Acta Anaesthesiol Scand 1989: 33: 5 13-5 17

Glycopyrrolate: pharmacokinetics and some

pharmacodynamic findings
T. ALI-MELKKILA,
T. KAILAand J. KANTO
Departments of Anaesthesiology and Clinical Pharmacology, Turku University Central Hospital, Turku, Finland

In the present study, a sensitive and reproducible radioreceptor assay (RRA) was used to evaluate the basic
pharmacokinetic properties of glycopyrrolate, a quaternary amine with peripheral antimuscarinic activity.
Based on the plasma levels after a single intravenous injection, 6 pg/kg (n = 6), the distribution phase half-
life (2.22 f 1.26 s.d. min) and the elimination phase half-life (0.83 f 0.29 h) of glycopyrrolate were short due
to the low distribution volume during the elimination phase (0.64 f 0.29 I/kg) and to the respectively high
total plasma clearance value (0.54f 0.14 l/kg/h). An intramuscular injection, 8 pg/kg (n = 6), was followed
by a fast and predictable systemic drug absorption and clinical effects (heart rate increase, dry mouth). In
this group the time to maximum plasma concentration (tmax)was 27.48 i 6.12 min and the maximum plasma
concentration (C,=) was 3.47 f 1.48 pg/l. After oral drug intake, 4 mg ( n = 6), an apparently low and
variable gastrointestinal absorption was found (tmU= 300.0 & 197.2 min, C,,, = 0.76 f 0.35 pg/l), thus
indicating that the oral route ofdrug administration is of no value as a routine premedication. T h e correlation
between the plasma concentration of glycopyrrolate and the drug effects appears to be variable. Because of
its sensitivity, the RRA method proved to be quite useful in evaluating the kinetics of glycopyrrolate and
its relationship to various clinical effects.
Received 12 December 1988, accepted f o r publication 28 March 1989
K v words: Glycopyrrolate; pharmacokinetics; pharmacodynamics; radioreceptor assay.

Glycopyrrolate (glycopyrroniurn bromide) is a quat-

ernary amine with long-acting peripheral antimuscar- PATIENTS AND METHODS
inic properties (1). I t is assumed that, in contrast T h e study was approved by the local ethical committee and informed
to atropine and scopolamine (Z),which are tertiary oral consent was obtained from the patients.
Three groups of patients were studied, cach consisting of 6 subjects.
arnines, glycopyrrolate does not cross the blood-brain Some characteristics of the three groups are shown in Table 1.
barrier or the placental barrier in significant amounts The patients were admitted to hospital for different intraocular
and thus seldom causes CNS or neonatal toxicity (3). operations to be performed under local or general anaesthesia. The
Glycopyrrolate has been used extensively for more patients in Group 1 were premedicated with glycopyrrolate 4 mg
than two decades to treat various gastrointestinal dis- orally and those in Group 2 with glycopyrrolate 8 pg/kg i.m. given
in the recovery room. In both groups the antisialogogue effect of thc
orders, and during the last decade it has been used in drug was subjectively estimated with a visual analogue scale (VAS)
anaesthetic practice as well (4-7). Despite its wide- of 10 cm numbered from 0 to 10, mouth normal to extremely dry,
spread use in clinical practice, very little is known respectively. In each group the blood pressure and the heart rate
about its basic pharrnacokinetics and related clinical were measured with a n automatic noninvasive device and the EGG
was continuously observed on a n oscilloscope. The pure effect of
significance. glycopyrrolate was followed in Group 1 for 2 h and in Group 2 for
T h r development of a sensitive enough radiorecep- 1 h before the beginning of surgery, and thercaftcr a slight i.v.
tor assay for the measurement of anticholinergics has sedation was given to the patients (fentanyl 50-100 pg or diazepam
enabled us to evaluate the basal kinetics of glycopyrro- 2.5 mg-5 rng i.v.). The retrobulbar block with 2% lidocaine c.
late (8). First of all, we were interested in its gastroin- adrenaline was performed by the ophthalmologist.
I n Group 3, the patients received a combination anaesthesia (thio-
testinal absorption, because its use as an oral premedi- pentone 3-5 mg/kg, vecuronium 0.1 mg/kg, N,O + O,, fentanyl 3
cation in combination with different benzodiazepine pg/kg and neostigmine as a n anticurarizing agent in incremental
derivatives seems to be increasing. Secondly, we doses up to 1.25 mg) and glycopyrrolate 6 pg/kg was injected i.v.
wanted to determine the basic pharmacokinetic par- just before the induction of anaesthesia. Glycopyrrolate was deter-
mined by using a sensitive radioreceptor assay described by Ensingrr
ameters of glycopyrrolate after intravenous and intra- et al. (9). NMS (N-methylscopolamine) was used as a marker for
muscular administration and to correlate them to the cholinergic muscarinic receptors obtained from the rat brain. The
anticholinergic action of the drug. sensitivity of the assay was 100 pg/ml and the assay precision (coef-
514 T. ALI-MELKKILA E T AL.
Table 1
Some patient characteristics (mean, range).
Age Weight Height ASA
years kg cm class
72 74 166 2: n=4
Group 1
(59-79) (60-85) (158-180) 3: n=2
65 66 159 2: n=3
Group 2
(60-70) (56-87) (155-164) 3: n=3
66 66 161 2: n = 4
Group 3
160-75) 155-89) 1150-170) 3: n = 2
Drug treatment
Group 1 Patient No 1 = amiloride + hydrochlorthiazide
Patient No 2 = amiloride + hydrochlorthiazide,
metoprolol, nitroglycerin.
Group 2 Patient No 1 = oxazepam. Patient No 2 = prednisolone
theophylline.
Patient No 3 = digoxin, triamteren + hydrochlorthiazide.
GrouD 3 Patient No 1 = indomethacine. Patient No 2 = damone.

