Primary open-angle glaucoma By Dr Luke Bereznicki

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1 Primary open-angle glaucoma By Dr Luke Bereznicki Case study Mabel, a regular customer, asks for advice about the different medications used in the treatment of glaucoma. She was diagnosed with glaucoma several years ago and currently uses Xalacom eye drops. Recently, her friend has been diagnosed with glaucoma but has been prescribed Tenopt eye drops instead. Mabel is concerned that her friend may not have been prescribed the best medication to treat her glaucoma. Pathophysiology of glaucoma Primary (or chronic) open-angle glaucoma is a common cause of legal blindness and visual impairment. Due to its insidious nature it has been Learning objectives After reading this article you should be able to: Define primary open-angle glaucoma. Discuss the role of pharmacological treatments. Discuss techniques which optimise the effectiveness of pharmacological treatments. Competency standards (2010) addressed: 3.1.2, 3.1.3, 3.2.2, Accreditation number: CAP110202e Dr Luke Bereznicki is Senior Lecturer in Pharmacy Practice at the Tasmanian School of Pharmacy. referred to as the sneak-thief of sight. The prevalence of open-angle glaucoma increases exponentially with age and in people aged over 50 years it is approximately 3%. 1 It is estimated that about half of all cases remain undiagnosed because the disease progression is slow, painless and visual acuity is only affected late in the disease. 2 Therefore, targeted screening is required to identify affected patients. Prevention or slowing of visual loss is possible with a range of management options, which include medical, surgical and laser therapies. This article will briefly review the pharmacological management of primary open angle glaucoma. Glaucoma describes a group of eye diseases in which there is progressive damage to the optic nerve characterised by specific structural abnormalities of the optic nerve head and associated patterns of visual field loss. 3 Elevated intraocular pressure (IOP) is not included in this definition as glaucoma may occur with or without a rise in IOP (the normal range is mmhg). Glaucoma is classified according to variations in the anterior segment of the eye, which may result in elevated IOP. The anterior segment of the eye features a circulatory system that nourishes the lens and the cornea, which lack their own blood supply. Aqueous humour is produced by the ciliary body, circulates through the anterior chamber of the eye and drains via the trabecular meshwork in the angle formed by the iris and the cornea (the iridocorneal angle) and the uveoscleral pathway via the interstitial spaces between the iris root and ciliary muscle. 4 Imbalances in the outflow of humour may result in elevated IOP leading to optic nerve damage. As the optic nerve is not capable of regenerating, deterioration of the optic nerve leads to permanent visual field loss. 4 Glaucoma is classified based on the appearance of the iridocorneal angle; there are open-angle, closedangle and developmental categories, of which there are primary and secondary types. Primary open-angle glaucoma is the predominant form in Western countries and represents approximately 90 95% of all reported cases of glaucomas. 5,6 It may occur with or without an elevation in IOP; and in the case that IOP is not elevated, it is referred to as normaltension glaucoma (NTG). 7 In the Baltimore Eye Survey, more than half of patients with newly diagnosed glaucoma had a normal IOP on a single tonometry assessment. 8 People with NTG may account for a third to a half of open-angle glaucoma cases. 8,9 Conversely some people have raised IOP but do not have glaucoma this is referred to as ocular hypertension. Closed angle glaucoma may be acute or chronic. Acute primary-angle closure causes a painful, unilateral red eye with markedly elevated IOP. 10 Chronic closed-angle glaucoma may also occur in some populations (e.g. Chinese and South-East Asian people). 1 Clinical presentation The main clinical features of primary open-angle glaucoma are an open iridocorneal angle and cupping of the optic-nerve head (or optic disc). Cupping of the optic disc is an important sign in diagnosis and management of patients with openangle glaucoma. The patterns of visual field changes that occur in glaucoma relate to the extent and location of optic nerve cupping

