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

peaks in 8 hours and persists beyond 12 hours. For more rapid action, acetazolamide may be given intravenously, which provides a peak effect in 15 minutes and lasts up to 4 hours. A useful routine for emergencies, such as acute angle-closure glaucoma, is to give 250 mg of acetazolamide intravenously if the patient is unable to tolerate oral administration of two 250-mg tablets.

aMinimal.

bDiamox Sustets, 250 mg, are available in Europe.

cPresumed.

dTrusopt is available in the United States as 2%, but it is also available as 0.5% and 1% formulations in Japan.

eThe percentage of drug metabolized is not published (21).

An alternative oral regimen with methazolamide is to begin with 25 mg of methazolamide given twice daily, advancing to 50 mg twice daily and up to 100 mg taken three times daily (23). The advantage is that the drug can be used in smaller dosages, which cause fewer side effects, because the drug has a longer plasma half-life than acetazolamide and a lower rate of protein binding, allowing the free drug to distribute into tissues and be more active on a weight basis in reducing aqueous production (24). A 500mg sustained-release capsule of acetazolamide had a greater ocular hypotensive effect and was better tolerated than methazolamide (25, 26). Generic acetazolamide tablets and sequels are commercially available, providing significant cost savings.

Topical Carbonic Anhydrase Inhibitors Dorzolamide

Approved in the United States in 1998, dorzolamide (Fig. 31.1) lowers the IOP by reducing aqueous

humor flow by inhibiting the CA II isoenzyme in the ciliary body (27). At 2 hours after dosing, dorzolamide causes 14.7% to 27% reduction in IOP, and at 8 hours after dosing, 12.9% to 17.5% reduction in IOP (28, 29). A 2% solution is the only strength available in the United States,

but 0.5% and 1% formulations are available in Japan. The recommended administration is three times daily because there is greater IOP lowering compared with two times daily. It is most frequently administered twice daily for adherence.

In a 1-year trial comparing timolol, 0.5%, and betaxolol, 0.5%, both given twice daily, the mean percentage IOP reduction with dorzolamide was 23%, compared with 25% and 21% with timolol and betaxolol, respectively (30). Adjunctive therapy studies have shown that twice-daily dorzolamide provides additional IOP lowering in patients being treated with timolol, 0.5%, twice daily (31). When compared with pilocarpine four times daily as a second drug in patients whose IOP was uncontrolled with timolol, 0.5%, dorzolamide three times daily gave similar additional IOP reduction and was preferred by patients because of reduced side effects (32). When dorzolamide, 2% three times daily, was added to once-daily latanoprost, IOP was reduced by an additional 15% (33).

Several studies have reported on the use of dorzolamide in the pediatric population. In a randomized study comparing dorzolamide, 2%, three times daily with timolol gel once daily combined with placebo two times daily in children with glaucoma or elevated IOP younger than 6 years, dorzolamide lowered IOP by as much as 23.3% and was well tolerated,

P.430

compared with timolol (34). In a review of published studies reported on childhood glaucoma, additive therapy of twicedaily dorzolamide to once-daily timolol appeared to be the most effective and best tolerated compared with a2-agonists and prostaglandin analogues (35).

Figure 31.1 Chemical structure of dorzolamide (Trusopt) and brinzolamide (Azopt), topical CAIs. The IOP-lowering effect of the fixed combination of dorzolamide, 2%, and timolol, 0.5%, (Cosopt) is similar to that of the same drugs dosed separately (36). In a randomized study comparing the 24-hour

efficacy and tolerability of a fixed combination of dorzolamide, 2%, and timolol, 0.5%, versus timolol, 0.5%, the dorzolamide-timolol combination exhibited greater IOP lowering than timolol during the daytime but not at night (37). It is now available in generic form, providing considerable cost savings. Brinzolamide

Approved in the United States in 1998, brinzolamide (Fig. 31.1) lowers IOP by inhibiting the CA II isoenzyme in the ciliary body (21). The Brinzolamide Dose-Response Study Group reported that brinzolamide caused a dose-related IOP reduction when dosed two times daily, with the 1% formulation being at the top of the dose-response curve (38). The IOP reduction at the peak effect 2 hours after dosing ranged from —3.3 to —5.3 mm Hg. At the troug h effect 12 hours after dosing, the IOP was lower by —2.8 to —4.9 mm Hg.

