Glaucoma Medical Therapy In Pediatric Patients

13.3.1 General Considerations. Children are more vulnerable to side effects, due to reduced body mass and blood volume for drug distribution (resulting in higher concentrations from the same absorbed dose). Also, they may be unable to verbally describe side effects caused by medications. Thus, children on chronic medical therapy need to be carefully monitored. The medical regimen must be frequently reevaluated in an effort to use the minimum medical regimen that will result in acceptable IOP control. Glaucoma medications commonly used in children are shown in table 13.2.

13.3.2 Specific Drug Classes

13.3.2.1 Prostaglandin analogs. In pediatric patients, latanoprost has been evaluated in a variety of diagnoses including Sturge-Weber syndrome.11-14 In one study of 31 eyes, 19% had a 34% reduction in IOP.15 The majority of the eyes did not respond to the therapy (figure 13.1).15 Juvenile-onset open-angle glaucoma was more likely to respond, most likely due to the anatomy of the angle more closely approximating that in the adult.16 In this study, while the response rate was low, latanoprost was well tolerated. In glaucoma associated with Sturge-Weber, between 17% and 28% of eyes responded with a decrease in IOP.11,12 The, majority of side effects were due to local hyperemia, with only 6% cessation of therapy from side

Table 13.2 Glaucoma Medications Commonly Used in Pediatric Patients

Beta Blockers

Betaxolol 0.25% (qd, bid) Levobunolol 0.25% (qd, bid) Timolol solution 0.25% (qd, bid) Timolol gel-forming solution 0.25% (qd)

Carbonic Anhydrase Inhibitors

Acetazolamide elixir, 5 to 15 mg/kg/day in divided doses (bid, tid) Brinzolamide 1% (bid, tid) Dorzolamide 2% (bid, tid)

Cholinergic drugs Pilocarpine 1%, 2% (tid, qid)

Prostaglandin-Related Drugs

Bimatoprost 0.03% (qd) Latanoprost 0.005% (qd) Travoprost 0.004% (qd)

effects.12 As an adjunctive therapy, latanoprost was well tolerated for a year with good IOP response.13 Although the response rate is low in the pediatric population, in those that do respond it is very effective and offers good 24-hour control.14 The once-daily dosing is convenient for parents, and the local systemic effects are manageable, although parents do need to be warned because they will likely note iris pigment changes, eyelash growth, and hyperemia. If used only to manage IOP prior to a definitive surgical procedure, then local side effects are seldom a problem. The frequency of these side effects in children on long-term therapy is not known.

13.3.2.2 Beta blockers. Prior to the commercial release of timolol, it was tested as an additional medication in uncontrolled pediatric glaucoma: 29% had a definitive improvement, 32% had a modest or equivocal improvement, while 39% demonstrated no improvement.16 In another study of pediatric glaucoma, timolol adjunctive therapy controlled 37% of patients to below 22 mm Hg.17 Only 7% had to discontinue timolol due to adverse events.17 However, in another study of 89 eyes, only 20% of eyes showed any effect of timolol on IOP.18 In another study of pediatric glaucoma, 45% of eyes had a significant drop in IOP after treatment with timolol alone (figure 13.2).19

As in adults, systemic levels of timolol can be found in pediatric patients after topical dosing, but at much higher levels.20 Much of the plasma level increase can be explained by the much smaller volume of distribution in children compared to adults, especially compared the relatively small change in ocular volume. Thus, the

Figure 13.1. Latanoprost lowers IOP effectively in a minority of pediatric glaucomas. (A) Of 31 eyes in a series, most failed to respond (defined as < 15% decrease in IOP). (B) IOP was reduced significantly in those that did respond to latanoprost. The average IOP reduction in latanoprost responders was 8.5 ± 3.6 mm Hg (34.0% ± 10.9%; *P = 0.002). Error bars indicate standard deviation. Adapted with permission from Enyedi LB, Freeman SF, Buckley EG. The effectiveness of latanoprost for the treatment of pediatric glaucoma. J AAPOS. 1999;3:33-39.

small amount of systemically absorbed timolol is diluted far less and is more concentrated. Lower levels of metabolic enzymes may also prolong the half-life of medications in children by a factor of 2 to 6.21

Children older than 5 years of age had an average decrease of 6 beats per minute in their resting pulse rate, while there was no observed change in those younger than 5.16 Various studies have shown rates of 4% to 13% in children,16,17 requiring cessation of therapy in 3% to 7%.17,18 Case reports of severe side effects have been reported in the literature, such as apnea.22-24 While asthma provocation has been reported with timolol, there are no data comparable to those in adults on betaxolol (selective beta-1 antagonist) showing decreased pulmonary effects. The above studies are all short term, with no long-term study data currently available.

