Ординатура / Офтальмология / Английские материалы / Clinical Pathways in Glaucoma_Zimmerman, Kooner_2001

440 Principles and Complications of Medical Therapy of Glaucoma

the scleral spur, which in turn results in improved aqueous outflow through the trabecular meshwork.53,54 Indirect-acting agents inactivate acetylcholinesterases. The reversible agent demecarium inactivates acetylcholinesterase by binding to it, and the action may be reversed by slow hydrolysis. The irreversible agents bind by alkyl phosphorylation to the enzyme, resulting in its inactivation. The end result is accumulation of acetylcholine at the muscarinic receptors, increasing their degree of stimulation. Pilocarpine is generally used four times daily, carbachol three times daily, and the indirect agents once or twice daily. The frequent dosing of the pilocarpine is difficult for most patients; a weekly Ocusert delivery system is available, and a slow-release 4% pilocarpine gel administered at bedtime is also available. The other advantage of Ocusert is that the pilocarpine base is free of preservatives.

Side effects occur with the use of miotics, and a few systemic medication considerations are important to keep in mind. These adverse effects are reviewed below.

What Are the Side Effects of Miotics?

Ocular side effects are quite common. Patients usually experience a temporal and/or supraorbital headache as the medication activates the ciliary muscle, but over a short period of time this resolves. The pupillary miosis results in reduced vision in lower illumination and considerable difficulty in patients with central lens opacities. Accommodative myopia is induced which is greater in younger patients, minimal in patients over 60, and nonexistent in pseudophakes. Retinal detachment may occur, shallowing of the lens/iris diaphragm may induce acuteor chronic-angle closure, and iris cysts may develop.55,56 Although the etiology and causality of retinal detachments are not proven, conservative recommendations before starting a patient on miotics include a 360-degree retinal exam and pretreatment of chorioretinal disease. Then it is recommended to start with the lowest dose, time-released delivery when possible, and patient education should be provided.55 Although time-released pilocarpine is considered safer, it has also been associated with retinal detachments.56 Cataracts may be exacerbated or formed with the use of these agents; they are dose related and will continue to develop after cessation of therapy.57 Patients over the age of 60 appear more vulnerable to this effect, although a 13- year-old girl developed lens opacities after the use miotics for treating esotropia.58 Increased permeability of the blood–aqueous barrier occurs, which is of concern when these patients undergo intraocular surgery. Increased conjunctival fibrosis and cicatricial pemphigoid have also been reported.11 All of the above-mentioned side effects can occur with all of the miotics, but are more prevalent with the stronger indirect-acting miotics.

Patients with angle recession have experienced IOP increases after being placed on miotics. These patients probably rely more on uveoscleral outflow, which the miotics decrease.59 The authors tested this theory, and found that the rare patient with an IOP increase on miotics may experience a therapeutic IOP decrease on mydriatics.

Systemic side effects include nausea and/or vomiting, slowing of the heart, sweating, pulmonary edema, diarrhea, and bronchospasm. The activation of the muscarinic receptors on these organs causes these side effects. Corneal

442 Principles and Complications of Medical Therapy of Glaucoma

Brimonidine decreases aqueous production and may also increase uveoscleral outflow.

What Are the Side Effects of the Nonselective

α-Adrenergic Agonists?

Initial vasoconstriction followed by vasodilatation can result in hyperemia, which is not clinically significant but may be cosmetically annoying to the patient. Tearing and irritation are also quite common, with occasional episodes of brow ache and even corneal edema. Mydriasis may result in photophobia, which may be enhanced by the use of beta-blockers and may precipitate angle closure. Allergic blepharoconjunctivitis may result after long-term use in about 10 to 15% of patients,61 and adrenochrome deposits have long been known to develop.32 They cause a breakdown of the blood–aqueous barrier, and 10 to 20% of aphakic patients may develop cystoid macular edema.62,63 The incidence is probably much greater as only more significant visual loss seems to be noticed; visual loss in people who were formerly 20/20 and have dropped to only 20/30 or 20/40 may go unnoticed.62 Angiographically, the macular edema was found to be completely reversible with cessation of its use.63

Systemic side effects include tachycardia, arrhythmias, extrasystoles, hypertension and headache.61 These agents should probably be avoided in patients with hyperthyroidism or cardiac disease and in patients being treated for depression with monoamine oxidase inhibitors and tricyclics.

