Glaucoma medical CLIVE MIGDAL treatment: philosophy, principles and practice Abstract assessment of these parameters. Indeed There have been numerous recent advances in compounds are under evaluation that affect the the management of glaucoma, not least the function of the optic nerve (via improved blood development of new drugs to help manage supply or improved neuronal cell physiology) raised intraocular pressure. In addition, the but may or may not lower lOP. It may even be concepts of improving blood flow to the optic possible in the future to therapeutically alter the nerve head and neuroprotection are currently human genome, genetically deliver provoking considerable interest. This article neuroprotective substances or aid regeneration considers the aims and philosophy of of the optic nerve axons. glaucoma drug therapy, summarises some of The main aim of glaucoma therapy must still the basic facts and principles of modem be the preservation of visual function. At the glaucoma medications, and suggests a same time, the therapy should not have adverse practical approach to the choice of therapy. side effects and should not affect the quality of life of the patient (by causing either side effects Key words Blood flow, Intraocular pressure, or inconvenience and disruption of daily Neuroprotection, Primary open angle glaucoma, Topical medications lifestyle). The cost of the therapy, both direct and indirect, must also be taken into consideration.s Currently, typical glaucoma management Philosophy consists of lowering the lOP to a satisfactory Primary open-angle glaucoma is a complex and safe target leve1.6 To determine the success disease for which a number of risk factors have of this treatment, the patient must be followed been identified, including intraocular pressure, long-term with routine assessment of lOP, discs age, race and family history.l,2 Due to our and fields to exclude progressive damage. lOP, relatively limited understanding of the although a vital criterion in the management of pathophysiology of glaucomatous optic the glaucoma patient, poses a number of neuropathy, therapy is currently limited to problems, including the fact that some dealing with one parameter, namely intraocular glaucoma patients continue to have progressive pressure (lOP). All glaucoma therapies damage despite an apparently satisfactory lOP (medical, laser or surgery) are designed to lower level, that others (i.e. with normal tension lOP. glaucoma) develop characteristic glaucomatous It has previously been shown that many damage despite normal lOPs, that damage patients on topical medications will not achieve cannot be reversed, and that long-term follow­ a satisfactory lOP level and, with the passage of up is required before the success of therapy can time, may lose visual field?A However, in be determined. Future glaucoma therapy will recent years several new drugs have been need to address these issues. developed to help manage elevated lOP. These In this century it may become possible to medications consist of new compounds within investigate the stability of the optic nerve at the classes of drugs already in use, combination time of lowering the lOP. Such tests might be products, or novel delivery systems. These have increased the options for the ophthalmologist. based on visual function or metabolism of the In the past, the effectiveness of a medication optic nerve in vivo. If, despite a lower lOP, no in the treatment of glaucoma was measured by improvement in visual function occurs, or an its ability to lower lOP. More recently, other abnormal metabolism is noted, this could factors have been considered, such as blood suggest that a lower target lOP is required or supply to the optic nerve and neuroprotection that other factors, such as blood flow, might Clive Migdal, MD, FRCS, of the ganglia. The clinical importance of these need to be addressed. It may be possible in the FRCOphth � variables has not yet been fully proven, but it is future to classify patients more accurately Western Eye Hospital anticipated that future improvements in the according to the factors that influence their Marylebone Road efficacy of glaucoma treatment may include disease, with therapy directed not only at lOP London NWl 5YE, UK Eye (2000) 14, 515-518 © 2000 Royal College of Ophthalmologists 515 but also to the optic nerve directly. The success or and similar, if less severe, complications may occur. otherwise of that therapy will also be determined in a Topical beta blockers are effective and well tolerated by shorter time. the majority of patients.12 Rarely these agents have been linked with patient fatality. It is important that the ophthalmologist identify those patients in whom the Principles product can safely be used and those in