolate. 63
Prolonged Effect? There were no strictly controlled studies showing prolonged effects on acid secretion
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CLINICAL TRENDS AND TOPICS
by any drug at recommended doses. Most studies using "long-acting" drugs were done only 1 or 2 hr after administration of the drug. 20 , 24, 26, 33, 36 Two drugs, isopropamide 21 and I-hyoscyamine (longacting),27,37 were shown, in doses well above those maximally recommended, to have an effect for more than 9 hr; for these doses, administration three times a day is the minimum required. Even here, the effect on acid secretion was falling off in the latter hours, and a more even effect with reduced side effects would be expected with administration every 6 hr. 71 No drugs at any dose were shown to have an effect for 12 hr, so administration twice a day cannot be justified.
Side Effects: Salivary Secretion All controlled studies in which salivary and gastric acid secretion have been measured concomitantly have shown that reduction of salivary secretion occurs when there is reduction of acid secretion. Grossman 21 found that doses of isopropamide sufficient to reduce salivary secretion (maximally recommended dose and above) also significantly reduced salivary secretion for corresponding periods of time. Kaye et al. 28 found that I-hyoscyamine, glycopyrronium, and poldine, in doses above those maximally recommended, reduced sub maximal histamine-stimulated acid secretion in at least 75% of subjects. At these doses, salivary secretion was also reduced in 100% of subjects, the mean reduction in acid secretion (27%) being identical to that of salivary secretion (27%). In both studies, the percentage of reduction in salivary secretion in the individual subject did not significantly correlate with that of acid secretion. Kaye et a1. 28 also carried out objective measurements on visual accommodation. In half the studies, this was impaired, although drugs varied considerably in this respect. I-hyoscyamine produced impaired accommodation in all subjects.
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results being inconclusive. Above maximum recommended doses of I-hyoscyamine (long-acting) given with antacid suspension caused a rise in intra gastric pH to above 4.5 for a mean of23 min compared to 11/2 min.74 This, however, is far from ideal. Lennard-Jones 3 compared pH of gastric contents throughout the day in 3 subjects given food plus antacid tablets sucked between meals with and without poldine in optimum effective doses. During the day there was a small mean increase in pH on anticholinergic (control mean 2.0, anticholinergic 2.3), but poldine did not prolong the effect of the dose of alkali given at night. Collyns and Fordtran 47 reported in abstract form that a 4-mg dose, but not a 2-mg dose of glycopyrrolate (4 times the recommended dose) significantly reduced gastric acidity after a steak meal, but only at 3 and 4 hr. Subsequently, the authors were unable to show in a controlled study any significant change in gastric pH after a steak meal followed by antacids (4 g of calcium carbonate, 1 hr pc) with or without optimum effective doses of glycopyrrolate administered 1/2 hr before the meal. 50 It should be stressed that all of these studies 3, 47,49,50,72-74 measured only acid concentration and not volume of fluid secreted. Nevertheless, the results have been disappointing.
Combination of Anticholinergic and Sedative on Acid Secretion One proprietary combination of anticholinergic and sedative, belladonna and phenobarbital (Donnatal) was studied in a controlled trial in the maximum recommended dose and failed to show a significant reduction in basal or histaminestimulated acid secretion. 38 This is not surprising when it is recognized that each tablet contains 0.1 mg of the active anticholinergic hyoscyamine sulfate and 16 mg of phenobarbital. To increase the dose of hyoscyamine sulfate to that found to reduce acid secretion by Dotevall et al.,27 Combined Antacid and Anticholinergic Walan,36 and Dotevall and Walan 37 (mean, Only a few, most inadequate,49,72,73 0.58 to 0.8 mg) would require toxic doses of studies have been carried out. the overall sedative. 39
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CLINICAL TRENDS AND TOPICS
Effect of Antispasmodics There were no controlled studies showing a reduction of basal or histaminestimulated acid secretion by any of the drugs listed as "antispasmodics," mebeverine, hyoscine-N-butyl bromide, dicyclomine Hel, atropine methylnitrate and mepenzolate bromide, tiemonium iodide, and tridihexethylchloride. Some workers believe that the pain of peptic ulcer is due to muscle spasm. Evidence for this is not convincing. II The effect of anti cholinergics on gastrointestinal motility will be reviewed fully elsewhere. It is sufficient to say that, just as for gastric acid secretion, effects on gastric and duodenal motility required at least maximally recommended and usually well above maximally recommended doses orally. Controlled Clinical Trials Only 15 studies on the following six drugs have been carried out: oxyphencyclimine, glycopyrrolate, propantheline , poldine, Lhyoscyamine (long-acting) , and belladonna i-hyoscyamine). 3. 4. 36. 75·84 Of these studies, somewhat fewer show a beneficial effect compared to no significant effect, six versus nine, as regards increased healin g, decreased symptoms , recurrence, or complication rate . Of these studies showing significant benefit, two studies, one with glycopyrrolate 78 and one with propantheline,78 were carried out in Nigerian subjects. In this study, placebo had virtually no effect (3 % healing rate), and, as the author himself stated, peptic ulcer in Nigerians may well have different etiologies from those in more technologically and socially advanced countries. Therefore, direct application in these results to such societies . must be guarded . The second study with propantheline was carried out by Sun and Ryan 81 on the effect of the drug in controlling recurrence rates in duodenal ulcer . The difference between drug and placebo was just significant. Sun and Ryan considered that the drug was "at most weakly effective over placebo" in controlling recurrences. The patients in Sun and Ryan 's81 studies with propantheline and Sun's76 studies with glycopyrrolate have
161
been noted for their high incidence of ulcer complications. Other series 79 , 80. 82 with both these drugs have been unable to confirm Sun 's results. Two controlled studies have been carried out on patients with gastric ulcer. The first is the well known study of Do1l83 on inpatients. Using a fixed but relatively large dose of belladonna (equivalent to 0.3 mg three times a day of the active ingredient L-hyoscyamine) he found no therapeutic advantage of the drug over control studies . The second was recently published by Baume et al. 77 using glycopyrrolate in maximum tolerated doses. 55 In contrast to Doll's study, they reported a significantly increased healing rate in inpatients taking anticholinergics: reduction in ulcer profile area by two-thirds in 90% of those taking anticholinergics, compared to 75% in controls. Apart from failure to use endoscopy to confirm reduction in ulcer area or complete ulcer disappearance, the major criticism of this part of the study is the failure to detail the number of aspirin takers in treated and placebo groups. In the second part of the study, they measured the effect of the drug on the rate of gastric ulcer recurrence as outpatients after initial healing had been achieved in the hospital. Results showed a significantly greater recurrence in the placebo group at 6 months (P = 0.02), and 12 months (P = 0.02), but not at 2 years (P = 0.06) . The overall recurrence rate was high in both control and treated groups: 77% placebo versus 50% glycopyrronium group. The study may be criticized for the fact that not all patients were X-rayed routinely, but only for symptoms, and endoscopy was not used at all. As it was not always easy to differentiate a residual scar from a tiny gastric ulcer recurrence, even on contrast radiology of the stomach , the use of upper gastrointestinal endoscopy would seem to have been essential. The question remains as to whether the majority of patients are willing to tolerate side effects from maximum tolerated doses for the reduction in ulcer symptoms. The fact that 30 patients tentatively allotted to the trial on an initial visit failed to return to the clinic suggests that many are not.
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Dosage of Anticholinergics in Clinical Studies All but one of the investigators showing a significant effect of anticholinergics in clinical studies 36 , 76, 77, 80, 81 recommend maximally tolerated doses. 55 These doses are above those recommended maximally by the manufacturers, An exception was the study on Nigerian subjects 78 where a fixed dose of one tablet three times a day was used; this produced side effects in 60 to 80% of these subjects however. Other studies using optimum effective dosage S5 failed to show an effect. 3, 42, 79, 80 The rationa le for using maximum tolerated doses is based on the need for such large doses to reduce gastric acid secretion. Walan 's36 detailed studies with L-hyoscyamine leave one uncertain as to the importance of reduction of acid secretion. Of his 7 patients who developed recurrences while on the drug, 3 had values for basal and maximum acid outputs above the mean, plus 2 SD values for patients without recurrences during treatment. The other 4 subjects, however, had normal to low acid secretory values. Low acid secretory values on treatment therefore did not guarantee that recurrences could not occur. In the placebo group, recurrences occurred both in patients with high , oridinary, and low secretory values. Patients with complications however tended to have higher secretory values, although of 5 patients on placebo who had gastrointestinal bleeding, none were endoscoped to prove that a bleeding ulcer was the cause. From these results , one could argue that 3 of the patients who developed recurrences while on anticholinergic treatment were inadequately controlled and should have been given even larger doses. Yet this was probably impractical since the mean daily dose of l-hyoscyamine in the patients with recurrences (1.64 mg) was greater than that in those without (1.46 mg). On the other hand, since many of the patients with recurrences had ordinary or low acid values on treatment, one might question if the degree of acid reduction achieved (mean 45% decrease in basal and 30% decrease in histamine-st imulated secretion) by the anticholinergic was of any
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significance. If one concludes from these results that acid reduction (no matter how little) is important in the prevention of ulcer recurrence , then one must use anticholinergics in maximal tolerated doses, if at all.
