Cardiovascular Considerations in Using Topical, Oral, and Intravenous Drugs for the Treatment of Glaucoma and Ocular Hypertension

Frishman, William H.; Kowalski, Marcin; Nagnur, Shreedhar; Warshafsky, Stephen; Sica, Dominic A.

doi:10.1097/00132580-200111000-00007

Cited by 57 publications

(28 citation statements)

References 111 publications

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“…LB has been approved in the United States for glaucoma due to effective reduction of intraocular pressure and has been well studied for its physicochemical properties, efficacy, selectivity, pharmacodynamic effects, and other side effects in rabbits and humans (Lesar, 1987;Zimmerman, 1993;Frishman et al, 2001). LB is clinically administered as 0.5% solution eye drops.…”

Section: Introductionmentioning

confidence: 99%

Ocular Metabolism of Levobunolol: Historic and Emerging Metabolic Pathways

Argikar

Dumouchel

Dunne

et al. 2016

Drug Metabolism and Disposition

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Although ocular transport and delivery have been well studied, metabolism in the eye is not well documented, even for clinically available medications such as levobunolol, a potent and nonselective b-adrenergic receptor antagonist. Recently, we reported an in vitro methodology that could be used to evaluate ocular metabolism across preclinical species and humans. The current investigation provides detailed in vitro ocular and liver metabolism of levobunolol in rat, rabbit, and human S9 fractions, including the formation of equipotent active metabolite, dihydrolevobunolol, with the help of high-resolution mass spectrometry. 11 of the 16 metabolites of levobunolol identified herein, including a direct acetyl conjugate of levobunolol observed in all ocular and liver fractions, have not been reported in the literature. The study documents the identification of six human ocular metabolites that have never been reported. The current investigation presents evidence for ocular and hepatic metabolism of levobunolol via non-cytochrome P450 pathways, which have not been comprehensively investigated to date. Our results indicated that rat liver S9 and human ocular S9 fractions formed the most metabolites. Furthermore, liver was a poor in vitro surrogate for eye, and rat and rabbit were poor surrogates for human in terms of the rate and extent of levobunolol metabolism.

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Section: Introductionmentioning

confidence: 99%

Ocular Metabolism of Levobunolol: Historic and Emerging Metabolic Pathways

Argikar

Dumouchel

Dunne

et al. 2016

Drug Metabolism and Disposition

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“…Timolol maleate is widely used worldwide as a standard medication to lower IOP and its efficacy and safety have been proven (Silverstone et al 1991;Brooks & Gillies 1992). Independent of its topical administration, its absorption by the systemic circulation, added to its non-selective beta-adrenergic receptor antagonist properties, limit its use in patients with pre-existing cardiovascular or respiratory disease (Nelson et al 1986;Everitt & Avorn 1990;Stewart & Garrison 1998;Frishman et al 2001;Sica 2001). Side-effects such as a reduction in heart rate during exercise, nocturnal hypotension, bradyarrhythmias and bronchospasm in patients with reactive airway or chronic obstructive pulmonary disease associated with the use of ophthalmic administration of timolol have been reported (Doyle et al 1984;Fraunfelder & Barker 1984;Atkins et al 1985;Leier et al 1986;Dickstein et al 1988;Hayreh et al 1999;Sharifi et al 2001).…”