ficient of variation percent) was within 10% in the intra-assay and
interassay determination of glycopyrrolate.
’lhe pharmacokinetic parameters were calculated using the com-
puter program ESTRIP (10).
The variance within the groups was determined by two-way aualy-
sis of variance. The results are expressed as means f standard devi-
ation. The relationship between the plasma concentration and the
heart rate or the antisialogogue cffect of glycopyrrolate was deter-
mined by linear regression analysis. The interpatient differences were
tested by the repeated-measures analysis of variance and further
comparisons were made using modified t-tests with Bonferroni’s cor-
rection.
RESULTS
The concentrations of glycopyrrolate in plasma in the
three groups of patients can be seen in Fig. 1 and 2.
Based on these concentrations, some pharmacokinetic
parameters are shown in Tables 2 and 3.
After an intravenous injection (dose 6 pg/kg),
glycopyrrolate disappeared very fast from the circu-
lation with a mean distribution phase half-life of
2.22 & 1.26 min and with a mean elimination phase
half-life of 0.83 f 0.27 h (Fig. 1, Table 2). There was
no linear relationship between the plasma level of
glycopyrrolate (Fig. 1) and the heart rate response
(Fig. 3).
Following intramuscular drug administration
(dose 8 pg/kg), a fast absorption rate was found with
a mean time to maximum plasma concentration
(t,,,,,) of 27.48 6.12 min and a mean maximum
plasma concentration (CmaX) of 3.47 & 1.48 pg/l (Fig.
2, Table 3). A statistically significant increase in the

I
..I&
0 1 2 3 6 8 12 h

o’12L61015’
rnin
; j 6
t
O h Fig. 2. Plasma concentrations of glycopyrrolate (mean f s.e.mcan)
following a single oral (4 mg; 0 - - - 0 )and intramuscular (8 pg/kg;
Fig. 1. Plasma concentrations of glycopyrrolate (mean +_ s.e.mean) 0---0) administration of the drug. Note the low absorption ratc:
after an i.v. injection (6 pg/kg) of the drug. after oral glycopyrrolate.
 PHARMACOKINETICS OF GLYCOPYRROLATE 515
Table 2
Basic pharmacokinetic parameters based on plasma concentrations determined with a radioreceptor assay following a single intravenous
injection of glycopyrrolate (6 pg/kg) in 6 elderly patients in connection with cataract operation. Mean f s.d.
Vdaxa
Mean age t1/2a t1/2 v, v”” CI AUCW3 h
(years] N (min) (h) (Wg) (l/kg) (l/kg) (l/kg/h) ( M / l x h)
66 (60-75) 6 2.222 1.26 0.83f0.27 0.08f0.06 0.42f0.22 0.64f0.29 0.54f0.14 8.64f1.49
t1,20= distribution phase half-life; t,,? = elimination phase half-life, V, = distribution volume during a-phase; V“ = distribution volume
during steady state; Vd““”= distribution volume during elimination phase (area method); CI = total plasma clearance; AUC = area under
curve.

