Medical Treatment of Glaucoma






  • 1.

    What classes of medications are used to treat glaucoma?


    See Table 18-1 .



    Table 18-1

    Commonly Used Agents for Glaucoma Management






















































































































































    Chemical Name Color Top Strength Usual Dosage Size (mL)
    Miotics
    Pilocarpine hydrochloride Green 1, 2, 4% 2-4 times/day 15
    Adrenergic Agonists
    Apraclonidine hydrochloride Purple 0.5, 1% 2-3 times/day 5
    Brimonidine tartrate Purple 0.1, 0.15, 0.2% 2-3 times/day 5, 10, 15
    Prostaglandin Analogs
    Latanoprost Teal 0.005% Daily 2.5
    Travoprost Teal 0.004% Daily 2.5, 5
    Bimatoprost Teal 0.03% Daily 2.5, 5
    Unoprostone isopropyl Teal 0.15% 2 times/day 5
    β-Blockers
    Betaxolol hydrochloride suspension Light blue 0.25% 2 times/day 2.5, 5, 15
    Betaxolol hydrochloride solution Dark blue 0.50% 2 times/day 2.5, 5, 10
    Levobunolol hydrochloride Yellow 0.25, 0.5% 1-2 times/day 5, 10
    Metipranolol Yellow 0.3% 1-2 times/day 5, 10
    Timolol maleate Yellow 0.25, 0.5% 1-2 times/day 2.5, 5, 10, 15
    Timolol XE gel-forming solution Yellow 0.25, 0.5% Daily 2.5, 5
    Carbonic Anhydrase Inhibitors
    Acetazolamide sodium (oral) NA 125, 250 mg 3-4 times/day po NA
    Acetazolamide sequels (oral) NA 500 mg 2 times/day po NA
    Methazolamide (oral) NA 25, 50, 100 mg 2-4 times/day po NA
    Dorzolamide Orange 2% 2-3 times/day 5, 10
    Brinzolamide Orange 1% 2-3 times/day 5, 10
    Hyperosmotic Agents
    Mannitol (intravenous) NA 20%, 50% (IV) 0.5-2 g/kg NA
    Fixed Combinations
    Timolol/dorzolamide Dark blue 0.5%/2% 2 times/day 5, 10
    Brinzolamide/brimonidine tartrate Pale green 1%/0.2% 3 times/day 10


  • 2.

    How do these medications work?





    • Prostaglandin analogs increase outflow through the uveoscleral outflow channels. Aqueous is absorbed into the face of the ciliary body or into the trabecular meshwork and then flows posteriorly around the longitudinal muscle fibers of the ciliary body posteriorly. It is absorbed into the choroid or passes out through the sclera.



    • β-Blockers and carbonic anhydrase inhibitors (CAIs) decrease aqueous production. β-Blockers decrease aqueous humor secretion by inhibiting cyclic adenosine monophosphate production in the ciliary epithelium. CAIs decrease aqueous humor production by directly antagonizing carbonic anhydrase in the ciliary epithelium.



    • The adrenergic agonist epinephrine initially decreases aqueous production slightly, but its major action is to increase outflow through the trabecular meshwork. Because epinephrine is no longer manufactured for topical ophthalmic use, apraclonidine and brimonidine are the currently available adrenergic agonists that follow in the footsteps of the original epinephrine and its prodrug dipivefrin (Propine), which is also no longer produced. Apraclonidine and brimonidine decrease aqueous production. Brimonidine may have some increased uveoscleral outflow as well.



    • Miotics constrict the longitudinal muscle of the ciliary body, which is attached to the scleral spur anteriorly and to the choroid posteriorly. When the longitudinal muscle constricts, it pulls the scleral spur posteriorly, pulling open the spaces between the trabecular beams and mechanically increasing the capacity for aqueous outflow.



    • Hyperosmotic agents increase the osmolarity of the blood, which in turn draws fluid from the posterior chamber into the blood vessels of the ciliary body.



  • 3.

    For patients in good health with primary open-angle glaucoma, what is the first drug to try?


    The short answer is that any of the topical medications can be used. The choice is based on the desired amount of intraocular pressure (IOP) reduction, the possible side effects, and the relative costs of the medicines. The advantage of having four commonly used classes of medications (β-blockers, prostaglandin analogs, topical CAIs, and adrenergic agonists) is that therapy can be customized for each patient. Prostaglandin analogs are the most commonly used first-line therapeutic agents because of their ease of use, powerful hypotensive effect, and favorable side-effect profile. Prior to the development of prostaglandins, most ophthalmologists chose a β-blocker as first-line therapy.


