T. Ali-Melkkilä

Pharmacokinetics and related pharmacodynamics of anticholinergic drugs

The pharmacokinetics and some pharmacodynamic properties of atropine, glycopyrrolate and scopolamine are reviewed. With the development of new analytical methods for drug determination, it is now possible to measure relatively low concentrations of these drugs in biological fluids and, consequently, some new kinetic data have been collected. Following intravenous administration, a fast disappearance from the circulation is observed and due to a high total clearance value their elimination phase half–lives vary from 1 to 4 h. All these agents are nonselective muscarinic receptor antagonists, but their actions on various organ systems with cholinergic innervation show considerable diversity. The cardiovascular effects are of short duration; other peripheral muscarinic effects and CNS effects can last up to 8 h or even longer. Differing from atropine and scopolamine, glycopyrrolate as a quaternary amine penetrates the biological membranes (blood–CNS, placental barriers) slowly and incompletely, making it the drug of choice for elderly patients with coexisting diseases and for obstetric use. Similarly, its oral absorption is slow and erratic, and hence it cannot be used as an oral premedicant. Atropine, scopolamine and glycopyrrolate have a definitely faster absorption rate, when injected into the deltoid muscle compared with administration into the gluteal or vastus lateralis muscles. There appear to be significant differences in the metabolism and renal excretion of these agents. Scopolamine is apparently excreted into the urine mainly as inactive metabolites, nearly half of the atropine dose administered is recovered in the urine as the parent drug or as active metabolites and about 80% of glycopyrrolate is excreted as unchanged drug or active metabolites. However, despite the diversity in some pharmacokinetic features, the differences in clinical effects are not very prominent in healthy patients.

Intramuscular dexmedetomidine as premedication for general anesthesia : a comparative multicenter study

Background:Dexmedetomidine is a new potent and selective α2-agonist that might prove useful as a preanesthetic agent Methods:A randomized, double-blind study design was used in 192 ASA physical status 1 and 2 patients scheduled for elective abdominal hysterectomy, cholecystectomy, or intraocular surgery under general anesthesia. Intramuscular injection of 2.5 µg/kg dexmedetomidine administered 60 mln before and intravenous saline placebo 2 min before induction of anesthesia (DEXPLA group, n=64) was compared with a combination of 0.08 mg/kg intramuscular midazolam 60 min and 1.5 µg/kg intravenous fentanyl 2 mln before induction (MIDFENT group, n=64), or a combination of intramuscular dexmedetomidine and intravenous fentanyl (DEXFENT group, n=64). After thlopental induction, anesthesia was maintained with 70% N2O/O2, and fentanyl was administered according to clinical and cardiovascular criteria. Patients undergoing cholecystectomy received additional enflurane. Results:Dexmedetomidine and midazolam induced comparable preoperative sedation and anxlolysls. The DEXFENT combination blunted the increases in blood pressure and heart rate induced by tracheal intubation more efficiently when compared with the DEXPLA and MIDFENT groups, in which approximately 25 mmHg and 15 beats/min greater increases were observed. The intraoperative fentanyl requirements were greater in MIDFENT patients when compared with both dexmedetomidine groups, in which 56% (DEXFENT group) and 31% (DEXPLA group) less fentanyl, respectively, was needed. Intraoperatively, fluids or vasopressors for hypotension and glycopyrrolate for bradycardia were administered more often to patients receiving dexmedetomidine than to those who did not. Postoperatively, there were no differences in oxygen saturation, analgesic, or antlemetlc requirements, but dexmedetomidlne- induced blood pressure and heart rate reductions were still evident at the end of the 3-h follow-up period. Bradycardia as an adverse event was reported more frequently in dexmedetomidine patients (20% in the DEXPLA and 33% in the DEXFENT groups) than in MIDFENT patients (8%). Conclusions:The results suggest that pretreatmeht with a single intramuscular injection of 2.5 µg/kg dexmedetomidine is efficacious, but significantly increases the incidence of intraoperative hypotension and bradycardia in ASA physical status 1 or 2 patients.

Glycopyrrolate: pharmacokinetics and some pharmacodynamic findings

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 μg/kg (n = 6), the distribution phase half‐life (2.22 ± 1.26 s.d. min) and the elimination phase half‐life (0.83 ± 0.29 h) of glycopyrrolate were short due to the low distribution volume during the elimination phase (0.64 ± 0.29 1/kg) and to the respectively high total plasma clearance value (0.54 ± 0.14 1/kg/h). An intramuscular injection, 8 μg/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 ± 6.12 min and the maximum plasma concentration (Cmax) was 3.47 ± 1.48 μg/1. After oral drug intake, 4 mg (n = 6), an apparently low and variable gastrointestinal absorption was found (tmax = 300.0 ± 197.2 min, Cmax = 0.76 ± 0.35 μg/1), thus indicating that the oral route of drug 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.

