Gut: first published as 10.1136/gut.3.1.65 on 1 March 1962. Downloaded from Gut, 1962, 3, 65

A comparison of a series of newer agents with as regards their effect on saliva flow and gastric secretion in man

D. W. PIPER AND MIRJAM C. STIEL From the Department ofMedicine, the University of Sydney, and the Unit of Clinical Investigation, the Royal North Shore Hospital of Sydney, Australia

SYNOPSIS The effect of anticholinergic agents-atropine, propantheline, oxyphencyclimine, and propionyl atropine methyl nitrate-on saliva flow and on hypoglycaemic stimulated gastric secretion has been studied. The acid secretion of the nervous phase of gastric secretion was inhibited by anticholinergic drugs. They influenced gastric secretion to a greater extent than saliva flow. Both propantheline and oxyphencyclimine have a selective action on the stomach superior to atropine. Propionyl atropine methyl nitrate appears to have only weak anticholinergic activity in the dose recommended and is not superior to atropine.

Three control readings were taken and subsequently Anticholinergic drugs are widely used in the treat- http://gut.bmj.com/ ment of peptic ulcer and with this aim new pre- readings at hourly intervals after the administration of parations are constantly being produced. One of the the drug until saliva flow returned to normal. Side-effects, advantages over atropine claimed for the newer particularly the presence of a dry mouth, blurred vision, or difficulty in micturition were noted. The volunteers preparations is that they produce fewer side-effects, used in this study were members of the resident medical which implies that they have a selective action on the staff; seven such studies were made. stomach. Apart from one French study (Lieber, The effect on gastric secretion was determined using 1956) that showed that the more recently developed hypoglycaemic stimulated secretion. For this, patients preparations were inferior to atropine in this respect, having insulin coma therapy for psychiatric reasons were on September 27, 2021 by guest. Protected copyright. there is no work in man, supported by the quantita- used. After fasting, the drug was given between 6.30 a.m. tive determination of their effect on gastric secretion and 6.45 a.m. followed by a large dose of insulin (the and of their side-effects, comparing atropine with dosage ranged between 200 and 1,600 units). The patient the newer anticholinergic agents. went into coma two to two and a half hours after the the of or not the administration of insulin and spent one hour in coma. Because of importance whether Coma was considered to be present when the patient no newer drugs have a selective action on the stomach, longer responded to painful stimuli and extensor plantar the present study was undertaken. Atropine and responses were present. It had previously been deter- three new preparations (propantheline, oxyphen- mined that under these conditions control studies gave cyclimine, and propionyl atropine methyl nitrate) reproducible responses. Gastric secretion was determined were compared as regards their effect on saliva flow during 30 minutes of the hour spent in coma, using con- and on hypoglycaemic stimulated gastric secretion. tinuous suction with a Cleland tube. Each patient had from one to four, usually two, control studies done; the METHOD control studies and the studies after the drugs were For several reasons it was not possible to determine both randomized. Eight patients were studied. Patients who responses in the same group of patients. Consequently showed more than a trace of bile in the gastric juice were one group of volunteers was studied as regards saliva not included in the series. flow and a second group as regards gastric secretion; the The acid concentration was estimated using phenol results were then analysed statistically. red as an indicator. The drugs administered were atropine Saliva flow was stimulated by chewing. Gum devoid of sulphate gr. 1/100, propantheline 30 mg., oxyphencycli- the outer flavoured coat was used; the gum was chewed mine 10 mg., and propionyl atropine methyl nitrate 18 for 10 minutes and the volume ofsaliva secreted measured. mg.; all were given orally. 65 Gut: first published as 10.1136/gut.3.1.65 on 1 March 1962. Downloaded from 66 D. W. Piper and Mirjam C. Stiel

RESULTS between the subjective side-effects and the degree of salivary inhibition produced. EFFECT ON SALIVA FLOW The effect on saliva flow during the four hours after the administration of the TABLE III drugs is given in Table I. The saliva flow is expressed SUBJECTIVE SEVERITY OF SIDE-EFFECTS AFTER ANTICHOLINERGIC DRUGS TABLE I Patient Atropine Propantheline Oxyphencyclimine P.A.M.N. EFFECT OF ANTICHOLINERGIC DRUGS ON SALIVA FLOW (gr. 1/100) (30 mg.) (10 mg.) (18 mg.)

