Ординатура / Офтальмология / Английские материалы / Glaucoma Medical Therapy Principles and Management_Netland_2008

148 Glaucoma Medical Therapy

19.Gugleta K, Orgul S, Flammer J. Experience with Cosopt, the fixed combination of timolol and dorzolamide, after switch from free combination of timolol and dorzolamide, in Swiss ophthalmologists’ offices. Curr Med Res Opin. 2003;19(4):330– 335.

20.Bacharach J, Delgado MF, Iwach AG. Comparison of the efficacy of the fixedcombination timolol/dorzolamide versus concomitant administration of timolol and dorzolamide. J Ocul Pharmacol Ther. 2003;19(2):93–96.

21.Honrubia FM, Larsson LI, Spiegel D. A comparison of the effects on intraocular pressure of latanoprost 0.005% and the fixed combination of dorzolamide 2% and timolol 0.5% in patients with open-angle glaucoma. Acta Ophthalmol Scand. 2002; 80(6):635–641.

22.Konstas AG, et al. Twenty-four-hour diurnal curve comparison of commercially available latanoprost 0.005% versus the timolol and dorzolamide fixed combination. Ophthalmology. 2003;110(7):1357–1360.

23.Orzalesi N, et al. Comparison of latanoprost, brimonidine and a fixed combination of timolol and dorzolamide on circadian intraocular pressure in patients with primary open-angle glaucoma and ocular hypertension. Acta Ophthalmol Scand. 2002; 236(suppl):55.

24.Fechtner RD, et al. Efficacy of the dorzolamide/timolol fixed combination versus latanoprost in the treatment of ocular hypertension or glaucoma: combined analysis of pooled data from two large randomized observer and patient-masked studies. J Ocul Pharmacol Ther. 2005;21(3):242–249.

25.Fechtner RD, et al. Efficacy and tolerability of the dorzolamide 2%/timolol 0.5% combination (Cosopt) versus 0.005% (Xalatan) in the treatment of ocular hypertension or glaucoma: results from two randomized clinical trials. Acta Ophthalmol Scand. 2004;82(1):42–48.

26.Day DG, et al. Timolol 0.5%/dorzolamide 2% fixed combination vs timolol maleate 0.5% and unoprostone 0.15% given twice daily to patients with primary open-angle glaucoma or ocular hypertension. Am J Ophthalmol. 2003;135(2):138–143.

27.Sall KN, et al. Dorzolamide/timolol combination versus concomitant administration of brimonidine and timolol: six-month comparison of efficacy and tolerability. Ophthalmology. 2003;110(3):615–624.

28.Zabriskie N, Netland PA. Comparison of brimonidine/latanoprost and timolol/dorzolamide: two randomized, double-masked, parallel clinical trials. Adv Ther. 2003; 20(2):92–100.

29.Alm A, et al. Latanoprost administered once daily caused a maintained reduction of intraocular pressure in glaucoma patients treated concomitantly with timolol. Br J Ophthalmol. 1995;79(1):12–16.

30.Rulo AH, Greve EL, Hoyng PF. Additive effect of latanoprost, a prostaglandin F2 alpha analogue, and timolol in patients with elevated intraocular pressure. Br J Ophthalmol. 1994;78(12):899–902.

31.Orengo-Nania S, et al. Evaluation of travoprost as adjunctive therapy in patients with uncontrolled intraocular pressure while using timolol 0.5%. Am J Ophthalmol. 2001; 132(6):860–868.

32.Higginbotham EJ, et al. Latanoprost and timolol combination therapy vs monotherapy: one-year randomized trial. Arch Ophthalmol. 2002;120(7):915–922.

33.Pfeiffer N. A comparison of the fixed combination of latanoprost and timolol with its individual components. Graefes Arch Clin Exp Ophthalmol. 2002;240(11):893– 899.

34.Bucci MG. Intraocular pressure-lowering effects of latanoprost monotherapy versus latanoprost or pilocarpine in combination with timolol: a randomized, observermasked multicenter study in patients with open-angle glaucoma. Italian Latanoprost Study Group. J Glaucoma. 1999;8(1):24–30.

