Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

patients with bronchial asthma, a history of bronchial asthma, or severe COPD. It is contraindicated in patients with bradycardia or severe heart block and overt cardiac failure and in patients with hypersensitivity to any of its components. As with timolol, caution should be used when considering levobunolol therapy in patients with any significant sign, symptom, or history for which systemic beta-blockade would be medically unwise.

Betaxolol

Pharmacology

Betaxolol exhibits relative specificity for the β1-adreno- ceptor. At the ocular β2-adrenoceptor, betaxolol is nearly two orders of magnitude less potent than timolol. β1-Adrenoceptors are involved in cardiac rate, rhythm, and force; β2-adrenoceptors are involved in pulmonary function. However, β receptors are also present in the vascular system. Approximately 10% to 30% of the β-adrenoceptors in the mammalian cardiac ventricles are of the β2 subtype, but most of the β-adrenoceptors in the heart are of the β1 subtype. In human lung tissue, the ratio of β2-adrenoceptors to β1-adrenoceptors is 3 to 1. This distribution suggests that the role of the various adrenoceptor subtypes is probably more complex than generally thought. In addition, this means that agents that exhibit a wide separation of selectivity in preclinical experiments may be less tissue or organ selective in actual clinical use.

Clinical doses of oral betaxolol result in plasma levels of 10 to 40 ng/ml. Given topically, 0.5% betaxolol solution results in plasma levels of approximately 0.5 ng/ml, or half that of timolol 0.25%.

As with other β-blockers, the ocular hypotensive mechanism of betaxolol is a reduction in aqueous production. Although effective in reducing aqueous humor production, betaxolol is less effective than levobunolol or timolol. Both timolol and levobunolol are more effective ocular hypotensive agents than betaxolol by approximately 2 mm Hg in IOP control.

In the late 1990s several investigators demonstrated that, in addition to its ocular hypotensive effects, betaxolol has the ability to block sodium and calcium channels in both vascular tissue and retinal ganglion cells. Animal models have shown that betaxolol may protect critical nerve tissues against retinal ischemic insults.Vasodilatation of retinal and other ocular vascular beds appears to be mediated by betaxolol’s calcium channel blocking properties. Moreover, betaxolol inhibits glutamate-induced increases in intracellular calcium in rat retinal ganglion cells. These pharmacologic actions suggest that betaxolol may have potential as a neuroprotective agent in glaucoma patients by promoting ganglion cell survival after ischemic damage or elevated glutamate levels.

Clinical Uses

Topical betaxolol is indicated in the chronic treatment of ocular hypertension and open-angle glaucoma. Given its

relative cardioselectivity, it may be used successfully in patients with coexistent glaucoma and pulmonary disease. Note, however, that topical betaxolol may still elicit adverse cardiovascular and pulmonary effects.

Overall, the selection of betaxolol is a relative benefit- to-risk decision. In head-to-head studies against the noncardioselective agents, betaxolol is generally a less effective ocular hypotensive agent. From a safety perspective, however, betaxolol induces less systemic beta-blockade than these other agents. Although some evidence indicates that betaxolol may differ from timolol in its effects on visual field progression, no significant clinical advantage to betaxolol use has been demonstrated.

Betaxolol is less effective than timolol or levobunolol in preventing elevations in IOP after cataract surgery, especially when a viscoelastic agent is used. Thus, it is probably not the agent of choice for this indication.

Betaxolol is supplied as a sterile suspension of 0.25% betaxolol HCl (Betoptic-S). The suspension is a unique formulation containing a polyacrylic acid polymer (carbomer 934P) and a cationic exchange resin, which is believed to increase the drug residence time in the eye (see Chapter 2). This product is the racemic compound, preserved with 0.01% BAC, and approved for twice-daily use.

Side Effects

Ocular Effects. Ocular discomfort on topical instillation is the primary local effect associated with the 0.25% betaxolol suspension.

Systemic Effects. Systemic betaxolol has, on average, less effect in attenuating pulmonary function than do the noncardioselective agents.A significant clinical advantage of topical betaxolol in the treatment of elevated IOP is its much reduced potential for inhibiting pulmonary function (see Figure 10-7).This finding has been replicated in many studies and substantiates the relative safety of betaxolol in patients with coexistent pulmonary disease and glaucoma.