whom it is This review will concentrate on the topical agents contraindicated, particularly as there are now adequate currently used to treat glaucoma, and will be restricted to alternative choices. the more commonly used agents. Current glaucoma drugs alter cellular functions Topical carbonic anhydrase inhibitors within the eye, either via interaction with receptors or via specific enzymes. Ion channels of the cells are probably Dorzolamide, a topical carbonic anhydrase inhibitor, important effectors of responses initiated by glaucoma differs in structure from the oral agents. It has increased drugs acting via receptors? Signal transduction mediated aqueous solubility and lipid-water solubility, allowing by drug receptors is an important concept, with new corneal penetration. Dorzolamide 2.0% reduced aqueous developments occurring particularly in two areas: firstly, flow by 38% (measured by fluorophotometry)Y the discovery (via molecular biology techniques) of new Mechanism: Inhibition of the carbonic anhydrase subtypes of receptors (this includes new subtypes of enzyme lowers lOP due to a decreased production of receptors relevant to current glaucoma medications) and, aqueous. In order to inhibit the enzyme, carbonic secondly, the improved understanding of the anhydrase inhibitors must inhibit nearly 100% of the biochemical events of signal tranduction initiated by enzyme at all times. Topical carbonic anhydrase receptor activation? inhibitors act locally in the ciliary body, inhibiting In basic terms, glaucoma drugs reduce lOP by causing aqueous production, but do not affect total body carbonic a decrease in aqueous production or by increasing anhydrase, thus minimising systemic symptoms. outflow (either through conventional channels, i.e. the Efficacy: Dorzolamide 2% used three times daily trabecular meshwork, or via uveoscleral outflow). The resulted in a peak reduction of lOP of 22%, with a trough concepts of improvement of blood flow to the optic nerve reduction of 18%.14 In a 12 month study comparing head and neuroprotection have recently been raised as dorzolamide thrice daily with timolol 0.5% b.d. and possible additional actions of certain drugs. betaxolol 0.5% b.d., timolol was more effective than the other two drugs. No statistical difference was found between dorzolamide and betaxolol.15 Specific agents Additivity: Dorzolamide has an additive effect with Beta blockers timolol, reducing the lOP by an additional 13_21%.16 Beta blockers have become the mainstay of glaucoma Comparing the additive effect of dorzolamide b.d. with medical therapy. Receptor selectivity is important, with pilocarpine 2% q.i.d., additional lOP reductions achieved non-selective beta blockers affecting both beta-I and were 13% and 10% respectively.17 Dorzolamide thus beta-2 receptors, in contrast to beta-I-selective agents appears to be a reasonable choice for adjuvant therapy. which are more selective for the beta-1 receptors. This Side effects: The only frequently reported systemic selectivity affects both safety and efficacy. effect is a bitter taste after drop instillation, and the drug Mechanism: Beta blockers reduce lOP by decreasing appears to be well tolerated, with only 5% discontinuing aqueous humour production by the ciliary body.8 the drug due to an adverse event in controlled clinical Efficacy: Mean peak lOP is lowered by 25% and mean trials. The majority of these side effects were ocular, and trough by 20% using non-selective agents.9.lD lOP included topical discomfort and allergy.15 Most patients lowering is less with betaxolol, the beta-I-selective tolerate the drug well. agent.ll If beta blockers alone do not achieve adequate pressure lowering, then one of the other classes of agents Prostaglandin analogues can be used as adjunctive therapy. Beta blockers are generally administered twice daily. Levobunolol may be Prostaglandins are derived from arachidonic acid and used once daily in some patients. Timolol XE is a once­ display a wide range of biological functions. daily formulation. If more than one concentration of the Mechanism: Prostaglandins reduce lOP by increasing drug is available, the lower concentration should be used uveoscleral outflow}8 possibly due to relaxation of the and is generally as effective in the majority of patients. ciliary muscle and creating dilated spaces between ciliary Side effects: Contraindications to beta blockers include muscle bundles, as well as due to alterations in the severe chronic obstructive airways disease, asthma, heart metabolism of the extracellular matrix that surrounds the block, bradycardia and congestive cardiac failure. Other ciliary muscle cells.19 Since uveoscleral flow is systemic side effects are also common, including independent of the episcleral venous