Pharmaceutical Journal Vol 263 No 7060 p324-329
August 28, 1999 Continuing Education

Eye disorders

Treatment of glaucoma: part 1

By Lucy C. Titcomb, BSc, MRPharmS

Glaucoma is the first topic in our series about eye disorders. In this, the first of a two part article, the pathogenesis of glaucoma is discussed and the drugs that reduce aqueous humour inflow are examined. The second part, in a subsequent issue, will review other drugs used to treat glaucoma

The term glaucoma does not represent a single pathological entity but a large group of disorders with widely differing clinical features. The glaucomatous disorders may generally be defined as "those conditions in which the intraocular pressure (IOP) is too high for the normal functioning of the optic nerve head."

Other articles in this eye disorders series

Pathogenesis

The glaucomas, which affect around one in 200 of the adult population,1 may be classified in a number of ways but classification is normally based upon a structural and aetiological basis:

  • appearance of the angle of the anterior chamber, ie, closed or open (Figure 1).
  • aetiology - primary, where no specific cause can be identified, or secondary where optic neuropathy follows a rise in IOP because of some condition in the eye, such as inflammation, trauma or abnormal pigment release into the anterior chamber (Figure 2).
Glaucoma may also be described as acute or chronic, congenital, juvenile and infantile. 		Figure 1 - full size
Figure 1: Cross section of the anterior segment of the eye. A: normal eye with deep anterior chamber and open angle. B: the path of aqueous humour in the normal eye. In primary open angle glaucoma, the outflow is reduced due to resistance to flow in the trabecular meshwork. C: an eye with a shallow anterior chamber is predisposed to closure of the angle by the peripheral iris resulting in a rapid increase in IOP, ACAG. D: Following an attack of ACAG, a peripheral iridectomy maintains an open angle (reproduced, with permission, from "Clinical Pharmacy and Therapeutics" London: Churchill Livingstone, 1999)
Figure 2
Figure 2: Classification of glaucoma

The most common glaucomatous disorders are primary open angle glaucoma (POAG), also known as chronic simple glaucoma, and acute closed angle glaucoma (ACAG), also known as primary angle closure glaucoma.
The incidence of POAG has been reported as between 0.4 and 2 per cent of the population over the age of 40, although it is thought that this level of detection accounts for only half the actual number.2
The incidence of POAG rises with age and is equally common in both sexes. Ten per cent of confirmed cases have first degree relatives (ie, parents, siblings or children) with the disease.3 It is more common in the Afro-Carribean population, with a risk of developing POAG five times greater than that in Caucasians.
Some ocular factors predispose a person to develop POAG. These include high myopia and elevated or asymmetric intraocular pressure. Non-ocular factors include diabetes mellitus, hypothyroidism and vasospasm.
In POAG, a relative obstruction to the outflow of aqueous humour through the trabecular meshwork results in a rise in intraocular pressure to a level above the normal range of 10-21mmHg. The raised pressure leads to direct damage of retinal nerve axons. Anoxia of these cells occurs due to compression of blood vessels and results in loss of visual field.
Related, but less common, disorders include normal pressure glaucoma (NPG), in which damage occurs despite the intraocular pressure being within the normal range, and ocular hypertension (OHT), a disorder characterised by intraocular pressure above the normal range without accompanying damage. These are symptomless disorders and the damage caused by POAG and NPG may not be recognised by the patient until a large area of the visual field has been lost. Diagnosis of these glaucomatous disorders is based upon visualisation of the angle of the anterior chamber with a gonioscopic contact lens (which contains angled mirrors to allow visualisation of the angle) and three main measurements: IOP measurement, optic disc examination and visual field testing.4 Management of the condition involves regular monitoring of these parameters.
The incidence of ACAG is approximately one in 1,000 in people over the age of 40, with a female to male ratio of 4:1. ACAG is characterised by an acute rise in IOP to levels as high as 70-80mmHg due to sudden obstruction of the angle of the anterior chamber by the peripheral iris (Figure 1). This happens in structurally predisposed eyes in which the angle of the anterior chamber is narrow. This may be a feature of a short (hypermetropic) eye or may be caused by a mature cataract causing shallowing of the anterior chamber. The attack can be provoked by dilatation of the pupil in dim light, as a result of the use of topical or systemic drugs5,6 or by stimulation of the sympathetic nervous system.
The symptoms of ACAG are pain in the eye, blurred vision (including haloes around lights due to corneal oedema) and nausea and vomiting (see Table 3, page 328). On occasion, non-ocular symptoms overshadow the primary ocular problem, delaying diagnosis and treatment.7
A wide range of drugs are used to treat glaucomatous disorders. The aim of treatment with any therapy is the same, ie, to reduce the intraocular pressure, preventing damage to the nerve fibres and the resulting development of visual defects. In ACAG, the reduction in intraocular pressure is followed by a peripheral laser iridotomy or surgical iridectomy, procedures in which holes are formed in the iris near the angle, to allow passage of aqueous humour through the iris and maintain an open angle (see Figure 1), in both eyes.8
The drugs used to treat glaucoma can be classified broadly into those that reduce the formation of aqueous humour and those that increase its outflow.

