Medical treatment of infantile glaucoma is frequently a temporizing or adjunctive measure until surgery can be performed. Medications are often inadequate to control intraocular pressure, side effects can be a concern especially if the expected duration of treatment is prolonged, and compliance in infants can be a challenge. When glaucoma develops later in childhood, medications play a greater role and surgical success may be less than with infantile types. The antiglaucoma medications include cholinergic agonists (miotics), sympathomimetics, beta-adrenergic antagonists, carbonic anhydrase inhibitors, alpha-2-selective agonists, and prostaglandin analogs. These medications can cause serious systemic side effects. This fact must be kept in mind when treating children who require long-term treatment, such as glaucoma secondary to ocular or systemic diseases. Most of these agents are classified as pregnancy category C drugs (i.e., animal studies show adverse fetal effect(s) but no controlled human studies or no animal or human studies have been done). The beta-adrenergic antagonists and the carbonic anhydrase inhibitor acetazolamide are both considered safe in lactation by the American Academy of Pediatrics, a fact that increases practitioner comfort levels with prescribing these agents to infants. Table 1 lists commonly used agents and their potential adverse effects.
Beta-adrenergic antagonists block beta-adrenergic receptor sites, decreasing aqueous production in the ciliary body. They are among the least expensive class of agents. The ubiquity of beta-adrenergic receptor sites in the body can lead to a variety of systemic effects, including bradycardia, hypotension, depression, arrhythmias, bronchospasm, apnea, and dizziness. One drop of 0.5% timolol can reach cardiac beta-blockade levels in infants under 2 years of age. Timolol (Timoptic®, Merck, Whitehouse Station, NJ) is commercially available as a 0.25% or 0.5% solution or in a gel form. It has been the most widely used standard treatment, thus most trials have and continue to compare drugs to timolol. Better responses are found in children over 10 years of age, in cases where glaucoma is mild, and where it is the sole agent. Betaxalol 0.5% (Betoptic®, Alcon, Ft. Worth, TX) is cardioselective, with significantly less effect on the pulmonary system. Severe cardiopulmonary reactions to timolol have been reportedone neonate developed Cheyne-Stokes breathing and apneic spells lasting up to 30 seconds that resolved after timolol 0.25% was discontinued, and there has been a report of multiple severe asthma exacerbations requiring hospitalization in an 18-month-old child. It is thus contraindicated in children with cardiac arrhythmias and bronchospasm, and should be used in the lowest possible dose for healthy children. Timoptic-XE® (0.25% and 0.5%) (Merck, Whitehouse Station, NJ), a gel-forming, sustained-release preparation of timolol administered once daily, was shown in adult patients to be as efficacious in reducing intraocular pressure as timolol ophthalmic solution (0.25% and 0.5%) twice daily, with measurably less systemic absorption. Timolol maleate gel-forming solution 0.5% is dosed once daily and is also available in 0.25% concentration. In one study of adults, it was found to be as efficacious as Timoptic-XE® in intraocular pressure reduction over a 12-month time period. The 0.25% dosage of either sustained-release preparation is often sufficient and is the preferred agent in pediatric glaucoma, due to the lower concentration, decreased systemic absorption, and once-daily dosing.
Carbonic anhydrase inhibitors are sulfonamide derivatives used topically or systemically to inhibit production and secretion of aqueous humor by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. The systemic forms are used as adjunctives to topical glaucoma treatment. The topical preparations are used for short-term treatment before laser surgeries to prevent postoperative pressure elevations. They are often used in combination with a beta-adrenergic antagonist or prostaglandin analog. Dorzolamide 2% (Trusopt®, Merck, Whitehouse Station, NJ) and brinzolamide 1% (Azopt®, Alcon, Ft. Worth, TX) are eye drops and acetazolamide is administered orally as a liquid suspension at a pediatric dose of 8-30 (generally 10-15) mg/kg/day. It can be prepared as a liquid suspension in any highly flavored carbohydrate syrup (elixirs containing alcohol or gelatin will not disguise the bitter taste and the drug will not dissolve in juice). Suspensions containing 125 mg/ml of syrup are palatable and are stable for up to 60 days refrigerated.
Although not as effective as oral acetazolamide, topical dorzolamide was reported to provide significant intraocular pressure reduction in one group of 11 pediatric glaucoma patients (35.7% and 27.4% mean reductions, respectively) and was well tolerated. In one study of adult patients, brinzolamide 1.0% twice daily, brinzolamide 1.0% three times daily, and dorzolamide 2.0% twice daily each lowered intraocular pressure by an average of 4-5 mmHg after 3 months of treatment. Cosopt® (Merck, Whitehouse Station, NJ) is a fixed combination of timolol 0.5% and dorzolamide 2% and it has been reported in adults to produce better reduction of intraocular pressure than the two agents taken separately, whether dorzolamide was dosed three times daily or twice daily, possibly due to improved compliance and reduced dilutional effect.[39,40] It is also less expensive than the two agents taken separately, even with twice-daily dosing, although it is more expensive than other glaucoma treatments per patient per year.
Use of the systemic agent acetazolamide is limited by side effects; it may be given with meals to minimize gastrointestinal upset. Anorexia is frequently seen when used in infants and hyperpnea is also common. Urinary frequency may develop, but usually normalizes after several weeks. Less frequently, renal calculi are seen. This class is contraindicated in patients with severe kidney or liver disease, as well as reduced sodium or potassium serum levels, or adrenal failure. It is also contraindicated in those with true sulfa allergies. Other reported reactions include metabolic acidosis severe enough to require administration of bicarbonate, blood dyscrasias, and Stevens-Johnson syndrome.
