Contents
Key Points
  • Eye drops have systemic effects which can impact on co-morbidities.
  • Concurrent use of verapamil and topical beta blockers is contraindicated.
  • Avoid topical beta blockers in veterans with bradycardia, decompensated heart failure and heart block.
  • Topical beta blockers and pilocarpine can cause bronchoconstriction; enquire about respiratory symptoms and inhaler use.
  • Ensure good communication between ophthalmologist, GP and patient.

Impact of Glaucoma Medications on Co-morbidities

In 2008 over 31,000 veterans were dispensed medicines for glaucoma.1 The systemic absorption of glaucoma eye drops can lead to adverse drug events and also impact on co-morbidities.

In particular topical beta blockers have well documented systemic effects due to the presence of beta adrenoreceptors in vascular smooth muscle, the heart and bronchial tree.2,3,4 DVA prescribing data indicates that the use of timolol eye drops is associated with an increase in bronchoconstriction as evidenced by increased use of beta agonists and inhaled steroids, and increased hospitalisation for respiratory conditions.1 This therapeutic brief aims to: outline the different drugs used in the management of primary open angle glaucoma, highlight how drug selection may impact on coexisting cardiovascular and respiratory disease and suggest how to minimise systemic absorption by optimising eye drop instillation.

A key principle in glaucoma management is optimal communication between the ophthalmologist, who typically initiates and monitors the glaucoma treatment, and the GP to whom the patient may be more likely to present with systemic side effects.

What is glaucoma?

Glaucoma is an optic neuropathy; retinal ganglion cell death results in progressive optic nerve dysfunction and peripheral visual field loss. If left untreated permanent blindness may result.

Primary open-angle glaucoma (POAG), the subject of this brief, is the most common type of glaucoma accounting for about ⅔ of cases.5 Development of POAG is strongly associated with elevated intraocular pressure (IOP); the risk for those with IOP>26mmHg is 13 times higher than that for those with lower IOP.6

POAG is asymptomatic. Intraocular pressure elevations up to 40 mmHg generally cause no pain or visual symptoms and patients can be unaware of visual field loss even when they have ‘tunnel vision’ of 10 to 20 degrees.

In a large proportion of patients IOP remains in the normal range (generally accepted as 10–20 mmHg). This normal-tension glaucoma is thought to account for up to 30% of glaucoma cases in Western countries.5 Similarly IOP may be elevated with no evidence of optic nerve damage (ocular hypertension). The pathophysiology of glaucoma is most likely a result of innate optic nerve vulnerability factors. Other risk factors for POAG include increasing age and family history.

In the general population the prevalence of POAG is approximately 1–4% but this increases with age. Analysis of the DVA database indicates that in 2008 approximately 10.6% of veterans were receiving treatment for glaucoma. This much higher prevalence in the veteran population (average age 80 yrs) correlates with previous studies in over 65 year olds including the Blue Mountains Eye Study which found evidence of definite or probable open angle glaucoma in 8.7% of people 75 to 85 years of age.7,8,9

Management of primary open angle glaucoma

The aim of glaucoma therapy is to reduce the IOP. This has been shown to reduce the risk of long term visual field loss in those with glaucoma and ocular hypertension.10 There is no threshold for the initiation of treatment and no standard guidelines for the optimal target IOP. Treatment is adjusted based on close follow up of visual fields and optic disc damage. Target pressures are lowered if there is disease progression despite treatment.

Intraocular pressure can be lowered by topical and systemic medical therapy (see table 1), laser therapy and surgery.

Glaucoma medications lower IOP by reducing the production of aqueous humour or increasing its outflow.

Prostaglandin analogues are considered first line therapy in POAG because of 1) the convenience of once daily dosing 2) their minimal systemic effects 3) their superiority in lowering IOP. A meta-analysis comparing latanoprost and timolol showed a 5% difference in IOP lowering effect in favour of latanoprost.11 Analysis of the DVA prescribing data shows that prostaglandin analogues are the most commonly prescribed medications to treat glaucoma, with latanoprost accounting for the majority of use.1

Beta blockers are second line therapy, with alpha2 agonists and carbonic anhydrase inhibitors both third line medical therapies. Pilocarpine is now used infrequently because of its side effects.

Table 1: Classes of drugs currently used

Class

Generic names

Brand names

Prostaglandin analogues

Latanoprost

Xalatan 0.005%

 

Travoprost

Bimatoprost

 

Travatan 0.004%

Lumigan 0.03%

Beta blockers

Timolol (beta1 and beta2 receptor blocker)

Tenopt, Timoptol, Timoptol-XE 0.25% and 0.5% and Nyogel 0.1%

 

Betaxolol (beta1 receptor blocker)

Betoptic S 0.25% and Betoptic 0.5%, BetoQuin 0.5%

Alpha2 agonists

Apraclonidine

Iopidine 0.5%

 

Brimonidine

Alphagan and Enidin 0.2%

Carbonic anhydrase inhibitors

Brinzolamide

Azopt and BrinzoQuin 1%

 

Dorzolamide

Acetazolamide (oral)

 