Thus, a key clinical advantage of betaxolol is in the treatment of patients with coexistent open-angle glaucoma and pulmonary disease. However, some pulmonary physicians strongly caution against the use of any β-blocker, irrespective of cardioselectivity or route of administration, in patients with existing respiratory disease.

The potential of betaxolol to elicit systemic β1-adreno- ceptor blockade has been investigated. In a study on resting cardiovascular function in older patients, topical instillation of timolol (0.25% and 0.5%), carteolol (1% and 2%), and metipranolol (0.3% and 0.6%) decreased mean heart rate 14% to 17%. However, topical betaxolol 0.5% did not have any significant effect. Some patients in all groups did exhibit a 15% to 20% reduction in systolic blood pressure. In a study of exercise-induced tachycardia in normal

152 CHAPTER 10 Ocular Hypotensive Drugs

volunteers, the maximal heart rate obtained on exercise decreased 9 bpm with topical timolol and 4 bpm with betaxolol. Other studies have shown that compared with a placebo, all β-blockers result in some degree of systemic beta-blockade, and the increasing order of potency is betaxolol (0.5%), metipranolol (0.6%), and timolol (0.5%). Patients who have various adverse experiences, such as dyspnea and bradycardia, with timolol may often successfully switch to betaxolol. Betaxolol therapy, however, may result in poorer control of IOP.

Although betaxolol generally elicits less systemic betablockade than do noncardioselective agents, it does cause undesirable systemic effects in some patients. Reported adverse experiences include congestive heart failure, myocardial infarction, respiratory difficulties strongly suggestive of obstructive airway disease, weakness with severe sinus bradycardia, and wheezing with objective reduction in pulmonary function.

The incidence of insomnia, depression, and diarrhea is less with betaxolol than with timolol.

Contraindications

Betaxolol is contraindicated in patients with sinus bradycardia, greater than first-degree atrioventricular block, cardiogenic shock, or overt cardiac failure. It is also contraindicated in patients with hypersensitivity to any of its components. As noted above, severe respiratory reactions have occurred, and the drug must therefore be used with caution in patients with asthma or COPD. Also, because minor changes in heart rate and blood pressure can occur, this agent must be used with caution, or avoided, in patients with a history of cardiac failure or heart block.

Metipranolol

Pharmacology

Like timolol and levobunolol, metipranolol is a noncardioselective β-blocker without significant local anesthetic activity or ISA. Metipranolol has been used worldwide, both orally in the treatment of systemic hypertension and topically for the treatment of elevated IOP.

Like levobunolol, metipranolol has an active metabo- lite,des-acetyl-metipranolol,which is an effective β-blocker. Metipranolol has been used in concentrations ranging from 0.1% to 0.6% and has ocular hypotensive efficacy within the range of other noncardioselective agents. As with other β-adrenoceptor antagonists, metipranolol decreases aqueous humor production. Retinal perfusion pressure and blood flow appear to increase during treatment with topical metipranolol.

Clinical Uses

Metipranolol is used for the chronic treatment of elevated IOP in ocular hypertension and open-angle glaucoma. Its utility in IOP elevations after laser or cataract surgery and its additivity with other ocular hypotensive agents have not yet been fully evaluated.

Metipranolol is available in the United States as OptiPranolol, a sterile ophthalmic solution of 0.3% racemic metipranolol HCl preserved with 0.004% BAC and approved for twice-daily use.

Side Effects

Ocular Effects. When given twice daily at the 0.6% strength to ocular hypertensive patients, metipranolol elicits greater discomfort than does levobunolol 0.5%. Metipranolol therapy has also been associated with allergic blepharoconjunctivitis or periorbital dermatitis similar to that reported for other ophthalmic β-blockers.

In 1990 approximately 50 cases of anterior uveitis were reported in the United Kingdom, where metipranolol had been available since 1986. At one hospital the incidence of uveitis in patients using 0.6% metipranolol was 14% (15 of 109). All cases resolved with appropriate management. Drug-induced anterior uveitis has also been reported as a rare event in the United States, but a true causal relationship has not been definitely established.

