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Pharmaceutical Journal Vol 263 No 7065 p526-530
October 2, 1999 Continuing Education

Eye disorders

Treatment of glaucoma: part 2

By Lucy C. Titcomb, MCPP, MRPharmS

In this second part of the article about glaucoma in our eye disorders series, drugs that increase aqueous humour outflow, drugs that both reduce inflow and increase outflow of humour and other treatments are discussed. Part one of this article, which examined the pathogenesis of glaucoma and drugs that reduce aqueous humour inflow, was published in an earlier issue

As discussed in part one of this article (August 28, p324), the aim of glaucoma treatment is to reduce the intraocular pressure. This prevents both damage to nerve fibres and the subsequent development of visual defects. The drugs used to treat glaucoma either reduce the formation of aqueous humour or increase its outflow. Drugs reducing the formation of aqueous humour were covered in the first part of this article.

Parasympathomimetics

Parasympathomimetics mimic the action of the parasympathetic nervous system, causing stimulation of the sphincter pupillae in the iris. The stimulation of the ciliary muscle leads to opening of the trabecular meshwork through a pulling action on ocular tissues, which increases aqueous outflow. However, it also results in near vision, an undesirable effect as far as the patient is concerned. Stimulation of the sphincter pupillae causes miosis, another adverse effect, which reduces both the amount of light entering the eye and the field of vision. Parasympathomimetics are used in the treatment of acute closed angle glaucoma (ACAG) after the intraocular pressure (IOP) has been lowered by acetazolamide and are also used in primary open angle glaucoma (POAG). They are contraindicated in glaucoma secondary to inflammatory disorders because pilocarpine will further break down the blood-aqueous barrier.

Other articles in this eye disorders series

Pilocarpine Pilocarpine, a naturally occurring alkaloid that is obtained from the leaves of south American shrubs of the genus Pilocarpus, has been used in ophthalmology for over 100 years. Pilocarpine leads to a large reduction in intraocular pressure, but the adverse effects of miosis and accommodative spasm, coupled with the high frequency of dosage, make it an unpopular drug, particularly with younger patients who are more affected by these side effects. Caution should be exercised in the use of pilocarpine in patients with shallow anterior chambers, as it can reduce the depth of the anterior chamber and precipitate ACAG. Long term use of pilocarpine can lead to permanent miosis, a disadvantage in patients who are likely to require cataract extraction or other procedures involving pupil dilation.1
Systemic side effects such as bronchoconstriction, salivation, lacrimation, sweating and increased tone and motility of the gastro-intestinal tract (leading to nausea, vomiting and diarrhoea) are rare but may be seen in patients receiving frequent instillations of the drug in the treatment of ACAG. Patients with underlying conduction system disease (His-Purkinje conduction) are at risk from developing atrioventricular block if pilocarpine is used intensively.2
Ocusert-Pilo is a slow release ophthalmic delivery system consisting of a reservoir of pilocarpine bordered by a semi-permeable membrane through which pilocarpine is slowly released to mix with the tear film. The small, elliptical device is placed under the upper or lower eyelid and left in place for seven days. It releases a dose of 20 or 40microg of pilocarpine per hour, which reduces the intensity of the drug's side effects.3 Ocusert-Pilo is a useful alternative for patients who can tolerate and retain the system.4
A more recent introduction is a gel formulation of pilocarpine, which, when applied at bedtime, gives 24 hour control of intraocular pressure5,6 and is as effective as twice daily timolol 0.5 per cent.7 The patient is relatively unaffected by the myopia which has, to a large extent, worn off after a night's sleep.8
Other parasympathomimetics The more potent, direct acting agent carbachol (a synthetic derivative of choline) and the indirectly acting cholinesterase inhibitors, demecarium bromide and ecothiopate iodide, are now rarely used, but are of value when a miotic is required in a patient allergic to pilocarpine.9,10

Prostaglandin analogue

The majority of the aqueous humour leaves the eye via the conventional route of the trabecular meshwork, Schlemm's canal and episcleral veins (Figure 1a). However, 10 to 20 per cent of outflow is via the non-conventional or uveoscleral route where the aqueous humour passes between the ciliary muscle bundles and into the episcleral tissues where it is reabsorbed into orbital blood vessels and drained via the conjunctival vessels (Figure 1b).
Figure 1a
Figure 1a: Trabecular outflow
(reproduced with the permission of Phamacia & Upjohn)
 Figure 2b
Figure 1b: Uveoscleral outflow
(reproduced with the permission of Phamacia & Upjohn)

