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

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185.Hesse RJ, Swan JL II. Aphakic cystoid macular edema secondary to betaxolol therapy. Ophthalmic Surg. 1988;19(8):562-564.

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192.Passo MS, Palmer EA, Van Buskirk EM. Plasma timolol in glaucoma patients. Ophthalmology. 1984;91(11):1361-1363.

193.Ohdo S, Grass GM, Lee VH. Improving the ocular to systemic ratio of topical timolol by varying the dosing time. Invest Ophthalmol Vis Sci. 1991;32(10):2790-2798.

194.Vuori ML, Ali-Melkkila T, Kaila T, et al. Plasma and aqueous humour concentrations and systemic effects of topical betaxolol and timolol in man. Acta Ophthalmol (Copenh). 1993;71(2):201-206.

195.Le Jeunne C, Munera Y, Hugues FC. Systemic effects of three beta-blocker eyedrops: comparison in healthy volunteers of beta 1- and beta 2-adrenoreceptor inhibition. Clin Pharmacol Ther. 1990;47 (5):578-583.

196.Caprioli J, Sears ML. Caution on the preoperative use of topical timolol. Am J Ophthalmol. 1983;95(4):561-562.

197.Doyle WJ, Weber PA, Meeks RH. Effect of topical timolol maleate on exercise performance. Arch Ophthalmol. 1984;102(10):1517-1518.

198.Leier CV, Baker ND, Weber PA. Cardiovascular effects of ophthalmic timolol. Ann Intern Med. 1986;104(2):197-199.

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201.Pringle SD, MacEwen CJ. Severe bradycardia due to interaction of timolol eye drops and verapamil. Br Med J (Clin Res Ed). 1987;294(6565):155-156.

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203.Zabel RW, MacDonald IM. Sinus arrest associated with betaxolol ophthalmic drops. Am J Ophthalmol. 1987;104(4):431.

204.Ball S. Congestive heart failure from betaxolol. Case report. Arch Ophthalmol. 1987;105(3):320.

205.Pinski SL. Continuing progress in the treatment of severe congestive heart failure. JAMA. 2003;289(6):754-756.

206.Jones FL Jr, Ekberg NL. Exacerbation of asthma by timolol. N Engl J Med. 1979;301(5):270.

207.Avorn J, Glynn RJ, Gurwitz JH, et al. Adverse pulmonary effects of topical beta blockers used in the treatment of glaucoma. J Glaucoma. 1993;2:158.

208.Van Buskirk EM, Fraunfelder FT. Ocular beta-blockers and systemic effects. Am J Ophthalmol. 1984;98(5):623-624.

209.Lustgarten JS, Podos SM. Topical timolol and the nursing mother. Arch Ophthalmol. 1983;101 (9):1381-1382.

210.Coyle J. Timoptic and depression. J Ocul Ther Surg. 1983;2(6):311.

211.Orlando RG. Clinical depression associated with betaxolol. Am J Ophthalmol. 1986;102(2):275.

212.Coleman AL, Diehl DL, Jampel HD, et al. Topical timolol decreases plasma high-density lipoprotein cholesterol level. Arch Ophthalmol. 1990;108(9):1260-1263.

213.West J, Longstaff S. Topical timolol and serum lipoproteins. Br J Ophthalmol. 1990;74(11):663-

214.Fraunfelder FT. Interim report: National Registry of Possible Drug-induced Ocular Side Effects. Ophthalmology. 1980;87(2):87-90.

215.Fraunfelder FT, Meyer SM, Menacker SJ. Alopecia possibly secondary to topical ophthalmic betablockers. JAMA. 1990;263(11):1493-1494.

216.Shaivitz SA. Timolol and myasthenia gravis. JAMA. 1979;242(15):1611-1612.

217.Velde TM, Kaiser FE. Ophthalmic timolol treatment causing altered hypoglycemic response in a diabetic patient. Arch Intern Med. 1983; 143(8):1627.

218.Wikberg-Matsson A, Uhlen S, Wikberg JE. Characterization of alpha(1)-adrenoceptor subtypes in the eye. Exp Eye Res. 2000;70(1):51-60.

