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BRIEF COMMUNICATION
Year : 2021  |  Volume : 9  |  Issue : 2  |  Page : 78-80

Sinus bradycardia following single-day use of timolol eye drops in a healthy young adult - A rare case report


1 Department of Ophthalmology, JIPMER Hospital, Puducherry, India
2 Department of Emergency Medicine, JIPMER Hospital, Puducherry, India

Date of Submission23-Jun-2020
Date of Decision05-Oct-2020
Date of Acceptance16-Oct-2020
Date of Web Publication31-Jul-2021

Correspondence Address:
Subashini Kaliaperumal
Department of Ophthalmology, JIPMER Hospital, Gorimedu, Puducherry - 605 006
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcor.jcor_91_20

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  Abstract 


We report the rare case of timolol-induced sinus bradycardia in an otherwise healthy young individual following just 1 day use of timolol eye drops. A 35-year-old male presented with dispersed hyphema and raised intraocular pressure following blunt trauma in the left eye. He was prescribed timolol eye drops and topical steroids. He presented next day with giddiness, sweating, and heart rate (HR) of 30/min. Electrocardiogram confirmed sinus bradycardia injection atropine 0.5 mg intravenous was given. Timolol was substituted with brimonidine-brinzolamide drops. HR returned to normal of 72/min after 2 days of observation. Our case, therefore, represents an exaggerated response to topical timolol.

Keywords: Hyphemia, sinus bradycardia, timolol


How to cite this article:
Sarkar S, Shankaralingappa P, Deb AK, Suneel S, Kaliaperumal S, Natarajan K, Mahalingam S. Sinus bradycardia following single-day use of timolol eye drops in a healthy young adult - A rare case report. J Clin Ophthalmol Res 2021;9:78-80

How to cite this URL:
Sarkar S, Shankaralingappa P, Deb AK, Suneel S, Kaliaperumal S, Natarajan K, Mahalingam S. Sinus bradycardia following single-day use of timolol eye drops in a healthy young adult - A rare case report. J Clin Ophthalmol Res [serial online] 2021 [cited 2022 Jul 2];9:78-80. Available from: https://www.jcor.in/text.asp?2021/9/2/78/322798



Timolol maleate is a nonselective beta-blocker used commonly as a first-line agent in all types of glaucoma. It acts by decreasing aqueous humor production. Timolol on topical application can reach the systemic circulation through the nasolacrimal duct bypassing the first pass metabolism. It can, therefore, cause systemic beta blockade effects such as syncope, bronchospasm, bradycardia, conduction blocks, and orthostatic hypotension. All these side effects are, however, common in the elderly population and in those with associated systemic comorbidities.[1],[2] Here, we report a rare case where a young individual without any systemic comorbidity presented with bradycardia following just 1-day use of timolol eye drops.


  Case Report Top


A 35-year-old male presented to the emergency with complaints of pain, redness, and diminution of vision in his left eye (LE) following blunt trauma with a shuttlecock. His visual acuity (VA) in the right eye (RE) was 20/20 and LE was hand movements. Slit-lamp and fundus examination of RE was unremarkable. LE examination revealed ciliary congestion, clear cornea, dispersed blood in the anterior chamber [Figure 1]a, and no view of the fundus. Goldmann applanation tonometry revealed intraocular pressures (IOP) of 10 mmHg in RE and 26 mmHg in LE. Ultrasound B scan of LE showed no evidence of vitreous hemorrhage or retinal detachment. The patient was advised Moxifloxacin-dexamethasone eyedrops (e/d) 2 hourly, homatropine eye drops twice daily, and timolol eyedrops twice daily in LE. Advice regarding nasolacrimal duct occlusion after timolol instillation was not done. He had no systemic comorbidity and was not on any other systemic medications. He was not admitted in view of the Covid situation and was asked to review the next day. When the patient was reviewed, he complained of giddiness, vomiting, and profuse sweating since previous night. He had no previous such history. The patient had a blood pressure (BP) recording of 120/80 mmhg, heart rate (HR) 30/min, SpO2 of 98%, respiratory rate of 17/min, and blood sugars of 115 mg%. Immediate consultation with the emergency medicine department was sought, and the patient was administered one pint normal saline. Electrocardiogram (ECG) done showed sinus bradycardia [Figure 2]a. As there was no other reason for the bradycardia to occur, instillation of β-blocker, timolol eye drops the previous night was suspected to be the culprit. His serum electrolytes were within the normal limits. The patient was subsequently managed with injection atropine 0.5 mg intravenous (IV) stat and another repeat dose after 2 h. Timolol was substituted by brimonidine-brinzolamide combination e/d for IOP control. After 2 days of observation, HR returned to normal of above 72 beats/min echocardiography and Holter monitoring ruled out any other cardiac disease. Repeat ECG showed normal sinus rhythm [Figure 2]b. A diagnosis of timolol induced sinus bradycardia was made due to this temporal association. One week later, VA in LE improved to 20/20. Anterior chamber showed occasional cells and the hyphema had completely disappeared; lens was clear [Figure 1]b, gonioscopy showed 3 clock hours of angle recession, and fundus examination was normal with indirect ophthalmoscopy. IOP in LE was 16 mm Hg.
Figure 1: Anterior segment images showing dispersed hyphema in the left eye at presentation (a) and clear lens with resolved hyphema after 1 week (b)

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Figure 2: Electrocardiogram at presentation showing prolonged interval between two QRS complexes (arrow) and sinus bradycardia (a), and repeat electrocardiogram showing normal heart rate with normal interval between QRS complexes (arrow) (b)