2 Submit your answers online at and receive automatic feedback Primary open-angle glaucoma is frequently missed as a diagnosis due to its lack of symptoms when compared with acute primary angle closure, which often presents with ocular pain, redness, blurred vision and nausea and vomiting. Progression of open-angle glaucoma is usually slow, painless and irreversible; visual acuity is affected late in the disease and symptoms of peripheral vision loss with mobility difficulties do not occur until the disease has progressed significantly. 10 In the Melbourne Visual Impairment Project, nearly half of the patients that were diagnosed with glaucoma during the survey had seen an eye-care practitioner in the preceding 12 months and had not been diagnosed with glaucoma. 12 The authors concluded that raised IOP should not be relied on as the only triggering factor for initiating glaucoma investigations. Glaucoma may be diagnosed at a normal IOP if there is characteristic optic disc and/ or visual field damage. 10 People who have glaucoma are at a higher risk of motor vehicle accidents than people without and are more likely to become dependent on others for daily activities. This may lead to a reduction in quality of life. 13,14 Risk factors and screening Early diagnosis with appropriate management is the best way to prevent, or at least slow, visual loss associated with primary openangle glaucoma. Evidence strongly supports a screening approach that targets individuals at high risk of developing glaucoma, rather than the general population. 3 Targeted screening may be more cost-effective in populations such as older adults, people of African descent and those with a family history of glaucoma. 3 There is currently no consensus on the optimal test or group of tests for glaucoma screening, but a combination of optic disc assessment, visual field assessment, IOP and angle assessment are suggested. 3 The most important risk factors for primary open-angle glaucoma are older age, African origin, elevated IOP and family history of openangle glaucoma. 3 Other risk factors include myopia, diabetes, smoking, steroid use, migraine, eye injury and high blood pressure (see Table 1). In patients who have an elevated IOP Table 1. Risk factors for glaucoma available from patient history. Modified from the NHMRC guidelines for the screening, prognosis, diagnosis, management and prevention of glaucoma. 3 Risk factors for developing glaucoma IOP > 21 mmhg Age over 80 years Age over 50 years Family history Specific ethnic origin Diabetes Myopia Rural location Strength of evidence* Risk of developing glaucoma A B Extremely high 12x or more A B High 3x or more A B Moderate 1.5x or more Quantitative risk increase (when compared with patients without these risk factors) Smoking* C Low Similar risk to baseline Steroid use* C Increased risk stated with no statistics provided Migraine D Eye injury High blood pressure Unknown IOP = intraocular pressure *Refers to the National Health and Medical Research Council (NHMRC) levels of evidence and grades for recommendations. An evidence grade of A and B is based on evidence from systematic reviews and randomised controlled trials, an evidence grade of C is based on evidence from controlled cohort studies and an evidence grade of D is based on evidence from observational studies. 141

3 relative corneal thinness is another major risk factor. 15 Regular eye checks and screening for glaucoma is recommended in those who have a moderate or greater risk for developing glaucoma. 3 Groups of patients who should be screened for glaucoma include people over the age of 50 years (40 years in those of African descent), first-degree relatives of people with glaucoma and those with other risk factors (e.g. myopia, high blood pressure, diabetes). 3 Management There are an effective range of options to manage glaucoma including topical medications, laser trabeculoplasty or surgery (e.g. trabeculectomy). The aim of treatment is to slow or halt disease progression so that any visual loss has the least impact of the patient s quality of life. 3 The reduction of IOP is the cornerstone of all current treatment options as it is the only modifiable risk factor. Topical ocular hypotensive medication is effective in delaying or preventing the onset of open-angle glaucoma in patients with elevated IOP. 16 Trials also demonstrate that lowering IOP decreases glaucoma progression 17,18 so adequate control of IOP in primary open-angle glaucoma is the aim of treatment. There is general consensus that medications should be the first choice for most patients with primary open-angle glaucoma. 