When brinzolamide, 1%, was compared with dorzolamide, 2%, the absolute IOP lowering and percentage IOP lowering were similar, with up to 19.1% lowering with brinzolamide dosed three times daily and 20.1% lowering with dorzolamide dosed similarly (39). In adjunctive studies, brinzolamide, 1%, dosed three times daily was added in patients with open-angle glaucoma or ocular hypertension

already treated with timolol, 0.5%, used twice daily and caused an additional IOP lowering up to 4.1 mm Hg, which was greater than with placebo (40). When comparing the additivity of twice-daily dorzolamide or brinzolamide with topical timolol, 0.5%, equivalence in IOP lowering was demonstrated for both dosing regimens (41). In a randomized trial comparing the additivity of twice-daily brinzolamide, 1%, with twice-daily brimonidine, 0.15%, in patients already receiving travoprost, the adjunctive brinzolamide therapy was marginally more effective than the adjunctive brimonidine therapy was at lowering the IOP (42). The fixed combination of brinzolamide, 1%, and timolol, 0.5%, is currently in phase III clinical trials (43, 44).

SIDE EFFECTS Ocular Side Effects

For the oral CAIs, an idiosyncratic, transient myopia is a sulfonamide-related reaction (45). Ultrasonography of a patient with induced myopia associated with sulfonamide therapy revealed shallowing of the anterior chamber without thickening of the lens, suggesting that ciliary body edema might cause forward movement of the lens-iris diaphragm (46), which can also account for a mechanism of angle closure due to the forward shift of the lens-iris diaphragm.

The most frequently experienced ocular adverse reactions with topical CAI use are irritation immediately after instillation, transient blurred vision, and occasional hypersensitivity reactions (47). It has been proposed that the lower pH of dorzolamide compared with brinzolamide possibly contributes to ocular discomfort (21). Periorbital dermatitis has been reported with topical CAI use, but benzalkonium chloride sensitivity is also an important consideration (48). In patients with open-angle glaucoma or ocular hypertension, mean corneal thickness increased after dorzolamide treatment, but this was not clinically significant (28, 49). Potentially serious effects on the cornea are theoretically possible because CA isoenzymes I and II are expressed in corneal endothelium and are involved in maintaining corneal transparency (50). In healthy eyes, CA inhibition of the cornea may not be clinically significant (51). However, in susceptible individuals, clinically significant corneal edema has been associated with use of topical dorzolamide (52).

Systemic Side Effects

Systemic side effects are common with oral CAI therapy, frequently necessitating altering medical therapy (53). Paresthesia of the fingers and toes and around the mouth is a common side effect. Increased urinary frequency from the diuretic action is experienced by nearly all patients initially, but this diuretic effect is not a factor in reducing the IOP (54).

Serum electrolyte imbalances may create more debilitating problems. Metabolic acidosis, associated with bicarbonate depletion, occurs with the higher dosages of CAIs and should be avoided in patients with hepatic insufficiency, renal failure, adrenocortical insufficiency, hyperchloremic acidosis, depressed sodium or potassium levels, or severe pulmonary obstruction (55). The risk in patients with liver disease was re-emphasized in a case report of a patient with cirrhosis who developed hepatic encephalopathy due to ammonia intoxication within days after starting acetazolamide therapy (56). A symptom complex of malaise, fatigue, weight loss, anorexia, depression, and decreased libido is common in patients receiving oral CAI therapy and has been correlated with the degree of metabolic acidosis (57, 58). High-dose aspirin combined with a CAI may cause serious acid-base imbalance and salicylate intoxication (59). Potassium depletion may occur during the initial phase of CAI therapy because of increased urinary excretion, especially if diuresis is brisk, and is the apparent explanation for the frequent paresthesias. However, this is normally transient and does not lead to significant hypokalemia unless it is given concomitantly with chlorothiazide diuretics, digitalis, corticosteroids, or adrenocorticotropic hormone, or in patients with hepatic cirrhosis (60). Potassium supplement is indicated only when significant hypokalemia is documented (61).

