The effects of glycopyrrolate on the motor functions of the esophagus

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Part of The Journal of the Philippine Medical Association

Title: The effects of glycopyrrolate on the motor functions of the esophagus
Creator: Laureta, Higino C.
Language: English
Source: The Journal of the Philippine Medical Association Volume 52 (Issue Nos. 9-10) September-October 1976
Year: 1976
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Fulltext: The Effects of Glycopyrrolate on the Motor Functions of the Esophagus * • *This study was supported in part by grants from the Rockefeller Foundation and A. H. Robins Cd., Inc., Richmond, Va. **Makati MediGal Center. „ ^Second. Prize PMA-Abbott Research Award on Basic Science 1976. HIGINO C. LAURETA, M.D. ** INTRODUCTION ATROPINE decreases the pressure at the high pressure zone (HPZ) at the gas troesophageal junction thereby compro mising its physiologic sphincter func tion. M Moreover, it inhibits esophageal peristaltic waves.3 These promote eso phageal reflux and produce esophagitis. This is particularly undesirable in a pa tient who suffers from esophageal reflux and chronic esophagitis. The effects of atropine on the motor functions of the esophagus are to be ex pected because the motor nerves of the esophagus, the vagi, are cholinergic nerves. The anticholinergic drugs that are used for the treatment of peptic ul cer can potentially produce the same ad verse effects on the motor functions of the esophagus as those by atropine. Whether these anticholinergic drugs actually produce these effects especially in the recommended dose is not known. The purpose of this study was to deter mine the effects of a potent anticholi nergic drug, glycopyrrolate, on the mo tor functions of the esophagus. MATERIALS AND METHODS Four young and healthy Pilipino vo lunteers, two men and two women, were tested for this study. The motor functions of the esophagus were studied by intraluminal pressure measurements. This method has been previously described.4 The pressure de tecting device consisted of three waterfilled polyethelene tubes (P.E. 190; in side diameter, 0.047 in., outside diame ter, 0.067 in.) 120 cm long, tied togeth er at the dital end so that the side open ings at the distal end were in tandem five cm apart. The tubes were attached to pressure transducers (Statham P32Db) and the pressures recorded on Grass polygraph. The apparatus was ca librated so that one mm Hg pressure produced one mm deflection oh the poly graph. The pressure recording tubing assemly was passed through the nose until the side openings of all three tubes at the distal end were in the stomach. Press ure recordings were made with the sub ject in the recumbent position. The tu bing assembly was withdiawn in stepwiise fashion at one half to one cm in263 264 Laureta terval. Pressure were recorded at the lower esophageal sphincter, body of the esophagus, and the upper esophageal sphincter. The responses to swallows of two ml of water were recorded at each level. The effects of both the injectable and tablet preparations of glycopyrrolate were determined. Two subjects were first tested with the injectable form and the other two with the tablet. In the subjects in whom the injectable form was first tested the normal pressures were first recorded then the tubing assembly was repositioned in the stomach. The recording were repeated half an hour after a subcutaneous injection of 1.5 mg glycopyrrolate, The same subjects were then instructed to take one tablet of glycopyrrolate 30 minutes before each meal and at bedtime for five days after which the intraluminal pressure record ings were repeated. The last tablet was given one hour before the pressure rec ordings were made. In the two subjects in whom the tablet was first tested the test was repeated with the injectable form at least five days after the last tablet was taken. The swallowing complex consists of a rise in the average baseline pressure and appears like a plateau and which may be preceded by a brief negative deflec tion, followed by a positive deflection which represents the peristaltic wave (J5g. 1). The amplitude of the peristal tic wave was determined by measuring the height of the wave from the mean resting pressure to the tip of the wave and expressed in mm Hg pressure. The velocity of a peristaltic wave was determined by dividing the distance bet ween the two catheter tips (five cm) by the time required for the peristaltic wave Sept.