Acta med. scand. Vol. 184, pp. 201-209, 1968

COMPARATIVE STUDIES ON INTRAMUSCULAR AND ORAL EFFECTIVE DOSES OF SOME ANTICHOLINERGIC DRUGS

Jan Moller and Anders RosCn

From the Department of Medicine, Section of Clinical Pharmacology, Karolinska Instituter at Serafimerlasarettet, Stockholm, Sweden

Abslract. Sixteen healthy volunteers received propan- theline, methylscopolamine or butylscopolamine in oral as well as i.m. administration. After propantheline and methylscopolamine salivary secretion was found to be more influenced than the heart rate and the near point of accommodation. The relations between i.m. and oral doses producing comparable total effects on salivation were 1 : 10 for propantheline and 1 : 100 for methyl- scopolamine. After oral butylscopolamine in doses up to 480 mg no anticholinergic effects were observed. In con- trast to the other compounds, i.m. butylscopolamine produced only transient effects and influenced mainly the near point of accommodation. It is concluded that presumably less than 10 per cent of methylscopolamine and probably only very little of butylscopolamine is ab- sorbed in the gastrointestinal tract.

The ratio between parenteral and oral effective doses of drugs reflects some of their pharma- cological properties, among which the gastroin- testinal absorption may be the most important. Although such a determination is relatively simple to perform, published observations of this kind are few.

In this investigation effective intramuscular and oral doses of propantheline, methyl- and butyl- scopolamine were studied in man on the salivary secretion, the heart rate and the accommodation of the eye. The responses to the two different administrations of each drug were compared quantitatively in the same subjects.

MATERIAL AND METHODS Fifty-one experiments were performed using 16 healthy volunteers aged between 20 and 35, comprising nine females and seven males. The salivary secretion, the heart rate and the near point of accommodation were studied in the following manner. The salivary secretion was stimulated by having the subject chew a tablet of

ascorbic acid (250 mg) during 30 sec. The saliva ob- tained, including that produced during the following 30 sec, was spat out and the total volume was measured as previously described (11). In this paper the term salivary secretion refers only to saliva obtained in this manner. The heart rate was taken as being that of the frequency of the radial pulse. The near point of accommodation was determined as the shortest distance at which the subject was able to read very fine print with one eye. In this test each subject consistently used the same eye.

The drugs were administered after the subjects had rested, in a sitting position, for 40 min. During this time three determinations of the three parameters were made at intervals of 15 min. At the beginning of the investiga- tion it was noted that the first of the three determina- tions of salivary secretion constantly showed a lower value than the following two and so this value was excluded. At the end of the investigation, when the intramuscular route was used with the same subjects, all three control values were similar.

Oral administration was in the form of commercially available tablets. The parameters were continuously de- termined at hourly intervals during the following eight hours. Placebo tablets containing lactose were also given. The experiments were carried out with a double blind technique.

The injections were given i.m. in the thigh. The para- meters were determined at intervals of 15 min during the first hour, at intervals of 30 min during the second hour, and at hourly intervals subsequently up to and including the eighth hour after the administration of the drug.

The subjects were either fasting or had had a light breakfast about two hours before the experiment. They usually had a light lunch three or four hours after the drugs had been given. The drugs studied, the doses used, the number of experiments and the compound each sub- ject received are shown in Table I. One subject received atropine. The effects of oral administration of propan- theline and methylscopolamine were studied in 11 sub- jects. The responses to intramuscular administration were studied on four of these subjects.

Quantitative comparisons between the effects of intra- muscular and oral administration of the drugs were car- ried out as follows. The mean of each parameter for the predrug estimations was drawn as a continuous baseline

Acta med. scnnd. 184

202 J . Moller and A . Rose'n

Table I. Participating subjects on each drug, route of administration and dose

Drug Intramuscular dose (mg) Subjects

Placebo (lactose) Atropine sulphate (Atropin, ACO)

RS, HB, lW, PH, E K 2 IJ 0.33 IJ 4 IJ 1 .O I J

Propantheline bromide 30 (Pro-Banthine, Searle) 60

120

(Skopyl, Pharmacia) 8 16

Butylscopolamine bromide 240 (Buscopan, Boehringer/ 480 Ingelheim)

Methylscopolamine nitrate 4

3.0 IJ CH, BK, EK, PH 3 CH, BK CH, BK, EK, PH 10 CH, BK CH, BK, EK, PH TM, IS, RT, BMC, E W 0.16 CO, J M CO, JM, RT, BMC 0.50 CO, JM CO, JM, RT, BMC IW, KO 10 IW, KO IW, KO 30 IW, K O

on a diagram. The hourly post-administration values, which formed an effect curve, were entered on this dia- gram. The area between the baseline and the effect curve was measured planimetrically for each subject, parameter and dose. These areas were then compared.

