Ophthalmic Timolol: Plasma Concentration and Systemic Cardiopulmonary Effects

Scand J Clin Lab Invest 2007; 67: 237–245

REVIEW OF A SCANDINAVIAN THESIS

Ophthalmic timolol: Plasma concentration and systemic cardiopulmonary effects

T. NIEMINEN1, T. LEHTIMA¨ KI2,J.MA¨ ENPA¨ A¨ 3, A. ROPO4, H. UUSITALO5 &M.KA¨ HO¨ NEN6

1Department of Pharmacological Sciences, Medical School, University of Tampere, Finland, 2Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Tampere University Hospital and Centre for Laboratory Medicine, Medical School, University of Tampere, Finland, 3Santen Oy, Tampere, Finland, 4Santen Oy, Helsinki, Finland, 5Department of Ophthalmology, Tampere University Hospital and Medical School, University of Tampere, Finland, and 6Department of Clinical Physiology, Tampere University Hospital and Medical School, University of Tampere, Finland

Abstract Timolol maleate is a non-selective b-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 b-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 For personal use only. 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 b-adrenergic tonus – the Scand J Clin Lab Invest Downloaded from informahealthcare.com by University of Tampere on 06/26/11 CYP2D6 poor metabolizers may be more prone to bradycardia during treatment with (aqueous) ophthalmic timolol.

Key Words: Adverse effects, cardiovascular, haemodynamics, pulmonary

Correspondence: Tuomo Nieminen, Department of Pharmacological Sciences, Medical School, FI-33014 University of Tampere, Finland. Tel: +358 50 9105 150. Fax: +358 3 2156 170. E-mail: [email protected]

(Received 26 June 2006; accepted 26 June 2006) ISSN 0036-5513 print/ISSN 1502-7686 online # 2007 Taylor & Francis DOI: 10.1080/00365510601034736 238 T. Nieminen et al.

Introduction Timolol maleate is a non-selective b-adrenergic receptor antagonist originally used in oral dose regimens for the treatment of cardiovascular diseases [1], but the current usage is mainly as an ocular preparation. Topically administered ophthalmic timolol reduces the intraocular pressure [2–4] by blocking the sympathetic nerve endings in the ciliary epithelium leading to a decrease in the production of aqueous humor [3]. Therefore, timolol is currently widely used in the treatment of glaucoma and ocular hypertension together with some other b-blockers, prostaglandin analogues, carbonic anhydrase inhibitors and a2-agonists. The sympathetic nervous system exerts various b-adrenergic receptor-mediated effects on cardiovascular and pulmonary systems (Table I). Despite the topical administration, ophthalmic timolol causes systemic adrenergic b-blocking caused by absorption from the eye through the conjunctival epithelium, lacrimal channels, nasal mucosa and gastro- intestinal tract into the systemic circulation (Figure 1) [2,5–10]. Gel formulations of ophthalmic timolol have been developed to reduce systemic absorption and adverse effects, For personal use only. Scand J Clin Lab Invest Downloaded from informahealthcare.com by University of Tampere on 06/26/11

Figure 1. A simplified diagram showing the origin of systemic cardiovascular and pulmonary effects of ophthalmic timolol. Ophthalmic timolol in systemic circulation 239

Table I. Responses of cardiovascular and pulmonary effector organs to sympathetic nerve impulses and circulating catecholamines. The direction and strength of the responses are indicated by the number and direction of the arrows [41,42].

Effector organ b1 b2

Heart S-A node HR qq HR % Atria Contractility and conduction Contractility and conduction velocity qq velocity q A-V node Conduction velocity qq Conduction velocity q His-Purkinje system Conduction velocity qqq Conduction velocity q Ventricles Contractility, conduction velocity, Contractility, conduction velocity, automaticity, rate of idioventricular automaticity, rate of pacemakers qqq idioventricular pacemakers qqq Arterioles Coronary Diameter qq Skin and mucosa Skeletal muscle Diameter qq Cerebral Pulmonary Diameter q Renal Diameter qq Systemic veins Diameter qq Lung Tracheal and bronchial muscle Relaxation q Bronchial glands Secretion q Kidney Renin Secretion qq

while maintaining the equivalent therapeutic activity in comparison with conventional ocular formulations such as aqueous solution [11,12]. Timolol is metabolized by the cytochrome P450 2D6 enzyme (CYP2D6) into inactive

