Range of Medications for Glaucoma May Reduce the Need for Surgery

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Range of Topically Active Medications for Treatment of Glaucoma May Reduce the Need for Surgery

[Drug & Ther Perspect 17(10):5-10, 2001. © 2001 Adis International Limited]

IntroductionGlaucoma is a relatively common eye disorder and can lead to blindness. Medical treatment should be initiated with topical ß-blockers as monotherapy provided the patient has no cardiac or pulmonary disease. Alternatively, other monotherapy [topical prostaglandins, carbonic anhydrase inhibitors (CAIs) or 2adrenergic agonists] should be tried. Combination therapy is used if monotherapy is ineffective. Laser treatment or ocular surgery is used in those patients who fail to respond to combination therapy.

If the option proves successful, drug treatment of open-angle glaucoma is likely to be lifelong. Therefore, careful consideration of the efficacy, ocular tolerance, systemic safety and convenience of usage needs to be made when choosing which drug or combination of drugs to use for each patient.

A Common Cause of BlindnessGlaucoma, an eye disease characterised by progressive optic neuropathy, is estimated to account for 15% of the incidence of blindness worldwide.[1] Primary open-angle glaucoma is the most common form of glaucoma seen in Western developed countries[2,3] affecting an estimated 1.3% of Caucasians and 3.5% of Blacks over the age of 30 years in the US.[4] Open-angle glaucoma is age related and typically characterised by raised intraocular pressure (IOP) of >21mm Hg, mid-peripheral visual field loss and excavation of the optic disk.[2] Raised IOP is not always present but it is a major risk factor and its reduction is the only medical intervention currently available which can halt or slow progression of the condition.[2,3] Five classes of drug are now available to treat glaucoma (see table 1 and Differential features table).

Drug Treatment Reduces IOPThe aim of glaucoma treatment is to reduce IOP to a target level at which progression of visual field defects is halted.[2,3,6] The target level is individualised for each patient.[2,3,7] Elevated IOP in patients with open-angle glaucoma is the result of impaired outflow of aqueous humour. IOP can be reduced by treatments which improve aqueous humour drainage and/or reduce its production (see Differential features table).[2]

Topical Application the Best ChoiceMost drugs used in the treatment of glaucoma are given topically rather than systemically. The major advantage of local drug administration is the reduced risk of inducing systemic adverse effects, because topically applied agents reach lower blood concentrations than those administered systemically.[2] To be able to penetrate the cornea, an ocular drug should possess both water and lipid soluble properties. In addition, formulations which are weak bases, weak acids or neutral pH are preferable since non-ionised compounds are more lipid permeable.[2]

The vehicle used also determines the amount of drug that penetrates the cornea. For instance, the addition of hydroxypropylmethylcellulose or polyvinyl alcohol to a topical formulation prolongs the contact time of the drug with the cornea. This results in better penetration, allowing a reduction of concentration or less frequent administration of the eye drop, thus improving the adverse effect profile.[2] Other vehicles inducing a prolonged cornea contact time are soluble gels, suspensions and emulsions. Finally, compounds can be released from an ocular insert device which is placed in the conjunctival fornices. Usually, ocular inserts consist of 2 polymeric membranes, from which the drug slowly diffuses and exerts its effect over a period of one week.[2]

ß-Blockers First Choice...Topical ß-blockers became the leading treatment for glaucoma soon after their introduction in the mid 1970s due to their efficacy, local tolerability and convenience of dosing (twice daily) compared with the available alternatives (i.e. miotics, nonselective adrenergic agonists and oral carbonic anhydrase inhibitors). They are still considered to be the treatment of first choice (see Patient care guidelines).[2,5]