Also common are gastrointestinal symptoms, including vague abdominal discomfort, a peculiar metallic taste experienced

P.431

particularly with ingestion of carbonated beverages, nausea, and diarrhea. These symptoms appear to be

unrelated to any serum chemical change, and the cause is unknown. Taking the medication with meals may help to reduce the symptoms (57). A less common but debilitating side effect is renal calculi formation, which reportedly is increased in patients receiving acetazolamide and methazolamide (62, 63).

The following sulfonamide-related reactions are typical with this drug class and constitute the most serious adverse reactions related to CAI therapy. Blood dyscrasias are rare, but thrombocytopenia, agranulocytosis, aplastic anemia, and neutropenia have been reported with acetazolamide or methazolamide therapy (64). The mechanism of this rare but serious reaction is suggested to be related to the development of immune-mediated mechanisms. These blood dyscrasias cannot be predicted by monitoring blood cell counts, and with the exception of aplastic anemia, the other blood dyscrasias are reversible on cessation of use of the drug. In contrast, aplastic anemia typically has a delayed, insidious onset and is frequently fatal. Most cases occur within less than 6 months of initiating therapy, and some patients have recovered after stopping use of the drug. Because monitoring blood cell counts is not a costeffective way to monitor for these rare CAI-associated blood dyscrasias, an interval patient history should be obtained in order to be vigilant of potentially relevant hematologic symptoms that may rarely develop after starting CAI therapy.

Other sulfonamide-related side effects include maculopapular and urticarial types of skin eruptions (65), as well as Stevens-Johnson syndrome (66). Teratogenic effects have been observed in rats and in one human case, although the patient's mother was also receiving the anticholinergic agent dicyclomine during weeks 8 to 12 of pregnancy (67, 68). Glaucoma treatment during pregnancy should be coordinated with the patient's obstetrician.

The main advantage of the topical CAIs, dorzolamide and brinzolamide, is the marked reduction in systemic side effects, compared with the oral agents. The minor, transient side effect of bitter taste has been reported after topical brinzolamide and dorzolamide administration (39). However, serious systemic reactions may occur in some patients, and thrombocytopenia and erythema multiforme have been reported with topical dorzolamide therapy (69, 70).

KEY POINTS

CAIs lower IOP by reducing aqueous humor production through an alteration in ion transport associated with aqueous humor secretion.

The oral CAIs, although effective and inexpensive, have numerous side effects that limit their use in most cases to short-term therapy.

The topical CAIs, although less potent than the systemic forms, have the advantage of causing fewer systemic side effects and are useful for the long-term management of glaucoma.

REFERENCES

3.Wistrand PJ. Carbonic anhydrase inhibition in ophthalmology: carbonic anhydrases in cornea, lens, retina and lacrimal gland. EXS. 2000;90: 413-424.

4.Krupin T, Sly WS, Whyte MP, et al. Failure of acetazolamide to decrease intraocular pressure in patients with carbonic anhydrase II deficiency. Am J Ophthalmol. 1985;99(4):396-399.

5.Maus TL, Larsson LI, McLaren JW, et al. Comparison of dorzolamide and acetazolamide as suppressors of aqueous humor flow in humans. Arch Ophthalmol. 1997;115(1):45-49.

6.Dailey RA, Brubaker RF, Bourne WM. The effects of timolol maleate and acetazolamide on the rate of aqueous formation in normal human subjects. Am J Opthalmol. 1982;93(2):232-237.

7.Wayman LL, Larsson LI, Maus TL, et al. Additive effect of dorzolamide on aqueous humor flow in patients receiving long-term treatment with timolol. Arch Ophthalmol. 1998;116(11):1438-1440.

8.To CH, Do CW, Zamudio AC, et al. Model of ionic transport for bovine ciliary epithelium: effects of acetazolamide and HCO. Am J Physiol Cell Physiol. 2001;280(6):C1521-C1530.

9.Bietti G, Virno M, Pecori-Giraldi J, et al. Acetazolamide, metabolic acidosis, and intraocular pressure. Am J Ophthalmol. 1975;80(3 pt 1): 360-369.

10.Mehra KS. Relationship of pH of aqueous and blood with acetazolamide. Ann Ophthalmol. 1979;11:63.

11.Costa VP, Harris A, Stefansson E, et al. The effects of antiglaucoma and systemic medications on ocular blood flow. Prog Retin Eye Res. 2003;22(6):769-805.

