Ophthalmic Timolol Research Articles

Severe systemic adverse reactions to ophthalmic timolol in a CYP2D6 homozygous *4 allele carrier: a case report.

A woman with ocular hypertension suffered from severe bradycardia, hypotensionand syncope attacks in temporal relation with ophthalmic timolol application. Topically applied timolol is nasally absorbed and has been shown to reach potentially relevant systemic concentrations. Timolol is mainly metabolized by CYP2D6, which exhibits interindividual metabolic capacity due to genetic variations. A reactive pharmacogeneticpanel test identified the patient as a CYP2D6 homozygous *4 allele carrier, which has been associated with a poor metabolizerphenotype and lacking enzyme activity. Thus, the adverse drug reactions possibly resulted from increased systemic timolol exposure. This case report highlights that pharmacogenetic panel testing can contribute to safe and effective pharmacotherapy, even for topically applied drugs.

Molecular Variants in Genes related to the Response to Ocular Hypotensive Drugs in an Afro-Colombian Population

Aims: This study aimed to conduct an exploratory analysis of the pharmacogenomic variants involved in ocular hypotensive drugs to understand the individual differential response in an Afro-descendant population. Background: Glaucoma is the leading cause of irreversible blindness worldwide. The pharmacologic treatment available consists of lowering intraocular pressure by administering topical drugs. In Asian and Caucasian people, pharmacogenomic variants associated with the efficacy of these treatments have been identified. However, in Afro-descendant populations, there is a profound gap in this knowledge. Objective: This study identified the pharmacogenomic variants related to ocular hypotensive efficacy treatment in Afro-descendant individuals from the Archipelago of San Andres and Providence, Colombia. Methods: An analysis of whole-exome sequencings (WES), functional annotation, and clinical significance was performed for pharmacogenomic variants reported in PharmGKB databases; in turn, an in silico available prediction analysis was carried out for the novel variants. Results: We identified six out of 18 non-synonymous variants with a clinical annotation in PharmGKB. Five were classified as level three evidence for the hypotensive drugs; rs1801252 and rs1801253 in the ADRB1 gene and rs1042714 in the ADRB2 gene. These pharmacogenomic variants have been involved in a lack of efficacy of topical beta-blockers and higher systolic and diastolic pressure under treatment with ophthalmic timolol drug. The rs1045642 in the ABCB1 gene was associated with greater efficacy of treatments with latanoprost drug. Also, we found the haplotypes *17 for CYP2D6 and *10 for CYP2C19; both related to reducing the enzyme activity to timolol drug metabolization. In addition, we observed 50 novel potentially actionable variants; 36 synonymous, two insertion variants that caused frameshift mutations, and 12 non-synonymous, where five were predicted to be pathogenic based on several pathogenicity predictions. Conclusion: Our results suggested that the pharmacogenomic variants were found to decrease the ocular hypotensive efficacy treatment in a Colombian Afro-descendant population and revealed a significant proportion of novel variants with a potential to influence drug response.

Clinical management of a rare Peters' anomaly-induced secondary childhood glaucoma: A case report.

Childhood glaucoma is a rare disorder that occurs from birth until teenage years caused by an abnormality of aqueous humor pathways. About 50-70% of Peters' anomaly is accompanied by secondary childhood glaucoma. The presence of glaucoma will affect the prognosis. We reported the evaluation and treatment of secondary childhood glaucoma due to Peters' anomaly. A 5 months-old boy was presented with the complaint of a enlarged left eye since 3 months old. The complaint was accompanied by a watering eye and frequently closed upon light exposure. The left eye looked opaquer than contralateral. Examination under anesthesia showed that the intraocular pressure (IOP) was 35 mmHg in the left eye and the corneal diameter was 14 mm. Other findings were keratopathy, diffuse corneal edema, buphthalmos, shallow anterior chamber, anterior synechiae, and linear slit shaped pupils in the nasal region. Patient was treated with ophthalmic timolol maleate which was later followed by trabeculectomy. After 1 week post-surgery, IOP assessment by palpation suggested the right eye within normal range while the IOP of left eye was higger than normal. Blepharospasm, epiphora, photophobia, bleb on superior, subconjunctiva bleeding, buphthalmos, keratopathy, minimal corneal edema, anterior chamber with shallow image, and posterior synechia were found in left eye anterior segment. In conclusion, trabeculotomy and trabeculectomy are recommended if there is no reduction of IOP observed after receiving timolol maleate therapy. The choice of surgical management is dependent on the feasibility of the protocol.