Recommendation for the Use of Anticholinergics in Peptic Ulcer Disease On the evidence reviewed , anticholinergics have a limited role, if any , in the management of peptic ulcer disease . Any such role that they may have exists only because of the lack of effective medical treatment for peptic ulcer. As the only alternative in many patients with persistent disabling symptoms or complications is surgery, then any group of drugs, such as the anticholinergics , which possibly reduce recurrence or complications, will be used until a better alternative (such as oral prostaglandins 85 . 86 or antihistamines blocking H 2 -receptors) is developed . Anticholinergics may be of value for: 1. Persistent pain, especially nocturnal , in acute peptic ulcer not responding to 2 to 3 day trials with routine measures, including large frequent doses of liquid antacid . The basis for the recommendation for use in nocturnal pain is mainly physiological. Patients with duodenal ulcer have night pain which is associated with raised acid secretion. 44 Anticholinergics may safely be given at bedtime in doses large enough to suppress acid secretion without concern for side effects in the sleeping patient. Objectively, however, no controlled studies appear to have been done to show that anticholinergics are of benefit in this situation. A recent double blind study did show a significantly (by sequential analysis) reduced incidence of night pain using atropine, 0.25 mg three times a day , after meals in patients with duodenal ulcer sy mptoms and functional dyspepsia. 89 2. Patients whose ulcer is failing to show definite signs of healing under routine management after several weeks, provided underlying causes have been excluded; and patients with recurrent ulcer interfering with their life on account of symptoms or complications. For gastric ulcer in ambula-
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CLINICAL TRENDS AND TOPICS
tory outpatients , carbenoxolone sodium is probably91 94 still the drug of first choice where the ulcer is failing to heal,90 although the concomitant use of anticholinergics with this drug is contraindicated by the manufacturers of carbenoxolone. To be effective, these drugs must be used in maximally tolerated doses so that the patient has , at least, occasional but bearable side effects. 55 Many patients will be unable to tolerate such high doses of these drugs for prolonged periods. Finally, the ability of frequent (1-hr) antacids to increase significantly, the healing rate of peptic ulcer (especially gastric) may be seriously underestimated. 95 0
Summary 1. Physiological Studies on Gastric Acid Secretion after Oral Administration. In only a dozen or so reasonably controlled studies have oral anticholinergics been shown to have a significant effect on gastric acid secretion. Of these, an effect could be shown on basal acid output in maximal doses recommended by the manufacturer to well above the maximal recommended dose (e.g., 10 times the recommended dose). Even at these doses, in only about six studies could an effect be shown on augmented histamine secretion . 2. Salivary secretion. At doses having an effect on gastric acid secretion salivary secretion was also reduced. There is no evidence for any drug of a selective effect on the stomach. 3. Controlled clinical trials. Only a small number of studies have been done. Of these slightly fewer show a beneficial effect (six for) compared to no significant effect (nine against), as regards increased healing rate, decreased symptoms, recurrence, or complication rate. The possible beneficial effects .of these drugs do not appear to be sufficiently clear cut in the majority of patients to warrant the side effects from the drugs. 4. Dosage. Anticholinergics must be given in optimal effective doses. 55The dose needed is usually at least that maximally recommended by the manufacturer at 6-hr intervals, even for so-called long-acting
drugs. At these doses, the incidence of side effects may be such that many patients will not tolerate these drugs for prolonged periods. In other cases safety factors may be a deterrent. 5. Drug type. For physicochemical reasons, tertiary ammonium compounds are better absorbed across the gastrointestinal tract of man than the synthetic quaternary ammonium compounds. The use of tertiary compounds (besides being much cheaper for the naturally occurring fompounds) is therefore to be generally recommended . Absence of side effects with quaternary ammonium drugs may be due to decreased gastrointestinal absorption. 6. Recommendations. If used at all in peptic ulcer disease, anticholinergics should be reserved for: (1) persistent pain, especially nocturnal pain not responding to routine measure; (2) patients whose ulcer is failing to heal after an adequate trial of routine measures, or (3) patients with a high ulcer recurrence rate interfering with their livelihood on account of symptoms or complications. REFERENCES 1. Prescription medicine industry in Australia. In
Fact Book, vol 2. Edited by W Gibbs. Health Economics Service, 1973, p 48 2. New Drug Analysis USA, vol VIII, Sect 1. Edited by Paul de Haen. New York, Paul de Haen Inc, 1967-1971, p 5 3. Lennard-Jones JE: Experimental and clinical observations on Poldine in treatment of duodenal ulcer. Br Med J 2:1071-1076, 1961 4. Melrose AG, Pinkerton IW: Clinical evaluation of Poldine methosulphate. Br Med J 2:1076-1078, 1961 5. Rand MJ, Raper C, McCulloch MW: An Introduction to the Physiology and Pharmacology of the Autonomic Nervous System. Melbourne, Australian Pharmaceutical Publishing Co, Ltd, 1971 6. Beerman B, Hellstrom K , Rosen A: Gastrointestinal absorption of certain,mticholinergic drugs. Eur J Clin Pharmacol 5:87-92, 1972 6b . Kaiser SC: The fate of atropine in man . Ann NY Acad Sci 179:667-683, 1971 7. Fordtran JS, Morawski SG, Richardson CT: In vivo and in vitro evaluation of liquid antacids. N Engl J Med 288:923-928, 1973 8. Ivey KJ: The gastric mucosal barrier. Gastroenterology 61 :247-257 , 1971
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CLINICAL TRENDS AND TOPICS
9. Overholt BF, Pollard HM: Acid diffusion into the human gastric mucosa. Gastroenterology 54:182-189, 1968 10. Chapman MA, Werther JL, Janowitz HD: Response of the normal and pathological human gastric mucosa to an instilled acid load. Gastroenterology 55:344-353, 1968 11. Woodward E, Schapiro S: Relationship of ulcer pain to pH and motility of stomach and duodenum. Proc Soc Exp Bioi Med 86:504-506, 1956 12. Ivey KJ: Pathogenesis of peptic ulcer. Aust NZ J Med 4:71-74, 1974 13. Calcium carbonate or cosmo-alko? Editorial. N Engl J Med 2'4:969-970, 1966 14. Ivey KJ, Clifton JA: Ionic movement across the gastric mucosa of man: reproducibility and effect of intravenous atropine. J Lab Clin Med 78:753-764, 1971 15. Ivey KJ: Gastric mucosal barrier. Recent advances. Acta Hepato-Gastroenterologica 20:524-534, 1973 16. Overholt BF, Brodie DA, Chase BJ: Effect of the vagus nerve and salicylate administration on the permeability characteristics of the rat gastric mucosal barrier. Gastroenterology 56:651-658, 1969 17. Safaie-Shirazi S, DenBesten L, Brubacher M: Effect of atropine and vagotomy on permeability of gastric mucosa to H+. Clin Res 21:522, 1973 18. Bank S, Marks IN, Louw JH: Histamine- and insulin-stimulated gastric acid secretion after selective and truncal vagotomy. Gut 8:36-41, 1967 19. Gillespie IE, Clark DH, Kay AW, et al: Effect of antrectomy, vagotomy with gastrojejunostomy, and antrectomy with vagotomy on the spontaneous and maximal gastric acid output in man. Gastroenterology 38:361-367, 1960 20. Berstad A, Myren J: The effect of oxyphencyclimine hydrochloride on the histamine and pentapeptide stimulated gastric secretion in man. Scand J Gastroenterol 4:305-309, 1969 21. Grossman MI: Inhibition of gastric and salivary secretion by Darbid. Gastroenterology 35:312315, 1958 22. Mullie A: The inhibition of basal gastric secretion and of the gastric secretory response to histamine by 2,2 - diphenyl- 4- diisopropylaminobutyramide methyliodide in man. Arch Intern Pharmacodyn Ther 106:447-456, 1956 23. Tasman-Jones C, Troughton WD: Inhibition of the maximum acid output of the stomach by Isopropamide iodide (Tyrimide). New Zeal J Med 65:758-760, 1966 24. Alp MH, Kerr Grant A: The effect of sustained release Hexocyclium tablets on gastric acid secretion. Med J Aust 1:447-449, 1969 25. Mitchell RD, Hunt IN, Grossman MI: Inhibition