12.Harris A, Tippke S, Sievers C, et al. Acetazolamide and CO2: acute effects on cerebral and

retrobulbar hemodynamics. J Glaucoma. 1996;5(1): 39-45.

13.Siesky B, Harris A, Brizendine E, et al. Literature review and metaanalysis of topical carbonic anhydrase inhibitors and ocular blood flow. Surv Ophthalmol. 2009;54(1):33-46.

14.Moldow B, Sander B, Larsen M, et al. Effects of acetazolamide on passive and active transport of fluorescein across the normal BRB. Invest Ophthalmol Vis Sci. 1999;40(8):1770-1775.

15.Marmor MF, Negi A. Pharmacologic modification of subretinal fluid absorption in the rabbit eye. Arch Ophthalmol. 1986;104(11):1674-1677.

16.Marmor MF, Maack T. Enhancement of retinal adhesion and subretinal fluid resorption by acetazolamide. Invest Ophthalmol Vis Sci. 1982; 23(1):121-124.

17.Cox SN, Hay E, Bird AC. Treatment of chronic macular edema with acetazolamide. Arch Ophthalmol. 1988;106(9):1190-1195.

18.Farber MD, Lam S, Tessler HH, et al. Reduction of macular oedema by acetazolamide in patients with chronic iridocyclitis: a randomised prospective crossover study [comment]. Br J Ophthalmol. 1994;78(1): 4-7.

19.Friedenwald JS. Current studies on acetazolamide (Diamox) and aqueous humor flow. Am J Ophthalmol. 1955;40:139.

20.Becker B. Misuse of acetazolamide. Am J Ophthalmol. 1957;43:799.

21.DeSantis L. Preclinical overview of brinzolamide. Surv Ophthalmol. 2000;44(suppl2):S119-S129.

22.Joyce PW, Mills KB, Richardson T, et al. Equivalence of conventional and sustained release oral dosage formulations of acetazolamide in primary open angle glaucoma. Br J Clin Pharmacol. 1989;27 (5):597-606.

23.Havener WH. Ocular Pharmacology. 5th ed. St. Louis, MO: CV Mosby; 1983.

24.Maren TH, Haywood JR, Chapman SK, et al. The pharmacology of methazolamide in relation to the treatment of glaucoma. Invest Ophthalmol Vis Sci. 1977;16(8):730-742.

25.Dahlen K, Epstein DL, Grant WM, et al. A repeated dose-response study of methazolamide in glaucoma. Arch Ophthalmol. 1978;96(12): 2214-2218.

26.Lichter PR, Newman LP, Wheeler NC, et al. Patient tolerance to carbonic anhydrase inhibitors. Am J Ophthalmol. 1978;85(4):495-502.

P.432

27.Wang R-F, Serle JB, Podos SM, et al. MK-507 (L-671,152), a topically active carbonic anhydrase inhibitor, reduces aqueous humor production in monkeys. Arch Ophthalmol. 109(9):1297-1299.

28.Wilkerson M, Cyrlin M, Lippa EA, et al. Four-week safety and efficacy study of dorzolamide, a novel, active topical carbonic anhydrase inhibitor. Arch Ophthalmol. 1993;111(10):1343-1350.

29.Strahlman E, Tipping R, Vogel R. A six-week dose-response study of the ocular hypotensive effect of dorzolamide with a one-year extension: Dorzolamide Dose-Response Study Group. [Erratum appears in Am J Ophthalmol. 1996;122:928.] Am J Ophthalmol. 1996;122:183-194.

30.Strahlman E, Tipping R, Vogel R, et al. A double-masked, randomized 1-year study comparing dorzolamide (Trusopt), timolol, and betaxolol. Arch Ophthalmol. 1995;113:1009.

31.Petounis A, Mylopoulos N, Kandarakis A, et al. Comparison of the additive intraocular pressurelowering effect of latanoprost and dorzolamide when added to timolol in patients with open-angle glaucoma or ocular hypertension: a randomized, open-label, multicenter study in Greece. J Glaucoma. 2001;10(4):316-324.

32.Laibovitz R, Strahlman ER, Barber BL, et al. Comparison of quality of life and patient preference of

dorzolamide and pilocarpine as adjunctive therapy to timolol in the treatment of glaucoma. J Glaucoma. 1995;4(5):306-313.