Latanoprost is the first of a new class of drugs to be launched in the UK. It is licensed for the treatment of POAG and ocular hypertension (OHT) in patients who are intolerant of or insufficiently responsive to other agents. It is a derivative of prostaglandin F2a which does not cause the conjunctival hyperaemia (red eye), irritation and foreign body sensation seen with other prostaglandins.11 Latanoprost doubles the outflow of aqueous humour through the non-conventional uveoscleral route12 and has been shown to be at least as effective as, or more effective than, timolol.13,14 It is instilled once daily, at night, a regimen that is more effective than application in the morning.15
Latanoprost is relatively free of systemic side effects but has some interesting local effects. Pigmentation of the iris occurs in patients with mixed colour irides (green-brown or blue-brown) after three to six months of use, which is a result of increased deposition of melanin in the melanocytes.16 An increase in the length and thickness of the eyelashes17 and pigmentation of the palpebral skin (skin of the eyelids) are side effects recognised since the product's launch and have only recently been added to the summary of product characteristics.
Infrequent incidents of uveitis and cystoid macular oedema (accumulation of fluid in the macular area of the retina) have also been reported with this agent. Although a causal relationship has not been established, the use of latanoprost in patients with a history of, or known risk factors associated with, cystoid macular oedema or uveitis, should be avoided. Recently, an article presenting three case studies that demonstrate a possible association between latanoprost and Herpes simplex keratitis has been published.18 The authors conclude that prostaglandins may be a final common pathway for stimulating recurrence of Herpes simplex keratitis.

Drugs which reduce aqueous humour inflow and increase aqueous humour outflow

The sympathomimetics used in the treatment of glaucoma can be divided into the older non-selective drugs which stimulate both a and b receptors and the newer, selective ones which stimulate a receptors only. Sympathetic stimulation in the eye is complex but may be summarised as follows:

Non-selective sympathomimetics

Adrenaline Adrenaline was the first sympathomimetic drug to be used in the treatment of primary open angle glaucoma. Its non-selective stimulation of a and b receptors leads to antagonistic increases and decreases in aqueous humour production. An increase in outflow through both trabecular and uveoscleral routes results in a net reduction in intraocular pressure19 (Figure 1). This complex mode of action helps to explain why the combination of betaxolol (a b1-selective blocker) and adrenaline results in a greater fall in intraocular pressure than that seen when adrenaline is combined with non-selective b-blockers.20,21
Adrenaline causes short lived conjunctival vasoconstriction followed by rebound vasodilatation and a severe red eye. The drug is subject to photo-oxidation and can cause conjunctival pigmentation.22 The pigmentation (oxidised drug) may build up to such an extent that lacrimal stones (deposits of the oxidised drug in the lacrimal system) are formed.23 Another local adverse effect of adrenaline is the occurrence of cystoid macular oedema in aphakic patients, ie, those without their natural lens.24 This effect is less likely to occur now that the majority of cataract extractions are undertaken using the phakoemulsification technique in which the posterior capsule of the lens is left intact. Being a mydriatic drug, adrenaline is contraindicated in patients with a shallow anterior chamber as it may precipitate ACAG. Systemic effects of adrenaline have also been reported, with an incidence of 25 per cent in one study.25 These unfortunate side effects of adrenaline have led drug companies to investigate how they can reduce the concentration of adrenaline applied to the eye.
Guanethidine Guanethidine, an adrenergic neurone blocker, produces a pharmacological denervation supersensitivity to adrenaline, which enables lower concentrations of adrenaline to be used in a combination of the two drugs.26
Guanethidine 1 per cent plus adrenaline in concentrations of 0.2 per cent, 0.25 per cent or 0.5 per cent, is as effective as adrenaline 1 per cent.27 Guanethidine 3 per cent plus adrenaline 0.5 per cent is more effective than pilocarpine 1 or 2 per cent.28
Ganda (guanethidine and adrenaline), originally launched in concentrations of 1+0.2, 3+0.5, 5+0.5 and 5+1, is now only available as the two lower strengths as a result of reports of conjunctival scarring and corneal ulceration following use of the higher strengths of guanethidine.
Dipivefrin Dipivefrin, or dipivalyl adrenaline, is a lipophilic pro-drug of adrenaline, broken down into adrenaline and pivalic acid molecules by esterases in the aqueous humour. As the drug's lipophilicity enhances penetration through the cornea,29 0.1 per cent dipivefrin causes a similar level of lowering intraocular pressure as 2 per cent adrenaline.30,31
In contrast to studies with adrenaline, dipivefrin has been shown to be effective when used in combination with non-selective b-blockers.32,33 Although use of the pro-drug does not prevent local side effects and the contraindication in patients with a shallow anterior chamber remains, some local side effects such as the discoloration of hydrophilic contact lenses do not occur34 and systemic cardiovascular effects are less common.25

