- Email: [email protected]
Effects of methantheline bromide and clonidine hydrochloride on salivary secretion
Effects of methantheline bromide and clonidine hydrochloride on salivary secretion Edwin L. Wilson, Jr., D.D.S.,* Lowell D. Whitsett, D.D.S.,** and Thomas L. Whitsett, M.D.*** University of Oklahoma, Collegesof Dentistry and Medicine, Oklahoma City, Okla.
T
he maintenance of an operative field free of moisture contamination is important in many dental procedures. Impression materials such as the silicones and polysulfides possess hydrophobic properties. Cements, amalgam, and composite resins exhibit weakened or altered physical properties when contaminated with moisture. Finally, equilibration procedures that require the use of inked ribbon are virtually impossible to perform without adequate saliva control. Many devices have been used to control saliva during dental treatment: cotton rolls, absorbent papers and other moisture absorbing materials, saliva ejectors, and high volume evacuators. Various drugs have also been successfully used but are often prohibited by potential side effects. Methantheline bromide was originally intended for use in the treatment of peptic ulcers.‘,’ It has long been considered an effective antisialagogue;3,4 however, potential side effects in both the healthy and compromised patient have prevented its widespread and routine use.2,3 An antihypertensive, clonidine hydrochloride, has shown merit recently in reducing saliva output with minimal side effects and fewer contraindications than methantheline bromide.5-9 The purposes of this study were 1) to compare in a double-blind fashion the inhibition of stimulated salivary output produced with clonidine hydrochloride, methantheline bromide, and a placebo in healthy volunteers and 2) to discern the effects of a standard meal on the action of clonidine hydrochloride.
METHODS Nine men and one woman from 18 to 48 years of age were selected for the study. Exclusion criteria were pregnancy, recent or present illness, glaucoma, cardio-
Funded by a grarlt from the Restorative Dentistry Study Club of Oklahoma City, Okla. *Associate Professor, Departments of Occlusion and Fixed Prosthodontics. **Professor and Chairman, Department of Occlusion. ***Professor, Department of Medicine, and Director, Clinical Pharmacology Program. THE JOURNAL
OF PROSTHETIC
DENTISTRY
vascular disease, presently taking medication, and known sensitivity to either of the medications being studied. According to a double-blind, Latin square cross-over design, each participant received clonidine hydrochloride (Catapres, Boehringer Ingelheim Ltd., Ridgefield, Conn.) 0.1 and 0.2 mg, methantheline bromide (Banthine, Searle & Co., Chicago, Ill.) 50 mg, and a placebo. Each medication was placed with a lactose filler in an opaque gelatin capsule. The tests were at least 48 hours apart. Oral intake was restricted to liquids during the 8 hours prior to receiving medication. Study parameters consisted of supine and standing blood pressure, heart rate, and salivary flow. Measurements were made immediately prior to administration of each medication and at 30,60,90, and 120 minutes after administration. Supine blood pressure was measured with a standard sphygmomanometer after 1 to 2 minutes’ rest, and standing blood pressure was obtained after 1 minute in the erect position. Each subject was given a piece of sugarless gum to chew immediately prior to each measurement to stimulate saliva flow. Participants were instructed to lick their lips and swallow immediately before the collection procedure began. During the collection process, the subjects were asked to manipulate their tongue, cheeks, and lips to stimulate maximum salivary flow. A timed 3-minute collection of saliva was obtained with a trap device installed in the line of a vacuum-energized saliva ejector (Fig. 1). The collected saliva was weighed and recorded. At the conclusion of each session, the subjects were questioned about noticeable side effects. After the ten participants had received the four test preparations, the identity of each medication was established and the effectiveness of the two doses of clonidine hydrochloride was assessed. One additional predetermined dose of clonidine hydrochloride (0.1, 0.2, or 0.3 mg) was administered to each participant immediately after a meal. Dose selection was based on desired effect. Blood pressure, pulse, and salivary flow measurements were made at the time intervals previously described. A three-way analysis of variance was performed to compare possible differences among treatment groups. A 663
WILSON,
WHITSETT,
AND
WHITSETT
Fig. 1. Saliva collection device consisting of saliva ejector (A), container (B), and vacuum tube (0. 0
80
eo
30 MINUTES
FOLLOWING
120
MEDICATION
Fig. 3. Saliva collection values for 0.2 mg clonidine hydrochloride taken after fasting and postprandial. Star indicates statistically significant change from zerominute measurement.
