Timo Kaila

Plasma kinetics and antagonist activity of topical ocular timolol in elderly patients

Abstract• Background: Systemic adverse effects of ocular timolol therapy are due to absorption of the drug from the eye into the systemic circulation. Elderly patients are frequently more susceptible to side effects than younger patients. This study was conducted to evaluate the plasma kinetics and antagonist activity of ocular timolol in elderly patients. • Methods: Plasma kinetics and antagonist activity of timolol were studied in 12 patients scheduled for extracapsular cataract extraction and intraocular lens implantation. The patients received 40 μl of 0.25% timolol into the lower cul-de-sacs of each eye. Blood samples were collected over a period of 12 h and plasma concentrations of timolol were analyzed using a radioreceptor assay. The corresponding ex vivo β1- and β2-receptor occupancies were calculated using radioligand binding techniques. • Results: Timolol was absorbed rapidly into the systemic circulation and occupied on average up to 68% of β1-receptors and up to 87% of β2-receptors. The β1- and β2-receptor occupancy decreased slowly and was on average 38% and 64%, respectively, 12 h after the single dose. The calculated mean area under concentration-time curve of timolol in plasma was 10.28 ng/ml per hour and the mean half-life was 4.8 h. Both values were about twice as high as those found in healthy young volunteers following an intravenous 0.25-mg dose of timolol. • Conclusions: In elderly patients the β-receptor antagonist effect of ocular timolol after a single dose is strong and long-lasting. This finding may explain the frequent reported systemic side effects of ophthalmic timolol.

Altered cardiovascular autonomic regulation after 2-week inhaled salbutamol treatment in asthmatic children

AbstractWe studied the effects of therapeutic 2-week inhaled salbutamol treatment on the cardiovascular and respiratory autonomic nervous regulation in eight children with asthma. In this randomized, double-blind, placebo-controlled crossover study our test subjects inhaled 200 μg salbutamol or placebo thrice daily for 14 days. After the 14-day treatment we continuously measured electrocardiogram, finger systolic arterial pressure (SAP) and flow-volume spirometry at baseline and the response to a single 600 μg salbutamol inhalation. The periodic variability components of R-R intervals (the time between successive heart beats) and SAP in relation to respiration were assessed using spectral analysis. Two-week salbutamol treatment increased baseline low frequency (LF) variability (P<0.05) and low frequency/high frequency (LF/HF) variability ratio of R-R intervals (P<0.05) when compared to the placebo treatment. As a response to the single salbutamol inhalation the increase in LF/HF ratio of R-R intervals was smaller after the 2-week salbutamol treatment (P<0.01). No significant differences were found in the bronchodilatory response after the treatment period.n Conclusion Two-week salbutamol treatment shifts the cardiovascular autonomic regulation to a new level characterized by greater sympathetic responsiveness and slight beta2-receptor tolerance. Because these effects were evident 18 h after cessation of the therapy they are likely to reflect the adaptation of organ responses to regular therapy or altered central autonomic regulation rather than direct drug effect. A slight tolerance developed in the sympathovagal cardiac response but not in the bronchodilatory response.

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.