Time after Salivary Output in 10 Minutes as % of Control Value + + ++ + Administration 2 ++ + Atropine Propantheline Oxyphen- P.A.M.N. 3 + + (gr. 1/100) (30 mg.) cyclimine (18 mg.) 4 + (10 mg.) S ++ 6 1 hour 77±10 80±11 69±11 89±5 7 ++ ++ ++ 2 hours 69± 9 69± 9 59± 7 87±6 3 hours 70± 6 77± 8 61± 9 90±7 + + = moderate side-effects, + = slight side-effects, - = no side- 4 hours 74± 5 88± 8 66± 7 97±3 effects. The ± figure is the S.E. of the mean. It is seen from Table I that the maximal action is reached during the second hour. At two hours there as a percentage of the mean of the control readings. is no significant difference in potency of the above Table II gives the effect of the drugs on saliva flow doses of atropine, propantheline, and oxyphen- three hours after the administration of the drugs, cyclimine but a significant difference between these three drugs and propionyl atropine methyl nitrate TABLE II (P = 0-01); and at three hours there is no significant EFFECT OF ANTICHOLINERGIC DRUGS ON SALIVA FLOW difference between atropine, propantheline, and THREE HOURS AFTER ADMINISTRATION OF THE DRUGS oxyphencyclimine, or between propantheline and propionyl atropine methyl nitrate; there is a signi- Patient Salivary Flow in 10 Minutes as % of Control Value ficant difference between oxyphencyclimine and http://gut.bmj.com/ Atropine Propantheline Oxyphen- P.A.M.N. propionyl atropine methyl nitrate (P = 0 02), and (gr. 1/100) (30 mg.) cyclimine (18 mg.) between atropine and propionyl atropine methyl (10 mg.) nitrate (P = 0.05). 50 82 56 2 88 70 78 3 58 90 76 THE EFFECT ON GASTRIC SECRETION The effect of the 4 76 100 80 series of anticholinergic drugs on hypoglycaemic 5 75 88 70 stimulated secretion is given in Table IV. This effect 6 66 73 50 on September 27, 2021 by guest. Protected copyright. 7 56 40 18 was usually determined two and a half to three hours Mean ± S.E. 70±6 77±8 61±9 after the administration of the drug. The response is expressed as a percentage ofthe mean control output. and Table III lists the severity of side-effects as In Table V the newer preparations are compared judged subjectively at this time interval by the seven with atropine and with one another, as regards their subjects studied; it is seen that there is a correlation effect on saliva flow and on gastric secretion. Each

