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 anticholinergic agents with atropine 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.