Selective sympathomimetics

Following the launch of the b-blockers, the use of the sympathomimetics declined. However, the introduction of the more selective apraclonidine renewed interest in this class of drugs.
Apraclonidine Apraclonidine stimulates predominantly a2 but also a1 receptors and lowers intraocular pressure by reducing aqueous humour formation. The lower strength (0.5 per cent) formulation is licensed for short-term use in patients with POAG on maximally tolerated medical therapy, eg, patients awaiting surgery. The 1 per cent concentration is approved for the treatment of intraocular pressure elevation associated with anterior segment laser surgery.
In POAG, apraclonidine is administered three times a day and, in the short term, produces an additional 20 per cent fall in intraocular pressure in patients on maximally tolerated medical therapy.35 However, tachyphylaxis develops rapidly. A result of this, and an unfavourable side effect profile – which includes mydriasis, conjunctival blanching, ciliary vasoconstriction and eyelid retraction, due to stimulation of a1-receptors36 – its place in the treatment of POAG has largely been taken by brimonidine.
Brimonidine Brimonidine is a highly selective a2-agonist which lowers intraocular pressure by reducing aqueous inflow and increasing aqueous outflow through the non-conventional or uveo-scleral route. The ocular hypotensive effect of brimonidine may also be mediated through stimulation of an imidazoline receptor.37 Although as effective as timolol at its peak of action, it is significantly less effective than timolol at trough.38 However, it is more effective than betaxolol at both its peak and trough of action.39 Brimonidine is licensed as adjunctive therapy in patients who have not responded to b-blockers alone and as monotherapy in patients who are intolerant of b-blockers as it causes no clinically significant effect on heart rate, blood pressure or FEV1.40 It is administered twice a day, an advantage over apraclonidine.
Comparison of selective sympathomimetics Both apraclonidine and brimonidine cause allergic reactions but the percentage of patients affected with brimonidine is roughly a third of that seen with apraclonidine. This may be related to apraclonidine's rapid oxidation to reactive agents that can produce antigens and trigger allergy. Other side effects include dry mouth, fatigue and, not surprisingly for derivatives of clonidine, depression. These drugs should not be used in depressed patients, especially those on tricyclic antidepressants or monoamine oxidase inhibitors. Mydriasis and eyelid retraction encountered with the less selective apraclonidine was not seen in a one-year study in 374 patients using brimonidine.41

Preservation of visual field

Although the majority of clinical trials using anti-glaucoma agents concentrate on the agent's ability to lower intraocular pressure, the aim of treatment is to preserve visual field. In ocular hypertensives, lowering IOP with a non-selective b-blocker did not prevent the development of glaucomatous field defects.42 Przydryga43 suggests that blockade of b2-receptors, seen to a greater extent with the non-selective b-blockers than with betaxolol, causes vasoconstriction of retinal arteries. In theory, the possession of intrinsic sympathomimetic activity (ISA) will also reduce b2-mediated vasoconstriction and evidence of favourable effects on retinal haemodynamics have been published for betaxolol,44 and carteolol 45,46 while timolol significantly reduces pulsatile ocular blood flow. Conversely, levobunolol, another non-selective b-blocker without ISA, has also been shown to increase ocular pulsatile blood flow.47
Latanoprost has been shown to increase ocular perfusion pressure to a greater extent than timolol in normal tension glaucoma 48 and dorzolamide increases capillary blood velocity in the retina suggesting enhancement of retinal perfusion.49 Interest has been aroused in the neuro-protective effect of betaxolol 50 and brimonidine,51 to date shown only in the rat eye.