Drugs that reduce aqueous humour inflow

Drugs that reduce the formation of aqueous humour include the b-blockers and carbonic anhydrase inhibitors. Parasympathomimetics and prostaglandins increase the outflow and sympathomimetics have a dual action.

Beta-blockers

Table 1: Properties of ophthalmic beta-blockers
Drug beta1 selectivity Intrinsic sympathomimetic activity Membrane stabilising activity Lipophilicity Forms available in UK Preservative content per cent w/v Frequency of instillation
Betaxolol ++ _ + ++ Suspension 0.25per cent Benzalkonium chloride 0.01  Twice a day
Solution 0.5per cent  Benzalkonium chloride 0.01 
Suspension single dose unit 0.25 per cent Nil
Carteolol  – ++ – – Solution 1,2 per cent Benzalkonium chloride 0.005 Twice a day
Levobunolol – – – + Solution 0.5 per cent  Benzalkonium chloride 0.004  Once to twice a day
Single dose unit 0.5 per cent Nil
Metipranolol  – – +   Single dose unit 0.1, 0.3 per cent Nil Twice a day
Timolol  – – – + Solution 0.25, 0.5 per cent 
 		 Benzalkonium chloride 0.01 
 		 Twice a day 
 
 
Gel forming solution 0.25, 0.5 per cent Benzododecinium bromide 0.012 Once a day
Single dose unit 0.25, 0.5 per cent Nil Twice a day

Shortly before the introduction of the first ophthalmic b-blocker, timolol, to the UK market in the late 1970s, Zimmerman9 stated: "b-adrenergic blocking agents and specifically timolol may be an important breakthrough for the medical management of glaucoma."
There are now five topical b-blockers on the market: betaxolol, carteolol, levobunolol, metipranolol and timolol. Their efficacy and tolerability has given them the position of first line drugs in the management of POAG for over 20 years. They are also used in the treatment of OHT, NPG and some secondary glaucomas.
Beta adrenoceptor antagonists reduce intraocular pressure by 20 to 30 per cent by inhibiting b-mediated production of aqueous humour by the ciliary epithelium. It has also been suggested that they have an indirect vasoactive mechanism as a result of the accumulation of noradrenaline which constricts the blood vessels supplying the ciliary processes. The predominant b-receptor in the ciliary processes is b2 in character which explains the more potent IOP lowering effect of non-selective b-blockers over b1-selective blockers.10
Beta-blockers vary in a number of ways, including frequency of instillation, selectivity, possession of intrinsic sympathomimetic activity, membrane stabilising activity and lipid solubility (Table 1).11,12 The selection of a particular b-blocker from those available will therefore be influenced by local and systemic tolerability and co-existing disease states (Table 2).
Table 2: side effects of topical beta-blockers
Side effect Comments
Ocular  
Allergic blepharitis  
Burning and itching Associated with membrane stabilising activity
Blurred vision  
Conjunctival hyperaemia  
Corneal anaesthesia Associated with membrane stabilising activity
Dryness Associated with membrane stabilising activity
Foreign body sensation Associated with membrane stabilising activity
Macular oedema  
Pain  
Punctate keratitis Associated with membrane stabilising activity
Uveitis Anterior granulomatous uveitis seen with metipranolol
Systemic  
Respiratory  
Bronchoconstriction beta2-effect, less prominent with beta-blockers with cardioselectivity or ISA
Dyspnoea  
Vascular  
Hypotension beta1-effect, less prominent with beta-blockers with ISA
Bradycardia beta1-effect, less prominent with beta-blockers with ISA
Reduced cardiac stroke volume beta1-effect, less prominent with beta-blockers with ISA
Arrhythmias beta1-effect, less prominent with beta-blockers with ISA
Peripheral vasoconstriction beta2-effect, less prominent with beta-blockers with cardioselectivity or ISA
Dyslipidaemia Less prominent with beta-blockers with ISA
Endocrine  
Hypoglycaemia beta2-effect, less prominent with beta-blockers with cardioselectivity or ISA
Masking of tachycardia associated with hypoglycaemia beta1-effect, less prominent with beta-blockers with ISA
CNS  
Depression All CNS effects are central effects, less prominent with hydrophilic beta-blockers
Anxiety
Nightmares
Irritability
Fatigue
Hallucinations

