Indian J Physiol Pharmacol 1998; 42 (3) : 395-400

COMPARATIVE EFFECTS OF HYOSCINE BUTYLBROMIDE AND ATROPINE SULPHATE ON SLEEP ARCHITECTURE IN HEALTHY HUMAN VOLUNTEERS

GAJENDRA PRASAD RAUNIAR, BATMANABANE GITANJALI* AND CHANOLEAN SHASHINDRAN

Sleep Disorders Laboratory, Department of Pharmacology, Jowaharlal btstit/lte of Postgraduate Medical Education & Research. Pondicherry - 605 006

(Received on July 24, 1997)

Abstract: The changes in sleep architecture, heart rate and respiratory rate to hyoscine butylbromide (HBBl, a peripherally acting anticholinergic was studied. These effects were compared with that of atropine sulphate, a drug known to cross the blood brain barrier. The study followed a single blind cross over design with a one week washout period. Atropine sulphate (0.4 mg) and HBB (10 mg) were gi'ten intravenously to ten adult healthy male volunteers before sleep onset. Normal saline was used as control. All night sleep polysomnography was done with the standard montage for sleep staging. Respiration and airnow were also monitored. Rapid eye movement (REM) latency was significantly increased with both the drugs whereas the duration of REM sleep was decreased only with atropine. Slow wave sleep ( SWS ) was also increased significantly by atropine. There was no change in heart rate, or respiratory rate during any of the sleep stages. HBD affects the initiation of REM sleep whereas atropine affects both its initiation lind maintenance. Key words: sleep polysomnography sleep stages atropine hyoscine butylbromide

INTRODUCTION cholinergic drugs given prior to the onset of sleep could be expected to tilt the balance Acetylcholine (ACh) hal' an important towards an increased sympathetic drive. role in wakefulness and vigilance. Cholinergic agonists elicit cortical activation Hyoscine butyl bromide (HBB), an and arousal while anticholinergic agents anticholinergic agent which does not cross produce a decrease in vigilance. ACh is the the blood brain barrier (BBB) is commonly main neurotransmitter implicated in Rapid used as an antispasmodic and as Eyc Movement (REM) sleep (1). During premedication prior to surgery (3,4). slecp, sympathetic activity decreases while However, the effect of this drug on sleep is parasympathetic activity increases (2). Anti not known. HBB was administered to young,

·Corresponding Author 396 Rauniar et a1 Indian J Physiol Pharmaeol 1998; 42(3) healthy male volunteers prior to sleep onset equipment from Healthdyne Technologies, with the aim of studying the alterations in Marietta, United States of America. The sleep architecture, heart rate and respiratory system was connected to an IBM 486 rates during the various stages of sleep. Personal Computer. All sleep data were These effects were compared with atropine stored on magneto-optical disks with a sulphate which is known to cross the BBB. capacity of 1.3 Gigabytes. Alice 3 version 1.19 software supplied by Healthdyne was METHODS used for analysis of sleep records.

