0022-534 7/78/12031-0328$02. 00/0
Vol. 120, September Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1978 by The Williams & Wilkins Co.
THE ANTICHOLINERGIC EFFECTS OF DICYCLOMINE HYDROCHLORIDE IN UNINHIBITED NEUROGENIC BLADDER DYSFUNCTION C. PETER FISCHER, ANANIAS DIOKNO
AND
JACK LAPIDES
From the Section of Urology, Department of Surgery, Uniuersity of Michigan Medical Center, Ann Arbor and the Wayne County General Hospital, Eloise, Michigan
ABSTRACT
A preliminary study to assess objectively the effects of dicyclomine upon uncontrolled detrusor contractions and bladder capacity was undertaken in 14 patients with a cystometric diagnosis of uninhibited neurogenic bladder. Response was measured by cystometry performed 1, 2 and 4 hours after a 20 mg. oral dose. Of the 14 patients 11 had significant blockade of uninhibited contractions and a concomitant increase in bladder capacity. Similar but less dramatic changes were noted in the remaining 3 patients. Dicyclomine seems to have effective anticholinergic properties. No remarkable side effects were observed. The uninhibited type of neurogenic bladder is caused by a defect in the inhibitory fibers of the corticoregulatory tract. It is characterized by the presence of uncontrolled detrusor contractions during cystometry. 1 Clinically, it presents with voiding symptoms of frequency, urgency and urge incontinence. Treatment is primarily symptomatic and has consisted mainly of pharmacologic agents, although selective neurectomy has been applied successfully to patients with intractable symptoms and contractions. 2 • :i Currently, blockade of uninhibited detrusor contractions using anticholinergic agents is the cornerstone of therapy. Belladonna derivatives, propantheline and oxybutynin4 have been used successfully. Significant and undesirable systemic antimuscarinic side effects can accompany these drugs and may occasionally compromise patient compliance. Consequently, there is a continued search for additional anticholinergic agents that are effective and well tolerated. Dicyclomine, a synthetic antimuscarinic, is thought to have a non-specific direct smooth muscle relaxant effect with no systemic side effects, except in large doses." It also has been shown to possess parasympathetic blocking properties." In vitro it has demonstrated anticholinergic effects similar to but less powerful than atropine. 7 In 2 studies dicyclomine was given to patients with reflex and uninhibited types of neurogenic bladder and was shown to increase bladder capacity and suppress involuntary detrusor contractions. 8 · 9 To confirm and analyze further these findings we conducted an objective study to measure the effects of oral dicyclomine upon bladder capacity, urge to void and involuntary contractions. Herein we report the results of our research.
uropathy, glaucoma, pregnancy, acute hemorrhage, bowel dysfunction and myasthenia gravis. The Merrill carbon dioxide cystometer was used in all patients. A base line supine carbon dioxide cystometrogram was obtained using a 16F Foley catheter, a 100 ml. per minute flow rate and a 1 inch per minute chart speed. The patients were instructed not to void voluntarily. The first sensation of filling and the first urge to urinate were recorded. Bladder capacity was measured at the point at which further filling was painful or involuntary (uninhibited) contractions with voiding around the catheter made further filling impossible. The patien.t. was administered an oral dose of 20 mg. dicyclomine hydrochloride. Cystometry was performed 1, 2 and 4 hours after ingestion of the medication. Each base line and interval cystometric examination was performed twice to assure the results were consistent and reproducible. Patients were questioned regarding antimuscarinic effects, dry mouth, abdominal distension, blurred vision, nausea, drowsiness, palpitation and flushing. Before the study we outlined the parameters for a positive response to the drug. An effective reaction to the dicyclomine was defined as an increase of at least 25 ml. in bladder capacity and/or a delay or suppression of the uncontrolled detrusor contraction by a minimum of 25 ml. in volume. Categories of response were designated excellent, good, fair and poor. The response was considered excellent if both parameters exceeded 100 ml., good if only 1 measurement was greater than 100 ml., fair if both measurements were less than 100 ml. and poor if either measurement was less than 25 ml. or there was no change.