3 However, laser therapy may be used as the first choice agent in some patients who are at risk of visual loss within their lifetime. 3 Pharmacological management Medication is generally the first management choice by prescribers for patients with open-angle glaucoma. Medications reduce IOP by reducing outflow and/ or formation. Table 2 shows the five main classes of medication used to manage glaucoma. Factors that influence the initial choice of medication include, IOP-lowering potency, additive effects, interactions with concomitant medications and disease states, adverse effects and ease of administration. 3 Table 3 shows a summary of the adverse effects associated with glaucoma medications. Using a target IOP is currently the best way to measure the short term Table 2. Medications available in Australia for the management of chronic open-angle glaucoma. Modified from the NHMRC guidelines for the screening, prognosis, diagnosis, management and prevention of glaucoma. 3 Preparations by class Prostaglandin analogues Bimatoprost 0.03% eye drops (Lumigan) Latanoprost 0.005% eye drops (Xalatan) Travoprost 0.004% eye drops (Travatan) Beta-blockers Non-selective Timolol 0.25%, 0.5%, 0.1% eye drops (Tenopt, Timoptol, Nyogel) b1-receptor selective Betaxolol 0.25%, 0.5% eye drops (Betoptic) Proprietary-fixed combinations Brimonidine 0.2%/ timolol 0.5% eye drops (Combigan) Dorzolomide 2%/timolol 0.5% eye drops (Cosopt) Bimatoprost 0.03%/timolol 0.5% eye drops (Ganfort) Latanoprost 0.005%/ timolol 0.5% eye drops (Xalacom) Travoprost 0.004%/timolol 0.5% eye drops (DuoTrav) Alpha-2 agonists Brimonidine 0.2% eye drops (Alphagen) Apraclonidine 0.5% eye drops (Iopidine) Carbonic anhydrase inhibitors Topical Brinzolamide 1% eye drops (Azopt, BrinzoQuin) Dorzolamide 2% eye drops (Trusopt) Systemic Acetazolamide 250 mg tablets (Diamox) Cholinergics Pilocarpine 1%, 2% eye drops (P.V. Carpine, Isopto Carpine Pilopt, Minims Pilocarpine Nitrate) Carbachol 1.5%, 3% eye drops (Isopto Carbachol, Miostat) Mechanism of action Increase outflow Decrease production As for individual components Increase outflow and decrease production Decrease production Increase outflow Efficacy Dosage frequency Washout period 25 30% Once daily 4 6 weeks First 20 25% Once to twice daily 2 5 weeks First 25 30% Twice daily As for individual components Once daily 20 25% Two to three 15 20% Two to three 25 30% Two to four 20 25% Three to four Order of treatment choices Second 1 3 weeks Second 1 week Second 3 days Third 3 days Third 142

4 Table 3. A summary of adverse effects associated with medications used to lower IOP. Modified from the NHMRC guidelines for the screening, prognosis, diagnosis, management and prevention of glaucoma. 3 Adverse effects Bradyarrhythmias/ hypotension Tachycardia/ hypertension Prostaglandin analogues Betablockers effectiveness of the chosen medication regimen. There is no fixed target for IOP the target IOP is a theoretical value that will minimise the progression of optic nerve damage and visual field loss. The target IOP typically is set as a 30 50% reduction in pre-treatment IOP. 3 Target IOPs are not static and may need to be modified based on the response to treatment. As glaucoma progression may still occur in patients with apparently stable IOP, continuing evaluation of the optic disc and visual field is more important than monitoring of the IOP in the longer term. Treatment usually begins with topical eye drops as they have a localised Class Alpha-2 agonists Depression Masking of hypoglycaemia Bronchospasm rare Elevated serum lipids Falls in elderly Anaphylaxis Altered taste Dizziness Paraesthesia Impotence Other minor systemic Drowsiness/ fatigue * ** Carbonic anhydrase inhibitors Systemic Topical Dry mouth Minor ocular symptoms Major ocular symptoms effect and a lower incidence of adverse effects. In some situations, such as an inability to instill eye drops, oral acetazolamide may be used. 3 Oral acetazolamide is poorly tolerated by up to 50% of patients, which significantly limits its use. Systemic beta-blockers are not as effective at reducing IOP as topical betablockers and their use in combination with topical beta-blockers is not recommended. 3,19 Initial treatment Cholinergics * Headaches, pruritis, urticaria ** Hearing dysfunction, gastrointestinal disturbance, reduced libido NB: While the same cautions apply to non-selective and relatively selective beta-blockers, there is a wider margin of safety for the latter (betaxolol) The initial choice of medication should be based on effectiveness, safety and convenience. Prostaglandin analogues and beta-blocker eye drops are the preferred first-line treatments for glaucoma. Over the past decade, prostaglandin analogues have gradually superseded older medications for the initial treatment of primary open-angle glaucoma. 