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β‐Blocking effects of timolol at low plasma concentrations
Author(s) -
Kaila Timo,
Huupponen Risto,
Karhuvaara Sakari,
Havula Pekka,
Scheinin Mika,
Iisalo Esko,
Salminen Lotta
Publication year - 1991
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1991.10
Subject(s) - timolol , quinidine , crossover study , chemistry , plasma concentration , pharmacology , blockade , heart rate , medicine , endocrinology , anesthesia , blood pressure , intraocular pressure , receptor , surgery , alternative medicine , pathology , placebo
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 β‐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 β‐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 β‐blockade occurring at low plasma levels can explain side effects and actions of ocularly applied timolol. Clinical Pharmacology and Therapeutics (1991) 49 , 53–58; doi: 10.1038/clpt.1991.10