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

Epidemiology and Importance

How Important Is Compliance?

Several studies have attributed a considerable amount of visual loss to noncompliance, which may make it a leading preventable cause of blindness from glaucoma.1,2 One analysis in an urban setting indicated that 80% of visual loss in glaucoma occurred prior to presenting for diagnosis and treatment. Another 10% occurred as a result of noncompliance.2 Improper compliance with nearly all types of medications seems to occur about 50% of the time.3 Thus, a large proportion of the potentially preventable visual loss occurs as a result of noncompliance, which includes patients not filling prescriptions, as well as the improper use of medications, such as not taking them continually, discontinuing them prematurely, or taking them inappropriately. Compliance studies have consistently documented this problem. One population-based study found that administration errors precluded optimal response to therapy about 60% of the time.4 The most significant errors in taking medications occur about 40% of the time due to failure to fill the medication prescription, not taking it continually, or stopping altogether.4 The errors occurred due to a lack of patient comprehension, inadequate education, and improper prescription writing and labeling by physicians and pharmacists.

Diagnosis and Differential Diagnosis

Are Physicians Able to Judge the Compliance of Their Patients?

Most physicians assume that they have a fairly good idea about how well patients are complying by knowing them, interviewing them, and through experience. Studies have shown, however, that the doctor’s judgment of patient compliance is about the same as chance. Some 30 to 50% of patients knowingly omit doses of their medications, but not all of them will admit it to their doctor. A study of chronically used medications demonstrated that doctors overestimated their patients’ adherence to the regimen by about 50%, and patients’ overstated their adherence by about 100%.5 A study looking specifically at the compliance with topical pilocarpine using an electronic eye-drop monitor revealed a mean compliance rate of 76% [standard deviation (SD) = 24.3%].6 Based on interview, the patients stated they had taken 97.1% (SD = 5.9%) of the prescribed doses, with the highest rate of actual compliance being the 24 hours prior to their return appointment. Clinician experience and patient demographics seemed to have little impact on these estimates. In fact, one study showed that the more senior a physician, the more likely he is to overestimate compliance.7 A study in an ophthalmology residents’ clinic for compliance with follow-up of patients found that many reasons exist for noncompliance, but the only modifiable step was to decrease the length of the wait in the doctor’s office.8 Noncompliant patients are more likely to be glaucoma suspects and not on any medications. Several reasons for dissatisfaction in study patients were present including insurance, transportation problems and fear—the only thing a doctor’s office can modify is waiting time and efficiency of appointment. Eye care providers must accept that they may never really know what medications a patient is using.

432 Principles and Complications of Medical Therapy of Glaucoma

Treatment and Management

How Can an Eye Care Provider Improve Patient

Compliance?

Patients who understand their disease and have realistic expectations of their doctor and treatment regimen tend to be more compliant and have greater satisfaction with their health care.3 Careful and frequent supervision is associated with better compliance. Psychological and emotional issues play a larger role in determining compliance than demographic factors. Regular contact with the doctor improves compliance, as does effective communication between the two.9

With the glaucoma patient, the physician should keep the treatment as minimal as possible. Each time a new medication is started, a one-eye trial should be performed. Each medication has about an 80% chance of succeeding in a given patient. Wide diurnal variations of pressure preclude starting a drop in both eyes, as one may mistakenly judge an intraocular pressure (IOP) decrease to be a successful trial when it is in fact only a diurnal variation. Eyes tend to vary their pressure in a symmetric manner, so if a drop is put in just one eye, the physician then has a frame of reference in the contralateral eye that has not had a treatment change.

The physician should instruct patients to instill eye drops at times each day when they have other routine things to do, such as eating meals or brushing teeth. Giving the patients two sets of drops, to keep at home and at work, may also be helpful. Schedules arranged by color-coding can help simplify a regimen that might otherwise be too confusing for a patient to follow. If the patient is unable to instill the drops, the help of family members should be enlisted or an instillation device used. A study determined that eye care providers can maximize compliance by instructing the patient how to instill the drops, observing the patient administering the drop, and using combination drops whenever possible.10

What Are the Possible Ways the Conjunctiva Can React to a Topical Medication?

The effects of medications on the conjunctiva are a concern for patient comfort and the potential success of filtration surgery in the future. Medications may cause cicatrizing conjunctivitis, allergic (acute or chronic) conjunctivitis, toxic conjunctivitis (pH, tonicity, contaminants), cumulative deposition as in adrenochrome deposits, microbial imbalance, nonspecific irritation, and other subclinical cellular and ultrastructural changes.11

What Should be Done to Help Patients Reduce

Their Side Effects from Any of These Medications?