Timolol Timolol is still taken as the gold standard in the treatment of glaucoma. It is the drug against which all others are tested in clinical trials. Timolol is non-selective and does not posses intrinsic sympathomimetic activity.
The drug is available in two strengths and in a variety of presentations, including a long acting gel-forming solution that is administered once daily. The once daily formulation has been shown to be as effective in lowering intraocular pressure as the twice daily solution,13 but gives rise to lower serum concentrations of timolol, resulting in significantly less attenuation of resting and peak heart rate.14
One study looking at an alternative method of administration of the drug showed that timolol was as effective in lowering intraocular pressure when administered sub-lingually as when administered topically.15 Although this method of administration is not licensed, the authors suggest that use of this alternative route of application may be useful in patients who have difficulty instilling eye-drops, or those who have ocular sensitivity to the drug or preservative system.
Metipranolol Metipranolol was originally available in three strengths in a multi-dose form. However, after reports of granulomatous fibrinous uveitis, the highest and then subsequently the two lower strengths of the multi-dose presentation were withdrawn. The only preparations currently available are the lower strength, single dose units.16
Like timolol, metipranolol is non-selective and does not possess intrinsic sympathomimetic activity. Its efficacy is similar to that of timolol and levobunolol but patient tolerability of the product is poor.17,18
Betaxolol Betaxolol is the only cardioselective drug among the topical b-blockers but it is not cardiospecific. After reports of bronchospasm following instillation of topical b-blockers, the Committee on Safety of Medicines warned that all b-blockers, including those with cardioselectivity, should be avoided in patients with obstructive airways disease.19 However, in patients who do not experience symptoms of obstructive airways disease, changing the topical b-blocker from timolol to betaxolol has been shown to improve cardiovascular and pulmonary parameters.20 In a small short term study of patients with glaucoma and asthma, patients intolerant of timolol used betaxolol without exacerbation of pulmonary symptoms or deterioration in measured pulmonary function tests.21
Betaxolol, due to its selective blockade of b1 receptors, does not lower the intraocular pressure as much as other topical b-blockers; however, it has shown a positive influence in visual field studies,22 and is the only b-blockers to include a reference to the beneficial effect on visual function in the summary of product characteristics.
Recently, a new formulation of betaxolol, a suspension using a novel ion exchange mechanism,23 was launched. The suspension, at a concentration of 0.25 per cent, has been shown to be as effective as the 0.5 per cent betaxolol solution.24
Carteolol Carteolol, uniquely among the topical b-blockers, possesses intrinsic sympathomimetic activity.11 Studies have shown that it is as effective as timolol,25 while the adverse local effects,26 cardiovascular effects27 and adverse changes in lipid profile,28 are less pronounced with carteolol than with timolol.
The efficacy and tolerability of carteolol has also been compared with that of betaxolol, as either drug may be preferred to timolol in patients with cardiorespiratory problems.
A small study of 20 patients found no significant difference in intraocular pressure lowering effect or cardiovascular or pulmonary parameters, although carteolol was better tolerated.29 Carteolol’s hydrophilicity may inhibit its passage across the blood-brain barrier, thereby reducing the possibility of adverse effects on the central nervous system.
Levobunolol Levobunolol, another non-selective b-blocker devoid of intrinsic sympathomimetic activity, was the first of the group to be licensed for once daily administration. In a three month study, once daily use of levobunolol 0.5 per cent was shown to be as effective in reducing the intraocular pressure as twice daily instillation.30 Although this study showed that levobunolol 0.5 per cent administered once daily was more effective than timolol 0.5 per cent solution once daily, a four year study conducted with twice daily instillation of both drugs showed similar ocular hypotensive efficacy.31 Moreover, a comparison of levobunolol with the recently introduced gel-forming solution of timolol showed no difference in intraocular pressure lowering or tolerability.32
Levobunolol is marketed by Allergan with the "C Cap", a compliance aid which the patient twists to denote the number of doses administered. This device has been shown to improve compliance in patients using twice daily regimens for glaucoma.33,34

