The medical treatment of glaucoma

The glaucomas are a major cause of blindness in Australians over 55 years of age. Much of this visual disability is preventable with early diagnosis and appropriate therapy. Acute angle-closure glaucoma presents dramatically with pain, redness and decreased vision. Prompt medical intervention followed by laser surgery minimises eyeball and visual damage. Most glaucomas are open-angle and asymptomatic. Medical treatment aims to reduce intra-ocular pressure to a level safe for the optic nerve fibres. Drug treatment may involve beta blockers, miotics, adrenergic agonists or systemic carbonic anhydrase inhibitors.

Inspected by candlelight, the iris in an attack of angle-closure glaucoma is 'sea-green', hence the Greek 'glaukos'. The term 'glaucoma' refers to ocular conditions in which the intra-ocular pressure (IOP) is high enough to damage optic disc nerve fibres. If left untreated, glaucoma usually results in blindness. The two main types of glaucoma are the dramatic acute angle-closure glaucoma and the far more common chronic open-angle glaucoma.

A combination of ocular pain and peri-corneal conjunctival redness with blurred vision in a middle-aged or elderly patient is acute angle-closure glaucoma till proven otherwise. The pain may be local, peri-orbital, cranial or referred as far a field as the abdomen the 'acute abdomen' differential diagnosis includes angle-closure glaucoma. (It is ischaemia of the eyeball which produces this symptom complex.) On examination, the pupil is mid-dilated and non-reactive, the cornea is oedematous (the clear specular reflex is absent) giving the iris a hazy appearance and the eyeball feels rock-hard.

Eyes with an anterior position of the lens-iris diaphragm are predisposed to acute angle-closure glaucoma. The anterior convexity of the iris is readily identifiable with a simple hand-held torch (Fig. 1).

As IOP is often markedly raised in this condition (5080 mmHg), management needs to be effective swiftly to minimise damage to vision and to ocular structures. Barring systemic contraindications, pilocarpine 2% and either timolol 0.5% or betaxolol 0.5% drops should be instilled, with two 250 mg tablets of oral acetazolamide. If it will take several hours to reach ophthalmic care, oral glycerol (100%1 mL per kg body weight diluted in an equal volume of sour juice) should be given. Definitive treatment consists of a laser peripheral iridectomy for both eyes.

Fig. 1 Simple estimation of anterior chamber depth.
a. In an eye with myopia or emmetropia in which the iris is flat or concave forwards, either the entire iris is evenly illuminated or there is a crescentic shadow close to the torch – sunrise on a plain or valley.	b. In an eye with hypermetropia in which the iris is convex forwards, the iris casts a shadow on the nasal side – sunrise on Mt Vesuvius. This is the anatomic configuration which predisposes to acute angle-closure glaucoma.
Deep anterior chamber	Shallow anterior chamber
Iris concave forwards a	Iris convex forwards b

This group of diseases is divided into primary idiopathic conditions and those secondary to ocular or systemic disease such as uveitis, trauma, cataract and structural developmental anomalies of the angle. Australian prevalence of all chronic glaucomas is estimated to range from 0.7% in those aged under 40 years to 4.8% among those over 60 years of age.

Damage is postulated to result from mechanical injury at the optic nerve head (i.e. the level of IOP becomes too high for nerve survival), and/or an inadequate vascular perfusion of the nerve fibres at the optic disc. The relative importance of these two mechanisms probably varies from patient to patient, and perhaps from time to time in the same eye. Only IOP reduction has been possible therapeutically, but in future it may become possible to identify and treat eyes in which reduced vascular perfusion is a significant cause of damage.

Approximately two-thirds of glaucoma patients are adequately controlled by topical therapy alone after two years. Argon laser trabeculoplasty and filtering surgery are available for those who require further lowering of IOP. However, surgery can be associated with significant morbidity in a minority of patients, and laser treatment, although initially often very helpful, may demonstrate decreasing effectiveness with time. New topical treatments are needed to supplement existing medications. Three drugs currently under investigation deserve mention: topical carbonic anhydrase inhibitors (MK-507), alpha adrenergic agonists (apra-clonidine) and prostaglandins (PhXA34).

The aim is to reduce IOP safely, effectively and asymptomatically, with minimal inconvenience. Four types of drugs are used: beta blockers, the miotics (para-sympathomimetics and anti-cholinesterases), adrenergic agonists and carbonic anhydrase inhibitors (Table 1).

Additivity

A drug from one class is often additive to the ocular hypotensive effect of those from each of the other groups. Two drugs from the same class are not additive; using them simultaneously simply increases the chances of adverse effects without improving efficacy.

Concentration

Both timolol and pilocarpine bind to melanin. Therefore, lower concentrations can be at the top of the dose-response curve for lighter coloured eyes, while higher concentrations are often needed for maximal efficacy in eyes with darker irises.

Systemic absorption

Eye drops deliver the drug to the tears (from which penetration of the cornea permits an intra-ocular effect). The conjunctiva and naso-pharynx are mucous membranes rich in blood vessels. Absorption of drugs directly into the general circulation is rapid and significant - particularly since such absorption gives drugs access to systemic receptors without first-pass hepatic metabolism. Drugs instilled as eye drops are as important as drugs taken orally or parenterally they must be sought in any drug history. Not only may a topically applied drug have undesirable and perhaps unsuspected systemic effects, but it can also interact with other drugs.

