Ophthalmic timolol: plasma concentration and systemic cardiopulmonary effects.
Timolol maleate is a non-selective beta-adrenoceptor antagonist currently used mainly as an ocular preparation for the treatment of glaucoma and ocular hypertension. Despite the topical administration, ophthalmic timolol causes systemic adrenergic beta-blocking because of absorption from the eye into the systemic circulation. Gel formulations of ophthalmic timolol have been developed to reduce systemic absorption and adverse effects in comparison with conventional aqueous solution formulations. Timolol is metabolized by the polymorphic cytochrome P450 2D6 enzyme (CYP2D6). The changes in heart rate (HR) are the most striking effects of the systematically absorbed fraction of ophthalmic timolol, with 0.5 % aqueous formulations presenting larger effects than 0.1 % hydrogel formulations, especially during exercise. Plasma levels of ophthalmic timolol correlate with the changes in HR. Neither 0.5 % aqueous nor 0.1 % hydrogel formulations of timolol have exerted noteworthy effects on systolic (SAP) or diastolic (DAP) arterial pressures, probably because of a compensatory increase in systemic vascular resistance due to the attenuation of HR. Ophthalmic timolol does not exert remarkable effects on pulmonary parameter peak expiratory flow (PEF) and forced expiratory volume in 1 s (FEV1) in non-asthmatic patients. CYP2D6 activity is clearly associated with the pharmacokinetic parameters, particularly when 0.5 % aqueous solution of timolol is used: peak plasma concentration, elimination half-life and area-under-the-curve are highest in CYP2D6 poor metabolizers. Finally, since there is a correlation between the plasma level of timolol and several haemodynamic effects - especially HR in the state of elevated beta-adrenergic tonus - the CYP2D6 poor metabolizers may be more prone to bradycardia during treatment with (aqueous) ophthalmic timolol.
Nieminen
T
T
Department of Pharmacological Sciences, Medical School, University of Tampere, Finland. tuomo.nieminen@iki.fi
Lehtimäki
T
T
Mäenpää
J
J
Ropo
A
A
Uusitalo
H
H
Kähönen
M
M
D000287:Administration, Topical; D000319:Adrenergic beta-Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D016503:Drug Delivery Systems; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D012129:Respiratory Function Tests; D013999:Timolol / Q000097:blood / Q000493:pharmacokinetics*
D000319:Adrenergic beta-Antagonists; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D013999:Timolol