Patient Care Guidelines. Possible treatment options for reducing intraocular pressure (IOP) in patients with open-angle glaucoma[2,3,7] Most of the available topical ß-blockers are nonselective, inhibiting both ß1 and ß2-adrenoceptors, and all appear to be similarly effective.[2] Timolol was the first ß-blocker to be approved and is still the benchmark against which most other ocular hypotensive agents are measured (see Differential features table).[2,3] Betaxolol is the only topical ß1-selective inhibitor available but has a less pronounced effect than timolol on IOP.[2] However, long term treatment (up to 30 months) with betaxolol had a better effect on preservation of the visual field than timolol.[8]

.. . . But Not Suitable For AllSystemic absorption occurs following topical administration of ß-blockers leading to possible blocking of ß1-adrenoceptors of the heart or ß2-adrenoceptors in the bronchioles.[2] This may result in systemic adverse events such as bradycardia, arrhythmia, congestive heart failure and bronchospasm, especially in patients susceptible to these effects (i.e. patients with cardiovascular disease, asthma or chronic obstructive pulmonary disease).[2,5] Betaxolol, given its relative ß1-selective properties, would be expected to have less effect than nonselective ß-blockers on pulmonary function. Although there is clinical evidence to support this hypothesis, betaxolol has been reported to reduce pulmonary function in patients with asthma in some clinical studies.[2] The UK's Committee on the Safety of Medicines currently advises that ß-blockers, even those with apparent cardioselectivity, should not be used in patients with asthma or a history of obstructive airways disease unless no alternative treatment is available.[5]

Lots More ChoicesIf monotherapy with a ß-blocker is contraindicated or does not induce a useful reduction in IOP after 1 month or is associated with unacceptable adverse effects, an alternative monotherapy should be tried. The topical prostaglandins, CAIs or 2-adrenergic agonists appear to represent the best options.[2,3]

Prostaglandins Look Promising . . .Latanoprost (see Differential features table) is the only currently available glaucoma treatment that compares as favourably to timolol in terms of efficacy and tolerability.[3] Latanoprost (0.005% solution once daily) produced a reduction in IOP which was 35 to 40% greater than that observed with timolol (0.5% solution twice daily) in 3 of 4 multicentre comparative trials[9-13] over treatment durations of 3[12] or 6 months.[9,10] Latanoprost also reduces IOP as effectively during the night as during the day in contrast to timolol which has no effect at night.[13] Furthermore, efficacy is maintained long term.[14] Latanoprost was as well tolerated as timolol in 6-month clinical trials with only 1 to 2% of patients withdrawing from each treatment group because of adverse reactions.[3]

Less information is available for the prostaglandin unoprostone but in one study the effect of unoprostone (0.12% solution twice daily) was similar to timolol(0.5% solution twice daily).[15]

.. . . But May Alter Eye ColourAlthough well tolerated, latanoprost is associated with darkening of iris colour and lengthening and darkening of eyelashes.[2,3,6] The effect is the result of increased synthesis of melanin in the melanocytes of the iris stroma.[6] Patients with green-brown eyes are most susceptible to increased pigmentation followed by patients with yellow-brown and blue-brown eyes.[16] Effects in uniformly coloured eyes are least likely to be noticed but treatment in only one eye revealed increases iris pigmentation even in brown eyes. Although long term follow-up is still limited, there is no indication that this effect is deleterious.[6] However, it is likely to be permanent.[6]

Unoprostone has mainly been tested in patients with brown eyes making this effect less likely to be observed.[6] However, one patient with increased iris pigmentation has been reported[17] and this effect has also been reported with the naturally occurring prostaglandins PGF2 and PGE2 making it likely that this is a class effect.[6]

Alpha2-Adrenergics are an OptionAlthough the nonselective adrenergic agonists are effective at reducing IOP, adverse events restrict their use.[3] More selective agonists of the 2-adrenoceptors (see table 1) became available in the 1990s. Brimonidine (see Differential features table) shows greater selectivity for the 2-receptor than apraclonidine and is approved for long term use in glaucoma patients whereas apraclonidine is only approved for short term use.[2,3]