The study was conducted in ten adult Electroencephalography (EEG), electro­ healthy male volunteers. Subjects in the age oculography {EO G), air-inflow, chest group of 18-31 years were included. All the movements, abdominal movements, oxygen volunteers were free from any systemic saturation and snoring sounds were disease, including sleep or breathing recorded during all night sleep. EEG, disorders. All subjects were non-smokers EOG and EMG were used to stage sleep. and did not take alcohol on a regular basis. ECG was used for calculating heart None of the volunteers had consumed rate while respiratory rate was recorded alcohol for 48 hours before the study nor from air-inflow, chest and abdominal were they taking any medication. Written movements. informed consent was obtained from the volunteers prior to the study. The study was Each subject was studied for 4 nights in approved by the JIPMER Ethics Committee. a split-type air-conditioned, partially sound­ proof room, while the recording was done The study followed a single blind in an adjacent room. The first night was an crossover design, where the subjects were acclimatization night, where the subjects blind to the nature of the drug. All subjects slept with all electrodes, respiratory belts received placebo and the two drugs in a and microphone fixed. No data was collected manner which eliminated bias due to order on this night since it is known that many of treatment. A washout period of one week subjects suffer from a "first night effect" was given between each treatment. (5). Data was collected only on subsequent nights. Subjects came to the Sleep Disorders Atropine sulphate (N.!. Pharmaceutical Laboratory at 8.45 P.M. after a light dinner Works Private Ltd, Calcutta) was given in at 8 P.M. The selection of sites for a dose of 0.4 mg intravenously, hyoscine placement of electrodes, and the number of butylbromide (German Remedies Ltd, Goa) electrodes used for the study were according was given in a dose of 10 mg intravenously to the standardized procedure for and normal saline was used as the placebo. cardiopulmonary sleep studies as accepted All drugs were injected in a volume of 0.5 by the Americal Thoracic Society (6). ml into the median cubital vein prior to lights off. After the electrodes, thermistor and other measurement belts were fixed to the All night sleep polysomnography was subject, he was made to lie down on the done using a computerized polysomnography bed. Ten minutes later, baseline parameters Indian J Phyaiol Pharmacol 1998; 42(3) Hyoscine and Atropine on Sleep Architecture 397

such as heart rate, respiratory rate, RESULTS temperature and blood pressure (by sphygmomanometer method) were recorded. The mean (S. D.) age and weight were Immediately after this the drugs or placebo 22.0 (4.76) years and 58.6 (4.81) kg were injected using standard aseptic respectively. There was no difference in the techniques. The heart and respiratory rates TST and the SPT between the two drug were once again determined five minutes treatments and the placebo. The sleep after the injection. This was calculated efficiency was 94.98% for saline, 96.33% for directly from the polysomnographic tracing atropine and 92.73% for HBB. These so that the subject would not be disturbed. changes were not statisticalty significant. Lights were switched off immediately after There was a statistically significant (P

TABLE I Effect of normal sRline, atropine sulphate Rnd hyoscine butylbromide on heart rate and respiratory rate, during wakefulness, before and after injection of drugs.

}leart Rate/nlln Respiratory Ratelmill Dru.gs Be{<,re Af/er Before After

Saline 0.5 ml iv 76.30±11.06 76.67±11.92 22.20±3.82 18.82%.4.25 Atropine 0.4 mg iv 71.60±10.62 72.89±10.57 22.90±2.84 20.13±3.06 Hyoscine 10 mg iv 75.00±11.79 102.20±8.99- 23.10±3.60 18.65±3.21 Values are mean ± S.D. in 10 normal human volunteers. -P< 0.001 compared to normal saline as well as basal value (before injection).

TABLE II : Effect of normal saline, atropine sulphate and hyoscine butylbromide on heart rate during various sleep stages in normal human volunteers.

Relfpir%ry Ratelmin Dru.gs BOlfefine Stage f Stage II Stnge III Stoge IV REM NREM

Saline 76.30d 1.06 68.62±!U8 66.2l±11.31 66.86:9.28 68.08±10.65 63.87±6.84 66.66%8.49 0.5 ml iv Atropine 71.60±10.62 66.11:1:12.00 61.45±8.27 64.09:1:8.34 66.60±9.02 62.27±8.57 62.94±7.95 OA mg iv Hyoscine 75.00±11.79 73.58±15.83 65.08±10.77 66.00±10.45 66.07±10.60 65.15±8A8 65.74±10.02 10 mg iv

Values are mean ±S.D. in 10 subjects. Indian ./ Phy~ioJ Pharmflcol 1998; 42(3) Hyoscine and Atropine on Sleep Architecture 399

TABLE III : Effect ornormfll saline, atropine sulllh:lto and hyoscine butylbromide on reSfliratory rate during the various stage~ of sleep.

