Ординатура / Офтальмология / Английские материалы / Shields Textbook of Glaucoma, 6th edition_Allingham, Damji, Freedman_2010

inflammatory cells (167). This may have implications regarding the success of glaucoma filtering surgery.

Most human and animal investigations have revealed no toxicity of topical timolol therapy to the corneal endothelium (168, 169, 170 and 171). A small subgroup of patients treated with timolol may have markedly diminished corneal sensitivity (162, 163). Corneal epithelial erosions were reported in two patients wearing gas permeable contact lenses soon after starting topical timolol therapy, and the combination of timolol and a contact lens in rabbits caused marked alterations in corneal epithelium and endothelium (172). Eight patients were described in which the combination of epithelial defects and topical steroid and ß-blocker therapy led to a prec ipitation of calcium phosphate deposits in the superficial stroma (173).

A potentially serious ocular effect that has been the focus of considerable investigation is the influence of ß-blockers on ocular blood flow (174). If the dr ug reduces vascular perfusion of the optic nerve head, this may cancel the benefit of reduced IOP. A rabbit study using injected microspheres indicated that both nonselective and cardioselective ß-blockers de crease ocular blood flow (175). However, highresolution Doppler ultrasonography suggested that timolol improves the flow velocity of the central retinal artery in healthy and diabetic individuals (176, 177), but other studies suggest that timolol has no significant effect on the choroidal vasculature in healthy persons or retinal hemodynamics in patients with normal-tension glaucoma (178, 179).

The most troublesome ocular reaction reported with metipranolol is a granulomatous anterior uveitis, characterized by mutton-fat keratic precipitates, flare and cells, and IOP elevation. In the United Kingdom, 15 cases were described in one report, with reference to 51 more cases from other parts of the country (180). Seven patients, rechallenged with metipranolol, all developed an adverse reaction within 14 days (181), and the drug was withdrawn from clinical use in the United Kingdom. A retrospective study of 1306 patients treated with metipranolol in Germany revealed a low risk of uveitis associated with the medication, and it was assumed that the problem was related to the unique formulation used in the United Kingdom (182). However, three cases have been reported in the United States (183, 184), one of which recurred when inadvertently rechallenged treatment (184).

For betaxolol, one case was reported in which aphakic cystoid macular edema was associated with therapy (185), and three cases have been described of periocular cutaneous pigmentary changes, which returned to normal after discontinuation of topical betaxolol treatment (186).

Systemic Toxicity

After widespread and long-term use of the topical ß -blockers in the treatment of glaucoma, it became apparent that topical use of this drug class can cause adverse systemic side effects (187). Systemic toxicity has been reported more often than ocular reactions and potentially constitutes the more significant adverse effect of topical ß-blocker the rapy (188). With the initial availability of timolol, there are notably more cases reporting the adverse systemic effects of this particular agent, but the other topical ß-blocker agents are also associated with s imilar side effects.

Systemic Absorption

Measurable plasma levels of timolol are present within 8 minutes or less of topical application (189). In comparing plasma levels of timolol from systemic absorption of once-daily gelforming solution compared with twice-daily solution in a crossover designed study, there appears to be slightly lower plasma levels detected when six healthy male participants were given the once-daily gel-forming solution instead of the twicedaily solution (190). The cardiovascular effects of these dosing regimens in 43 patients showed a comparable decrease in mean 24-hour heart rate, compared with placebo (191). Given the concerns for systemic absorption of both the gel-forming and solution formulations of timolol, the role of punctal occlusion after instillation of the drug (see Chapter 27) is important because there is evidence that this action significantly reduces plasma timolol levels (192), which may help to minimize the systemic side effects. In one study, drug instillation at 12 pm was shown to optimize the ratio of ocular to systemic absorption, possibly relating to drug absorption into the eye and bloodstream (193). There is a reported difference in plasma concentrations comparing topical betaxolol, 0.5%, or timolol, 0.25%, which were given before cataract surgery. The plasma concentrations of betaxolol were lower

than those of timolol, whereas the aqueous levels were twice as high for betaxolol as for timolol (194). In a related study, these same investigators determined that the higher plasma levels of the absorbed timolol compared with betaxolol could functionally bind with the ß 1- and ß 2-adrenergic receptors based