-Oct., 1976 J. P. M. A. to traverse the segment (based on paper speed) as shown in Figure. 1. Only the waves that were Nearly progressive were employed in these calculations. The duration of a swallowing complex was measured from the time of initial deflection to return of the pressure to the baseline (Fig. 1). The duration of the peristaltic wave was calculated from the point of upsweep of the wave to the point where the downsweep reached the baseline. The number and percentage of swallows initiating peristaltic waves and fall in pressure at the lower sphincter were determined for each patient; Respiratory movements were recorded with a belt pneumograph. RESULTS The Normal Pressure Profile of the Esophagus. Sphincter Pressure. In these four normal Pilipinos the lower esopha geal sphincter (HPZ) was three to four cm long, the pressure gradually rising from the atmospheric pressure at the fundus of the stomach and abruptly drop ping to five mm Hg below the baseline fundal atmospheric pressure as it entered the chest through the biatus. The mean resting pressure at the peak of the HPZ was seven mm Hg (Fig. 2A). The lower esophageal sphincter responded to 79% of wet swallows with relaxation in the •usual manner as indicated by a drop in the resting pressure very shortly after a swallow (Fig. 3). The upper or pharyngoesophageal sphincter was five to six cm long and the mean resting peak pressure was 15 mm Hg (Fig. 2B). Unlike the lower sphincter the upper sphincter responded everytime to a wet swallow in the usual manner with relaxation indicated by a quick drop in pressure followed just as quickly with a contraction indicated by a Volume 52 Nos. 9-10 Esophagus 265 quick rise in pressure. Peristaltic Waves. The mean ampli tude, duration, and velocity of the peris taltic waves are shown in Figure 4. These varied throughout the length of the eso phagus originating just below the upper sphincter and dying out before reaching the lower sphincter. The amplitude, du ration, and velocity of a peristaltic wave paralleled one another,, i.e. the biggest wave was also the longest and fastest * The biggest waves were about 45 mm Hg with a mean duration of 3.8 seconds and mean velocity of five cm/sec were generated by the middle third of the eso phagus. The smallest waves were gene rated just beyond the distal periphery of the upper sphincter. Effects of Giycopyrrolate on the Mo tor Functions of the Esophagus. Sphinc -ter Pressure. The effects of glycopy rrolate on the lower sphincter are shown in Figure 2A and 3. When given by a single subcutaneous injection 1.5 mg of giycopyrrolate reduced the mean resting pressure of the lower sphincter by half. Only 26% of wet swallows initiated re laxation compared to the control of 79% (Figure 3). When given orally one mg before meals and at bedtime as recommended for five days the last tablet being given an hour before the pressure recordings were made there was no significant effect on the resting pressure. Sixty percent of wet swallows initiated response as com pared to the control of 79% (Figure 3). Whether given by subcutaneous inject ion or orally as above giycopyrrolate did not have any significant effect on the upper sphincter (Fig. 2B). Peristaltic Waves. Figure 5 shows the percentage of swallows initiating peris talsis in the four subjects tested. Eighty to 100% of swallows (mean of 94%) ini tiated peristaltic waves during the con trol studies. This dropped to 81-95% (mean