Alpha-adrenergic agonists decrease aqueous production and may increase uveoscleral outflow. Brimonidine 0.15% (Alphagan P®, Allergan, Irvine, CA) and 0.2% crosses the blood-brain barrier. They are relatively contraindicated in children, due to side effects of somnolence and fatigue, presumably due to central nervous system depression. It was recently reported that two infants, both younger than 2 months, experienced apnea, lethargy, hypotension, hypothermia, and hypotonia, after the administration of one drop in each eye of topical brimonidine. Both infants recovered without sequelae after brimonidine was discontinued. There have also been reports of syncopal episodes in two children, both 10 years of age. A case of intermittent coma in a neonate treated with brimonidine was remarkable for findings of plasma brimonidine concentrations 12-24 times higher than the mean plasma concentration observed in adults (1,459 pg/mL and 700 pg/mL versus 60 pg/ml). Symptoms were reversed temporarily with naloxone and ceased after brimonidine was discontinued.
A study of pediatric glaucoma patients found they did not respond to brimonidine 0.2% twice daily as well as reported for a heterogeneous group of adult patients (10-14.7% versus 21-35% mmHg reduction in intraocular pressure after an average of 7 months). As monotherapy, they require dosing every 8 hours, which may make compliance a problem. They should not be used in infants younger than 2 years of age and should be used with caution in children younger than 6 years of age. Brimonidine 0.2% is associated with a higher allergy rate than other agents; allergy onset is usually after 4 months, making it useful for short-term therapy. The other agent in this class, apraclonidine 0.5%/1.0% (Iopidine®, Alcon, Ft. Worth, TX) is much less selective for alpha-2 adrenoreceptors than is brimonidine, and it is also more useful for short-term rather than long-term therapy, as up to 48% of patients will experience tachyphylaxis within 3 months.
Prostaglandin analogs are a newer class of medications with impressive potency in adults, once-daily dosing, flat diurnal curve effects, and few side effects.[48,49] This class includes latanoprost 0.005% (Xalatan®, Pfizer, New York, NY), bimatoprost 0.03% (Lumigan®, Allergan, Irvine, CA), travaprost 0.004% (Travatan®, Alcon, Ft. Worth, TX), and unoprostone 0.15% (Rescula®, Novartis, Duluth, GA). These agents are analogs of endogenous F2-alpha prostamides, and they activate matrix metalloproteinases to remodel the extracellular matrix of the uveoscleral pathway, facilitating flow of aqueous humor. This effect is enhanced by their ability to relax nocturnal ciliary muscle tone.[50,51] Dosing more often than once daily may mediate inflammatory effects, causing an increase in intraocular pressure. Latanoprost is approved as a first-line adult glaucoma treatment; however, it has shown disappointingly little effect in most of the children studied.[46,52] A small subgroup of children with juvenile-onset open-angle glaucoma, aphakic glaucoma, and (rarely) glaucoma associated with Sturge-Weber syndrome did have a significant response to latanoprost.[46,52] However, it is difficult to draw definite conclusions from these data as they were obtained from patients who were concurrently treated with other glaucoma medications and had in many cases undergone glaucoma surgeries. Unoprostone is a prostaglandin derivative and is less potent, requiring twice-daily dosing, with comparable ocular side effects to latanoprost in adults. Bimatoprost and travaprost were reported to have equal intraocular pressure-reducing efficacy to latanoprost in one study of adults, and latanoprost was better tolerated. Side effects of this class of agents include increased eyelash growth, periorbital skin changes due to increased melanin production, and changes in eye color for those patients with mixed color irides. Sleep disturbances and sweating have been reported in some children.
Miotics and sympathomimetics are historically first-line agents that are rarely used today. Miotics may be used pre- or postoperatively in glaucoma surgery to constrict the pupil and pull the iris away from the anterior chamber angle. Because the muscle-tendon attachments are not well formed in infants, miotics have only a minor influence on aqueous outflow in this age group. Sympathomimetics work by decreasing aqueous production via vasoconstriction of blood vessels in the ciliary body. With prolonged use they improve aqueous outflow, likely in part by desensitization of beta-adrenergic responses. To a lesser extent, they improve uveoscleral output as well. The adrenergic agonist dipivefrin 0.1% (Propine®, Allergan, Irvine, CA) is a prodrug of epinephrine and causes fewer systemic side effects than epinephrine 0.5%/1%/2% (Epifrin® Allergan, Irvine, CA; Glaucon®, Alcon, Fort Worth, TX) (FDA/Center for Drug Evaluation and Research, NDA 21-598 Page 3, 4/15/03).
In summary, the aqueous suppressors timolol gel once daily and brinzolamide are recommended first-line glaucoma agents often used together, with timolol gel providing the advantage of low cost and once-daily dosing and brinzolamide preferred by patients for comfort. Brinzolamide is contraindicated in the presence of sulfa allergies. Additional medications are added as required for optimal control. Miotics, such as pilocarpine, while well tolerated, are infrequently used because of the required frequency of dosing. Brimonidine is contraindicated in young children and the sympathomimetics usually add little to treatment. Further large-scale study for longer follow-up periods of the prostaglandin analogs may elucidate additional uses for these promising newer agents with excellent safety profiles, which have shown efficacy in some older juvenile-onset open-angle glaucoma patients.
Cosopt® (Merck, Whitehouse Station, NJ) is a combination of timolol and dorzolamide and is both more efficacious and more convenient than taking the concomitant medications. However, it does not have the systemic advantages of sustained-release that timolol gel-for ms afford and dorzolamide has more reported stinging than brinzolamide, which can deter pediatric compliance.
Compr Ophthalmol Update. 2005;6(2):85-101. © 2005 Comprehensive Ophthalmology Update, LLC
Cite this: Ophthalmic Medications in Pediatric Patients - Medscape - Mar 01, 2005.