MATERIALS AND METHODS
RESULTS
This was an open label, pilot study of 6 men and 8 women, ranging in age from 26 to 76 years old. Each patient had a diagnosis of uninhibited neurogenic bladder made by standard carbon dioxide cystometry. Residual urine was less than 60 ml. in all cases. All patients were competent, ambulatory, outpatient adults who previously had undergone complete physical examination and urologic evaluation, including urinalysis, excretory urography, cystometrography and cystourethroscopy. Measures were taken to ensure that no subject was on an anticholinergic agent before the study. Contraindications to inclusion in the investigation were obstructive
All patients tolerated the study without complication. The only reported side effect was drowsiness, noted by 1 patient and limited to 2 hours. The cystometric response in all patients was positive: 10 were considered excellent (71.4 per cent), 1 good (7.1 per cent) and 3 fair (21.5 per cent). The effects of 20 mg. oral dicyclomine hydrochloride upon bladder capacity, delay of contractions and urge to void were noted (see table). The base line bladder capacities ranged from 75 to 550 ml., with a mean of 195 ml. The first uninhibited contractions ranged from 40 to 550 ml., with a mean of 154. 7 ml. The peak increase in bladder capacity ranged from 35 to 250 ml. The greatest delay or suppression of uninhibited contractions Accepted for publication November 11, 1977. Read at annual meeting of North Central Section, American ranged from 55 to 214 ml. The urge to void was similarly Urological Association, San Diego, California, November 6-12, 1977. analyzed and showed a base line range of 30 to 280 ml., with a 328
DIC-fCLOIVII:t¼iE I-{':lDROC!-:~LORIDE Il""J tJNII·'"T}!IBI'l"ED f\-JE-UROGEl'}IC EL.,_4-DDER DYSFUl\JCTION-
!Vlean e,ff'ect o.f20 rng. oral dicyclom£ne hydrochloride upon bladder capacity, delay of' contractions and urg~uoid Delay or Suppression of Contractions
Bladder Capacity Interval
Mean Capacity
Mean Increase
Iviean Increase
Mean Onset
Mean Increase
(ml.)
(mL)
(ml.i
(ml.)
(ml.I
97.5 133.8 138.5 118.5
36.3 41.0 21.0
----------
-
(ml.) ---
----
Base line 1 hr. 2 hrs. 4 hrs.
Urge to Void
195.0 271.8 273.9 247.1
76.8 78.5 52.1
----------------
-------------
154. 7 253.0 244.0 216.9
98.3 89.5 62.2
8
V1
C
~
this method we confirmed the and associates" and the observations of Thompson and Lauvetz,X that oral is an effective anticholinergic that increases capacity and suppresses involuntary contractions. Our objectively defines the immediate effects of dicyclomine upon these parameters as well as the urge to void. The responses were achieved with a relatively low dose and might have been enhanced with a higher dose, particularly in those patients who manifested only a fair response. Based upon our observations a prospective double-blind study has been initiated to assess clinically the effects of dicyclomine upon the subjective voiding symptoms of patients with uninhibited neurogenic bladders, as well as its long-term effects upon involuntary detrusor contractions and bladder capacity.
