Open-angle glaucoma and ocular hypertension

This article reviews topical and systemic medication used to reduce intraocular pressure in open-angle glaucoma and ocular hypertension, and summarises the characteristics of each intraocular pressure-lowering drug class

Andreas Katsanos MD PhD

Assistant Professor of Ophthalmology, University of Ioannina, Ioannina, Greece

Márta Tóth MD PhD

Glaucoma Fellow, Moorfields Eye Hospital, London, UK

Research Collaborator, Glaucoma Unit, Department of Ophthalmology,

Semmelweis University, Budapest, Hungary

Gábor Holló MD PhD DSc

Professor of Ophthalmology, Head,

Glaucoma Unit, Department of Ophthalmology, Semmelweis University, Budapest, Hungary

Email: [email protected]

Glaucoma is a leading cause of blindness worldwide. Beside the rare congenital forms, most glaucomas are adult-onset. Depending on the anatomical and pathological characteristics of the anterior segment of the eye, adult-onset glaucomas can be subdivided into primary/secondary open-angle glaucomas and primary/secondary angle-closure glaucomas.¹ In all types, the common pathomechanism is accelerated apoptosis of the retinal ganglion cells. Open-angle glaucoma is the most common glaucoma type in the western world.

It is a progressive optic neuropathy, which leads to characteristic alterations of the retinal nerve fibre layer and the optic disc, and as a consequence, irreversible visual field defects. Besides the several non-modifiable risk factors of the development and progression of glaucoma (for example, age, family history, race, myopia), intraocular pressure (IOP) remains the only modifiable risk factor. To reduce the risk related to significantly elevated IOP for the development and progression of open-angle glaucoma, effective and long-lasting IOP reduction is needed.

Individuals with elevated IOP but with no optic disc and visual field damage have ocular hypertension. Depending on the IOP level and individual risk profile, IOP-lowering medication may also be indicated in ocular hypertension to prevent conversion to glaucoma. Pharmacotherapy is the mainstay treatment for the majority of open-angle glaucoma patients, whereas surgery is needed for patients with medically uncontrolled disease. The goal of all treatment modalities is to reduce IOP to a level that prevents further deterioration of the visual functions (target IOP).¹

General aspects of intraocular pressure-lowering medication

To reduce IOP in open-angle glaucoma and ocular hypertension, the most common drug delivery form is topical medication (eye drops). This provides optimal transcorneal penetration and high drug concentration in the ocular target tissues, and at the same time is associated with less systemic side effects. Topical therapy can be a monotherapy when one active molecule is used, or a combination therapy when two or more IOP-lowering molecules are applied. Combination therapy can be either an unfixed therapy (the different active molecules are applied from different bottles) or a fixed combination therapy (Table 1) when the active molecules are manufactured in the same bottle.

Prostaglandin derivatives

Prostaglandin analogues (latanoprost, travoprost and tafluprost) and the prostamide bimatoprost have become the most commonly used IOP lowering medications. This is mainly due to their high IOP-lowering efficacy, favourable side effect profile and the convenient once-daily dosing frequency.

The primary mechanism of action of the prostaglandin analogues is increase of aqueous humour outflow through the uveoscleral outflow. This is mediated via modified extracellular matrix remodelling. The average IOP reduction achieved with prostaglandin analogues is 25–35%.^2,3 The ocular hypotensive effect starts 2–4 hours after instillation, reaches its peak within 8–12 hours and is maintained for 24 hours or longer. Evening administration of the prostaglandin analogues may offer a better 24-hour IOP reduction than morning administration.

Maximal efficacy is usually reached at 3–5 weeks following the commencement of treatment. The different members of this class have efficacy differences of 1–2mmHg in most patients. A smaller than expected hypotensive effect (less than 10–15% IOP reduction) has been described in fewer than 10% of the patients (non-responders). These patients may still respond adequately to another member of the class. Systemic side effects (for example, dyspnoea, chest pain) are rare.⁴

The local side effects⁴ include conjunctival hyperaemia that generally decreases with time, eyelid and iris hyperpigmentation, eyelash growth, orbital fat atrophy and, rarely, cystoid macular oedema (after complicated cataract surgery or in eyes with other risk factors for macular oedema). Association between use of topical prostaglandin analogues and reactivation of herpetic keratitis or uveitis is debated.

