Medical therapy is the most common method used for the reduction of the intraocular pressure (IOP) associated with ocular hypertension (OHT) and open-angle glaucoma (OAG). Several classes of drugs (prostaglandin derivatives, beta-adrenergic antagonists, carbonic anhydrase inhibitors, adrenergic agonists and cholinergic agonists) may be used to reduce the IOP. Medications are classified based upon several areas: efficacy, safety, tolerability and patient acceptance. Efficacy refers to how well the medication reduces IOP, both in the short- and long-term. What is the drug’s response rate? For example, how many individuals will have their IOPs reduced from the baseline level by 15%, 20%, 25%, 30% or more? How often will the IOP creep back towards pre-treatment levels months to years later? Tolerability refers to how well the drug is tolerated and accepted. How often does the patient or doctor feel that side effects preclude continuing the medication? In the perfect world, the clinician would like to select an agent that shows excellent efficacy and persistency, as well as being safe and well-tolerated.

Cholinergic agents, such as pilocarpine, were the drug of choice for many years. In 1978, beta-adrenergic antagonists were introduced and soon thereafter became the drug of choice. Their popularity stemmed from improved efficacy, reduced dosing schedule and a favorable side effect profile. Over the next two decades, other drug classes (topical carbonic anhydrase inhibitors, adrenergic agonists, cholinergic agents) were used to complement beta-adrenergic blockers. During this period, adrenergic agonists (epinephrine, dipivefrin) became obsolete as newer drugs with significant advantages came to the market. In 1996, a further evolution occurred with the introduction of prostaglandins (PGs). The first PG introduced, latanoprost (Xalatan), soon replaced beta-adrenergic blockers, such as timolol, as the primary agent for the treatment of OHT and open-angle glaucoma. With the use of PGs, IOPs once obtainable with multiple medications were within reach using a single agent. In addition, compliance improved, and diurnal IOP variation was reduced.

Beta-adrenergic antagonists were introduced in 1978 with the introduction of timolol maleate. Since then, additional beta-adrenergic antagonists include levobunolol, betaxolol, metipranolol and carteolol. Betaxolol is different from other medications in this class in that it is a cardio-selective agent that primarily blocks beta1 adrenergic receptors. Carteolol is also unique in that, in addition to being a nonselective beta-adrenergic antagonist, it has intrinsic sympathomimetic activity (ISA).

Nonselective adrenergic antagonists are available in both solution and gel formulations. A gel formulation increases the drug’s contact time, enhances efficacy and reduces systemic absorption, but it is usually uncomfortable. Istalol is a specific formulation of timolol maleate that increases the drug’s penetration into the eye, allowing it to be used once per day. The beta-adrenergic antagonists reduce IOP between 22 -28% by inhibiting the production of aqueous humor. While the dosage for solutions is listed as bid, the nighttime dosage has little impact on IOP reduction. The morning instillation is the more important for the patient to remember to perform. Topically, the drugs are well-tolerated. The larger concern with the use of topical adrenergic antagonists is their systemic absorption and potential side effects. Side effects include confusion, lethargy, fatigue, bronchospasm and bradycardia. While beta-adrenergic blockers appear to be safe as long as patients with known contraindications (such as pulmonary conditions) avoid them, their use nonetheless has declined over the past decade with the introduction of PGs. PGs are more efficacious with fewer side effects and a better dosing schedule. Also, oral adrenergic antagonists are increasingly being used by internists and cardiologists to treat many cardiovascular conditions. When given systemically, they often reduce the IOP, minimizing the impact if a topical beta blocker is also utilized. In most situations when patients requiring IOP reduction are on oral beta-adrenergic antagonists, PGs become the drug of choice. Still, one advantage of this drug class is that drugs such as timolol or levobunolol are available as generics, which are less expensive than branded medications.

Apraclonidine (Iopidine) was the first drug in a class known as adrenergic agonists. Brimonidine is the other member of this category. Adrenergic agonists inhibit the production of aqueous humor and enhance outflow mechanisms, which leads to an IOP reduction of 22% to 28%. Several side effects occur with apraclonidine, including the development of an allergic follicular conjunctivitis and loss of effect over time (tachyphylaxis). Brimonidine is still affected to some extent by these same side effects, but it has replaced Apraclonidine as the adrenergic agonist of choice. One important difference between adrenergic agonists and beta-adrenergic antagonists is the duration of action. The short duration of action of adrenergic agonists requires that they be used on a tid dosage when they are the only medication utilized. This peak-and-trough effect associated with adrenergic agonists is one reason why they are commonly used in a secondary role. When used in conjunction with other agents, they can be used on a bid basis. Brimonidine is available in a branded product (Alphagan P, 0.10%, 0.15%) and a generic formulation (0.2%). Adrenergic agonists are relatively safe medications, though they should not be used in children due to concerns regarding lethargy. Other side effects include dry mouth, fatigue and drowsiness.