6-
(0
l'.L
REFERENCES
c54-
--
1. Lapides, J.: Fundamentals of Urology, 1st ed. Philadelphia: W.
,._ Cl)
E2-
--
--
I
::i
z
0
1 Hour
2 Hour
I 4 Hour
Peak response in bladder capacity and delay of contractions after 20 mg. oral dicyclomine.
mean of 138.5 ml. at mean of97.5 ml. This increased to a 2 hours. The interval for response in bladder and of uncontrolled contractions was depicted (see figure). Of the 14 patients 12 had a peak effect within 2 hours after taking dicyclomine. The duration of drug effects, measured by values greater than base line, was 2 hours in 6 patients and 4 hours in 8. DISCUSSION
Serial cystometry provides an excellent and reproducible method to assess the effects of anticholinergic agents upon uninhibited detrusor contractions, bladder capacity and urge
B. Saunders Co., p. 211, 1976. 2. Diokno, A. C., Vinson, R. K. and McGillicuddy, J.: Treatment of the severe uninhibited neurogenic bladder by selective sacral rhizotomy. J. Ural., 118: 299, 1977. 3. Torrens, M. j_ and Griffith, H.B.: The control of the uninhibited bladder by selective sacral neurectomy. Brit. J. Ural., 46: 639, 1974. 4. Diokno, A. C. and Lapides, J.: Oxybutynin: a new drug with analgesic and anticholinergic properties. J. Urol., Hl8: 307, 1972.
5. Goodman, L. S. and Gilman, A.: The Pharmacological Basis of Therapeutics, 4th ed. New York: Macmillan Co., p. 540, 1970. 6. Brown, B. B., Thompson, C.R., Klahm, G. R. and Werner, H. W.: Pharmacological studies on the antispasmodic, /3-diethylaminoethyl 1-cyclohexylcyclohexane-carboxylate hydrochloride. J. Amer. Pharm. Ass. Sci. Ed., 39: 305, 1950. 7. McGrath, W.R., Lewis, R. E. and Kuhn, W. L.: The dual mode of the antispasmotic effect of dicyclomine hydrochloride. J. Pharma.col. Exp. Ther., 146: 354, 1954. 8. Thompson, I. M. and Lauvetz, R.: bladder spasms, neurogenic bladder and enuresis. 8: 452, 1976. 9. Awad, S. A., Bryniak, S., Downie, J. W. and Bruce, A. W.: The treatment of the uninhibited bladder with dicyclomine. J. Ural., 117: 161, 1977.
Vol. 120, September Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1978 by The Williams & Wilkins Co.
THE ANTICHOLINERGIC EFFECTS OF DICYCLOMINE HYDROCHLORIDE IN UNINHIBITED NEUROGENIC BLADDER DYSFUNCTION C. PETER FISCHER, ANANIAS DIOKNO
AND
JACK LAPIDES
From the Section of Urology, Department of Surgery, Uniuersity of Michigan Medical Center, Ann Arbor and the Wayne County General Hospital, Eloise, Michigan
ABSTRACT
A preliminary study to assess objectively the effects of dicyclomine upon uncontrolled detrusor contractions and bladder capacity was undertaken in 14 patients with a cystometric diagnosis of uninhibited neurogenic bladder. Response was measured by cystometry performed 1, 2 and 4 hours after a 20 mg. oral dose. Of the 14 patients 11 had significant blockade of uninhibited contractions and a concomitant increase in bladder capacity. Similar but less dramatic changes were noted in the remaining 3 patients. Dicyclomine seems to have effective anticholinergic properties. No remarkable side effects were observed. The uninhibited type of neurogenic bladder is caused by a defect in the inhibitory fibers of the corticoregulatory tract. It is characterized by the presence of uncontrolled detrusor contractions during cystometry. 1 Clinically, it presents with voiding symptoms of frequency, urgency and urge incontinence. Treatment is primarily symptomatic and has consisted mainly of pharmacologic agents, although selective neurectomy has been applied successfully to patients with intractable symptoms and contractions. 2 • :i Currently, blockade of uninhibited detrusor contractions using anticholinergic agents is the cornerstone of therapy. Belladonna derivatives, propantheline and oxybutynin4 have been used successfully. Significant and undesirable systemic antimuscarinic side effects can accompany these drugs and may occasionally compromise patient compliance. Consequently, there is a continued search for additional anticholinergic agents that are effective and well tolerated. Dicyclomine, a synthetic antimuscarinic, is thought to have a non-specific direct smooth muscle relaxant effect with no systemic side effects, except in large doses." It also has been shown to possess parasympathetic blocking properties." In vitro it has demonstrated anticholinergic effects similar to but less powerful than atropine. 7 In 2 studies dicyclomine was given to patients with reflex and uninhibited types of neurogenic bladder and was shown to increase bladder capacity and suppress involuntary detrusor contractions. 8 · 9 To confirm and analyze further these findings we conducted an objective study to measure the effects of oral dicyclomine upon bladder capacity, urge to void and involuntary contractions. Herein we report the results of our research.