β-blockers

Topical β-adrenergic blockers have been used for more than 30 years for the treatment of glaucoma and ocular hypertension. They decrease the sympathetically driven portion of aqueous humour production. The class contains a member that selectively inhibits the β1-adrenergic receptors (betaxolol), and members which non-selectively block both β1 and β2-receptors (timolol, levobunolol, metipranolol, carteolol, befunolol).⁵

Various formulations and concentrations of the active compounds are available. Timolol, the most commonly used agent of the class, is available in 0.25% and 0.5% solutions for once or twice-daily instillation, and in 0.1%, 0.25% or 0.5% gel formulation for once-daily (morning or evening) administration. The IOP-lowering efficacy of the non-selective β-blockers is 20–25%, while the efficacy of betaxolol is approximately 20%.

Since sympathetic activation and the related aqueous production are decreased in humans during sleep, the nocturnal IOP-lowering efficacy of the β-receptor blockers is relatively low.

The local side effects are relatively mild and include burning/stinging, conjunctival hyperaemia and superficial corneal erosions. The systemic side effects are mainly related to cardiovascular and pulmonary β-receptor blockade, and can be serious (bradycardia, arrhythmia, hypotension, syncope, heart failure and bronchospasm). Other, less common side effects include hypoglycemia, depression and erectile dysfunction. Instructing the patient to keep the eyelids closed while exerting pressure on the medial canthus for three minutes after the instillation of β-receptor blockers (punctal occlusion) is therefore recommended.

Punctal occlusion limits the drainage of topical medication to the nasal mucosa (where systemic absorption occurs) through the nasolacrimal duct, and therefore reduces the occurrence of the systemic side effects.

Topical carbonic anhydrase inhibitors (CAIs)

Inhibition of carbonic anhydrase in the ciliary body decreases aqueous humour production by reducing sodium and fluid transport.^6,7 The currently available topical CAIs (dorzolamide 2% and brinzolamide 1%) are given 2–3 times daily, and their IOP-lowering efficacy is 15–20%. The relatively common side effects of the topical CAIs are bitter taste feeling and ocular allergy. Brinzolamide is formulated as a suspension and therefore often causes a short temporary blurring of vision after instillation.

The systemic side effects of topical CAIs are significantly milder than those of the orally or parenterally administered CAIs. All CAIs are sulphonamides. Thus they are contraindicated in patients with sulphonamide allergy. Topical CAIs should be used with caution in patients with compromised corneal endothelial function since they inhibit carbonic anhydrase also in the corneal endothelial cells, and therefore exacerbate hydration of the cornea (corneal oedema).

α2-adrenergic receptor agonists

Activation of α2-receptors inhibits the activity of adenylate cyclase. This reduces cAMP and hence aqueous production by the ciliary body.⁸ The IOP-lowering effect is due to both the decreased aqueous production and the improved outflow via the trabecular and the uveoscleral pathways. α2 agonists are given 2–3 times daily, and their IOP-lowering efficacy is approximately 20–25%. Ocular allergy (allergic conjunctivitis and dermatitis) due to α2-receptor agonists is not uncommon.

The most commonly used member of the class is brimonidine. Brimonidine is a highly selective α2 agonist. It is lipophilic, thus it penetrates the blood–brain barrier and causes somnolence and lethargy in children. Therefore, brimonidine is contraindicated in patients younger than two years old. Apraclonidine is a less commonly used hydrophilic clonidine derivative without significant blood-brain barrier penetration. Its α2 selectivity is moderate, resulting in α1-adrenergic side effects (conjunctival blanching, mydriasis and eyelid retraction).

Systemic side effects of the α-receptor agonists include bradycardia, hypotension, and dryness of mouth and nose. Brimonidine and apraclonidine are contraindicated in patients receiving monoamine oxidase inhibitors or tricyclic antidepressants. In animal models brimonidine has been shown to exert a neuroprotective effect, which is independent from the IOP decrease.9,10 Human studies however, have failed to show indisputable protective effects.

Pilocarpine

In the past parasympathomimetics were widely used to reduce IOP in glaucoma. Pilocarpine in 1–4% solutions is still used in open-angle glaucoma, though less commonly than in angle-closure glaucoma. Pilocarpine exerts its effects by inducing contraction of the ciliary body and pupillary sphincter muscle fibres. This pulls the trabecular tissue and enlarges the pores of the trabecular meshwork, thereby increasing trabecular outflow of aqueous humour.