219.Moroi SE, Hao Y, Inoue-Matsuhisa E, et al. Cell signaling in bovine ciliary epithelial organ culture. J Ocul Pharmacol Ther. 2000;16(1):65-74.

220.Wand M, Grant WM. Thymoxamine hydrochloride: an alpha-adrenergic blocker. Surv Ophthalmol. 1980;25(2):75-84.

221.Wand M, Grant WM. Thymoxamine hydrochloride: effects on the facility of outflow and intraocular pressure. Invest Ophthalmol 1976;15(5):400-403.

222.Lee DA, Brubaker RF, Nagataki S. Effect of thymoxamine on aqueous humor formation in the normal human eye as measured by fluorophotometry Invest Ophthalmol Vis Sci. 1981;21(6):805-811.

223.Relf SJ, Gharagozloo NZ, Skuta GL, et al. Thymoxamine reverses phenylephrine-induced mydriasis. Am J Ophthalmol. 1988; 106(3):251-255.

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Shields > SECTION III - Management of Glaucoma >

30 - Adrenergic Stimulators

Authors: Allingham, R. Rand

Title: Shields Textbook of Glaucoma, 6th Edition Copyright ©2011 Lippincott Williams & Wilkins

> Table of Contents > SECTION III - Management of Glaucoma > 30 - Adrenergic Stimulators 30

Adrenergic Stimulators

Like the ß-adrenergic receptors, the a-adrenergic r eceptors are part of the sympathetic nervous system that play a major role to regulate in part aqueous humor dynamics (see Chapter 1). Development of this class of glaucoma medications was based on the observation that a topical formulation of the antihypertensive agent clonidine lowered intraocular pressure (IOP) (1). The clinical value of clonidine as an ocular hypotensive agent was limited by the fact that it penetrates the blood-brain barrier, occasionally causing significant systemic hypotensive episodes, even with topical administration. Further research led to the approval of several a2-adrenergic agonists for use in managing glaucoma.

The nonselective a- and ß- adrenergic receptor agon ists epinephrine and the prodrug dipivefrin are no longer available but are summarized in this chapter for historical reasons.

MECHANISMS OF ACTION

The mechanism of action by which apraclonidine, clonidine, and brimonidine tartrate lower IOP is through reducing aqueous production (2). These agents have little, if any, effect on blood-aqueous barrier permeability (3). In one clinical trial, there was also a suggestion that apraclonidine may increase outflow facility and reduce episcleral venous pressure (4). Given the presence of a2A-adrenergic

receptors in cultured human trabecular meshwork cells (5), these agents may exert some effect on outflow facility. In contrast, brimonidine does not appear to have an effect on conventional aqueous humor outflow or epi-scleral venous pressure, but it increases uveoscleral outflow (6).

Another possible mechanism may involve an increase in prostaglandin levels. However, in studies involving healthy volunteers and patients with either ocular hypertension or glaucoma, pretreatment with flurbiprofen had no influenc on the IOP-lowering effect of apraclonidine (7, 8).

Epinephrine, a neurohumoral transmitter, and norepinephrine, a neurotransmitter, stimulate adrenergic receptors and mediate the physiologic sympathetic actions on aqueous humor dynamics. Early studies of epinephrine and the prodrug dipivefrin showed multiple effects on aqueous humor dynamics. The effects of epinephrine have been described in three phases. In the early phase, within minutes after instillation of epinephrine, aqueous inflow is reduced, presumably due to the a-adrenergic effect of vasoconstriction, which reduces the ultrafiltration of plasma into the stroma of the ciliary processes (9). This a-adrenergic effect on aqueous production, however, is transient and not of sufficient magnitude to significantly influence IOP. The middle phase overlaps with the first phase and is believed to be an early, moderate-sized a-adrenergic effect on true outflow facility. Fluorophotometric and tonographic studies in healthy (10, 11) and ocular hypertensive human eyes suggest that IOP reduction for at least

the first several hours after topical instillation of epinephrine is associated with improved facility of outflow (12). The late phase is believed to occur weeks to months after continued administration of epinephrine. The mechanism is thought to be related to metabolism of glycosaminoglycans in the trabecular meshwork (13).