Systemic Effects. Based on its pharmacologic activity, metipranolol theoretically shares with timolol and levobunolol the same potential for systemic beta-blockade. However, several studies show that the β-adrenoceptor blockade elicited by topical metipranolol may be less than that observed with timolol but more than that observed with betaxolol.

Contraindications

The contraindications for metipranolol are the same as those for the other nonselective β-blockers.

Carteolol

Pharmacology

Carteolol is a noncardioselective β-blocker similar to timolol, levobunolol, and metipranolol.As with levobunolol and metipranolol, a primary metabolite of carteolol, 8-hydroxycarteolol, is also an ocular β-blocker. In contrast to other topical β-adrenoceptor antagonists, carteolol possesses intrinsic sympathomimetic ISA.The mechanism of carteolol’s ocular hypotensive effect is a reduction in aqueous humor production, without any apparent effect on outflow.

Several studies compared the ocular hypotensive efficacy of carteolol and timolol. In general, carteolol 1% demonstrates an ocular hypotensive effect similar to that of timolol maleate 0.5% solution (Figure 10-8). Carteolol is usually well tolerated, effective, and safe in patients who have been switched from other β-blockers.

Clinical Uses

Carteolol is used for the chronic treatment of elevated IOP in patients with ocular hypertension and open-angle glaucoma. Its ocular hypotensive effects are additive to

those of latanoprost, but its utility in IOP elevations after laser or cataract surgery and its additivity with other ocular hypotensive agents have not been fully evaluated.

Carteolol is supplied in the United States as Ocupress, a sterile ophthalmic solution of 1.0% racemic carteolol HCl, preserved with 0.005% BAC, and approved for twice-daily use.

Side Effects

Ocular Effects. Carteolol 1% is less irritating than 0.5% timolol. However, unlike other topical β-blockers, use of carteolol 1% can cause a moderate corneal anesthesia.

Systemic Effects. Although the ISA of carteolol might provide some reduced potential for systemic effects, carteolol theoretically shares with other noncardioselective β-blockers the same potential for systemic betablockade. When compared with timolol and levobunolol, carteolol appears to be similar in its reduction of mean heart rate. In asthmatics, carteolol has slightly less effect on mean forced expiratory volume in 1 second than does metipranolol. In elderly patients, carteolol has an effect on resting heart rate similar to that of timolol and metipranolol but greater than that of betaxolol. Carteolol causes significantly less nocturnal bradycardia than does timolol in patients with ocular hypertension or primary open-angle glaucoma. In contrast to topical timolol, changes in serum lipid levels, including highdensity lipoprotein cholesterol, appear to be negligible with carteolol.

Contraindications

The contraindications for carteolol are the same as for other nonselective β-blockers.

Choice of b-Blocker

Many factors must be considered in choosing an appropriate treatment regimen for glaucoma patients.

Although many β-blockers can be used interchangeably, some may be favored in selected patients.These choices are summarized in Table 10-3.

ADRENERGIC AGONISTS

Since the early 1920s, when epinephrine was applied topically to the eye to reduce IOP, several adrenergic agonists have proved useful as ocular hypotensive agents. Because of their relatively high potential for both ocular and systemic side effects, the nonselective α and β receptor agonists epinephrine and dipivefrin have been supplanted by the α2 receptor agonists apraclonidine and brimonidine. These agents are currently the adrenergic agonists of choice for glaucoma management.

α2 Receptor Agonists

α2 Receptors have been identified on presynaptic adrenergic nerve terminals and postjunctionally in the ciliary body. Activation of the presynaptic α2 receptors inhibits

Table 10-3

Selection of β-Blockers

neurotransmitter release. The amount of norepinephrine available for receptor activation, including postsynaptic β receptors on the ciliary epithelium, is decreased. Administration of α2 agonists lowers IOP in normal and glaucomatous eyes. At the cellular level, activation of the postsynaptic ciliary body α2 receptor reduces intracellular levels of cyclic adenosine monophosphate and may also affect other cellular pathways. Therefore aqueous production may be mediated via α2 receptor activity. The search for suitable α2 agonists for topical ocular use has resulted in the development of apraclonidine and brimonidine (Table 10-4).