Section: Introductionmentioning

confidence: 99%

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

Uusitalo

Niño

Tahvanainen

et al. 2005

Acta Ophthalmologica Scandinavica

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ABSTRACT.Purpose: The objective of this randomized, double-blind, controlled crossover trial was to compare 0.1% timolol hydrogel formulation eyedrops with 0.5% timolol aqueous solution in terms of systemic effects, hypotensive efficacy and pharmacodynamics. Methods: Twenty-four healthy subjects underwent careful ocular, cardiovascular and pulmonary function evaluation before and after 2 weeks of topical treatment with 0.1% timolol hydrogel or 0.5% aqueous timolol maleate. Intraocular pressure (IOP), heart rate, blood pressure, forced expiratory volume and plasma levels of timolol were measured. Results: There was a statistically significant difference in the systemic absorption of timolol between these two ophthalmic timolol solutions. The peak concentration and mean area under the plasma drug concentration-time curve (AUC) were about 10-fold higher after 0.5% timolol aqueous solution. The mean peak heart rate during exercise was reduced by 19 bpm (SD 6.4 bpm) after 0.5% timolol aqueous solution and by only 4.6 bpm (SD 3.8 bpm) after 0.1% timolol hydrogel (p < 0.0001). There was no difference between the two formulations in efficacy in reducing IOP. No differences between treatments were found in respect of pulmonary function. Conclusions: The lower timolol concentration in the hydrogel vehicle and its better bioavailability resulted in reduced systemic absorption and side-effects without loss of efficacy.

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“…Timolol is contraindicated in patients with sinus bradycardia, secondor third-degree atrio-ventricular block, overt cardiac failure, cardiogenic shock, cerebrovascular insufficiency, and asthma (Taniguchi and Kitazawa, 1997;Frishman et al, 2001). Systemically absorbed timolol may cause severe respiratory problems in patients who have bronchial hyper-reactivity or asthma.…”

Section: Introductionmentioning

confidence: 99%

Paroxetine Markedly Increases Plasma Concentrations of Ophthalmic Timolol; CYP2D6 Inhibitors May Increase the Risk of Cardiovascular Adverse Effects of 0.5% Timolol Eye Drops

et al. 2014

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Although ophthalmic timolol is generally well tolerated, a significant fraction of topically administered timolol can be systemically absorbed. We investigated the effect of the strong CYP2D6 inhibitor paroxetine on the pharmacokinetics of timolol after ophthalmic administration. In a four-phase crossover study, 12 healthy volunteers ingested either paroxetine (20 mg) or placebo daily for 3 days. In phases 1-2, timolol 0.1% gel, and in phases 3-4, timolol 0.5% drops were administered to both eyes. Paroxetine increased the plasma concentrations of timolol with both timolol formulations to a similar degree. The geometric mean ratio (95% confidence interval) of timolol peak concentration was 1.53-fold (1.23-1.91) with 0.1% timolol and 1.49-fold (0.94-2.36) with 0.5% timolol, and that of timolol area under the plasma concentration-time curve (AUC) from time 0 to 12 hours was 1.61-fold (1.26-to 2.06-fold) and 1.78-fold (1.21-2.62), respectively. During paroxetine administration, six subjects on 0.5% timolol drops, but none on 0.1% timolol gel, had plasma timolol concentrations exceeding 0.7 ng/ml, which can cause systemic adverse effects in patients at risk. There was a positive correlation between the AUC from time 0 to 13 hours of paroxetine and the placebo phase AUC from time 0 to infinity of timolol after timolol 0.5% drops (P < 0.05), and a nonsignificant trend after timolol 0.1% gel, consistent with the role of CYP2D6 in the metabolism of both agents. In the orthostatic test, heart rate immediately after upright standing was significantly lower (P < 0.05) during the paroxetine phase than during the placebo phase at 1 and 3 hours after 0.5% timolol dosing. In conclusion, paroxetine and other CYP2D6 inhibitors can have a clinically important interaction with ophthalmic timolol, particularly when patients are using 0.5% timolol formulations.

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Cardiovascular Considerations in Using Topical, Oral, and Intravenous Drugs for the Treatment of Glaucoma and Ocular Hypertension

Cited by 57 publications

References 111 publications

Ocular Metabolism of Levobunolol: Historic and Emerging Metabolic Pathways

Ocular Metabolism of Levobunolol: Historic and Emerging Metabolic Pathways

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

Paroxetine Markedly Increases Plasma Concentrations of Ophthalmic Timolol; CYP2D6 Inhibitors May Increase the Risk of Cardiovascular Adverse Effects of 0.5% Timolol Eye Drops

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