For personal use only. metabolites that are excreted via the kidney. CYP2D6 is highly polymorphic (Table II) with about 100 alleles [13,14]. Individuals with certain combinations of the CYP2D6 gene alleles can be classified into different categories according to the total metabolizing activity of the combination. The most typical classification of phenotypes comprises four stages: If the level of total CYP2D6 activity is very low or nil, the individuals are referred to as poor metabolizers (PMs), while individuals with a fully functional enzyme are called extensive metabolizers (EMs). Those with CYP2D6 activity between poor and extensive are

Table II. The most common alleles of the gene CYP2D6: mutation frequencies in Caucasians and consequences in enzyme activity.

Allele Scand J Clin Lab Invest Downloaded from informahealthcare.com by University of Tampere on 06/26/11 code Frequency in Caucasians ( %) Mutation description Enzyme activity

*1 36.4 Wild-type Normal *2 32.4 1661GwC, 4180GwC Slightly decreased *3 2.0 2549Awdel, frameshift None *4 20.7 1846GwA, splicing defect None *5 2.0 Gene deletion None *6 0.9 1707Twdel, frameshift None *9 1.8 2613-2615delAGA Decreased *10 1.5 100CwT Decreased 6N 2.0 Duplication or multiplication Increased 240 .Neie tal. et Nieminen T.

Table III. Studies with changes in heart rate at baseline and during peak exercise when treated with ophthalmic timolol preparations.

Concentration DHR (bmp) at baseline DHR (bpm), exercise

Patients Age Design Gel Aq. Gel Aq. Gel Aq. Timolol preparation Ref.

11, Healthy 21–36 Crossover 2, NS 7 0.5 % s [5] 24, Healthy 22–45 Crossover 10 0.5 % s [43] 20, Healthy 21–35 3 14 0.5 % s [6] 6, Healthy 33–57 Crossover NS 12 0.5 % s [2] 12, Healthy 21–46 Crossover 6, NS 11 0.5 % s [18] 45, Cataract 1.05 5 0.25 % s [8] 42, Healthy 55–65 Crossover 0.71 0.91 8.5 11.0 11.9 15.6 0.5 % s, 0.5 % g [7] 8, Healthy 21–24 Crossover 6 22 0.5 % s [19] 14, Healthy >18 Crossover 11 13 0.5 % hh, 0.5 % g [20] 141, Glaucoma 3.4 0.5 % s [4] 43, Glaucoma 63¡8 Crossover 3.2 4.3 0.5 % s, 0.5 % g [24] For personal use only. For personal 8, Healthy 25–34 Crossover 1.14 11 0.5 % s [10] 20, Healthy 25¡7 Crossover 14 0.5 % s [22] 30, Healthy 18–37 Crossover 10.9 0.5 % s [21] 24, Healthy Crossover 0.14 1.38 1. NS 3, NS 0.5 % s, 0.1 % g [9] 24, Healthy 20–27 Crossover 0.18 1.72 4.6 19 0.5 % s, 0.1 % g [11] 5, Healthy 25–31 Crossover 1.5 2.0 Ns 0.5 % s, 0.5 % g [23] 25, Glaucoma 60¡9 Crossover 0.13 0.82 2 6 5.1 13.5 0.5 % s, 0.1 % g [12]

Abbreviations: HR5heart rate; Aq.5aqueous solution; NS5not significant; s5solution; g5hydrogel; hh5hemihydrate. Scand J Clin Lab Invest Downloaded from informahealthcare.com by University of Tampere on 06/26/11 on of Tampere University by informahealthcare.com from Downloaded Invest J Clin Lab Scand Ophthalmic timolol in systemic circulation 241

intermediate metabolizers (IM), and the individuals with duplicated or multiplicated functional CYP2D6 genes are ultra-rapid metabolizers (UM). In cases where many drugs are metabolized through CYP2D6, the CYP2D6 polymorphism is important regarding adverse effects, since PMs are at risk of having higher drug plasma levels [13]. Conversely, drug plasma levels in UMs are often below therapeutic ranges [13]. This review deals with the association between the cardiopulmonary effects of ophthalmic timolol and the plasma concentration of timolol. Moreover, the influence of CYP2D6 polymorphism on the plasma concentration and cardiovascular effects of ophthalmic timolol is discussed.