35.Konstas AG, et al. A comparison of once-daily morning vs evening dosing of concomitant latanoprost/timolol. Am J Ophthalmol. 2002;133(6):753–757.

36.Stewart WC, et al. Efficacy and safety of timolol maleate/latanoprost fixed combination versus timolol maleate and brimonidine given twice daily. Acta Ophthalmol Scand. 2003;81(3):242–246.

37.Konstas AG, et al. Daytime diurnal curve comparison between the fixed combinations of latanoprost 0.005%/timolol maleate 0.5% and dorzolamide 2%/timolol maleate 0.5%. Eye. 2004;18(12):1264–1269.

38.Shin DH, Feldman RM, Sheu WP. Efficacy and safety of the fixed combinations latanoprost/timolol versus dorzolamide/timolol in patients with elevated intraocular pressure. Ophthalmology. 2004;111(2):276–282.

39.Barnebey HS, et al. The safety and efficacy of travoprost 0.004%/timolol 0.5% fixed combination ophthalmic solution. Am J Ophthalmol. 2005;140(1):1–7.

40.Hughes BA, et al. A three-month, multicenter, double-masked study of the safety and efficacy of travoprost 0.004%/timolol 0.5% ophthalmic solution compared to travoprost 0.004% ophthalmic solution and timolol 0.5% dosed concomitantly in subjects with open angle glaucoma or ocular hypertension. J Glaucoma. 2005;14(5):392–399.

41.Schuman JS, et al. Efficacy and safety of a fixed combination of travoprost 0.004%/ timolol 0.5% ophthalmic solution once daily for open-angle glaucoma or ocular hypertension. Am J Ophthalmol. 2005;140(2):242–250.

42.Craven ER, et al. Brimonidine and timolol fixed-combination therapy versus monotherapy: a 3-month randomized trial in patients with glaucoma or ocular hypertension. J Ocul Pharmacol Ther. 2005;21(4):337–348.

43.Sherwood MB, et al. Twice-daily 0.2% brimonidine-0.5% timolol fixed-combination therapy vs monotherapy with timolol or brimonidine in patients with glaucoma or ocular hypertension: a 12-month randomized trial. Arch Ophthalmol. 2006;124(9): 1230–1238.

44.Goni FJ. 12-Week study comparing the fixed combination of brimonidine and timolol with concomitant use of the individual components in patients with glaucoma and ocular hypertension. Eur J Ophthalmol. 2005;15(5):581–590.

45.Realini T, Fechtner RD. 56,000 ways to treat glaucoma. Ophthalmology. 2002; 109(11):1955–1956.

This page intentionally left blank

152 Glaucoma Medical Therapy

Figure 8.1. Osmotic drugs.

8.1 MECHANISM OF ACTION

Osmotic drugs lower IOP by increasing the osmotic gradient between the blood and the ocular fluids. Following administration of osmotic drugs, the blood osmolality is increased by up to 20 to 30mOsm/L, which results in loss of water from the eye to the hyperosmotic plasma. This movement of water from the eye to the circulation is associated with a lowering of IOP.

The mechanism of reduction of IOP is likely due to reduction of vitreous volume, which probably results from the water transfer caused by the osmotic gradient

Table 8.1 Factors Affecting Osmotic Gradient

1.Ocular penetration

2.Distribution in body fluids

3.Molecular weight and concentration

4.Dosage

5.Rate and route of administration

6.Rate of systemic clearance

7.Type of diuresis

between the retina–choroid and the vitreous.9,10 Water absorption by the iris appears to play an insignificant role in the hypotony induced by osmotic agents.11 Although aqueous formation rates were not measured, conventional outflow facility does not change after administration of an osmotic agent.12 A mechanism mediated by the central nervous system has been proposed,13 perhaps via central osmoreceptors; however, this possibility has been disputed.14

The degree of IOP lowering is determined by the osmotic gradient caused by these drugs. The following factors influence degree and duration of the osmotic gradient (table 8.1)15:

1.Ocular penetration. Drugs that enter the eye rapidly produce less of an osmotic gradient compared with drugs that penetrate slowly or not at all. Ocular permeability to some drugs is greatly increased when the eye is inflamed and congested. This reduction of the osmotic gradient in inflamed eyes has been demonstrated after

administration of urea, which is of relatively low molecular weight, and was less pronounced following treatment with glycerol and mannitol.16,17 Although certain drugs (e.g., ethyl alcohol) enter the aqueous rapidly, part of their ocular hypotensive effect is due to relatively slow penetration in the avascular vitreous.

2.Distribution in body fluids. Drugs confined to the extracellular fluid space (e.g., mannitol) produce a greater effect on blood osmolality at the same dosage compared with drugs distributed in total body water (e.g., urea). For this reason, a larger dose in milliosmoles is required of urea compared with mannitol to produce the same osmotic gradient.

3.Molecular weight and concentration. Because the blood osmolality depends on the number of milliosmoles of substance administered, drugs with low molecular weight have potentially greater effect compared with compounds of high molecular weight at the same dosage in grams per kilogram. Thus, the lower molecular weight of urea compared with mannitol compensates for the greater distribution in body water of urea compared with mannitol. Also, osmotic drugs are administered as solutions, with osmolality directly proportional to the concentration. Drugs with low solubility require larger volumes of solution, with subsequently less effect on blood osmolality. Also, ingestion of fluids after osmotic drug use decreases blood osmolality, which decreases the osmotic gradient between the blood and the eye. This may occur following intake of fluids intended to make oral osmotic drugs more palatable.

154 Glaucoma Medical Therapy

4.Dosage. The change in blood osmolality depends on the total dose administered and the weight of the patient. With other factors being equal, a heavier patient has more body water and requires more drug compared with a lighter patient to achieve an equivalent osmotic gradient.

5.Rate and route of administration. Drugs administered intravenously bypass absorption from the gastrointestinal tract, generally producing a more rapid and greater osmotic gradient compared with orally administered drugs. When drugs are infused intravenously, a rate of 60 to 100 drops per minute is recommended.

6.Rate of systemic clearance. The rate of drug clearance from the systemic circulation influences the duration of action. Most osmotic drugs are excreted rapidly in the urine. Glycerol and ethyl alcohol, for example, are also metabolized.

7.Type of diuresis. Most osmotic drugs induce a diuresis, which may be hyper-, iso-, or hypoosmotic. After administration of ethyl alcohol, for example, the excreted urine is hypoosmotic, which can further increase the effect of the drug on blood osmolality.

8.2 INDICATIONS

Osmotic drugs are indicated for the short-term treatment of acute and marked elevation of IOP, including angle-closure glaucoma, aqueous misdirection (malignant glaucoma), and certain secondary glaucomas. These drugs are also indicated in the preoperative preparation of select patients for intraocular surgery. Long-term use is avoided because of the risk of dehydration, electrolyte imbalance, and other adverse effects.

8.3 CONTRAINDICATIONS

Osmotic drugs are contraindicated in patients with well-established anuria, severe dehydration, frank or impending acute pulmonary edema, severe cardiac decompensation, or hypersensitivity to any component of the preparations.

These drugs should be administered with caution to patients with cardiac, renal, or hepatic diseases. In patients with severe impairment of renal function, a test dose (0.2g/kg of body weight, to produce urine flow of at least 30 to 50mL/h) should be performed by the internist prior to use of intravenous mannitol. Caution should be exercised, in particular, in patients with congestive heart disease, hypervolemia, electrolyte abnormalities, confused mental states, and dehydration. Oral glycerol should be used with caution in diabetic patients because the blood glucose may rise after metabolism of the drug. When osmotic drugs are administered prior to surgery, the patient’s bladder should be empty.