Carbonic anhydrase inhibitors

This group of drugs inhibits carbonic anhydrase, an enzyme which facilitates the production of bicarbonate involved in the formation of aqueous humour in the ciliary process. Thus, inhibition of carbonic anhydrase II, the form of the enzyme found in the ciliary epithelium, results in a decrease in the production of aqueous humour.35 There are two carbonic anhydrase inhibitors available in the UK: acetazolamide, which is administered orally or by intramuscular or intravenous injection, and dorzolamide, which is used topically.
Acetazolamide Acetazolamide is indicated for the reduction of IOP in open angle and secondary glaucoma, and is used peri-operatively in ACAG. Near optimal effects are seen at a plasma concentration of 5-10 µg/ml. However, due to inter-patient differences in renal elimination, a standard dose will give large variations in plasma concentration and a difference of as much as six-fold in maintenance dose is required to achieve the optimal response.
The conventional dose of 250mg four times a day of acetazolamide tablets often gives rise to plasma concentrations above the optimal level. This does not always result in reductions in intraocular pressure any greater than those attained by 5-10 µg/ml, but may be associated with a higher incidence of untoward effects due to inhibition of carbonic anhydrases in other tissues.
Such side effects include malaise, fatigue, depression, anorexia and loss of weight and libido, correlated with metabolic acidosis from renal enzyme inhibition, altered taste due to carbonic anhydrase inhibition in the mouth, and gastritis, stomach burning, abdominal cramping and diarrhoea due to enzyme inhibition in the gastrointestinal tract.
Ocular side effects of transient myopia and blurred vision may result from the presence of carbonic anhydrase isoenzyme I, and perhaps isoenzyme II, in the corneal endothelium and carbonic anhydrase isoenzyme II in the lens.35
Acetazolamide is contraindicated in patients allergic to sulphonamides, to which the drug is chemically related. Other side effects of acetazolamide shared with sulphonamides include fever, blood dyscrasias and crystalluria.
Acetazolamide is more slowly absorbed from the slow release (SR) capsules than from the tablets. A study in healthy, elderly people has shown a relative bioavailability of acetazolamide from the SR formulation to be 79.1 per cent in plasma and 83.8 per cent in whole blood compared with the tablet formulation. The SR formulation still produces acetazolamide’s recognised adverse effects, but for those which are serum level dependent, the incidence and severity is reduced (data on file, Wyeth laboratories).
An injection of acetazolamide is normally the first drug administered in the treatment of ACAG. However, as a result of the unpleasant side effects and potentially life-threatening blood dyscrasias,36 oral acetazolamide is usually only used short term in this condition and as a "last resort" in the treatment of POAG. Acetazolamide should be used with care in elderly patients, who may have unrecognised renal impairment, as its use can lead to metabolic acidosis.37 An initial loss of potassium occurs but this is self-limiting, as is the diuresis, so potassium supplements are unnecessary unless the patient is hypokalaemic.38
Dorzolamide Dorzolamide, a potent and selective inhibitor of carbonic anhydrase isoenzyme II, is the only topical carbonic anhydrase inhibitor available in the UK. It is licensed as an adjunct to b-blockers in OHT, POAG and pseudoexfoliative glaucoma (a secondary open angle glaucoma from decreased aqueous outflow due to exfoliated material in the trabecular meshwork) in patients unresponsive to b-blockers, or used alone if b-blockers are contraindicated.
Dorzolamide has been shown to be as effective as betaxolol, but is less effective than timolol. It does not cause the metabolic acidosis or electrolyte imbalances that are generally associated with long term use of systemic carbonic anhydrase inhibitors39 and has been shown to be a well tolerated and effective substitute for these drugs in POAG.40 However, it is ineffective in ACAG.41 Dorzolamide is administered three times a day when used as a single agent but twice a day when used in combination with a b-blocker.42
As carbonic anhydrases are present in the cornea, a potential concern with the use of topical carbonic anhydrase inhibitors is their effect on corneal parameters. Studies have allayed these concerns as corneal permeability, thickness and hydration control parameters appear to be unaffected by dorzolamide.43-45
The most frequently reported symptoms and adverse effects with dorzolamide were transient bitter taste and burning and stinging of the eyes.
Other adverse effects and local symptoms include blurred vision, eye itching, tearing, headache, nausea, eyelid inflammation and asthenia/fatigue.
Rosenberg et al have suggested that topical dorzolamide and oral acetazolamide should not be used concurrently as their effects are not additive, either drug alone producing a maximum reduction in IOP and aqueous humour formation.46 However, Larsson and Alm concluded that dorzolamide suppresses aqueous flow to a lesser degree than a maximum dose of acetazolamide. They showed an additional 16 per cent reduction in aqueous flow when acetazolamide 250mg was administered to patients using topical dorzolamide.47 Additional IOP reduction by concomitant use of topical and oral carbonic anhydrase inhibitors was confirmed by Sonty et al, although no dosage details were given.48
A recently launched preparation called Cosopt combines dorzolamide with timolol 0.5 per cent. The combination has been shown to be well tolerated and as effective as its components when administered separately.49,50 The combination has a number of advantages, including abolition of the potential for dilution and wash out that can occur when two drugs are used concomitantly in separate formulations, and a lower exposure to preservative.