33.Kimal Arici M, Topalkara A, Guler C. Additive effect of latanoprost and dorzolamide in patients with elevated intraocular pressure. Int Ophthalmol. 1998;22(1):37-42.

34.Ott EZ, Mills MD, Arango S, et al. A randomized trial assessing dorzolamide in patients with glaucoma who are younger than 6 years. Arch Ophthalmol. 2005;123(9):1177-1186.

35.Coppens G, Stalmans I, Zeyen T, et al. The safety and efficacy of glaucoma medication in the pediatric population. J Pediatr Ophthalmol Strabismus. 2009;46(1):12-18.

36.Hutzelmann J, Owens S, Shedden A, et al. Comparison of the safety and efficacy of the fixed combination of dorzolamide/timolol and the concomitant administration of dorzolamide and timolol: a clinical equivalence study. International Clinical Equivalence Study Group. Br J Ophthalmol. 1998;82 (11):1249-1253.

37.Feldman RM, Stewart RH, Stewart WC, et al. 24-hour control of intraocular pressure with 2% dorzolamide/0.5% timolol fixed-combination ophthalmic solution in open-angle glaucoma. Curr Med Res Opin. 2008;24(8):2403-2412.

38.Silver LH. Dose-response evaluation of the ocular hypotensive effect of brinzolamide ophthalmic suspension (Azopt): Brinzolamide Dose-Response Study Group. Surv Ophthalmol. 2000;44(suppl 2):S147-S153.

39.Sall K. The efficacy and safety of brinzolamide 1% ophthalmic suspension (Azopt) as a primary therapy in patients with open-angle glaucoma or ocular hypertension: Brinzolamide Primary Therapy Study Group. Surv Ophthalmol. 2000;44(suppl 2):S155-S162.

40.Shin D. Adjunctive therapy with brinzolamide 1% ophthalmic suspension (Azopt) in patients with open angle glaucoma or ocular hypertension maintained on timolol therapy. Surv Ophthalmol. 2000;44 (suppl 2):S163-S168.

41.Michaud JE, Friren B. Comparison of topical brinzolamide 1% and dorzolamide 2% eye drops given twice daily in addition to timolol 0.5% in patients with primary open-angle glaucoma or ocular hypertension. Am J Ophthalmol. 2001;132(2):235-243.

42.Feldman RM, Tanna AP, Gross RL, et al. Comparison of the ocular hypotensive efficacy of adjunctive brimonidine 0.15% or brinzolamide 1% in combination with travoprost 0.004%. Ophthalmology. 2007;114(7): 1248-1254.

43.Hollo G, Bozkurt B, Irkec M. Brinzolamide/timolol fixed combination: a new ocular suspension for the treatment of open-angle glaucoma and ocular hypertension. Expert Opin Pharmacother. 2009;10 (12):2015-2024.

44.Manni G, Denis P, Chew P, et al. The safety and efficacy of brinzolamide 1%/timolol 0.5% fixed combination versus dorzolamide 2%/timolol 0.5% in patients with open-angle glaucoma or ocular hypertension. J Glaucoma. 2009;18(4):293-300.

45.Grant W, Leopold I, eds. Symposium on Ocular Therapy. Vol 6. St. Louis, MO:Mosby; 1972:19.

46.Bovino JA, Marcus DF. The mechanism of transient myopia induced by sulfonamide therapy. Am J Ophthalmol. 1982;94(1):99-102.

47.Barnebey H, Kwok SY. Patients' acceptance of a switch from dorzolamide to brinzolamide for the treatment of glaucoma in a clinical practice setting. Clin Ther. 2000;22(10):1204-1212.

48.Delaney YM, Salmon JF, Mossa F, et al. Periorbital dermatitis as a side effect of topical dorzolamide. Br J Ophthalmol. 2002;86(4):378-380.

49.Inoue K, Okugawa K, Oshika T, et al. Influence of dorzolamide on corneal endothelium. Jpn J Ophthalmol. 2003;47(2):129-133.

50.Srinivas SP, Ong A, Zhai CB, et al. Inhibition of carbonic anhydrase activity in cultured bovine corneal endothelial cells by dorzolamide. Invest Ophthalmol Vis Sci. 2002;43(10):3273-3278.

51.Egan CA, Hodge DO, McLaren JW, et al. Effect of dorzolamide on corneal endothelial function in normal human eyes. Invest Ophthalmol Vis Sci. 1998;39(1):23-29.

