TIMOLOL MALEATE

Timolol maleate (Timoptic™, Merck, West Point, Penn and generics) is a nonselective β ₁ – and β ₂ -adrenergic antagonist that lacks substantial intrinsic sympathomimetic activity and membrane-stabilizing properties (see Table 25-1 ). The drug is about five times more potent than is propranolol. Timolol reduces IOP in normal and glaucomatous eyes without changing visual acuity, accommodation, or pupil size. On average, timolol lowers IOP by about 5 mmHg over a 6–12 month period. While timolol (and the other β-blockers) do a reasonable job of flattening the diurnal curve, the β-blockers are less effective during the night-time hours, possibly because the secretion of aqueous is lowest during the night. The only effect of timolol on the pupil is a clinically insignificant decrease in the amplitude of redilation as detected by pupillography. Timolol binds to melanin and is not metabolized by ocular tissues. Timolol is excreted in the urine in the form of unknown metabolites. The ocular hypotensive effect of timolol is greater in human eyes than in animal eyes; in animals, the effect can often only be demonstrated in experimental ocular hypertensive conditions such as water loading. This is a good example of the importance of species differences in the ocular response to adrenergic drugs.

Timolol is supplied in 0.25% and 0.5% concentrations, each of which is administered every 12–24 hours. The 0.25% concentration is the top of the dose–response curve for most individuals with lightly pigmented irides, whereas the 0.5% concentration is more effective for most patients with dark irides. In some patients with light irides, the 0.5% concentration produces a longer duration of effect rather than a greater reduction in IOP. Timolol was thought to be equally effective in black and white patients when administered in the appropriate concentration. However, more recent studies suggest that the β-blockers may be less effective in those of African descent than in those of European descent.

Timolol penetrates the eye rapidly; following topical administration, IOP begins to fall in 30–60 minutes, reaches a low in 2 hours, and returns to baseline in 24–48 hours. Some residual effect of timolol on IOP may be detected for as long as 2–3 weeks, and β-blockade can be detected up to 1 month after discontinuation of the drug. Many patients are controlled on once-daily administration of timolol ; however, this requires confirmation by measuring IOP 24–26 hours after the last administration of the drug.

Timolol maleate in a gel solution (Timoptic XE, Merck Inc., West Point, PA; timolol in gel-forming solution (GFS), Falcon Pharmaceuticals Ltd., Fort Worth, TX) for once-daily use has been found to prolong the contact time of timolol with the ocular surface and, therefore, theoretically, more gets into the anterior chamber, prolonging the action. The gel formulations have been found to be nearly equivalent to timolol maleate given twice daily. The two most popular gel formulations in the US appear to be equivalent in effectiveness and side effects. The gel formulation, because of its once-a-day dosing, theoretically reduces the systemic side effects compared with the twice-daily aqueous preparation. Although the gel has been compared in clinical studies to twice-daily aqueous administration, no study has compared the gel to once-daily timolol maleate solution. Studies with levobunolol and timolol hemihydrate suggest that the pressure-lowering effect of these agents administered once daily compares favorably with once-daily administration of timolol maleate gel. A non-preserved timolol gel formulation has recently become available in single-dose units with equivalent effect to multidose preserved doses.

A new formulation of timolol in potassium sorbate (timolol LA, Istalol ® , Senju Pharmaceuticals, Osaka, Japan) has recently been shown in a double-masked, randomized, prospective study in the US to have equivalent IOP-lowering effect as timolol maleate 0.5% given twice daily, with a similar safety profile. It differed only in a higher rate of stinging on administration than the solution. The drug has been approved by the US Food and Drug Administration. Theoretically, the potassium sorbate makes the timolol more bioavailable to the tissues inside the eye through increased anterior chamber concentration, perhaps by increasing lipophilicity. The solution also has a lower dose of benzalkonium chloride than the standard solutions of timolol maleate.

Approximately 90% of patients respond to the initial administration of timolol. Often the response to the first few doses is a reduction in IOP of 40% or more. However, this effect diminishes over several days to a few weeks. This decline in efficacy has been termed the ‘short-term escape’ by Boger and co-workers and may relate to an increase in the number of β-adrenergic receptors in the ciliary processes under the condition of prolonged β-adrenergic blockade. Unfortunately, the response to timolol at 1 month is not predicted by the response to a single administration given in the office. After this initial adjustment process, most patients maintain a reduction in IOP for months to years. However, 10–20% of patients demonstrate some loss of drug effect over subsequent months. Fluorophotometric studies indicate that aqueous humor production is reduced 47% after 1 week of timolol treatment but only 25% after 1 year of treatment. This process has been termed the ‘long-term drift’ by Steinert and co-workers and may be explained by a time-dependent decrease in cellular sensitivity to adrenergic antagonists.