SPECIFIC AGENTS Apraclonidine

Apraclonidine is a para-amino derivative of clonidine, an a2-adrenergic agonist that is used clinically as

a potent systemic antihypertensive agent. Topical apraclonidine hydrochloride is available in a 1% concentration for the treatment of short-term IOP elevation, especially after anterior segment laser procedures, and in a 0.5% preparation for the long-term management of glaucoma. In a 90-day study comparing apraclonidine, 0.25% or 0.5%, three times a day and timolol, 0.5%, twice a day, the apraclonidine, 0.5%, reduced IOP more than apraclonidine, 0.25%, but no significant difference was observed between apraclonidine, 0.5%, and timolol, 0.5% (14).

Brimonidine

Brimonidine tartrate, 0.2%, has been similar to timolol, 0.5%, and greater than betaxolol, 0.25%, in IOPlowering efficacy (15). As with apraclonidine, brimonidine is useful in controlling the IOP rise after anterior segment laser surgery. In two vehicle-controlled, multicenter trials involving 480 patients undergoing 360% argon laser trabeculoplasty, brimonidine, 0.5%, provided effective postoperative pressure control, whether it was given before, after, or before and after the procedure (16). Brimonidine, 0.2%, is as effective as apraclonidine, 0.5%, in preventing postoperative IOP elevation after anterior segment laser procedures (17).

In addition to lowering the IOP, brimonidine may prevent optic nerve damage through a neuroprotective mechanism. Brimonidine reduces loss of retinal ganglion cells in an optic nerve crush injury model in rats and mice (18). These findings have been supported by later studies examining the effect of brimonidine on retinal ganglion cell death in retinal ischemia models and laser-induced glaucoma models (19). However, these models of optic nerve injury are not directly comparable to glaucoma occurring in humans. Whether brimonidine

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provides neuroprotection in humans with glaucoma remains unknown. Dipivefrin and Epinephrine

Dipivefrin, a prodrug of epinephrine, is a direct-acting sympathomimetic that stimulates both a- and ß - adrenergic receptors. Neither dipivefrin nor epinephrine is currently available. Dipivefrin, or dipivalyl epinephrine, was a modification of epinephrine in which two pivalic acid groups were added to the parent drug. It was significantly more lipophilic than epinephrine, which increases the corneal penetration 17-fold (20). Dipivefrin was hydrolyzed to epinephrine after absorption into the eye, with most of the hydrolysis occurring in the cornea (21). Clinical trials indicate that the pressure-lowering effect of dipivefrin, 0.1%, is similar to that of betaxolol, 0.5% (22).

ADMINISTRATION

Topical 1% apraclonidine is indicated for short-term use generally to prevent and to manage postlaser IOP elevation. In a double-masked, randomized, 90-day trial involving patients with chronic open-angle glaucoma (COAG), apraclonidine, 0.25% and 0.5%, given three times daily, reduced the IOP an average of 3.6 and 5.4 mm Hg, respectively, compared with 5.0 mm Hg with timolol, 0.5%, administered twice daily (14). Ap — raclonidine also had a similar eff ect to ß-adrenergic antagonists on daytime aqueous flow, with an average reduction of 30% (23). Unlike timolol, however, which does not affect aqueous flow during sleep, apraclonidine caused a 27% reduction of the spontaneous nocturnal rate (23). Brimonidine is an effective agent for long-term management of glaucoma. For optimal IOP-lowering effect, it is recommended that brimonidine, 0.2%, be administered three times daily. Its effect is similar to that of timolol maleate, 0.5%, and superior to betaxolol, 0.25%, when administered twice daily (24). Given the additive effects of brimonidine and timolol, 0.5%, the fixed combination of these two medications was developed and shown to be slightly more effective compared with monotherapy alone

(25). In another study, brimonidine, 0.2%, had an IOP effect similar to dorzolamide, 2%, when administered three times daily (26). Compared with latanoprost administered once daily, twicedaily brimonidine had a similar IOP-lowering effect at peak but did not lower IOP as effectively at trough (27).

Dipivefrin is available as a 0.1% solution. Like its predecessor epinephrine, dipivefrin is administered twice daily for maximal effect.