    If a patient would not be a good candidate for a prostaglandin, one of the other three classes of medicines can be used. Nonselective β-blockers are the most potent. The cardioselective β-blocker (betaxolol), topical CAIs, and adrenergic agonists are all about equal in hypotensive effect. When used alone, topical CAIs and α-adrenergic agonists should be used three times/day to prevent possible IOP fluctuation.


  • 4.

    What medicine should be used as second-line therapy? Third-line therapy?


    As in the case of first-line therapy, any of the medicine classes can be used as second- or third-line therapy. With several options available, the physician can attempt to tailor the choice to the patient’s particular situation. If a prostaglandin has been used as first-line therapy, a β-blocker is often chosen as second-line therapy, and vice versa. As these medicines are the most potent ones available and are both typically once-a-day medicines (most commonly a β-blocker once per day in the morning and prostaglandin once per day in the evening), this regimen typically results in a very good hypotensive effect for the number of drops used.


    The availability of the fixed combination of timolol/dorzolamide makes it easy to add dorzolamide as a second-line agent after timolol. This reduces the drop count from three or four to two per day, and fewer drops per day is likely to result in greater compliance.


    Brimonidine or a topical CAI can be an excellent choice for additive therapy. The fixed combination of brimonidine/brinzolamide can, like timolol/dorzolamide, play a role in simplifying the drop regimen, especially if the patient cannot tolerate a β-blocker.


    Miotics are more difficult to use because of the drop frequency and side effects, but can be quite effective, especially in aphakic (no crystalline lens in the eye) patients. In phakic patients with little remaining accommodation and little cataract, pilocarpine is often well tolerated. It provides a pinhole effect that gives an increased depth of field for most patients. Many patients can read without reading glasses when taking pilocarpine, and no one needs trifocals if the pupils are adequately miotic.


    Oral CAIs were once quite commonly used and are among the most potent of all hypotensive medications. Their side-effect profile and the availability of a variety of topical medicines limit their use today.


  • 5.

    What are some prescribing pearls and key side effects of prostaglandin analogs?


    The prostaglandin analogs available today are all extremely effective at lowering intraocular pressure and are generally used as first-line therapy. They can be additive with any medicine, but tend not to work as well if added beyond second-line therapy.


    Latanoprost, now available in generic form, was released first and remains the most commonly used of the four medicines. As a prostaglandin analog, latanoprost is a powerful ocular hypotensive agent. Latanoprost in a 0.005% concentration is 100 times more powerful than 0.5% timolol. Travoprost is equally effective compared to latanoprost, with greater conjunctival erythema but less effect on increased iris pigmentation. Bimatoprost appears to offer on average about 0.5 mm greater IOP reduction than the other prostaglandins, and in selected individuals, it may be significantly more powerful. The increased concentration of bimatoprost is accompanied by greater local ocular side effects. In 2013, unoprostone isopropyl (Rescula) was approved for use in the United States. The exact mechanism of IOP reduction is not clear, but it is hypothesized to increase aqueous outflow through the trabecular meshwork while having little to no effect on aqueous production and uveoscleral outflow like other prostaglandins. Unoprostone isopropyl has been reported potentially to have fewer known ocular side effects such as iris and lid pigmentation, although because it is so new, future studies will probably address this.


    Although there have been rare reports of systemic side effects, such as flu-like symptoms, numerous ocular side effects can occur. The most common are conjunctival injection, increased pigmentation of the iris and eyelid skin, growth of eyelashes, and prostaglandin-associated periorbitopathy (PAP). PAP is a term used to describe the constellation of eyelid and periorbital changes that occur with chronic use of topical prostaglandins; such changes include upper lid ptosis, deepening of upper lid sulcus, periorbital fat atrophy, loss of lower eyelid fullness, and relative enophthalmos. These changes appear to be partially reversible with discontinuation of the medication. Increased iris pigmentation is the result of increased amount of melanin within iris melanocytes and seems to occur much more frequently in patients with hazel irides or who have iris nevi. Whereas the other side effects are reversible, increased iris pigmentation is not. Ocular inflammation, including anterior uveitis and keratitis, has been rarely reported, so in patients with a history of uveitis it may not be the drug of choice. Prostaglandin analogs have been associated with cystoid macular edema, especially in pseudophakic eyes. However, these eyes typically have other risk factors that may be responsible. Herpetic keratitis may be reactivated or exacerbated. It also has been reported to produce a herpes-like keratitis that clears when the drops are stopped.