on radioligand binding methods (60). In another study, timolol and carteolol (also a nonselective ß- blocker) blocked both the ß 1 and ß 2 effects of isoproterenol, but betaxolol had minimal influence on

either receptor effect (195). The latter investigators suggest that the low rate of systemic diffusion with betaxolol may relate to the high lipophilic and protein-binding properties, which favor a high level of local diffusion and a fixation to lacrimal proteins before the drug reaches the general circulation, where it binds to plasma proteins, leaving only a small amount to circulate freely (195).

Cardiovascular Effects

Blockade of ß 1-adrenergic receptors slows the pulse rate and weakens myocardial contractility. In most

healthy patients, these effects are of no consequence, but healthy individuals may be at risk under certain circumstances, such as the stress of surgery or heavy exercise (196, 197 and 198). Topical timolol therapy has been associated with severe bradycardia, arrhythmias, heart failure, and syncope (159, 199). The induced bradycardia may be more pronounced when timolol is used concomitantly with

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other drugs, such as quinidine or the calcium antagonist, verapamil (200, 201). Topical betaxolol has also been associated with similar cardiovascular side effects, including arrhythmia, bradycardia, sinus arrest, and decompensation of congestive heart failure (202, 203 and 204). Selecting another glaucoma drug class is prudent because of the potential for serious complications in patients with preexisting cardiac conditions such as sinus bradycardia, greater than first-degree heart block, and congestive heart failure. Oral ß-blockers have a role in the managem ent of patients with congestive heart failure (148, 149, 205). Obtaining an accurate medical history and assessing pulse rate and rhythm before initiating a topical ß-blocker should identify most patients wit h potential cardiovascular contraindications (188). Communication with the patient's primary care physician about potential systemic side effects from topical antiglaucoma medical therapy should also be considered.

Respiratory Effects

Blockade of ß 2-adrenergic receptors produces contraction of bronchial smooth muscle, which may cause

bronchospasm and airway obstruction, especially in asthmatics or any patient with bronchospasm requiring xanthines or inhaled steroids (159, 206, 207). Thirteen cases of death in status asthmaticus after initiation of timolol therapy had been reported to the National Registry of Drug-Induced Ocular Side Effects by 1984 (208). Dyspnea and apneic spells may be more common in young children, and caution must be taken by nursing mothers, because high levels of timolol were found in the milk of a mother receiving topical timolol (209).

Central Nervous System Effects

Central nervous system effects can occur with timolol therapy and include depression, anxiety, confusion, dysarthria, hallucinations, lightheadedness, drowsiness, weakness, fatigue, tranquilization, dissociative behavior, disorientation, and emotional lability (159, 210). Similar side effects have also been reported in association with betaxolol therapy (211).

Effect on Cholesterol Levels

Oral ß-blockers are known to adversely alter plasma lipid profiles, and topical timolol, 0.5%, twice daily for 2 months, without nasolacrimal occlusion, has been shown to decrease plasma HDL cholesterol levels, which increases the risk of coronary artery disease (212). Another study found no significant adverse effects of topical timolol on serum lipoprotein levels (213), although the sample size was small in a heterogenous patient population with no controls. The issue of ß-blockers on cholesterol is considered further in this chapter under the discussion of carteolol.

Other Systemic Reactions

Other systemic reactions that have been reported in association with timolol therapy include gastrointestinal distress (nausea, diarrhea, and cramping), dermatologic disorders (maculopapular rash,

alopecia, and hives), and sexual impotence (159, 162, 214, 215). Because these observations were made in a predominantly elderly population, it is difficult to confirm a cause-and-effect relationship in all cases. Of greater concern with timolol therapy, however, is the exacerbation of myasthenia gravis and the altered response to hypoglycemic episodes in diabetic patients, which may mask symptoms of the attack (216, 217).

a-ADRENERGIC RECEPTOR ANTAGONISTS Mechanisms of Action

As mentioned in the introduction, a-adrenergic receptor antagonists are available. These receptors mediate the action of the neurotransmitter norepinephrine in the end-organ targets for the sympathetic nervous system. In the iris, the stimulation of the dilator muscle with a-adrenergic receptor agonists causes mydriasis or dilation of the pupil. Although a-adrenergic receptors have been detected by pharmacology receptor binding studies in the ciliary body of various species (218, 219), their functional role in aqueous humor dynamics is not known. The clinical use of these agents is limited.