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of basal and post-prandial gastric secretion by Poldine and Atropine in patients with peptic ulcer. Gastroenterology 43:400-406, 1962 26. Seidel in R: Effect of Poldine methosulphate on gastric secretion of acid. Br Med J 1:1079-1080, 1961 27. Dotevall G, Schroder G, Walan A: The effect of Poldine, Glycopyrrolate and L-Hyoscyamine on gastric acid secretion in man. Acta Med Scand 177: 169-184, 1965 28. Kaye M, Rhodes J, Sweetnam P: Clinical evaluation of three long acting anticholinergic drugs. Gut 9:590-596, 1968 29. Texter EC Jr, Smith HW, Barborka CJ: Evaluation of newer anticholinergic agents. Gastroenterology 30:772-778, 1956 30. Klotz AP: Depression of gastric secretion by a new anticholinergic agent. Am J Dig Dis 1:108-115, 1956 31. Tripathy BB: Effect of oxyphenonium bromide (Antrenyl) on gastric secretion. Indian Practitioner 10: 1059-1068, 1957 32. Mattman PE, Strutner L: Preliminary evaluation of a new drug, Antrenyl. Effect on gastric secretion, motility and results in the symptomatic care of peptic ulcer. Am J Dig Dis 20:126-130, 1953 33. Posey EL Jr: Management of peptic ulcer with glycopyrrolate. Am J Dig Dis 7:863-872, 1962 34. Ingegno AP, Kertzner L: Effects on gastric secretion of WIN -4369 (Monodral) a synthetic anticholinergic. NY State J Med 54:1185-1187, 1954 35. Kirsner JB, Levin E, Palmer WL: Pamine bromide: gastric antisecretory effects and therapeutic usefulness in peptic ulcer and other gastrointestinal disorders. Gastroenterology 26:852-867, 1956 36. Walan A: Studies on peptic ulcer disease with special reference to the effect of L-hyoscyamine. Acta Med Scand 516 (suppl):1-57, 1970 37. Dotevall G, Walan A: The effect of I-hyoscyamine in tablets with sustained release on gastric secretion of acid in man. Acta Med Scand 178:759-764, 1965 38. Steigmann L, Kaminski L: Belladonna alkaloid sedative mixture. Effects on gastric acidity and motility. Am J Dig Dis 1:174-190, 1956 39. Asher LM: The choice of anticholinergic drugs in the treatment of functional digestive disease. Am J Dig Dis 4:260-275, 1959 40. Piper DW, Stiel MC: A comparison of a series of newer anticholinergic agents with atropine as regards their effects on saliva flow and gastric secretion in man. Gut 3:65-69, 1962 41. Piper DW, Elliot FM: The effect of a new anticholinergic agent oxyphencyclimine hydrochloride on gastric secretion. Med J Aust 1:236-240, 1960 42. Hunt IN, Wales RC: Progress in patients with peptic ulceration treated for more than five years
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CLINICAL TRENDS AND TOPICS
with poldine including a double blind trial. Br Med J 3:13- 16, 1966 43. Vincent PC, Fenton BH, Beeston D: The effect of pipenzolate on gastric secretion in man . Med J Aust 1:546- 548, 1967 44 . Bachrach WH, Rowen BR, Halsted JA, et al: A critical analysis of the criteria for the clinical evaluation of anticholinergic and spasmolytic drug in gastroenterology. Acta Med Scand 148 (suppl 288):1- 78, 1954 45. McGowan JA Jr, Stanley M: Comparative effects of newer anticholinergic agents on human gastric secret ion . J Lab Clin Med 43 :359- 366, 1954 46. Weisiger BB, Burke JO , Plummer K: Experimental effect of two recent anticholinergic drugs on insulin induced gastric secretion in duodenal ulcer. Gastroenterology 27:469-473, 1954 47. Collyns AH, Fordtran JS: Controlled analysis of antacids and anticholinergics in modifying gastric acidity and peptic activity after steak in patients with duodenal ulcer (abstr). Gastroenterology 48:812, 1965 48 . Bromster D, Carlberger G, Lundh G, et al : The effect of some oral anticholinergics on gastric emptying, pH and osmolality in man . Scand J Gastroenterol 4:185-192,1969 49 . Caroli J : Intragastric radio-probe evaluation of the efficacy and duration of action of various buffer substances and anticholinergic drugs administered by mouth. Rev Mal Foie, no. 4, 1971 50. Fordtran JS, Collyns JAH: Antacid pharmacology in duodenal ulcer. Effect of antacids on post-cibal gastric acidity and peptic activity. N Engl J Med 274:921-927,1966 51. Douthwaite A, Hunt J : Effect of "Nacton" In patients with duodenal ulcer. Br Med J 1:1030-1034, 1958 52. Douthwaite AH, Hills TH, Hunt IN: Long continued inhibition of gastric secretion by Poldine methosulphate in patients with peptic ulcer. Br Med J 3:1575- 1579, 1961 53. Hollander F: Gastric secretion of electrolytes. Fed Proc 11:706- 714, 1952 54. Fisher RB, Hunt IN: The inorganic components of gastric secretion. J Physiol (Lond) 3: 138-149, 1950 55. Sun DCH, Shay H: Optimal effective dose of an ticholinergic drug in peptic ulcer therapy . Arch Intern Med 97:442-452, 1956 56. Hunt IN: The secretory pattern of the stomach of man . J Physiol (Lond) 113:169-184, 1951 57. Janowitz HD, Hollander F: Effect of atropine on histamine-stimulated gastric secretion in the dog. Am J Physiol 186:373-376, 1956 58. Bramwell Cook H, Lennard-Jones JE: Effect of antisecretory drugs on gastric hypersecretion in endocrine-adenoma syndrome. Lancet 2:247-250, 1966
165
59. Oberhelman HA Jr, Nelson TS: Surgical consideration in the management of ulcerogenic tumours of the pancreas and duodenum. Am J Surg 180:132-141, 1964 60. Clarke AM , Glen AI, Illingworth C: ZollingerEllison syndrome without gastric surgery. Lancet 1:1360-1363, 1964 61. Herxheimer A, Haefeli L: Human pharmacology of hyoscine butyl bromide, Lancet 2:418-421, 1966 62. Pennefather IN, McCullogh MW, Rand MJ : Observations on the efficacy of oral hyoscine-nbutylbromide . J Ph arm Pharmacol 20:867-872, 1968 63. Kaye MD, Beck P, Rhodes J, et al: Gastric acid secretion in patients with duodenal ulcer treated for 1 year with anticholinergic drugs. Gut 10:774- 778, 1969 64. Lawrie RS, Williamson AW, Hunt IN: ZollingerEllison syndrome treated with poldine methyl methosulphate . Lancet 1:1002-1005, 1962 65. Lawrie R, Hunt IN, Williamson AWR: Treatment of Zollinger-Ellison syndrome. Lancet 1:203, 1966 66. Melnyk CS , Krippaehne WW, Benson JA Jr, et al: Spontaneous remission of Zollinger-Ellison syndrome . Arch Intern Med 115:42-47, 1965 67. Winship DH, Ellison EH: Variability of gastric secretion in patients with and without the Zollinger-Ellison syndrome. Lancet 1:1128-1130, 1967 68. Thompson JC, Reeder DD, Bunchman HH: Clinical role of serum gastrin measurements in the Zollinger-Ellison syndrome. Am J Surg 124:250-261 , 1972 69. Hansky J, Soveny C, Korman MG: Value of serum gastrin in the diagnosis of the ZollingerEllison syndrome. Aust NZ J Med 3:349-354, 1973 70. Ivey KJ : Problems in diagnosis and management of Zollinger-Ellison syndrome. Aust NZ J Med 4: 108-109, 1974 71. Piper DW, Heap TR: Medical management of Peptic Ulcer II. New Ethicals (April) 13:95-100, 1972 72. Steigmann F, Pamukcu F, Chung KS: Studies on a new anticholinergic substance with marked antisecretory effect (abstr) . Am J Gastroenterol 33:1-3, 1960 73. Penny JL, Bonanno C, Grace WJ: Clinical studies on anticholinergic drugs using intra gastric pH meter. Curr Ther Res 4:258-262, 1962 74. Marcussen JM, Vilsik JS: The effect of combined antacid-anticholinergic treatment on the intragastric pH in peptic ulcer disease. Scand J GastroenteroI 3: 170-176,1968 75. Goyal RK, Bhardwaj OP, Chuttani HK: Parasympatholytic agents in duodenal ulcer. Double blind controlled trial with oxyphencyclimine hy-
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CLINICAL TRENDS AND TOPICS
drochloride . Indian Med Assoc J 50:365~367, 1968 76. Sun DC: Longterm anticholinergic therapy for prevention of recurrences in duodenal ulcer. Am J Dig Dis 9 : 706~716, 1964 77. Baume PE, Hunt JH, Piper DW: Glycopyrronium bromide·in the treatment of chronic gastric ulcer. Gastroenterology 63:399~406 , 1972 78. Amure 0 : Anticholinergic drugs in the management of duodenal tilcer. Practitioner 195:335~339, 1965 79. Trevino H, Anderson J, Davey PG et al: Effect of glycopyrrolate on the course of symptomatic duodenal ulcer. Am J Dig Dis 12:983~987, 1967 80. Kaye MD, Rhodes J, Beck P, et al: A controlled trial of glycopyrronium and I-hyoscyamine in the long term treatment of duodenal ulcer. Gut 11:559~566, 1970 81. Sun DC, Ryan ML: A controlled study on the use of propantheline and amylopectin sulphate (SN-263) for recurrences in duodenal ulcer. Gastroenterology 58:756~761, 1970 82. Cocking JB: A trial of amylopectin sulphate (SN-263) and propantheline bromide in the long term treat ment of chronic duodenal ulcer. Gastroenterology 62:6~ 1O, 1972 83. Doll R: Medical treatment of gastric ulcer. Scott Med J 9 : 183~196, 1964 84. Banks S , Mark IW: Maintainance carbenoxolone sodium in the prevention of gastric ulcer recurrence. Carbenoxolone Sodium Symposium at the Fourth World Congress of Gastroenterology. Edited by JH Baron, FM Sullivan. London, Butterworths, 1970, p 103~106 85. Karim SM, Carter DC , Bhana D, et al: Effect of orally administered prostaglandin E, and its 15-methyl analogues on gastric secretion. Br Med J 1:143 ~ 146. 1973
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86. Robert A, Magerlein BJ: 15-methyl PGE, and 16,16-dimethyl PGE, : potent inhibitors of gastric secretion . In International Symposium of Prostaglandins, Advances in Biosciences , Elmsford, NY, Pergamon Press Inc, 1973 87. Black JW, Duncan WA, Durant CJ, et al: Definition and antagonism of histamine H2-receptors. Nature 236:385~390, 1972 88. Wyllie JH, Hesselbo T , Black JW: Effects in man of histamine H2-receptor blockade by Burimamide. Lancet 2:1117~1120, 1972 89. Gutz H-J, Berndt H: Outpatient treatment of duodenal ulcer by pentamethyl-tetra-hydro-pyridine-HCI (PTH) . Acta Hepato-Gastroenterol 20:242~247 , 1973 90. Doll R, Hill !D, Hutton C, et al: Clinical trial of a triterpenoid liquorice compound in gastric and duodenal ulcer. Lancet 2:793~796, 1962 91. Middleton WR, Cooke AR, Stephen D, et al: Biogastrone in inpatient treatment of gastric ulcer. Lancet 1:1030~ 1033, 1965 92. Geismar P , Mosbech J , Myren J: A double blind study of the effect of carbenoxolone in the treatment of gastric ulcer. Scand J Gastroenterol 8:251~256, 1973 93. Ivey KJ, Gray C: Effect of carbenoxolone on the gastric mucosal barrier in man after administration of taurocholic acid . Gastroenterology 64: 1l01~ 1105, 1973 94. Ivey KJ, Gray C: Effect of carbenoxolone on ionic fluxes across normal gastric mucosa and that associated with gastric ulcer. Aust NZ J Med 3:451 ~ 456 , 1973 95. Hollander D, Harlan J : Antacids vs placebos in peptic ulcer therapy. A controlled double blind investigation. JAMA 226:1181~1185, 1973
Vol. 68, :"10. 1 Printed in U.S.A.