0
I
I 0
30
MINUTES
60
FOLLOWING
I 00
I 120
MEDICATION
Fig. 2. Saliva measurements for each drug and placebo recorded at five time intervals. Star indicates statistically significant change from zero-minute measurement of each drug. paired t test was performed to compare possible treatment differences with controls within each treatment group.
RESULTS All participants completed the study according to the protocol without experiencing unusual side effects. The saliva flow measurements for each drug were averaged and plotted for all time intervals (Fig. 2). Methantheline bromide began its onset of action within 30 minutes, while the effect of clonidine hydrochloride was not significantly different from initial measurements until 60 minutes after the medication was administered. Methantheline bromide and clonidine hydrochloride 0.2 mg showed significant reductions in salivation @ <.Ol) at the 60- and 120-minute intervals, with a highly significant decrease (p <.OOl) at 90 minutes. Clonidine hydrochloride 0.1 mg showed significant reductions in salivation @I <.05) at the 90- and 120-minute intervals. All showed a marked difference from the placebo measurement at the 90- and 120-minute intervals. 664
MINUTES
FOLLOWING
MEDICATION
Fig. 4. Supine and standing blood pressure values for 0.2 mg clonidine hydrochloride recorded at five time intervals. Star indicates statistically significant change from zero-minute measurement. The results of the clonidine hydrochloride postprandial administration were compared with the fasting values (Fig. 3). The fasting measurements showed a statistically significant decrease (p < .Ol) in salivation from the postprandial values. The onset of action and time to peak effect were similar for both conditions, as was the magnitude of response. Supine and standing blood pressure results for clonidine hydrochloride 0.2 mg were also compared (Fig. 4). The 0.2 mg dose of clonidine hydrochloride was associated with a statistically significant lower standing blood pressure for both the 90- and 120-minute intervals and a significant decrease in supine pressure at the 120-minute measurement. None of the subjects was symptomatic. Neither methantheline bromide nor the placebo had a statistically significant effect on blood pressure. Mean heart rate values did not change significantly NOVEMBER
1984
VOLUME
52
NUMBER
5
SALIVA
SUPPRESSION
WITH
DRUGS
with any of the treatment groups. In one participant, the heart rate increased from Y70to 110 beats/min after methantheline bromide ingestion. Two individuals had a IO-beat/min slowing of heart rate with clonidine hydrochloride. Neither was symptomatic.