Specific Agents

Thymoxamine

Thymoxamine hydrochloride competes with norepinephrine for a-adrenergic receptors. As a result, it produces miosis by inhibiting the dilator muscle of the iris without influencing the ciliary muscleinduced facility of aqueous outflow (220). Thus, it has no effect on open-angle glaucoma (221). It does not affect the rate of aqueous humor formation, IOP, or anterior chamber volume (222). Because this agent does not cause shallowing of the anterior chamber or ciliary spasm, it provides safe, rapid reversal of the effects of an adrenergic mydriatic drug. Thymoxamine, 0.1%, is used to reverse mydriasis from phenylephrine (223).

Thymoxamine has a role in the management of angle-closure glaucoma because it causes miosis despite the presence of pressure-induced ischemia of the iris sphincter. Furthermore, it does not increase the posterior vector force of the iris, and thus does not potentially aggravate the pupillary block. In a study of patients with acute angle-closure glaucoma, thymoxamine, 0.5%, administered every minute for five times and then every 15 minutes for 2 to 3 hours broke the attack in all cases, except those with peripheral anterior synechiae or prolonged angle closure (224).

One theory for the mechanism of pigment dispersion in pigmentary glaucoma, as discussed in Section II, is contact between the iris pigment epithelium and packets of lens zonules. It has been suggested that miosis without cyclotropia, as produced by thymoxamine, provides an effective means of minimizing this effect (225).

Thymoxamine, 0.5%, causes a substantial narrowing of the palpebral fissure in many patients with eyelid retraction, especially cases occurring secondary to thyroid disease, and it

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has been suggested that this may have value in the diagnosis of thyroid eye disease and possibly in the medical treatment of eyelid retraction (226).

Dapiprazole

This a1-adrenergic antagonist is similar in action to thymoxa — mine and is commercially available for

the reversal of mydriasis after an ocular examination. It was evaluated in human volunteers and found to produce miosis and IOP reduction (227).

Other a1-Adrenergic Receptor Antagonists

Other agents in this class have been examined but were not further developed for commercial use. Bunazosin lowers IOP in healthy persons in single doses of 0.025% to 0.2% and was effective for 1 week in a concentration of 0.1% (228). The mechanism of IOP reduction is presumed to be increased uveoscleral outflow, because it does not influence aqueous production, conventional outflow, or episcleral venous pressure (228). Prazosin is used as an oral medication to lower blood pressure and produce peripheral vasodilatation. Rabbit studies have shown that topical administration of prazosin, 0.001% to 0.1%, causes a dose-related lowering of IOP by reducing aqueous humor formation (229).

Corynanthine is a selective a1-adrenergic antagonist produced IOP reduction in animals without altering

conventional outflow facility or the rate of aqueous humor flow (230). Thus, it was postulated that the mechanism of pressure reduction might be an increase in uveoscleral outflow. In a clinical trial, 2% and 5% concentrations of corynanthine did lower the IOP, although a 3-week study with the 2% concentration did not reveal a sustained pressure reduction (231).

Labetalol is a combined a- and ß-adrenergic blockin g agent that has been shown to produce a significant, dose-related IOP reduction in rabbits (232, 233), although it has a poor ocular hypotensive effect in human eyes (233, 234).

KEY POINTS

Topical ß-blockers significantly lower IOP by reduc ing aqueous humor flow.

Given the availability of generic formulations, this drug class is an inexpensive and effective antiglaucoma medication.

Careful monitoring of potentially serious ß-blocker -associated pulmonary and cardiac side effects is warranted to minimize prolonged exposure with this drug class.

a-Adrenergic antagonists produce miosis by inhibiting the dilator muscle of the iris but have no clinically significant effect on aqueous humor dynamics.

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