2.5, 5

, 10, 15

BAK 0.01%

Data from Physicians' Desk Reference for Ophthalmic Medicines, 34th edition, 2006.

Data from Physicians' Desk Reference for Ophthalmic Medicines, 34th edition, 2006.

topical timolol has occasionally been associated with more serious ocular surface disease such as cicatricial pemphigoid.23 Allergic blepharoconjunctivitis develops in about 3% of patients using OBBs.24

Transient blurred vision following administration is a common adverse side effect associated with OBBs. With timolol gel-forming solutions, blurring is likely due to the gel, which can also cause crusting of the lashes.

Metipranolol as manufactured in the United Kingdom was associated with granulomatous uveitis that was confirmed upon rechallenge in some eyes.25-27 The exact cause was not determined, although the manufacturing process was implicated. There have been only isolated case reports of this association in the United States.28,29

3.6.2 Systemic Adverse Effects. Many of the systemic adverse effects of OBBs can be predicted by an understanding of the sympathetic nervous system. Topically applied OBBs are absorbed systemically, largely via drainage into the nasolacrimal system and absorption through the nasal mucosa.30 This is analogous to an intravenous dose of medication.

Topically applied timolol can be detected in the systemic circulation, but levels do not approach those achieved with common oral doses. A typical dose of oral timolol for the treatment of systemic hypertension is 20 to 60 mg daily. Although the oral dose undergoes first-pass hepatic metabolism, the bioavailability is still approximately

50% (10 to 30 mg). Each 1 mL of timolol 0.5% ophthalmic solution contains 5 mg timolol. Assuming a drop volume of approximately 30 mL, if the entire drop were absorbed, the total daily systemic exposure of timolol 0.5% administered in both eyes twice daily would be approximately 600 mg. Thus, the systemic burden of timolol 0.5% used in both eyes twice daily is less than 6% of a 20-mg oral dose of timolol.

Peak plasma concentrations following chronic systemic administration of timolol (7 days) in seven normal volunteers was 64 ± 4 ng/mL.31 When 20 mg was administered as a single dose in seven normal volunteers (mean body weight = 67.5 kg), the range of peak values was between 50 and 103 ng/mL, and trough levels were between 0.8 and 7.2 ng/mL.32 In contrast, following ocular administration of two drops of 0.5% timolol solution in adults, plasma levels achieved a range from 5.0 to 9.6 ng/ mL.33,34 Thus, plasma levels of topically applied timolol can approach trough levels of systemic administration but are typically much less than peak plasma levels following systemic administration of therapeutic doses of timolol. This strongly suggests that while systemic adverse effects are possible with ophthalmic beta blockers, thoughtful patient selection should make this relatively uncommon compared with oral use of this very popular class of medications.

Systemic absorption of timolol (and other topical ophthalmic drugs) and the likelihood of systemic effects can be decreased through passive eyelid closure or active nasolacrimal occlusion. This has been shown to decrease plasma levels of timolol by 60%.35 Patients should be instructed in these techniques.

3.6.3 Central Nervous System Adverse Effects. Central nervous system (CNS) adverse effects are often overlooked because of their subjective and sometimes subtle nature. Only a detailed history is likely to elicit these complaints. The list of CNS effects associated with OBBs is long: anxiety, depression, fatigue, lethargy, confusion, sleep disturbance, memory loss, and dizziness.36-39 The beta-1-selective OBB betaxolol may be associated with fewer CNS effects, particularly in susceptible individu-als.40,41 This may be due to the higher volume of distribution of betaxolol.

Sexual dysfunction associated with OBB use has been reported. Symptoms include decreased libido in men and women and impotence in men.40 With physicians' improved awareness of drug effects on quality of life, it is the responsibility of the physician to elicit this complaint. Patients are often reluctant to discuss sexual dysfunction, or they may attribute it to different causes. With the popularity of oral medications for the treatment of erectile dysfunction, it may be easier to broach this topic, especially with symptomatic male patients. Certainly, any patient using a medication for erective dysfunction should be considered for a beta blocker holiday or a switch to another therapeutic class.

3.6.4 Cardiovascular System Adverse Effects. The effects of systemic beta blockade are used therapeutically in the treatment of conditions such as systemic hypertension, angina, and supraventricular as well as ventricular arrhythmias, as prophylaxis after myocardial infarction, and as a disease-modifying agent as well as for mortality reduction in congestive heart failure (CHF).42 The mortality reduction following myocardial infarction and in CHF appears to be largely due to a reduction in sudden arrhythmic death. In addition, beta blockers also reduce pathologic ventricular remodeling and improve cardiac function in such patients.43-46

Blocking the beta-1 receptors interferes with normal sympathetic stimulation of the heart. The results are lower heart rate and blood pressure, decreased myocardial contractility, and slowed conduction time. However, these same effects may become adverse effects in susceptible patients or in those with other underlying illnesses.

Topical OBB use may be associated with decrease in heart rate.47,48 In some individuals, particularly those with conduction system abnormalities, this decrease may lead to a significant bradycardia. In early experience with timolol, 41% of 32 deaths attributed to ocular timolol use were classified as cardiovascular. Half of these occurred within 2 days of initiation of therapy.49 These associations were circumstantial, not causative, and were reported during an era of increased vigilance for possible adverse effects of OBBs. Better understanding of relative contraindications for this class of drugs and the availability of other classes has decreased the likelihood of such events.