Timolol has become the ‘gold’ standard against which all newer glaucoma hypotensive agents are compared. It is less potent than the major prostaglandin analogs and equivalent to unoprostone, brimonidine, and the topical carbonic anhydrase inhibitors. Over the short term, timolol is more effective in reducing IOP than is pilocarpine or epinephrine.

The ocular hypotensive effect of timolol is additive to that of the miotics and the carbonic anhydrase inhibitors (CAIs). It should be emphasized that timolol and the CAIs are only somewhat additive in their effects on IOP. In one study, timolol alone reduced aqueous humor formation by 33%, acetazolamide alone reduced aqueous formation by 27%, and the combination reduced aqueous humor formation by 44% (i.e., the combination was more effective than either agent alone but less effective than the sum of the two drugs). On the other hand, timolol adds well to the topical carbonic anhydrase inhibitors with a decrease in aqueous humor formation and IOP with the two drugs greater than either alone. While timolol’s effect on reducing aqueous formation is somewhat greater than brimonidine’s (note brimonidine also improves uveoscleral outflow so only some of its effect is from reduction of aqueous flow), there is additivity of brimonidine’s effect to timolol both in reducing aqueous formation and IOP. Timolol even is additive to bunazosin, an α-adrenergic antagonist.

The question arises as to whether topical timolol reduces IOP in patients treated with systemically administered β-adrenergic antagonists. The IOP response depends on the dose of the systemic agent. Topical timolol reduces IOP in patients treated with lower doses of the oral β-adrenergic antagonists (e.g., propranolol, 10–80 mg/day). However, there is little additional reduction in IOP when topical timolol is administered to patients treated with larger doses of the systemic drugs (e.g., propranolol, 160 mg/day, or oral timolol, 20 mg/day). A recent study confirmed the reduced efficacy of timolol in patients taking systemic β-blocking agents for hypertension, possibly because the systemic β-blocker has already blocked most of the β receptors and the topical agent can only block a few more. If the use of topical β-blockers are being considered in this situation, a one-eye trial would be indicated to assess the effect of adding the topical agent, although the effectiveness in one-eye trials has been called into question especially with the use of β-blocking agents as they have contralateral effects.

Timolol (and probably all the other β-adrenergic antagonists) can be affected by other drugs. For example, cimetidine, a histamine H ₂ antagonist causes an increase in β-blockade when used concomitantly with topical timolol. Quinidine retards the metabolism of β-blockers and thus enhances their action.

TIMOLOL HEMIHYDRATE

Timolol hemihydrate (Betimol®, Ciba Vision, Duluth, GA) is a recently introduced new salt of timolol. Its clinical effectiveness and side effects are similar to those of timolol maleate. The major advantage of this formulation seems to lie in its cost, which may be less than Timoptic but usually more than generic timolol maleate. Timolol hemihydrate is available in 0.25% and 0.5% solutions for use once or twice daily.

BETAXOLOL

Betaxolol (Betoptic, Alcon Laboratories, Fort Worth, TX) is a relatively selective β ₁ -adrenergic antagonist that lacks intrinsic sympathomimetic activity and membrane-stabilizing properties (see Table 25-1 ). It is puzzling why a β ₁ -adrenergic antagonist should lower IOP because the β receptors in the ciliary epithelium are thought to be β ₂ in type. The most likely explanation is that betaxolol reaches the ciliary epithelium in sufficient concentration to inhibit β ₂ receptors. Other possible explanations include the presence of β ₁ receptors in the ciliary body or a non-adrenergic effect of betaxolol on IOP. Betaxolol is supplied either in a 0.5% solution or a 0.25% microsuspension for administration every 12 hours. The drug reduces IOP by decreasing aqueous humor formation. Betaxalol is effective at reducing IOP and flattening the diurnal curve. Although a few studies indicate that betaxolol and timolol are equipotent, most physicians believe timolol is more effective at lowering IOP. The latter impression is supported by experiments indicating that selective β-adrenergic antagonists are less effective than are non-selective antagonists in reducing IOP in animal models of ocular hypertension. Clinical studies have also supported the slight superiority of timolol to betaxalol. Betaxalol has similar IOP-lowering efficacy to dorzolamide.

Some clinical and animal studies suggest that tachyphylaxis is common with selective β-adrenergic antagonists; this has not been a major problem with long-term betaxolol treatment, although it does occur to some extent. Betaxolol appears to be additive in its ocular hypotensive effect with the prostanoids, brimonidine, miotics, and the CAIs. Because of its relative β ₁ specificity, betaxolol may not block the effect of epinephrine on aqueous outflow. A few studies suggest that betaxolol and epinephrine are more additive in their ocular hypotensive effects than are timolol or levobunolol and epinephrine.