Apraclonidine

Pharmacology

Apraclonidine, a relatively selective α2-adrenoceptor agonist, was developed as a derivative of the antihypertensive agent clonidine. Apraclonidine lowers IOP by decreasing aqueous production and enhancing uveoscleral outflow. It does not appear to enhance conventional trabecular outflow as measured by tonography. Apraclonidine may also have additional ocular hypotensive effects by influencing ocular blood flow. It can affect vascular tone because it also stimulates α1 receptors in vascular smooth muscle, causing vasoconstriction.

Apraclonidine lowers IOP in both normal volunteers and patients with elevated IOP. Within 1 hour of instillation, there is a significant drop in pressure that lasts about

12 hours.This initial effect has been attributed primarily to a decrease in aqueous flow. The peak effect occurs between 3 and 5 hours, lowering IOP by 30% to 40% at peak with a trough level of IOP reduction of 20% to 30%. Within 8 days of continuous apraclonidine treatment, the magnitude of aqueous flow reduction is diminished, whereas outflow facility appears to be significantly increased. When compared at 0.5% and 1.0% concentrations, apraclonidine produces the same percentage decrease in IOP regardless of the initial level of pressure (Figure 10-9). Most patients treated with apraclonidine show at least a 20% reduction from baseline pressures with the 0.5% or 1.0% solution. However, with chronic treatment tachyphylaxis often occurs, which manifests as a diminished ocular hypotensive effect. Moreover, patients often develop an ocular allergy that may warrant discontinuation of the drug.

Clinical Uses

When administered three times daily for 3 months, apraclonidine 0.5% has an ocular hypotensive effect comparable with that of timolol 0.5% administered twice daily. Age, race, and iris color do not seem to affect the ocular hypotensive response to apraclonidine.

Apraclonidine is commercially available as apraclonidine hydrochloride 0.5% and 1.0% (Iopidine), preserved with BAC 0.01%. The current labeled indications for the 1.0% concentration are control or prevention of postsurgical elevations in IOP after anterior segment laser surgery and for short-term IOP control in open-angle glaucoma before filtering procedures. Apraclonidine can also lower IOP in the initial treatment of acute angleclosure glaucoma (see Chapter 34).

Apraclonidine 0.5% can be used for short-term therapy of patients on maximally tolerated medical therapy who require additional reductions in IOP. Patients with primary or secondary glaucoma do not appear to differ in either the magnitude or duration of ocular hypotensive response, but patients with developmental or congenital glaucomas tend to respond less satisfactorily.

TIME (hr)

Figure 10-9 Mean intraocular pressure (IOP) for subjects with increased baseline IOP. Both 0.5% and 1.0% apraclonidine lowered IOP significantly more than did the placebo. There was no significant difference between 0.5% and 1.0% apraclonidine. Bars represent one standard error. (Reprinted with permission from Am J Ophthalmol 1989;108:230–237. Copyright by the Ophthalmic Publishing Company.)

Moreover, because of the development of tachyphylaxis, the benefit for most patients does not last more than several months.

An acute rise in IOP is a risk factor in laser iridotomy, trabeculoplasty, and posterior capsulotomy. Topical apraclonidine can significantly reduce both the incidence and magnitude of increases in IOP after anterior segment laser surgery. Apraclonidine 1.0% has also been used for prophylaxis of postcycloplegic spikes in IOP. In eyes with open-angle glaucoma dilated with tropicamide 1.0% and phenylephrine 2.5%, apraclonidine can both minimize the incidence of spiking and reduce the spike height.

To control or prevent postsurgical IOP elevations, one drop of the 1% concentration is instilled 1 hour before and a second drop immediately on completion of the laser procedure. As adjunctive therapy for patients with glaucoma inadequately controlled with otherwise maximal therapy, the 0.5% concentration is administered up to three times per day.