uropathy, glaucoma, pregnancy, acute hemorrhage, bowel dysfunction and myasthenia gravis. The Merrill carbon dioxide cystometer was used in all patients. A base line supine carbon dioxide cystometrogram was obtained using a 16F Foley catheter, a 100 ml. per minute flow rate and a 1 inch per minute chart speed. The patients were instructed not to void voluntarily. The first sensation of filling and the first urge to urinate were recorded. Bladder capacity was measured at the point at which further filling was painful or involuntary (uninhibited) contractions with voiding around the catheter made further filling impossible. The patien.t. was administered an oral dose of 20 mg. dicyclomine hydrochloride. Cystometry was performed 1, 2 and 4 hours after ingestion of the medication. Each base line and interval cystometric examination was performed twice to assure the results were consistent and reproducible. Patients were questioned regarding antimuscarinic effects, dry mouth, abdominal distension, blurred vision, nausea, drowsiness, palpitation and flushing. Before the study we outlined the parameters for a positive response to the drug. An effective reaction to the dicyclomine was defined as an increase of at least 25 ml. in bladder capacity and/or a delay or suppression of the uncontrolled detrusor contraction by a minimum of 25 ml. in volume. Categories of response were designated excellent, good, fair and poor. The response was considered excellent if both parameters exceeded 100 ml., good if only 1 measurement was greater than 100 ml., fair if both measurements were less than 100 ml. and poor if either measurement was less than 25 ml. or there was no change.
MATERIALS AND METHODS
RESULTS
This was an open label, pilot study of 6 men and 8 women, ranging in age from 26 to 76 years old. Each patient had a diagnosis of uninhibited neurogenic bladder made by standard carbon dioxide cystometry. Residual urine was less than 60 ml. in all cases. All patients were competent, ambulatory, outpatient adults who previously had undergone complete physical examination and urologic evaluation, including urinalysis, excretory urography, cystometrography and cystourethroscopy. Measures were taken to ensure that no subject was on an anticholinergic agent before the study. Contraindications to inclusion in the investigation were obstructive
All patients tolerated the study without complication. The only reported side effect was drowsiness, noted by 1 patient and limited to 2 hours. The cystometric response in all patients was positive: 10 were considered excellent (71.4 per cent), 1 good (7.1 per cent) and 3 fair (21.5 per cent). The effects of 20 mg. oral dicyclomine hydrochloride upon bladder capacity, delay of contractions and urge to void were noted (see table). The base line bladder capacities ranged from 75 to 550 ml., with a mean of 195 ml. The first uninhibited contractions ranged from 40 to 550 ml., with a mean of 154. 7 ml. The peak increase in bladder capacity ranged from 35 to 250 ml. The greatest delay or suppression of uninhibited contractions Accepted for publication November 11, 1977. Read at annual meeting of North Central Section, American ranged from 55 to 214 ml. The urge to void was similarly Urological Association, San Diego, California, November 6-12, 1977. analyzed and showed a base line range of 30 to 280 ml., with a 328
DIC-fCLOIVII:t¼iE I-{':lDROC!-:~LORIDE Il""J tJNII·'"T}!IBI'l"ED f\-JE-UROGEl'}IC EL.,_4-DDER DYSFUl\JCTION-
!Vlean e,ff'ect o.f20 rng. oral dicyclom£ne hydrochloride upon bladder capacity, delay of' contractions and urg~uoid Delay or Suppression of Contractions
Bladder Capacity Interval
Mean Capacity
Mean Increase
Iviean Increase
Mean Onset
Mean Increase
(ml.)