Other drug treatments

A number of other drugs have been shown to reduce intraocular pressure. Forskolin, a diterpene derivative of the plant Coleus forskoli, lowers IOP in normal eyes. A solution of 1 per cent forskolin reduced IOP by increasing intracellular cyclic adenosine monophosphate. It acted directly on adenylate cyclase for at least five hours without any significant change in pulse rate or blood pressure.55
In healthy volunteers, bromocriptine eye-drops 0.025 per cent and 0.05 per cent significantly reduced IOP without affecting pupil diameter or prolactin concentrations. The authors suggest that the drug may have a-adrenoceptor antagonist actions or its effect is mediated via stimulation of intraocular dopamine receptors.56
The active principle of cannabis, 39-tetra-hydrocannabinol, has been shown to lower IOP when smoked by glaucomatous patients 57 but observations on other routes of administration have been limited to animal experiments.

Non-medical therapy

If medical therapy fails to control the intraocular pressure and visual field loss continues, the aqueous outflow may be increased by surgical intervention. Laser trabeculoplasty involves placing 50 to 100 laser burns on the anterior portion of the trabecular meshwork. Such treatment induces mechanical, cellular and biochemical changes within the trabecular meshwork, causing decreased outflow resistance.
Surgical trabeculectomy involves making a new channel for aqueous humour to flow out of the eye under the conjunctiva. An anti-metabolite, 5-fluor-ouracil or mitomycin, is sometimes applied locally as an adjunct to surgery to reduce postoperative scarring. If these measures fail, the insertion of a silicone tube, or the destruction or detachment of the ciliary body, may be undertaken.58 Some ophthalmologists argue that early trabeculectomy gives the best prognosis for maintenance of the visual field59 and there is growing evidence that chronic topical medical therapy has a deleterious effect on surgical outcome due to the adverse effects of topical antiglaucomatous agents on the conjunctiva.60 However, ocular surgery is not without risks and subconjunctival scarring resulting in surgical failure, choroidal and retinal detachment, cataract formation and endophthalmitis (a sight threatening intraocular infection) may follow surgery.

Conclusion

In the next few years we may expect to see other topical carbonic anhydrase inhibitors, selective sympathomimetics and prostaglandin analogues introduced. Therapeutic options available to the ophthalmologist for the treatment of primary open angle glaucoma are wide and varied and patients unable to tolerate any of the drugs available are rarely encountered. With an ageing population, the cost of treating glaucoma (Figure 2) has become a topic of interest and various studies concentrating on cost have been published.61-63 The availability of free eye tests for first degree relatives of glaucoma sufferers over the age of 40, and the re-introduction of free eye tests for the over 60s, more timely diagnosis and better treatments give rise to hope for this group of patients.

Figure 2
Figure 2: Annual cost of glaucoma treatment for one eye (prices from MIMS and Drug Tariff, May 1999)

