Cardiovascular considerations in using topical, oral, and intravenous drugs for the treatment of glaucoma and ocular hypertension: focus on beta-adrenergic blockade

Glaucoma and ocular hypertension are highly prevalent conditions in individuals over the age of 40 and are commonly seen together in patients with cardiovascular disease. Many of the antiglaucoma medications, when systemically absorbed, affect the sympathetic and parasympathetic nervous systems of patients and can cause cardiovascular toxicity. Such adverse effects are frequently associated with the long-term use of potentially toxic agents in elderly people, who are most prone to chronic eye disease. Moreover, patients may not associate their symptoms with the topical eye medications, and consequently may not report adverse drug effects. Drug-drug interactions can also occur when patients are taking medications for both cardiovascular disease and glaucoma. This review focuses on beta-adrenergic blockers as topical antiglaucoma medications and other topical antiglaucoma drugs. The systemic toxicity of these agents is reviewed, along with the possible drug interactions. Brief mention is also made of other antiglaucoma medications used alone and in combination with topical beta-blockers.     

Cardiovascular effects of commonly used ophthalmic medications

Eye disease and cardiovascular disease frequently coexist. As a result, cardiologists and ophthalmologists often treat the same patients. Among ophthalmologists it is well known that topical ophthalmic medications are capable of producing serious cardiovascular effects, including congestive heart failure, arrhythmias, and death. However, cardiologists may not be aware of these potential complications. This article reviews the cardiovascular effects of commonly prescribed topical ocular medications and describes important contraindications to their use in patients with cardiovascular disease. Cardiologists, by making themselves and their patients more aware of the cardiovascular effects of topical ocular medications, may be able to avoid the adverse and potentially fatal complications of these agents.     

Pharmacotherapy in congestive heart failure: Cardiopulmonary effects of ophthalmically administered beta-blockers

Early clinical studies reported that timolol and other topical beta-blockers were effective in reducing intraocular pressure, without the side effects associated with other antiglaucoma agents. However, because people 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 beta-blockade became "old news." Despite this new found recognition, many treating physicians still remained unaware of the potential for systemic beta-blockade from topical applied beta-blockers. A significant portion of a topically administered dose of a beta-blocker can be absorbed and thereby effect systemic beta-blockade. Sensitivity to systemic beta-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 beta-blockade.     

New glaucoma medications in the geriatric population: efficacy and safety

Glaucoma can be considered a disease of the aging eye. Most medications used to treat glaucoma are in topical eyedrop form and may cause numerous untoward systemic effects in older persons. In recent years, several new ocular hypotensive medications have become available. These medications are being used more commonly because there is a growing trend by ophthalmologists to aggressively lower intraocular pressure. Therefore, geriatricians require a comprehensive knowledge of medications used to treat glaucoma, in addition to an understanding of their mechanism of action profiles of untoward effects and possible interactions with other diseases or medications. Therefore, we performed a review of the medications recently introduced into clinical practice. We selected drugs approved by the U.S. Food and Drug Administration between 1996 and September 2001. The safety profiles of these agents and their untoward side effects were reviewed by class: topical carbonic anhydrase inhibitors (brinzolamide: ocular tolerance, taste perversion), beta-adrenoceptor antagonists (timolol: bradycardia and bronchospasm), alpha-adrenergic agonists (brimonidine: oral dryness, headache, and fatigue), and prostaglandin analogs (latanoprost, bimatoprost, travoprost, and unoprostone isopropyl: ocular hyperemia, iris color changes). The function of this review is to make geriatricians more aware of the efficacy and untoward effects of medications recently introduced into clinical practice. We recommend that geriatricians perform a medication review on all medications their patients use, including eye drops.     

Systemic effects of medications used to treat glaucoma

Medications used to treat glaucoma can have clinically important systemic effects in some patients; these effects may not be recognized in elderly patients who have chronic medical problems and who are taking several systemic medications. Beta-blocking ophthalmic agents are generally safe, but can be absorbed systemically to induce bronchospasm, worsen heart block, decompensate congestive heart failure, or create central nervous system effects in some patients. Reports of adverse systemic effects from miotics, such as pilocarpine, are rare, although cardiovascular decompensation has been seen in patients with acute angle closure who were given excessive doses before surgery. Topical sympathomimetic agents such as epinephrine may increase ventricular extrasystoles and have, on occasion, caused severe hypertensive reactions. Nearly 50% of patients taking carbonic anhydrase inhibitors must discontinue their use because of various adverse constitutional and central nervous system symptoms. Although these drugs are not usually part of internal medicine regimens, they can produce adverse effects that mimic primary disease in nonocular organ systems.     