Copyright © 1975 by The Williams & Wilkins Co.
CLINICAL TRENDS AND TOPICS ANTICHOLINERGICS: DO THEY WORK IN PEPTIC ULCER? KEVIN J. IVEY, M.D. (Q'ld), M.R.C.P. (LONDON)
A. W. Morrow Department of Gastroenterology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
The cost of anticholinergic drugs for gastrointestinal disorders is very high. In 1972, it was 9.4 out of a total drug bill of $177 million in Australia 1 and in 1970 amounted to $62.5 million in the United States. 2 Because of doubt about their efficacy an evaluation of anticholinergic drugs in the treatment of gastrointestinal disorders was carried out at the request of the Australian Drug Evaluation Committee. Manufacturers were requested to supply all literature supporting the use of their drugs in gastrointestinal disease. Review of the 300 papers in table 1, of other drugs not listed on the Australian Pharmaceutical Benefits Scheme (e.g., l-hyoscamine sulfate long acting) plus papers not supplied by the manufacturers related to drugs in table 1 (e.g., poldine 3 ,4) brought the total reviewed to approximately 400 papers. As manufacturers were asked only to supply studies supporting the effectiveness of their drug, not those failing to do SO,34 the studies evaluated could be biased towards the anticholinergic drug. Each paper submitted has been reviewed in detail elsewhere (Report to the Australian Drug Evaluation Committee on the effect of anticholinergic drugs on the gastrointestinal tract of man, 1973). This review summarizes the Received November 29, 1973. Accepted May 31, 1974. Address requests for reprints to: Dr. Kevin J. Ivey, Division of Gastroenterology, Department of Medi· cine, School of Medicine, University of Missouri, Columbia, Missouri 65201. This work was supported in part by the National Health and Medical Research Council and the Australian Tobacco Research Foundation. Based on a review for the Australian Drug Evaluation Committee.
findings with regard to peptic ulcer disease, particularly in regard to the following questions: (1) Do these drugs given orally have any physiological effect on the stomach, especially on gastric acid secretion? (2) Have they been shown by controlled clinical trials to be of value in the management of peptic ulcer? (3) Are they being administered in optimal doses and do thes'e correspond to manufacturer's recommendations? (4) What recommendations can be made regarding use of these drugs?
Pharmacology and Gastrointestinal Absorption of Anticholinergics Anticholinergics are competitive antagonists of acetylcholine released at the terminal ending of the parasympathetic nerve supply to the gastrointestinal tract (muscarinic activity). Cholinergic receptor antagonists are of two types: (1) Tertiary ammonium compounds with three bonds attached to the nitrogen atom. These antagonize muscarinic activity. They include naturally occurring anticholinergics, atropine, belladonna, I-hyoscyamine, and the synthetic drug, oxyphencyclimine (Daricon); (2) Quaternary ammonium compounds (these make up the majority of the synthetic anticholinergics) with four bonds attached to the nitrogen atom. This has two effects: (1) the molecule has some ganglion-blocking (nicotinic) activity, and (2) is less lipid-soluble and so less well absorbed from the gastrointestinal tract. Given parenterally, these agents may have greater anti parasympathetic activity than the tertiary ammonium compounds because of the former property; given orally they are poorly absorbed and, unless given
154
January 1975
155
CLINICAL TRENDS AND TOPICS TABLE
Approved name
1. Anticholinergic drugs reviewed
Trade name
Manufacturing company
No. of papers
reviewedO
Glycopyrrolate Oxyphenonium bromide
Robinul (Q)' Antrenyl (Q)
A. H. Robins Ciba
12 53
Isopropamide iodide
Smith Kline & French McNeil Searle
16
Hyoscine-n-butyl bromide
Tryrimide (Q) Darbid Nacton (Q) Pro-Ban thine (Q) Buscopan (Q)
11
Oxyphenycyclimine Hexocyclium methylsulfate Pipenzolate bromide
Daricon (T) Tral(Q) Piptal (Q)
Boehringer Ingelheim Beecham Abbott Lakeside
22 10 26
Mepenzolate bromide Methscopolamine bromide
Cantil (Q) Pamine (Q)
Lakeside Upjohn
15 15
Mebeverined
Duspatal d Colofac Merbentyl (T) Monodral (Q) Donnatal (T)
Philips Duphar
Pol dine methymethosulfate Propantheline bromide
Dicyclomine hydrochloride Penthienate bromide Belladona and phenobarbital Tiemonium iodide Atropine methylnitrate Tridihexethyl chloride Atropine sulfate
Merrell Winthrop A. H . Robins
Visceralgin (Q) Fawns and McAlian Eumydrin (Q) Winthrop Pathilon (Q) Lederle (T)
15 17
9 31 11 7 20 10 0 0
---
Manufacturer's recom· mended dose'
Maximum single reCOffi-
mended dose'
1 mg 3 times daily 5-10 mg several times daily 5 mg twice daily
2mg 10mg
4 mg every 6 hr 15 mg 3 times daily, 2 at night 20 mg 4 times daily
6mg 30 mg
5-10 mg twice daily 50-75 mg twice daily 5-10 mg 3 times daily and at night 25-50 mg every 6 hr 2.5 mg 3 times daily and at night 100 mg 3-4 times daily
10mg
5 mgat night
10-20 mg 3-4 times daily 5 mg 3-4 times daily 10mg 1-2 tablets 3-4 times daily 50 mg 3 times daily and at night 1 mg 25-50 mg 3-4 times daily 0.6 mg
300' Other drugs I-Hyoscyamine sulfate"
I
Egazil (T) Egacen
HassleAB Astra, Sweden
Relevant papers of studies on gastrointestinal tract in man supplied by manufacturer, "1973 Physician's Handbook of Drugs, New Ethicals Pty ., Ltd., Balgowlah, New South Wales. 'T or Q refer to tertiary or quaternary ammonium compound . d Not strictly an anticholinergic drug. 'Review of relevant papers not supplied by manufacturers brought total reviewed close to 400. I Not on Australian Pharmaceutical Benefits scheme .
o
in large doses, have less effect. 5 Beerman et al. 6 found almost 100% absorption of orally administered radioactive-labeled tertiary atropine, but only 15 to 25% absorption of quaternary ammonium methylatropine , propantheline, and methylscopolamine, and less than 5% absorption of hyoscine butyl bromide. 6 Fewer side effects after oral administration of quaternary ammonium drugs may be due to reduced gastrointestinal absorption . 5 Little is known
about the metabolism of anticholinergic agents in man apart from atropine, 50% of which appears in the urine 4 hr after an intramuscular injection. 6 The longer action of certain synthetic anticholinergics is attributed to delay in gastrointestinal absorption. 37
Physiological Basis of Use Use of anticholinergics in peptic ulcer disease is based largely on the role of the
156
CLINICAL TRENDS AND TOPICS
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In the majority of these studies the mean reduction in basal acid output was about 50%. As most subjects studied were hypersecretors with duodenal ulcer, this degree of reduction in acid output resulted in an output in the normal range. Table 2 shows clearly that in the great majority of studies , for drugs to have an effect even on basal acid output, they must be given at least in the maximal dose recommended by the manufacturer, or in doses up to 10 times 21 , 22 the recommended dose. Of the apparent exceptions, hexocyclium (Tral) is a "long-acting" drug which has a recommended dose (50 mg or 75 mg) 2 or 3 times that of the short-acting drug (25 mg). The gastric secretory studies were carried out shortly after administration, which is really equivalent to using the maximum recommended dose of the short-acting drug. The oxyphenonium I'tudy was carried out in Indian patients 31 ; 5 times the recom mended dose was needed to have a similar effect on American subjects.32 The final exception was a study on both pipenzolate and propantheline,29 which measured only "free acidity" by titrating with Topfer's reagent. A second controlled study, using the same dose of pipenzolate, found no significant reduction of basal or histaminestimulated acid secretion during prolonged administration of this drug. 30 Many of the studies listed in table 2 were not strictly controlled, and their design would not be acceptable to publishers of similar studies of acid secretion in animals. In many studies,20, 23-33, 35 basal (and/or Clinical Studies Showing Reduced Gasstimulated) acid secretion was measured tric Acid Secretion initially shortly after admission to hospiBecause of the variable absorption of tal. The ulcer patient was then treated for anticholinergic drugs, particularly the syn- several weeks with bed rest, cessation of thetic quaternary ammonium agents, stud- smoking, antacids , and anticholinergics, ies of acid secretion after oral administra- and the acid measurements repeated and tion are essential. Of the 400 papers re- compared with the initial pretreatment viewed on anticholinergic drugs , only a studies. 20, 23-33. 35Only a few workers made dozen or so reasonably well controlled any attempt to assess reproducibility of studies could be found to show any reduc- acid measurements under the conditions of tion of basal or histamine-stimulated acid their trial. 23, 28. 36 The sole well designed secretion in man by an anticholinergic drug study of acid secretion during prolonged given orally. These studies are listed in anticholinergic therapy was that of Watable 2,20-37 and manufacturers' recom- lan,36 who also determined reproducibility mended doses in table 1. of acid output during placebo therapy.