20 Prostaglandin analogues are highly effective with a lower risk of systemic adverse effects when compared with beta-blockers, although they are more expensive. 21 Beta-blockers should generally be avoided in patients with reactive airways disease (although as betaxolol is selective for beta1 receptors it can be used with care) 22 or cardiac conduction defects as systemic absorption may lead to significant adverse effects. Prostaglandin analogues have a lower risk of systemic adverse effects, but may increase eyelash growth, and result in iris and eyelash pigmentation changes. 23 If topical prostaglandin analogues or betablocker therapies cannot be tolerated or are contraindicated, either an alpha-2-adrenergic agonist or carbonic anhydrase inhibitor should be considered. 3 It is recommended that treatment begin in one eye only (the worst eye), using the other eye as a control to test for effectiveness. 3 Response to lowering the IOP should be checked within 2 6 weeks, as this is considered a reasonable time-frame for the medication to reach full effect before treatment is extended to the other eye. Subsequent treatment Depending on the response to the initial topical medication, the patient may require either a change in medication or an additional topical agent. A change to therapy is justified if there is an inadequate response despite optimal patient adherence to the initial agent. 3 Switching to an alternative agent within a class or an alternative class is recommended if the initial response is poor. Increasing the dose of the initial agent is not recommended as it will not lower the IOP further and may expose the patient to a higher risk of adverse effects. In this case, a wash out period should be followed by another trial in one eye. It is worth noting that prostaglandin analogues are structurally different to each other and patient response to agents within the class may differ. 22 If an adequate response (a response, but not to the target level) has been achieved with the initial medication, 144

5 Submit your answers online at and receive automatic feedback an additional medication is normally added. There is currently no consensus on the optimal combination of topical medications to manage primary open-angle glaucoma. No specific combination of medications has been identified as optimal in terms of visual field preservation or optic nerve head health. 3 The bulk of the literature focuses on combinations of a beta-blocker with either a prostaglandin analogue or carbonic anhydrase inhibitor. 24 There are a number of fixed combination products available that combine timolol with a prostaglandin analogue, carbonic anhydrase inhibitor or alpha- 2-adrenergic agonist. One advantage of the prostaglandin analogue/ timolol combinations are that they can be administered once daily to optimise adherence. Medications from the same class should not be combined and if combination products are used, it is important that existing medications are not duplicated (e.g. timolol or betaxolol drops should not be used with any of the fixed-dose combination products currently available). Combinations of prostaglandin analogues may result in a paradoxical increase in IOP and should be avoided. 22 The combination of topical and systemic beta-blocker occurs quite commonly in Australian practice, one study finding that approximately 20% of patients supplied topical beta-blockers were also supplied systemic beta-blockers. 25 This combination should be avoided because research shows that patients using both topical and systemic betablockers have significantly smaller decreases in IOP compared to those using a topical beta-blocker alone. They also have significantly greater variations in systolic and diastolic blood pressure and a notably greater decrease in heart rate. 19 If more than two topical medications are required to lower the IOP then other options, such as laser therapy or surgery, should be considered as alternatives to additional medications. 