Evidence is beginning to accumulate that betaxolol may be more ‘neuroprotective’ than its more non-selective cousins despite a weaker effect on IOP lowering. Betaxolol seems to reduce the progression of visual field defects compared with timolol and may even increase retinal sensitivity. Betaxolol relaxes the smooth muscle in the walls of retinal microarterioles. Using Doppler color imaging of retinal vessels, which is an indirect measure of blood flow, topical betaxolol seems to increase retinal blood flow. This appears to be particularly true in patients with normal-pressure glaucoma. The clinical significance of these observations remains unknown, but the implication is that some property of betaxolol other than its pressure-lowering effect may improve blood flow and/or nerve function.

Betaxolol is less likely than is timolol to induce β ₂ -adrenergic-mediated bronchial constriction and therefore is a better choice for patients with reactive airway disease. It must be emphasized that the β-adrenergic specificity of betaxolol is relative, and the drug can induce or exacerbate pulmonary problems in susceptible patients. Some investigators postulate that betaxolol is less likely than is timolol to produce cardiovascular and central nervous system side effects, perhaps because of decreased systemic effectiveness or more rapid metabolism. This impression requires further study. Betaxolol is less likely than is timolol to interfere with exercise tolerance. Betaxolol in solution form produces more burning and stinging on instillation than does timolol, whereas the microsuspension form has an ocular discomfort profile more like timolol.

Levobetaxolol is the l -isomer of betaxolol which is a mixture of the isomers. Levobetaxolol (Betaxon™, Alcon Laboratories, Ft Worth, TX) is a more potent β ₁ antagonist than betaxolol or the R -isomer. Whether this will make a better clinical agent than betaxolol remains to be demonstrated.

LEVOBUNOLOL

Levobunolol (Betagan, Allergan, Irvine, Calif) is a non-selective β ₁ – and β ₂ -adrenergic antagonist that lacks intrinsic sympatho-mimetic activity and local anesthetic properties. The drug is used systemically to treat hypertension, ventricular arrhythmias, and angina. Levobunolol is supplied as either a 0.25% or a 0.5% solution, which is administered every 12–24 hours. The drug appears to be similar to timolol with regard to both efficacy and safety. It has been suggested that levobunolol is more likely than timolol to control IOP with once-daily administration. However, the two drugs seem to have similar durations of action. Levobunolol produces blepharoconjunctivitis more frequently than does timolol. The metabolites of levobunolol also appear to have ocular hypotensive effects.

CARTEOLOL

Carteolol (Ocupress, Otsuka America Pharmaceutical, Inc., Seattle; generics) is a non-selective, β-adrenergic antagonist. It is chemically related to timolol, metipranolol, levobunolol, and betaxolol with a potency 10 times that of propranolol; it has partial intrinsic agonist properties toward both β ₁ and β ₂ adrenoreceptors but no local anesthetic activity. Carteolol is available as a 1% or 2% solution for use every 12 hours; the drug has a significant effect on IOP by 1 hour after administration and reaches its peak effect at about 4 hours after administration. Carteolol 1% appears to produce a pressure-lowering effect similar to that of timolol 0.5% when administered every 12 hours. Carteolol seemed to produce fewer local side effects than does timolol.

Because of its intrinsic sympathomimetic activity, carteolol might be expected to produce fewer cardiovascular side effects, such as bradycardia and systemic hypotension, and perhaps fewer pulmonary effects. Carteolol produced less bradycardia, lowering of blood pressure, dizziness, and headache and had less of an effect on pulmonary function studies than did topical timolol. However, the differences are small and may be of only modest clinical significance. All of these side effects tend to occur more frequently with any of the non-selective β-blocking agents in a general population and with longer-term use compared to the carefully selected patients in formal studies.

Recently, a solution of carteolol 1% in alginate solution has been described; because the alginate prolongs the contact time, once-daily dosing seems reasonable. In a 2-month, masked clinical study, carteolol 1% in alginate given once daily in the morning was equivalent to carteolol 1% solution given twice daily. Plasma levels of carteolol are lower after prolonged use of the long-acting gel formulation used once daily than in the patients using the standard solution twice daily.

METIPRANOLOL

Metipranolol (Optipranolol®, Bausch & Lomb, Tampa, FL) is a non-selective β ₁ – and β ₂ -adrenergic antagonist with a receptor selectivity similar to that of timolol and levobunolol. After several successful trials in Europe, a double-masked, randomized study in the United States showed that metipranolol effectively reduces IOP by suppressing aqueous outflow in ocular hypertensive eyes. The agent is similar in most respects to timolol in terms of effectiveness and side effects. It is available in the United States as a 0.3% solution for use twice daily.