DRUG INTERACTIONS

A 4-month study (n = 120) was designed to compare the efficacy of brimonidine, dorzolamide, and brinzolamide in reducing IOP when used as adjunctive therapy to a once-daily prostaglandin analog of bimatoprost, latanoprost, or travoprost (28). Study eyes were randomly assigned to adjunctive treatment of three times daily brimonidine tartrate, 0.15% (n = 41); dorzolamide hydrochloride, 2% (n = 40); or brinzolamide, 1% (n = 39). At 4 months of adjunctive therapy, the mean IOP was lower and the mean change from baseline IOP was greater in the brimonidine group than in either the dorzolamide group or the brinzolamide group at 10 am and 4 pm. The mean IOP reduction from baseline at 10 am and 4 pm was 4.8 mm Hg (21%) and 3.8 mm Hg (19%) with brimonidine, 3.4 mm Hg (16%) and 2.8 mm Hg (14%) with dorzolamide, and 3.4 mm Hg (16%) and 2.6 mm Hg (13%) with brinzolamide. The addition of brimonidine to a prostaglandin agent provided greater IOP lowering than the addition of either dorzolamide or brinzolamide.

A pooled data analysis (n = 180) compared the IOP-lowering efficacy and ocular tolerability of the fixed-combination drugs brimonidine, 0.2%, with timolol, 0.5%, and dorzolamide, 2%, with timolol, 0.5%. Patients with glaucoma or ocular hypertension had been assigned to one of the two fixedcombination drugs, used as monotherapy or as an adjunctive to prostaglandin therapy. At 3 months, the mean (± SD) IOP reduction from baseline with fixed-combination monotherapy was 7.7 ± 4.2 mm Hg (32.3%) for brimonidine-timolol versus 6.7 ± 5.0 mm Hg (26.1%) for dorzolamide-timolol. The mean IOP reduction from prostaglandin-treated baseline with fixed-combination adjunctive therapy was 6.9 ± 4.8 mm Hg (29.3%) for brimonidine-timolol and 5.2 ± 3.7 mm Hg (23.5%) for dorzolamide-timolol (P = 0.2). At 3 months, the fixed-combination brimonidine-timolol provided the same or greater IOP lowering compared with fixedcombination dorzolamide-timolol (29).

Brimonidine is generally additive to other glaucoma agents, with the exception of apraclonidine, which is chemically and functionally similar. Brimonidine further reduced IOP by 17% to 19% when administered to healthy participants taking timolol maleate, 0.5% (30). As mentioned earlier, this additive effect leads to the development and release of the fixed combination of brimonidine, 0.2%, with timolol, 0.5%.

The interaction between epinephrine and dipivefrin with ß-adrenergic blockers is less clear because epinephrine stimulates and ß-blockers inhibit ß-adr energic receptors. When epinephrine therapy was added to eyes already receiving timolol, an additional reduction in IOP is usually small or absent (31). Continued therapy with dipivefrin in combination with timolol historically provided only a 1- to 3-mm Hg additional IOP reduction in most patients over that achieved with timolol alone (32).

SIDE EFFECTS

Ocular Toxicity

The most significant ocular side effect with apraclonidine is a follicular conjunctivitis with or without contact dermatitis. Of 64 patients on long-term therapy with the 1% concentration, 48% developed an allergic reaction (33). Similar ocular side effects have been reported for brimonidine. The rate of ocular allergies is substantially less than that encountered with the use of apraclonidine. In one study, 15% of patients developed ocular allergies, compared with a reported 36% or

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more of those taking apraclonidine (33). In a study of patients with known ocular allergy to apraclonidine, 10.5% developed allergic symptoms to brimonidine during 18-month follow-up (34). Other ocular side effects that have been reported with apraclonidine include eyelid retraction, mydriasis, and conjunctival blanching (35), which are due to cross-reactivity with a1-adrenergic receptors in Müller

muscle, iris sphincter muscle, and arterial smooth muscle, respectively.

