Beta-blocking effects of timolol at low plasma concentrations.
The concentration-effect relationship of 0.25 mg intravenous timolol with and without pretreatment with 100 mg quinidine was studied in six healthy young volunteers with a randomized, double-blind, crossover study design. Blockade of cardiac beta-adrenoceptors was assessed by determining the dose ratios (DR) of isoproterenol infusions required to increase heart rate by 25 beats/min before and after timolol infusion. The logarithm of timolol concentration in plasma was linearly related to the logarithm (DR-1) of isoproterenol infusion, with a mean Pearson correlation coefficient of 0.89 +/- 0.11 (+/- SD; n = 24) at timolol concentrations well below 1 ng/ml. The increases in cyclic adenosine monophosphate (cAMP) and norepinephrine plasma levels caused by isoproterenol infusions were attenuated after timolol. Quinidine administration increased timolol plasma levels and cardiac beta-blocking effects by 10% to 40%. It was concluded that timolol at concentrations below 1 ng/ml in plasma competitively antagonizes cardiac and noncardiac effects of isoproterenol infusions. Timolol effects are augmented after quinidine administration. The beta-blockade occurring at low plasma levels can explain side effects and actions of ocularly applied timolol.
Kaila
T
T
Department of Clinical Pharmacology, University of Turku, Finland.
Huupponen
R
R
Karhuvaara
S
S
Havula
P
P
Scheinin
M
M
Iisalo
E
E
Salminen
L
L
D000328:Adult; D000242:Cyclic AMP / Q000097:blood; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D013999:Timolol / Q000097:blood / Q000494:pharmacology*
D007527:Isoenzymes; D011943:Receptors, Adrenergic, beta; D013999:Timolol; D003577:Cytochrome P-450 Enzyme System; D000242:Cyclic AMP; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D007545:Isoproterenol