Concern about metipranolol developed when several case reports of granulomatous uveitis appeared in association with its use. Although uveitis had been reported with the use of other topical β-blockers, the cases involving metipranolol seemed more virulent and occurred with greater frequency. Most of the reported cases seemed to come from Great Britain, where the agent differed from the American variety not only in concentration but also in preservative, pH, and method of sterilization. A subsequent retrospective study in the United States failed to find any evidence of uveitis associated with the 0.3% solution of metipranolol. However, one case report of a patient developing non-granulomatous anterior uveitis that reappeared after re-challenge with metipranolol appeared in the literature. Subsequent reports have not appeared, suggesting that this is a rare phenomenon in the US.

Metipranolol seems to have a reduced effect on exercise-induced tachycardia compared with timolol in healthy volunteers. Based on this study, it may be inferred that metipranolol could have fewer systemic cardiovascular side effects, although this has not been proven in a direct comparison. Metipranolol has achieved some success in the United States because it is less expensive than most of the other brand name β-blocking agents.

PROPRANOLOL

Propranolol (Inderal, Wyeth-Ayerst Laboratory, Philadelphia) is a non-selective β-adrenergic antagonist that is used widely for the treatment of a diverse group of medical conditions including arrhythmia, angina, hypertension, and migraine. Propranolol lowers IOP when administered topically, orally, or intravenously. The drug has been shown to reduce aqueous humor formation in both monkey and human eyes. Most physicians have abandoned propranolol as a treatment for glaucoma because its membrane-stabilizing properties produce corneal anesthesia. Patients who are treated with oral propranolol for a medical condition such as hypertension generally experience a decrease in IOP, particularly when the dose exceeds 10 mg/day.

ATENOLOL

Atenolol (Tenormin, Zeneca Pharmaceuticals, Wilmington, DE) is a relatively selective β-adrenergic antagonist that lacks intrinsic sympathomimetic activity and membrane-stabilizing properties. The drug reduces IOP in normal and glaucomatous eyes when administered topically in a 1–4% concentration or orally in a dose of 50 mg/day. There are a few reports of tachyphylaxis with atenolol treatment. While oral atenolol is commonly used to treat systemic hypertension, neither topical nor oral atenolol is in clinical use for glaucoma treatment at this time.

PINDOLOL

Pindolol is a relatively selective β ₁ -adrenergic antagonist that has some intrinsic sympathomimetic activity but lacks local anesthetic properties. Pindolol reduces IOP when administered orally or topically in a 0.25–0.5% concentration.

NADOLOL

Nadolol is a non-selective β-adrenergic antagonist that lacks intrinsic sympathomimetic activity and membrane-stabilizing properties. Nadolol is two to four times more potent than propranolol. The drug reduces IOP when administered topically in a concentration of 0.3–2% or orally in a dose of 20–40 mg. A prodrug of nadolol, diacetylnadolol, penetrates the eye more rapidly than does the parent compound and is only a little less effective than 0.5% timolol in reducing IOP. Like atenolol, nadolol has not yet become available for ophthalmic use in the United States.

METAPROLOL

Metaprolol is a relatively selective β ₁ -adrenergic antagonist that has weak membrane-stabilizing properties but lacks intrinsic sympathomimetic activity. Metaprolol reduces IOP when administered orally in a dose of 50 mg three times daily. Administered topically in a 3% concentration, metaprolol reduces IOP as effectively as does 2% pilocarpine. Unfortunately, the drug commonly causes local irritation and superficial punctate keratitis.

LABETOLOL

Labetolol is a mixed α- and β-adrenergic antagonist. When administered topically in concentrations of 0.1–1%, the drug reduces IOP without changing outflow facility.

OPEN-ANGLE GLAUCOMA

The β-adrenergic antagonists have their greatest use in the treatment of open-angle glaucoma; they have become the treatment of first choice in this condition unless systemic conditions preclude their use.

ANGLE-CLOSURE GLAUCOMA

In some patients, a β-adrenergic antagonist may lower IOP sufficiently to allow subsequent topical pilocarpine administration to produce miosis and stop an attack of acute angle-closure glaucoma. In other patients, the β-adrenergic antagonist must be used along with an α ₂ agonist, CAI, or hyperosmotic drug. It should be emphasized that the medical treatment of acute angle-closure glaucoma is not a substitute for surgical therapy. The physician should not be lulled into a false sense of security when IOP drops to normal after an attack of acute angle-closure glaucoma. Iridectomy remains the treatment of choice for angle-closure glaucoma caused by pupillary block.

The topical β-adrenergic antagonists are also useful in treating late IOP elevations (chronic and residual angle-closure glaucoma) after laser or standard surgical iridectomy.