heart rate was found after 60 rnin (P<O.Ol) (Fig.
4). An antisialogogue effect could be seen, but it was
not statistically significant (Fig. 5). The relationships
between the plasma concentration of glycopyrrolate
(Fig. 2) and the heart rate (Fig. 4) and the anti-
sialogogue effect (Fig. 5) are shown in Table 4.
Oral drug administration (dose 4 mg) produced
extremely variable and apparently incomplete drug
absorption with almost no exact t,, values (Fig. 2,
Table 3). Oral plycopyrrolate (4 mg) had only a minor
effect on the heart rate (Fig. 4), but produced a signifi-
cant antisialogogue effect (Fig. 5) after 6 h (PcO.01).
The relationship between the plasma concentration
and the drug effect is shown in Table 4.
In the systolic and diastolic blood pressures no sig-
nificant changes were observed following the three
administration routes of glycopyrrolate.
DISCUSSION
It should be kept in mind that RRA measures all the
drugs bound to the muscarinic receptors and, there-
fore, all the possible active metabolites of glycopyrrol-
ate are measured as well.
The basic pharmacokinetic parameters of glycopyr-
rolate based on plasma levels after an intravenous
injection were quite comparable to those of atropine
(8, 11--15) and those of scopolamine (16). Its elimina-
tion phase half-life, however, appears to be the shortest
due to its higher clearance value and the lowest vol-
ume of distribution. All these anticholinergic agents
have a very short distribution phase half-life of a few
minutes, and their elimination phase lasts only a few
hours. This kind of pharmacokinetic profile was to be
expected from the results of the early studies with a
radioactive agent (17) and the preliminary studies
performed with a gas chromatographic method ( 18).
After an intramuscular injection into the deltoid
muscle, glycopyrrolate had a fast absorption rate
(mean t,,,, = 27.48 & 6.12 min) and a predictable clin-
ical response. A similar fast systemic absorption after
injection into the deltoid muscle has been found with
scopolamine (16, 19) and atropine (20), but an injec-
tion into the gluteal muscle has produced peak serum
levels of atropine approximately 1 h after drug admin-
istration (12, 19, 21, 22). The poor correlation be-
tween the plasma concentration after intramuscular
glycopyrrolate and the antisialogogue effect of the
drug is possibly due to the slow membrane penetration
of this quaternary amine (3).
An interesting finding of the present study was the
extremely variable and incomplete gastrointestinal ab-
sorption of oral glycopyrrolate followed by a late clin-
ical response. The low plasma concentration after an
oral intake did produce a distinct, statistically signifi-
cant antisialogogue effect. However, the effect of the
adjuvants (fentanyl and diazepam) used in connection
with the retrobulbar block performed with lidocaine
should be taken into consideration, too. Atropine, on

Table 3
Maximum serum level (C,,,), time to C,,, (tmaX) and area under
curvc (AUC) of glycopyrrolate in elderly patients following an oral
(4 mg) or intramuscular (8 pg/kg) administration (mean f s.d.).