Trusopt 2%

Diamox 250mg

Cholinergics

Pilocarpine

Pilopt, PV Carpine, Isopto Carpine 1%/2%/4%; Pilopt, PV Carpine 6%

Combination Products

Timolol 0.5%/Brimonidine 0.2%

Combigan

 

Timolol 0.5%/Dorzolamide 2%

Cosopt

 

Timolol 0.5%/Latanoprost 0.005%

Xalacom

 

Timolol 0.5%/Travoprost 0.004%

Duotrav

 

Timolol 0.5%/Bimatoprost 0.03%

Ganfort

Glaucoma treatment and co-morbidities

Eye drops used in the treatment of glaucoma have significant systemic absorption. After instillation 80% drains through the nasolacrimal duct and enters the systemic circulation through the nasal mucosa avoiding first pass metabolism in the liver.2 Glaucoma medications may then impact on co-morbidities, particularly cardiovascular and respiratory disease. The incidence of adverse effects in clinical practice depends on the risk profile of the population being treated.

The systemic side effects of topical beta blockers – bradycardia, bronchospasm, hypotension, syncope –are especially relevant to the elderly veteran population (average age 80 yrs with 7 co-morbidities).

Local and systemic adverse effects of glaucoma medications can limit their use (see table 2). However, systemic adverse effects can be reduced by correct installation of eye drops (see page 3).

Table 2: Adverse effects of topical glaucoma medications12,5

Medication

Local effect

Systemic effect

Prostaglandin analogues

Ocular irritation and redness, blepharitis, bitter taste, irreversible increase in iris pigmentation, thickening and darkening of eyelashes, keratitis

Headache, asthma, dyspnoea

Beta blockers

Stinging on instillation

Bradycardia, hypotension, syncope, fatigue, bronchospasm

Alpha2 agonists

Ocular irritation and allergic reaction

Dry mouth, taste disturbance, headache, dizziness, drowsiness, hypotension, palpitations
Rare: syncope

Carbonic anhydrase inhibitors

Ocular irritation, blurred vision

Bitter taste, GI disturbance, headache, dizziness
Rare: Allergic reactions

Cholinergics

Fluctuating blurred vision, ocular irritation

Frontal headache
Rare: bronchospasm, bradycardia, hypotension

Rare: incidence less than 0.1%

Cardiovascular disease and glaucoma

Topical beta blockers should be avoided in those with bradycardia, decompensated heart failure and heart block. The co-prescribing of a topical beta blocker and verapamil should be avoided because of the risk of profound bradycardia.12 Analysis of the DVA prescribing data for 2008 showed 830 veterans were dispensed verapamil and were also receiving treatment for glaucoma. Of these, 38% had been prescribed topical timolol to treat their glaucoma.1

Topical and systemic beta blockers are co-prescribed in about 20% of patients with glaucoma.14 It is important that ophthalmologists are made aware that a patient is taking systemic beta blockers as the IOP lowering efficacy of the topical beta blocker will be reduced and the risk of systemic side effects increased. This is particularly relevant in veterans with chronic heart failure where systemic beta blockers are frequently used. In 2008, 46% of veterans with chronic heart failure and glaucoma were treated with topical beta blockers.

Apraclonidine should be used with caution in those with cardiovascular disease, coronary insufficiency and recent MI as it can rarely cause hypotension and chest pain.12 Brimonidine can also cause hypotension and should similarly be used with caution in those with severe cardiovascular disease and postural hypotension.15 For both drugs there is a potential additive effect with antihypertensives.

Prostaglandin analogues do not appear to have significant cardiovascular adverse effects and are suitable for use in veterans with stable co-morbid cardiovascular disease.

Respiratory disease and glaucoma

Studies indicate that topical beta blockers used in the treatment of glaucoma and ocular hypertension can cause bronchospasm in those predisposed (including those with no previous diagnosis of asthma).3,4 They should be used with caution in veterans with asthma or COPD. Analyses performed on the DVA prescribing data indicate use of timolol is associated with increased bronchoconstriction as evidenced by increased use of beta agonists and inhaled corticosteroids and hospitalisation for respiratory conditions.1 Beta1 selective beta blockers (such as betaxolol) have a higher affinity for beta1 receptors in the heart with less effect on beta2 receptors in bronchi and peripheral vasculature, however this effect is dose-dependent and diminishes at higher doses.12,2

Pilocarpine can cause bronchoconstriction due to its cholinergic effects and should also be used with caution in veterans with asthma or COPD.

Large doses of prostaglandins can cause bronchoconstriction and cases of asthma and dyspnoea have uncommonly been reported with prostaglandin analogue eye drops.16,17 Analysis of the DVA prescribing data indicates latanoprost was associated with increased use of inhaled beta agonists.1 In view of this, exercise caution when prescribing prostaglandin analogues for veteran patients with reactive airways disease and, at follow up appointments, enquire specifically about shortness of breath or increased use of inhaled beta agonists.

Corticosteroids and glaucoma

Corticosteroids may raise intraocular pressure when administered in any form, including inhaled steroids used in the management of asthma and COPD, and nasal sprays. However topical corticosteroid eye drops are the most potent cause of raised intraocular pressure. All corticosteroids should be used with caution in those with POAG.