(mL)
(ml.i
(ml.)
(ml.I
97.5 133.8 138.5 118.5
36.3 41.0 21.0
----------
-
(ml.) ---
----
Base line 1 hr. 2 hrs. 4 hrs.
Urge to Void
195.0 271.8 273.9 247.1
76.8 78.5 52.1
----------------
-------------
154. 7 253.0 244.0 216.9
98.3 89.5 62.2
8
V1
C
~
this method we confirmed the and associates" and the observations of Thompson and Lauvetz,X that oral is an effective anticholinergic that increases capacity and suppresses involuntary contractions. Our objectively defines the immediate effects of dicyclomine upon these parameters as well as the urge to void. The responses were achieved with a relatively low dose and might have been enhanced with a higher dose, particularly in those patients who manifested only a fair response. Based upon our observations a prospective double-blind study has been initiated to assess clinically the effects of dicyclomine upon the subjective voiding symptoms of patients with uninhibited neurogenic bladders, as well as its long-term effects upon involuntary detrusor contractions and bladder capacity.
6-
(0
l'.L
REFERENCES
c54-
--
1. Lapides, J.: Fundamentals of Urology, 1st ed. Philadelphia: W.
,._ Cl)
E2-
--
--
I
::i
z
0
1 Hour
2 Hour
I 4 Hour
Peak response in bladder capacity and delay of contractions after 20 mg. oral dicyclomine.
mean of 138.5 ml. at mean of97.5 ml. This increased to a 2 hours. The interval for response in bladder and of uncontrolled contractions was depicted (see figure). Of the 14 patients 12 had a peak effect within 2 hours after taking dicyclomine. The duration of drug effects, measured by values greater than base line, was 2 hours in 6 patients and 4 hours in 8. DISCUSSION
Serial cystometry provides an excellent and reproducible method to assess the effects of anticholinergic agents upon uninhibited detrusor contractions, bladder capacity and urge
B. Saunders Co., p. 211, 1976. 2. Diokno, A. C., Vinson, R. K. and McGillicuddy, J.: Treatment of the severe uninhibited neurogenic bladder by selective sacral rhizotomy. J. Ural., 118: 299, 1977. 3. Torrens, M. j_ and Griffith, H.B.: The control of the uninhibited bladder by selective sacral neurectomy. Brit. J. Ural., 46: 639, 1974. 4. Diokno, A. C. and Lapides, J.: Oxybutynin: a new drug with analgesic and anticholinergic properties. J. Urol., Hl8: 307, 1972.
5. Goodman, L. S. and Gilman, A.: The Pharmacological Basis of Therapeutics, 4th ed. New York: Macmillan Co., p. 540, 1970. 6. Brown, B. B., Thompson, C.R., Klahm, G. R. and Werner, H. W.: Pharmacological studies on the antispasmodic, /3-diethylaminoethyl 1-cyclohexylcyclohexane-carboxylate hydrochloride. J. Amer. Pharm. Ass. Sci. Ed., 39: 305, 1950. 7. McGrath, W.R., Lewis, R. E. and Kuhn, W. L.: The dual mode of the antispasmotic effect of dicyclomine hydrochloride. J. Pharma.col. Exp. Ther., 146: 354, 1954. 8. Thompson, I. M. and Lauvetz, R.: bladder spasms, neurogenic bladder and enuresis. 8: 452, 1976. 9. Awad, S. A., Bryniak, S., Downie, J. W. and Bruce, A. W.: The treatment of the uninhibited bladder with dicyclomine. J. Ural., 117: 161, 1977.