1
I I )
4 mg p.0. 6 0.76 f 0.35 300.0 f 197.2 5.20 f 2.43* 6 Bh
rnin
0.008 mg/kg i.m. 6 3.47 f 1.48 27.48 f 6.12 6.64f 2.33**
Fig. 3. Heart rate response to glycopyrrolate (mean f s.e.mean) fol-
* 0-12 h. ** 0-8 h. lowing a single i.v. 6 pg/kg injection of the drug.
516 T. ALI-MELKKILA E T AL.
Table 4

A
The relationship of the plasma concentration of glycopyrrolate vcrsus
the heart rate and the antisialogogue effect determined with visual
analogue scale.
loot
Mode of administra- Heart rate Antisialogogue efkct

.
,c 9 0 -
E
I
0
2 n.s.
80-
70 - n.s. = nonsignificant; *** = P<O.OOI,
I
I 1
0 1 2 3 6 8 12 h
E'ig. 4. Heart rate response to glycopyrrolate (mean f s.e.mean) fol-
lowing a single oral (4 mg; 0 - - - 0 )and intramuscular (8 bg/kg;
0-- -0)administration of the drug.
the other hand, has been shown to have a clear gastro-
intestinal absorption (23, 24) and dose-related CNS-
effects have been reported (24). The oral dose of atro-
pine should be at least twice as high as the intramus-
cular dose to produce the same degree of tachycardia
(2), indicating a 50% absorption to the systemic circu-
lation. Our results show that the systemic availability
of glycopyrrolate appears to be only a few per cent of
the orally administered dose. This and the slow onset
of action of the antisialogogue effect argue against the
use of oral glycopyrrolate as premedication. Surpris-
ingly, however, 10% of Finnish anaesthetists use this
kind of premedication (25).
Another finding of interest in the present study was
that even very low plasma concentrations of glycopyr-
rolate were associated with an antisialogogue effect,
whereas the heart effects were only seen in connection
with the higher plasma levels.
A thesia. Anesthesioloa 1978: 49: 370-371.
I t J 1
tion
i.m. 0.008 mg/kg &I h Q-8 h 0-1 h 0-8 h
*** ns. 11,s.
p.0. 4 mg 0-2 h 0-12 h 0-2 h 0-12 h
ns. (*I n.s. **
** = P<O.OI, * = P<0.05.
( * ) = inverse relationship, P<0.05.
In conclusion, based on the present kinetic data,
residual clinical effects are not likely to occur after the
administration of a single dose i.m. or i.v. of glycopyr-
rolate, especially as this anticholinergic agent is devoid
of central antimuscarinic actions. Long-lasting but low
plasma levels following the oral drug intake could in
theory produce some undesirable effects like urinary
retention during the postoperative period. Basically,
however, the antisialogogue effect of orally adminis-
tered glycopyrrolate, 4 mg, was far too slow to be
useful in everyday clinical practice.
REFERENCES
1. Greenblatt D J, Shader R J. Anticholinergics. JV Engl J Med
1973: 293: 1215-1219.
2. Kanto J, Klotz U. Pbarmacokinetic implications for the clinical
use of atropine, scopolamine and glycopyrrolate. Acta Anaesthesiol
Scand 1988: 32: 69-78.
3. Proakis A G, Harris G B. Comparative penetration of glycopyr-
rolate and atropine across the blood-brain and placental barriers
in anesthetized dogs. Anesthesiology 1978: 48: 339-344.
4. Ramamurthy S, Shaker M H, Winnie A P. Glycopyrrolate as a
substitute for atropine in neostigmine reversal of muscle relaxant
drugs. Can Anaesth Soc J 1972: 19: 399-41 1.
5. Meyers E F, Charles P. Glycopyrrolate compared with atropine
in patients undergoing intraocular operations with local anes-
6. Baraka A, Saab M, Salem M R, Winnie A P. Control of gastric
acidity by glycopyrrolate premedication in the parturient. Aneslh
Analg 1977: 5 6 642-645.
7. Cozanitis D A, Dundee J W, Khan M M. Comparative study
of atropine and glycopyrrolate on suxamethonium-induced
changes in cardiac rate and rhythm. Rr J Anaesth 1980: 52:
291-293.
8. Aaltonen L, Kanto J, Iisalo E, Pihlajamaki K. Comparison of
radioreceptor assay and radioimmunoassay for atropine: phar-
macokinetic application. EurJ Clin Pharmacol 1984: 26:613-61 7.
9. Ensinger H A, Wahl D, Brantt U. Radioreceptor assay for deter-
mination of the antimuscarinic drug ipratropium in man. Eur J
Clin Pharmacol 1987: 33: 459-462.

