Acta Anaesthesiol Scand zyxwvutsrqp 1989: 33: 5 13-5 17 Glycopyrrolate: pharmacokinetics and some pharmacodynamic findings T. zyxwvutsr ALI-MELKKILA, T. KAILA and 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 zyxw = 6), the distribution phase half- life (2.22 zyxwvuts 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 zyxw 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. The 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. zyxwvuts Received zyxwvutsrqpo 12 December 1988, accepted for publication 28 March 1989 Kv words: Glycopyrrolate; pharmacokinetics; pharmacodynamics; radioreceptor assay. Glycopyrrolate (glycopyrroniurn bromide) is a quat- ernary amine with long-acting peripheral antimuscar- inic properties (1). It is assumed that, in contrast to atropine and scopolamine (Z), which are tertiary arnines, glycopyrrolate does not cross the blood-brain barrier or the placental barrier in significant amounts and thus seldom causes CNS or neonatal toxicity (3). Glycopyrrolate has been used extensively for more than two decades to treat various gastrointestinal dis- orders, and during the last decade it has been used in anaesthetic practice as well (4-7). Despite its wide- spread use in clinical practice, very little is known about its basic pharrnacokinetics and related clinical significance. Thr development of a sensitive enough radiorecep- tor assay for the measurement of anticholinergics has enabled us to evaluate the basal kinetics of glycopyrro- late (8). First of all, we were interested in its gastroin- testinal absorption, because its use as an oral premedi- cation in combination with different benzodiazepine derivatives seems to be increasing. Secondly, we wanted to determine the basic pharmacokinetic par- ameters of glycopyrrolate after intravenous and intra- muscular administration and to correlate them to the anticholinergic action of the drug. PATIENTS AND METHODS The study was approved by the local ethical committee and informed oral consent was obtained from the patients. Three groups of patients were studied, cach consisting of 6 subjects. Some characteristics of the three groups are shown in Table 1. The patients were admitted to hospital for different intraocular operations to be performed under local or general anaesthesia. The patients in Group 1 were premedicated with glycopyrrolate 4 mg 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 drug was subjectively estimated with a visual analogue scale (VAS) of 10 cm numbered from 0 to 10, mouth normal to extremely dry, respectively. In each group the blood pressure and the heart rate were measured with an automatic noninvasive device and the EGG was continuously observed on an oscilloscope. The pure effect of glycopyrrolate was followed in Group 1 for 2 h and in Group 2 for 1 h before the beginning of surgery, and thercaftcr a slight i.v. sedation was given to the patients (fentanyl 50-100 zyx pg or diazepam 2.5 mg-5 rng i.v.). The retrobulbar block with 2% lidocaine c. adrenaline was performed by the ophthalmologist. In Group 3, the patients received a combination anaesthesia (thio- pentone 3-5 mg/kg, vecuronium 0.1 mg/kg, N,O + O,, fentanyl 3 pg/kg and neostigmine as an anticurarizing agent in incremental doses up to 1.25 mg) and glycopyrrolate 6 pg/kg was injected i.v. just before the induction of anaesthesia. Glycopyrrolate was deter- mined by using a sensitive radioreceptor assay described by Ensingrr et al. (9). NMS (N-methylscopolamine) was used as a marker for cholinergic muscarinic receptors obtained from the rat brain. The sensitivity of the assay was 100 pg/ml and the assay precision (coef-