The IOP reduction achieved with pilocarpine in open-angle glaucoma is 20–25%. Several side effects are related to pupil contraction: transient myopia, eye pain and decrease of the visual field. These side effects have significantly limited the use of pilocarpine in clinical practice. Gastrointestinal and cardiac side effects, and increased risk for retinal detachment have also been described.

Combination therapies

Pharmacotherapy in glaucoma is instituted in a stepwise fashion. Topical monotherapy is the first step. If IOP-lowering efficacy of the first medication is less than expected (that is, the patient is a non-responder) or the medication is not tolerated, an alternative monotherapy should be tried. In a significant proportion of patients, however, the target IOP cannot be achieved with any monotherapy.

For these patients, combination therapy is needed.^1,11 In general, combination therapy comprises molecules with different mechanism of action. Since additivity of the IOP-lowering efficacies of these molecules is always partial, only the best performing combinations are manufactured in fixed combination formulations (Table 1).

The use of unfixed combination therapy is associated with a number of concerns.^12,13 Instillation of the second drug reduces the absorption of the first drug (washout effect) unless several minutes are allowed to pass between the instillations. The patients’ compliance decreases when the number of prescribed eye drops is increased. Chronic exposure to preservatives (especially benzalkonium chloride, BAK) may lead to inflammatory and fibrotic conjunctival changes, which frequently leads to ocular surface disease.

These reactive tissue changes can also unfavourably influence the success of later glaucoma filtration surgery.¹⁴ Therefore various fixed combinations have recently been manufactured in BAK-free or preservative-free formulations.¹⁵ In Europe the preservative-free formulations are produced in single-dose containers. For elderly patients with tremor, arthritis and similar conditions handling this formulation may cause difficulties.¹⁶

Systemic IOP-lowering medication

Acetazolamide, a systemic carbonic anhydrase inhibitor is rarely used in open-angle glaucoma, but in severe cases it may be used before glaucoma surgery. The IOP decrease is detectable already within one hour, the peak effect is reached after two hours, and the duration of action is 6–8 hours.^1,6 The side effects of systemic acetazolamide therapy are usually dose-related, and include paresthesias, lassitude, anorexia, unpleasant taste, loss of libido and abdominal discomfort.

There is an increased risk of hypokalaemia, acidosis and formation of renal stones. Dose independent severe or even lethal allergic reactions (aplastic anaemia, thrombocytopenia and agranulocytosis) can also occur. As acetazolamide is excreted in the urine, patients with impaired renal function require lower doses and careful monitoring. Since systemic acatazolamide may cause significant side effects, the lowest dose that results in an acceptable IOP level should be used.

The therapeutic dosage varies between 250 and 1000mg per day. Sustained-release formulations may have somewhat fewer side effects. Similarly to topical CAIs, acetazolamide is contraindicated in patients allergic to sulfonamides. Hyperosmolar agents (oral glycerol and intravenous mannitol) are very rarely used in open-angle glaucoma.

Conclusion

Modern topical glaucoma medications provide powerful pressure reduction in open-angle glaucoma and ocular hypertension. Use of fixed dose combinations simplifies the treatment regimen and therefore improves adherence and reduces the preservative-related negative effects on the ocular surface. In addition, the preservative-free fixed combinations fully eliminate the preservative-related ocular surface toxicity without being less effective than the similar preserved products.

Though fixed combinations are not proposed as first step drugs in the treatment of open-angle glaucoma and ocular hypertension, their early introduction to the treatment regimen is recommended when the target IOP is not reached with monotherapy.

Key points

The goal of IOP-lowering treatment in glaucoma is to reduce IOP to a level that prevents further deterioration of the visual functions.
Pharmacotherapy in glaucoma is instituted in a stepwise fashion: topical monotherapy is the first step, and combination therapy is indicated only when monotherapy fails.
The most commonly used IOP-lowering molecules belong to the prostaglandin derivative, β receptor blocker, carbonic anhydrase inhibitor and α2 receptor agonist classes.
Chronic exposure to preservatives (especially BAK) may lead to inflammatory conjunctival changes, therefore various IOP-lowering eye drops are manufactured in BAK-free or preservative-free formulations.
When combination therapy is needed use of fixed dose combinations simplifies the treatment regimen and therefore improves adherence, and reduces the preservative-related negative effects on the ocular surface.

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Open-angle glaucoma and ocular hypertension

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