vagus nerve in the control of gastric acid secretion. The aim of therapy is to reduce acid secretion. The role of acid in the causation of pain of peptic ulcer is not as clear cut as might first appear. Antacids frequently relieve ulcer pain, but in a dose usually insufficient to neutralize intragastric contents. 7 Neither can pain in peptic ulcer always be attributed to acid alone . In studies of the gastric mucosal barrier in gastric ulcer patients large amounts of acid (32 mEq per 15 min) may be instilled consecutively without pain developing. 8-1o Although it is known that acid plays a major role in the pathogenesis of peptic ulcer12 there is no objective evidence as yet that "less acid will form less ulcer," 13 although this is possible. Neither medical vagotomy with atropine (man},14. 15 nor surgical vagotomy (animals)16. 17 has a protective effect on the gastric mucosal barrier. Surgical vagotomy (truncal or selective) does reduce acid output. In two separate series, basal acid output was reduced by a mean of approximately 65% and histamine-stimulated acid output by 70%.18, 19 In spite of incomplete inhibition of acid secretions, surgical vagotomy does reduce peptic ulcer recurrence. The rationale, therefore, of anticholinergic therapy in peptic ulcer may be reasonable if it can be supported by (1) evidence of acid reduction; (2) improvement in ulcer symptoms; or (3) increased healing and/or decreased recurrence rate.
TABLE
157
CLINICAL TRENDS AND TOPICS
January 1975
2. Controlled studies showing reduced human gastric acid secretion and drug dose a Drug
Oxyphencyclimine Isopropamide Hexocyclium b Poldine Pipenzolate Oxyphenonium Glycopyrrolate Penthienate Hyoscine methobromide 1-Hyoscyamine b Atropine sulfate Propantheline
Basal acid output
Maximum'· Maximum 2l and above 2l· 22 Recommended" C Above maximum"-" Recommended" No effect recommended'· Recommended" c. e Above maximum" Above maximum'" 33 Above maximum" Above maximum 35 Above maximum'" ' •. 37 Above maximum" Recommended29
Histamine-stimulated acid output
Maximum'· Recommended" Maximum" Above'.-28 d
C
C
Above maximum"
Above maximum'" ' •.
37
C
a Studies in which doses are listed as "above maximum" used side effects to determine dose." Dose "recommended" by manufacturer for maintenance therapy; "maximum" dose recommended: "above maximum" dose recommended by manufacturer. b "Long-acting" formulation. c See text. d Sub maximal histamine stimulation. 28 e Indian subjects.
This study showed enormous variations in basal acid output in subjects treated with placebo studied over periods of up to 2 years, the mean coefficient of variation in basal acid output between initial and final studies being 47%. Walan 36 concluded that basal acid output was so variable it should not be used alone as a measure of a drug effect. The remaining studies, in Table 2,21,22,34 were all short term; i.e., acid secretion was measured shortly after administration of single doses of the anticholinergic. In these studies, either no placebo was given,21 or it was always given in the first study 34 or while a placebo was given the dose of anticholinergic was such (6 times the recommended dose 22 ) that the patient could have had little trouble distinguishing drug and placebo by side effects. Studies showing negative results were not included in table 2, apart from one study with pipenzolate. 30 In addition, results of studies in which the 1st hr was taken as the basal, then the drug given, and the 3rd or 4th hr compared with the 1st hr, were excluded. 30- 3 4 Doses required to reduce histaminestimulated acid secretion were those maxi-
mally recommended by manufacturers or above (table 2). Mean percentage reduction of acid secretion ranged from 15 to 50%_ 20,23 Isopropamide was reported to produce a mean reduction of 50% of total acid output in subjects taking the recommended dose (5 mg twice daily) for 1 to 10 weeks. This reduction resulted in acid outputs in the normal range (10 to 20 mEq per hr).23 In this study, reproducibility was tested in 5 patients by repeating the study before the subject was started on anticholinergics. In 4 of the 5 subjects, basal and stimulated acid secretion were reduced in the second test. Of the six drugs shown in table 2 to reduce histamine-stimulated acid secretion, five are advertised as longacting and are recommended to be given twice daily, but acid studies were carried out mostly within 2 hr of administration. 20, 24, 26-28, 36
Effect on Non-Histamine-Stimulated Gastric Acid Secretion Several drugs were studied by means of stimulation other than histamine or pentagastrin (table 3). These include liquid test meals,40-43 food,3, 25, 34, 44, 45, 47, 50
158
CLINICAL TRENDS AND TOPICS TABLE
Drug Oxyphencyclimine
Vol. 68, No.1
3. Controlled studies on nonhistamine-stimulated acid secretion a Dose'
Stimulus
Effect on secretion'
Above maximum Maximum-above maximum
Liquid meal'· Insulin coma ' •.
Pol dine
Maximum-above maximum Maximum-above maximum Maximum-above maximum
Food, 25 milk meal' Food' Liquid meal"
Reduction (pH) No effect (pH) No effect"
Pipenzolate
Above maximum (2 subjects)
Insulin coma"
No effect
Oxyphenonium
Above maximum Maximum and above maximum Above maximum Recommended
Food" Food" Insulin (Hollander)'· Alcohol'l
No effect (pH) Reduction in 50% (pH) No effect Reduction"' e
Glycopyrrolate
Above maximum Maximum Maximum-above maximum
Food" Food" Food + CaCO,'·
Reduction (pH) No effect (pH) No effect (pH)
Penthienate
Recommended-above maximum (3 subjects) Recommended-above maximum (3 subjects) Above maximum Maximum-above maximum
Food"
No effect
Insulin (Hollander)"
Reduction
Food,25 milk meal'· Insulin coma '., 41
Reduction (pH) Reduction
Atropine sulfate
41
No effect" Reduction
c
Piopantheline
Above maximum Above maximum
Insulin coma'., .1 Milk meal'·
Reduction Reduction (pH)
Hyoscine-N-butylbromide
Above maximum Above maximum (3 subjects)
Milk meal'· Milk meal"
No effect (pH) Reduction (pH)
a Studies in which doses are listed as "maximum" or "maximum-above maximum" used side effects to determine dose. • Dose "recommended" by manufacturer for maintenance therapy; "maximum" dose recommended; "above maximum" dose recommended. C In most food-stimulated studies, pH only was measured. Acid secretion during insulin coma studies was measured by liquid meal technique.'· No effect ~ no significant effect. "See text. e Indian subjects.
alcohol,31 insulin (Hollander test), 34, 46 and insulin coma. 40 , 41, 43 The results of these tests were more variable and more difficult to interpret, For example, the majority of studies of food-stimulated acid secretion measured only pH in timed samples from the stomach, It is possible that studies which measure only pH may miss an effect of the drug on volume, and therefore on total gastric acid output. 57, 60 In general, as for basal and histamine-stimulated acid output, reduction in acid output occurred with doses of anticholinergics above those maximally recommended, but not with
routine recommended doses. Some of the inherent difficulties and the need for adequate controls are exemplified by the studies of Hunt and Wales,.2 Douthwaite and Hunt,51 and Douthwaite et al. 52 with poldine. Liquid test meals of 750-ml volume containing 50 g per liter of glucose and nonabsorbable indicator were used. Acid secretion was calculated on the basis of Hollander's two-component hypothesis. 5 3, 54 The drug was given in "optimal effective dose," 55 i.e., the dose of ~rug was increased until side effects occurred, and then was reduced by one or two tablets
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CLINICAL TRENDS AND TOPICS
per day. Most patients studied had duodenal ulcer and were inpatients initially. A test meal was done on admission and again after placebo every 6 hr for 3 to 4 days. From then on, poldine was given and the patient was studied from time to time. Results of these studies showed a reduction in calculated acid secretion in the majority of patients, compared to the initial study. Studies repeated in the subjects as outpatients showed a similar reduction in acid secretion. In 9 of the 14 patients, gastric secretion of acid after stopping treatment in the hospital was less than in the control studies before treatment. 51 These patients were then followed up as outpatients on poldine for periods of up to 3 years, and acid secretion continued to be "inhibited." 5 2 The problems of interpreting this study are as follows: 1. No control studies were done with placebo given throughout the duration of therapy. Studies were only compared with an initial two studies within the first 3 days of admission. Thus, allowance for the effect of therapy or getting used to the procedure was not made. This is especially relevant since 9 of the 14 subjects showed acid secretion lower than initial "control" studies after cessation of therapy. 2. Measurements of acid secretion based on the Hunt test meal are dependent on the acid concentration of the fluid emptying through the pylorus. Acid concentration is calculated on the assumption that gastric emptying is linear, whereas, in fact, it is exponential. 56 When the volume of fluid leaving the pylorus is small, this may not be so important, but where large volumes of gastric emptying such as 250 to 450 ml are concerned, as in this study, the errors in estimating the H+ ion concentration may be large, giving rise to errors in calculation of H+ ion secretion. 3. H + ion secretion was not directly measured , but was calculated from Hollander's two-component hypothesis. 53. 5. The assumptions inherent in this hypothesis have been discussed elsewhere, 14 but , in particular, no allowance is made for movement of H+ or Na+ ions by diffusion. 8 In support of these objections when these
159
patients were subsequently studied in a double blind manner with poldine, no significant difference in gastric acid secretion between control and drug-treated groups was found. 42 Although the authors suggested that gastric secretion was reduced long term in both groups, compared to initial control studies, the reasons are more likely to be found in the above objections than to any prolonged effect of poldine for over 2 years after stopping the drug.