Topical carbonic anhydrase inhibitors (CAI) inhibit the production of aqueous humor and reduce the IOP by 16% to 22%. Originally, CAIs were available only in an oral form (acetazolamide, methazolamide) and were known to induce systemic side effects, such as paresthesias, depression, diarrhea, metallic taste, kidney stones and aplastic anemia. Because CAIs reduce IOP so effectively, a topical formulation was developed. With topical preparations, the inhibition of the carbonic anhydrase enzyme is limited to the eye, dramatically reducing systemic side effects. Dorzolamide 2% (Trusopt) was the original drug in this class, followed by brinzolamide 1% (Azopt). These topical formulations have been shown to be safe, with the most common side effects being local irritation, such as burning and stinging (more pronounced with dorzolamide). However, one concern is that the drugs are from the sulfa family and are therefore contraindicated in individuals with sulfa allergies. CAIs are rarely a primary medication and are almost always used with other agents. Topical CAIs are quite effective when employed in combination with other agents. When combined with timolol to produce Cosopt (timolol-dorzolamide), they form half of the only fixed-combination glaucoma medication approved by the Food and Drug Administration (FDA). Cosopt is used twice per day. Many individuals feel that the topical CAIs are the best secondary agent to be used when the individual’s primary drug is effective and tolerated, but further IOP reduction is needed.

Cholinergic agents reduce the IOP by causing the ciliary muscle to contract, leading to improved flow through the trabecular meshwork. Pilocarpine is the most common of the agents making up this class and is available in concentrations ranging from 0.5% to 12%. The most frequently used strengths are 1%, 2% and 4%. Pilocarpine is rarely used due to its qid dosing schedule and commonly induced local side effects, including brow-ache, dim vision, blurred vision and headache. It is an extremely safe drug, systemically, and can reduce IOP up to 25%.

The introduction of timolol led to a quiet revolution in the way glaucoma was managed. Therapy went from an irritating, difficultto- tolerate agent (pilocarpine) to one that was well-tolerated and effective (timolol). A further revolution occurred in 1996 with the introduction of latanoprost. Dosage was reduced to once per day, IOP reduction enhanced (26% to 34%) and systemic or local side effects reduced. PGs reduce the IOP by enhancing uveoscleral outflow, leading to IOP levels never before seen with single topical agents. The increase in uveoscleral outflow is caused by the elevated presence of metalloproteinases, which break down the collagen matrix within the uveoscleral region that surrounds the ciliary muscle bundles. New channels for aqueous outflow are created, boosting uveoscleral outflow to greater than 50% of total flow from the eye. Since the introduction of latanoprost, additional PGs have become available, including travoprost (Travatan) and bimatoprost (Lumigan). Both latanoprost and bimatoprost are listed on the drug’s package insert as capable of being a primary agent. PGs have a long duration of action, allowing them to be used once per day while still maintaining a flattened diurnal curve throughout a 24-hour period. If needed, other glaucoma agents may be added to PGs. Tachyphlaxis and systemic side effects are rare with local side effects that, while irritating, are not serious. Hyperemia is the most common side effect and is seen least commonly with latanoprost, followed by travoprost, with bimatoprost causing hyperemia most often. Other side effects include iris darkening, which is most commonly seen in individuals with mixed-colored iris, periorbital skin darkening, eyelash growth, anterior uveitis, cystoid macula edema (CME) and irritation. Travatan Z is a new form of travoprost, with Sofzia being used as the preservative instead of benzalkonium chloride (BAK). The intent with the introduction of a non-BAK preserved solution is to reduce symptoms that may be associated with chronic BAK use. CME and anterior uveitis are rare and, when present, almost always occur in eyes with a risk factor, such as prior intraocular surgery or a history of iritis. Eyelash growth is reasonably common, but fortunately is only a cosmetic concern. The iris color change has received a great deal of attention. It is caused by an increase in the size and number of melanin granules within the iris stromal melanocytes. The pigment is contained within the iris, and no signs of increased pigmentation are seen anywhere else in the eye. Periorbital skin darkening is another commonly encountered side effect that typically disappears upon discontinuation of the agent.

There has been controversy as to which of the PGs most effectively reduces IOP. Well-conducted studies have not demonstrated that any of the PGs is superior in reducing IOP. For example, the XLT study, evaluating all the PGs, showed that the three PGs were comparable in regard to efficacy, while hyperemia was most common with bimatoprost. A meta-analysis recently published by van der Valk et al also showed PGs to be similar in efficacy. Another area of question is whether switching PGs within the class is an effective strategy. There are several reasons why a PG may not be effective in a particular patient. Different studies have shown that approximately 9% of individuals will show <15% IOP reduction when any of the PGs are utilized. Will switching from one PG to another lead to a greater IOP drop? Possibly, but the studies used to evaluate this question are confusing. Switch studies have shown that, no matter what the first or second drug is, IOPs will be lower on the second drug. Reasons why the IOP may be reduced include improved compliance or a phenomenon called regression to the mean. Regression to the mean describes the situation in which it takes several IOP readings (data points) to know what the true IOP range is throughout the day (diurnal variation). Whether a switch within class lowers IOP over the long term is still open to question. We do know that if a person is experiencing side effects from one PG, then switching to another is an advisable first step in reducing these symptoms.

Glaucoma medications have evolved over time. We are now at a point where PGs have become the primary agent for therapy, and timolol is used less often in a primary role. Other agents may be used to complement PGs, always with the aim of reducing the IOP to the needed target levels while keeping side effects to a minimum.

Suggested Readings

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