Cardiovascular adverse effects of ophthalmic timolol The systemic adrenergic b-blocking effects of the absorbed fraction of ophthalmic timolol are most evident in the changes in heart rate (HR) (Table III). Since timolol as an aqueous solution has caused an average plasma concentration of 0.46–1.72 ng/mL [7.9–12.15–17] and timolol hydrogel formulation correspondingly only 0.13–0.71 ng/mL [7,9,11,12,15], these two basic types of ophthalmic timolol preparation also exert a different bradycardic influence, especially during physical exercise. Resting HR decreased from negligible to 11 bpm with 0.25–0.5 % aqueous timolol [2,4–10,18–24] and from negligible to 9 bpm with 0.1–0.5 % hydrogel formulations [7,9,11,23,24]. Average reductions in the peak HR during exercise with treadmill or bicycle ergometer have been 7–22 bpm (aqueous) [2,5– 7,11,18,19,21,22] and 5–12 bpm (gel) [7,11,19,20]. Neither aqueous nor hydrogel formulations of timolol have exerted noteworthy effects on systolic (SAP) or diastolic (DAP) arterial pressures [2,9,10,21,22,25], with the exception of a slight reduction in the nocturnal DAP in patients prescribed 0.5 % aqueous eyedrops [26]. Following instillation of 1 mg timolol maleate in each eye, HR and stroke index (SI) decreased, and systemic vascular resistance index (SVRI) increased sig-

For personal use only. nificantly [27]. However, a contemporary timolol drop only contains approximately 150 mg timolol in 0.5 % aqueous and 30 mg in 0.1 % hydrogel formulations (manufac- turers’ documents).

Pulmonary adverse effects of ophthalmic timolol

As a result of b2 blockade, the average reductions in pulmonary parameter peak expiratory flow (PEF) have varied from 0 to 7 %, and in forced expiratory volume in 1 s (FEV1) between 0 and 3 % of the original values in non-asthmatic patients or healthy volunteers [4,10,12,18,25,28]. However, even deaths caused by bronchoconstriction have been reported [29], and timolol is contraindicated in patients with asthma or severe bronchial Scand J Clin Lab Invest Downloaded from informahealthcare.com by University of Tampere on 06/26/11 hyperreactivity.

Specific correlations between cardiopulmonary influences and plasma concentration of timolol Per oral timolol 0.4 mg/kg shows a correlation between the plasma concentration of timolol (highest value 123 ng/mL) and circulatory influences [30], whereas per oral and/or intravenous metoprolol and propranolol do not exhibit this correlation [30,31]. Owing to these conflicting results with different b-adrenoceptor blockers, we launched a study to 242 T. Nieminen et al.

evaluate whether the low plasma levels caused by ophthalmic timolol carry an association with cardiovascular actions [32]. In that study, 25 patients with glaucoma or ocular hypertension were subjected to passive head-up tilt and bicycle ergometer exercise tests for assessment of detailed haemodynamic changes. All the patients were treated with both aqueous and hydrogel formulations of timolol using a crossover design. Since the study was aimed to estimate the quantitative relation between timolol concentration and the cardiovascular effects, the data on the two treatments were combined, and, thereafter, the correlations between the plasma level of timolol and the circulatory effects were calculated. The resting HR (R520.52, p50.001) and pulse-wave velocity (R520.34, p50.04), an index of arterial stiffness, were inversely correlated with timolol level [32]. SI did not change with timolol concentration, while cardiac index (CI) diminished as timolol concentration rose (R520.39, p50.02). The vasoconstrictory effect of timolol was reflected in the positive correlation between the drug concentration and SVRI in the tilt test (R50.38, p50.02). This was probably mostly a compensatory reaction caused by the attenuation of HR, even though the blockade of vasodilatory b2-adrenoceptors might also play a part. In the exercise test, correlation between HR and plasma concentration of timolol gradually enhanced as the load increased, reaching R520.60 (pv0.0001) at the maximum load [32]. SAP and DAP were not associated with the timolol level, which is probably due to sufficiently strong baroreceptor-activated compensatory vasoconstriction following the drop in HR. Evidently, higher plasma levels after per os administration of timolol overweigh the compensatory mechanisms and lower blood pressure, since the oral dose regimens with plasma levels of around 100 ng/mL [30,33] have been used successfully as antihypertensive treatment [34,35]. Following the drop in HR, the CI in our patients decreased, while SI was unchanged by the drug at these low plasma levels. Changes in the pulmonary parameter FEV1 did not correlate with the concentration of timolol in our own study (unpublished observation). For personal use only.

