Gen. Pharmac. Vol. 12. pp. 423 to 427, 1981 0306-3623/81/060423.05505.

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Printed in Great Britain• All rights reserved Copyright © 1981 Pergamon Press Ltd

MINIREVIEW

GLYCOPYRROLATE

R. K. MIRAKHUR* and J. W. DUNDEE

Department of Anaesthetics, Queens University of Belfast, Belfast, BT9 7BL, U.K.

(Received 27 M a r c h 1981)

Anticholinergic drugs, particularly atropine, have The detailed pharmacological actions in animals
been used clinically for many years. Their most wide- were first described by Franko and his colleagues
spread use has been for the treatment of gastrointesti- (Franko et al., 1962).
nal disorders, in ophthalmology and in anaesthetic
premedication. However, atropine has been super- Cardiovascular effects
seded by more specific drugs without its undesirable There are very few reports of the direct effects on
side-effects for the treatment of peptic ulcer and as a the cardiovascular system of this drug. An absence of
mydriatic in ophthalmic practice. Indeed it is now any significant cardiovascular effects had been a gen-
considered that anticholinergic drugs do not have any eral feature of the earlier studies. There were no
significant r61e in the treatment of peptic ulceration. effects on heart rate or carotid arterial pressure in
Their use in anaesthetic practice is, however, still anaesthetised dogs (Franko et al., 1962). In healthy
widespread--both in pre anaesthetic medication and volunteers the effects on heart rate are insignificant
as the antimuscarinic agent for use with neostigmine following intramuscular administration (Taylor et al.,
at the time of reversal of curare-type neuromuscular 1970; Mirakhur et al., 1978c). Following intravenous
block. administration of the drug in doses ranging from 0.1
Atropine suffers from several drawbacks, the im- to 0.4 rag, Wyant & Kao (1974) and Mirakhur (1979)
portant ones being unwanted central and ocular observed no significant changes in heart rate in volun-
effects when used in moderate to large doses, produc- teers. However, the pulse rates of patients rose signifi-
tion of cardiac dysrhythmias, a relatively short dur- cantly when the drug was administered as a premedi-
ation of action in some situations and an unpredic- cant (Oduro, 1975; Mirakhur et al., 1979).
table antisalivary effect. Although other anticholiner- In anaesthetised patients Mirakhur et al. (1981b)
gic drugs including quaternary ammonium derivatives found the drug to be approximately twice as potent as
of atropine and hyoscine have been evaluated, none atropine regarding its ability to increase the heart rate
have been found to be consistently superior to the although the peak effect of glycopyrrolate occurred
traditionally used drugs. later than that of atropine. When administered to
The present article reviews the position of glycopyr- children, glycopyrrolate like atropine, produced a
rolate in this respect. greater degree of tachycardia during halothane than
Glycopyrrolate (glycopyrronium bromide; Pyrro- enflurane anaesthesia (Samra & Cohen, 1980). The
lidinium 3-[(cyclopentylhydroxyphenylacetyl)oxy]- effects of glycopyrrolate when given with neostigmine
1,1-dimethyl bromide; Robinul) the structure of which will be discussed later.
is shown in Fig. 1 is a quaternary ammonium anti-
cholinergic agent synthesised in 1960 and subse- Respiratory system
quently introduced for the management of peptic Animal studies by Franko et al. (1962) or the volun-
ulceration in which situation it has probably now teer studies referred to earlier (Taylor et al., 1970) did
been replaced by H2 receptor antagonists. The first not reveal any noticeable effects on ventilation. How-
reported use in anaesthetic practice for the pre- ever, a recent study by Gotta and his colleagues
vention of hazards of accidental aspiration of gastric (Gotta et al., 1980) showed that glycopyrrolate in-
contents was in 1970 by Boatright and his colleagues creased dead space in a similar manner to atropine
(Boatright et al., 1970). Subsequent to this, prelimi- but for a more prolonged period consistent with the
nary reports of its use with neostigmine for the rever- lung duration of action of this drug. This effect is do"
sal of neuromuscular block appeared but the results to anticholinergic-induced bronchodilation.
of the first comprehensive clinical pharmacological
study in man were published only recently (Mirakhur
et al,, 1978c).
Pharmacology
Glycopyrrolate is a white crystalline powder with a
melting point of 193°C and a molecular weight of
C c/-°½ O

Br-

393.3 and is very water soluble.