Side Effects

Common ocular side effects associated with topical apraclonidine include conjunctival blanching, eyelid retraction, and mydriasis. These effects are mediated via α1 receptor stimulation. Although it may be difficult to detect in bilaterally treated patients, conjunctival blanching is the most common side effect, occurring in approximately 85% of patients. However, rebound conjunctival hyperemia associated with other α1 receptor agonists does not appear to occur with topical administration. Pupillary dilation of less than 1 mm occurs in approximately 45% of eyes treated with 0.5% apraclonidine.The mydriasis has limited clinical significance. Patients sometimes report discomfort, burning, itching, dryness of the eyes, and blurred vision.

Ocular intolerance or allergy is a rare occurrence with short-term use but can be the most serious side effect in chronic therapy. The prevalence of symptoms of itching and conjunctival inflammation can average 20%, and increase to 50% with long-term use. Decreasing the concentration to 0.5% and the frequency of administration lowers the incidence of side effects. The symptoms usually resolve within 3 to 5 days after the medication is discontinued. It has been proposed that the mechanism underlying apraclonidine’s allergic response is drug oxidation and conjugation with thiols to form an apraclonidine– protein hapten that elicits the immune response.

The most common nonocular side effect associated with apraclonidine is a sensation of dry mouth or dry nose. These symptoms are dose related. Although the increased polarity of apraclonidine compared with clonidine reduces the drug’s potential for systemic absorption, cardiovascular, respiratory, and CNS effects can occur with topical application. However, in both normal volunteers and patients with elevated IOP, topical administration appears to cause only minimal effects on resting heart rate, arterial blood pressure, and respiration.

Fatigue or lethargy is the most frequently reported CNS effect.The incidence ranges between 5% and 15% in studies of 1-week duration. Other possible side effects include headache,sensation of head cold,chest heaviness,shortness of breath, sweaty palms, and taste abnormalities.

Contraindications

Apraclonidine is contraindicated in patients sensitive to clonidine and those taking monoamine oxidase inhibitors. Caution should be exercised in patients with severe cardiovascular disease, including hypertension.The possibility of vasovagal episodes exists during laser surgery, particularly in patients with a history of such events.

Brimonidine

Pharmacology

Brimonidine tartrate is a relatively potent and highly selective α2-adrenoceptor agonist. Radioligand binding studies indicate that brimonidine is about 30 times more selective for α2 receptors than is apraclonidine. Specific binding sites for brimonidine have been identified on human iris and ciliary epithelium, with a smaller number located on tissues of the retina, retinal pigment epithelium, and choroid. Studies in albino and pigmented rabbit eyes indicate that brimonidine binds to ocular melanin. Half-life calculations further suggest that the pigment acts as a drug reservoir, slowly releasing drug to the adjacent ocular sites.

After topical instillation, brimonidine penetrates into the aqueous humor and produces a dose-dependent reduction in IOP in both normal and glaucomatous eyes. Fluorophotometric studies suggest that brimonidine lowers IOP by a dual mechanism, involving a reduction of aqueous production and an increase in aqueous outflow via the uveoscleral pathway.The initial effect of brimonidine on IOP can be attributed to a decrease in aqueous flow. After 8 days, similar to apraclonidine, the initial effect is attenuated, and uveoscleral flow increases.

There is also evidence from animal models that brimonidine may provide neuroprotective properties that could spare retinal ganglion cells and the optic nerve. Using different models to achieve neuronal insult, including mechanical and acute retinal ischemic/reperfusion injury, brimonidine appears to protect the optic nerve and retinal ganglion cells from further degeneration.

Brimonidine also does not appear to alter retinal capillary blood flow or vasomotor activity of the anterior optic nerve. Measurements of blood flow velocities in central retinal, ophthalmic, nasal, and temporal posterior ciliary arteries do not change when 0.2% brimonidine is administered twice daily. When applied to human eyes, brimonidine appears to have little or no contralateral lowering effect on IOP.

Clinical Uses

For topical application to the eye, brimonidine is commercially available as a 0.2% formulation preserved

Mean IOP (mm Hg)

A

Mean IOP (mm Hg)

B

with 0.001% BAC and a 0.10% and 0.15% solution preserved with Purite (see Table 10-4). In patients with either open-angle glaucoma or ocular hypertension, an overall mean peak IOP reduction of 6.5 mm Hg from baseline values has been achieved with brimonidine 0.2%. The peak hypotensive effect occurs approximately 2 hours postdose and lasts up to 12 hours. Twice-daily dosing of brimonidine 0.15% with Purite has an ocular hypotensive effect equal to that of brimonidine 0.2% administered twice daily (Figure 10-10).