The amount of systemic absorption can be reduced by up to two thirds by correct instillation of eye drops.

The ‘double DOT’ technique – Don’t Open eyes Technique and Digital Occlusion of the Tear duct13

  • Administer the eye drop then close the eye and apply digital pressure over the lacrimal sac for 2 to 3 minutes
  • If 2 or more drops are being administered wait at least 5 minutes between drops

Optimising glaucoma management

Optimal treatment of glaucoma requires a high level of adherence to therapy; for a condition which is frequently asymptomatic this can be difficult to achieve. Non adherence rates in glaucoma have been reported to vary from 24 to 59%18. Patient adherence can be improved by:

  • Educating the patient about glaucoma and the importance of ongoing effective treatment.
  • Simplifying the treatment regimen as much as possible.
  • Observing the patient or carer instilling eye drops.
  • Providing written instructions to the patient or carer including technique for correct instillation of eye drops.
  • Enquiring about changes to health, new medications and possible side effects.

Consider a medicines review by an accredited pharmacist which may reveal potential drug interactions, systemic side effects or difficulties with administration of eye drops.

It is essential to optimise communication between all healthcare providers:

  • in particular that the ophthalmologist is made aware of the patient’s current medication regime and co-morbidities and
  • the GP is aware of all treatments prescribed by the ophthalmologist.

This is especially relevant when the initial referral was made by an optometrist not the GP.

Further reading

Australian Medicines Handbook12

Terminology and Guidelines for Glaucoma, 3rd Edition. European Glaucoma Society 2008. www.eugs.org6

Soon to be released Guidelines for Screening, Prognosis, Diagnosis, Management and Prevention of Glaucoma. www.nhmrc.gov.au

We acknowledge the contribution of the Fellows of The Royal Australian and New Zealand College of Ophthalmologists (RANZCO) in developing this material.

References

  1. Veteran's Datamart, University of South Australia, QUMPRC. Accessed November 2009
  2. Frishman WH et al. Cardiovascular considerations in using topical, oral and intravenous drugs for the treatment of glaucoma and ocular hypertension; focus on ᵦ blockade. Heart Disease 2001; 3: 386-397
  3. Kirwan JF et al. ß blockers for glaucoma and excess risk of airways obstruction: population based cohort study. BMJ 2002; 325: 1396-7
  4. Kirwan JF, Nightingale JA, Bunce C and Wormald R. Do selective topical ß antagonists for glaucoma have respiratory side effects? Br J Ophthalmol 2004 February; 88: 196-198
  5. Marquis RE, Whitson JT. Management of glaucoma: focus on pharmacological therapy. Drugs and Aging 2005; 22 (1):1-21
  6. Terminology and Guidelines for Glaucoma, 3rd Edition. European Glaucoma Society 2008. www.eugs.org
  7. Reidy A et al. Prevalence of serious eye disease and visual impairment in a north London population: population based cross sectional study. BMJ 1998; 316:1643-6
  8. Lee PP et al. Longitudinal prevalence of major eye diseases. Arch Ophthalmol. 2003; 121:1303-1310
  9. Mitchell P, Smith W, Attebo K and Healey P. Prevalence of open-angle glaucoma in Australia: the Blue Mountains eye study. Ophthalmology 1996; 103: 1661-1669
  10. Maier et al. Treatment of ocular hypertension and open angle glaucoma: meta-analysis of randomised controlled trials. BMJ 2005: 331: 134-138
  11. Van der Valk R et al. Intraocular pressure-lowering effects of all commonly used glaucoma drugs: a meta-analysis of randomized clinical trials. Ophthalmology 2005; 112: 1177-1185
  12. Australian Medicines Handbook, Adelaide: Australian Medicines Handbook Pty Ltd 2010
  13. Goldberg I, Moloney G and McCluskey P. Topical ophthalmic medications: what potential for systemic side effects and interactions with other medications? MJA 2008 189; (7): 356-357
  14. Goldberg I and Adena MA. Co-prescribing of topical and systemic beta-blockers in patients with glaucoma: a quality use of medicines issue in Australian practice. Clinical and Experimental Ophthalmology 2007; 35: 700-705
  15. Brimonidine Product information: www.medicines.org.au Viewed 29th March 2010
  16. Latanoprost Product Information: www.medicines.org.au Viewed 29th March 2010
  17. ADRAC Summary for Latanoprost, Bimatoprost and Travoprost. Adverse Drug Reactions Advisory Committee, www.tga.gov.au Viewed 12th January 2010
  18. Tsai JC. Medication adherence in glaucoma: approaches for optimizing patient compliance. Current Opinions in Ophthalmology 2006, 17:190-195

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Key Points
  • Eye drops have systemic effects which can impact on co-morbidities.
  • Concurrent use of verapamil and topical beta blockers is contraindicated.
  • Avoid topical beta blockers in veterans with bradycardia, decompensated heart failure and heart block.
  • Topical beta blockers and pilocarpine can cause bronchoconstriction; enquire about respiratory symptoms and inhaler use.
  • Ensure good communication between ophthalmologist, GP and patient.