Clinical management of a rare Peters’ anomaly-induced secondary childhood glaucoma: A case report

Childhood glaucoma is a rare disorder that occurs from birth until teenage years caused by an abnormality of aqueous humor pathways. About 50–70% of Peters' anomaly is accompanied by secondary childhood glaucoma. The presence of glaucoma will affect the prognosis. We reported the evaluation and treatment of secondary childhood glaucoma due to Peters’ anomaly. A 5 months-old boy was presented with the complaint of a enlarged left eye since 3 months old. The complaint was accompanied by a watering eye and frequently closed upon light exposure. The left eye looked opaquer than contralateral. Examination under anesthesia showed that the intraocular pressure (IOP) was 35 mmHg in the left eye and the corneal diameter was 14 mm. Other findings were keratopathy, diffuse corneal edema, buphthalmos, shallow anterior chamber, anterior synechiae, and linear slit shaped pupils in the nasal region. Patient was treated with ophthalmic timolol maleate which was later followed by trabeculectomy. After 1 week post-surgery, IOP assessment by palpation suggested the right eye within normal range while the IOP of left eye was higger than normal. Blepharospasm, epiphora, photophobia, bleb on superior, subconjunctiva bleeding, buphthalmos, keratopathy, minimal corneal edema, anterior chamber with shallow image, and posterior synechia were found in left eye anterior segment. In conclusion, trabeculotomy and trabeculectomy are recommended if there is no reduction of IOP observed after receiving timolol maleate therapy. The choice of surgical management is dependent on the feasibility of the protocol.

Repurposing Ophthalmologic Timolol for Dermatologic Use: Caveats and Historical Review of Adverse Events.

Ophthalmic timolol solution is increasingly being repurposed as a topical therapeutic for a variety of dermatologic diseases, including pyogenic granulomas, infantile hemangiomas, and chronic wounds. There are no published guidelines or protocols for use in these indications in adults, and the dermatologic community may not be familiar with adverse events that have been extensively documented relating to its ophthalmic use. We review the evidence available relating to adverse events to topical timolol use to evaluate its safety in dermatologic applications and to alert clinicians to screening and monitoring that is needed when repurposing this drug for dermatologic use. The majority of serious adverse events associated with ophthalmic timolol were reported in the first 7 years of use, between 1978 and 1985, of which most common were cardiovascular and respiratory events, but also included 32 deaths. The available evidence suggests that ophthalmic timolol safety profiling may have been incomplete prior to widespread use. Recent clinical trials for dermatologic indications have focused on documenting efficacy and have not had rigorous monitoring for potential adverse events. Topical timolol may be safe and effective for the treatment of various dermatologic conditions in patients whose medical histories have been carefully reviewed for evidence of pre-existing cardiac or pulmonary disease and are monitored for potential adverse events. Despite the wide use of timolol in ophthalmologic practice, safe dermatologic repurposing requires recognition of the potential for facilitated systemic absorption though the skin and appreciation of its history of adverse events.

Complete atrioventricular block due to timolol eye drops: a case report and literature review

BackgroundTimolol Maleate is a non-selective beta-adrenergic blocker that is commonly used to treat open-angle glaucoma. Despite its topical administration, ophthalmic timolol enters systemic circulation and produces a systemic beta-adrenergic blockade. We report a case of long-term timolol use that uncovered and worsened an underlying cardiac conduction defect demonstrated as a third degree atrioventricular (AV) block.Case presentationA 62-year old male with a 13-year history of glaucoma was hospitalized due to shortness of breath, dizziness, and amaurosis. Electrocardiography indicated a heart rate (HR) of 29 bpm with complete atrioventricular (AV) block, and the HR was significantly increased with the treatment of isoprenaline. However, the patient experienced bradycardic episodes (− 20 Δbpm) immediately after self-administration of timolol eye drops. The AV block and bradycardia resolved 48-h after timolol cessation. The man was discharged 1 week later with an asymptomatic first-degree A-V block. However, he presented with a worsened A-V block at his one-year checkup.ConclusionWe conclude that chronic topical timolol administration may aggravate a cardiac conduction defect leading to an AV block that is only temporarily resolved by timolol cessation. Patients taking timolol should be routinely monitored for cardiovascular aberrations and if any detected, immediately discontinue timolol therapy. Individuals experiencing timolol induced cardiovascular side effects should receive long term follow-up even if symptoms resolve, as they may be indicative of an underlying conduction defect.