3 If patients are not candidates for laser therapy or surgery then systemic therapy is another option at this stage. The purpose of laser therapy and surgery is to make a selective lesion in one or more structures of the eye to reduce the IOP. Currently Australian guidelines recommend the use of argon laser trabeculoplasty in older patients with open-angle glaucoma who are at risk of visual loss within their lifetime, particularly when they have difficulty administering eye drops, are unresponsive to medication alone or are poor candidates for incisional surgery. 3 Patients who have undergone laser therapy require continual monitoring due to the diminishing treatment benefit over time. Surgical interventions are at least as effective as medication for reducing IOP in open-angle glaucoma and are currently recommended when target IOP is not being achieved with two or more medications, adherence is problematic, and when laser therapy has failed or is not likely to succeed. 3 Optimising adherence and persistence Current therapy relies heavily on patient cooperation in selfadministration. So it is not surprising, given the asymptomatic nature of open-angle glaucoma, that adherence and persistence is often reported to be poor. Adherence rates to glaucoma medications of 24% to 59% have been reported in the literature To maximise adherence it is important to simplify the medication regimen wherever possible. The lowest dose of the most effective medication should be used to reach the target IOP and prevent progression of visual field defects. 3 Once daily dosing has been shown to improve patient satisfaction and adherence, and is often possible when only one or two topical medications are required. 31 Patient education and informed participation in treatment decisions also improves adherence. 32 Pharmacists can assist patients with glaucoma to optimise their adherence by: encouraging patient adherence and persistence with using their glaucoma medications educating patients about the risks and prognosis of their disease providing a medication profile; it is important to include the name of their glaucoma medications, the time of day to administer them, the number of drops and information on how to identify the medications (e.g. colour of bottle cap) ensuring that all medications have clear labels and patients know how to use them providing information to patients about their disease to improve their understanding, such as publications from Glaucoma Australia providing contact details for consumer groups that provide support and education. 3 Instillation of topical medications Patients need to understand how to instill drops effectively and efficiently. The preferred method for eye drop self-instillation included holding the head horizontal with tear duct occlusion and eyelid closure for 2 3 minutes (DOUBLE DOT: Digital Occlusion of Tear Duct and Don t Open Technique). Systemic absorption can be reduced by up to 70% using this technique. 3,33 If two or more drops are being instilled then there should be an interval of at least five minutes between drops. Videos and printed material are available from the Glaucoma Australia website for patients and there are also devices available that can aid with instillation of eye drops if patients require them. Further information can be found at: Advice for Mabel Primary open-angle glaucoma is an irreversible optic neuropathy that is a leading cause of blindness. Medications are generally the first management choice and a range of considerations influence the choice of initial treatment. The pharmacist should advise Mabel that there are many different treatment options available for glaucoma and that treatment for each patient is individualised. Combination products are often used when one medication alone is not sufficient to meet the target IOP. Pharmacists can encourage patients who have a greater risk of developing glaucoma to see their eye-care professional for screening and advice. Topical medications have an important role in the management of primary open angle glaucoma. Pharmacists play a central role in helping patients to achieve the true benefits of treatment providing education on glaucoma medications; encouraging adherence; and identifying and assisting patients who are experiencing adverse effects from their medication or having difficulty instilling their eye drops. 145