The ocular hypotensive effect of brimonidine is similar to that of timolol at peak drug concentrations (2 hours after application of eye drops). However, at trough concentrations (12 hours after application of eye drops) timolol is more effective.[2,18,19] Therefore, to maintain a hypotensive effect brimonidine must be administered 3 times daily.[2,3]

Brimonidine was not as well tolerated as timolol in clinical trials; in 1-year treatment trials 18 to 26% of brimonidine recipients compared with 4 to 5% of timolol recipients withdrew because of adverse events.[18,19]

.. . . And So are Topical CAIsSystemic CAIs are highly effective at reducing IOP but are rarely used for long term treatment because of systemic adverse effects.[2] Topical CAIs were developed to improve systemic tolerability (see table 1 and Differential features table).[3] Dorzolamide (2% solution 3 times daily) and brinzolamide (1% solution twice daily) both show similar reductions in IOP after 3 months but neither drug is as effective as timolol (0.5% solution twice daily).[20] Dorzolamide is also less effective than timolol at lowering IOP long term (1 year) but shows similar efficacy to betaxolol.[21]

Dorzolamide produces a higher incidence of ocular adverse effects than timolol but systemic adverse events, other than a bitter taste, are rare.[3] Brinzolamide appears to produce less ocular discomfort[20] and fewer taste abnormalities (~8%) than dorzolamide.[20] As both dorzolamide and brinzolamide are sulphonamide derivatives, they may theoretically cause the type of adverse event associated with this class of drugs (i.e. hypersensitivity reactions and blood disorders).[3]

Combining Treatments May Be SuccessfulIf monotherapy fails to produce the desired reduction in IOP or if there is further deterioration in visual fields, combining 2 or more treatments may be effective and circumvent the need for laser or filtering surgery (see Patient care guidelines).[2,3] When 2 agents are combined the aim is to achieve a >15% additional reduction of IOP.[2] Ideally the drugs should have different modes of action or act on different receptor sites or enzymes. Consideration of dosage regimens also becomes important when combining medications as compliance is likely to decrease with increasingly complex regimens.[2,3] Opinions differ as to whether 3[2] or 4[3] drugs should be the maximum used in combination. The choice of which drugs to use in combination is also controversial without any firm evidence to support any one combination over another.[2,3] Combinations of drugs which may have an additive effect over the use of each agent alone are shown in table 2.

ß-Blocker Combinations Often TriedAll classes of drugs have been added to ß-blocker therapy with most showing additive activity (see table 2). A fixed-dose combination of timolol 0.5%/ dorzolamide 2% is available which permits more convenient dosage administration (2 applications daily compared with 5 applications of the individual drugs).[2,22] The timolol/dorzolamide combination is as effective as both agents applied concomitantly and results in additional IOP reductions of up to 20% at peak concentrations compared with timolol alone.[2,22]

The timolol/dorzolamide combination has also been compared with concomitant timolol (0.5% solution twice daily) and pilocarpine (2% solution 4 times daily) in patient preference studies.[23] Both regimens resulted in similar reductions in IOP but the timolol/dorzolamide combination was better tolerated and preferred by patients.[23] Another effective combination is that of latanoprost with timolol; additional IOP reductions of 13 to 37% have been reported with this combination in patients with IOPs uncontrolled on timolol alone.[2]

Data on Other Combinations are LimitedCombinations of latanoprost with dipivefrine (dipivefrin), the oral CAI acetazolamide and pilocarpine have all resulted in additional reductions of IOP.[2,6] Combinations of topical CAIs, and brimonidine, with agents other than ß-blockers is limited although there has been one report that the combination of dorzolamide and latanoprost resulted in an additional IOP reduction of 15%.[24]

Table 1. Agents available for glaucoma treatment according to drug class[2,5]

Drug class

Subclass or feature

Generic name

ß-Blockers

Nonselective

TimololLevobunololCarteololMetipranolol

ß1-Selective

Betaxolol

Prostaglandins

LatanoprostIsopropylUnoprostone

Carbonic anhydrase inhibitors

Oral

AcetazolamideMethazolamide

Topical

DorzolamideBrinzolamide

Adrenergic agonists (sympathomimetics)