of 87%) after five days of four tablets a day and 27-60% (mean of 45%) after a subcutaneous injection of 1.5 mg of giycopyrrolate. The effect of giycopyrrolate on the amplitude of peristaltic waves are shown in Figure 6. Both the tablet and inject able form reduced the amplitude of the peristaltic waves; the effect of the for mer was less and was confined to the middle third of the esophagus. Follow ing an injection of the drug the waves of the whole esophagus but particularly the distal two-third was affected and the waves that managed to appear were at most half as big as those during the con trol studies (Fig. 7). Figure 8 shows the effects of glycopyrrolate on the duration of the peristal tic waves. The duration of peristaltic waves in the distal two-third of the eso phagus decreased after both the tablet and injectable giycopyrrolate; the effects of the latter on the peristaltic waves were so profound to allow accurate meas urements (Fig. 7). TTiere was no significant effect of oral giycopyrrolate for five days on the ve locities of peristaltic waves as shown in Figure 9. TSie velocities could not be determined after the injection because the effects were so great that there were not enough measureable (Fig. 7). Swallowing Complex. Figure 10 shows the swallowing complexes during control periods and after five days of tablet giy copyrrolate. There was no significant ef fect although there was a consistent tendency of the swallowing complexes to be longer after oral medication espe cially on the distal two-third of the eso266 Laureta - phagus. This was associated with a dec rease in the duration of the peristaltic waves. DISCUSSION The resting and deglutition esophageal pressures obtained during the control studies in these four subjects are simi lar to those obtained by others using the same technique.5,6 The pressures were reproducible in the same subject. Not only the pressures but also the pro file are similar to those obtained else where.3 Locally only one published da ta using the same technique is avail able;4 the present data are similar to these. It has been shown that the motor func tions of the espohagus are profoundly af fected by atropine.1*3 The resting press ure at the lower sphincter was reduced and this was accompanied by acid re flux into the esophagus. The amplitude of the peristaltic waves in the distal twothird of the esophagus were reduced and the percentage of response in terms of initiation of waves to swallows was markedly reduced. These effects are to be expected because the motor nerves of the esophagus, the vagi, are choliner gic. Because of the foregoing any potent anticholinergic agent would potentially have the same effects. If these effects are produced two things can be expect ed to follow, namely, varying degrees of dysphagia and esophageal reflux. The dysphagia may not be troublesome but the reduction of pressure at the high pressure zone would incapacitate its phy siologic sphincter function and promote esophageal reflux and subsequently a troublesome esophagitis. This effect is very undesirable in a patient who, to begin with, has esophageal reflux for one reason or another. Sept.-Oct., 1976 J. P. M. A. A number of potent anticholinergic agents are commonly used in the treat ment of peptic ulcer. One of these is giycopyrrolate. The intramuscular in jection of 1.5 mg of giycopyrrolate red uced the volume of acid and pepsin out put by about 90% in patients with pep tic ulcer.7 It has also been shown cap able of suppressing the antral, small in testinal, and colonic motor activities.8*10 The present study showed that glycopyr rolate, like atropine, can markedly de press the motor functions of the esopha gus particularly when given in sufficient dose and parenterally; the high pressure at the physiologic sphincter was reduced by 50% and the number of peristaltic waves initiated by swallows by as much as 57%. Moreover, the waves that were initiated were likewise markedly red uced