DISCUSSION This study d.emonstrated that 50 mg methantheline bromide and 0.1 and 0.2 mg clonidine hydrochloride significantly reduced stimulated salivary flow in healthy volunteers. The 0.2 mg dose of clonidine hydrochloride was as effective as the 50 mg of methantheline bromide but had a slight1.y slower onset of action. The 0.1 mg dose of clonidine hydrochloride was more effective than the placebo but less than the 0.2 mg dose of clonidine hydrochloride. While considerable reduction occurred in stimulated salivary secretion, two questions remain. Was this experimental model greater or less than the stimulation expected with a dental procedure? Was the degree of inhibition satisfactory to maintain an operative field free from moisture contamination? While blood pressure and heart rate were not adversely affected by the drugs studied, it is likely that individuals with hypertension would experience some lowering of blood pressure with 0.2 mg clonidine hydrochloride. Although it is speculative, clonidine hydrochloride could attenuate the hypertensive response some patients have during a dental procedure. It is hoped that work in progress will shed further light on this matter. Surprisingly, the postprandial administration of clonidine hydrochloride produced a reduction in salivary flow equivalent to the fasting values. Thus patients who are not in a fasting state might. have an adequate response without unusual delay. Known side effects of methantheline bromide include blurring of vision due to dilation of the pupils, loss of accommodation, tachycardia, constipation, urinary retention, and dry skin.’ In addition, it may precipitate glaucoma and cause excessive reactions in the elderly. While these side effects were not seen in this study, it should be pointed out that the participants were healthy volunteers wh.o received no other drugs. Numerous drugs have ant icholinergic properties and could produce additive effects with methantheline bromide; thus, special caution should be used in administering methantheline bromide. The most common side effects of clonidine hydrochloride include dry mouth and drowsiness.‘0 Postural hypotension is umommon unless it is present prior to clonidine hydrochloride administration. In general, it should be used cautiously in patients who receive other antihypertensive drugs. Importantly, it is a drug without listed contraindications. Of the two drugs tested, clonidine hydrochloride is the drug of choice because its most likely side effect is that of THE JOURNAL
OF PROSTHETIC
DENTISTRY
sedation, which is not usually considered an undesirable condition for dental treatment. It should be pointed out that there is no drug that is officially approved by the U.S. Food and Drug Administration for inhibiting salivary secretion during dental procedures. However, this does not preclude the careful and limited use of effective drugs when clinically indicated.
CONCLUSIONS 1. Methantheline bromide (50 mg) and clonidine hydrochloride (0.1 and 0.2 mg) both reduced salivary output. 2. Methantheline bromide (50 mg) and clonidine hydrochloride (0.2 mg) were equally effective in the reduction of salivation 60, 90, and 120 minutes after medication was administered. 3. The reduction in supine blood pressures was not clinically significant for either drug at any dose tested. 4. Clonidine hydrochloride was sufficiently effective in salivary reduction after fasting and postprandial. The assistance of Robert Murphree in the statistical analysis of data is gratefully acknowledged.
REFERENCES 1.
2. 3. 4. 5.
6.
7.
8.
9.
10.
Levin. E., Kirsner, J. B., and Palmer, W. L.: The elrect of Banthine on gastric secretion in man. Gastroenterology 21:339, 1952. Winkelstein, A.: Banthine for peptic ulcer: Clinical and physiologic considerations. Gastroenterology 20:464, 1952. Council on Dental Therapeutics: Accepted Dental Therapeutics, ed 38. Chicago, 1979, American Dental Association, p 247. Gurney, B. F.: Chemotherapy in dental practice. Antisialogogues. Dent Digest 73:270, 1967. Findlay, D., and Lawrence, J. R.: An alternative method of assessing changes in salivary How: Comparison of the effects of clonidine and tiamenidine (HOE 440). Eur J Clin Pharmacol 14:231, 1978. Wing, L. M. H., Reid, J. L., Davies, D. S., Neill, E. A. M., Tippett, P., and Dollery, C. T.: Pharmarokinetic and concentration-Effect relationships of clonidine in essential hypertension. Eur J Clin Pharmacol 12:463, 1977. Davies, D. S., Wing, L. M. H., Reid, J. L., Neill, E. A. M., Tippett, P., and Dollery, C. T.: Pharmacokinetics and concentrations--Effect relationships of intravenous and oral clonidine. Clin Pharmacol Ther 21:593, 1977. Reid, J. L., Wing, L. M. H., Mathias, C. J., Frankel, H. L., and Neill, E. A. M.: The central hypotensive effect of clonidine. Clin Pharmacol Ther 21:375, 1977. Rand, hi. J., Rush, M., and Wilson, J.: Some observations on the inhibition of salivation by St 155{2-(2,6-Dichlorophenylamine)-2-Imidazoline hydrochloride, Catapres, Catapresan. Eur J Pharmacol 5~168, 1969. AMA Department of Drugs: AMA Drug Evaluations, ed 4. New York, 1980, American Medical Association, pp 567, 991,
Neprm1
rrl/U'Jl.\
111.'