Ophthalmically Administered β Blockers and Their Cardiopulmonary Effects

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.     

Ocular toxicity of systemic asthma and allergy treatments

Systemic medications, such as antihistaminic and antiin .ammatory agents used in the treatment of asthma and allergy, may have adverse effects on the eye. The major adverse effects on the eye have included cataracts, glaucoma, and tear-.lm dysfunction (dry-eye syndrome). The use of inhaled corticosteroids (bronchial and nasal) has been associated with mild systemic effects when compared with oral corticosteroids. The development of cataracts and glaucoma has been more commonly associated with earlier “hard” oral and inhaled steroids that affected individuals with an inherent high susceptibility or those who used them for several years. Whereas oral antihistamines commonly have an effect on allergies within hours, they also may exacerbate dry-eye complaints that commonly complicate symptoms with various forms of tear .lm dysfunction or conjunctival hyperreactivity. Clinicians should be aware that other systemic agents may complicate their attempts to maximize the treatment of ocular allergies.     

Interactions of grapefruit juice and cardiovascular medications: A potential risk of toxicity

Recently, drug interactions with grapefruit juice (GFJ) have received considerable attention from basic scientists, physicians, industry and drug regulatory agencies. GFJ has been shown to inhibit cytochrome P-450 3A4 isoenzyme and P-glycoprotein transporters in the intestine and liver. The GFJ-induced inhibitory effects are considered to be responsible for alterations in drug bioavailability, and pharmacokinetic and pharmacodynamic changes when drugs are ingested concurrently with GFJ. However, little or no interaction is observed when GFJ is taken concomitantly with parentally administered drugs. It is well known that risk factors for cardiovascular disease increase with advancing age, while hepatic metabolic activity decreases in elderly individuals. It is, therefore, possible that the combination of GFJ and cardiovascular medications may pose a health risk, especially in elderly patients. A number of studies have shown interactions of GFJ with cardiovascular drugs such as calcium-channel blockers, angiotensin II receptor antagonists, beta-blockers, and statins. Such interactions are likely to change the pharmacokinetics and pharmacodynamics of these drugs, consequently causing undesirable health effects. Therefore, health care professionals and the public need to be advised of the potential risks associated with the concomitant use of GFJ and interacting medications, especially cardiovascular drugs and agents with a narrow therapeutic index. This review focuses on the adverse interactions of GFJ and cardiovascular medications, and the proposed underlying mechanisms of such interactions.     

Glaucoma

In 2000 an estimated 66.8 million people worldwide will have glaucoma, 6.7 million of whom will be bilaterally blind from irreversible optic-nerve damage. Yet even in developed countries with public educational programmes that target glaucoma, half of the individuals with glaucoma remain undiagnosed. Patients with even mild visual impairment secondary to glaucoma may have difficulties with mobility, driving, and social interactions. Although glaucoma may be associated with increased eye pressures, its diagnosis does not rely on a specific level of eye pressure. Diagnosis of glaucoma often relies on examination of the optic disc and assessment of the visual field. The two most common types of glaucoma--primary open-angle glaucoma and primary angle-closure glaucoma--have different risk factors. Although similar medications can be used to treat these two types of glaucoma, the overall management of patients differs in important ways. Until recently, there were no randomised clinical trials that showed the effectiveness of lowering eye pressures with medications or surgery in patients with glaucoma. However, in 1998 a randomised clinical trial showed the benefit of lowering eye pressure in patients with glaucoma who had eye pressures of 24 mm Hg or less. Because glaucoma is treatable, and because the visual impairment from glaucoma is irreversible, early detection of the disease is critically important.     