The ocular side effects of dipivefrin can include those described earlier, but in addition there are some side effects that are unique to this epinephrine prodrug. After an initial vasoconstrictive effect, reactive hyperemia occurs with epinephrine, and to a lesser extent with dipivefrin. Oxidation and polymerization of epinephrine convert the drug to adrenochrome, a pigment of the melanin family, which historically appears as dark deposits in several ocular structures. Another well-recognized side effect is epinephrineassociated cystoid macular edema, which was observed in some aphakic eyes receiving topical epinephrine.

Systemic Toxicity

Systemic side effects are similar between topical apraclonidine and brimonidine because they both act at the same receptors. Systemic effects of topically applied brimonidine include oral dryness, sedation, drowsiness, headache, and fatigue (36). These effects may be more common in the elderly and in the very young. Because of risks of pronounced central nervous system depression, brimonidine should be used with great caution or not at all in children younger than 5 years (37).

Since dipivefrin was a prodrug of epinephrine, there were less sympathetic adverse reactions, which included elevated blood pressure, tachycardia, arrhythmias, headaches, tremor, nervousness, and anxiety. Since dipivefrin is not converted to active epinephrine until it enters the eye, there were fewer systemic effects than the standard forms of epinephrine.

INDICATIONS

Among the adrenergic stimulators, apraclonidine and brimonidine are a2-adrenergic agonists that are

useful in controlling short-term pressure elevations, especially in association with certain laser procedures, as well as the long-term management of glaucoma. Since brimonidine is now available in several generic formulations, it is affordable. The main value of apraclonidine is to minimize short-term IOP elevations after laser procedures and after phacoemulsification and intraocular lens implantation (38). Apraclonidine, 0.5%, can be used in the long-term management of glaucoma, but the benefit is limited by the high incidence of allergic reactions (33). Brimonidine is an effective choice as a secondline drug for glaucoma management in adults but should be used cautiously, if at all, in young children. Epinephrine and dipivefrin, a prodrug of epinephrine, are no longer available.

KEY POINTS

The a2-adrenergic agonists include apraclonidine and brimonidine. They are useful to lower acute pressure elevations following laser procedures.

These agents are considered second-line drugs for long-term management of COAG in adults.

Given the ability of these drugs to cross the blood-brain barrier in young children and infants, they should not be used in this patient population due to reports of apnea and systemic hypotension.

REFERENCES

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2.Lee DA, Topper JE, Brubaker RE, Effect of clonidine on aqueous humor flow in normal human eyes. Exp Eye Res. 1984;38(3):239-246.

3.Gharagozloo NZ, Relf SJ, Brubaker RE, Aqueous flow is reduced by the alpha-adrenergic agonist, apraclonidine hydrochloride (ALO 2145). Ophthalmology. 1988;95(9):1217-1220.

4.Toris CB, Tafoya ME, Camras CB, et al. Effects of apraclonidine on aqueous humor dynamics in human eyes. Ophthalmology. 1995;102(3):456-461.

5.Stamer WD, Huang Y, Seftor RE, et al. Cultured human trabecular meshwork cells express functional alpha 2A adrenergic receptors. Invest Ophthalmol Vis Sci. 1996;37(12):2426-2433.

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14.Stewart WC, Laibovitz R, Horwitz B, et al. A 90-day study of the efficacy and side effects of 0.25% and 0.5% apraclonidine vs 0.5% timolol. Apraclonidine Primary Therapy Study Group. Arch Ophthalmol. 1996; 114(8):938-942.

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Shields > SECTION III - Management of Glaucoma >

31 - Carbonic Anhydrase Inhibitors

Authors: Allingham, R. Rand

Title: Shields Textbook of Glaucoma, 6th Edition Copyright ©2011 Lippincott Williams & Wilkins

> Table of Contents > SECTION III - Management of Glaucoma > 31 - Carbonic Anhydrase Inhibitors 31

Carbonic Anhydrase Inhibitors

Carbonic anhydrase inhibitors (CAIs) are the only class of drugs that are used as systemically administered agents in chronic glaucoma therapy. The CAIs belong to the sulfonamide class of drugs. In 1954, acetazolamide was introduced as an ocular hypotensive drug, and most of the information in this chapter is based on experience with this drug. Methazolamide is another commercially available systemic CAI, but dichlorphenamide (available in Europe and Australia) and ethoxyzolamide are no longer available in the United States. After overcoming the challenges for topical drug delivery due to limited ocular absorption and bioavailability, both topical CAI drugs, dorzolamide and brinzolamide, have assumed a role in the management of glaucoma. The CAIs all share the same basic mechanism of action of lowering intraocular pressure (IOP) by decreasing aqueous humor flow through inhibition of carbonic anhydrase (CA) in ciliary epithelium. Side effects of the oral compounds essentially differ only in degree and are much less with the use of topical drugs.