Nasolacrimal duct occlusion and eyelid closure are well-established ways to increase ocular absorption while decreasing absorption into the blood.12,13 The ocular hypotensive effects of pilocarpine, timolol, and carbachol were increased by nasolacrimal occlusion, allowing half the concentration to be used as well as less frequent application.13 At the very least, patients should close their eyes for 1 minute after the drop is instilled. The most optimal application

of drops would be nasolacrimal duct occlusion combined with eyelid closure for 5 minutes, but most patients find it difficult to sustain eyelid closure for 5 minutes, so 3 minutes is a good compromise. Patients taking timolol reduced serum levels by 65% with eyelid closure and 67% with nasolacrimal duct occlusion.14 Another study showed that nasolacrimal duct occlusion reduced blood levels of timolol by 71%.12 Fluorescein concentration was increased by 69% in the anterior chamber by nasolacrimal duct occlusion, and lid closure alone increased it by 46%, indicating that these methods increase the concentration of the medication in the eye while decreasing the amount of drug delivered to the nasal mucosa.14

How Do Beta-Blockers Lower IOP?

β-Adrenergic antagonists reduce the production of aqueous humor. β- Adrenergic receptors have been found on the iris, ciliary body, and trabecular meshwork. A plausible theory on the mechanism of action is that beta-blockade reduces the adenylyl cyclase activity, which reduces aqueous production.15

What Are the Differences Between the Beta-Blockers?

The nonselective beta-blockers are timolol maleate, timolol hemihydrate, carteolol, levobunolol, and metipranolol. Timolol maleate is also available in a solution that forms a gel in the eye after applying. The gel maintains the medication in contact with the eye for a longer period of time and may increase efficacy and lower side effects.16 However, a study comparing the systemic effects of once daily timolol hemihydrate and timolol gel-forming solution demonstrated that there was no significant difference in IOP reduction or in systemic beta-blockade between the two medications.17 Levobunolol has the longest half-life. Metipranolol is similarly effective, although clinicians need to be aware of the reports of granulomatous uveitis in patients treated with this drug.18,19 Carteolol may have some different pharmacologic features from the other beta-blocker because of its intrinsic sympathomimetic activity, although clinical studies have not yet demonstrated this.20

Betaxolol is cardioselective by minimizing β2-inhibition. Betaxolol 0.5% stings when applied, so a 0.25% suspension was developed for comfort, and it is equally efficacious.21 The suspension is thought to slow the delivery and enable a lower concentration to be used, lessening the local irritation produced by a bolus delivery of betaxolol. Most studies have found betaxolol to be less effective than timolol and levobunolol.22,23 Timolol 0.5% lowered IOP an average of 29% compared to 26% for betaxolol 0.5%; levobunolol lowered the IOP by 6.2 mm Hg compared to 3.7 mm Hg for betaxolol 0.5% in patients with an average baseline IOP of 25 mm Hg. Betaxolol is safer to use in patients with pulmonary disease, although it may still provoke asthma.24

Daily cost of β-adrenergic therapy should also be a consideration. A comparison of drop size, cost, and wasted medication found that generic timolol maleate and Betimol were the least expensive, at 55 and 57 cents per drop, respectively. Betoptic-S and Betagan were the most costly, at $1.60 and $1.35, respectively. Timopticxe had the largest drop volume (49 µL), whereas Ocupress (31 µL) had the smallest.25

What Happens When Systemic and Topical

Beta-Blockers Are Used at the Same Time?

All of the side effects of the topical beta-blockers may be exacerbated. It is important to remember that systemic administration of beta-blockers lowers IOP, and that topical administration is often less efficacious when these agents are taken orally.34 Special consideration must always be given to the cardiopulmonary status of any patient on topical and systemic beta-blockers concomitantly.

What About the Effects of Beta-Blockers on Blood Lipid Profiles?