TABILE IV EFFECT OF ANTICHOLINERGIC DRUGS ON GASTRIC ACID SECRETION Patient Mean Control Output Output after Drugs as %/* of Control Secretion (mEq./30 min.) Atropine Propantheline Oxyphencyclimine P.A.M.N. (gr. 1/100) (30 mg.) (10 mg.) (18 mg.) 6-20 19 8 19 73 2 2-70 61 13 39 29 3 7-06 46 36 121 4 11-52 62 29 34 70 S 18-00 47 47 99 6 10-73 52 88 65 7 8-42 3 15 42 8 1-82 35 S 24 70 Mean ± S.E. 46±7 18 ±E 7 28 1 5 71±10 Gut: first published as 10.1136/gut.3.1.65 on 1 March 1962. Downloaded from Comparison ofanticholinergic agents with atropine and their effect on saliva flow and gastric secretion 67 TABLE V COMPARISON OF EFFECTS OF SERIES OF DRUGS ON SALIVA FLOW AND GASTRIC SECRETION Comparison Saliva Flow Gastric Secretion Mean Difference between Means Significance P Mean Difference between Means Significance P Atropine 70±6 9 03 47±7 19 005 Oxyphencyclimine 61±9 27±5 Atropine 70+6 7 0-5 44±11 31 005 Propantheline 77 ±8 13±6 Atropine 70+6 20 0.05 46±7 25 0.1 P.A.M.N. 90±7 71± 12 Propantheline 77±8 16 0-2 18±7 12 0.2>P>0l1 Oxyphencyclimine 61±9 30±5 Oxyphencyclimine 61±9 29 0-02 28±5 43 001 P.A.M.N. 90±7 71±10 All results are expressed as a % of the mean control secretion; the saliva flow and gastric secretion are assessed three hours after administration of the drug. In this table each response, either saliva flow or gastric secretion, is compared between drugs only in patients who had both drugs. drug's effect, either on saliva flow or gastric secretion, in the case of atropine and most marked in the case is only compared in those individuals who actually of propantheline, with oxyphencyclimine in an had both drugs, thus removing the factor ofvariation intermediate position. A measure of this degree of between individuals. selectivity is given by the ratio comparing their It is seen that though there was no significant effect on gastric secretion with their effect on saliva difference between the effect of atropine and either flow (Table VI). It was only in the case of propionyl oxyphencyclimine or propantheline as regards their atropine methyl nitrate that a selective action on the effect on saliva flow, both propantheline and stomach was not demonstrated using this type of oxyphencyclimine had a significantly greater effect comparison. than atropine on gastric secretion. Hence it appears The relative effect of propantheline and oxyphen- from this analysis that two of the newer preparations cyclimine deserves further mention. It is seen from studied have a selective action on the stomach when Tables II and IV that when compared three hours http://gut.bmj.com/ compared with atropine. after administration, in the dosage used, oxyphen- In the previous analysis the drugs were compared cyclimine had, in six of the seven cases studied, a as regards their relative potency only in those more marked effect on saliva flow, whereas when patients who had received both drugs. If we assume their comparative effect on gastric secretion is that both groups, those who were studied as regards studied, oxyphencyclimine had less inhibitory effect saliva flow and those studied as regards gastric on gastric secretion than propantheline in five cases, secretion, were analogous groups we can compare and an equivalent effect in one case. When the two on September 27, 2021 by guest. Protected copyright. statistically the effect of the two drugs on saliva flow preparations are compared as in Table V it is seen and gastric secretion. From their modes of selection, that 30 mg. of propantheline had a more marked this is a reasonable assumption as both groups were effect on gastric secretion than 10 mg. of oxyphen- physically healthy men in the 18 to 35 age groups. It cyclimine, whereas the latter had a more marked is seen (Table VI) that atropine, propantheline, and effect on saliva flow than 30 mg. of propantheline; oxyphencyclimine had a significantly more marked neither of these differences were significant at the effect on gastric secretion than on saliva flow, this 5 % level, however. It must be realized in such a preponderant effect on gastric secretion being least comparison as this that we are-comparing two drugs TABLE VI COMPARISON OF EFFECTS OF SERIES OF DRUGS ON SALIVA FLOW AND GASTRIC SECRETION Atropine Propantheline Oxyphencyclimine P.A.M.N. (gr. 1/100) (30 mg.) (10 mg.) (18 mg.) Effect on saliva flow 70±6 77±8 61±9 90±7 Effect on gastric secretion 46±7 18±7 28±5 71±10 Difference 24 59 33 21 Significance of difference (P) 0-02 001 001 0-2