Student's f-test was used when a statistical analysis of the material was performed.

RESULTS The placebo group had a constant response to stimulation of salivary secretion during the eight hours of the experiment (Fig. 1). The heart rate showed no noteworthy variations with the excep- tion of a slight increase at the determination that followed lunch (the fourth hour). The near point

of accommodation was increased in some of the subjects at the last two determinations.

Atropine, 2 mg orally, caused a moderate in- hibition of the salivary secretion within one hour; a 4 mg oral dose produced a greater inhibition at this time. However, during the period of eight hours there was no significant difference between the total effects of the two doses (Fig. 2 4 . Intra- muscular administration of 3 mg of atropine caused a corresponding degree of inhibition of salivary secretion during the eight-hour period (Fig. 2 b). During the same period of observation the effect on heart rate of 4 mg of atropine orally was approximately equal to that of 1 mg intra-

- ern

NEAR-POINT OF

ACC OM MO D AT ION 1 9 80 beqplmin

HEART RATE

SAL I VARY

SECRETION

c c i 7 0 1 To 6 I

4

2

hours 1 placebo orally

Fig. I . The influence of oral placebo on three cholinergic €unctions in five subjects (means

Acru w e d . scand. 184

s.E.).

12

1C

0

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ACCOMMODATION 9

I

6

H E A R T RATE

Effective doses of anticholinergic drugs 203

cm

SALl VARY

S E C R E T I O N

I.J. 1 9 4 2

cm

ACCOMMODATION

NEAR-POINT OF

w - -

k

L -- t atropine sulfate orally

a

HEART RATE

_ _ _ _ _ 0 33 m g - 1 0 m g - 30 rng

0 O 3 3 m g SALIVARY

SECRETION B 1 0 mg

I 3.0 mg

I J hours

1942 t atropine sulfate im.

b Fig. 2. (a) Anticholinergic effects of atropine, 2 and 4 mg orally, in suhject I. J. (b) Anticholinergic effects of atropine, 0.33, 1.0 and 3.0 mg i.m., in subject I. J.

muscularly. The near point of accommodation 120 mg resulted in a substantial inhibition of the tended to increase after the largest doses of secretion (p<O.Ol) and, at the higher dose, in atropine (Fig. 2 a and b) . tachycardia as well ( p < 0.05) (Fig. 3). No effect

Propantheline, 30 mg orally, caused a slight on the near point of accommodation was observed decrease in the salivary secretion. Sixty mg and in two subjects, while in the remaining two the

Acta med. scand. 184

204 J . Moller and A . Rose‘n

crn

NEAR-POINT OF

ACCOMMODATION

H E A R T RATE

S A L I V A R Y

SECRETION 4

2

-112-1t. 0 1 2 3 4 5 6 7 8-v2-%0 1 2 3 4 5 6 7 8-m-uO 1 2 3 4 5 6 7 8 hours

n=4 f 30mg 1 60mg t 120mg

Fig. 3. Anticholinergic effects of propantheline, 30, 60 and 120 mg orally, in four subjects (means+s.E.).

distance increased moderately after the highest dose.

Thirty mg of propantheline orally depressed salivation during eight hours approximately as much as 3 mg intramuscularly in the same sub- jects. The effect of 60 mg orally corresponded rather well to that of 10 mg intramuscularly. The results from one of the two subjects are shown in Fig. 4 a and b. The other subject showed similar results. Propantheline, 120 mg orally, in- creased the heart rate in both subjects to the same degree as 10 mg intramuscularly.

Methylscopolamine, 16 mg orally, caused an inhibition of salivation (p<O.O5) and a tachy- cardia (Fig. 5). It was found that the effect on salivation obtained with this dose corresponded quantitatively to that of 0.16 mg administered intramuscularly (Fig. 6 a and b). In one subject the increase in the heart rate following 16 mg of methylscopolamine orally was somewhat less than that of 0.50 mg intramuscularly (Fig. 6 a and b). In the other subject 16 mg orally increased the heart rate half as much as 0.50 mg intra- muscularly. At the doses used, neither oral nor parenteral administration had any effect on the near point of accommodation.

Butylscopolamine in the doses of 240 and 480 mg orally and 10 mg intramuscularly did not influence salivation, heart rate or the near point of accommodation. The results from one of the

Acta med. scand. 184

subjects are shown in Fig. 7 a and b. Thirty mg intramuscularly caused in this subject a slight inhibition af salivary secretion, an increase in heart rate and a very pronounced increase in the near point of accommodation. In the other sub- ject the effects were quantitatively less. In both subjects the effects were of very short duration.