Neuropsychiatric Adverse Events from Topical Ophthalmic Timolol.

Timolol is a commonly-used topical antiglaucoma medication and has proven to be highly efficacious for most recipients. Among the reported adverse events, the neuropsychiatric spectrum has been cited, albeit for a small proportion of those treated. This review summarizes the cumulative published experience of such side effects and assesses the quality of evidence. As for other beta-blockers, whether orally or topically administered, various central nervous systems dysfunctions have been detailed in either case reports or larger patient series. The adverse event commonly resolves following drug termination. Rigorous and more definitive studies of causation are lacking, and to some, such paucity has reduced the belief of a cause and effect relationship. Until otherwise proven, deference should be afforded to the potential for topical timolol to cause neuropsychiatric side effects, and at-risk patients should be closely monitored when they are prescribed this pharmacological agent.

Impact of Combination Glaucoma Therapies on β-Blocker Exposure.

β-adrenergic receptor antagonists (β-blockers) used in the treatment of glaucoma are an often-overlooked source of systemic adverse events. Ophthalmic timolol has been associated with severe systemic adverse events including numerous cases resulting in death. In recent years the number of fixed-dose combination therapies for glaucoma has grown rapidly, and among available combination therapies only the nonselective β-blocker timolol is used as the β-blocker component. A population-based study was conducted in Ontario, Canada between January 1, 2001 and December 31, 2012 to assess the shift to combination therapies in the management of glaucoma, and to investigate the impact of this shift on the relative use of selective and nonselective β-blockers in patients with this disease. Between 2001 and 2012 timolol (nonselective β-blocker) use grew at an average annual rate of 2.2% (P<0.0001), whereas betaxolol (selective β-blocker) use declined by 14.1% per year (P<0.0001). These changes in the relative use of betaxolol and timolol coincided with changes in the relative use of combination and single-drug therapies. Over the study period, the use of β-blockers as single-drug therapy decreased by 7.7% annually (P<0.0001). In contrast, the use of combination therapies containing a β-blocker increased by 7.6% annually (P<0.0001). The introduction of fixed combination glaucoma therapies has been associated with a significant shift to greater use of nonselective β-blockers. In vulnerable older populations, this may have an important impact on patient safety that warrants further study.

Topical Timolol Maleate Treatment of Infantile Hemangiomas.

There has been a dramatic increase in the off-label use of ophthalmic timolol maleate, a β-blocker used for infantile hemangioma (IH) treatment as a topical counterpart to oral propranolol. Its safety and efficacy in a pediatric population with IH have not been evaluated in a large cohort. Our goal was to retrospectively assess timolol's effectiveness, discern characteristics associated with response, and document reported adverse events. A multicenter retrospective cohort study of 731 patients treated with topical timolol was completed at 9 centers. Inclusion required an IH suitable for timolol in the treating physician's judgment and access to clinical details including photographs. Logistic regression analysis and descriptive statistics were performed. Primary outcome measures were efficacy assessed by using visual analog scales for color and for size, extent, and volume from review of digital photographs taken as standard of care. Most IHs were localized (80.1%) and superficial (55.3%). Risk of disfigurement was the most common indication for therapy (74.3%). Duration of therapy (P < .0001), initial thinness (P = .008), and subtype (P = .031) were significant predictors of response. Best response occurred in superficial IHs <1 mm thick. Fifty-three (7.3%) required subsequent therapy with systemic β-blocker. Adverse events were mild, occurring in 25 (3.4%) patients. No cardiovascular side effects were documented. Timolol seems to be a well-tolerated, safe treatment option with moderate to good effectiveness, demonstrating best response in thin, superficial IHs regardless of pretreatment size. Timolol can be recommended as an alternative to systemic β-blockers and watchful waiting for many patients.