• ~
V-Y '°H ,4, CH 3 CH 3
* Present address: Consultant Anaesthetist, Royal Vic-
toria Hospital, Grosvenor Road, Belfast BTI2 6BA, U.K. Fig. 1. Structural formula of glycopyrrolate.
423
424 R.K. MIRAKHURand J. W. DUNDEE

Central nervous system no significant increase in pupiUary size or intraocular

It is well known that atropine and hyoscine possess pressure nor any recession of the near point of vision.
significant central effects. However, the quaternary However, conjunctival application in animals leads to
ammonium structure of glycopyrrolate limits its pass- pupillary dilatation (Franko et al., 1962).
age across lipid membranes such as the blood-brain Absorption, metabolism and excretion
and placental barriers. This has been demonstrated in
dogs by Proakis & Harris (1978). As indicated earlier, the drug is poorly absorbed
The occurrence of central effects is thus minimal. following oral administration due to its highly ionised
Another pointer to the absence of such effects was the and water soluble nature. Following i.v. administra-
demonstration by Franko et al. (1962) of the lack of tion of 14C labelled glycopyrrolate to the mouse
antagonism by glycopyrrolate of the central effects of Kagiwada et al. (1973) observed peak radioactivity in
tremorine in the dog. all organs except the brain at 5-10min. Absorption

Gastrointestinal system
C~PUPIL ~RIGHT LIGHT)
The effects of glycopyrrolate on both the motility • NEARPOINT
and secretions of the gastrointestinal tract (GIT) have O PUPIL (DIM LIGHT)
been extensively studied. Even low doses of the drug • TEN~PEIb~TURE
antagonise the spasmogenic effects of acetylcholine on ~" HEARTRATE
ILLOC)D PRESSURE
isolated guinea-pig ileum (Franko et al., 1962). Sun
.TIALIVARy SECRETION
(1962} and Moeller (1962) in the earliest studies of the • SWEATGLANDS
effects of the orally administered drug on the GIT
noticed a significant decrease in the average volume
and acidity of gastric secretions. Although some sub-
sequent studies also demonstrated this effect, it is un- 100,
likely to be due to systemically absorbed drug. Glyco-
pyrrolate is thought to be 7-8 times as potent as atro-
pine in its effect on gastric secretions and acidity
(Taylor et al., 1970). In practice however, glycopyrro-
late, like other anticholinergic drugs, has been re-
placed by H: receptor blocking agents in the medical
treatment of peptic ulcer disease.
In common with other drugs with similar effects
glycopyrrolate also lowers the opening pressure of the
lower oesophageal sphincter (Brock-Utne et al., 1978).
The implications of this action may be important for
anaesthetists. In addition it is likely that gastric emp-
tying would be delayed. Y
Secretions
The overall effect of glycopyrrolate on salivary se-
cretions is more intense and prolonged than that of
atropine. The first comprehensive evaluation of the
antimuscarinic effects of this drug in conscious human
volunteers (Mirakhur et al., 1978c) showed the anti- 30,

sialogogue effect along with a similar effect on sweat

gland activity to be profound, prolonged and dose
related; other effector organs were relatively unaffec-
ted (Fig. 2). Although Wyant & Kao (1974) suggested
that glycopyrrolate was twice as potent as atropine in
its antisialogogue effect; more accurate studies with
dose--response curves (Mirakhur & Dundee, 1980)
showed it to be five times (Fig. 3). In addition the
latter authors showed the similarities and contrasts 0.5 I 2 3 4 5 6
between the two drugs. Whereas both glycopyrrolate HOURS
and atropine exerted dose-related antisialogogue
effects, only the latter produced an increase in heart Fig. 2. Effects of 0.2 mg glycopyrrolate intravenously on
various parameters of cholinergic function. ( A - - A I sali-
rate and elicited ocular effects. vary secretion, ( A - - A ) sweat gland activity, ( ' R - - ¢ t )
Antisialogogue effect following oral administration, heart rate. (~r - - "k')blood pressure, (O------O) near point
however, is poor and very large doses are required to of vision, (11 II) temperature, (H ES) pupil size (dim
have any effect. light), (O O) pupil size (bright light). The profound and
prolonged effect of glycopyrrolate on salivary and sweat
Ocular effects gland activity and the lack of effect on other organs is
clearly shown. From Mirakhur et al. (1978c) reproduced
Studies in volunteers by Taylor et al. (1970), Mirak- with the courtesy of the Editor of British Journal of Clinical
hur et al. (1978c) and Cozanitis et al. (1979) showed Pharmacology.
 Glycopyrrolate 425

I00

90

sM
sS
80 sS
sS
~Ds S S
70 I
I
I
S
I
S
50 I
I
/
S
z SO S
I
S
S
L
~,O

~O

mmu ATROPINE

GLYCOPYRROLATE
20

IO
o.i o'.7 o'.,, d~.s I .lO 2 .'0

DOSE (HG)