What Are the Advantages

of the Prodrug Dipivefrin?

Its concentration is one-twentieth that of epinephrine, and as a result cardiovascular and systemic side effects are not clinically significant; furthermore, it must be activated by corneal esterases. Its local side effects are less, except that long-term use often results in a follicular conjunctivitis and hyperemia, but no adrenochrome deposits.64 Cystoid macular edema seems to occur less frequently with dipivefrin than with epinephrine, although the incidence would be expected to be similar since its efficacy is based on the intraocular concentration of epinephrine.65

What Are the Side Effects of Selective

α-Adrenergic Agonists?

Ocular effects include lid retraction, conjunctival blanching and subsequent redilatation. The most annoying and common problems that occur in 10 to 50% of patients are allergic blepharoconjunctivitis and dermatitis.66 They are much more common and severe with apraclonidine, which is infrequently used today since brimonidine became available. The allergy occurs in 10 to 15% of patients on brimonidine after 3 to 9 months of treatment.

Systemic side effects are most commonly dry mouth and/or nose. The advantage of apraclonidine is that it does not easily cross the blood–brain barrier, lessening the chance of centrally mediated effects, which include inhibited

central sympathetic activity resulting in fatigue, drowsiness, and hypotension.66 Brimonidine is more lipophilic and thus crosses the blood–brain barrier more easily and may cause these side effects.67

What Are Some Possible Effects Nonsteroidal Drugs or Aspirin May Have When Used with α-Adrenergics?

Both of these agents can decrease the IOP-lowering effect of the adrenergics. Sometimes when they are used together they may increase blood pressure.32

Are There Interactions

with Angiotensin-Converting Enzyme Inhibitors?

α-Adrenergics may decrease their efficacy.

What About Calcium Channel Blockers

and Diuretics?

Both drugs may increase the possibility of nausea/vomiting, diarrhea, and abdominal pain. Diuretics may also increase the chances of palpitations and headache.

Are There Any Concerns in Diabetics or Patients on Thyroid Supplements?

The α-adrenergics can stimulate hyperglycemia and decrease the effect of insulin. Thyroxin can increase the efficacy of adrenergics and make a patient more susceptible to a pressor response.

What Are the Available Prostaglandins?

Presently, in the United States, latanoprost 0.005% is the only available agent. Unoprostone is under investigation here and is becoming widely used in Japan and Latin America, and it seems to have fewer local ocular side effects in preliminary studies.68,69

What Are the Side Effects of Latanoprost?

The most common and disturbing side effect to patients and practitioners is the deepening of the iris color. It is much more common, up to 20 to 30%, in mixedcolor irides compared to solid-color irides.70 A case report indicated that after 5 months of treatment a 13-month-old infant developed increased pigmentation with blue-gray eyes.71 Patients may experience conjunctival hyperemia when instilling latanoprost and possibly cystoid macular edema. Another side effect has become better known with unilateral use of the medication—thick- ening and lengthening of lashes.72 An investigator found an average of 19.5% increase in lash length, increased number of lashes, more abundant vellus hairs in the lateral canthal area, hyperpigmentation of the lashes, and increased curl-

444 Principles and Complications of Medical Therapy of Glaucoma

ing. The effect is more prominent with more darkly pigmented hair. One of the first case reports of lash changes demonstrated that the changes became obvious at 14 weeks in a single-treated eye, and 8 weeks after latanoprost 0.005% was added to the contralateral eye the lashes appeared the same in both eyes.73 Systemic side effects are limited due to the low concentration and short halflife in the blood. The multicenter trials did not reveal any serious systemic side effects, but some patients do experience a flu-like syndrome, upper respiratory symptoms, and headache.32 The study involving 277 patients for 24 months in

the United Kingdom did not reveal any systemic side effects.74

What Is Known About Latanoprost

and Cystoid Macular Edema?