in amplitude. The subjects had to wait for six to eight hours before at tempting to eat because the food would not go down. However * when given by mouth in the recommended dose for five days the effects were significantly less; the high pressure at the physiologic sphincter was not affected and the re duction in the number of waves initiated was not significant and did not produce dysphagia in the subjects. Nonetheless, they complained of dryness of the throat and slight blurring of vision. The subjects tested in this study were healthy and young. Whether the same effects could be produced in older or, more importantly, those with esophageal disease like hiatal hernia or esophagitis due to esophageal reflux was not deter mined. Giycopyrrolate or any anticholi nergic agent should therefore be used cautiously in these patients. SUMMARY The resting and deglutition intralumi nal pressures in the lower and upper Volume 52 Nos. 9-10 sphincters and body of the esophagus were recorded in four healthy young Pilipino volunteers, two men and two wo men. The amplitude, duration, and ve locity of the peristaltic waves and the duration of the swallowing complex throughout the body of the esophagus were determined. The average resting peak pressure was 7 mm Hg at the low er and 15 mm Hg at the upper esopha geal sphincter. In these four subjects 79% of wet swallows initiated a relaxa tion of the lower sphincter; the upper sphincter responded to every swallow. The swallowing complex increased more or less linearly from 4 seconds just be low the upper sphincter to 12 seconds just above the lower sphincter. Ninety four percent of wet swallows initiated peristaltic waves. The amplitude, dura tion, and velocity of a peristaltic wave more or less paralleled one another, i. e. the biggest wave was also the long est and fastest. The peristaltic waves decreased toward the distal portion of the proximal 3rd then increased to its peak at the distal portion ©f the middle and the proximal portion of the distal third of the esophagus and decreased again and dying out before reaching the lower sphincter. The biggest waves were about 45 mm Hg, maan duration of 3.8 seconds, and mean velocity of 5 cm/sec. The same subjects were studied aja hour after an injection of 1.5 mg and again after taking one 1 mg tablet four times a day of giycopyrrolate for five days. The injection of 1.5 mg of gly copyrrolate had the following effects: 1. The resting pressure at the lower esophageal sphincter decreased 50% and only 26% of wet swallows initiated a re laxation. The upper esophageal sphinc ter was not effected. Esophagus 267 2. Twenty seven to 60% of wet swal lows initiated peristaltic waves. Of the peristaltic waves that managed to ap pear the amplitude were profoundly red uced especially in the distal two-third of the esophagus. The effects on the du ration and velocity of the waves could not be determined. 3. The effect on the swallowing com plex could not be determined because the peristaltic waves that were initiated could not be measured accurately. With four mg of giycopyrrolate by mouth per day for five days the follow ing results were obtained in the same subjects: 1. The resting pressures of both the lower and upper sphincters were not af fected. However, only 60% of the wet swallows produced a relaxation of the lower sphincter compared to 79% during the control test; the upper sphincter res ponded to all the swallows. 2. Eighty seven percent of the wet swallows initiated peristaltic waves (compared to 94% during control tests). The amplitude of the peristaltic waves particularly in the middle third of the esophagus were reduced but the reduc tion was not as profound as those prod uced by the injection of 1.5 mg. The duration of the waves particularly the proximal portion of the distal third and the distal portion of the middle third of the esophagus was likewise reduced. There was no effect on the velocity of the waves. 