Cardiac safety of ophthalmic timolol

ABSTRACTIntroduction: It is generally believed that topical administration of eye drops safeguards against harmful systemic effects. However, about 80% of the drug in the ophthalmic products is systemically absorbed and the first-pass metabolism is avoided. Ophthalmic timolol is widely prescribed in the treatment of glaucoma either alone or in the combination eye drop products, many of which have been launched fairly recently. Ophthalmic timolol may cause serious adverse effects such as symptomatic bradycardia, various conduction disorders in the heart, orthostatic hypotension, syncope and falls.Areas covered: In this review we document a number of factors associated with the properties of ophthalmic timolol and specific features of a patient, which may jeopardize patient’s cardiac safety even after topical treatment.Expert opinion: Plasma timolol levels are correlated with cardiovascular adverse effects in patients, since timolol is mainly metabolized by cytochrome P450 2D6 (CYP2D6) enzyme in the liver. Patients who are lacking the functional CYP2D6 or who are concomitantly using potent CYP2D6 inhibitor drugs (e.g. paroxetine or fluoxetine) or verapamil or other beta-blockers are at risk of getting serious cardiac adverse effects. Prior to treatment initiation, ECG should be always performed and CYP2D6 genotyping should be considered, if routinely available.

Avaliação eletrocardiográfica de cães clinicamente hígidos sob tratamento com solução oftálmica de maleato de timolol 0,5%: estudo preliminar

&lt;p&gt;O maleato de timolol 0,5% é um fármaco recomendado para tratamento de glaucoma em cães. Após instilação, e absorvido para a circulação sistêmica e por ser um antagonista beta-adrenérgico pode promover efeitos colaterais sistêmicos importantes sobre a condução elétrica cardíaca. No presente estudo, foi avaliada a alteração causada pelo timolol 0,5% oftálmico no eletrocardiograma. Foram selecionados seis cães hígidos para participar de dois tratamentos oftálmicos diferentes: no primeiro foi instilado placebo (hipromelose 0,5%) e no segundo utilizou-se timolol 0,5%. O colírio foi instilado a cada 12 horas por 14 dias. Os parâmetros eletrocardiográficos foram mensurados nos tempos: zero, 10, 60, 120, 240, 360 e 720 minutos após instilação da solução ocular nos dias primeiro, sétimo e décimo quarto de cada tratamento. As alterações eletrocardiográficas foram mais evidentes entre 120 e 240 minutos pós-instilação de timolol 0,5% quando comparado com o tratamento placebo. O ritmo foi irregular, com momentos de arritmia sinusal e bradicardia sinusal. Os intervalos RR e PR prolongaram significativamente (p &amp;lt; 0,05) desde o primeiro dia de instilação de timolol, sendo o prolongamento mais expressivo no décimo quarto dia de tratamento. O intervalo QT demonstrou pouca variação, apenas prolongando significativamente (p &amp;lt; 0,05) no décimo quarto dia de aplicação de timolol. O intervalo QTc não demonstrou alteração significativa (p &amp;gt; 0,05). Apesar das alterações encontradas, não foram observadas manifestações clínicas relacionadas ao timolol nos animais estudados. Deve-se considerar, porém, que os animais em questão eram hígidos e, portanto, as alterações decorrentes do uso do timolol em animais com cardiopatias preexistentes poderiam promover sinais clínicos, sendo recomendada a avaliação cardíaca de pacientes previamente à prescrição do timolol oftálmico.&lt;/p&gt;

Association between Ophthalmic Timolol and Hospitalisation for Bradycardia.

Introduction. Ophthalmic timolol, a topical nonselective beta-blocker, has the potential to be absorbed systemically which may cause adverse cardiovascular effects. This study was conducted to determine whether initiation of ophthalmic timolol was associated with an increased risk of hospitalisation for bradycardia. Materials and Methods. A self-controlled case-series study was undertaken in patients who were hospitalised for bradycardia and were exposed to timolol. Person-time after timolol initiation was partitioned into risk periods: 1–30 days, 31–180 days, and >180 days. A 30-day risk period prior to initiating timolol was also included. All remaining time was considered unexposed. Results. There were 6,373 patients with at least one hospitalisation for bradycardia during the study period; 267 were exposed to timolol. Risk of bradycardia was significantly increased in the 31–180 days after timolol initiation (incidence rate ratio (IRR) = 1.93; 95% confidence interval (CI) 1.00–1.87). No increased risk was observed in the first 30 days or beyond 180 days of continuous exposure (IRR = 1.40; 95% CI 0.87–2.26 and IRR = 1.21; 95% CI 0.64–2.31, resp.). Conclusion. Bradycardia is a potential adverse event following timolol initiation. Practitioners should consider patient history before choosing a glaucoma regime and closely monitor patients after treatment initiation with topical nonselective beta-blocker eye drops.