Adverse effects of herbal treatment of cardiovascular disease: what the physician must know

The increasing use of herbal products by patients with cardiovascular disease represents a clinical challenge to physicians. The use of herbal products is increasing in our society, and less than 50% of patients using herbal products report this information to their physicians. In addition, physicians often lack the knowledge base for herbal medications to effectively counsel patients regarding adverse effects and potential herb-drug interactions. This article reviews Western and traditional Chinese herbs that are commonly used by patients with cardiovascular diseases, herbs noted to have adverse cardiovascular effects, and herbs that may potentially interact with commonly prescribed cardiovascular medications.     

Evaluating the safety and tolerability profile of acute treatments for migraine

Among the medications that have been used as acute treatments for migraine are nonspecific agents, including nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics (either single or combination), and narcotics, as well as migraine-specific medications, including ergot alkaloids and triptans (5-hydroxytryptamine 1B/1D agonists). All of these drugs have side effects that vary in type and severity. Side effects of nonspecific medications, including gastrointestinal (GI) and renal effects with NSAIDs and cognitive effects and the potential for abuse with narcotics and butalbital-containing medications, have been documented over time, as these medications have been used for various indications. Side effects of the migraine-specific medications include GI and vascular symptoms with the ergots; for the triptans, they include chest and neurologic symptoms. Although adverse events are reported fairly frequently in patients receiving triptans, they are usually mild, and few patients discontinue therapy because of them. The most serious adverse events are cardiovascular. Because of potential vasoconstrictor effects--mild and transient increases in blood pressure and mild and transient effects on coronary artery tone--triptans as a class are contraindicated in patients with established or clinically suspected cardiovascular disease, specifically ischemic heart disease and uncontrolled hypertension. Other adverse events, including the potential for drug-drug interactions, are less common. Therefore, consideration should be given to the tolerability and safety of medications before their use as abortive medications for the treatment of migraine headache.     

Pharmacogenetics of the response to statins

Statins (inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase) are widely prescribed medications for the prevention of incident and recurrent cardiovascular disease events and death. They are powerful assets in the current arsenal of cardiovascular medications, with high efficacy and minimal toxicity. However, heterogeneity exists with respect to the response to statin medications, and there has been considerable investigation into the genetic determinants of the statin response. In this review, we separate the response to statins into 1) measures of efficacy (low-density lipoprotein cholesterol lowering and protection from cardiovascular events) and 2) effects of toxicity (musculoskeletal adverse effects and nonadherence to statin therapy). The current data suggest that prospective genotyping for certain variants may be of use in tailoring statin therapy to reduce cardiovascular events and to avoid statin-induced adverse effects.     

Diabetic Agents,From Metformin to SGLT2 Inhibitors and GLP1 Receptor Agonists: JACC Focus Seminar

Given the intersection between diabetes mellitus and cardiovascular disease (CVD), pharmacologic agents used to treat type 2 diabetes mellitus must show cardiovascular safety. Comorbid conditions, including heart failure and chronic kidney disease, are increasingly prevalent in patients with diabetes; therefore, they also play a large role in drug safety. Although biguanides, sulfonylurea, glitazones, and dipeptidyl peptidase 4 inhibitors have variable effects on cardiovascular events, sodium glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists have consistently shown safety and reduction in cardiovascular events in patients with established CVD. These medications are becoming essential tools for cardioprotection for patients with diabetes and CVD. They may also have roles in primary prevention and renal protection. This paper will review the cardiovascular impact, adverse effects, and possible mechanisms of action of pharmacologic agents used to treat patients with type 2 diabetes.     

Bradycardia Shock Caused by the Combined Use of Carteolol Eye Drops and Verapamil in an Elderly Patient with Atrial Fibrillation and Chronic Kidney Disease

Ophthalmic carteolol is often used to treat glaucoma. Elderly patients with atrial fibrillation (AF) and chronic kidney disease (CKD) are common among the super-elderly in Japan. Because these patients are exposed to polypharmacy, they are at a high-risk of adverse drug interactions. We herein report an elderly patient with CKD who suffered bradycardia shock after the combined use of carteolol eye drops and verapamil for glaucoma and paroxysmal AF. This case highlights the fact that eye drops have a similar systemic effect to oral drugs, and especially in elderly patients with polypharmacy, drug interactions can unwittingly lead to serious events.     