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  Discussion Top


Bioavailability of topical timolol is <10% as corneal epithelium serves as a tight barrier to its absorption. Each drop of 0.5% timolol is around 40 μL which contains around 200 μg of the drug. Considering 10% of 200 μg, only around 20 μg of timolol reaches the site of action in the ciliary body while around 80% or 160 μg of the drug gains entry into the systemic circulation. After topical instillation, the drug enters the nose through the nasolacrimal duct. It then reaches the systemic circulation through absorption mainly from the nasal mucosa and partly from the upper gastrointestinal tract. Topical timolol, thus, bypasses first-pass metabolism and its pharmacokinetics mimics IV administration.[3],[4] Timolol has a relative potency of around six times that of propranolol. The instillation of one drop of 0.5% timolol may lead to a serum concentration of Timolol that equals the intake of an oral 10 mg non selective beta-blocker.[5] Therefore, even if small doses of topical timolol gets absorbed, it can lead to systemic side effects.[6] Therapeutic range for timolol is around 10–40 ng/mL. However, systemic beta-adrenergic blockade effects of timolol have been observed even with the plasma concentrations of <2.8 ng/mL.[7] The common systemic side effects of timolol consist of bradycardia, conduction block, syncope, and hypotension. These systemic effects are often inconsequential and unheeded if an individual has normal cardiovascular health.[1] However, it is prudent to avoid timolol in those with overt or latent sinus node or atrioventricular node dysfunction, cardiac failure, asthma, or pulmonary insufficiency. Topical timolol is also relatively contraindicated in those on concomitant verapamil, digitalis, etc., or another beta blocker.[1],[7] Systemic metabolism of timolol involves CYP2D6 enzyme and concomitant use of CYP2D6 inhibitors such as fluoxetine, ranitidine, etc., should also be avoided.[8] In our case, the patient had no other cardiac disease as evident from normal ECHO and Holter monitoring. He was neither on any other concomitant systemic medication which could have otherwise been the inciting agent or the cause for a possible drug interaction.

Sinus bradycardia implies a HR of <60 beats/min (bpm). Extensive literature already exists on bradycardia following ophthalmic timolol formulation usage.[3],[9] However, the negative inotropic action of timolol is described either in only the elderly population or only after usage of timolol for a considerable length of time. In a study by Pratt et al., risk of bradycardia was significantly higher in the group who had 31–180 days of exposure to timolol.[1] There was no increased risk in those with <30 days of timolol usage. Our case was unique in terms of reporting an incidence of severe sinus bradycardia (30 bpm) in an otherwise young healthy individual following a single-day use of topical timolol. It, therefore, represents an exaggerated drug reaction. Few studies have, however, reported possible reduction in HR following first dose of timolol. In a study by Leier et al., baseline HR and BP showed a dip after first-dose ophthalmic timolol. Similar finding of HR reduction during exercise was noted after single-dose topical timolol in studies by Atkins et al.[7],[10] However, baseline HR variation in these two studies was minimal (<10 bpm) and was not as widely variable as in our case (80 bpm to 30 bpm). We did not rechallenge our patient with timolol in view of the severity of his bradycardia. However, the temporal relationship between his single-day use of timolol and the subsequent bradycardia strongly implicated timolol as the inciting agent. The return of the symptoms and HR to normalcy following stopping of the β-blocker is also enough proof.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Pratt NL, Ramsay EN, Kalisch Ellett LM, Nguyen TA, Roughead EE. Association between ophthalmic timolol and hospitalisation for bradycardia. J Ophthalmol 2015;2015:567387.  Back to cited text no. 1
    
2.
Müller ME, van der Velde N, Krulder JW, van der Cammen TJ. Syncope and falls due to timolol eye drops. BMJ 2006;332:960-1.  Back to cited text no. 2
    
3.
Mäenpää J, Pelkonen O. Cardiac safety of ophthalmic timolol. Expert Opin Drug Saf 2016;15:1549-61.  Back to cited text no. 3
    
4.
Ghate D, Edelhauser HF. Barriers to glaucoma drug delivery. J Glaucoma 2008;17:147-56.  Back to cited text no. 4
    
5.
Korte JM, Kaila T, Saari KM. Systemic bioavailability and cardiopulmonary effects of 0.5% timolol eyedrops. Graefes Arch Clin Exp Ophthalmol 2002;240:430-5.  Back to cited text no. 5
    
6.
Prince DS, Carliner NH. Respiratory arrest following first dose of timolol ophthalmic solution. Chest 1983;84:640-1.  Back to cited text no. 6
    
7.
Leier CV, Baker ND, Weber PA. Cardiovascular effects of ophthalmic timolol. Ann Intern Med 1986;104:197-9.  Back to cited text no. 7
    
8.
Wang Z, Denys I, Chen F, Cai L, Wang X, Kapusta DR, et al. Complete atrioventricular block due to timolol eye drops: A case report and literature review. BMC Pharmacol Toxicol 2019;20:73.  Back to cited text no. 8
    
9.
Vogler J, Breithardt G, Eckardt L. Bradyarrhythmias and conduction blocks. Rev Esp Cardiol (Engl Ed) 2012;65:656-67.  Back to cited text no. 9
    
10.
Atkins JM, Pugh BR Jr, Timewell RM. Cardiovascular effects of topical beta-blockers during exercise. Am J Ophthalmol 1985;99:173-5.  Back to cited text no. 10
    


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  [Figure 1], [Figure 2]



 

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