Mrs Titcomb is directorate pharmacist, ophthalmology, Birmingham and Midland eye centre, City hospital NHS trust, Birmingham

References

1. Hitchings RA. Screening for glaucoma. BMJ 1986;292:505-6.
2. Pitts Crick R. Epidemiology and screening of open-angle glaucoma. Curr Opinion Ophthalmol 1994;5:3-9.
3. Tuck MW, Pitts Crick R. The proportion of confirmed glaucomas who have a family history of the disease. Ophthalmic Physiol Opt 1996;16:86-7.
4. Infield DA, O’Shea JG. Glaucoma: diagnosis and management. Postgrad Med J 1998;74:709-15.
5. Ritch R, Krupin T, Henry C, Kurata F. Oral imipramine and acute closure glaucoma. Arch Ophthalmol 1994;112:67-81.6.
6. Reuser T, Flanagan DW, Borland C, Bannerjee DK. Acute angle closure glaucoma occurring after nebulized bronchodilator treatment with ipratropium bromide. J R Soc Med 1992;85:499-500.
7. Dayan M, Turner B, McGhee C. Acute angle closure glaucoma masquerading as systemic illness. BMJ 1996;313:413-5.
8. Campbell DG. Angle-closure glaucoma, an update. Perspect Ophthalmol 1980;4:123-7.
9. Zimmerman TJ. Timolol. A b-adrenergic blocking agent for the treatment of glaucoma. Arch Ophthalmol 1977;95:601-4.
10. Trope GE, Clark B. Beta adrenergic receptors in pigmented ciliary processes. Br J Ophthalmol 1982;66:788-92.
11. Zimmerman TJ. Topical ophthalmic beta blockers: a comparative review. Journ Ocul Pharmacol 1993;9:373-84.
12. Novack GD. Ophthalmic beta-blockers since timolol. Surv Ophthalmol 1987;31:307-27.
13. Shedden AH. Timolol maleate in gel-forming solution: a novel formulation of timolol maleate. Chibret Internat Journ Ophthalmol 1994;10:32-6.
14. Dickstein K, Aarsland T. Comparison of the effects of aqueous and gellan ophthalmic timolol on peak exercise performance in middle-aged men. Am J Ophthalmol 1996;121:367-71.
15. Sadiq SA, Vernon SA. Sublingual timolol-an alternative to topical medication in glaucoma? Br J Ophthalmol 1996;80:532-5.
16. Akingbehin T, Villada JR. Metipranolol-associated granulomatous anterior uveitis. Ibid 1991;75:519-23.
17. Mills KB, Wright G. A blind randomised cross-over trial comparing metipranolol 0.3 per cent with timolol 0.25 per cent in open-angle glaucoma: a pilot study. Ibid 1986;70:39-42.
18. Krieglstein GK, Novack GD, Voepel E, Schwarzbach G, Lange U, Schunck KP et al. Levobunolol and metipranolol: comparative ocular hypotensive efficacy, safety and comfort. Ibid 1987;71:250-3.
19. Committee on Safety of Medicines. Bronchospasm associated with cardioselective and topical B-blockers. Current problems no.28, May 1990.
20. Diggory P, Cassels-Brown A, Vail A, Abbey LM, Stewart Hillman J. Avoiding unsuspected respiratory side-effects of topical timolol with cardioselective or sympathomimetic agents. Lancet 1995;345:1604-6.