Fig. 3. The relationship between intramuscular dose and antisialogogue activity for glycopyrrolate
(O O) and atropine (O---O). Glycopyrrolate is approximately five times as potent as atropine.
From Mirakhur & Dundee (1980) reproduced with the courtesy of the Editor of Journal ~[ the Royal
Society of Medicine.

following intramuscular administration is fairly rapid mixture with neostigmine for the reversal of neuro-
as shown by effects on salivary secretion, (Mirakhur muscular block and it is in this situation that glyco-
et al., 1978c). pyrrolate is likely to be most widely used. The com-
In animal studies the drug has been shown to cross monly used combination of atropine and neostigmine
both into the CNS and across the placenta in only is not ideal since the administration of this mixture is
trace amounts (Proakis & Harris, 1978) and Abboud invariably associated with an initial tachycardia and a
et al. (1981) observed a lack of effect of glycopyrrolate subsequent bradycardia. Moreover, increasing the
on human fetal heart rate. dose of atropine to overcome this bradycardia results
The main metabolic pathways appear to be hy- in an even greater initial tachycardia (Mirakhur eta/.,
droxylation and oxidation. 1981a). The main reason for this is the different times
More than 90?/o of the radioactivity following i.v. of onset of effects of atropine and neostigmine.
administration of [3H]glycopyrrolate to humans From a pharmacological point of view glycopyrro-
disappears from the plasma in 5 min and almost all of late has a slower onset of action which is more in
it in 30 min (Kaltiala et al., 1974). Urinary excretion phase with that of neostigmine. Many publications on
accounts for nearly 85~o of the radio label over a the use of glycopyrrolate in reversal have since
period of I-2 days. Orally administered drug is appeared (Ramamurthy et al., 1972; Mirakhur eta/.,
mostly excreted in the faeces. The detailed pharmaco- 1977, 1981a,c; Ostheimer, 1977; Cozanitis et al., 1980;
kinetics in man have yet to be studied. Black et al., 1980) and have confirmed the superiority
of glycopyrrolate in terms of stability of heart rates.
Glycopyrrolate in anaesthetic practice Another consistent feature is the superior control of
At present the main uses of glycopyrrolate are oropharyngeal secretions.
related to anaesthetic practice. These will be discussed The largest series of patients studied during reversal
briefly. of neuromuscular block has been those of Cozanitis et
In view of the effects of glycopyrrolate on gastric al. (1980). In this study of more than 600 patients
secretions it was not surprising that the first clinical administered 20/~g/kg of atropine or 10/tg/kg of gly-
use in anaesthetic practice by Boatright and his col- copyrrolate on a double blind basis in a mixture with
leagues (Boatright et al., 1970) was in premedication 50/~g/kg of neostigmine, the greater stability of heart
for the prevention of the serious effects of aspiration rates in the patients receiving glycopyrrolate was
of acid gastric contents. A preliminary study by clearly shown. Furthermore patients with pre existing
Ramamurthy et al. (1971) showed that the drug was cardiovascular disease appeared to be the ones bene-
useful as a substitute for atropine when used in a fitting best from the use of glycopyrrolate. A typical
426 R. K. MIRAKHURand J. W. DUNDEE

over lowering of the opening pressure of the lower

, - - . GLYCOPYRROLATE oesophageal sphincter and possible delay in gastric
~--~ ATROPINE emptying would be conducive to passive regurgitation
and aspiration.
The absence of undesirable central effects is an
obvious advantage and this has been demonstrated by
~ 80-
earlier arousal in the immediate postoperative period
(Baraka et al., 1980).
In conclusion there is little doubt that glycopyrro-
1 late is an effective and potent anticholinergic agent
with more selective effects than atropine and a wel-
come addition to the anaesthetists armamentarium. It
is an effective premedicant, and is effective in counter-
acting bradycaria of vagal origin but the best use of
the drug would appear to be as an alternative to atro-
pine in the reversal of residual neuromuscular block.
TIME(Mins)
Its place in this situation is firmly established.
Fig. 4. Heart rate changes following reversal with neo- More studies would need to be carried out to deter-
stigmine 50/ag/kg with either atropine 20~ug/kg (O Q) mine the pharmacokinetic profile of the drug.
or glycopyrrolate 10/~g/kg (am m). From Mirakhur et
al. (1981c) reproduced with the courtesy of the Editor of Acknowledgements--The authors would like to thank C.
Indian Journal of Anaesthesia. J. Jones, Manager, Clinical Research at A. H. Robins Co.
Ltd., Horsham, West Sussex for his help and encourage-
ment during the research programme on glycopyrrolate in
response in heart rate to the administration of neo- our department.
stigmine 50/~g/kg with atropine 20 #g/kg or glycopyr-
rolate 10/~g/kg is shown in Fig. 4 (Mirakhur et al.,
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