Symptoms. None of the subjects in the placebo group experienced any symptoms. The others felt dryness of the mouth simultaneously with demonstrable inhibition of salivation. In two subjects this feeling was reported without measur- able salivary inhibition. When the decrease of the salivary secretion was pronounced, the subjects also complained of roughness or slight pain in the throat. One subject reported “tired eyelids” after 16 mg of methylscopolamine orally, while another complained of headache after 0.5 mg intra- muscularly. One subject became drowsy after 10 mg of propantheline, another after 10 mg of butylscopolamine intramuscularly.

DISCUSSION

As the results are based on repeated measure- ments of three parameters during more than eight hours, it was considered important to evaluate the possible appearance of other than drug-induced fluctuations in the parameters. In the placebo studies no such significant variations were ob-

Effective doses of anticholinergic drugs 205

NEAR- POINT OF

ACCOMMODATION

cm

13 1 P

HEART RATE

SALIVARY

SECRETION

B.K. 1943

cm

t propantheline bromide ora l l y

a

HEART RATE

SALIVARY

SECRETION

B.K. 1943

-112 --1/4

_ _ _ _ 30 mg

__ 60 mg

-120 mg

13 12

10

NEAR-POINT OF ACCOMMODATION 11

3 mg

___ 10 mg

_ - _ -

/' , \ r' '\

0 3mg

a10rng

hours

t propantheline bromide i.m.

b Fig. 4. (a) Anticholinergic effets of propantheline, 30, 60 and 120 mg orally, in subject B. K. (b) Anticholinergic

effects of propantheline, 3 and 30 mg i.m., in subject B. K.

Acfa med. scnnd. 184

206 J . Moller and A . Rose'n

'5 AL I VARY

SECRETION

-v2-114 0 1 2 3 4 5 6 7 8 -1n-tN 0 1 2 3 4 5 6 7 8 - t u - 1 ~ 0 1 2 3 4 5 6 7 8 hours

t 4mg

n= 5 Fig. 5. Anticholinergic effects of methylscopolamine, 4, 8 and 16 mg orally, in four subjects (means+s.E.).

served apart from a moderate increase in heart rate in connection with lunch and a mild decrease in the accommodation of the eye during the seventh and eighth hour, possibly due to fatigue.

For further evaluation of the method the ef- fects of atropine were studied and found to be in accordance with earlier observations (2) and with the known fact that atropine is well absorbed from the gastrointestinal tract.

The ratio between the effective intramuscular and oral doses of propantheline was found to be approximately 1 : 10. There seem to be no earlier published studies comparing the effects of par- enteral and oral propantheline in the same sub- ject. The effective oral dose is similar to that previously observed by other authors describing effects on the salivary secretion (14) and the gastric acidity (6, 8, 10, 13).

The ratio between intramuscular and oral ef- fective doses of methylscopolamine on salivation was found to be approximately 1 : 100. The mini- mum oral dose of methylscopolamine required to produce any effect on the studied parameters was about 8 mg. As 0.16 mg intramuscularly produced extensive effects lasting a couple of hours, it is likely that less than 10 per cent of the dose ad-

Acrcd nied. scand. 184

t 8mg

n=4

t 16mg

ministered orally was absorbed. Levine (9) showed that 10 to 30 per cent of methylscopolamine is absorbed from ligated intestinal loops in rats.

Investigations of cholinergic functions other than those studied here have also given results that indicate an incomplete absorption of methyl- scopolamine in the gastrointestinal tract. The ratio between the parenteral and oral effective dose of the compound on gastric secretion has been found to be 1 : 500 (6, 7). These authors have used the bromide salt of the compound, while the nitrate was used in the present study.

The effects of parenteral butylscopolamine were found to differ both qualitatively and quantita- tively from those caused by the other drugs. Firstly, butylscopolamine caused effects of re- markably short duration. Secondly, its effect on the near point of accommodation was extensive in a dose which produced only a moderate effect on salivary secretion. The other compounds were distinguished by more protracted effects and by a more extensive effect on the salivary secretion than on the other parameters studied. Such effects are considered to characterize anticholinergic drugs (4, 12).