21. Van Buskirk EM, Weinreb RN, Berry DP, Lustgarten JS, Podos SM, Drake MM. Betaxolol in patients with glaucoma and asthma. Am J Ophthalmol 1986;101:531-4.
22. Collingnon-Brach J. Longterm effect of topical beta-blockers on intraocular pressure and visual field sensitivity in ocular hypertension and chronic open-angle glaucoma. Surv Ophthalmol 1994;38(Suppl):S149-55.
23. Weinreb RN, Jani R. A novel formulation of an ophthalmic beta-adrenoceptor antagonist. Journ Parenteral Sci Technol 1992;46:51-3.
24. Weinreb RN, Caldwell DR, Goode SM, Horwitz BL, Laibovitz R, Shrader CE et al. A double-masked three-month comparison between 0.25 per cent betaxolol suspension and 0.5 per cent betaxolol ophthalmic solution. Am J Ophthalmol 1990;110:189-92.
25. Stewart WC, Cohen JS, Netland PA, Weiss H, Nussbaum LL and the nocturnal investigation of glaucoma hemodynamics trial study group. Efficacy of carteolol hydrochloride 1 per cent vs. timolol maleate 0.5 per cent in patients with increased intraocular preure. Ibid 1997;124:498-505.
26. Scoville B, Mueller B, White BG, Krieglstein GK. A double-masked comparison of carteolol and timolol in ocular hypertension. Ibid 1988;105:150-4.
27. Netland PA, Weiss HS, Stewart WC, Cohen JS, Nussbaum LL and the night study group. Cardiovascular effects of topical carteolol hydrochloride and timolol maleate in patients with ocular hypertension and primary open-angle glaucoma. Ibid 1997;123:465-77.
28. Freedman SF, Freedman NJ, Shields MB, Lobaugh B, Samsa GP, Keates E et al. Effects of ocular carteolol and timolol on plasma high-density lipoprotein cholesterol level. Ibid 1993;116:600-11.
29. Sunder Raj P, Agarwal P, Dang MS. Carteolol 2 per cent and betaxolol 0.5 per cent: A comparison of efficacy and side effects. Glaucoma 1993;15:151-7.
30. Wandel T, Charap AD, Lewis RA, Partamian L, Cobb S, Lue JC et al. Glaucoma treatment with once-daily levobunolol. Am J Ophthalmol 1986;101:298-304.
31. The levobunolol study group. Levobunolol. A four year study of efficacy and safety in glaucoma treatment. Ophthalmol 1989;96:642-5.
32. Cantor LB, Alvi NP, Hoop JS, Katz LJ, Flartey K, Brizendine EJ et al. Comparison of once daily levobunolol 0.5 per cent versus timolol xe 0.5 per cent for the control of intraocular pressure and patient comfort. Invest Ophthalmol Vis Sci 1997;38:S558.
33. Sclar DA, Skaer TL, Chin A, Okamoto MP, Nakahiro RK, Gill MA. Effectiveness of the C Cap in promoting prescription refill compliance among patients with glaucoma. Clin Ther 1991;13:396-400.
34. Chang JS, Lee DA, Petursson G. Spaeth G, Zimmerman TJ, Hoskins HD et al. The effect of a glaucoma medication reminder cap on patient compliance and intraocular pressure. J Ocular Pharmacol 1991;7:117-24.
