Cardiac safety of ophthalmic timolol

Abstract

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.

High-precision piezo-ejection Ocular microdosing: Phase II Study on Local and Systemic Effects of Topical Phenylephrine

“…Timolol effectively treats glaucoma, but is rapidly absorbed from the eye, with peak plasma levels occurring only 15 min after dosing, and bioavailability equivalent to 78% of the same intravenous dose [28]. Ophthalmic timolol can cause symptomatic bradycardia, cardiac conduction disorders, orthostatic hypotension, and syncope and falls, particularly in geriatrics [29], and impairs pulmonary function in asthmatics [30]. Similarly, reducing the size of clonidine eyedrops (from 70 to 15 μl) in glaucomatous volunteers prevented the hypotensive effect that occurred with the larger drops [31].…”

An Unexpected Cause of Bradycardia in a Patient with Bacterial Meningitis

“…Since the patient was symptomatic and an obvious cause of bradycardia could not be identified after a work-up with a 24-hour rhythm recording (Holter) and a transthoracic heart ultrasound, placement of a permanent pacemaker was considered. In our surprise, even though the patient's medications were revised daily in order to identify any missing medication that could be causing the bradycardia, the patient's wife was (accidentally) found to be giving to the patient beta-blocker (timolol) containing eye drops for glaucoma, which are known to be causing bradycardia [10]. Interestingly, no other cause of bradycardia has been found, implying that a missing medication was the reason for the patient's bradycardia.…”

40 years of topical beta-blockers for glaucoma

“…The effect of topical timolol on heart rate and blood pressure is well established. [19] For example, a double-masked crossover study including 43 subjects with glaucoma evaluated the effect of timolol 0.5% eye drops twice per day on 24-h heart rate compared to placebo. [20] There was a significant decrease in heart rate, with an average decline of 6 beats per minute, although the decline was more pronounced if patients were coprescribed an oral beta-blocker.…”

“…[26,27] A rarer side effect is the impact of beta-blockers on cardiac conduction, and there are several reports of previously healthy patients developing complete heart block following treatment with topical timolol, with some patients requiring implantation of permanent pacemakers. [19]…”

“…Before prescribing beta-blockers, it is essential to take a thorough past medical and medication history, and if beta-blockers are considered, we would recommend checking blood pressure and pulse rate before starting treatment. A recent review article went as far as to recommend patients should have their CYP2D6 genotype assessed prior to commencing treatment with topical betablockers; [19] however, this is unlikely to be practical in clinical practice and advising patients to be aware of possible side effects and monitoring pulse rate and blood pressure may be more realistic. The use of topical beta-blockers, while not absolutely contraindicated, should also be reconsidered if patients are the elderly, have multiple comorbidities, or are using multiple systemic medications, particularly systemic beta-blockers.…”