SECONDARY GLAUCOMA

The β-adrenergic antagonists are effective in reducing IOP in most of the secondary glaucomas. Because these agents do not produce either mydriasis or miosis, they are helpful in conditions in which movement of the pupil is of concern (i.e., hyphema with associated IOP elevation or early postoperative IOP rise after cataract surgery). The topical β-adrenergic antagonists can be used to treat inflamed eyes with secondary elevations of IOP. Although some authorities believe timolol breaks the blood–aqueous barrier, the bulk of the evidence suggests that there is no increased vascular permeability as determined by fluorescein angiography of the iris or aqueous humor protein measurements. Timolol is ineffective in reducing the immediate IOP elevation that occurs after penetrating keratoplasty but is effective in the intermediate and late postoperative course.

GLAUCOMA IN CHILDREN

The β-adrenergic antagonists produce a substantial IOP reduction in approximately two-thirds of children with glaucoma. The response to treatment seems to be better in older children and in those without detectable congenital anomalies of the anterior segment of the eye. Unfortunately, complications are seen more often in children, perhaps because they have higher blood levels of the drug. Common complications in children include asthma, bradycardia, dizziness, drowsiness, and hyperactivity. Neonates and small infants must be monitored carefully for the development of apnea. When children are treated with β-adrenergic antagonists, lower concentrations should be used and punctal occlusion should be applied. It is likely that betaxolol is a safer choice for children with glaucoma, but no studies have been done to confirm this.

Whether the topical β-adrenergic antagonists can be administered safely to pregnant women is unclear. Systemic propranolol has been given to large numbers of pregnant women without teratogenic effect even though the drug does slow fetal heart rate. Given the lack of specific information regarding the effect of these agents on pregnancy and the fetus, however, topical β-adrenergic antagonists must be prescribed with caution for pregnant women and women of childbearing age.

Timolol is actively secreted into mothers’ milk; that is, the drug concentration is higher in milk than in plasma. Although the total dose reaching the infant is relatively small, little is known about the long-term effects of even small amounts of β-blockade in neonates and infants; therefore, caution is indicated.

BLOOD FLOW AND NEUROPROTECTION

Neuroprotection has been defined in many different ways. Certainly, lowering IOP is neuroprotective. However, in general ophthalmologic use, neuroprotection refers to a property of a drug independent of its pressure-lowering capability. Neuroprotection may mean interfering chemically with the intracellular pathway of ganglion cell damage, enhancing cell survival characteristics, or possibly improving blood flow if it indeed is defective either chronically or intermittently in one or more types of glaucoma. Many studies have confirmed that some defect in ophthalmic, retinal, and/or optic nerve blood flow exists in glaucoma. Whether these defects are causative of or contribute to the pathophysiology of damage in glaucoma, secondary to the death of ganglion cells by some other mechanism, or are incidental findings remains conjectural. A large literature exists on neuroprotection and blood flow as they may be affected by β-adrenergic antagonists.

Controversy exists as to the effect of β-blocker agents on retinal and optic nerve blood flow. Some investigators believe that topical timolol treatment may have an adverse effect on optic nerve circulation and visual function. Some studies have suggested that β-blocking agents, especially the non-selective ones without intrinsic sympathomimetic activity, may decrease optic nerve blood flow by inducing vasospasm; this activity may have the long-term effect of competing with the IOP-lowering effect of these agents and ultimately lead to progression of optic nerve damage. Although there is no general clinical impression that patients treated with timolol have a worse prognosis than patients treated with other antiglaucoma medications, this matter requires careful study. At least one study has shown that betaxalol, despite having weaker IOP-lowering efficacy than timolol, is more likely to preserve visual function. This observation has not been confirmed in all studies.

Unfortunately, the methodology to date is relatively crude and can only give an indirect measure of capillary blood flow to the optic nerve, peripapillary choroid, and retina. One method is to use pulsatile blood flow measurements. These are gross measurements of total ocular blood flow and do not measure non-pulsatile blood flow at all. Another method measures the velocity of blood flow in capillaries by the laser Doppler method. This indirect method is akin to measuring the speed of cars on a busy freeway and inferring from their average speed the total volume of traffic. The methodology has become more sophisticated with time but the clinical and pathophysiologic meaning has not become any clearer. Some studies have pointed out that patients differ in their responses and that not all patients have similar responses in their blood flow to the same agent. In addition, for example, patients with non-progressive glaucoma seem to have no real demonstrable vascular dysfunction and timolol has no effect on this essentially normal picture. Moreover, studies differ in whether they use a single dose or long-term application. Some compare the active agent to placebo and others to alternative β-blocking agents. Depending on the study chosen, one can find no effect, a small positive effect, or a negative effect of non-selective β-blockers on retinal circulation.