  • 6.

    What are some prescribing pearls and key side effects of topical β-blockers?


    Timolol was the first β-blocker and is still considered the gold standard against which all other ocular hypotensive medications are judged. It has been formulated as both a nonviscous and a viscous drop. The viscous formation (Timoptic XE from Merck, Timolol GFS from Falcon) remains in the tear film longer; consequently, intraocular absorption is greater, and systemic absorption is reduced. This drug provides the best diurnal curve for pressure control with once-daily dosing and can reduce the possibility of systemic side effects.


    Nonselective β-blockers may be effective with the 0.25% dosage once daily for patients with light irides and the 0.5% dosage once daily for patients with dark irides. β-Blockers block intrinsic β1 and β2 receptor tone; thus, when patients are asleep, β-blockers are ineffective because there is little tone. However, because aqueous production also declines at night, this fact is usually considered inconsequential. Although β-blockers are labeled as twice a day and very frequently prescribed twice a day, many ophthalmologists will prescribe β-blockers once daily when patients awake in the morning to effectively minimize pressure rise as well as medication-induced hypoperfusion to the optic nerve. For patients with more advanced disease, a twice-daily regimen of 0.25% for lighter irides and 0.5% for darker irides is common. This regimen guards against going for a full day without medication in patients who miss one prescribed drop. Betaxolol as a selective β1 antagonist has far fewer systemic side effects than the nonselective β-blockers, but is not as potent. Betaxolol results in a roughly 25% drop in intraocular pressure, whereas nonselective β-blockers achieve about a 30% reduction. β-Blockers should be started as a one-eyed trial because 10% of patients show no effect from topical nonselective β-blockers, and 10% of patients who had a significant effect from nonselective β-blockers have no effect from selective β-blockers.


    In general, the side effects of this class of medications are identical to those of the oral β-blockers. Patients, and even physicians, often forget that eyedrops have systemic effects. Physicians must remember to ask about eyedrops when taking a complete medical history.


    β-Blockers can exacerbate asthma or chronic obstructive pulmonary disease and can cause arrhythmia, bradycardia, lowered blood pressure, increased heart block, lethargy, cardiac arrest, cardiac failure, alteration of serum lipids, exercise intolerance, impotence, altered mental status, and central nervous system (CNS) depression. The selective β-blocker betaxolol is much less likely to trigger bronchospasm but still must be used with caution. In diabetics, they may cause reduced glucose tolerance and mask the symptoms of hypoglycemia. In hyperthyroidism, symptoms can be exacerbated with abrupt withdrawal of ocular β-blocker use. β-Blockers have been linked with impaired neuromuscular transmission; thus, myasthenia gravis symptoms can be exacerbated. Ocular side effects include blurred vision, irritation, corneal anesthesia, punctate keratitis, and allergy.


    Concomitant use of topical and systemic β-blockers should be done judiciously. Although it is not clear what the additive effects of systemic and topical use are, there have been reports of patients taking both systemic and topical β-blockers with reduced ocular hypotensive efficacy and greater systemic side effects compared with patients who were taking a systemic β-blocker and a different class of topical IOP-lowering agent. One of the concerning systemic side effects is the exacerbation of blood pressure fluctuation. Such fluctuations (especially in diastolic blood pressure) leading to hypoperfusion potentially reduce ocular perfusion and increase susceptibility of the optic nerve to relative ischemic injury.


  • 7.

    What are some prescribing pearls and key side effects of adrenergic agonists?


    Adrenergic agonists may be classified into two groups. The first group, which comprises epinephrine and dipivefrin, increases trabecular meshwork outflow. These drugs are no longer commonly used in the management of glaucoma as other classes of drugs have been found to be more effective in IOP control. Apraclonidine and brimonidine make up the second group. They are α2-selective agonists that reduce aqueous production. Brimonidine also may increase uveoscleral outflow.


    The α-adrenergic compounds are characterized by a high allergic-reaction rate. Epinephrine is said to have an allergic rate of 50% by 5 years, and apraclonidine has an allergic rate of approximately 20% by 1 year. Because of its high allergy rate, apraclonidine is used almost exclusively for acute pressure control or to prevent acute pressure rise after laser procedures.