From Eye Drops to ICU, a Case Report of Three Side Effects of Ophthalmic Timolol Maleate in the Same Patient.

Timolol Maleate (also called Timolol) is a nonselective beta-adrenergic blocker and a class II antiarrhythmic drug, which is used to treat intraocular hypertension. It has been reported to cause systemic side effects especially in elderly patients with other comorbidities. These side effects are due to systemic absorption of the drug and it is known that Timolol is measurable in the serum following ophthalmic use. Chances of life threatening side effects increase if these are coprescribed with other cardiodepressant drugs like calcium channel or systemic beta blockers. We report a case where an elderly patient was admitted with three side effects of Timolol and his condition required ICU admission with mechanical ventilation and temporary transvenous pacing. The case emphasizes the need of raising awareness among physicians of such medications about the potential side effects and drug interactions. A close liaison among patient's physicians is suggested.

Paroxetine markedly increases plasma concentrations of ophthalmic timolol; CYP2D6 inhibitors may increase the risk of cardiovascular adverse effects of 0.5% timolol eye drops.

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.

Severe bradycardia and syncope due to topical ophthalmic timolol

Severe bradycardia and syncope due to topical ophthalmic timolol

Novel ophthalmic timolol meleate liposomal-hydrogel and its improved local glaucomatous therapeutic effect in vivo

To overcome the limitations of common eye drops, the study developed a novel timolol mealate (TM) liposomal-hydrogel to enhance drug permeability and prolong residence time in the precorneal region, which achieved more effective local glaucomatous therapeutic effect. Firstly, TM liposome was prepared by an ammonium sulfate gradient-pH regulation method, which its entrapment efficiency reached up to 94% and its averaged particle size is 187 nm with narrow distribution. The corneal permeability through isolated rabbit cornea was measured by modified Franz-type diffusion cells. The results of trans-corneal penetration exhibited that the apparent permeability coefficients (Papp) and the flow rates of steady state (Jss) of TM liposome was 1.50-fold higher than that of the commercialized eye drop, while TM liposome with 0.02% transcutol P was 2.19 times. In order to increase the retention time and improve the stability of liposome, we further developed a TM liposomal-hydrogel formulation by adding 1.0% HPMC K4M in TM liposome. The results showed an stability during a 120 days storage period than TM liposome. Precorneal retention study in vivo indicated that the optimal liposomal-hydrogel formulation had improved bioavailability and its retention time on rabbit corneal surface were significantly longer than that of pure liposomes or eye-drops. No obvious irritations to rabbit eyes were observed by histopathology microscopy after 7 days exposure.. Comparing to the eye drops, the TM liposomal-gel displayed prolonged therapeutic effect in cornea and greatly lowered the intraocular pressure IOP on the eyes of normal and glaucomatous pigmented rabbits.

Metabolism of Ophthalmic Timolol: New Aspects of an Old Drug

Glaucoma is a common eye disease that can cause irreversible blindness if not diagnosed and treated in the early stages of progression. This disease is often, albeit not always, associated with increased intraocular pressure, which is also the most important risk factor for glaucoma. Currently, the only treatment option of glaucoma is reduction of intraocular pressure. A β-adrenergic antagonist, timolol, has been used for the treatment of glaucoma and increased intraocular pressure for more than 30 years and still remains the drug of choice. Locally, timolol is well tolerated. However, it has been reported that approximately 80% of a topically administered eye drop is systemically absorbed. Thus, ophthalmic timolol may cause severe adverse cardiovascular and respiratory effects. On the basis of the aforementioned situation, it is somewhat surprising to notice that the metabolism of timolol has only recently been studied in detail even though the drug has been used for decades. Earlier clinical studies have suggested that timolol is metabolized by CYP2D6, an important member of the cytochrome P450 family. Our recent in vitro studies demonstrated convincingly that CYP2D6 is the main enzyme contributing to timolol metabolism, although also CYP2C19 may have a minor role. Liver is the principal site of timolol metabolism, because - according to our recent findings - only negligible amounts of CYP2D6 are expressed in human ocular tissues. After topical administration, systemic timolol concentrations may be high enough to cause cardiovascular and respiratory adverse effects especially in patients who are CYP2D6 poor metabolizers or use concomitant CYP2D6 inhibitors.