52.Konowal A, Morrison JC, Brown SV, et al. Irreversible corneal decompensation in patients treated with topical dorzolamide. Am J Ophthalmol. 1999;127(4):403-406.

53.Lichter PR. Reducing side effects of carbonic anhydrase inhibitors. Ophthalmology. 1981;88(3):266-

54.Becker B. The mechanism of the fall in intraocular pressure induced by the carbonic anhydrase inhibitor, Diamox. Am J Ophthalmol. 1955; 39(2 pt 2):177-184.

55.Block ER, Rostand RA. Carbonic anhydrase inhibition in glaucoma: hazard or benefit for the chronic lunger? Surv Ophthalmol. 1978;23(3): 169-172.

56.Margo CE. Acetazolamide and advanced liver disease. Am J Ophthalmol. 1986;101(5):611-612.

57.Epstein DL, Grant WM. Carbonic anhydrase inhibitor side effects: serum chemical analysis. Arch Ophthalmol. 1977;95(8):1378-1382.

58.Wallace TR, Fraunfelder FT, Petursson GJ, et al. Decreased libido: a side effect of carbonic anhydrase inhibitor. Ann Ophthalmol. 1979;11(10): 1563-1566.

59.Anderson CJ, Kaufman PL, Sturm RJ. Toxicity of combined therapy with carbonic anhydrase inhibitors and aspirin. Am J Ophthalmol. 1978;86(4): 516-519.

60.Spaeth GL. Potassium, acetazolamide, and intraocular pressure. Arch Ophthalmol. 1967;78(5):578-

61.Critchlow AS, Freeborn S, Roddie RA. Potassium supplements during treatment of glaucoma with acetazolamide. Br Med J. 1984;289:21.

62.Kass MA, Kolker AE, Gordon M, et al. Acetazolamide and urolithiasis. Ophthalmology. 1981;88 (3):261-265.

63.Ellis PP. Urinary calculi with methazolamide therapy. Doc Ophthalmol. 1973;34(1):137-142.

64.Fraundfelder FT, Meyer SM, Bagby GC Jr, et al. Hematologic reactions to carbonic anhydrase inhibitors. Am J Ophthalmol. 1985;100(1):79-81.

65.Gandham SB, Spaeth GL, Di Leonardo M, et al. Methazolamide-induced skin eruptions. Arch Ophthalmol. 1993;111(3):370-372.

66.Flach AJ, Smith RE, Fraunfelder FT. Stevens-Johnson syndrome associated with methazolamide treatment reported in two Japanese-American women. Ophthalmology. 1995;102(11):1677-1680.

67.Maren TH. Teratology and carbonic anhydrase inhibition. Arch Ophthalmol. 1971;85(1):1-2.

68.Worsham F, Beckman EN, Mitchell EH. Sacrococcygeal teratoma in a neonate. JAMA. 1978;240 (3):251-252.

69.Martin XD, Danese M. Dorzolamide-induced immune thrombocytopenia: a case report and literature review. J Glaucoma. 2001;10(2):133-135.

70.Munshi V, Ahluwalia H. Erythema multiforme after use of topical dorzolamide. J Ocul Pharmacol Ther. 2008;24(1):91-93.

Say thanks please

Shields > SECTION III - Management of Glaucoma >

32 - Cholinergic Stimulators and Hyperosmotic Agents

Authors: Allingham, R. Rand

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

> Table of Contents > SECTION III - Management of Glaucoma > 32 - Cholinergic Stimulators and Hyperosmotic Agents

32

Cholinergic Stimulators and Hyperosmotic Agents

With the introduction of newer medications that have improved efficacy and few side effects, the cholinergic stimulators and hyperosmotic agents have a limited role in glaucoma management. Introduced in the 1870s, pharmacologic agents that mimic the cholinergic effects of acetylcholine are referred to as cholinergic agonists, parasympathomimetics stimulators, or miotics because of their effect

on the pupil (Fig. 32.1). Among the acetylcholinesterase inhibitors, which have limited availability, only echothiophate iodide is discussed. The hyperosmotic agents are another class of compounds administered systemically (orally or intravenously) in short-term, emergency situations, such as with acute angle-closure glaucoma or other glaucomas involving dangerously high intraocular pressures (IOPs). Although many consider these drugs of historical interest, the cholinergic stimulators and hyperosmotic agents remain useful in specific clinical situations.