There are case reports of possible cystoid macular edema, but the causality is not clear.75 In general, these cases have occurred in eyes with a past history of retinal disease and aphakia. A recent study demonstrated increased blood aqueous disruption and an increased incidence of angiographically documented cystoid macular edema in early postoperative pseudophakes, and that aqueous flare was increased over the eyes of patients not taking latanoprost 0.005%. The aqueous flare difference was not present on the first postoperative day but rather at 3 days and 2 weeks, suggesting that latanoprost enhances the production of inflammatory mediators. However, the concurrent use of topical nonsteroidals significantly prevented these side effects while not decreasing the IOP lowering effect of latanoprost.76

Does the Time of Instillation Matter?

The clinical trials of the drug had protocols with a standardized application at 8:00 P.M. No evidence clearly indicates that the time of instillation affects the drug’s efficacy. Latanoprost was felt to be more effective when used at night because of the results of the Scandinavian arm of the clinical trials. Scandinavian patients were found to have significantly greater IOP reduction when latanoprost 0.005% was instilled in the evening compared to the morning.77 This has not been produced in any other studies and may have been caused by a difference in study design or patient population. Around-the-clock efficacy has been well demonstrated by a study instilling latanoprost 0.005% in the morning and monitoring IOP around the clock.78 The results demonstrated equally efficacious IOP reduction during the day and during the night.

How Does the Efficacy of Latanoprost Compare to that of Timolol?

Studies routinely use timolol as the standard against which other drugs are compared. Latanoprost is the only drug that has shown around-the-clock better control than timolol.70 One study has shown that latanoprost offers a significantly lower IOP than timolol, and when patients were switched to latanoprost a significantly greater IOP reduction was obtained.78 Patients who

had been treated with timolol 0.5% twice daily for 1 year were switched to latanoprost 0.005% once a day, and showed an additional 8% IOP reduction.

Does Latanoprost Work with Miotics?

Logically these two medications would seem to be antagonistic because miotics decrease uveoscleral outflow by contracting the ciliary muscle, and the mechanism of action of latanoprost is to increase uveoscleral outflow. Uveoscleral outflow is theorized to occur through the interstitial spaces of the ciliary muscle, which are decreased by cholinergic agonists.79,80 A study using supramaximal dosages of physostigmine in conjunction with latanoprost found the effects to be mostly additive, although the maximal effect was less than in previous studies where latanoprost 0.005% was the only eye medication.81 Eyes suboptimally controlled on maximum tolerated medications demonstrated significantly lower IOP when latanoprost was added, and any strength of pilocarpine did not have a significant effect on its efficacy.82 The only factors in this study found to decrease its efficacy were a starting IOP of greater than 24 mm Hg and more than two previous incisional glaucoma surgeries.

How Well Does Latanoprost Work

with Topical Carbonic Anhydrase Inhibitors?

Fluorophotometry revealed that latanoprost had no effect on the aqueous suppression of dorzolamide and that the two agents were additive.44,83 Aqueous humor was suppressed 13% by dorzolamide 2%, and no suppression was found with latanoprost 0.005%. The two drugs are additive but do not enhance the activity of the second drug. The authors recommend that both drugs be tried separately and then added together to see if the effect of the agents used together is superior to either drug used alone.83

Are There Drug Interactions?

No significant drug interactions have yet been reported.

What Is the Role of Hyperosmotic Agents

in the Treatment of Glaucoma?

The hyperosmotic agents are used as a short-term or emergency treatment of glaucoma, such as acute angle-closure glaucoma, preparation for intraocular surgery, and with other acute IOP elevations.

What Are the Available Hyperosmotic Agents?