3. The swallowing complex increased slightly particularly in the distal twothird of the esophagus. Potent anticholinergic drugs like giy copyrrolate can potentially compromise the sphincter function of the lower eso phageal sphincter by decreasing the 268 Laureta Sept.-Oct., 1976 £ P. M. A. PNEUMOGRAPH SCC' 1 1 * ‘ i » i i SWALLOW Figure. 1. This strip of tracing shows the norma} response of the esophagus four to 14 cm above the lower sphincter to a swallow. The method in determining the amplitude, duration, and velocity of peristaltic waves and the swallowing complex is indicated. Volume 52 Nos. 9-10 Esophagus 269 MM HG 10 - A ---- ~<GLYCOPYFt^ S.c. *‘"»GLYCOPYR< TABLET? Figure »A. Mean pressures at the lower esophageal Sphincter of four normal subjects before and after giycopyrrolate 1.5 mg by subcutaneous injection and one mg tablet ,q.i.d. for five days. MM HG Figure 2B. Mean pressures at the upper esophageal sphincter of four normal subjects before and after giycopyrrolate 1.5 rag by subcutaneous ihjectton and one mg tablet g.i.d. for five days. Sept.-Oct., 1976 J.P. M. A. 270 Laureta □ CONTROL DUB GLYCOP YR., S.c. tagore 8. Percentage of swallows initiating fall in pressure at the lower eso phageal sphincter in four normal subjects before and after giycopyrrolate 1.5 mg by subcutaneous injection and one mg tablet q.i.d. for five days. SEC mm HG CA * ABOVE LOW8R SPH/NCTER "Pjgure 4 * Mean amplitude, duration, and velocity of peristaltic waves of the sophagus of four normal subjects. Esophagus 271 Volume 52 Nos. 9-10 Table 1. LOWER ESOPHAGEAL SPHINCTERIC PRESSURES IN NORMAL SUBJECTS BEFORE AND AFTER AN INJECTION OF ONE MG OF ATROPINE. Esophagel Sphincteric Pressures and Pulse Rates Before Atropine After Atropine Pressure * Pulse Rate Pressure * Pulse Rate Subject mm H per min mm Hg pre min A 14.0 77 1.5 101 B 8.0 62 1 5 118 C 11.0 68 3.0 102 D 4.0 63 1.0 109 E 9.5 68 2.0 111 •Mean of three pressure recordings. □ CONTROL fQD GLYCOPYR.t S.C. % E3 glycopyr., tablet sUBJects Figure 5. Percentage of swallows initiating esophageal peristaltic waves in four normal subjects before and after giycopyrrolate 1.5 mg by subcutaneous inject ion and one mg tablet q.i.d. for five days. 272 Laureta Sept.-Oct., 1976 J. P. M. A. CM ABOVE LOWER SPHINCTER Figure 6. Mean amplitude of esophageal peristaltic waves of four normal sub jects before and after giycopyrrolate 1.5 mg by subcutaneous injection and one mg tablet q.i.d. for five days. T i(7 13- * ir 4 ft x I 4. ? \ \ 3 \ 'S ' 1 1 ’ It 4 (I ■’■ fl < 7 r** '*-*3 rflB* X Figure 7. These tracings of one of the subjects show the normal responses of the distal esophagus to wet swallows (upper tracing) and one hour after a subcu taneous injection of 1.5 mg of giycopyrrolate (lower tracing). Volume 52 tics. 9-TO Esophagus 273 SEC 1 3 5 7 9 11 13 15 17 19 21 CM ABOVE LOWER SPHINCTER Figure 8. Mean duration of peristaltic waves of four normal subjects before and after giycopyrrolate one mg tablet q.i.d. for five days * CM / SEC CONTROL GLYCO'"'?., TABLET I 3 -«------------ ‘----------- L----------- 1----------- L_------- 1----------- 1 5 7 9 f| 13 15 |7 |9 Figure 9. Mean velocity of esophageal peristaltic waves of four normal sub jects before and after giycopyrrolate one mg tablet q.i.d. for five days. Sept .-Oct., 1976 J. P. M. A. 274 Laureta 13 5 7 9 II 13 15 17 19 21 CM ABOVE LOWER SPHINCTER Figure 10. Mean duration of swallowing complexes (S.C.) and esophageal pe ristaltic waves (P.W.) of four normal subjects before and after giycopyrrolate one mg tablet q.i.d. for five days. pressure at the HPZ. Potent anticholi- reflux or any problem affecting the disnergic drugs should be used with parti- tai esophagus. cular caution in patients with esophageal REFERENCES 1. Bettarello, A., S.G. Tuttle, M.l. Grossman, 1960. Effect of autonomic drugs on gastroesophageal re flux. Gastroenterology, 39:340-346. 2. Laureta, H.C., Unpublished data, see Table 1. 