Respira/ory Rate I min Drugs StQge 1 StQge 11 Stage III Slage TV REM

Saline U.5 ml iv 16.24:1:.1.70 16.4<\:1:2.70 16.110:t;2.'18 16.64:1:2.36 16.64:t;2.04 AtrolJine 0.'1 mg iv 16.llh3.92 16.tl4:t;2.'14 16.30:t;2.26 16.80:t;2.08 16.60:t;2.54 Hyosl;inc 10 mg iv 15.64 :t;3.80 16.04:t;3.10 15.9<\:1:2.12 16.60;1:2.72 17.Sh3.56

Valucs IHC mcan 1 s.n. in 10 subjects. the injection of HBB but not with atropine the site which maintains REM sleep is when compared to the saline controls probably protected by the BBB to a certain (Table I). However, once sleep onset extent. At the present time the site for occurred there was no difference in heart initiation and maintenance of sleep have not rate (Table II) or in the respiratory rates been precisely located, though it has been (Table 111) with either of the two treatments postulated that an extrinsic cholinergic during any stage of sleep. input "primes" the cholinoceptive REM sleep neurons in the medial pontine reticular DISCUSSION formation. These neurons in turn may trigger the discrete nuclei individually Anticholinergics are known to decrease responsible for the various components of total REM time and increase REM latency REM sleep such as muscle atonia, eye (8). Our results show that total REM time movements etc., (8). is decreased with atropine but not with HBB whereas both drugs increased REM latency. In the present study, SWS is increased Atropine which crosses the BBB, probably significantly in the atropine treated group. affects mechanisms which control the This is contrary to an earlier finding where maintenance of REM sleep. Since HBB does the percentage of SWS was decreased in a not cross the BBB there was no appreciable segment of sleep timed to fall between 2 effect on the duration of total REM sleep. and 4 hours from sleep onset (10). However, There was no modification of the sleep in the same study, when the whole night pattern in man when they used was considered, there was no difference. methscopolamine bromide, a quarternary Since SWS is abundant only in the early ammonium antimuscarinic compound, which part of the night, a segmental division of does not cross the BBB (9), This further the night into 2 hour slots m::ay not reveal reiterates the fact that mechanisms for the any increase in this stage in the second hour initiation and maintenance of REM sleep slot. The implications of prolonged SWS may may be separate, independent and in be twofold. Firstly, SWS is closely linked different parts of the eNS. It is possible to with the secretion of growth hormone (11). hypothesize that the mechanism or stimuli Would this prolongation result in longer which initiates REM sleep is probably periods of GH secretion? Secondly, SWS is situated at a site outside the BBB, while a stage associated with dual autonomic tone 400 Rauniar et al Indian J Physiol Pharmacol 1998; 42(8)

(12). The association of SWS with dual blockade of Ml receptors on postganglionic autonomic tone is derived from observations parasympathetic neurons, thereby relieving in animals that cardiac arrhythmias are the inhibitory effects of synaptic ACh on more common and abundant in this period release of transmitter (3). In our study, (12). It is possible that the increase in SWS injection of HBB but not atropine caused a caused by an anticholinergic drug like very significant increase in heart rate prior atropine may put those subjects who are to the onset of sleep. This may mean that vulnerable to cardiac rhythm abnormalities the dose of atropine necessary to produce at a greater risk towards the development an increase in heart rate needs to be higher of arrhythmias. From this study we could whereas the dose of HBB is sufficient. This conclude that HBB does not modify sleep is in accordance with an earlier study using architecture significantly and therefore may 3 different doses of atropine (0). A dose of be preferred over atropine as an 0.25 mg of atropine failed to elicit a change anticholinergic agent in patients with in heart rate whereas larger doses of 5 mg cardiac disease. and 10 mg caused an initial bradycardia and a tachycardia which lasted till the next The injection of clinical doses of atropine morning. The effect of HBB seems to be very into humans are known to cause an initial transient and is probably related to the high bradycardia without changes in BP or plasma levels reached immediately after the cardiac output. This vagal effect was due to injection of the drug intravenously. REFERENCES

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