Intravenous agents include urea, mannitol, ascorbic acid, and sorbitol and glycerol solutions. Oral agents include isosorbide, glycerol, and ethyl alcohol. The oral agents are slightly less effective and take effect a little more slowly than the intravenous agents.84

ation of mental status. Long-term side effects are at least emphysematous changes to the lungs and possibly changes in the hormonal system and brain.96 In a disease that requires 24-hour control and a lifetime commitment to treatment, these side effects are unacceptable. Additionally, smoking marijuana lowers IOP for only 3 to 4 hours, and control would require frequent administration. About 3,000 marijuana cigarettes would need to be smoked each year.94 In spite of these drawbacks, a recent review of the medicinal uses of marijuana has stated that further research needs to be done on its potential uses to treat glaucoma, and that there may be some settings where its use may be helpful.97

How May Cannabinoids Become a Part

of Glaucoma Regimens in the Future?

Cannabinoid analogues are being developed that are capable of reducing IOP without the side effects of marijuana.98 Newer topical delivery systems and oral formulations that lack the psychoactive aspects or marijuana may make routine use of this class of drugs more feasible.94 Further research may develop this class as a new and useful medication to treat some glaucoma patients.

What Is The Best Way to Decide on and Begin Treatment?

Figure 18–1 is a simple methodical paradigm that facilitates successful, simple, and effective glaucoma treatment for every patient. Table 18–2 highlights classes of glaucoma medications to avoid with certain medical conditions and medications.

Future Considerations

What Are Some Possible Agents Being Developed for the Treatment of Glaucoma?

These include cytoskeletal agents, lipids, neuroprotective agents, and calcium channel blockers.

Cytoskeletal agents include latrunculins, cytochalasins, ethacrynic acid, protein kinase inhibitors such as staurosporin, and calcium chelators.99,100 In general, these agents seem to work by altering the architecture of the conventional outflow channels in the eye to create better outflow. Actin cytoskeleton disorganization in the trabecular meshwork can increase the outflow facility, which appears to be the mechanism of these agents.100 In monkey eyes treated with latrunculin-A, outflow facility was significantly increased without serious adverse side effects. Mechanism seems to be destabilization of the actin filament network, decreasing outflow resistance.101 Another class of agents has been designed to degrade hyaluronic acid, which seems to improve aqueous outflow.102 Preliminary studies have been encouraging.

Several ocular hypotensive lipids are being actively investigated. One of these agents, AGN-192024 0.03%, used once daily was compared to latanoprost 0.005% once daily and found to offer at least equal efficacy in lowering IOP and

448 Principles and Complications of Medical Therapy of Glaucoma

better diurnal pressure control.103 The lipid was found to be well tolerated and safe, with the most common side effect being mild hyperemia.

Ethacrynic acid is a loop diuretic that has been under investigation in the treatment of glaucoma since the late 1980s.104 Studies have shown that it may increase outflow facility by creating changes in Schlemm’s canal that may be related to its inhibition of microtubule assembly. The initial study showed that it significantly increased outflow facility acutely in human cadaver eyes with no obvious toxic effects.104 A topical ethacrynic acid ointment was found to effectively lower IOP in monkeys by the fifth day, and its efficacy was similar to that of timolol 0.5%. Mild eyelid edema, conjunctival hyperemia, discharge, and one corneal erosion were noted.105 Introduction of the drug has been limited by its potential for local and systemic toxicity and short duration of action. The other agents have similar challenges and potential at this time.

What Is the Role of Calcium Channel Blockers

in the Treatment of Glaucoma?

Calcium channel blockers act by binding membrane-bound calcium channels and inhibiting the influx of calcium. These drugs have been under investigation for potential ophthalmic uses due to the interest in vasospasm in normal tension glaucoma and their ability to lower IOP. Studies have had variable results on the topical effects of verapamil, most demonstrating a significantly lower IOP.106,107 Topical administration was found to increase facility of outflow by 64%.106 However, an earlier study has shown that the topical use of nifedipine, diltiazem, and verapamil caused transient elevations of IOP in both humans and rabbits.108 The increase in IOP was found to be greater in rabbits than humans and may have been related to the detected increase in blood flow to the treated eye, causing a greater production of aqueous. Another investigator used a similar protocol with a much lower concentration of topical vera- pamil—0.125% versus 1 to 2%—and found a significant reduction in IOP.109 A biphasic response to verapamil may be present, and even with the smaller concentrations a contralateral effect was present. It remains clear that a more conclusive study needs to be performed before topical agents will have any role in the treatment of glaucoma.