Long Term Treatment and Gastric Acid Secretion The studies of Hunt and Wales!2 Douthwaite and Hunt,51 and Douthwaite et al. 52 have often been quoted as indicating that long term treatment with anticholinergics will reduce gastric secretion for long periods after cessation of the drug, but the evidence does not support this conclusion. In 1962, Lawrie et aI., 64 using the test meal technique,56 reported reduction in acid secretion in a patient with the ZollingerEllison syndrome which continued for 5 months after the drug was discontinued. These authors subsequently reported 65 that acid secretion began to rise 3 months later, and in the following year the patient was operated on for a complicated duodenal ulcer. Although it is possible that pol dine did in fact reduce acid secretion for a prolonged period in this patient, it is equally possible that this represented a spontaneous temporary remission. 66 -7o Walan 36 found no significant difference between initial values for basal and maximal acid outputs after histamine and values 3 weeks after stopping therapy for 2-year duration with l-hyoscyamine in sustained release tablets. Kaye and associates 63 repeated studies of basal and maximal acid outputs 1 year after treatment with l-hyoscyamine in sustained release tablets, glycopyrrolate, and placebo. No significant changes occurred in maximal acid output, but basal acid output was significantly increased compared to initial values after glycopyrrolate. 63
Prolonged Effect? There were no strictly controlled studies showing prolonged effects on acid secretion
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CLINICAL TRENDS AND TOPICS
by any drug at recommended doses. Most studies using "long-acting" drugs were done only 1 or 2 hr after administration of the drug. 20 , 24, 26, 33, 36 Two drugs, isopropamide 21 and I-hyoscyamine (longacting),27,37 were shown, in doses well above those maximally recommended, to have an effect for more than 9 hr; for these doses, administration three times a day is the minimum required. Even here, the effect on acid secretion was falling off in the latter hours, and a more even effect with reduced side effects would be expected with administration every 6 hr. 71 No drugs at any dose were shown to have an effect for 12 hr, so administration twice a day cannot be justified.
Side Effects: Salivary Secretion All controlled studies in which salivary and gastric acid secretion have been measured concomitantly have shown that reduction of salivary secretion occurs when there is reduction of acid secretion. Grossman 21 found that doses of isopropamide sufficient to reduce salivary secretion (maximally recommended dose and above) also significantly reduced salivary secretion for corresponding periods of time. Kaye et al. 28 found that I-hyoscyamine, glycopyrronium, and poldine, in doses above those maximally recommended, reduced sub maximal histamine-stimulated acid secretion in at least 75% of subjects. At these doses, salivary secretion was also reduced in 100% of subjects, the mean reduction in acid secretion (27%) being identical to that of salivary secretion (27%). In both studies, the percentage of reduction in salivary secretion in the individual subject did not significantly correlate with that of acid secretion. Kaye et a1. 28 also carried out objective measurements on visual accommodation. In half the studies, this was impaired, although drugs varied considerably in this respect. I-hyoscyamine produced impaired accommodation in all subjects.
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results being inconclusive. Above maximum recommended doses of I-hyoscyamine (long-acting) given with antacid suspension caused a rise in intra gastric pH to above 4.5 for a mean of23 min compared to 11/2 min.74 This, however, is far from ideal. Lennard-Jones 3 compared pH of gastric contents throughout the day in 3 subjects given food plus antacid tablets sucked between meals with and without poldine in optimum effective doses. During the day there was a small mean increase in pH on anticholinergic (control mean 2.0, anticholinergic 2.3), but poldine did not prolong the effect of the dose of alkali given at night. Collyns and Fordtran 47 reported in abstract form that a 4-mg dose, but not a 2-mg dose of glycopyrrolate (4 times the recommended dose) significantly reduced gastric acidity after a steak meal, but only at 3 and 4 hr. Subsequently, the authors were unable to show in a controlled study any significant change in gastric pH after a steak meal followed by antacids (4 g of calcium carbonate, 1 hr pc) with or without optimum effective doses of glycopyrrolate administered 1/2 hr before the meal. 50 It should be stressed that all of these studies 3, 47,49,50,72-74 measured only acid concentration and not volume of fluid secreted. Nevertheless, the results have been disappointing.
Combination of Anticholinergic and Sedative on Acid Secretion One proprietary combination of anticholinergic and sedative, belladonna and phenobarbital (Donnatal) was studied in a controlled trial in the maximum recommended dose and failed to show a significant reduction in basal or histaminestimulated acid secretion. 38 This is not surprising when it is recognized that each tablet contains 0.1 mg of the active anticholinergic hyoscyamine sulfate and 16 mg of phenobarbital. To increase the dose of hyoscyamine sulfate to that found to reduce acid secretion by Dotevall et al.,27 Combined Antacid and Anticholinergic Walan,36 and Dotevall and Walan 37 (mean, Only a few, most inadequate,49,72,73 0.58 to 0.8 mg) would require toxic doses of studies have been carried out. the overall sedative. 39
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CLINICAL TRENDS AND TOPICS
Effect of Antispasmodics There were no controlled studies showing a reduction of basal or histaminestimulated acid secretion by any of the drugs listed as "antispasmodics," mebeverine, hyoscine-N-butyl bromide, dicyclomine Hel, atropine methylnitrate and mepenzolate bromide, tiemonium iodide, and tridihexethylchloride. Some workers believe that the pain of peptic ulcer is due to muscle spasm. Evidence for this is not convincing. II The effect of anti cholinergics on gastrointestinal motility will be reviewed fully elsewhere. It is sufficient to say that, just as for gastric acid secretion, effects on gastric and duodenal motility required at least maximally recommended and usually well above maximally recommended doses orally. Controlled Clinical Trials Only 15 studies on the following six drugs have been carried out: oxyphencyclimine, glycopyrrolate, propantheline , poldine, Lhyoscyamine (long-acting) , and belladonna i-hyoscyamine). 3. 4. 36. 75·84 Of these studies, somewhat fewer show a beneficial effect compared to no significant effect, six versus nine, as regards increased healin g, decreased symptoms , recurrence, or complication rate . Of these studies showing significant benefit, two studies, one with glycopyrrolate 78 and one with propantheline,78 were carried out in Nigerian subjects. In this study, placebo had virtually no effect (3 % healing rate), and, as the author himself stated, peptic ulcer in Nigerians may well have different etiologies from those in more technologically and socially advanced countries. Therefore, direct application in these results to such societies . must be guarded . The second study with propantheline was carried out by Sun and Ryan 81 on the effect of the drug in controlling recurrence rates in duodenal ulcer . The difference between drug and placebo was just significant. Sun and Ryan considered that the drug was "at most weakly effective over placebo" in controlling recurrences. The patients in Sun and Ryan 's81 studies with propantheline and Sun's76 studies with glycopyrrolate have
161
been noted for their high incidence of ulcer complications. Other series 79 , 80. 82 with both these drugs have been unable to confirm Sun 's results. Two controlled studies have been carried out on patients with gastric ulcer. The first is the well known study of Do1l83 on inpatients. Using a fixed but relatively large dose of belladonna (equivalent to 0.3 mg three times a day of the active ingredient L-hyoscyamine) he found no therapeutic advantage of the drug over control studies . The second was recently published by Baume et al. 77 using glycopyrrolate in maximum tolerated doses. 55 In contrast to Doll's study, they reported a significantly increased healing rate in inpatients taking anticholinergics: reduction in ulcer profile area by two-thirds in 90% of those taking anticholinergics, compared to 75% in controls. Apart from failure to use endoscopy to confirm reduction in ulcer area or complete ulcer disappearance, the major criticism of this part of the study is the failure to detail the number of aspirin takers in treated and placebo groups. In the second part of the study, they measured the effect of the drug on the rate of gastric ulcer recurrence as outpatients after initial healing had been achieved in the hospital. Results showed a significantly greater recurrence in the placebo group at 6 months (P = 0.02), and 12 months (P = 0.02), but not at 2 years (P = 0.06) . The overall recurrence rate was high in both control and treated groups: 77% placebo versus 50% glycopyrronium group. The study may be criticized for the fact that not all patients were X-rayed routinely, but only for symptoms, and endoscopy was not used at all. As it was not always easy to differentiate a residual scar from a tiny gastric ulcer recurrence, even on contrast radiology of the stomach , the use of upper gastrointestinal endoscopy would seem to have been essential. The question remains as to whether the majority of patients are willing to tolerate side effects from maximum tolerated doses for the reduction in ulcer symptoms. The fact that 30 patients tentatively allotted to the trial on an initial visit failed to return to the clinic suggests that many are not.