Resting heart rate and blood pressure are statistically significantly reduced following short- or long-term dosing with timolol maleate solution in healthy individ-uals.47,48 Timolol also decreases exercise-induced tachycardia in healthy individu-als.50 Betaxolol, however, was no different from placebo in cardiovascular effects in one study.51 However, these studies were conducted in healthy individuals. Patients requiring IOP-lowering therapy are often of advanced age and have coexisting systemic medical conditions, making them more susceptible to beta blockade.

While betaxolol is classified as a relatively cardioselective (beta-1) beta blocker, it is less potent in its beta-blocking activity than either timolol or levobunolol. That does not make it free of cardiovascular adverse effects. There are isolated case reports of betaxolol use associated with effects such as sinus arrest and symptomatic bradycardia.38,52 Causality could not be ascertained.

In a small crossover study of timolol maleate solution and Timoptic-XE, plasma levels and heart-rate effects from the gel-forming preparation were less than those from the solution following 1 week of therapy.53 One interpretation of this finding is that the gel-forming solution may decrease systemic absorption and adverse effects.

Carteolol (Ocupress) is a beta blocker with intrinsic sympathomimetic activity (ISA). It has partial agonist activity, which has not uniformly translated into a more favorable cardiovascular adverse effect profile. Rather, carteolol has been demonstrated to reduce heart rate and blood pressure similar to other OBBs without ISA. It is interesting to note that carteolol reduced heart rate for subjects with a resting rate above 70 beats per minute but did not affect heart rate for those with rates below 70 beats per minute.54,55 It has not been demonstrated that this translates into an advantage for glaucoma patients.

3.6.5 Pulmonary Adverse Effects. Subjects with pulmonary disease were excluded in the preapproval trials of timolol. The original package labeling approved by the FDA warned against use in patients with pulmonary disease, but these precautions were not widely disseminated. It was only after the widespread use of ophthalmic timolol that the potential for pulmonary complications became better appreciated.56,57 In the first 8 years of timolol use in the United States, 12 deaths were attributed to respiratory adverse events from the drug. More than 50% of these patients had a history of pulmonary disease.51 In one early case report, respiratory arrest was reported within 30 minutes after the initial dose of timolol 0.5% solution in a 67-year-old man with stable COPD.58

The published data regarding topical and systemic beta blockers and pulmonary disease are not entirely consistent. Topical nonselective OBBs are reported to have the potential to exacerbate reactive airway disease in patients who are previously controlled. In a study of a large group of patients receiving bronchodilator therapy, those who were using timolol were 47% more likely to need additional broncho-dilator drugs.59 Of greater concern is the administration of OBBs to patients with undetected or asymptomatic reactive airway disease. Severe asthmatic attacks have been reported in association with OBB use in such patients.60

Betaxolol is a beta-1-selective adrenergic antagonist. Because the pulmonary adverse effects of OBBs are mediated through beta-2 receptor blockade, it is expected that betaxolol should have a more favorable pulmonary adverse effect profile. This has been supported in clinical trials. In a masked crossover study of patients with reactive airway disease challenged with timolol or betaxolol, timolol produced a significant decrease in forced expiratory volume in 1 second (FEV1), while betaxolol produced no such decrease in the same subjects.61 In a group of asymptomatic elderly patients, pulmonary function improved when they were switched from a nonselective OBB to betaxolol.62

Betaxolol has been used successfully in patients with pulmonary disease,63-65 but it is not entirely free of potential pulmonary adverse effects: There have been several reports of pulmonary symptoms associated with betaxolol use.38,66,67

There are interesting data more recently published in the medical literature from a meta-analysis evaluating the use of systemic beta-1-selective beta blockers in asthmatics and patients with COPD. Acute administration in asthmatics reduced FEV1 by 7.46%, indicating increased airway resistance, but chronically FEV1 did not change. Symptoms and inhaler use were no different between those on beta blockers and placebo. In patients with COPD, there was no difference between those that received beta blockers versus those that received placebo acutely and chronically with respect to FEV1, symptoms, and inhaler use. Responsiveness to inhalers was in fact better in the beta blocker group, presumably as a result of beta receptor up-regulation mediated by chronic beta blockade.68,69 Despite these reports, the potential for pulmonary adverse effects exists, and we do not advocate the use of OBBs in asthmatics and patients with COPD. With the introduction of new classes of drugs such as the topical CAIs and prostaglandin analogues, there are attractive alternatives to OBB therapy as initial treatment to lower IOP in patients with pulmonary disease.

3.6.6 Metabolic Adverse Effects. The OBBs have been reported to affect lipid metabolism. In normal volunteers taking topical timolol, triglyceride levels increased 12%, and high-density lipoproteins decreased 9%. Theoretically, this negative alteration in the blood-lipid profile could increase the risk of coronary heart disease.70 Similar information has not been collected in older patients with glaucoma. A different study did not reproduce these results.71 These studies had marked limitations:

They lacked placebo control, and only two lipid measurements were made, one at baseline and a second 6 weeks later. In another study, carteolol was shown to have less effect on blood-lipid parameters, possibly due to its ISA.72 In summary, the evidence regarding the effects of OBBs on the lipid profile is inconclusive.

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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