Association of CYP2D6 Single-Nucleotide Polymorphism with Response to Ophthalmic Timolol in Primary Open-Angle Glaucoma—A Pilot Study

We aimed to investigate whether CYP2D6 polymorphisms were associated with the intraocular pressure (IOP)-lowering effect and systemic complications (especially bradycardia) of ophthalmic timolol. One hundred twenty-three primary open-angle glaucoma subjects (123 eyes) were treated with 0.5% aqueous formulations of ophthalmic timolol. IOP and heart rate were measured before and after timolol administration. DNA was extracted from venous leukocytes of all the subjects. Two single-nucleotide polymorphisms (SNPs) of CYP2D6, for example, rs16947 (2850C>T, R296C) and rs1135840 (4180C>G, S486T), were detected by restriction fragment length polymorphism analysis. Neither rs16947 (P = 0.339) nor rs1135840 (P = 0.903) genotype was statistically correlated with the IOP-lowering effect of timolol eye drops. The rs16947 genotype was significantly associated with occurrence of bradycardia in primary open-angle glaucoma patients (P = 0.021). The patients with rs16947 CT (P = 0.043) or TT (P = 0.043) were more inclined to bradycardia than those with rs16947 CC, although there was no significant difference between CT and TT (P = 0.177). The analysis of variance showed no significant difference in heart rate (P = 0.559) among GG, GC, and CC groups. CYP2D6 SNP rs16947 may confer susceptibility to timolol-induced bradycardia. Patients with CC genotype were unlikely to suffer from timolol-induced bradycardia, whereas those with TT genotype were found to suffer from timolol-induced bradycardia.

Timolol Eye Drops Induced Bradycardia

We report a 25‐year‐old man with bradycardia after administration of ophthalmic timolol. The patient was asymptomatic, and his bradycardia resolved after stopping the eye drop. He was discharged after a four‐hour observation. This case demonstrated that topical timolol eye drop may cause systemic adverse reaction. The use of timolol and its possible side‐effects are discussed.

Cytochrome Oxidase 2D6 Gene Polymorphism in Primary Open-Angle Glaucoma With Various Effects to Ophthalmic Timolol

Timolol is used topically for the treatment of glaucoma and metabolized by cytochrome P450 (CYP) 2D6 in the liver. The aim of this study is to test the hypothesis that CYP 2D6 single-nucleotide polymorphism (SNP) is associated with drug effects of ophthalmic timolol. A total of 133 primary open-angle glaucoma (POAG) subjects underwent the ophthalmic single timolol administration and the drug effects were observed, including lowering the effects of intraocular pressure (IOP) and side effects (i.e., appearing bradycardia). Eight SNPs of CYP2D6 were investigated in 73 subjects by a SNPstream genotyping system. The relationship between the effects of timolol and CYP2D6 Arg296Cys and Ser486Thr genotype distribution in these POAG subjects was analyzed. Topical timolol administration had significant effect on IOP (P = 0.000) and heart rate (HR) (P = 0.000) in all 133 subjects, and individual ocular hypotensive effect of timolol varied between 0 and 23 mmHg. Individual effect of HR varied between -31 and 10 beats per minute, in the present study. According to SNP genotyping in 73 subjects, there was no significant difference of IOP between subjects with different CYP2D6 Arg296Cys (P = 0.308) or Ser486Thr genotypes (P = 0.741). The effect of timolol on HR was significantly different between subjects with different Arg296Cys genotypes (P = 0.046). Timolol-induced bradycardia tended to occur in subjects with Arg296Cys CT and TT genotype when compared with CC genotype (P = 0.009). CYP2D6 SNP Arg296Cys appeared to be correlative with the intersubject variability seen with timolol in POAG subjects. Subjects with CC genotype trended to avoid timolol-induced bradycardia, and subjects with TT genotype trended to have poorer timolol-induced ocular hypotensive effects.