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CLINICAL TRENDS AND TOPICS
Dosage of Anticholinergics in Clinical Studies All but one of the investigators showing a significant effect of anticholinergics in clinical studies 36 , 76, 77, 80, 81 recommend maximally tolerated doses. 55 These doses are above those recommended maximally by the manufacturers, An exception was the study on Nigerian subjects 78 where a fixed dose of one tablet three times a day was used; this produced side effects in 60 to 80% of these subjects however. Other studies using optimum effective dosage S5 failed to show an effect. 3, 42, 79, 80 The rationa le for using maximum tolerated doses is based on the need for such large doses to reduce gastric acid secretion. Walan 's36 detailed studies with L-hyoscyamine leave one uncertain as to the importance of reduction of acid secretion. Of his 7 patients who developed recurrences while on the drug, 3 had values for basal and maximum acid outputs above the mean, plus 2 SD values for patients without recurrences during treatment. The other 4 subjects, however, had normal to low acid secretory values. Low acid secretory values on treatment therefore did not guarantee that recurrences could not occur. In the placebo group, recurrences occurred both in patients with high , oridinary, and low secretory values. Patients with complications however tended to have higher secretory values, although of 5 patients on placebo who had gastrointestinal bleeding, none were endoscoped to prove that a bleeding ulcer was the cause. From these results , one could argue that 3 of the patients who developed recurrences while on anticholinergic treatment were inadequately controlled and should have been given even larger doses. Yet this was probably impractical since the mean daily dose of l-hyoscyamine in the patients with recurrences (1.64 mg) was greater than that in those without (1.46 mg). On the other hand, since many of the patients with recurrences had ordinary or low acid values on treatment, one might question if the degree of acid reduction achieved (mean 45% decrease in basal and 30% decrease in histamine-st imulated secretion) by the anticholinergic was of any
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significance. If one concludes from these results that acid reduction (no matter how little) is important in the prevention of ulcer recurrence , then one must use anticholinergics in maximal tolerated doses, if at all.
Recommendation for the Use of Anticholinergics in Peptic Ulcer Disease On the evidence reviewed , anticholinergics have a limited role, if any , in the management of peptic ulcer disease . Any such role that they may have exists only because of the lack of effective medical treatment for peptic ulcer. As the only alternative in many patients with persistent disabling symptoms or complications is surgery, then any group of drugs, such as the anticholinergics , which possibly reduce recurrence or complications, will be used until a better alternative (such as oral prostaglandins 85 . 86 or antihistamines blocking H 2 -receptors) is developed . Anticholinergics may be of value for: 1. Persistent pain, especially nocturnal , in acute peptic ulcer not responding to 2 to 3 day trials with routine measures, including large frequent doses of liquid antacid . The basis for the recommendation for use in nocturnal pain is mainly physiological. Patients with duodenal ulcer have night pain which is associated with raised acid secretion. 44 Anticholinergics may safely be given at bedtime in doses large enough to suppress acid secretion without concern for side effects in the sleeping patient. Objectively, however, no controlled studies appear to have been done to show that anticholinergics are of benefit in this situation. A recent double blind study did show a significantly (by sequential analysis) reduced incidence of night pain using atropine, 0.25 mg three times a day , after meals in patients with duodenal ulcer sy mptoms and functional dyspepsia. 89 2. Patients whose ulcer is failing to show definite signs of healing under routine management after several weeks, provided underlying causes have been excluded; and patients with recurrent ulcer interfering with their life on account of symptoms or complications. For gastric ulcer in ambula-
January 1"975
163
CLINICAL TRENDS AND TOPICS
tory outpatients , carbenoxolone sodium is probably91 94 still the drug of first choice where the ulcer is failing to heal,90 although the concomitant use of anticholinergics with this drug is contraindicated by the manufacturers of carbenoxolone. To be effective, these drugs must be used in maximally tolerated doses so that the patient has , at least, occasional but bearable side effects. 55 Many patients will be unable to tolerate such high doses of these drugs for prolonged periods. Finally, the ability of frequent (1-hr) antacids to increase significantly, the healing rate of peptic ulcer (especially gastric) may be seriously underestimated. 95 0
Summary 1. Physiological Studies on Gastric Acid Secretion after Oral Administration. In only a dozen or so reasonably controlled studies have oral anticholinergics been shown to have a significant effect on gastric acid secretion. Of these, an effect could be shown on basal acid output in maximal doses recommended by the manufacturer to well above the maximal recommended dose (e.g., 10 times the recommended dose). Even at these doses, in only about six studies could an effect be shown on augmented histamine secretion . 2. Salivary secretion. At doses having an effect on gastric acid secretion salivary secretion was also reduced. There is no evidence for any drug of a selective effect on the stomach. 3. Controlled clinical trials. Only a small number of studies have been done. Of these slightly fewer show a beneficial effect (six for) compared to no significant effect (nine against), as regards increased healing rate, decreased symptoms, recurrence, or complication rate. The possible beneficial effects .of these drugs do not appear to be sufficiently clear cut in the majority of patients to warrant the side effects from the drugs. 4. Dosage. Anticholinergics must be given in optimal effective doses. 55The dose needed is usually at least that maximally recommended by the manufacturer at 6-hr intervals, even for so-called long-acting
drugs. At these doses, the incidence of side effects may be such that many patients will not tolerate these drugs for prolonged periods. In other cases safety factors may be a deterrent. 5. Drug type. For physicochemical reasons, tertiary ammonium compounds are better absorbed across the gastrointestinal tract of man than the synthetic quaternary ammonium compounds. The use of tertiary compounds (besides being much cheaper for the naturally occurring fompounds) is therefore to be generally recommended . Absence of side effects with quaternary ammonium drugs may be due to decreased gastrointestinal absorption. 6. Recommendations. If used at all in peptic ulcer disease, anticholinergics should be reserved for: (1) persistent pain, especially nocturnal pain not responding to routine measure; (2) patients whose ulcer is failing to heal after an adequate trial of routine measures, or (3) patients with a high ulcer recurrence rate interfering with their livelihood on account of symptoms or complications. REFERENCES 1. Prescription medicine industry in Australia. In
Fact Book, vol 2. Edited by W Gibbs. Health Economics Service, 1973, p 48 2. New Drug Analysis USA, vol VIII, Sect 1. Edited by Paul de Haen. New York, Paul de Haen Inc, 1967-1971, p 5 3. Lennard-Jones JE: Experimental and clinical observations on Poldine in treatment of duodenal ulcer. Br Med J 2:1071-1076, 1961 4. Melrose AG, Pinkerton IW: Clinical evaluation of Poldine methosulphate. Br Med J 2:1076-1078, 1961 5. Rand MJ, Raper C, McCulloch MW: An Introduction to the Physiology and Pharmacology of the Autonomic Nervous System. Melbourne, Australian Pharmaceutical Publishing Co, Ltd, 1971 6. Beerman B, Hellstrom K , Rosen A: Gastrointestinal absorption of certain,mticholinergic drugs. Eur J Clin Pharmacol 5:87-92, 1972 6b . Kaiser SC: The fate of atropine in man . Ann NY Acad Sci 179:667-683, 1971 7. Fordtran JS, Morawski SG, Richardson CT: In vivo and in vitro evaluation of liquid antacids. N Engl J Med 288:923-928, 1973 8. Ivey KJ: The gastric mucosal barrier. Gastroenterology 61 :247-257 , 1971