Nonselective beta-blockers have been shown to unfavorably affect the lipid profile by reducing high-density lipoprotein (HDL) levels and increasing triglycerides35; at present there is no evidence to indicate that these changes affect the clinical outcome of the patient. Carteolol may have a slight advantage over other beta-blockers in that one study demonstrated a 3.3% reduction of HDL compared to an 8% reduction with timolol.35 The 58 healthy males in this study also showed a 4.0% increase in the total cholesterol (TC) to HDL ratio while taking carteolol, and a 10.0% increase in this ratio while on timolol 0.5%. The drugs were taken twice a day with no nasolacrimal duct occlusion. A recent 12-week study compared timolol 0.5% twice daily to carteolol 1% twice daily in women over 60 with open-angle glaucoma or ocular hypertension. The investigators found no change in HDL and TC/HDL while the patients were on carteolol, but found a decrease of HDL and an adverse effect on TC/HDL while the patients were on timolol.17 This may be due to the intrinsic sympathomimetic activity of carteolol. Although the studies are still considered preliminary, some ophthalmologists prefer carteolol to other beta-blockers in patients with unfavorable lipid profiles.

What About Patients Being Treated for Diabetes?

Adult-onset diabetes is an important risk factor in treating glaucoma. With multiple medical regimens for a patient to follow, compliance will become even more difficult, increasing the likelihood of complications. One of the most important complications of diabetic treatment is hypoglycemia. Beta-blockers can blunt or mask the symptoms of hypoglycemia, lower blood sugar, and delay recovery.32

Are There Other Systemic Medications to Keep in Mind

When Treating a Patient with a Topical Beta-Blocker?

Hormonal replacement therapy in women may increase headache when used with a beta-blocker. Some beta-blockers have shown increased effect when used concomitantly.16 Aspirin and nonsteroidal antiinflammatory drugs can decrease the effect of beta-blockers. A patient treated with thyroid hormonal supplementation and converted to an euthyroid state may have a reduced effect of the beta-blocker.

436 Principles and Complications of Medical Therapy of Glaucoma

How Do Carbonic Anhydrase Inhibitors Work?

They primarily work to decrease aqueous humor production by inhibiting the formation of bicarbonate in the ciliary processes, which is linked to sodium secretion to form aqueous. Systemic acidosis decreases aqueous formation, and although oral carbonic anhydrase inhibitors create a metabolic acidosis, it is unclear what amount of reduction in aqueous production this may cause.36

What Are the Different Carbonic

Anhydrase Inhibitors Available?

Oral and topical carbonic anhydrase inhibitors are used to treat glaucoma. The oral agents that have been used in the chronic treatment of glaucoma include acetazolamide, methazolamide, ethoxzolamide (no longer available), and dichlorphenamide. Topical agents include dorzolamide and brinzolamide.

Acetazolamide is available in tablets, and is generally taken in doses of 125 to 250 mg four times a day. A twice-a-day slow-release capsule (Diamox Sequel 500 mg) is available. Methazolamide is available in 25and 50-mg 50-tablets and administration is two or three times a day, up to 100 mg three times a day. Its half-life is 14 hours compared to 5 hours for acetazolamide. It produces less metabolic acidosis and fewer side effects compared to acetazolamide tablets, but is slightly less efficacious.37 One study showed a greater tolerance for Sequel compared to methazolamide.38 Dichlorphenamide has similar or perhaps greater efficacy at 25 to 50 mg up to three times a day, but is less well tolerated.38 The investigators in this study questioned whether maximal efficacy is associated with more severe side effects, which may indicate more extensive biochemical alterations from the medication.

Dorzolamide 2% was the first topical agent available, with brinzolamide 1% recently becoming available (used two to three times a day).

How Well Do the Topical Carbonic Anhydrase

Inhibitors Work Compared to Timolol?

Dorzolamide 2% three times a day reduced the IOP by 22% at peak and 18% at trough.39 A 12-month double-masked study comparing timolol maleate 0.5% and betaxolol 0.5% twice daily and dorzolamide 2% three times daily found that peak IOP reduction measured 2 hours after instillation was not statistically different between the three medications.40 The trough IOP at 5 and 8 hours after instillation revealed that timolol’s IOP reduction was significantly better than betaxolol and brinzolamide, although the trough IOPs of the latter two were not significantly different from one another. Brinzolamide 1% administered twice and three times daily was compared to dorzolamide 2.0% three times daily and timolol maleate 0.5% twice daily.41 In both dosing regimens brinzolamide was statistically equivalent to dorzolamide thrice daily, although neither of the drugs was as effective as timolol.

How Well Does Dorzolamide Work

with Timolol, Now that the New Timolol/Dorzolamide Combination Drop has Become Available?

