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ADVANCES IN THE MEDICAL
TREATMENT OF GLAUCOMA

This article was written by Dr Mark Walland Royal Victorian Eye and Ear and Royal Melbourne Hospitals

The relationship of raised intraocular pressure (IOP) to damage of the optic nerve in glaucoma has been known to Western medicine since the 1850s. Treatment to decrease this pressure forms the mainstay of therapy for the condition, and may be achieved by medication, laser or surgery. Despite promising research into ways of influencing blood flow to the optic nerve, and into other ways in which we might protect the nerve from glaucoma damage (neuroprotection), all our current therapies have so far been proven to benefit glaucoma patients through their effect on lowering IOP.

For many years the treatments available, while quite effective, were few in number: principally timolol (or its cousin levobunolol), oral acetazolamide or pilocarpine. Through the extensive research that has been undertaken into glaucoma treatment, we are fortunate now to have available a whole range of new treatments, which have been progressively introduced into clinical use over the last 6 to 7 years. Ophthalmologists now have access to a dozen different therapies to treat glaucoma. This means that patients are more likely to be able to find a combination of medications that will prove effective in controlling the IOP, as well as avoiding unacceptable side effects. As a consequence of these more numerous options, we have seen a decrease in the need for laser or surgery to control the IOP, and the number of glaucoma operations performed has progressively declined over the last few years.

There is a distinct logic to the treatment of IOP. If one imagines the eye as a closed container or sphere, it is easy to imagine that the pressure inside will depend on how much fluid is pushed into the eye and how much is allowed to flow out. The ciliary body is a structure inside the eye that makes the fluid (aqueous), while the drainage of aqueous occurs through the ‘meshwork’ – much like a tiny gully-trap around the inside circumference of the front of the eye – in the drainage ‘angle’ inside the eye. Increased pressure leading to glaucoma occurs from a degree of blockage in the meshwork, but it can be seen that if one was able either to increase the drainage out of the eye, or to decrease the amount of aqueous fluid the eye produced, then the fluid balance would be changed and the IOP would decrease. Each of the medications used to treat glaucoma works by one of these mechanisms: either decreasing aqueous production or increasing aqueous outflow (one or two drugs may have both skills!)

The medications now available fall into 5 classes:

beta-blockers
miotics
prostaglandin analogues
alpha-agonists
carbonic anhydrase inhibitors

Beta-blockers
These are the well-known drugs such as timolol (many brand-names) and levobunolol (Betagan). They were introduced to treat glaucoma in about 1979 and have been first-line therapy until recently. They work to decrease fluid production. While very effective, with only mild local side-effects such as stinging on instillation in the eyes, care has been needed to avoid general body side-effects in susceptible people. The drugs need to be avoided, for example, in those with asthma, heart failure, poor circulation or depression. The eye drop betaxolol (Betoptic) was introduced in 1990 in an attempt to avoid some of these unwanted effects, and it has a compensatory slightly lesser effect in lowering the IOP compared to the other drugs in this class.

Miotics
Pilocarpine was for many years the mainstay of treatment for glaucoma, especially before the introduction of timolol. It is a very effective drug for lowering IOP by increasing aqueous drainage through the meshwork. Although it has a number of local side-effects such as stinging and it produces a small pupil, which can be a problem for focussing and also for adapting to the change in light level on going from a bright day outside into a darkened room. It is used less frequently now because it requires dosing 4 times a day. (It has become increasingly evident that – much though the doctor might believe that the patient follows instructions on how to use their medication– many patients either neglect or are unable to comply with such a frequent dosing program!) Many of the newer medications can be used far less frequently each day, and so are a more attractive option if they can be shown to work just as well for the patient in lowering IOP.

Prostaglandin analogues
This group of medications has had the biggest impact in the last 10 years on the way glaucoma is treated. The drugs are cousins to a substance that occurs naturally in the body. While it had been known for some time that natural prostaglandins could lower IOP, this was usually associated with producing unacceptable inflammation as a side-effect. There was for many years, therefore, scepticism about the use of prostaglandins for glaucoma treatment. But it was found after some years of dedicated research that by slightly modifying the prostaglandin molecule, one could still achieve IOP lowering, but with much reduced inflammation. The first drug in this class was latanoprost (Xalatan), and this has been followed recently by travoprost (Travatan) and bimatoprost (Lumigan). All three drugs are very effective at lowering pressure: so much so that prostaglandins have now superseded timolol as first line therapy for many glaucoma patients. Apart from an occasional patient who experiences headache, they are largely free of general body side-effects, and the once a day dosing is particularly popular with patients. Prostaglandins work to lower IOP by increasing aqueous outflow, although they do this in a slightly curious way, through an alternative pathway - the uveoscleral pathway - that is little-used normally. Side-effects in the eye are also curious. There may be a degree of redness of the white of the eye for the first few weeks of use. In the longer term – after several months – there may be a change in the colour of the iris (the coloured part of the eye) to brown. This change tends to occur in those who start with green or hazel eyes and is less seen in blue-eyed people. The change is permanent, but there is no evidence that it is anything other than a cosmetic change. Ladies also enjoy the ‘luscious lashes’ that may also be a side-effect, although this is less popular in male patients!

Alpha-agonists
This new class of drugs is vaguely related to an older drug called dipivefrin (Propine) that fell from favour because of the redness of the eye that it could cause, as well as often having a limited benefit in lowering IOP when used in combination with other glaucoma medications. The new drugs are apraclonidine (Iopidine) and brimonidine (Alphagan). They can be effective in lowering IOP quickly, and have been used for this reason in patients who are having glaucoma laser treatment to prevent an IOP ‘spike’ from the laser energy. They may work by both mechanisms to decrease IOP, and can be used twice a day in combination with other drugs, or sometimes three times a day if used alone. There is a tendency for a number of patients to develop allergy to the drops after several months: this propensity does not mean that the drugs should not be used but merely that if allergy develops they should be stopped and an alternative treatment sought. There is some hopeful research to suggest that brimonidine may have a ‘neuroprotective’ effect, but this is yet to be proven clinically.

Carbonic anhydrase inhibitors
The two drugs in this class are dorzolamide (Trusopt) and brinzolamide (Azopt), and they are cousins of a tablet medication – acetazolamide (Diamox) – that has been used for many years to treat acute glaucoma. They work by decreasing aqueous production in the ciliary body, much like the beta-blockers do. Stinging is the major side effect, sometimes with a slightly bitter taste if the drops are allowed to run into the tear ducts and into the nose and back of the throat. (Punctal occlusion - using a finger to block off the opening of the tear duct at the inner end of the eyelid -should be a technique familiar to all glaucoma patients. If you are unfamiliar with this, ask your doctor to demonstrate it to you.)

Combination medication
In addition to the 5 separate classes of drugs, further developments have allowed various pairs of drugs to be put together in one bottle. This reduces expense for the patient and is more convenient to use, simplifying both the number of bottles and the dosing schedule. The most commonly used combinations are Timpilo (timolol and pilocarpine) or Cosopt (timolol and dorzolamide). Another combination is Xalacom (latanoprost and timolol), although this so far has Government approval only for Veterans Affairs patients.

Summary
These developments in glaucoma treatment are exciting advances for patients and doctors alike. The multiple combinations of drops that can be tried for each patient mean that it is very likely that a suitable combination can be found to lower the pressure and thus slow or even arrest the damage to sight from glaucoma. Whilst there is still a place for laser or surgery, fewer patients these days require these interventions. Ongoing, promising research holds the prospect of yet further treatments, so the future has never looked brighter for glaucoma patients.

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