8.4 TREATMENT REGIMEN

Glycerol is also known as glycerin, which is available as a 99.5% anhydrous solution. Although a commercial product is unavailable, a 50% solution of glycerol can

Table 8.2 Dosage and Administration of Commonly Used

Osmotic Drugs

be prepared by most pharmacies, which use glycerol to formulate other medications. Glycerol is prepared as a 50% vol/vol (0.628g/mL) solution for oral administration and may be stored at room temperature. The usual dose is 1 to 1.5g/kg, which is about 2 to 3mL/kg body weight (*4 to 6 ounces per individual). Flavoring and pouring the glycerol solution over ice improve palatability.

Isosorbide for oral administration is no longer available as a commercial product. Isosorbide is prepared as a 45% wt/vol solution in a flavored vehicle and is chemically stable at room temperature. The usual dose is 1 to 2g/kg of body weight, which is equivalent to 1.5mL/lb body weight. Because the osmotic effect persists up to 5 or 6 hours, doses may be repeated two to four times per day during the shortterm use of the drug.

The usual dose of mannitol for reduction of IOP is 0.5 to 2g/kg of body weight, given as an intravenous infusion of a 20% solution over a period of 30 to 60 minutes. Doses as low as 0.25g/kg may be effective. A single low dose of 12.5 g lowered IOP in normal subjects.18 Alternative concentrations for ophthalmic use include 10%, 15%, and 25% mannitol. The dose may be lowered if the IOP is not too high or increased if there is pronounced intraocular inflammation. Less than the full dose may be administered by terminating the intravenous infusion when the desired effect on IOP is achieved. The solution is stored at room temperature, and higher concentrations may require slight warming for complete solution. Crystals may form at temperatures below room temperature. When mannitol concentrations of 20% or 25% are infused, the administration set should include a filter.

When an intravenous osmotic drug is required, mannitol is preferable to urea. Although urea is not commonly used, the dosage of intravenous urea is 2 to 7mL/kg of a 30% solution. The solution of urea is unstable and must be prepared just prior to intravenous administration.

Osmotic drugs in common clinical use are shown in table 8.2.

8.5 SIDE EFFECTS

A potential ocular side effect of osmotic drugs is IOP ‘‘rebound.’’ The creation of a blood–vitreous osmotic gradient causes transfer of water from the eye into the blood, thereby increasing the osmolality of the vitreous. During clearance of the drug from the circulation, the osmolality of the blood may decrease to a level below that in the vitreous. The hyperosmotic vitreous may then draw water into the eye,

Iatrogenic intoxication with osmotic drugs may occur, especially after treatment with mannitol.28,29 Because it is confined to the extracellular fluid space, mannitol may greatly increase the blood volume. The ensuing dehydration of the brain may lead to central nervous system involvement, including lethargy and disorientation. Patients with mannitol intoxication may develop severe hyponatremia, a large osmolality gap (high measured minus calculated serum osmolality), and fluid overload. The treatment for this disorder is hemodialysis or peritoneal dialysis.

Increased blood volume after administration of osmotic drugs may overload the cardiac reserve, causing congestive heart failure or pulmonary edema. Elderly patients with borderline cardiac or renal function are especially at risk for these problems. Mannitol is retained in the extracellular fluid space, which causes expansion of blood volume, and intravenous administration may be more rapid than the gastrointestinal absorption of oral osmotic drugs. Thus, patients may be at higher risk for cardiovascular complications after treatment with mannitol compared with oral osmotic drugs.

Although hypersensitivity to osmotic drugs is uncommon, serious allergic reactions have been reported after the administration of intravenous mannitol.30,31 Patients with a history of atopy and asthma may be at high risk for hypersensitivity reaction to mannitol. High-risk patients may be identified with skin testing, which can produce a positive reaction shortly after lightly scratching the skin where a drop of mannitol has been placed.30 If a reaction occurs, mannitol infusion is discontinued and supportive therapy is instituted, including, as warranted, epinephrine, diphenhydramine, corticosteroids, or aminophylline.

Side effects of osmotic drugs are summarized in table 8.3.

Table 8.3 Side Effects of Osmotic Drugs