Brimonidine’s efficacy has been compared with that of prostaglandin analogues, topical CAIs, and β-blockers. Results in patients with glaucoma and ocular hypertension indicate that the peak ocular hypotensive effect of 0.2% brimonidine is comparable with that of 0.5% timolol (Figure 10-11).When dosed twice daily, 0.2% brimonidine is less effective than latanoprost 0.005% administered once daily. Brimonidine 0.15% with Purite is similar to dorzolamide 2% when used twice daily for treatment of primary open-angle glaucoma or ocular hypertension.

Brimonidine, like apraclonidine, is additive to other glaucoma medications. When used either as additive or replacement therapy, it can further lower IOP in patients inadequately controlled on one or more ocular hypotensive drugs. Brimonidine and latanoprost have an additive ocular hypotensive effect, further decreasing IOP approximately 3 mm Hg compared with that of latanoprost alone.

Studies have suggested that brimonidine 0.15% with Purite and dorzolamide 2%, each added to latanoprost, have similar ocular hypotensive efficacy in patients with primary open-angle glaucoma or ocular hypertension (Figure 10-12). Moreover, the combination of brimonidine 0.2% and latanoprost 0.005% provides IOP control superior to that of the fixed combination of

Figure 10-11 Effect of brimonidine 0.2% and timolol 0.5% at peak 2 hours after morning drug instillation. Asterisks indicate statistically lower intraocular pressure with brimonidine at week 1, week 2, month 3, and month 12. (Adapted from Katz LJ. Brimonidine tartrate 0.2% twice daily versus timolol 0.5% twice daily: 1-year results in glaucoma patients.Am J Ophthalmol 1999;127:20–26.)

timolol/dorzolamide (Cosopt). A fixed combination of brimonidine 0.2% and timolol 0.5% provides significantly better IOP control compared with either brimonidine or timolol used alone.

Brimonidine is as effective as apraclonidine in preventing or attenuating IOP spiking after argon laser trabeculoplasty,YAG laser posterior capsulotomy,and laser peripheral iridotomy procedures. Apraclonidine tends to dilate the pupil, whereas brimonidine tends to constrict the pupil.

In addition to its ocular hypotensive effect, brimonidine can be used to improve vision function under scotopic conditions in patients who have had refractive surgery. Brimonidine causes a significant miosis, greater under

6 hours. For postrefractive surgery patients who have difficulty with glare, halos, star bursts, or other nightvision symptoms associated with a large pupil, brimonidine can be instilled about 30 minutes before engaging in night vision activities such as driving. Repeated daily use should be avoided, however, because of the possibility of tachyphylaxis and rebound mydriasis.

The clinician should note that brimonidine may not consistently decrease IOP from untreated levels at 10 to 12 hours after dosing. Thus, the recommended dosage of brimonidine for patients with open-angle glaucoma or ocular hypertension is three times per day when used as monotherapy. However, twice-daily administration appears to be effective for many patients when brimonidine is used in combination with other ocular hypotensive agents.

Side Effects

mild to moderate and are similar with twice-daily and three-times-daily administration.The most frequent ocular adverse events are hyperemia, burning, stinging, blurred vision, and foreign body sensation. A slight miotic effect has also been observed, which does not appear to be accompanied by refractive changes nor by changes in anterior chamber depth or angle.

As with apraclonidine ocular allergic reactions, including blepharitis, blepharoconjunctivitis, and conjunctival follicles, have occurred with brimonidine. The incidence of allergy with brimonidine 0.2% ranges from 4.8% during 3 months of therapy to 9% over 12 months but is much lower than the range of 20% to 50% reported for apraclonidine 0.5% or 1.0% for similar time periods. Brimonidine, unlike apraclonidine, lacks the hydroquinone subunit and does not undergo thiol conjugation reactions. Brimonidine 0.15% with Purite has a significantly reduced incidence of allergic reactions compared with the 0.2% concentration.