6 References 1. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and Br J Ophthalmol. 2006;90: Rochtchina E, Mitchell P. Projected number of Australians with glaucoma in 2000 and Clin Experiment Ophthalmol. 2000;28: National Health and Medical Research Council. NHMRC guidelines for the screening, prognosis, diagnosis, management and prevention of glaucoma Canberra: National Health and Medical Research Council; At: synopses/cp113syn.htm 4. Distelhorst JS, Hughes GM. Open-angle glaucoma. Am Fam Physician. 2003;67: Adatia FA, Damji KF. Chronic open-angle glaucoma. Review for primary care physicians. Can Fam Physician. 2005;51: Kwon YH, Fingert JH, Kuehn MH, Alward WL. Primary open-angle glaucoma. N Engl J Med. 2009;360: Kroese M, Burton H. Primary open angle glaucoma. The need for a consensus case definition. J Epidemiol Community Health. 2003;57: Sommer A, Tielsch JM, Katz J, Quigley HA, Gottsch JD, Javitt J, Singh K. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol. 1991;109: Klein BE, Klein R, Sponsel WE, Franke T, Cantor LB, Martone J, Menage MJ. Prevalence of glaucoma. The Beaver Dam Eye Study. Ophthalmology. 1992;99: Walland MJ. On the lookout: how to save the sight of Australians who have glaucoma. Med J Aust. 2008;188: Harris A, Rechtman E, Siesky B, Jonescu-Cuypers C, McCranor L, Garzozi HJ. The role of optic nerve blood flow in the pathogenesis of glaucoma. Ophthalmol Clin North Am. 2005; 18: , v. 12. Wong EY, Keeffe JE, Rait JL, Vu HT, Le A, McCarty Ph DC, Taylor HR. Detection of undiagnosed glaucoma by eye health professionals. Ophthalmology. 2004;111: Johnson CA, Keltner JL. Incidence of visual field loss in 20,000 eyes and its relationship to driving performance. Arch Ophthalmol. 1983;101: Gutierrez P, Wilson MR, Johnson C, Gordon M, Cioffi GA, Ritch R, Sherwood M, Meng K, Mangione CM. Influence of glaucomatous visual field loss on healthrelated quality of life. Arch Ophthalmol. 1997;115: Gordon MO, Beiser JA, Brandt JD, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK, 2nd, Wilson MR, Kass MA. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:714 20; discussion Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK, 2nd, Wilson MR, Gordon MO. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701 13; discussion Heijl A, Leske MC, Bengtsson B, Hyman L, Hussein M. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120: Leske MC, Heijl A, Hussein M, Bengtsson B, Hyman L, Komaroff E. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol. 2003;121: Schuman JS. Effects of systemic beta-blocker therapy on the efficacy and safety of topical brimonidine and timolol. Brimonidine Study Groups 1 and 2. Ophthalmology. 2000; 107: Charles J, Britt H, Fahridin S. Glaucoma. Aust Fam Physician. 2009;38: Hedman K, Alm A. A pooled-data analysis of three randomized, double-masked, six-month clinical studies comparing the intraocular pressure reducing effect of latanoprost and timolol. Eur J Ophthalmol. 2000;10: Australian Medicines Handbook Pty Ltd. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook; Alm A, Widengard I. Latanoprost: experience of 2-year treatment in Scandinavia. Acta Ophthalmol Scand. 2000;78: Webers CA, Beckers HJ, Nuijts RM, Schouten JS. Pharmacological management of primary open-angle glaucoma: second-line options and beyond. Drugs Aging. 2008;25: Goldberg I, Adena MA. 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N Engl J Med. 2005;353: Goldberg I, Moloney G, McCluskey P. Topical ophthalmic medications: what potential for systemic side effects and interactions with other medications? Med J Aust. 2008;189: Questions A score of 4 out of 5 attracts 1 CPD credit. 1. The prevalence of open-angle glaucoma in people aged over 50 years is approximately? a) 1%. b) 2%. c) 3%. d) 5%. 2. Which one of the following characteristics is not included in the definition of primary open-angle glaucoma? a) Progressive damage to the optic nerve. b) Elevated intraocular pressure. c) Patterns of visual loss. d) Structural abnormalities of the optic nerve head. 3. Which one of the following medications is not regarded as a first-line treatment in the management of primary open angle glaucoma? a) Latanoprost. b) Brimonidine. c) Bimatoprost. d) Timolol. 4. Which one of the following statements concerning pharmacological treatment of primary open angle glaucoma is incorrect? a) There is no fixed target for intraocular pressure (IOP) monitoring. b) Systemic beta-blockers are as effective at reducing IOP as topical beta-blockers. c) Prostaglandin analogues have a lower risk of systemic adverse effects compared to beta-blockers. d) Combinations of prostaglandin analogues may result in a paradoxical increase in IOP and should be avoided. 5. Which one of the following medication classes is associated with major ocular adverse effects? a) Prostaglandin analogues. b) Beta-blockers. c) Carbonic anhydrase inhibitors. d) Cholinergics. 146