Several studies suggest that the selective β-blocking agent betaxolol may have a beneficial effect on optic nerve blood flow. One study showed a smaller decrease in ocular pulsatile blood flow with long-term betaxolol treatment compared with long-term timolol treatment. Other studies have shown an improvement in pulsatile blood flow with non-selective agents and with non-selective agents having intrinsic sympathomimetic activity. One study has shown concurrent improvement in blood flow and slightly improved contrast sensitivity with betaxolol treatment versus timolol treatment in primary open-angle glaucoma patients. Two studies have shown a beneficial effect of betaxolol compared with timolol on visual fields; these data would seem to correlate with those derived from the blood flow studies. However, a well-done, double-masked study failed to show any difference in the corrected loss variance between betaxolol- and timolol-treated eyes after 2 years. In another randomized study comparing timolol, betaxalol, and pilocarpine, the betaxalol-treated patients did marginally better than timolol on short-wavelength automated perimetry after 2 years despite better IOP reduction with timolol. Other studies have shown only a small, probably clinically insignificant, difference between timolol- and betaxolol-treated eyes. Furthermore, studies both in vitro and in experimental animals have shown some direct neuroprotective effects of betaxolol. Similar properties were found with metipranolol. Nipradilol, a β-adrenergic blocking agent with nitric oxide donor properties in use in Japan, has been shown to have neuroprotective and regenerative properties on retinal ganglion cells in tissue culture.

What these many findings really mean for the management of glaucoma remains to be determined. While the β-adrenoreceptor antagonists may have theoretical neuroprotective properties, no agent or group of agents have been shown to have a decided advantage clinically, in terms of improving or protecting optic nerve function other than as relates to the agent’s IOP-lowering capacity. Clearly, further study is needed.

OCULAR

The topical β-adrenergic antagonists cause a relatively low incidence of ocular side effects, especially when compared with other antiglaucoma preparations ( Box 25-1 ). Although most of the studies have been done with timolol, the side effects of the other topical β-blocking agents are the same as timolol except when specifically indicated. Although the topical β antagonists do not generally cause severe discomfort on administration, stinging, burning, or itching does occur in 5–10% of patients. This rate increases to 40% for betaxolol solution. Even with betaxolol, however, the discomfort is fleeting and rarely a cause for discontinuing the medication. Carteolol seems to cause less discomfort on administration than does timolol. The incidence of significant ocular side effects for timolol is about 0.15%. These include periocular dermatitis, allergic conjunctivitis, and punctuate keratitis.

Ocular allergy to topical timolol is quite uncommon. In one large, long-term study, the incidence was about 1%. Other ocular reactions to β antagonists include punctate keratitis, photophobia, ptosis, and blepharoconjunctivitis. This latter reaction may be allergic in nature and seems to be less common with carteolol. Should it occur, switching to a different class of medication would probably be most effective in reversing it. Some patients report decreased vision soon after initiating β-blocker treatment. In most cases, this symptom is related to the loss of miosis and depth of field when miotic treatment is discontinued. However, in other cases, the symptom appears to be related to the β-blocker treatment through some unknown mechanism.

Topical timolol treatment can reduce baseline and reflex tearing (Schirmer I and II tests) and tear breakup time and can initiate or exacerbate keratoconjunctivitis sicca. This can be a problem particularly in contact lens wearers and can be aggravated by the development of corneal anesthesia, which has been reported in a few patients. The combination of gas-permeable contact lenses and topical timolol administration alters the corneal epithelium and endothelium in rabbits. Benzalkonium chloride is absorbed by some types of soft contact lenses, and patients who use these lenses should administer their drops with the lenses out of the eye. One study reported that topical timolol treatment reduces tear lysosome concentration, but this was not confirmed in a second investigation. Levobunalol seems to have equivalent effect on the cornea and tear film as timolol. Both timolol hemihydrate and carteolol may have less effect on the corneal epithelium and tear film than timolol maleate. Clinically, the other β-adrenergic antagonists seem to have similar effects on the cornea as timolol maleate.

Timolol does not retard corneal re-epithelialization in rabbits, nor is it toxic to cultured bovine corneal endothelial cells. Long-term use is unlikely to affect the corneal endothelium in humans with normal corneas to start with. The effect of these agents on abnormal endothelial cells has not been documented but general experience has suggested that they are not particularly toxic even in those with advanced endothelial dysfunction.