Metabolic and cardiovascular adverse effects associated with antipsychotic drugs

Antipsychotic medications can induce cardiovascular and metabolic abnormalities (such as obesity, hyperglycemia, dyslipidemia and the metabolic syndrome) that are associated with an increased risk of type 2 diabetes mellitus and cardiovascular disease. Controversy remains about the contribution of individual antipsychotic drugs to this increased risk and whether they cause sudden cardiac death through prolongation of the corrected QT interval. Although some drug receptor-binding affinities correlate with specific cardiovascular and metabolic abnormalities, the exact pharmacological mechanisms underlying these associations remain unclear. Antipsychotic agents with prominent metabolic adverse effects might cause abnormalities in glucose and lipid metabolism via both obesity-related and obesity-unrelated molecular mechanisms. Despite existing guidelines and recommendations, many antipsychotic-drug-treated patients are not assessed for even the most easily measurable metabolic and cardiac risk factors, such as obesity and blood pressure. Subsequently, concerns have been raised over the use of these medications, especially pronounced in vulnerable pediatric patients, among whom their use has increased markedly in the past decade and seems to have especially orexigenic effects. This Review outlines the metabolic and cardiovascular risks of various antipsychotic medications in adults and children, defines the disparities in health care and finally makes recommendations for screening and monitoring of patients taking these agents.     

Iatrogenic glaucoma secondary to medications

Glaucoma is a progressive optic neuropathy with primary and secondary forms. Iatrogenic glaucoma secondary to medications is potentially blinding but preventable. Most drug profiles listing glaucoma as a contraindication or an adverse effect are concerned with inducing acute angle-closure glaucoma. Anticholinergic or adrenergic agents are the most common for inducing “pupillary block” angle-closure glaucoma. Patients with a narrow irido-corneal angle are at high risk. Sulfa drugs induce “non-pupillary block” angle-closure glaucoma as an idiosyncratic reaction to the drug in patients with an open or narrow irido-corneal angle. Steroids and a few antineoplastic agents induce open-angle glaucoma. The risk is higher with topical rather than systemic steroids. The first step in the management is discontinuation of the drug, followed by medical, laser, and, if necessary, surgical intervention.     

Current overview of statin-induced myopathy

Statins are an efficacious and well-tolerated class of lipid-altering agents that have been shown to reduce the risk of initial and recurrent cardiovascular events. However, cerivastatin was withdrawn from the world market because of its potential for severe myotoxic effects. Since the benefits of statin treatment outweigh the small risk of adverse events, statins remain the first-line therapy for lipid lowering and preventing atherosclerotic cardiovascular diseases. The risk of myopathy may be minimized with the appropriate choice of agent and by identifying patients at risk of myotoxic effects. Elderly or female patients, or those with concomitant medications or impaired metabolic processes, may be at increased risk and should be monitored closely. The risk of myopathy may also be inferred from the pharmacologic and pharmacokinetic properties of the statin used. Since myotoxic events are more frequent at higher doses, statins that are effective in reducing cholesterol levels and helping patients to reach target levels at start doses may be useful. The lipophilicity of a statin and its potential for drug-drug interactions may also help to determine the likelihood of muscular effects. Drug-drug interactions may be avoided by selecting a statin that does not share the same metabolic pathway.     

The effect of nebulized bronchodilator therapy on intraocular pressures in patients with glaucoma

A controlled double-blind crossover study of ocular complications associated with nebulized ipratropium bromide and salbutamol therapy for respiratory distress was undertaken in 46 chronic bronchitis patients. There was no significant rise in intraocular pressure or change in anterior chamber angle in patients with open-angle glaucoma, narrow-angle glaucoma or control subjects following treatment with either drug. However, when the two drugs were used in combination, intraocular pressure rose in patients with narrow-angle glaucoma but not in patients with open-angle glaucoma or in control subjects. Transient angle closure was seen in five of these patients. Intraocular pressures did not rise when swimming goggles were used to protect the eyes or when antiglaucoma treatment was continued. Nebulized bronchodilator therapy is safe in nonglaucomatous patients and those with open-angle glaucoma. Ocular complications can follow combined ipratropium bromide and salbutamol nebulization in patients with narrow-angle glaucoma, but can be prevented by using the drugs separately, protecting the eyes and ensuring continued antiglaucoma measures.