2-Adrenergic agonists

BrimonidineApraclonidine

Nonselective

Epinephrine(adrenaline)Dipivefrine(dipivefrin)

Miotics

PilocarpineCarbachol

Table 2. Combinations of antiglaucoma drugs that have an additive effect over the use of each agent alone[2]

Class

ß-Blockers

Miotics

Adrenergicagonists

2-Adrenergicagonists

Prostaglandins

Miotics

+

Adrenergic agonists

±

+

2-Adrenergic agonists

+

?

?

Prostaglandins

+

+

+

?

Carbonic anhydrase inhibitors

+

+

+

?

+= additive effect; ± = small effect; ? = effect of combination not known.

References

Thylefors B, Negrel AD. The global impact of glaucoma. Bull World Health Organ 1994; 72 (3): 323-6 Hoyng PFJ, van Beek LM. Pharmacological therapy for glaucoma. A review. Drugs 2000 Mar; 59 (3): 411-34 Camras CB, Toris CB, Tamesis RR. Efficacy and adverse effects of medications used in the treatment of glaucoma. Drugs Aging 1999 Nov; 15 (5): 377-88 Quigley HA, Vitale S. Models of open-angle glaucoma prevalence and incidence in the United States. Invest Ophthalmol Vis Sci 1997 Jan; 38 (1): 83-91 British National Formulary. No. 40. London: The Pharmaceutical Press, 2000 Sep: 485-90 Lindén C, Alm A. Prostaglandin analogues in the treatment of glaucoma. Drugs Aging 1999 May; 14 (5): 387-98 Glaucoma guidelines: a way to improve care? Drugs Ther Perspect 2000 Jan; 15 (1): 8-10 Kaiser HJ, Flammer J, Messmer C. Thirty month visual field follow up of glaucoma patients treated with beta blockers. J Glauc 1992; 1: 153 Alm A, Stjernschantz J, the Scandinavian Latanoprost Study Group. Effects on intraocular pressure and side-effects of 0.005% latanoprost applied once daily, evening or morning: a comparison with timolol. Ophthalmology 1995; 102 (12): 1743-52 Camras CB, the United States Latanoprost Study Group. Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma: a six-month, masked, multicenter trial in the United States. Ophthalmology 1996; 103 (1): 138-47 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. Ophthalmology 1996; 103 (1): 126-37 Mishima HK, Masuda K, Kitazawa Y, et al. A comparison of latanoprost and timolol in primary open-angle glaucoma and ocular hypertension: a 12 week study. Arch Ophthalmol 1996; 114(8): 929-32 Mishima HK, Kiuchi Y, Takamatsu M, et al. Circadian intraocular pressure management with latanoprost: diurnal and nocturnal intraocular pressure reduction and increased uveoscleral outflow [review]. Surv Ophthalmol 1997; 41 Suppl.2: S139-44 Camras CB, Alm A, P, et al. Latanoprost, a prostaglandin analog, for glaucoma therapy: efficacy and safety after 1 year of treatment in 198 patients (Latanoprost Study Groups). Ophthalmology 1996; 103 (11): 1916-24 Azuma I, Masada K, Kitazawa Y, et al. Double-masked comparative study of UF-021 and timolol ophthalmic solutions in patients with primary open-angle glaucoma or ocular hypertension. Jpn J Ophthalmol 1993; 37 (4): 514-25 Wistrand PJ, Stjernschantz J, Olsson K. The incidence and time-course of latanoprost-induced iridial pigmentation as a function of eye color. Surv Ophthalmol 1997; 41 Suppl. 2: S129-38 Yamamoto T, Kitazawa Y. Iris-color change developed after topical isopropyl unoprostone treatment. J Glaucoma 1997; 6: 430-2 LeBlanc RP, for the Brimonidine Study Group 2. Twelve-month results of an ongoing randomized trial comparing brimonidine tartrate 0.2% and timolol 0.5% given twice daily in patients with glaucoma or ocular hypertension. Ophthalmology 1998; 105 (10): 1960-7 Schuman JS, Horwitz B, Choplin NT, et al. A 1-year study of brimonidine twice daily in glaucoma and ocular hypertension: a controlled, randomized, multicenter clinical trial. Arch Ophthalmol 1997; 115 (7): 847-52 Silver LH, the Brinzolamide Primary Therapy Study Group. Clinical efficacy and safety of brinzolamide (AzoptTM), a new topical carbonic anhydrase inhibitor for primary open-angle glaucoma and ocular hypertension. Am J Ophthalmol 1998; 126 (3): 400-8 Strahlman E, Tipping R, Vogel R, et al. A double-masked, randomized 1-year study comparing dorzolamide (TrusoptTM), timolol, and betaxolol. Arch Ophthalmol 1995; 113 (8): 1009-16 Ormrod D, McClellan K. Topical dorzolamide 2%/timolol 0.5%: a review of its use in the treatment of open-angle glaucoma. Drugs Aging 2000 Dec; 17 (6): 477-96 Sverrisson T, Gross R, Pearson J, et al. The dorzolamide/timolol combination versus timolol plus pilocarpine: patient preference and impact on daily life. J Glaucoma 1999 Oct; 8: 315-24 Kimal AM, Topalkara A, Guler C. Additive effect of latanoprost and dorzolamide in patients with elevated intraocular pressure. Int Ophthalmol 1998; 22 (1): 37-42

