β-Blocking effects of timolol at low plasma concentrations

Abstract

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.

Systemic bioavailability and cardiopulmonary effects of 0.5% timolol eyedrops

“…The decreases in heart rate (Fig. 2) were expected, because plasma concentrations of timolol even after ocular administration are known to be high enough to block cardiac beta-adrenoceptors [7]. The small IOP decrease after intravenous timolol administration (Fig.…”

“…Regrettably, there are no published studies investigating to what extent these factors, common in aged patients, could affect systemic timolol absorption. In our study the mean peak concentrations of ophthalmic timolol were high enough to exceed approximately sixfold the minimum plasma level required to antagonize systemic catecholamine actions [7].…”

“…The individual concentration-time curves are presented 431 ceed a threshold level of approximately 200 pg/ml [7]. However, no human data are available on the systemic bioavailability of ophthalmic timolol.…”

Efficacy and systemic side‐effects of topical 0.5% timolol aqueous solution and 0.1% timolol hydrogel

“…The systemic absorption of timolol was much less with 0.1% hydrogel than with 0.5% aqueous solution, with both the maximal drug concentration in plasma and its AUC value being approximately 10-fold smaller after the hydrogel than after the aqueous solution. In a study by Kaila et al (1991), the dissociation constant (pA2) for timolol against isoproterenol-induced tachycardia was about 0.17 ng/ml. In the present study, the timolol plasma concentrations after 0.5% timolol aqueous solution exceeded the pA2 value, while concentrations remained around the pA2 value after 0.1% timolol hydrogel.…”

Timolol Metabolism in Human Liver Microsomes Is Mediated Principally by CYP2D6

“…Earlier investigators have suggested that in humans at least two major metabolites are formed from timolol by cleavage of the morpholine ring (Tocco et al, 1975(Tocco et al, , 1980. Timolol has been suggested to be metabolized by cytochrome P450 enzyme CYP2D6 (Kaila et al, 1991;Edeki et al, 1995, Nieminen et al, 2005a. Due to the highly polymorphic nature of CYP2D6, individuals are classified into extensive (EMs) and poor metabolizers (PMs), the latter being unable to metabolize many clinically used drugs (Pelkonen et al, 1998;Zanger et al, 2004).…”