Studies suggest that long-term use of topical β-blocking agents (specifically timolol maleate) may be associated with an increase in the number of fibroblasts and inflammatory cells in the conjunctiva. These changes may contribute to keratoconjunctivitis sicca and, perhaps more ominously, interfere with the subsequent success rate of filtering surgery. Furthermore, the changes can be reversed by discontinuing the β-blocker some weeks before surgery and pretreating the eye with topical corticosteroids. Not all investigators have confirmed the histopathologic changes associated with topical β-adrenergic antagonist therapy. Both timolol and betaxolol accumulate in Tenon’s capsule where a reservoir effect may occur allowing gradual release of these agents long after they have been discontinued. Presumably, similar changes are seen with the other members of this class of drugs.

Benzalkonium chloride (BAK) has been implicated as a causative agent in the conjunctival inflammation and keratopathy associated with topical β-blocker use. Benzalkonium chloride seems to induce apoptosis in conjunctival cells in patients using topical antiglaucoma agents as measured by impression cytology. However, not all of the β-blockers’ conjunctival effects are due to preservative; also evidence suggests that some of these changes are not reversible. All of the β-adrenergic antagonists contain benzalkonium chloride as the preservative except for Timoptic XE (the gel form), which has an analogue of benzalkonium. The concentrations differ, however, and patients who are sensitive to BAK may get some local relief by switching to an agent with a lower concentration such as Timoptic XE, Istalol, carteolol, metipranolol, and levobunolol. Finally, Merck has made on and off a non-preserved Timoptic, in addition, compounding pharmacists such as Leiter’s in San Jose, CA, will also make a non-preserved timolol solution by prescription.

Furthermore, BAK has been shown to increase apoptosis in cultured trabecular meshwork cells suggesting that this may be one mechanism that may explain the increased rate of trabecular cell loss in patients with glaucoma. In addition, both timolol and BAK have been implicated as causative agents in post-cataract surgery cystoid macular edema, with BAK playing an exacerbating role. Presumably, both BAK and timolol lead to disruption of the blood–aqueous barrier in newly operated eyes thus causing additional prostaglandins and other inflammatory cytokines to reach the retina. On another note, levobunolol may contain sodium metabisulfite, an antioxidizing agent commonly used in foods for preservation; patients allergic to this preservative may experience severe local reactions on administration.

The combination of timolol and epinephrine produces greater mydriasis than does epinephrine alone, especially in eyes with light-colored irides. Combined treatment with these two drugs can precipitate angle-closure glaucoma in susceptible individuals and should be used with great caution in patients with anatomically narrow angles.

SYSTEMIC

The topical β-adrenergic antagonists are capable of producing systemic side effects through β-adrenergic blockade. Although topical timolol treatment generally yields serum drug concentrations of less than 5 ng/ml in adults, this level is apparently sufficient to produce systemic β-adrenergic blockade in susceptible individuals.

The effect may be cumulative and requires some time to manifest. Systemic drug levels can be reduced by using the lowest possible concentration of the drug and the fewest administrations necessary to control IOP. Drug concentrations in plasma can also be lowered by instructing patients to limit instillation to one drop of medication per eye and to use eyelid closure and punctal occlusion after administration. β-Blockers reaching the oral and nasal mucosa are absorbed rapidly and distributed to the body without first-pass metabolism in the liver; that is, the drug acts as if it has been given by a slow intravenous injection. Topical β-adrenergic antagonists should be used with great caution in patients with asthma or other reactive airway disease (including a history of asthma in childhood), heart failure, sinus bradycardia, hypotension, greater than first-degree heart block, hypokalemia, and brittle diabetes mellitus. Possible drug interactions with topical β-adrenergic antagonists include digitalis and calcium-channel blockers (bradycardia), reserpine (excessive β-blockade), sympathomimetics and the xanthene drugs (inhibit therapeutic effect of the drugs), and other systemic β-adrenergic antagonists (additive systemic β-adrenergic blockade). Concomitant use of quinidine can inhibit the metabolism of topical timolol, producing profound systemic β-blockade; it has been suggested that this effect may be genetically determined.

Symptoms related to the central nervous system are common in patients receiving topical β-adrenergic antagonists and include mood changes, emotional lability, fatigue, trouble concentrating, confusion, and depression (see Box 25-1 ). These symptoms usually appear after a few days to several months of treatment, although they may be transient in nature. The symptoms may be subtle, develop slowly, and be interpreted by the patient and family as a ‘normal’ part of aging. Many patients may be unaware of the problem until the drug is discontinued. Patients should be questioned specifically about these symptoms. However, large-scale evidence that topical β-blocker therapy leads to previously unrecognized clinical depression is lacking and, in one study, topical β-blockers were not associated with an increased risk of treatment for depression. There is some evidence that the more selective β-blocker betaxolol may be less likely to produce these symptoms, and patients may show improvement when switched from a non-selective agent to a selective one.