Differential FeaturesComparison of some features of selected topical ocular hypotensive agents used for the treatment of patients with open-angle glaucoma[2,3]

Feature

Timolol

Betaxolol

Latanoprost

Dorzolamide

Brimonidine

Class

Nonselective ß-adrenoceptor blocker

ß1-Selective adrenoceptor blocker

Prostaglandin

Carbonic anhydrase inhibitor

2-Adrenergic agonist

Mechanism of action

Inhibits aqueous humour production

Inhibits aqueous humour production

Increases uveoscleral outflow

Inhibits aqueous humour production

Reduces aqueous humour production, possibly increases uveoscleral outflow

Dosage regimen

Solution: 0.25-0.5% twice dailyGel: 0.25% once daily

Solution: 0.25-0.5%Suspension: 0.25% twice daily

0.005% solution once daily (preferably at night)

2% solution twice daily

0.2% solution twice daily

Efficacy

Reduction in IOP in clinical studies (%)

27-35

18-26

27-35

=23

20-27

Adverse events

Ocular

Conjunctival hyperaemia, burning, stinging, superficial punctate keratitis, reduced tear flow, dry eye syndrome

As for timolol

Iris pigmentation, hypertrichosis and darkening of eyelashes, conjunctival hyperaemia, stinging, burning or tearing, punctate keratitis, blurred vision, eye pain and foreign body sensation

Stinging, burning, temporarily blurred vision, itching, tearing, eye lid oedema, conjunctivitis

Allergic reactions, conjunctival hyperaemia, conjunctival follicles, corneal staining, blurred vision, foreign body sensation

Systemic

Bradycardia, arrhythmia, congestive heart failure, bronchospasm in patients with asthma or chronic obstructive pulmonary disease

As for timolol but frequency of events is lower

None reported

Bitter taste, nephrolithiasis

Dry mouth, fatigue, headache

Contraindications

Cardiovascular diseasea

x

x

-

-

-

Asthma/COPD

xb

xb

-

-

-

Severe renal impairment/hyperchloraemic acidosis

-

-

-

x

-

Pregnancy/breastfeeding

-

-

-

x

-a Bradycardia, heart block, uncontrolled heart failure.b If no alternative available, use with caution.COPD = chronic obstructive pulmonary disease; IOP = intraocular pressure; x = contraindicated; - = not a contraindication.

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