The brief effect of butylscopolamine indicates

Effective doses of anticholinergic drugs 207

11 - 10 - 9 -

N E A R - P O I N T OF

ACCOMMODATION - 8rng

H E A R T RATE

SALl VARY

SECRETION

J. M.

1935

NEAR-POINT OF

ACCOMMODATION

H E A R T R A T E

SA L I VARY

SECRETION

J.M. 1935

1 8rng

16mg

-1/2 -1/4 0 1 2 hours

1 methylscopolamine nitrate orally

a

c m

d' \*.---

I

1 methylscopolamine nitrate orally

a

c m 13 ;:I -,- d' \*.--- 10 -140beo151mln

-130

-120

-110

-100

-90

t methylscopolamine nitrute i.m

b Fig . 6. (a) Anticholinergic effects of methylscopolamine, 8 and 16 mg orally, in subject J. M. (b) Anticholinergic

effects of methylscopolamine, 0.16 and 0.50 mg i.m., im subject J. M.

a rapid inactivation and/or a rapid excretion. Herxheimer and Haefeli (5) estimated this to be about 20 mg per hour for a 70 kg adult, which is far from sufficient to explain the ineffectiveness of oral administration of 480 mg. Probably only

a very small amount of administered butylscopol- amine is absorbed in the gastrointestinal tract, as. has previously been pointed out (3, 5). The in- effectiveness of oral butylscopolamine has also been demonstrated on gastric acidity, osmolarity

Acta rned. scand. 184

208 J . Moller and Rosin

NEAR-POINT OF

ACCOMMODATION

H E A R T R A T E

SALIVARY

S E C R E T I O N

I

NEAR-POINT O F

ACCOMMODATION

H E A R T RATE

I . '

A .

W. 1946

c m 22 - 21 - 20- 19 - 18 - 17- 16- 15- 14 - 13- 12- 11,

cm 14 i

_ _ _ _ _ 2 4 0 m g I__ 4 8 0 m g

6 1

t butylscopolarnine bromide orally U

SALIVARY

SECRETION

I .w. 1946 t butylscopolamine bromide i.m.

h Fig. 7. (a) The influence of butylscopolamine, 240 and 480 mg orally, on three cholinergic functions in subject

and gastric evacuation rate. Thus 480 mg pro- duced only slight effects on these parameters,

I. W. (6 ) The influence of butylscopolamine, 10 and 30 mg i.m., on three cholinergic functions in subject I. W.

ACKNOWLEDGEMENTS while small amounts of oral atropine and pro- pantheline elicited extensive anticholinergic re- sponses (1).

The present investigation was supported by the Swedish

the Association of the Swedish Pharmaceutical Industry. Medical Research Council (Project No. B68-14X-227)

Arta med. scand. 184

REFERENCES 1. Bromster, D., Carlberger, G., Lundh, G., Moller, J.

& Rosbn, A.: The influence of some oral anticho- linergics on gastric emptying and osmolarity. To be published.

2. Cullumbine, H., McKee, W. H. E. & Creasey, N. H.: The effects of atropine sulphate upon healthy male subjects. Quart. J. exp. Physiol. 40: 309, 1955.

3. Drug Therap. Bull. 1: 39, 1963. 4. Herxheimer, A,: A comparison of some atropine-like

drugs in man, with particular reference to their end- organ specificity. Brit. J. Pharmacol. 13: 184, 1958.

5 . Herxheimer, A. & Haefeli, L.: Human pharmacology of hyoscine butylbromide. Lancet 2: 418, 1966.

6. Kirsner, J. B. & Palmer, W. L.: Newer gastric anti- secretory compounds. Amer. med. Ass. J. 151: 798, 1953.

7 . Kirsner, J. B., Levin, E. & Palmer, W. L.: Pamine bromide: Gastric antisecretory effects and thera- peutic usefulness in peptic ulcer and other gastro- intestinal disorders. Gastroenterology 26: 852, 1954.

Effective doses of anticholinergic drugs 209

8. Kirsner, J. B., Ford, H. & Kassriel, R. S.: Anti- cholinergic drugs in peptic ulcer. Med. Clin. N. Amer. 41: 495, 1957.

9. Levine Mitchell, R.: The intestinal absorption of the quaternary derivates of atropine and scopolamine. Arch. int. Pharmacodyn. 121: 146, 1959.

10. McKenna, R. D., Bourne, R. H. & Arendt, E.: A comparative study of three anticholinergic drugs - Monodral, Pamine and Pro-Banthine. Canad. med. Ass. J. 74: 685, 1956.

11 . Miiller, J. & Rosbn, A.: Pharmacological studies of the effectiveness of anticholinergic drugs administered perorally. Lakartidn. Suppl. 2: 63, 1967.

12. Nyman, E.: Studien iiber die Atropingruppe. Acta physiol. scand. Suppl. 10, 1942.

13. Sun, D. C. H. C Shay, H.: Optimal effective dose of anticholinergic drugs in peptic ulcer treatment. Arch. intern. Med. 97: 442, 1956.

14. Zupko, A. G. & Prokop, L. D.: The newer anti- cholinergic agents. 11. Effectiveness as antisialogogues. J. Amer. pharm. Ass. 43: 219, 1954.

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