    Brimonidine is less likely to cause an immediate allergic reaction, but many patients develop an intolerance or allergy months after starting the drug. Ocular adverse effects include contact blepharoconjunctivitis and follicular conjunctivitis. The generic form of brimonidine packaged with benzalkonium chloride preservative is available in two concentrations—0.15% and 0.2%. The brand form of brimonidine (Alphagan-P 0.1%) is available in only one concentration. Though Alphagan-P has a lower concentration of brimonidine, it is found to be comparable in lowering IOP. Alphagan-P is packaged with a less allergy-provoking preservative (Purite) than generic brimonidine and has a reduced incidence of allergic side effects.


    Brimonidine has become an important drug for treating glaucoma. It works as well as a nonselective β-blocker at peak effect, although less well at trough 6 to 12 hours later, and almost all patients have some reduction in pressure. Aside from allergy, it is well tolerated by the eye. Systemically, it can cause dry mouth and fatigue, which can be debilitating. Brimonidine is contraindicated in infants because it causes CNS depression and apnea. Avoid coadministering brimonidine with a monoamine oxidase inhibitor or tricyclic antidepressant therapy, as potentiating or additive effects of CNS depression and/or adverse cardiovascular events can occur. There is some evidence from animal models of glaucoma that brimonidine may protect ganglion cells from death. There is no evidence of this property in humans, but this drug has sparked interest in treating glaucoma by mechanisms other than pressure reduction.


  • 8.

    What are some prescribing pearls and key side effects of carbonic anhydrase inhibitors?


    Topical CAIs took more than 40 years to develop and were particularly welcome, as oral CAIs cause a myriad of side effects. The most common complaints with oral CAIs are lack of energy and lethargy, lack of appetite and weight loss, nausea and/or an upset stomach, paresthesias of extremities, and a metallic taste to foods. CAIs are chemically derived from sulfa drugs and should be avoided in patients with known sulfa allergies. The most dangerous side effect is hypokalemia, especially when a CAI is combined with a potassium-reducing diuretic. This combination is dangerous in patients taking digitalis. Severe mental depression and aplastic anemia are other serious side effects. The same sort of side effects can be seen with the topical medications, but they are extremely rare. Because complaints are frequent with oral CAIs, most ophthalmologists rarely use them unless there is a need for acute pressure control or if topical CAIs are not effective.


    There is no additional benefit to using topical CAIs concurrently with oral CAIs in the same patient. Although topical dorzolamide has an IOP fluctuation when used twice daily, twice-daily usage gives an adequate response when combined with a topical β-blocker, which diminishes the washout effect of aqueous production. Brinzolamide can often be used twice daily when combined with another aqueous suppressant.


    The two topical CAIs are equally effective, but brinzolamide is less irritating to the eye. Dorzolamide has been reported to augment blood flow to the optic nerve. This may help reduce the impact of free radicals that have been postulated to be a cause of glaucoma.


  • 9.

    What are some prescribing pearls and key side effects of topical combination therapies?


    Many patients medically managed for glaucoma are treated with more than one drug class for IOP control. Combining two different topical drug classes in a single formulation provides the benefit of improved convenience and compliance, less exposure to preservatives, and reduced cost. However, combination therapies are not generally used as a first-line therapy in initially treating a patient with glaucoma.


    Combigan (brimonidine 0.2%/timolol 0.5%), Cosopt (dorzolamide 2%/timolol 0.5%), and Simbrinza (brinzolamide 1%/brimonidine 0.2%) are fixed-combination therapies available in the United States. All three fixed combinations have a greater IOP-lowering effect than their component medications dosed separately as a monotherapy. Combigan is clinically associated with 50% lower incidence in ocular allergy compared to monotherapy with brimonidine. Cosopt, which is available generically, has ocular side effects similar for both drugs individually. Simbrinza is a recent addition to the topical therapy landscape of glaucoma. Fixed-combination medications with prostaglandin analogs are available internationally, but not yet in the United States: Xalacom (latanoprost 0.005%/timolol 0.5%), Ganfort (bimataprost 0.03%/timolol 0.5%), and DuoTrav or Extravan (travoprost 0.004%/timolol 0.5%).



Jul 8, 2019 | Posted by in OPHTHALMOLOGY | Comments Off on Medical Treatment of Glaucoma

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