All results are expressed as a % of the mean control value. In this table both responses, saliva flow and gastric secretion, are compared for each drug; it is assumed that both groups of subjects were similar. Gut: first published as 10.1136/gut.3.1.65 on 1 March 1962. Downloaded from 68 D. W. Piper and Mirjam C. Stiel whose length of action is dissimilar (Piper, Elliott, that no drug consistently reduced gastric secretion Sietsma, and Pryor, 1960). It was noted that when without side-effects. Rock and Rohrer (1958) com- two 15-minute specimens were taken, two and a half pared the effect of propantheline, 30 mg., and atro- to three hours after propantheline, the second was pine, 1 mg., on insulin-stimulated gastric secretion usually greater than the first, whereas after oxyphen- and found that both significantly reduced acid output cyclimine both specimens tended to be equal. but, though the output after propantheline was less marked than after atropine, the difference was not DISCUSSION significantly different. The present study has shown that though the four drugs investigated, including One would expect the most accurate method to use atropine, reduced the nervous phase of gastric to assess the action ofanticholinergic drugs on gastric secretion more readily than they did saliva flow, secretion would be the investigation of their effect only propantheline and oxyphencyclimine had a on vagally stimulated secretion. If one surveys, how- selective action on the stomach superior to atropine, ever, the recorded work on the effect of anti- these differences being statistically significant. drugs on hypoglycaemic stimulated Oxyphencyclimine was first studied pharmaco- secretion, it is found that many workers have logically by Finkelstein, P'an, Niesler, Johnson, found that the acid output is unaffected (Bayer and Schneider (1959); they found it to be in animals and Bradford, 1952; Bayer, Plummer, and Bradford, a powerful anticholinergic agent, with a marked 1952; Levin, Kirsner, and Palmer, 1952; Winkelstein, effect on the stomach and a prolonged duration of 1952; Roback and Beal, 1953; Weisiger, Burke, action. A subsequent study of its effect on saliva and Plummer, 1954; McKenna, Smith, and Wyse, flow and gastric secretion by Piper et al. (1960) con- 1954; Kasich, Boleman, and Rafsky, 1956; Bachrach, firmed its prolonged action in humans. The present 1958). Others, nevertheless, have observed an investigation showed that it has a more selective inhibitory effect (Lieber, 1956; Plummer, Burke, action on the stomach than atropine but that it is and Bradford, 1951; Rock and Rohrer, 1958) and not as selective two and a half hours after its our own observations support these findings (Piper, administration as propantheline. Its chief advantage Elliott, Sietsma, and Pryor, 1960). The failure to appears to be its prolonged action which is almost observe a drop after anticholinergic drugs by some twice as long as that of propantheline (Piper et al., http://gut.bmj.com/ workers appears to have been due to inadequate 1960); thereby night secretion can be controlled dosage of the drug and the inability to make and, with three doses during the day, a constant repeated observations on the same patient. We found, inhibitory effect can be obtained. However, if the using the method outlined, control readings with a length of action is of no importance, it appears that coefficient of variation of 3.7 % could be obtained in propantheline is superior to oxyphencyclimine those patients secreting more than 3 ml. of gastric because of its more selective action on the stomach. juice per minute and in all patients a diminution of Propionyl atropine methyl nitrate is a quaternary acid output could be produced by most anti- ammonium ester of atropine and was considered on September 27, 2021 by guest. Protected copyright. cholinergic drugs. Those drugs that produced no by Herman, Shaw, and Rosenblum (1958) after effect were considered not to have been given in animal experiments to be worthy of clinical trial. adequate dosage. Subsequently, Herman and Shaw (1958) showed One of the main problems involved in the clinical that it reduced the volume and acidity of the gastric use of anticholinergic agents has been the deter- secretory response to an test meal and slowed mination of the extent to which they are superior to gastric motility as measured by the rate of glucose atropine. Assessment of drugs that produce side- absorption. Both these methods can be criticised effects by the use of clinical trials in diseases with as methods of assessment of an anticholinergic agent the variable course for which they are commonly because the response to a meal is partially under used is fraught with many difficulties. The only chemical and partially under vagal control (Wood- previous similar study comparing quantitatively the ward, Lyon, Landor, and Dragstedt, 1954) and there therapeutic effect and side-effects of a similar series is no evidence to show that there is a correlation of drugs was made by Lieber (1956). He studied between anticholinergic-induced hypomotility and hypoglycaemic stimulated secretion and found that sucrose absorption. Giving doses of Banthine that atropine was superior to propantheline and oxyphe- inhibited bowel motility, as shown by balloon nonium when the effect of a given dose on gastric observations, and produced marked side-effects, secretion and on the intensity of side-effects was Cummins and Almy (1953) found that the adsorption compared. The detailed investigation of Kirsner, of glucose was not affected. The maximum dose Levin, and Palmer (1953) on the relation of side- recommended by the manufacturers is three tablets, effects to the inhibition of basal secretion showed with one tablet as the usual dose. It would appear Gut: first published as 10.1136/gut.3.1.65 on 1 March 1962. Downloaded from Comparison ofanticholinergic agents with atropine and their effect on saliva flow and gastric secretion 69 from the findings of the present study that this Sydney who participated in the investigation, and Miss maximum dose is relatively ineffective in inhibiting Barbara Fenton, B.Sc., for her technical assistance. This gastric secretion; as an antisecretory agent it is project was made possible by a grant from the Post inferior to propantheline and oxyphencyclimine and Graduate Medical Foundation of the University of not superior to atropine. Sydney. In the final assessment of the place of any anti- cholinergic preparation, many factors must be con- REFERENCES sidered. Its effect should be determined by pharma- Bachrach, W. H. (1958). Anticholinergic drugs. Amer. J. dig. Dis., cological studies and confirmed, if possible, by 3, 743-799. clinical trial. It should have a selective action on the Bayer, A. E., and Bradford, S. (1952). 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Gastroenterology, 27, We wish to acknowledge the help given throughout the 469-473. study by the Superintendent and staff of Broughton Hall Winkelstein, A. (1952). Banthine for peptic ulcer: clinical and physio- made our studies logical considerations. Ibid., 20, 464-470. Psychiatric Hospital, whose cooperation Woodward, E. R., Lyon, E. S., Landor, J., and Dragstedt, L. R. possible. We also wish to thank those members of the (1954). The physiology of the gastric antrum; experimental resident staff of the Royal North Shore Hospital of studies on isolated antrum pouches in dogs. Ibid., 27, 766-785.