Topical β-adrenergic antagonists reduce forced expiratory volume and forced vital capacity in patients with asthma or other reactive airway disease, including cystic fibrosis and bronchitis. Severe asthma leading to hospitalization or even death has occurred. Topical β-blockers can induce bronchospasm in patients who have only a history of asthma and no active current disease. Susceptible patients are more likely to develop pulmonary problems when they have an upper respiratory infection or allergy. The topical β-adrenergic antagonists can initiate, exacerbate, or prolong bronchitis, cystic fibrosis, and other respiratory problems. Even in asymptomatic older patients without a history of bronchospastic disease, a measurable reduction in respiratory function is present as a result of topical β-blocker therapy although this may not be clinically significant; in fact, asymptomatic respiratory depression and reduced expiratory facility may be seen in otherwise normal patients in as little as 3 months after initiation of topical timolol therapy. While most of the effects on the respiratory system disappear when the drug is discontinued, what is worrisome is that some of these effects may persist for months or even years after the topical β-blocker has been stopped.

Betaxolol is less likely to induce bronchial constriction. However, the β ₁ -adrenergic selectivity of betaxolol is only relative, and the drug is capable of inducing pulmonary side effects in susceptible patients. The non-selective β-blocking agents are contraindicated in patients with active bronchorestrictive airway disease and in those with a recent past history of asthma or similar respiratory problems. In those cases, if β-blocker therapy is indicated, a selective agent (betaxalol) should be used with careful respiratory monitoring, particularly over the long haul.

Topical timolol treatment can decrease resting and maximal heart rate, oxygen consumption at maximal exercise, cardiac sympathetic tone, and ventricular inotropy. In fact, topical timolol’s cardiovascular effects, plasma concentrations, half-life, and bioavailability mimic intravenously injected timolol. The cardiovascular effects of timolol are directly proportional to its plasma concentration. It has been suggested that betaxolol is less likely than is timolol to affect cardiac function, perhaps because of decreased systemic effectiveness, generally weaker activity, or a more rapid metabolism. β-Adrenergic antagonists can exacerbate congestive heart failure and should be used with caution in patients with this condition, although cardiologic opinion seems to be switching to utilization of β-blockers again in congestive heart failure. Severe atrioventricular heart block and bradycardia have been noted. Although severe cardiovascular events are rare, these agents should be used with caution in elderly patients with underlying cardiovascular disease. Certainly, consultation with the primary care physician and cardiologist would be indicated if topical therapy were to be initiated or continued in any patient with heart disease. In patients with low blood pressure, especially those with nocturnal hypotension, caution should be observed in the use of topical non-selective β-blockers; in these patients, if β-blockers are necessary, perhaps once-daily dosing in the morning might be safer.

Timolol can also slow the fetal heart rate and even induce fetal arrhythmias; therefore, this agent and any of the other non-selective β-blockers should be used with extreme caution or not at all in pregnant women.

Long-term use of topical timolol maleate has been shown to increase plasma triglycerides by an average of 12% and decrease high density lipoprotein (good) cholesterol levels by 9%. The authors estimated that over a period of years this could result in an increase of coronary heart disease by 21%; it is wise to remember, however, that this is an estimate and not a measurement. However, the Blue Mountains Eye Study from Australia did find a correlation between topical timolol use and cardiovascular mortality. There are no data to prove that the risk of heart disease is actually increased by use of topical β-blocking agents.

Because of its intrinsic sympathomimetic activity, carteolol does not appear to affect plasma lipid levels as much as does timolol. Thus carteolol may have a slightly better therapeutic index than does timolol in these patients with hyperlipidemia or hypercholesterolemia.

Although some studies have failed to show an effect of topical β-blockers on exercise tolerance, reduced exercise tolerance has been seen with topical β-blocker use in otherwise healthy individuals. Because some of the effects of β-blocking agents are cumulative, the longer someone has been taking the agent the more likely systemic effects will be seen. Some of the differences in studies on exercise tolerance may relate to different lengths of time the patients were using the drug. Competitive athletes and those involved in heavy exercise should be warned that their peak capability may be reduced with the use of topical β-blockers.

Topical β-adrenergic antagonists should be administered with caution to diabetic patients who are prone to episodes of hypoglycemia. Systemic β-adrenergic blockade may mask the common symptoms of hypoglycemia and substitute unusual symptoms. Diabetic patients treated with topical β-adrenergic antagonists may experience an increased frequency of hypoglycemia and a relative resistance to glucose treatment. A recent study suggests that certain polymorphisms of the gene CYP2D6 may be associated with increased susceptibility to the systemic side effects of β-blocking agents due to ‘slow’ metabolism of the drugs and raises the possibility that, in the future, we will be able to adjust our therapy from the individual genotype of the patient. One study has shown not only an improvement in glaucoma control, but in quality of life, when switching from β-adrenergic antagonists to prostaglandin analogs.