MECHANISMS OF ACTION Cholinergic Stimulators

The cholinergic agents (Table 32.1) (1) are indicated for use in all forms of open-angle glaucoma where the aqueous outflow system is functionally intact. They share a common mechanism of action by stimulating muscarinic cholinergic receptors. Among the five receptor subtypes (2), the m3 muscarinic receptor is the predominant subtype expressed in human ciliary muscle cells and iris sphincter (3). They lower IOP by increasing facility of aqueous outflow (see the modified Goldmann equation in Chapter 2) by ciliary muscle contraction, which causes traction on the scleral spur and alters the configuration of the trabecular meshwork and Schlemm canal (Fig. 32.2). This mechanism is supported by primate and human studies. Disinserting the ciliary muscle from the scleral spur in monkeys eliminates the effect of pilocarpine on IOP and facility of outflow (4). Histologic studies of human eyes treated with pilocarpine before enucleation for malignant melanoma demonstrate a posterior, internal pull on the scleral spur, with trabecular space widening, endothelial meshwork distention, an increase in giant vacuoles, and larger, more frequent pores in the inner endothelium of the Schlemm canal (5). Primate studies suggest that the increase in giant vacuoles is a result of enhanced aqueous flow through the outflow system rather than a direct action of pilocarpine on the endothelium of the Schlemm canal (6).

Figure 32.1 Chemical structures of the direct acting muscarinic agent, pilocarpine (A), and the indirect acting muscarinic agent, echothiophate (B).

Other aqueous humor dynamic effects have been investigated. Fluorophotometric studies in humans show minimal stimulation of aqueous humor formation with pilocarpine (7). Pilocarpine decreases uveoscleral outflow (8), which may have clinical significance in eyes with markedly reduced conventional or trabecular outflow. As these eyes become increasingly dependent on unconventional or uveoscleral drainage, pilocarpine may cause a paradoxical rise in IOP (9). Episcleral venous pressure does not appear to be altered by pilocarpine (10).

The miotic effect, caused by pilocarpine and related compounds, is produced by stimulating muscarinic receptors of the iris sphincter muscle. This effect “tightens” the iris and helps open the anterior ch amber island, making pilocarpine a useful adjunct in the short-term management of angle closure resulting from relative pupillary block (see Chapter 12).

Hyperosmotic Agents

The most widely accepted mechanism of action for the hyperosmotic agents is reduction of vitreous volume due to a change in osmotic gradient between the blood and ocular tissues, which lowers IOP. This concept is supported by rabbit studies that demonstrate a reduction in vitreous body weight of approximately 3% to 4% after administration of mannitol (11). With time, a variable amount of the hyperosmotic agent may enter the eye, depending on the permeability of the bloodocular barriers to the drug and the size of the drug molecules. As the compound is cleared from the systemic circulation, there may be a reversal of the osmotic gradient in some cases, resulting in a transient rise in IOP.

P.434

Table 32.1 Commercial Miotic Preparations

Data from Physicians' Desk Reference for Ophthalmic Medicines. 36th ed. Montvale, NJ: Thomson; 2008.

ADMINISTRATION Cholinergic Stimulators

Pilocarpine solution is applied topically and is largely degraded in the cornea (12), with less than 3% entering the anterior chamber (13). The IOP-lowering effect is dose related up to pilocarpine, 4% (14, 15). In darkly pigmented eyes, pilocarpine, 6%, may produce additional IOP reduction (16). Based on pharmacokinetic studies in animals and pharmacodynamic studies in humans (13, 14, 17), pilocarpine is given four times daily. However, one study reported that pilocarpine, 2%, administered twice daily, followed by nasolacrimal occlusion gave maximal IOP response (18).

Although not commonly prescribed, another formulation of 4% pilocarpine hydrochloride is a highviscosity acrylic vehicle (Pilopine), which is applied at bedtime and produces a significant IOP reduction for 24 hours (19). It was comparable to pilocarpine hydrochloride drops, four times daily (20, 21), with less induced myopia and impaired visual acuity.