Systemic administration of nifedipine showed improvement and stability in visual fields of some normal-tension glaucoma patients.110–112 One study demonstrated that normal-tension glaucoma patients had a much lower rate of progression on their visual fields—11% versus 56%—than controls not taking oral calcium channel blockers.110 Similarly, the treated low-tension glaucoma patients showed no progression of optic nerve damage compared to 44% who showed progression without the calcium channel blocker. No benefit was found in taking calcium channel blockers for open-angle glaucoma.110 One of the larger studies investigating calcium channel blockers found no benefit in visual field, IOP, or optic disc changes in 83 treated patients compared to a control group of patients.113 No detrimental side effects were noted.

A series has shown improvement of visual fields in patients taking systemic calcium channel blockers. Patients with normal-tension glaucoma felt to be associated with vasospasm tended to show improvement in visual field while taking calcium channel blockers.111 Vasospasm was determined by improved

cold recovery rate in peripheral vessels while on nifedipine. Focal defects were the least responsive. A study comparing repeat performance of visual fields and measured color vision found that some normal-tension glaucoma patients on calcium channel blockers had significant performance-corrected improvement.112 Another study failed to show uniform improvement in visual field tests, but noted significant improvement in contrast sensitivity in patients who showed improved retrobulbar blood flow with nimodipine administration.114 A newer calcium channel blocker, nilvadipine, has demonstrated potential for treatment in normal-tension glaucoma.115 It has the advantage of not lowering blood pressure in normotensive patients while increasing perfusion of the optic nerve, retina, and choroid in patients with normal-tension glaucoma. This study suggests that calcium channel blockers may be beneficial for a certain subgroup of normal-tension glaucoma patients. More conclusive and prospective studies are needed before calcium channel blockers are routinely applied to the treatment of patients.

What Has Generated All the Interest in Neuroprotection?

It is well known that even in spite of good treatment, IOP reduction, and compliance, many patients will go blind from glaucoma.116 This has created a desperate search for a better way to control the damage from glaucoma. Although the etiology of visual loss in glaucoma is multifactorial and not clear in many instances, ophthalmologists concur that it is caused by the death of retinal ganglion cells. Neuroprotection therapy could potential prevent visual loss in any glaucoma patient independent of which type of glaucoma the patient has.117

Areas of research include heat shock proteins,118 glutamate toxicity, and many others. Hyperthermia prior to ischemic exposure has been found to be neuroprotective in the rat model. Isolation of these protective substrates may yield a source of neuroprotective agents.118 Brimonidine has come into the limelight recently due to a study with axonal rat crush injury that demonstrated axons survived better when treated with brimonidine.119 Retinal ganglion cells and nerve fibers treated with brimonidine showed significantly less cell death than those treated with timolol or the saline control. Additionally, the neuroprotective effect was blocked by rauwolscine, the α2-adrenoreceptor antagonist.119 Additional studies have also shown that brimonidine was also protective against several other mechanisms of nerve injury including light stress, ischemia, and calibrated nerve compression.120 This is an actively researched area by the pharmaceutical company, but as of yet no clinically relevant studies have been completed and the information is only theoretical at this point.

N-methyl-D-aspartate (NMDA) receptor antagonists are thought to have therapeutic potential in numerous central nervous system disorders ranging from acute neurodegeneration, such as strokes and trauma, to chronic neurodegeneration, such as Parkinson’s disease.121 Memantine is felt to be one of the most well-tolerated drugs in this class. It has become of interest in treating glaucoma because it was shown to block toxicity caused by glutamate.122 Clinical studies using memantine to treat glaucoma are presently in progress. Investigators found that the NMDA antagonist eliprodil was protective against glutamate cytotoxicity in retinal neurons.123