DR. EDWIN L. WILSON, JR. UNIVERSITYOF OKLAHOMA COLI.EGEOF DENTISTRY P.O. Box 26901 OKLAHOMA CITY, OK 73190
665
T
he maintenance of an operative field free of moisture contamination is important in many dental procedures. Impression materials such as the silicones and polysulfides possess hydrophobic properties. Cements, amalgam, and composite resins exhibit weakened or altered physical properties when contaminated with moisture. Finally, equilibration procedures that require the use of inked ribbon are virtually impossible to perform without adequate saliva control. Many devices have been used to control saliva during dental treatment: cotton rolls, absorbent papers and other moisture absorbing materials, saliva ejectors, and high volume evacuators. Various drugs have also been successfully used but are often prohibited by potential side effects. Methantheline bromide was originally intended for use in the treatment of peptic ulcers.‘,’ It has long been considered an effective antisialagogue;3,4 however, potential side effects in both the healthy and compromised patient have prevented its widespread and routine use.2,3 An antihypertensive, clonidine hydrochloride, has shown merit recently in reducing saliva output with minimal side effects and fewer contraindications than methantheline bromide.5-9 The purposes of this study were 1) to compare in a double-blind fashion the inhibition of stimulated salivary output produced with clonidine hydrochloride, methantheline bromide, and a placebo in healthy volunteers and 2) to discern the effects of a standard meal on the action of clonidine hydrochloride.
METHODS Nine men and one woman from 18 to 48 years of age were selected for the study. Exclusion criteria were pregnancy, recent or present illness, glaucoma, cardio-
Funded by a grarlt from the Restorative Dentistry Study Club of Oklahoma City, Okla. *Associate Professor, Departments of Occlusion and Fixed Prosthodontics. **Professor and Chairman, Department of Occlusion. ***Professor, Department of Medicine, and Director, Clinical Pharmacology Program. THE JOURNAL
OF PROSTHETIC
DENTISTRY
vascular disease, presently taking medication, and known sensitivity to either of the medications being studied. According to a double-blind, Latin square cross-over design, each participant received clonidine hydrochloride (Catapres, Boehringer Ingelheim Ltd., Ridgefield, Conn.) 0.1 and 0.2 mg, methantheline bromide (Banthine, Searle & Co., Chicago, Ill.) 50 mg, and a placebo. Each medication was placed with a lactose filler in an opaque gelatin capsule. The tests were at least 48 hours apart. Oral intake was restricted to liquids during the 8 hours prior to receiving medication. Study parameters consisted of supine and standing blood pressure, heart rate, and salivary flow. Measurements were made immediately prior to administration of each medication and at 30,60,90, and 120 minutes after administration. Supine blood pressure was measured with a standard sphygmomanometer after 1 to 2 minutes’ rest, and standing blood pressure was obtained after 1 minute in the erect position. Each subject was given a piece of sugarless gum to chew immediately prior to each measurement to stimulate saliva flow. Participants were instructed to lick their lips and swallow immediately before the collection procedure began. During the collection process, the subjects were asked to manipulate their tongue, cheeks, and lips to stimulate maximum salivary flow. A timed 3-minute collection of saliva was obtained with a trap device installed in the line of a vacuum-energized saliva ejector (Fig. 1). The collected saliva was weighed and recorded. At the conclusion of each session, the subjects were questioned about noticeable side effects. After the ten participants had received the four test preparations, the identity of each medication was established and the effectiveness of the two doses of clonidine hydrochloride was assessed. One additional predetermined dose of clonidine hydrochloride (0.1, 0.2, or 0.3 mg) was administered to each participant immediately after a meal. Dose selection was based on desired effect. Blood pressure, pulse, and salivary flow measurements were made at the time intervals previously described. A three-way analysis of variance was performed to compare possible differences among treatment groups. A 663
WILSON,
WHITSETT,
AND
WHITSETT
Fig. 1. Saliva collection device consisting of saliva ejector (A), container (B), and vacuum tube (0. 0
80
eo
30 MINUTES
FOLLOWING
120
MEDICATION
Fig. 3. Saliva collection values for 0.2 mg clonidine hydrochloride taken after fasting and postprandial. Star indicates statistically significant change from zerominute measurement.