Aqueous flow reduction was found to be 18% for dorzolamide alone and 47% for timolol alone, and that the two used together were nearly completely additive at 55%.42 Note that in this study the aqueous inhibitory affect of timolol was 2.6 times as great as dorzolamide. The Dorzolamide Timolol Study found that the combination drop was comparable to timolol 0.5% twice a day and dorzolamide 2.0% three times in efficacy and tolerability.43 The study did find that the group of patients taking the timolol 0.5% twice a day and dorzolamide 2.0% three times a day had a slightly lower IOP in the early morning and the greatest IOP difference at hour 8, which was 2 hours after the midday dose of dorzolamide. The slightly lower IOP in the morning and afternoon are small and not thought to be significant. Other studies have shown that dorzolamide is additive to other aqueous suppressants that have been in previous long-term use by patients prior to instituting treatment with dorzolamide.44

Are Topical Agents as Effective

as Oral Agents?

From anecdotal evidence, many physicians have felt that the topical agents are not as effective as oral agents, and the answers in the literature are still not clear. Some studies have shown that the agents are equally effective. Eyes treated with dorzolamide 2.0% three times a day were compared to those treated with acetazolamide 250 mg four times a day and were found to have similar reductions in aqueous humor formation and IOP.45 Also, the previous study did not demonstrate a further reduction in IOP when dorzolamide was added to patients on acetazolamide and vice versa, concluding that they are not addictive. A different study has demonstrated that dorzolamide reduced aqueous production by 17%, whereas acetazolamide reduced it by 30%. Adding acetazolamide to dorzolamide-treated eyes reduced aqueous production by an additional 16%.46 A single dose of dorzolamide was found to have a comparable high efficacy to a single dose of acetazolamide 125 mg in preventing pressure spikes following yttrium-aluminum-garnet (YAG) posterior capsulotomy.47 Other studies have shown that there is not a significant benefit when adding acetazolamide to an eye already treated with topical carbonic anhydrase inhibitors, and they are equally efficacious in eyes already on maximal medical therapy.48

Does Dorzolamide Have Any Influence on Visual Function?

Normal-tension glaucoma patients placed on dorzolamide had improved contrast sensitivity after 2 to 4 weeks of treatment compared to controls who received placebo.49 Patients were also found to have accelerated arteriovenous passage time, but no change in blood flow in retrobulbar vessels.

438 Principles and Complications of Medical Therapy of Glaucoma

How Does Dorzolamide Compare to the More Recently

Released Brinzolamide?

Brinzolamide 1% twice daily and brinzolamide 1% three times daily were found to be equally efficacious to one another and to dorzolamide three times daily.41 Ocular complaints were significantly less with brinzolamide, with only 2 to 3% complaining of ocular discomfort compared to 16.4% taking dorzolamide.41 Brinzolamide has a more physiologic pH, requiring it to be delivered as a suspension, compared to dorzolamide, which is more acidic but is delivered as a solution.

What Are the Side Effects

of Carbonic Anhydrase Inhibitors?

Fortunately, the most common side effects are the most benign, albeit annoying. Most patients experience transient paresthesias, urinary frequency, and a metallic taste. Other annoying side effects, such as diarrhea, fatigue, malaise, nausea, renal colic, decreased libido, abdominal pain, and depression, may continue throughout the course of treatment. More serious side effects include renal stone formation, hirsutism, and the most rare but dreaded bone marrow suppression.32 Serious and near-fatal complications such as Stevens-Johnson syndrome can occur after even one dose of an oral carbonic anhydrase inhibitor, such as after a cataract surgery or laser procedure when a single dose may be given, even when no sulfa allergy is present.50 The agents all include a sulfonamide group on their ring structure, so sulfa allergy is a contraindication. All of these side effects are much less common, but possible, with topically applied carbonic anhydrase inhibitors. During clinical trials with dorzolamide, urinary and hematologic tests were routinely performed and did not find any disturbances.51 This study suggests that the systemic inhibition of carbonic anhydrase is insufficient to produce biochemical adverse effects. Five percent of patients discontinue topical carbonic anhydrase inhibitors due to adverse reactions, most of which are ocular.

Many systemic drug interactions occur with carbonic anhydrase inhibitors and some important interactions to keep in mind are described below.

What Are Some Concerns When a Patient

on Carbonic Anhydrase Inhibitors Is Being Treated with Calcium Channel Blockers?

The side effects of nausea and/or vomiting and malaise may become worse. Both of these drugs can cause paresthesias.

Is Concomitant Use of Carbonic Anhydrase Inhibitors and Diuretics a Special Concern?

Both drugs can lead to hypokalemia, which makes the adverse effects of carbonic anhydrase inhibitors worse and also causes a greater chance of toxicity from cardiac glycosides.32 The chance of developing agranulocytosis is greater when they are used together.