35. Wistrand PJ. The use of carbonic anhydrase inhibitors in ophthalmology and clinical medicine. Ann N Y Acad Sci 1984;429:609-19.
36. Everitt DE, Avorn J. Systemic effects of medications used to treat glaucoma. Ann Intern Med 1990;112:120-5.
37. Maisey DN, Brown RD. Acetazolamide and symptomatic metabolic acidosis in mild renal failure. BMJ 1981;283:1527-8.
38. Critchlow AS, Freeborn SF, Roddie RA. Potassium supplements during treatment of glaucoma with acetazolamide. BMJ 1984;289:21.
39. Strahlman E, Tipping R, Vogel R and the International Dorzolamide Study Group. A double-masked, randomized, one year study comparing dorzolamide (Trusopt), timolol and betaxolol. Arch Ophthalmol 1995;113:1009-16.
40. Kitazawa Y, Azuma I, Araie M ,Shirato S. Topical dorzolamide hydrochloride can be a substitute for oral carbonic anhydrase inhibitors. Invest Ophthalmol Vis Sci 1994;35:2177.
41. Pfeiffer N, Sell E, Winkgen A, Hochgesand D, Pitz S, Schwenn O et al. Dorzolamide in acute angle-closure glaucoma. Ibid 1996;37:S1009.
42. Gamero GE, Robison MY, Harmon H, Goldsmith LJ, Fechtner RD, Zimmerman TJ. The duration of action of dorzolamide 2 per cent with concomitant use of a topical beta adrenergic antagonist. Ibid 1997;37:S1102.
43. Park IK, Kim JY, Wee WR, Kim DM. Effect of dorzolamide on corneal endothelial permeability. Ibid 1997;38:S1095.
44. Kappil JC, Bouchard CS, Savitt ML, Kopitas E. The effect of dorzolamide on corneal thickness in pseudophakic patients. Ibid 1997;38:S559.
45. Nguyen TQT, Boisjoly HM, Giasson C, Charest M, Amyot M, Lesk M et al. Corneal hydration control after short-term use of Trusopt. Ibid 1997;38:S1095.
46. Rosenberg LF, Krupin T, Tang LQ, Hong PH, Ruderman JM. Combination of systemic acetazolamide and topical dorzolamide in reducing intraocular pressure and aqueous humor formation. Ophthalmol 1998;105:88-93.
47. Larsson LI, Alm A. Aqueous humor flow in human eyes treated with dorzolamide and different doses of acetazolamide. Arch Ophthalmol 1998;116:19-24.
48. Sonty S, Villivalam V, Sonty SP, Viana MAG. Additive ocular hypotensive effect of oral CAInhibitors to topical CAInhibitors and vice versa in glaucomatous eyes on maximum tolerated medical therapy (MTMT). Invest Ophthalmol Vis Sci 1997;38:S561.
49. Strohmaier K, Snyder E, DuBiner H, Adamsons I, the Dorzolamide Study Group. The efficacy and safety of the dorzolamide-timolol combination versus the concomitant administration of its components. Ophthalmol 1998;105:1936-44.
50. Boyle JE, Ghosh K, Gieser DK, Adamsons IA, the Dorzolamide-Timolol Study Group. A randomized trial comparing the dorzolamide-timolol combination given twice daily to monotherapy with timolol and dorzolamide. Ibid 1998;105:1945-51.