Although not commonly prescribed, carbachol is a dual-action parasympathomimetic that produces direct muscarinic receptor stimulation and an indirect parasympathomimetic effect by inhibiting acetylcholinesterase. Carbachol has poor corneal penetration and requires an adjuvant, such as benzalkonium chloride, to achieve therapeutic levels (22). The usual dosage is three times daily. A carbachol, 1.5%, three times daily—the usual dosage —was as potent and effective as pilocarpine, 2%, four times a day (23). There appears to be no significant difference in the effectiveness of pilocarpine compared with carbachol.

Figure 32.2 Schematic mechanism of ciliary muscle contraction on anterior segment anatomy. After applying a topical cholinergic medication, the ciliary muscle fibers contract, leading to traction on the scleral spur and altering aqueous outflow through the trabecular meshwork and Schlemm canal. An accommodative effect is also mediated by a decrease in concentric diameter of the ciliary body with

“ rounding” of the lens and a slight decrease in the anterior chamber depth.

Even less commonly used are the acetylcholinesterase inhibitors, and only echothiophate iodide (phospholine iodide), 0.125%, is currently available in the United States. Echothiophate had the advantage of a prolonged duration of action, with the maximum effect occurring in 4 to 6 hours and a substantial residual present after 24 hours, allowing it to be used on a twice-daily regimen.

Another route of administration is intracameral injection of either carbachol or acetylcholine to achieve miosis during surgery. After cataract surgery, intracameral carbachol has been shown to provide better IOP control in the early postoperative period, compared with intracameral acetylcholine or placebo using balanced salt solution (24, 25).

Hyperosmotic Agents

The systemic administration of a hyperosmotic agent is occasionally used as an emergency method of lowering the IOP or preoperatively to minimize the “posterior pressure” effect of the vitreous in a su pine position. Although not widely used, glycerin (Osmoglyn) is administered orally in a dose of 1 to 1.5 g/kg (or 2 to 3 cc/kg) of body weight of a 50% solution (26, 27). The ocular hypotensive effect occurs within 10 minutes of administration, peaks in 30 minutes, and lasts for approximately 5 hours (26, 27). Mannitol is administered intravenously with a filter administration set over 30 minutes in a dose of 1 to 2 g/kg of body weight of a 25% solution (27). If crystals are present in this 25% solution, then the vial should be warmed up to 60°C to 80°C to dissolve the crystals, and the solution should cool to body temperature before injection. However, lower doses are equally effective. In a study of patients awaiting cataract surgery, 100 mL of 20% mannitol, which is 20 g, given over 20 minutes had the same magnitude of IOP reduction and

P.435

deepening of the anterior chamber as 200 mL did, although the latter had a more rapid and sustained ocular hypotensive effect (27). The onset of action is in 20 to 60 minutes, and the duration varies from 2 to 6 hours (27, 28). Mannitol may be indicated when glycerin is thought to be insufficient or when it is not tolerated. The drug is distributed in the extracellular fluid compartments and has poor ocular penetration (27).

DRUG INTERACTIONS

Cholinergic Stimulators and Other Glaucoma Medications

Since the miotic agents share a similar mechanism of action, they do not show an additive IOP-lowering effect within this drug class (29). In general with other drug classes' having a different mechanism of action, there is an additive effect using the combination of pilocarpine and the a2-agonists apraclonidine

and brimonidine (see Chapter 30). For the adrenergic receptor agonists, the fixed combinations of epinephrine and pilocarpine are no longer available. For adrenergic antagonists, two fixed combinations of timolol and pilocarpine (Timpilo and Fotil) are available in some parts of the world (30). Aqueous humor levels of pilocarpine, 2%, and timolol, 0.5%, in rabbits were not different whether the drugs were given alone or in fixed combination (31). Although pilocarpine reduces and prostaglandins increase uveoscleral outflow, the prostaglandin agents have an additive IOP-lowering effect when used with pilocarpine (Chapter 28). Pilocarpine may also be used effectively in combination with carbonic anhydrase inhibitors (see Chapter 31).

Hyperosmotic Agents and Other Glaucoma Medications

This drug class is not used for long-term medical management of glaucoma. SIDE EFFECTS

Cholinergic Stimulators

The systemic effects of topically applied pilocarpine are uncommon but are similar to those of muscarine, with stimulation of glands, contraction of smooth muscle, and cardiac and central cognitive