Systemic effects associated with topical ocular brimonidine include dry mouth, headache, and fatigue or drowsiness. Dry mouth is generally the most common complaint, occurring in 16% to 30% of patients treated with brimonidine 0.2% twice daily. Other observed effects include decreases in systolic and diastolic blood pressure and heart rate, but these effects generally are clinically insignificant. Compared with β-blockers, brimonidine has excellent systemic tolerability and may be useful in elderly patients to improve quality of life and enhance patient satisfaction with glaucoma therapy.

Contraindications

Both local and systemic dose-related adverse events can occur with topical brimonidine.The effects are generally

Brimonidine is contraindicated in patients receiving monoamine oxidase inhibitors. It is not contraindicated

in patients with cardiopulmonary disease but should be used with caution in patients with severe cardiovascular disease. Although brimonidine is effective in lowering IOP in children, its use has been associated with excessive sleepiness, lethargy, and fatigue (Figure 10-13). This drug should be used with caution or avoided in young children, especially those weighing less than 20 kg and those younger than 6 years of age.

CARBONIC ANHYDRASE INHIBITORS

Mechanism of Action

Bicarbonate formation is an essential component of aqueous production. A relatively high concentration of bicarbonate can be found in the aqueous humor.The presence of carbonic anhydrase in the ciliary processes can also be

demonstrated in both animals and humans. The earliest reported ocular hypotensive properties of acetazolamide, a carbonic anhydrase inhibitor (CAI) demonstrated a decrease in IOP induced from inhibition of aqueous humor production. Other studies have confirmed these results with various CAIs commercially available for use in the treatment of all types of glaucoma.

All commercially available CAIs are unsubstituted aromatic sulfonamides (ARYL-SO2NH2). The resonating heterocyclic side group confers a high inhibitory activity to these agents.These compounds produce their primary pharmacologic effects through reversible noncompetitive binding with the enzyme carbonic anhydrase.

Carbonic anhydrase catalyzes the first step (I) in the following reaction:

III

CO2 + H2O H2CO3 H+ + HCO3−

Reaction II is an ionic dissociation reaction that occurs very rapidly and is not under enzymatic control. Therefore carbonic anhydrase catalyzes the cellular production of H2CO3 and thus the formation of H+ and HCO3−. Although body tissues contain several isoenzymes of carbonic anhydrase, the C-type, sulfonamide-sensitive carbonic anhydrase (also known as type II), is the predominant isoenzyme in the human ciliary processes.

Inhibition of carbonic anhydrase activity in the ciliary processes is probably the mechanism responsible for decreased aqueous formation produced by CAIs. The production of bicarbonate in the ciliary epithelium appears to play a key role in the formation of aqueous humor. Bicarbonate is the key anion associated with the decrease in aqueous formation produced by inhibition of carbonic anhydrase.

Inhibition of carbonic anhydrase also decreases sodium entry into the posterior chamber. Sodium, transported by Na+-K+-adenosine triphosphatase, probably acts as the counter-ion for newly formed bicarbonate. These two ions are linked such that inhibition of either carbonic anhydrase or Na+-K+-adenosine triphosphatase reduces sodium movement into the posterior chamber.

Fluid movement from the stroma of the ciliary processes into the posterior chamber requires the transepithelial movement of several ions. Assuming that Na+, HCO3−, and Cl– are the major ions involved in secretion, Figure 10-14 illustrates how these ions may function in fluid movement across the nonpigmented ciliary epithelium and into the posterior chamber. Inhibition of carbonic anhydrase in the ciliary processes decreases bicarbonate, sodium, and fluid movement into the posterior chamber, with the net result being decreased aqueous humor formation.

It was initially believed that the reduction of IOP produced by the systemic CAIs was attributed in part to the accompanying metabolic acidosis that occurs secondary to

the renal effects of these agents. However,since those initial reports, it does not appear that the metabolic acidosis from CAIs influences IOP.