0
I
I 0
30
MINUTES
60
FOLLOWING
I 00
I 120
MEDICATION
Fig. 2. Saliva measurements for each drug and placebo recorded at five time intervals. Star indicates statistically significant change from zero-minute measurement of each drug. paired t test was performed to compare possible treatment differences with controls within each treatment group.
RESULTS All participants completed the study according to the protocol without experiencing unusual side effects. The saliva flow measurements for each drug were averaged and plotted for all time intervals (Fig. 2). Methantheline bromide began its onset of action within 30 minutes, while the effect of clonidine hydrochloride was not significantly different from initial measurements until 60 minutes after the medication was administered. Methantheline bromide and clonidine hydrochloride 0.2 mg showed significant reductions in salivation @ <.Ol) at the 60- and 120-minute intervals, with a highly significant decrease (p <.OOl) at 90 minutes. Clonidine hydrochloride 0.1 mg showed significant reductions in salivation @I <.05) at the 90- and 120-minute intervals. All showed a marked difference from the placebo measurement at the 90- and 120-minute intervals. 664
MINUTES
FOLLOWING
MEDICATION
Fig. 4. Supine and standing blood pressure values for 0.2 mg clonidine hydrochloride recorded at five time intervals. Star indicates statistically significant change from zero-minute measurement. The results of the clonidine hydrochloride postprandial administration were compared with the fasting values (Fig. 3). The fasting measurements showed a statistically significant decrease (p < .Ol) in salivation from the postprandial values. The onset of action and time to peak effect were similar for both conditions, as was the magnitude of response. Supine and standing blood pressure results for clonidine hydrochloride 0.2 mg were also compared (Fig. 4). The 0.2 mg dose of clonidine hydrochloride was associated with a statistically significant lower standing blood pressure for both the 90- and 120-minute intervals and a significant decrease in supine pressure at the 120-minute measurement. None of the subjects was symptomatic. Neither methantheline bromide nor the placebo had a statistically significant effect on blood pressure. Mean heart rate values did not change significantly NOVEMBER
1984
VOLUME
52
NUMBER
5
SALIVA
SUPPRESSION
WITH
DRUGS
with any of the treatment groups. In one participant, the heart rate increased from Y70to 110 beats/min after methantheline bromide ingestion. Two individuals had a IO-beat/min slowing of heart rate with clonidine hydrochloride. Neither was symptomatic.
DISCUSSION This study d.emonstrated that 50 mg methantheline bromide and 0.1 and 0.2 mg clonidine hydrochloride significantly reduced stimulated salivary flow in healthy volunteers. The 0.2 mg dose of clonidine hydrochloride was as effective as the 50 mg of methantheline bromide but had a slight1.y slower onset of action. The 0.1 mg dose of clonidine hydrochloride was more effective than the placebo but less than the 0.2 mg dose of clonidine hydrochloride. While considerable reduction occurred in stimulated salivary secretion, two questions remain. Was this experimental model greater or less than the stimulation expected with a dental procedure? Was the degree of inhibition satisfactory to maintain an operative field free from moisture contamination? While blood pressure and heart rate were not adversely affected by the drugs studied, it is likely that individuals with hypertension would experience some lowering of blood pressure with 0.2 mg clonidine hydrochloride. Although it is speculative, clonidine hydrochloride could attenuate the hypertensive response some patients have during a dental procedure. It is hoped that work in progress will shed further light on this matter. Surprisingly, the postprandial administration of clonidine hydrochloride produced a reduction in salivary flow equivalent to the fasting values. Thus patients who are not in a fasting state might. have an adequate response without unusual delay. Known side effects of methantheline bromide include blurring of vision due to dilation of the pupils, loss of accommodation, tachycardia, constipation, urinary retention, and dry skin.’ In addition, it may precipitate glaucoma and cause excessive reactions in the elderly. While these side effects were not seen in this study, it should be pointed out that the participants were healthy volunteers wh.o received no other drugs. Numerous drugs have ant icholinergic properties and could produce additive effects with methantheline bromide; thus, special caution should be used in administering methantheline bromide. The most common side effects of clonidine hydrochloride include dry mouth and drowsiness.‘0 Postural hypotension is umommon unless it is present prior to clonidine hydrochloride administration. In general, it should be used cautiously in patients who receive other antihypertensive drugs. Importantly, it is a drug without listed contraindications. Of the two drugs tested, clonidine hydrochloride is the drug of choice because its most likely side effect is that of THE JOURNAL
OF PROSTHETIC
DENTISTRY
sedation, which is not usually considered an undesirable condition for dental treatment. It should be pointed out that there is no drug that is officially approved by the U.S. Food and Drug Administration for inhibiting salivary secretion during dental procedures. However, this does not preclude the careful and limited use of effective drugs when clinically indicated.