3. Kantrowitz, P.A., C.l. Siegel, and T.R. Hendrix, 1966. Differences in motility of the upper and lower esophagus in man and its alteration by atropine. Bull. John Hopkins Hosp., 118:476-491. 4. Laureta, H.C., 1966 Intraluminal pressure record ing in the study of the motor activities of the esophagus in health and disease. Acta Med. Phil., 2:228-231. 5. Code, C.F. and J.F. Schlegel. 1968. Motor actions of the esophagus and its sphincters. In C.F. Code, ed., Handbook of Physiology, Alimentary Canal, Vol. IV., Motility. American Physiological So ciety, Washington, * D.C., pages 1821-1838. 6. Texter, E.C., Jr., C-c Chou, H.C. Laureta, and G. Vantrappen, 1968. Physiology of the Gastrointes tinal Tract. The C.V. Mosby, Co., St. Louis. 7. Bitsch, V. and M. Kristensen 1966. Determination of peptic activity in gastric juice of patients with peptic disease before and after administration of glycopyrolate. Acta Med. Scand., 180:385-393. 8. Young, R. and D.C.H. Sun, 1962. Effect of gly copyrrolate on antral motility, gastric emptying and intestinal transit. Ann. New York Acad. ScL, 99:174-178. 9. Fleshier, B., 1962. The effect of giycopyrrolate on normal human small bowel activity. J. New Drugs, 2:211-214. 10. Kasich, A.M., and H.D. Fein, 1963. Experimental observations on the effects of giycopyrrolate on the acidity of gastric secretion and on the moti lity of the gastrointestinal tract. Am. X Gas troenterol., 39:61-68. Volume 32 Nq< 9-TO SEC Esophagus 273 1 3 5 7 9 11 13 15 17 19 21 CM ABOVE LOWER SPHINCTER Figure 8. Mean duration of peristaltic waves of four normal subjects before and after giycopyrrolate one mg tablet q.i.d. for five days * CM / SEC CONTROL GLYCO'"'?., TABLET I ‘-------------1------------ 1----------L_______L_ 3 5 7 9 H -L_---------1----------- 1------------1 13 15 17 19 Figure 9. Mean velocity of esophageal peristaltic waves of four normal sub jects before and after giycopyrrolate one mg tablet q.i.d, for five days. Sept .-Oct., 1976 J. P. M. A. 274 Laureta 13 5 7 9 II 13 15 17 19 21 CM ABOVE LOWER SPHINCTER Figure 10. Mean duration of swallowing complexes (S.C.) and esophageal pe ristaltic waves (P.W.) of four normal subjects before and after giycopyrrolate one mg tablet q.i.d. for five days. pressure at the HPZ. Potent anticholi- reflux or any problem affecting the disnergic drugs should be used with parti- tai esophagus. cular caution in patients with esophageal REFERENCES 1. Bettarello, A., S.G. Tuttle, M.l. Grossman, 1960. Effect of autonomic drugs on gastroesophageal re flux. Gastroenterology, 39:340-346. 2. Laureta, H.C., Unpublished data, see Table 1. 3. Kantrowitz, P.A., C.l. Siegel, and T.R. Hendrix, 1966. Differences in motility of the upper and lower esophagus in man and its alteration by atropine. Bull. John Hopkins Hosp., 118:476-491. 4. Laureta, H.C., 1966 Intraluminal pressure record ing in the study of the motor activities of the esophagus in health and disease. Acta Med. Phil., 2:228-231. 5. Code, C.F. and J.F. Schlegel. 1968. Motor actions of the esophagus and its sphincters. In C.F. Code, ed., Handbook of Physiology, Alimentary Canal, Vol. IV., Motility. American Physiological So ciety, Washington, * D.C., pages 1821-1838. 6. Texter, E.C., Jr., C-c Chou, H.C. Laureta, and G. Vantrappen, 1968. Physiology of the Gastrointes tinal Tract. The C.V. Mosby, Co., St. Louis. 7. Bitsch, V. and M. Kristensen 1966. Determination of peptic activity in gastric juice of patients with peptic disease before and after administration of glycopyrolate. Acta Med. Scand., 180:385-393. 8. Young, R. and D.C.H. Sun, 1962. Effect of gly copyrrolate on antral motility, gastric emptying and intestinal transit. Ann. New York Acad. Scl., 99:174-178. 9. Fleshier, B., 1962. The effect of giycopyrrolate on normal human small bowel activity. J. New Drugs, 2:211-214. 10. Kasich, A.M., and H.D. Fein, 1963. Experimental observations on the effects of giycopyrrolate on the acidity of gastric secretion and on the moti lity of the gastrointestinal tract. Am. X Gas troenterol., 39:61-68.
pages: 263-274