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

References

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2. Littman L, Kempler P, Rohla M, Fenyvesi T. Severe symptomatic atrioventricular block induced by pilocarpine eye drops. Arch Intern Med 1987;147:586-7.
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12. Toris CB, Camras CB, Yablonski ME. Effects of PhXA41, a new prostaglandin F2a analog, on aqueous humor dynamics in human eyes. Ophthalmol 1993;100:1297-304.
13. Camras CB, the United States latanoprost study group. Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma. Ibid 1996;103:138-47.
14. Mishima HK, Masuda K, Kitazawa Y, Azuma I, Araie M. A comparison of latanoprost and timolol in primary open angle glaucoma and ocular hypertension, a 12-week study. Arch Ophthalmol 1996;114:929-32.
15. Alm A, Stjernschantz J, the Scandinavian latanoprost study group. Effects on intraocular pressure and side effects of 0.005 per cent latanoprost applied once daily, evening or morning. Ophthalmol 1995;102:1743-52.7.
16. Watson P, Stjernschantz J, the latanoprost study group. A six-month, randomized, double-masked study comparing latanoprost with timolol in open-angle glaucoma and ocular hypertension. Ibid 1996;103:126-37.
17. Wand M. Latanoprost and hyperpigmentation of eyelashes. Arch Ophthalmol 1997;155:1206-8.
18. Wand M, Mitchell Gilbert C, Leisegang TJ. Latanoprost and herpes simplex keratitis. Am J Ophthalmol 1999;127:602-604.
19. Thomas JV, Epstein DL. Timolol and epinephrine in primary open angle glaucoma. Transient additive effect. Arch Ophthalmol 1981;99:91-5.
20. Allen RC, Epstein DL. Additive effect of betaxolol and epinephine in primary open angle glaucoma. Ibid 1986;104:1178-84.
21. Goldberg I, Ashburn FS, Palmberg PF. Timolol and epinephrine, a clinical study of ocular interactions. Ibid 1980;98:484-6.
22. Corwin ME, Spencer WJ. Conjunctival melanin depositions: a side effect of topical epinephrine therapy. Ibid 1963;69:317-21.
23. Podos SM. Pharmacology of ocular drugs. 2. Epinephrine. Ophthalmology 1980;87:721-3.
24. Kolker AE, Becker B. Epinephrine maculopathy. Arch Ophthalmol 1968;79:552-62.
25. Kerr CR, Hass I, Drance SM, Walters MB, Schulzer M. Cardiovascular effects of epinephrine and dipivalyl epinephrine applied topically to the eye in patients with glaucoma. Br J Ophthalmol 1982;66:109-14.
26. Paterson GD, Paterson G. Drug therapy of glaucoma. Ibid 1972;56:288-94.
27. Murray A, Glover D, Hitchings RA. Low-dose combined guanethidine 1 per cent and adrenaline 0.5 per cent in the treatment of chronic simple glaucoma: a prospective study. Ibid 1981;65:533-5.
28. Romano J, Patterson G. Evaluation of a 5 per cent guanethidine and 0.5 per cent adrenaline mixture (Ganda 5.05) and of a 3 per cent guanethidine and 0.5 per cent adrenaline mixture (Ganda 3.05) in the treatment of open angle glaucoma. Ibid 1979;63:52-5.
29. Mandell AI, Stentz F, Kitabchi AE. Dipivalyl epinephrine: a new pro-drug in the treatment of glaucoma. Ophthalmol 1978;85:268-75.
30. Kass MA, Mandell AI, Goldberg I, Paine JM, Becker B. Dipivefrin and epinephrine treatment of elevated intraocular pressure. A comparative study. Arch Ophthalmol 1979;97:1865-6.
31. Kohn AN, Moss AP, Hargett NA, Ritch R, Smith H Jr., Podos SM. Clinical comparison of dipivalyl epinephrine and epinephrine in the treatment of glaucoma. Am J Ophthalmol 1979;87:196-201.
32. Allen RC, Robin AL, Long D, Novack GD, Lue JC, Kaplan G. A combination of levobunolol and dipivefrin for the treatment of glaucoma. Arch Ophthalmol 1988;106:904-7.
33. Plane C, Steen C, Borrmann L, Chen K, Duzman E, Leon J. Additive ocular hypotensive effect of dipivefrin and timolol. Glaucoma 1990;12:16-9.
34. Newton MJ, Nesburn AB. Lack of hydrophilic lens discoloration in patients using dipivalyl epinephrine for glaucoma. Am J Ophthalmol 1979;87:193-5.
35. Robin AL, Ritch R, Shin DH, Smythe B, Mundorf T, Lehmann RP and the apraclonidine maximum tolerated medical therapy study group. Short-term efficacy of apraclonidine hydrochloride added to maximum-tolerated medical therapy for glaucoma. Ibid 1995;120:423-32.