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9. Overholt BF, Pollard HM: Acid diffusion into the human gastric mucosa. Gastroenterology 54:182-189, 1968 10. Chapman MA, Werther JL, Janowitz HD: Response of the normal and pathological human gastric mucosa to an instilled acid load. Gastroenterology 55:344-353, 1968 11. Woodward E, Schapiro S: Relationship of ulcer pain to pH and motility of stomach and duodenum. Proc Soc Exp Bioi Med 86:504-506, 1956 12. Ivey KJ: Pathogenesis of peptic ulcer. Aust NZ J Med 4:71-74, 1974 13. Calcium carbonate or cosmo-alko? Editorial. N Engl J Med 2'4:969-970, 1966 14. Ivey KJ, Clifton JA: Ionic movement across the gastric mucosa of man: reproducibility and effect of intravenous atropine. J Lab Clin Med 78:753-764, 1971 15. Ivey KJ: Gastric mucosal barrier. Recent advances. Acta Hepato-Gastroenterologica 20:524-534, 1973 16. Overholt BF, Brodie DA, Chase BJ: Effect of the vagus nerve and salicylate administration on the permeability characteristics of the rat gastric mucosal barrier. Gastroenterology 56:651-658, 1969 17. Safaie-Shirazi S, DenBesten L, Brubacher M: Effect of atropine and vagotomy on permeability of gastric mucosa to H+. Clin Res 21:522, 1973 18. Bank S, Marks IN, Louw JH: Histamine- and insulin-stimulated gastric acid secretion after selective and truncal vagotomy. Gut 8:36-41, 1967 19. Gillespie IE, Clark DH, Kay AW, et al: Effect of antrectomy, vagotomy with gastrojejunostomy, and antrectomy with vagotomy on the spontaneous and maximal gastric acid output in man. Gastroenterology 38:361-367, 1960 20. Berstad A, Myren J: The effect of oxyphencyclimine hydrochloride on the histamine and pentapeptide stimulated gastric secretion in man. Scand J Gastroenterol 4:305-309, 1969 21. Grossman MI: Inhibition of gastric and salivary secretion by Darbid. Gastroenterology 35:312315, 1958 22. Mullie A: The inhibition of basal gastric secretion and of the gastric secretory response to histamine by 2,2 - diphenyl- 4- diisopropylaminobutyramide methyliodide in man. Arch Intern Pharmacodyn Ther 106:447-456, 1956 23. Tasman-Jones C, Troughton WD: Inhibition of the maximum acid output of the stomach by Isopropamide iodide (Tyrimide). New Zeal J Med 65:758-760, 1966 24. Alp MH, Kerr Grant A: The effect of sustained release Hexocyclium tablets on gastric acid secretion. Med J Aust 1:447-449, 1969 25. Mitchell RD, Hunt IN, Grossman MI: Inhibition
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of basal and post-prandial gastric secretion by Poldine and Atropine in patients with peptic ulcer. Gastroenterology 43:400-406, 1962 26. Seidel in R: Effect of Poldine methosulphate on gastric secretion of acid. Br Med J 1:1079-1080, 1961 27. Dotevall G, Schroder G, Walan A: The effect of Poldine, Glycopyrrolate and L-Hyoscyamine on gastric acid secretion in man. Acta Med Scand 177: 169-184, 1965 28. Kaye M, Rhodes J, Sweetnam P: Clinical evaluation of three long acting anticholinergic drugs. Gut 9:590-596, 1968 29. Texter EC Jr, Smith HW, Barborka CJ: Evaluation of newer anticholinergic agents. Gastroenterology 30:772-778, 1956 30. Klotz AP: Depression of gastric secretion by a new anticholinergic agent. Am J Dig Dis 1:108-115, 1956 31. Tripathy BB: Effect of oxyphenonium bromide (Antrenyl) on gastric secretion. Indian Practitioner 10: 1059-1068, 1957 32. Mattman PE, Strutner L: Preliminary evaluation of a new drug, Antrenyl. Effect on gastric secretion, motility and results in the symptomatic care of peptic ulcer. Am J Dig Dis 20:126-130, 1953 33. Posey EL Jr: Management of peptic ulcer with glycopyrrolate. Am J Dig Dis 7:863-872, 1962 34. Ingegno AP, Kertzner L: Effects on gastric secretion of WIN -4369 (Monodral) a synthetic anticholinergic. NY State J Med 54:1185-1187, 1954 35. Kirsner JB, Levin E, Palmer WL: Pamine bromide: gastric antisecretory effects and therapeutic usefulness in peptic ulcer and other gastrointestinal disorders. Gastroenterology 26:852-867, 1956 36. Walan A: Studies on peptic ulcer disease with special reference to the effect of L-hyoscyamine. Acta Med Scand 516 (suppl):1-57, 1970 37. Dotevall G, Walan A: The effect of I-hyoscyamine in tablets with sustained release on gastric secretion of acid in man. Acta Med Scand 178:759-764, 1965 38. Steigmann L, Kaminski L: Belladonna alkaloid sedative mixture. Effects on gastric acidity and motility. Am J Dig Dis 1:174-190, 1956 39. Asher LM: The choice of anticholinergic drugs in the treatment of functional digestive disease. Am J Dig Dis 4:260-275, 1959 40. Piper DW, Stiel MC: A comparison of a series of newer anticholinergic agents with atropine as regards their effects on saliva flow and gastric secretion in man. Gut 3:65-69, 1962 41. Piper DW, Elliot FM: The effect of a new anticholinergic agent oxyphencyclimine hydrochloride on gastric secretion. Med J Aust 1:236-240, 1960 42. Hunt IN, Wales RC: Progress in patients with peptic ulceration treated for more than five years
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with poldine including a double blind trial. Br Med J 3:13- 16, 1966 43. Vincent PC, Fenton BH, Beeston D: The effect of pipenzolate on gastric secretion in man . Med J Aust 1:546- 548, 1967 44 . Bachrach WH, Rowen BR, Halsted JA, et al: A critical analysis of the criteria for the clinical evaluation of anticholinergic and spasmolytic drug in gastroenterology. Acta Med Scand 148 (suppl 288):1- 78, 1954 45. McGowan JA Jr, Stanley M: Comparative effects of newer anticholinergic agents on human gastric secret ion . J Lab Clin Med 43 :359- 366, 1954 46. Weisiger BB, Burke JO , Plummer K: Experimental effect of two recent anticholinergic drugs on insulin induced gastric secretion in duodenal ulcer. Gastroenterology 27:469-473, 1954 47. Collyns AH, Fordtran JS: Controlled analysis of antacids and anticholinergics in modifying gastric acidity and peptic activity after steak in patients with duodenal ulcer (abstr). Gastroenterology 48:812, 1965 48 . Bromster D, Carlberger G, Lundh G, et al : The effect of some oral anticholinergics on gastric emptying, pH and osmolality in man . Scand J Gastroenterol 4:185-192,1969 49 . Caroli J : Intragastric radio-probe evaluation of the efficacy and duration of action of various buffer substances and anticholinergic drugs administered by mouth. Rev Mal Foie, no. 4, 1971 50. Fordtran JS, Collyns JAH: Antacid pharmacology in duodenal ulcer. Effect of antacids on post-cibal gastric acidity and peptic activity. N Engl J Med 274:921-927,1966 51. Douthwaite A, Hunt J : Effect of "Nacton" In patients with duodenal ulcer. Br Med J 1:1030-1034, 1958 52. Douthwaite AH, Hills TH, Hunt IN: Long continued inhibition of gastric secretion by Poldine methosulphate in patients with peptic ulcer. Br Med J 3:1575- 1579, 1961 53. Hollander F: Gastric secretion of electrolytes. Fed Proc 11:706- 714, 1952 54. Fisher RB, Hunt IN: The inorganic components of gastric secretion. J Physiol (Lond) 3: 138-149, 1950 55. Sun DCH, Shay H: Optimal effective dose of an ticholinergic drug in peptic ulcer therapy . Arch Intern Med 97:442-452, 1956 56. Hunt IN: The secretory pattern of the stomach of man . J Physiol (Lond) 113:169-184, 1951 57. Janowitz HD, Hollander F: Effect of atropine on histamine-stimulated gastric secretion in the dog. Am J Physiol 186:373-376, 1956 58. Bramwell Cook H, Lennard-Jones JE: Effect of antisecretory drugs on gastric hypersecretion in endocrine-adenoma syndrome. Lancet 2:247-250, 1966
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59. Oberhelman HA Jr, Nelson TS: Surgical consideration in the management of ulcerogenic tumours of the pancreas and duodenum. Am J Surg 180:132-141, 1964 60. Clarke AM , Glen AI, Illingworth C: ZollingerEllison syndrome without gastric surgery. Lancet 1:1360-1363, 1964 61. Herxheimer A, Haefeli L: Human pharmacology of hyoscine butyl bromide, Lancet 2:418-421, 1966 62. Pennefather IN, McCullogh MW, Rand MJ : Observations on the efficacy of oral hyoscine-nbutylbromide . J Ph arm Pharmacol 20:867-872, 1968 63. Kaye MD, Beck P, Rhodes J, et al: Gastric acid secretion in patients with duodenal ulcer treated for 1 year with anticholinergic drugs. Gut 10:774- 778, 1969 64. Lawrie RS, Williamson AW, Hunt IN: ZollingerEllison syndrome treated with poldine methyl methosulphate . Lancet 1:1002-1005, 1962 65. Lawrie R, Hunt IN, Williamson AWR: Treatment of Zollinger-Ellison syndrome. Lancet 1:203, 1966 66. Melnyk CS , Krippaehne WW, Benson JA Jr, et al: Spontaneous remission of Zollinger-Ellison syndrome . Arch Intern Med 115:42-47, 1965 67. Winship DH, Ellison EH: Variability of gastric secretion in patients with and without the Zollinger-Ellison syndrome. Lancet 1:1128-1130, 1967 68. Thompson JC, Reeder DD, Bunchman HH: Clinical role of serum gastrin measurements in the Zollinger-Ellison syndrome. Am J Surg 124:250-261 , 1972 69. Hansky J, Soveny C, Korman MG: Value of serum gastrin in the diagnosis of the ZollingerEllison syndrome. Aust NZ J Med 3:349-354, 1973 70. Ivey KJ : Problems in diagnosis and management of Zollinger-Ellison syndrome. Aust NZ J Med 4: 108-109, 1974 71. Piper DW, Heap TR: Medical management of Peptic Ulcer II. New Ethicals (April) 13:95-100, 1972 72. Steigmann F, Pamukcu F, Chung KS: Studies on a new anticholinergic substance with marked antisecretory effect (abstr) . Am J Gastroenterol 33:1-3, 1960 73. Penny JL, Bonanno C, Grace WJ: Clinical studies on anticholinergic drugs using intra gastric pH meter. Curr Ther Res 4:258-262, 1962 74. Marcussen JM, Vilsik JS: The effect of combined antacid-anticholinergic treatment on the intragastric pH in peptic ulcer disease. Scand J GastroenteroI 3: 170-176,1968 75. Goyal RK, Bhardwaj OP, Chuttani HK: Parasympatholytic agents in duodenal ulcer. Double blind controlled trial with oxyphencyclimine hy-
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