Ophthalmically Administered β Blockers and Their Cardiopulmonary Effects

Abstract

Early clinical studies revealed that timolol and other topical β blockers were effective in reducing intra‐ocular pressure, without the side effects associated with other antiglaucoma agents. However, because persons with cardiovascular or respiratory diseases were generally excluded from many of these early studies, the risk of serious cardiovascular and respiratory side effects was seriously underestimated. Once these drugs were made available to the general population, reports of systemic side effects began to proliferate. Very quickly, adverse effects from topical β blockade became “old news.” Despite this recognition, many treating physicians remained unaware of the potential for systemic β blockade from topically applied β blockers. A significant portion of a topically administered dose of a β blocker can be absorbed and thereby affect systemic β blockade. Sensitivity to systemic β blockade can be quite dramatic in certain highly susceptible patients, particularly those with either cardiac or pulmonary abnormalities. Careful review of patients' medications will generally lessen, but not completely eliminate, the risk of undesired complications attributable to topical P blockade.

Glaucoma is a condition associated with elevated intraocular pressure and is ubiquitous in the general medical population. It is the leading cause of irreversible blindness throughout the world. Most forms of glaucoma are painless; thus, if loss of vision occurs with glaucoma, it is typically insidious. ¹ , ² This heterogeneous family of conditions causes progressive optic nerve damage in roughly 2% of the general population, a figure that rises several‐fold in elderly and African American populations. This is the same patient base in whom congestive heart failure (CHF) and hypertension are so widely prevalent. Worldwide, over 100 million people are estimated to have elevated intraocular pressure. ³ Many glaucoma patients receive one or more topical or, less commonly, oral agents for glaucoma management.

Glaucoma is unique among illnesses in that it is best treated with topically applied medications, a therapeutic maxim that is now more than a quarter century old. The origin of topical therapy for glaucoma was serendipitous. It derived from an early observation by Phillips et al. ⁴ that oral propranolol, the prototypical β‐adrenoreceptor blocker, when used in the treatment of systemic hypertension, also lowered intraocular pressure in patients with concomitant glaucoma. Shortly thereafter, topical application of propranolol was demonstrated to reduce intraocular pressure. ⁵

Glaucoma therapy has been progressively refined over the past several years. The goal of any glaucoma treatment measure is sustained reduction in intraocular pressure. ¹ , ² Drugs used for the long‐term management of glaucoma fall into a broadening group of categories, including β blockers, selective adrenergic agonists, carbonic anhydrase inhibitors, prostaglandin agonists, and cholinergic agonists. ¹ , ²

PHYSIOLOGY OF DRUG ABSORPTION

Most glaucoma medications are applied topically. The limited contact time and the relative impermeability of the eye dictate that such drug solutions are concentrated to optimize local drug delivery. Residual drug can readily gain access to the systemic circulation. Most typically, drainage occurs by way of the nasolacrimal duct, with subsequent presentation of drug to the nasal mucosa (and more distal mucosal surfaces). Ophthalmically administered medications can also gain access to the systemic circulation by way of the conjunctival vascular system. The exact contribution of the latter to systemic drug availability is poorly characterized.

The occurrence of systemic absorption was recognized very early in the development of topical ophthalmic preparations. For example, when the β blocker timolol was administered in one eye, its systemic absorption was sufficient to cause a measurable decrease in intraocular pressure in the contralateral eye. ⁶ , ⁷ As much as 80% of a topically administered ophthalmic drug has been estimated to drain through the nasolacrimal duct. ⁸ This amount can be lessened if the nasolacrimal duct is occluded with either digital pressure or simple eyelid closure for about 5 minutes. Either of these maneuvers will improve intraocular drug partitioning and thereby decrease systemic absorption. ⁹

SCOPE OF THE PROBLEM

A number of problems are evident in considering the treatment of glaucoma in the elderly. First, elderly patients are generally multiply medicated, typically with many physicians involved in their care. Second, patients may not keep their physicians completely informed about their glaucoma therapy, unless they are specifically questioned about the use of “eye medications.” When this is the case, systemic symptoms directly linked to topical β blockers may be incorrectly attributed to coexisting disease, the aging process, or concomitant medications. Consequently, patients may be treated presumptively for an underlying cardiac or pulmonary disorder, with limited success, when the true factor that has caused or aggravated the condition remains in place. Third, the ophthalmic route of administration may determine the plasma concentration of a β blocker. Like sublingual drug administration, topical ophthalmic dosing is probably more akin to intravenous delivery than to oral dosing; thus, the “first‐pass” effect in a drug's metabolism may be negated by delivery via this route.