36. Stewart WC, Ritch R, Shin DH, Lehmann RP, Shrader CE, van Buskirk EM and the apraclonidine adjunctive therapy study group. The efficacy of apraclonidine as an adjunct to timolol therapy. Arch Ophthalmol 1995;113:287-92.
37. Toris CB, Gleason ML, Camras CB, Yablonski ME. Effects of brimonidine on aqueous humor dynamics in human eyes. Ibid 1995;113:1514-7.
38. Schuman JS. Clinical experience with brimonidine 0.2 per cent and timolol 0.5 per cent in glaucoma and ocular hypertension. Surv Ophthalmol 1996;41(Suppl 1):S27-37.
39. Serle JB. The brimonidine study group. A comparison of the safety and efficacy of twice daily brimonidine 0.2 per cent versus betaxolol 0.25 per cent in subjects with elevated intraocular pressure. Ibid 1996:41(Suppl 1):S39-47.
40. Cantor LB, Burke J. Drug evaluation. Pulmonary-allergy, dermatological, gastrointestinal and arthritis. Brimonidine. Exp Opin Investigat Drugs 1997;6:1063-83.
41. Schuman JS, Horwitz B, Choplin NT, David R, Albracht D, Chen K et al. A one year study of brimonidine twice daily in glaucoma and ocular hypertension. Arch Ophthalmol 1997;115:847-52.
42. Schulzer M, Drance SM, Douglas GR. A comparison of treated and untreated glaucoma suspects. Ophthalmol 1991;98:30193.
43. Przydryga J. Is there more to glaucoma than control of IOP? An overview of possible vascular effects of beta-blockers. New Trend Ophthalmol 1992;38(Suppl):S118-24.
44. Boles Carenini A, Sibour G, Boles Carenini B. Differences in the long term effect of timolol and betaxolol on the pulsatile ocular blood flow. Surv Ophthalmol 1994;38(Suppl):S118-24.
45. Mihara M, Matsuo N, Koyama T, Tsuji T. Studies on the retinal mean circulation time in eyes treated with carteolol (Mikelan) by means of fluorescein video-angiography and image analysis. Ther Res 1989;10:161-7.
46. Yamazaki S, Baba H. Acute effect of topical carteolol on ocular pulsatile volume change. Acta Ophthalmol 1993;71:760-4.
47. Bosem ME, Lusky M, Weinreb RN. Short-term effects of levobunolol on ocular pulsatile blood flow. Am J Ophthalmol 1992;114:280-6.
48. Drance SM, Crichton A, Mills RP. Comparison of the effect of latanoprost 0.005 per cent and timolol 0.5 per cent on the calculated ocular perfusion pressure in patients with normal-tension glaucoma. Ibid 1998;125:585-92.
49. Harris A, Arend O, Arend S, Martin B. Effects of topical dorzolamide on retinal and retrobulbar hemodynamics. Acta Ophthalmol Scand 1996;74:569-72.
50. Osborne NN, Cazevieille C, Carvalho AL, Larsen AK, DeSantis L. In vivo and in vitro experiments show that betaxolol is a retinal neuroprotective agent. Brain Res 1997;751:113-23.
51. Burke J, Schwartz M. Preclinical evaluation of brimonidine. Surv Ophthalmol 1996;41:S9-18.
52. Kooner KS, Zimmerman TJ. Antiglaucoma therapy during pregnancy - part I. Annal Ophthalmol 1988;20:166-9.
53. Kooner KS, Zimmerman TJ. Antiglaucoma therapy during pregnancy - part II. Ibid 1988;20:208-11.
54. Samples JR, Meyer SM. Use of ophthalmic medications in pregnant and nursing women. Am J Ophthalmol 1988;106:616-23.
55. Caprioli J, Sears M. Forskolin lowers intraocular pressure in rabbits, monkeys and man. Lancet 1983;8331:958-60.
56. Mekki QA, Warrington SJ, Turner P. Bromocriptine eyedrops lower intraocular pressure without affecting prolactin levels. Ibid 1984;8371:287-8.
57. Meritt JC, Crawford WJ, Alexander PC, Anduze AL, Gelbart SS. Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmol 1980;87:222-8.
58. Khaw PT. The surgical treatment of glaucoma. Optician 1994;208:26-9.
59. Jay JL, Murray SB. Early trabeculectomy versus conventional management in primary open angle glaucoma. Br J Ophthalmol 1988;72:881-9.
60. Broadway D, Grierson I, Hitchings R. Adverse effects of topical antiglaucomatous medications on the conjunctiva. Ibid 1993;77:590-6.
61. Rocchi A, Tingey D. Economic evaluation of dorzolamide vs pilocarpine for primary open-angle glaucoma. Can J Ophthalmol 1997;32:414-8.
62. Ellis PP, Price PK, Kelmenson R, Rendi MA. Effectiveness of generic acetazolamide. Arch Ophthalmol 1982;100:1920-2.
63. Ainsworth JR, Jay JL. Cost analysis of early trabeculectomy v conventional management in primary open angle glaucoma. Eye 1991;5:322-32.