CONCLUSIONS 1. Methantheline bromide (50 mg) and clonidine hydrochloride (0.1 and 0.2 mg) both reduced salivary output. 2. Methantheline bromide (50 mg) and clonidine hydrochloride (0.2 mg) were equally effective in the reduction of salivation 60, 90, and 120 minutes after medication was administered. 3. The reduction in supine blood pressures was not clinically significant for either drug at any dose tested. 4. Clonidine hydrochloride was sufficiently effective in salivary reduction after fasting and postprandial. The assistance of Robert Murphree in the statistical analysis of data is gratefully acknowledged.
REFERENCES 1.
2. 3. 4. 5.
6.
7.
8.
9.
10.
Levin. E., Kirsner, J. B., and Palmer, W. L.: The elrect of Banthine on gastric secretion in man. Gastroenterology 21:339, 1952. Winkelstein, A.: Banthine for peptic ulcer: Clinical and physiologic considerations. Gastroenterology 20:464, 1952. Council on Dental Therapeutics: Accepted Dental Therapeutics, ed 38. Chicago, 1979, American Dental Association, p 247. Gurney, B. F.: Chemotherapy in dental practice. Antisialogogues. Dent Digest 73:270, 1967. Findlay, D., and Lawrence, J. R.: An alternative method of assessing changes in salivary How: Comparison of the effects of clonidine and tiamenidine (HOE 440). Eur J Clin Pharmacol 14:231, 1978. Wing, L. M. H., Reid, J. L., Davies, D. S., Neill, E. A. M., Tippett, P., and Dollery, C. T.: Pharmarokinetic and concentration-Effect relationships of clonidine in essential hypertension. Eur J Clin Pharmacol 12:463, 1977. Davies, D. S., Wing, L. M. H., Reid, J. L., Neill, E. A. M., Tippett, P., and Dollery, C. T.: Pharmacokinetics and concentrations--Effect relationships of intravenous and oral clonidine. Clin Pharmacol Ther 21:593, 1977. Reid, J. L., Wing, L. M. H., Mathias, C. J., Frankel, H. L., and Neill, E. A. M.: The central hypotensive effect of clonidine. Clin Pharmacol Ther 21:375, 1977. Rand, hi. J., Rush, M., and Wilson, J.: Some observations on the inhibition of salivation by St 155{2-(2,6-Dichlorophenylamine)-2-Imidazoline hydrochloride, Catapres, Catapresan. Eur J Pharmacol 5~168, 1969. AMA Department of Drugs: AMA Drug Evaluations, ed 4. New York, 1980, American Medical Association, pp 567, 991,
Neprm1
rrl/U'Jl.\
111.'
DR. EDWIN L. WILSON, JR. UNIVERSITYOF OKLAHOMA COLI.EGEOF DENTISTRY P.O. Box 26901 OKLAHOMA CITY, OK 73190
665