Dexmedetomidine as intramuscular premedication in outpatient cataract surgery : a placebo-controlled dose-ranging study

Alpha2 agonists have been shown to decrease intra‐ocular pressure in ophthalmic surgery. We studied the effects of dexmedetomidine, a new a2 agonist, on intra‐ocular pressure, haemodynamic parameters, sedation, anxiolysis and dryness of mouth in 35 (Asa physical status 1–3) patients undergoing day‐case cataract surgery under peri‐ocular anaesthesia. Five different doses of dexmedetomidine (0.25, 0.5, 0.75, 1.0 and 1.5 μg.kg−1) were used in this double‐blind, randomised and placebo‐controlled study. The trial drug was administered into the deltoid muscle 60 min before surgery. The 1.0 μg.kg−1 dose of dexmedetomidine produced a 32% reduction of intra‐ocular pressure (p = 0.002). This dose induced moderate sedation, but was not associated with significant haemodynamic changes. A significant decrease in heart rate and systolic blood pressure was seen only with the highest dose of dexmedetomidine. Our results suggest that dexmedetomidine 1.0 μg.kg−1 produces sedation and a reduction of intra‐ocular pressure with minimal haemodynamic side effects when given intramuscularly as premedication before cataract surgery under regional anaesthesia.

Pharmacokinetics of glycopyrronium in parturients.

A sensitive radioreceptor assay was used to determine the pharmacokinetics of glycopyrronium 6 μg/kg after intramuscular (deltoid muscle) administration in eight Caesarean section patients. A fast absorption rate was found with a mean maximum plasma concentration (Cmax of 6.3 (SD 1.5) ng/ml, a mean time to Cmax (Tmax) of 10.0 (3.8) minutes and the elimination half‐life (Tl of 33.4 (1.92). The respective AUC0–8 h value was 5.61 (1.27) hours ng/ml. This dose produced a significant increase in the maternal heart rate after 10 minutes (p < 0.05) and an antisialogogue effect after 30 minutes (p < 0.05) of the drug injection. Almost half of drug (48.3%) was excreted into the urine within 3 hours. There were no measurable levels of glycopyrronium in the lumbar cerebrospinal fluid (CSF) after 60 minutes of drug injection. The concentrations of glycopyrronium in the umbilical venous (0.28 (0.25) ng/ml) and in the umbilical arterial (0.18 (0.11) ng/ml) plasma after 86 minutes of drug injection were low and clinically insignificant, as was the case in the amniotic fluid (0.15 (0.08) ng/ml).

Pharmacokinetics of glycopyrrolate in children

Abstract Study Objective: To investigate the pharmacokinetics of glycopyrrolate in children. Design: Open study with three parallel groups. Setting: Pediatric surgery department at a university hospital. Patients: 26 healthy ASA physical status I children undergoing minor surgery. Interventions: Patients were assigned to 1 of 3 groups: under 1 year of age (Group 1, n=8), between 1 and 3 years of age (Group 2, n=7), and over 3 years of age (Group 3, n=11). Glycopyrrolate 5 μg/kg was given as a single intravenous (IV) injection before induction of general anesthesia. Blood samples (for determination of drug concentrations in plasma) were collected via venous cannula inserted into the contralateral antecubital vein. Measurements and Main Results: ECG was observed continuously, blood pressure was measured with an automatic noninvasive device, and blood samples were taken just before and at 2, 4, 6, 10, 15, 30, 60, 120, 180, 240, 360, and 480 minutes after injection of glycopyrrolate. Glycopyrrolate concentrations in plasma were determined with a radioreceptor assay. The only significant difference in the pharmacokinetic parameters was the shortened elimination half-life in patients between 1 and 3 years of age. Glycopyrrolate 5 μg/kg N did not cause any significant alterations in heart rate. Conclusions: There were no significant changes in the distribution volume or clearance of glycopyrrolate in children of different ages. The shortened elimination half-life in children between 1 and 3 years of age is of minor clinical importance.

PHARMACOKINETICS OF GLYCOPYRROLATE IN CHILDREN

STUDY OBJECTIVE To investigate the pharmacokinetics of glycopyrrolate in children. DESIGN Open study with three parallel groups. SETTING Pediatric surgery department at a university hospital. PATIENTS 26 healthy ASA physical status I children undergoing minor surgery. INTERVENTIONS Patients were assigned to 1 of 3 groups: under 1 year of age (Group 1, n = 8), between 1 and 3 years of age (Group 2, n = 7), and over 3 years of age (Group 3, n = 11). Glycopyrrolate 5 micrograms/kg was given as a single intravenous (i.v.) injection before induction of general anesthesia. Blood samples (for determination of drug concentrations in plasma) were collected via venous cannula inserted into the contralateral antecubital vein. MEASUREMENTS AND MAIN RESULTS ECG was observed continuously, blood pressure was measured with an automatic noninvasive device, and blood samples were taken just before and at 2, 4, 6, 10, 15, 30, 60, 120, 180, 240, 360, and 480 minutes after injection of glycopyrrolate. Glycopyrrolate concentrations in plasma were determined with a radioreceptor assay. The only significant difference in the pharmacokinetic parameters was the shortened elimination half-life in patients between 1 and 3 years of age. Glycopyrrolate 5 micrograms/kg i.v. did not cause any significant alterations in heart rate. CONCLUSIONS There were no significant changes in the distribution volume or clearance of glycopyrrolate in children of different ages. The shortened elimination half-life in children between 1 and 3 years of age is of minor clinical importance.