Association between low plasma levels of ophthalmic timolol and haemodynamics in glaucoma patients

Nieminen, Tuomo; Uusitalo, Hannu; Turjanmaa, Väinö; Bjärnhall, Gunilla; Hedenström, Hans; Mäenpää, J; Ropo, Auli; Heikkilä, Pekka; Kähönen, Mika

doi:10.1007/s00228-005-0945-2

Cited by 39 publications

(30 citation statements)

References 24 publications

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“…Previous reports on ophthalmic timolol suggest its effects on blood pressure and heart rate in spite of low plasma concentration [12][13][14] mainly during night time. It is contraindicated in patients with bronchial asthma, severe chronic obstructive pulmonary disease, and sinus bradycardia.…”

Section: Discussionmentioning

confidence: 94%

“…7,8) Although some clinical trials have reported that topical PGF2α analogs are safe, [9][10][11] they are thought to cause systemic adverse events. Some examples include ophthalmic timolol or brimonidine, which reduce systemic blood pressure by β-receptor blocking [12][13][14] or α-receptor stimulating actions. 15) It would be difficult to demonstrate the relationship using an epidemiologic study, since the systemic drug adverse events caused by eye drops are very rare.…”

mentioning

confidence: 99%

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Blood Pressure Elevation Associated with Topical Prostaglandin F2α Analogs: An Analysis of the Different Spontaneous Adverse Event Report Databases

Ohyama

Kawakami

Inoue

2017

Biological & Pharmaceutical Bulletin

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Topical prostaglandin F2α (PGF2α) analogs are widely used as the first line of therapy for glaucoma. Systemic PGF2α is suggested to increase blood pressure. Some ophthalmic formulations with β-receptor blocking or α-receptor stimulating actions are reported to cause systemic adverse events such as a decrease in heart rate and blood pressure. The objective of this study was to evaluate the association between topical Key words prostaglandin F2α analog; blood pressure elevation; spontaneous reporting database; adverse event; reporting odds ratio Glaucoma is a progressive, chronic condition prevalent worldwide that causes damage to the optic nerve, resulting in irreversible visual impairment and blindness. Based on the status of the internal drainage system, this condition is divided into two major subtypes i.e., open angle and angle closure.1) Reducing intraocular pressure (IOP) is one of the best ways to prevent the development of glaucoma, although there is a kind of open angle glaucoma in which optic neuropathy occurs without IOP exceeding the normal range. The approximate number of glaucoma patients was 60.5 million in 2010 and is estimated to increase to 79.6 million by 2020.2)

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Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 99%

Blood Pressure Elevation Associated with Topical Prostaglandin F2α Analogs: An Analysis of the Different Spontaneous Adverse Event Report Databases

Ohyama

Kawakami

Inoue

2017

Biological & Pharmaceutical Bulletin

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“…The present study indicates that plasma timolol levels after using 0.1% timolol hydrogel remain low even when the metabolism of timolol is inhibited by paroxetine; the C max of timolol varied between 0.056 and 0.322 ng/ml, i.e., below the suggested threshold of 0.7 ng/ml (Nieminen et al, 2005b;Volotinen et al, 2007). These results imply that paroxetine is unlikely to have a clinically significant effect on the benefit-risk ratio of 0.1% timolol hydrogel.…”

Section: Cyp2d6 Inhibition Raises Ophthalmic Timolol Concentrations 2073mentioning

confidence: 56%

“…In a previous study, the maximum heart rate in an exercise test was decreased by at least 20 beats/min in four of 25 patients after ophthalmic application of 0.5% aqueous timolol (Nieminen et al, 2005b). In these four patients, plasma timolol concentration exceeded 0.7 ng/ml.…”

Section: Cyp2d6 Inhibition Raises Ophthalmic Timolol Concentrations 2073mentioning

confidence: 65%

“…Plasma timolol concentrations over 0.7 ng/ml are regularly associated with a heart rate reduction of 10 beats per minute or more at the maximal load in exercise tests (Nieminen et al, 2005b;Uusitalo et al, 2006). To minimize systemic effects caused by timolol eye drops, their viscosity has been increased, so that the mean residence time of timolol on the ocular surface has increased.…”

Section: Introductionmentioning

confidence: 99%

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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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Urinary excretion patterns and potential risks of beta‐blocker ophthalmic drops in sports

Lin

Chiang

Chang

et al. 2022

Drug Testing and Analysis

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Beta-blockers have been prohibited by the World Anti-Doping Agency (WADA) in certain sports, but insufficient research data make it difficult to distinguish between therapeutic uses or misuses. This study aimed at investigating the urinary excretion pattern following beta-blocker ophthalmic drops and the potential risk of constituting an adverse analytical finding (AAF) in sports. Prescribed timolol and carteolol ophthalmic drops were used in healthy participants and glaucoma patients. The urine samples were then collected to investigate the urinary excretion pattern following acute and chronic administration of the above beta-blocker ophthalmic drops. The liquid chromatograph-tandem mass spectrometry method was applied for measuring urinary beta-blockers. Our results demonstrated that the levels of both urinary timolol and carteolol exceeded the minimum reporting levels (MRL) following acute and chronic administration. The highest levels of urinary timolol and carteolol observed in the present study were 255.7 and 923.8 ng/ml, respectively. Regarding the acute administration of timolol ophthalmic drop, 26.19 (11/42) of urine samples were detected with timolol higher than the MRL in timed and random sampling. In contrast, the acute administration of carteolol ophthalmic drops made the carteolol levels higher than the MRL among most urine samples. On the other hand, 36.36% (4/11) of urine samples were detected with beta-blockers higher than the MRL during the chronic administration of timolol and carteolol ophthalmic drops. In the context of receiving ophthalmic beta-blocker medications, the present study has highlighted the potential risk of constituting an AAF in specific sports and suggests strengthening athletes' awareness of therapeutic use exemptions.

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Association between low plasma levels of ophthalmic timolol and haemodynamics in glaucoma patients

Abstract: The plasma concentration of ophthalmic timolol correlates with several haemodynamic effects. As HR decreases, SVRI increases and blood pressure is kept unchanged.

Cited by 39 publications

References 24 publications

Blood Pressure Elevation Associated with Topical Prostaglandin F2α Analogs: An Analysis of the Different Spontaneous Adverse Event Report Databases

Blood Pressure Elevation Associated with Topical Prostaglandin F2α Analogs: An Analysis of the Different Spontaneous Adverse Event Report Databases

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

Urinary excretion patterns and potential risks of beta‐blocker ophthalmic drops in sports

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