O
L A"'; ; ; I
6 8
I I
12 h
10. Brown D R, Manno J E. ES'I'RIP, a basic computer program
for obtaining initial polyexponential parameter estimates. J
E'ig. 5. Antisialogogue effect following a single oral (4 mg; 0 - - - 0 ) Pharm Sci 1978: 67: 1687-1691.
and intramusrular (8 pg/kg; 0-- -0)administration of glycopyrro- 11. Kanto J, Pihlajamaki K , Hovi-Viander M . Elimination and
latr (mean f s.e.mean) determined by the patient with a visual ana- heart rate response to atropine in the elderly are indepcndent
logur scale (VAS). of sex. Acta Anaesthesiol Scand 1987: 31: 202-204.
 PHARMACOKINETICS O F GLYCOPYRROLATE
12. KantoJ, Virtanen R , h a l o E, Maenpaa K , Liukko P. Placental
transfer and pharmacokinetics of atropine after a single maternal
intravenous and intramuscular administration. Acta Anaesthesiol
Sr-and 1981: 25: 85-88.
13. Virtanen R, Kanto J, Iisalo E, Iisalo E U M, Salo M, Sjovall
S. Pharmacokinetic studies on atropine with special reference to
age. Acta Anaesthesiol Scand 1982: 2 6 297-300.
14. Adams R G , Verma P, Jackson A J, Miller R L. Plasma pharma-
cokinctics of intravenously administered atropine in normal hu-
man subjects. 3 Clin Phanacol 1982: 22: 477-481.
15. Hindrrling P H, Gundert-Remy U, Schmidlin 0. Integrated
pharmarokinetics and pharmacodynamics of atropine in healthy
humans. I: Pharmacokinetics. 3 P h a n Sci 1985: 74: 703-710.
16. Pihlajamaki K K, Kanto J H, Oksman-Caldentey K-M. Phar-
macokinetics and clinical effects of scopolamine in caesarean
section patients. Acta Pharmacol Toxicol 1986: 59: 259-262.
17. Kaltiala E, Penttila A, Vapaatalo H, Larmi T. The fate of
intravenous (3H) glycopyrrolate in man. 3 Pharm Pharmacol
1974: 26: 352-354.
18. Murray G R, Calvey T N, Williams N E. Quantitative capillary
column gas chromatographic method for the determination of
glycopyrronium in human plasma. 3 Chromatogr 1984: 308:
143-1 5 1.
19. Kanto J, Kentala E, Kaila T, Pihlajamaki K. Pharmacokinetics
of scopolamine during caesarean section: relationship between
serum concentration and effect. Acta Anaesthesiol Scand. I n press.
20. Kentala E, Kaila T, Kanto J . Intramuscular atropine in the
51 7
elderly: pharrnacokinetic studies using the radioreceptor assay
and some pharmacodynamic responses. Pharmacol Toxicol. In
press.
21. Pihlajamaki K , Hovi-Viander M, Kanto J. Effect of induced
hypotension on serum concentrations of atropine after intramus-
cular administration. Acta Anaesthesiol Scand 1986: 30: 64-65.
22. Harrison L J, Smallbridge R C, Lasseter K C. Comparative
absorption of inhaled and intramuscularly administered atro-
pine. A m Rev Respir D i s 1986: 134: 254-257.
23. Beerman B, Hellstrom K, Rosen A. The gastrointestinal absorp-
tion of atropine in man. Clin Sci 1971: 40: 95-106.
24. Saarnivaara L, Kautto U-M, Iisalo E, Pihlajamaki K. Compari-
son of pharmacokinetic and pharmacodynamic parameters fol-
lowing oral or intramuscular atropine in children. Atropine
overdose in two small children. Acta Anaesthesiol Scand 1985: 29:
529-536.
25. Kentala E, Salonen M, Kanto J. Anticholinergic prcmedication
in Finland 1988. Acta Anaesthesiol Scand. I n press.
Address:
Jussi Kanto, M.D.
Department of Anaesthesiology
Turku University Central Hospital
Kiinanmyllynk. 4-8
SF-20500 Turku
Finland