Some of these problems can be avoided: systemic absorption can be reduced by about two-thirds if the patient does not blink and digitally occludes the naso-lacrimal pathway for at least two minutes after every drop instillation. Furthermore, by generating higher tear concentrations of instilled drug for longer, these procedures enhance absorption by the eyeball and IOP reduction.

Systemic levels can be reduced further by using the lowest effective drug concentration (e.g. timolol 0.25% rather than 0.5%) and by reducing instillation frequency (once rather than twice daily timolol may be as potent over 24 hours).

Ensure efficacy

IOP fluctuates significantly, especially in glaucomatous eyes. Pharmacological manipulation has to be judged against a changing baseline. Initiating or adding a drug to one eye means the fellow eye can be used as a 'control' an equal fall in IOP in treated and untreated eyes suggests spontaneous fluctuations, whereas a greater fall in the treated eye implies drug effect. No patient should be asked to instil a drug chronically which has not been demonstrated to be effective.

If ineffective, a drug should be withdrawn, and another substituted. Simply adding one drug to another contributes to patient confusion and non-compliance (except on the day they visit the doctor!).

Educate the patient

The techniques of efficient drop instillation as well as the reasons for using each drug, its mechanism of action and its anticipated adverse effects (Table 2) need to be explained if we expect patients to comply for years with therapy which is inconvenient to administer and often causes some adverse effects for a disease which is almost always asymptomatic. Included here is the need for the patient and the family to understand the nature of the disease, the reasons for that particular approach to therapy, and to have reasonable expectations of what is being offered. Physician time constraints as well as patient forgetfulness of information communicated during a consultation make it essential that patients have regular access to updated, clearly written and well presented information. The doctor can provide appropriate support by informing the patient about the Glaucoma Foundation of Australia.

Beta blockers

By inhibiting the beta receptors on the ciliary epithelium, beta blockers reduce the rate of aqueous production by about 40%, thereby lowering IOP by about 25% in 90% of treated eyes. Because of efficacy, relative safety, once or twice daily instillation, and the absence of any effect on pupil size or accommodation, these drugs have become first-line therapy.

Timolol was the first topical beta blocker available. It is a non-specific beta 1 and beta 2 receptor antagonist. Topical use may have adverse systemic effects due to beta blockade (Table 2). Betaxolol is selective for beta 1 receptors and may have a wider margin of safety, but nevertheless can still cause systemic effects. Recently, betaxolol has been shown experimentally to have calcium channel blocking properties; it may therefore enhance circulation within the optic nerve head. It needs to be instilled twice daily and is slightly less potent in reducing IOP than timolol.

Miotics

These para-sympathomimetic drugs are derived from plant species and have been available for over 100 years. Until the advent of the beta blockers, they were the most commonly prescribed anti-glaucoma medications. By stimulating ciliary muscle contraction, these drugs increase traction on the scleral spur and trabecular meshwork. This mechanical change separates the trabecular sheets from one another, prevents Schlemm's canal from collapsing and increases aqueous outflow. Miotics have become second- or third-line drugs because they need to be instilled up to 4 times daily, produce dimness of vision from the miosis and blurred vision from the accommodative spasm. These adverse effects are particularly troublesome to younger patients and to those with cataracts, but can be reduced by use of a sustained release pilocarpine conjunctival forniceal insert which is worn beneath the upper or lower eyelid and changed weekly. Once the patient has adjusted to this device, the more consistent miosis and myopia it provokes are easier to tolerate than the fluctuations associated with the instillation of pilocarpine eye drops.

Adrenergic agonists

When instilled into the eye, adrenaline lowers IOP, probably by increasing aqueous outflow. Local and systemic adverse effects are relatively common. Although the pro-drug dipivefrine increases the systemic safety of this class of anti-glaucoma drugs and reduces the incidence of local intolerance, the ocular hypotensive effect may not be dramatic and is not particularly additive to that of the beta blockers. It is more effective with betaxolol than with timolol, and is additive to the hypotensive effects of both miotics and carbonic anhydrase inhibitors.

Because it has a mild mydriatic effect, dipivefrine may visually assist patients with axial lens opacities, and it may partly offset visual dimness caused by miotics. Its twice daily instillation frequency is more convenient for patients than the 4 times daily administration of miotics.

Systemic carbonic anhydrase inhibitors (CAI)

There drugs act on the ciliary epithelium, decreasing the rate of aqueous formation by about 40%. CAIs are contraindicated in patients allergic to sulphonamides, due to their related structure, and may rarely precipitate Stevens-Johnson syndrome. When necessary, CAIs should only be used for short-term therapy because of their potential for adverse effects.

Shields MB. Textbook of glaucoma. 2nd ed. Baltimore: Williams & Wilkins, 1987.
Kanski JJ, McAllister JA. Glaucoma. A colour manual of diagnosis and treatment. London: Butter worths, 1989.