The influence of CYP2D6 polymorphism on the plasma concentration and cardiovascular effects of timolol

After oral ingestion of timolol, the maximal plasma concentration (Cmax) and area under the curve (AUC) were significantly higher and the elimination half-life (TK) longer in CYP2D6 PMs than in EMs [36,37]. Three reports have been published to evaluate whether the CYP2D6 polymorphism also differentiates the pharmacokinetics of ophthalmic timolol. In the first of these reports [38], ocular drug administration paradoxically caused higher peak plasma levels in the subjects with the EM phenotype

Scand J Clin Lab Invest Downloaded from informahealthcare.com by University of Tampere on 06/26/11 than PMs. Apparently, variation in the instillation techniques, and, consequently, different fractions of absorbed timolol contributed more to the timolol plasma levels than the CYP2D6 phenotype. In another study, after timolol eyedrops were applied, exercise HR was reduced significantly more in the PMs than in EMs, and plasma timolol concentration was higher in PMs [39]. However, timolol was applied directly to the nasal mucosa in this latter study, not to the cul de sac as applied when used as ocular treatment. As the investigators reported, this change in the instillation routine most probably increased the bioavailability of timolol, leading to elevated plasma concentrations of timolol with less interpersonal variation within each phenotype. Ophthalmic timolol in systemic circulation 243

In our own study, 19 patients with glaucoma and 18 healthy volunteers applied 0.5 % aqueous and 0.1 % hydrogel timolol to the cul de sac [40]. We classified the individuals with 0, 1, 2 and at least 3 functional CYP2D6 alleles as PMs, IMs, EMs and UMs, respectively (Table II). This CYP2D6 activity grouping had a clear association to the pharmacokinetic parameters: Cmax,TK and AUC were highest in PMs and lowest in UMs. For AUC, the values after 0.5 % aqueous timolol were 21.40 ng?h/mL for PMs, 11.32 ng?h/mL for IMs, 8.52 ng?h/mL for EMs and 6.55 ng?h/mL for UMs. The differences in relation to the PM group reached statistical significance with aqueous solution, but not with 0.1 % timolol hydrogel. The plasma concentrations of timolol remained essentially lower after 0.1 % timolol hydrogel than after 0.5 % timolol aqueous preparation. Relatively low CYP2D6 activity may be sufficient to metabolize low concentrations of timolol, which could – in addition to the limited sample size – explain why the pharmacokinetics of timolol hydrogel was not dependent on the CYP2D6 group. For healthy volunteers, the increase in HR during maximal exercise after instillation of the 0.5 % aqueous timolol solution test was 15 bpm lower among PMs than EMs [40]. The results with 0.1 % timolol hydrogel had the same trend towards CYP2D6 dependence without reaching statistical significance, probably partly owing to the sample size. These findings have relevance in clinical practice because of the great number of people receiving treatment with ophthalmic timolol and the relatively high prevalence of the PM genotype: e.g. 5–10 % among Caucasians, 1–2 % among the Asians, and 0–19 % among African Americans [14].

Conclusions Ophthalmic timolol induces fewer cardiovascular adverse effects in 0.1 % hydrogel formulation than in 0.5 % aqueous solution. The pharmacokinetics of ophthalmic timolol is dependent on the CYP2D6 genotype. This is particularly evident when 0.5 % aqueous

For personal use only. formulation of timolol is used. Since there is a correlation between the plasma level of timolol and several haemodynamic effects – especially in the state of elevated b-adrenergic tonus – the CYP2D6 PMs may be more prone to bradycardia than EMs during treatment with timolol. Therefore, knowing the actual CYP2D6 genotype might be particularly valuable in patients who experience adverse effects. Routine genotyping of CYP2D6 is becoming more readily available in many clinical centres. However, it should be remembered that inter-individual variation in plasma concentration of ophthalmic timolol depends not only on pharmacokinetics, but also on dosing technique.

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