MECHANISMS OF ACTION

CA is responsible for the catalytic hydration of CO2 and dehydration of H2CO3:

The physiologic effects of CAIs are related to ion transport, metabolic acidosis, blood flow, and fluid transport that are described in the following text. There are 14 gene forms of CA encoding for CA isoenzymes that have various cellular and tissue distributions and physiologic effects (1, 2). In the eye, four CA isoenzymes, CA I through CA IV, have been identified (3). The main therapeutic target of CAIs in the ciliary processes is the cytosolic CA II isoform (formerly called type C). In patients who have CA II deficiency, acetazolamide fails to decrease IOP, suggesting that this isozyme is inhibited by the drug

(4).

Based on the catalytic reaction described earlier, the two effects of ion transport and acidosis are closely related. Changes in ion transport associated with aqueous humor secretion are expected to be altered by CAIs, which is the main mechanism of action of the CAIs to decrease aqueous humor formation.

Acetazolamide decreases aqueous humor formation in the human eye about 30% compared with only 18% for topical dorzolamide (5). When added to timolol, which alone reduced daytime flow by 33%, the combination of the two aqueous suppressants reduced the flow rate by 44% (6). When dorzolamide is added to timolol, there is an additive effect to suppress aqueous humor flow (7).

Acetazolamide creates a local acidic environment (8) that inhibits net chloride flux across the ciliary epithelium, but the principal ions affected by CAIs have not been established in human eyes. Metabolic acidosis is known to reduce IOP and may be another mechanism of action for oral CAIs (9). However, the ocular hypotensive effect of these drugs does not depend on alterations of pH in the blood or aqueous humor (10).

Ocular blood flow is complex and involves consideration of the various vascular beds, including the retinal, choroidal, and retrobulbar vessels located within their respective tissues (11). Acetazolamide increases blood flow and blood-flow velocity within the middle cerebral artery of the brain but not in the ophthalmic and central retinal arteries (12). In a recent review of 35 specific studies, the meta-analysis provided the evidence that topical CAIs increase ocular blood-flow velocities in the retinal circulation, central retinal, and short posterior ciliary arteries but not in the ophthalmic artery (13).

The other clinical effect of CA relates to the fluid movement from the retina toward the choroid (14). Acetazolamide has been shown to increase the rate of subretinal fluid absorption in experimental retinal detachment (15) and to increase the adhesion between retina and pigment epithelium (16). It may also be effective in the treatment of macular edema in patients with retinal pigment epithelial cell disease and uveitis (17, 18). However, CAIs do not reduce macular edema associated with primary retinal vascular diseases (17).

ADMINISTRATION

Oral Carbonic Anhydrase Inhibitors

To achieve the therapeutic effect of reducing aqueous humor production, more than 90% of the CA activity needs to be inhibited (19). For this reason, the drug must be used in adequate doses (20). Because the free amount of drug determines the pharmacologic effect, understanding the protein binding of the drug (i.e., how much drug is taken up by serum proteins and blood cells) is important. Acetazolamide is highly bound compared with methazolamide, which explains why larger doses are required for acetazolamide to achieve its therapeutic effect compared with methazolamide. The drugs are not extensively metabolized and are primarily excreted in the urine (Table 31.1). The traditional oral dose for long-term acetazolamide therapy in adults is 250-mg tablets every 6 hours or 500-mg sustainedrelease capsules twice each day (22). For children, the

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recommended dose of acetazolamide is 5 to 10 mg/kg of body weight every 4 to 6 hours (23). In tablet form, the ocular hypotensive effect peaks in 2 hours and lasts up to 6 hours, whereas that of the capsule