Topical β-adrenergic antagonists lower IOP by inhibiting cyclic adenosine monophosphate (cAMP) production in ciliary epithelium, thereby reducing aqueous humor secretion 20%–50% (2.5 µL/min to 1.9 µL/min), with a corresponding IOP reduction of 20%–30%. The effect of β-adrenergic antagonists, or beta-blockers, on aqueous production occurs within 1 hour of instillation and can be present for up to 4 weeks after discontinuation. Evidence suggests that beta-blockers decrease aqueous production during the day but have much less effect during sleep. As systemic absorption occurs, a contralateral IOP-lowering effect in the untreated eye can also be observed. Most beta-blockers are approved for twice-daily therapy. In many cases, once daily with the nonselective agents is possible. Generally, dosing first thing in the morning is preferred in order to effectively blunt an early-morning pressure rise while minimizing the risk of systemic hypotension during sleep, when aqueous production is diminished. Many nonselective beta-blockers are available in more than 1 concentration. For example, timolol 0.25% is as effective in lowering IOP as timolol 0.5% in many patients.
Beta-blockers are additive in combination with miotics, adrenergic agonists, CAIs (both topical and systemic), and prostaglandin analogs. Combinations of beta-blockers and nonselective adrenergic agonists are only slightly additive, whereas more effect can be expected when beta-blockers are combined with an α2-adrenergic agonist. The magnitude of additional IOP lowering with prostaglandin analogs remains indeterminate. Approximately 10%–20% of the patients treated with topical beta-blockers fail to respond with significant lowering of the IOP. It should be noted that if a patient is on systemic beta-blocker therapy, the addition of a topical beta-blocker may be significantly less effective. Extended use of beta-blockers may reduce their effectiveness, because the response of beta receptors is affected by constant exposure to an agonist (long-term drift, tachyphylaxis). Similarly, receptor saturation (drug-induced up-regulation of beta receptors) may occur within a few weeks, with loss of effectiveness (short-term escape).
Six topical β-adrenergic antagonists are approved for use for the treatment of glaucoma in the United States: betaxolol, carteolol, levobunolol, metipranolol, timolol maleate, and timolol hemihydrate. All except betaxolol are nonselective β1 and β2 antagonists. The activity of β1 is largely cardiac and that of β2, largely pulmonary. Because betaxolol is a selective β1 antagonist, it is safer than the nonselective beta-blockers for use in patients with pulmonary, CNS, or other systemic conditions, but beta-blocker–related adverse effects can still occur. The IOP-lowering effect of betaxolol is less than that of the nonselective β-adrenergic antagonists.
Carteolol demonstrates intrinsic sympathomimetic activity, which means that, while acting as a competitive antagonist, it also causes a slight to moderate activation of receptors. Thus, even though carteolol produces beta-blocking effects, these may be tempered, reducing the effect on cardiovascular and respiratory systems.
Both ocular and systemic adverse effects of β-adrenergic antagonists are listed in Table 7-1. They include bronchospasm, bradycardia, increased heart block, lowered blood pressure, reduced exercise tolerance, and CNS depression. Patients with diabetes may experience reduced glucose tolerance and masking of hypoglycemic signs and symptoms. Abrupt withdrawal of ocular beta-blockers can exacerbate symptoms of hyperthyroidism. Although betaxolol is somewhat less effective than the other β-adrenergic antagonists in lowering IOP, it may be a safer alternative in some patients.
Before the clinician prescribes a beta-blocking agent, it is important to determine whether the patient has ever had asthma, because beta-blockers may induce severe bronchospasm in susceptible patients. The pulse should be measured and the beta-blocker withheld if the pulse rate is slow or if more than first-degree heart block is present. Myasthenia gravis may be aggravated by the use of these drugs. The use of a gel vehicle has been shown to decrease the plasma concentration of beta-blockers compared to the solution modalities.
Other adverse effects of beta-blockers include lethargy, mood changes, depression, altered mentation, light-headedness, syncope, visual disturbance, corneal anesthesia, punctate keratitis, allergy, impotence, reduced libido, and alteration of serum lipids. In children, beta-blockers should be used with caution, because of the relatively high systemic levels achieved. Although topical beta-blockers have been shown to decrease high-density lipoprotein and increase cholesterol levels, there is no evidence that this translates into an actual increase in cardiovascular risk. However, this effect on the plasma lipid profile should be considered, particularly in those patients taking medications that affect plasma lipids. Carteolol may have less effect on serum lipid levels than timolol.
The use of nasolacrimal occlusion or eyelid closure decreases systemic absorption and increases intraocular penetration of medications; nasolacrimal occlusion is particularly important with the use of beta-blockers. For patients who use multiple medications, these procedures may also facilitate a time interval between the instillation of different medications.
Many of the beta-blockers are available as generic agents. Although the generic agents may be less expensive, it is important to realize that in most cases few data are available to prove or disprove equivalent efficacy or similar side effect profiles between branded and generic medications. In addition, because multiple generics are available for a given agent, there is the possibility that differences exist among generic agents—differences that could affect patient care.
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. Adverse reactions from timolol administration.. 1980;87:447–450.