TOPICAL β‐ADRENERGIC ANTAGONISTS

Currently, the most commonly used agents in the therapy of glaucoma are the topically applied B‐adrenergic antagonists. The formation of aqueous humor in the ciliary body appears to be mediated, in part, by tonic sympathetic stimulation. ¹⁰ Production of aqueous humor decreases by about one third in response to β‐adrenergic antagonists. ¹¹ The majority of these agents block both the β1‐ and β2‐adrenergic receptors, with the exception of betaxolol. The use of β‐adrenergic antagonist ophthalmic preparations is not uncommonly associated with systemic side effects, most of which are either pulmonary or cardiac in nature (Table).

Table TABLE.

CARDIAC AND PULMONARY SIDE EFFECTS OF OPHTHALMICALLY ADMINISTERED β‐ADRENERGIC ANTAGONISTS

Pulmonary

Bronchospasm 12 , 13 , 14 , 15

Reduced pulmonary function 16 , 17

Cardiovascular

Bradycardia 28 , 30 , 31 , 32 , 38 , 39 , 40 , 41

Complete heart block 29 , 31

Syncope 12 , 32

Hypotension 12 , 32

Decreased cardiac contractility with worsening/onset of congestive heart failure 33

Blunted heart rate change with exercise 30 , 34 , 36

Alteration in lipoprotein profiles 37 , 47 , 48 , 49

Systemic Effects

Nightmares 50

PULMONARY EFFECTS

A number of adverse pulmonary sequelae can accompany β2 blockade with β‐adrenergic antagonist ophthalmic preparations. These untoward consequences can range from a simple worsening of asthmatic symptoms to bronchospasm, and to respiratory failure and death attributable to bronchospastic complications. ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ In one study, ¹⁵ the use of timolol maleate increased the need for bronchodilator therapy in 47% of patients with glaucoma. Respiratory arrest occurred in one asthmatic patient within 20 minutes of receiving a first drop of timolol maleate, and 12 respiratory arrests were recorded in the first 8 years of the commercial production of timolol. ¹⁸ , ¹⁹ Such respiratory complications are not surprising, in that one drop of 0.5% timolol solution to each eye approximates a 10‐mg oral dose of this compound. ²⁰ , ²¹

Certain physicochemical characteristics of β‐adrenergic antagonists, such as intrinsic sympathomimetic activity or β1 receptor selectivity, have been suggested to cause fewer pulmonary side effects. Betaxolol is a relatively selective β1‐adrenergic receptor antagonist with a tendency to cause fewer pulmonary problems than occur with nonselective compounds, ²² , ²³ although it can do so in patients with severe asthma or other pulmonary diseases. ²⁴ , ²⁵ This presumed benefit must be counterbalanced with the observation that betaxolol reduces intraocular pressure to a lesser extent than do the nonselective drugs. ²⁶ In addition, agents with intrinsic sympathomimetic activity may not confer greater pulmonary benefit than those without this property. Topical carteolol, a β receptor antagonist with intrinsic sympathomimetic activity, has demonstrated a detrimental effect on pulmonary function in excess of that observed with betaxolol. ²⁷

CARDIAC EFFECTS

The observation that potentially serious cardiovascular complications may occur with topical β blockade is not new; it is simply underappreciated. These can include either physiologic β blocker effects (e.g., bradycardia) or complications known to accompany use of this drug class. Thus, it should be no great surprise that topical β blockade can lead to bradyarrhythmias, syncope, daytime and/or nocturnal hypotension, congestive heart failure, reduced exercise tolerance, and/or lipid abnormalities. ¹² , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷

The issues with topical β blockade and cardiovascular medicine are multiple and include recognition of the frequency with which topical β blockade is employed, an understanding of the fractional volume of an administered drop that can be systemically absorbed, and the likelihood of a patient being inherently sensitive to β blockade. Other confounding variables can intensify the cardiovascular impact of topical β blockade. For example, bradycardia can be particularly severe in patients comedicated with either verapamil ³⁸ or quinidine. ³⁹ , ⁴⁰ One such case report describes the development of sinus node dysfunction and severe bradycardia when topical timolol was administered together with oral verapamil. ³⁸ The induction of significant bradycardia when quinidine is given together with ophthalmic timolol is likely an additive phenomenon, resulting from the direct negative chronotropic effect of quinidine and the simultaneous reduction in sinus rate by timolol‐related β receptor blockade. In addition, quinidine inhibits the cytochrome P₄₅₀ enzyme CYP2D6 that is responsible for the metabolism of timolol. This drug‐drug interaction can further exaggerate the β‐blocking properties of timolol. ⁴⁰ A similar drug‐drug interaction is possible when cimetidine—another inhibitor of the P450 enzyme CYP2D6—is given with ophthalmically delivered timolol. ⁴¹

Topical β blockers can influence daytime blood pressure in those susceptible to the systemic effects of β blockers. Of more interest is the observation that topical β blockade may affect nocturnal blood pressure. Unfortunately, the vasodepressor response to bedtime topical β blockade has not been carefully evaluated. Thus, the degree to which topical β blockade modifies the normal circadian blood pressure rhythm is unclear. This is important in that nocturnal hypotension may cause progression of chronic open‐angle glaucoma, among other ophthalmologic diseases. ⁴² , ⁴³ , ⁴⁴ , ⁴⁵

It is not entirely clear whether true differences exist among the topically applied β blockers in how they influence various cardiovascular parameters. For example, exercise tolerance may improve with betaxolol, ³⁴ though this attribute of the compound may be less clinically relevant for patients inherently sensitive to customary doses of topical β blockers. Alternatively, timolol causes significantly lower mean heart rate during the nighttime and more nocturnal bradycardia than carteolol does in patients with ocular hypertension and primary open‐angle glaucoma. ⁴⁶ These differences may result from intrinsic sympathomimetic activity of carteolol. In addition, how a change in exercise tolerance is defined may influence whether topical β blockade is considered to impair exercise tolerance. Also, Doyle et al. ³⁶ have demonstrated a statistically significant effect of topical timolol on both maximal heart rate and time to exhaustion, whereas in these same studies it had no effect on the physiologic parameters of VO₂, respiratory rate, VCO₂, or respiratory quotient.

Changes in lipid parameters, as a function of topical β blockade, have also been viewed as a way to distinguish among the various topical β blockers. In general, serum triglycerides increase, and serum high‐density lipoprotein cholesterol concentrations decrease, with topical β blockade. ³⁷ , ⁴⁷ , ⁴⁸ , ⁴⁹ Topically administered carteolol may offer some advantages in this regard. In a recent study by Stewart et al., ⁴⁹ patients treated with carteolol did not experience any adverse effects on plasma lipid profiles, whereas in those treated with topically applied timolol, high‐density lipoprotein levels and total cholesterol‐high density lipoprotein ratios were significantly affected.

CONCLUSIONS

This review should reinforce the awareness that extreme caution should be taken with the use of topical (β blockers in patients in whom β blockade presents a significant risk to health. Medications administered ophthalmically are not just locally active. The fraction of an administered dose that can be systemically absorbed can be substantial. In addition, ophthalmically administered medications do not undergo first‐pass hepatic clearance; thus, the systemic concentration of such compounds can easily reach that necessary for significant systemic β blockade.

It is comforting that a recent review disclosed that major cardiovascular side effects did not occur at an increased rate in a population‐based study of elderly patients using topical β blockers or other glaucoma medications, compared to normal subjects. ³⁵ These observations are in line with the belief that individuals with underlying pulmonary and/or cardiac abnormalities are likely to be those most susceptible to adverse effects from systemic β blockade. Such at‐risk patients should be carefully observed at the onset of therapy with topical β blockers. Unfortunately, monitoring the use of these agents can prove quite challenging. Multiple health care providers can prescribe these medications and physician‐to‐physician communication regarding their use may sometimes be lacking. In addition, many patients do not believe that topical ophthalmic medications have effects beyond those that occur in the eye. Thus, it is not uncommon that patients fail to routinely provide information concerning their use to their primary physicians. Needless to say, cardiopulmonary complications from these medications are avoidable if their usage pattern is recognized and there is accurate understanding of the absorption characteristics of these drugs.