Most tissues contain carbonic anhydrase in quantities that exceed physiologic requirements. Because of this excess, at least 99% of carbonic anhydrase activity must be inhibited to depress aqueous production significantly. Drug levels sufficient to reduce aqueous humor formation are readily achieved after systemic and topical administration of CAIs. However, systemic use has the disadvantage of significantly inhibiting the activity of carbonic anhydrase throughout the body.

Of the currently available CAIs (Table 10-5), acetazolamide is the prototype drug and has been studied extensively. Other agents within this class include methazolamide and dichlorphenamide. Systemic administration of any of these agents produces a 45% to 55% inhibition of aqueous formation in humans.

Acetazolamide

Pharmacology

In the treatment of all types of glaucoma, acetazolamide is the most widely used orally administered CAI. Acetazolamide is commercially available as 125and 250-mg tablets, 500-mg sustained-release capsules (Diamox Sequels), and a 500-mg vial formulated for parenteral administration. In glaucoma therapy in adults, acetazolamide is usually administered in doses of 250 mg every 6 hours or a single 500-mg sustained-release capsule twice daily. The recommended acetazolamide dose for children is 5 to 10 mg/kg body weight, administered every 4 to 6 hours.

Acetazolamide is readily absorbed from the gastrointestinal tract after oral administration. After ingestion of acetazolamide tablets, the drug attains peak plasma levels within 2 to 4 hours. Peak levels are maintained for 4 to 6 hours. Drug levels are higher after acetazolamide tablets are ingested than after an equivalent dose of the sustained-release formulation. The time-release capsules produce maximum drug levels in 3 to 4 hours, and levels of 10 mg/ml are maintained for approximately 10 hours.

The time course of acetazolamide’s ocular hypotensive effect parallels its plasma concentration. Oral acetazolamide tablets, in dosages greater than 63 mg, produce a significant ocular hypotensive response within 2 hours, and the effects last beyond 6 hours (Table 10-6). The ocular hypotensive effect of the sustained-release capsules begins within 2 hours, and the maximum reduction in IOP occurs 6 to 18 hours after oral administration.

Although a 500-mg capsule administered once daily produces a substantial decrease in IOP lasting at least 24 hours, the magnitude of the pressure drop is greater when the drug is administered twice daily. The sustainedrelease capsules, administered in dosages of 500 mg twice daily, are as effective in reducing IOP as are 250-mg acetazolamide tablets administered every 6 hours.

Plasma levels sufficient to decrease IOP occur only minutes after intravenous administration of acetazolamide, but this route of administration is generally reserved for situations, such as in acute angle-closure glaucoma, when vomiting precludes the oral route. The duration of action of acetazolamide after intravenous administration is approximately 4 hours.

In humans, 90% to 95% of acetazolamide in the blood binds to plasma proteins. Therefore relatively large dosages of acetazolamide are required to produce a significant plasma level of the unbound drug. At plasma pH (7.4), half the unbound acetazolamide (pKa = 7.4) exists in the un-ionized form, which is the form that penetrates tissues and inhibits carbonic anhydrase.

Acetazolamide is not metabolized; it is excreted, primarily by tubular secretion, into the urine. Because of its action on the kidney, acetazolamide increases urinary excretion of HCO3– and produces an alkaline urine. This alteration of urinary pH favors excretion of acetazolamide, because more drug exists in the water-soluble, ionized form.

Clinical Uses

In the treatment of elevated IOP, oral acetazolamide is often reserved for short-term IOP reduction only. The development of topical dosage forms of CAIs and the availability of safer ocular hypotensive agents provide a more attractive therapeutic alternative for long-term administration. Acetazolamide produces an additional decrease in IOP when added to drug regimens including miotics, β-blockers, and prostaglandins.

Although both timolol and acetazolamide inhibit aqueous formation, concurrent administration of these agents produces a nearly additive effect on IOP. In contrast to timolol, which has no significant effect on aqueous flow in sleeping humans, acetazolamide reduces aqueous flow during sleep. In humans, the aqueous flow rate normally decreases approximately 60% during sleep.Acetazolamide suppresses aqueous flow an additional 24% below the nocturnal flow rate.

In acute angle-closure glaucoma, acetazolamide is often administered soon after the diagnosis is made. Use of acetazolamide in the management of acute angle-closure