Due to the much higher level of systemic absorption in children, lower concentration 0.25% timolol rather than the 0.5% is preferred in younger children, and these children still should be thoroughly evaluated for systemic abnormalities such as cardiac disease and asthma. Systemic absorption can be reduced in the pediatric population by simple methods such as punctal occlusion, eyelid closure, or blotting the excess drops away during administration.20

13.3.2.3 Carbonic anhydrase inhibitors. In children, oral carbonic anhydrase inhibitor (CAI) administration can cause growth retardation and metabolic acidosis.25,26 At doses of 5 to 15 mg/kg per day (divided twice or three times daily), oral acetazolamide is well tolerated, and reduces IOP and improves corneal edema presurgically.27,28 A study of children 3 to 12 years of age comparing the effect of systemic administration of acetazolamide and topical dorzolamide showed that both were effective at lowering IOP (36% vs. 27%) in pediatric glaucoma (figure 13.3).29

Since the rate of side effects is lower, topical treatment is preferred, unless systemic administration is found to be more effective in the patient. In another study of children younger than age 6, the rate of discontinuation of topical dorzolamide was

Figure 13.2. Timolol is effective in the majority of pediatric glaucomas: change from baseline IOP in 40 eyes receiving timolol therapy without additional surgery or medications. Thirty-one eyes (78%) demonstrated reduced IOP after timolol treatment. Adapted with permission from Hoskins HD Jr, Hetherington J Jr, Magee SD, Naykhin R, Migliazzo CV. Clinical experience with timolol in childhood glaucoma. Arch Ophthalmol. 1985;103:1163-1165.

Figure 13.2. Timolol is effective in the majority of pediatric glaucomas: change from baseline IOP in 40 eyes receiving timolol therapy without additional surgery or medications. Thirty-one eyes (78%) demonstrated reduced IOP after timolol treatment. Adapted with permission from Hoskins HD Jr, Hetherington J Jr, Magee SD, Naykhin R, Migliazzo CV. Clinical experience with timolol in childhood glaucoma. Arch Ophthalmol. 1985;103:1163-1165.

only 1.8% in those younger than 2 and 3.0% in those between 2 and 6 years of age due to adverse reactions.30

13.3.2.4 Fixed combinations. Cosopt is a fixed-combination medication composed of dorzolamide 2% and timolol 0.5%. There is very little information in the literature about the use of the fixed combination in children. However, one study that compared dorzolamide to timolol in children used a combination if either alone was not sufficient. In this study, treatment was with 2% dorzolamide three times daily and 0.25% timolol gel-forming solution once daily in children younger than 2, and fixed combination (2%/0.5%) twice daily in older children.30 One patient (1.8%) younger than 2 who was on 2% dorzolamide and 0.25% timolol discontinued due to bradycardia, while none of the patients on 0.25% timolol alone had such side effect.30 Of the older patients (ages 2 to 6 years), one patient (2.9%) discontinued timolol secondary to hyperemia.30

13.3.2.5 Cholinergic drugs. Cholinergic agonists were the first medical treatment for glaucoma but are now seldom used for pediatric patients. Topical use of both pilocarpine and carbachol can be associated with cholinergic side effects, including gastrointestinal cramping, diarrhea, vomiting, headaches, hypotension, sweating, salivation, and syncope. The degree to which side effects are experienced is highly dependent on systemic absorption, which can be greater in pediatric patients.

Since the majority of pediatric glaucomas result from structural and developmental abnormalities of the angle and associated structures, these drugs may be less effective in lowering IOP. Pilocarpine (2% applied three or four times daily) has been used to a limited degree in pediatric patients.27 This drug may be used for induction of miosis pre- and postoperatively for surgical goniotomy. The induction of myopia can significantly affect vision in pediatric patients. However, pseudophakic or aphakic

Figure 13.3. Carbonic anhydrase inhibitors in pediatric patients are additive with beta blockers. Both oral and topical medicines significantly reduced IOP from baseline (beta blocker alone). Acetazolamide decreased the IOP by 35.7% ± 15.6%, and dorzolamide by 27.4% ± 17.1%. *P < 0.01 compared with baseline. Adapted with permission from Portellos M, Buckley EG, Freedman SF. Topical versus oral carbonic anhydrase inhibitor therapy for pediatric glaucoma. J AAPOS. 1998;2:43-47.

Figure 13.3. Carbonic anhydrase inhibitors in pediatric patients are additive with beta blockers. Both oral and topical medicines significantly reduced IOP from baseline (beta blocker alone). Acetazolamide decreased the IOP by 35.7% ± 15.6%, and dorzolamide by 27.4% ± 17.1%. *P < 0.01 compared with baseline. Adapted with permission from Portellos M, Buckley EG, Freedman SF. Topical versus oral carbonic anhydrase inhibitor therapy for pediatric glaucoma. J AAPOS. 1998;2:43-47.

patients have fewer side effects. Ocusert, a slow-release pilocarpine system, resulted in less myopic spasm from burst release but is not currently available commercially.31 Long-acting anticholinesterases, such as echothiophate iodide (Phospholine Iodide), are used mostly for the treatment of accommodative esotropia. Since the agents are of poor availability, with no advantages over pilocarpine and with more serious side effects, they are seldom used for glaucoma therapy. Reported side effects in children include ciliary spasms and angle closure.32 In addition, systemic inhibition of cholinesterase activity and pseudocholinesterase in serum can cause signs of excessive parasympathetic stimulation, such as generalized weakness, nausea, diarrhea, vomiting, decreased heart rate, and salivation. When systemic levels of cholinesterase and pseudocholinesterase are reduced, the risks of anesthesia are significantly increased, due to the interaction with succinylcholine (a commonly used paralytic), which is degraded by this pathway. With low metabolism, prolonged ap-nea can result after surgery.

13.3.2.6 Adrenergic agonists. Epinephrine and dipivefrin, nonspecific adrenergic agonists, are rarely used in pediatric patients. When considered for medical therapy, systemic side effects may limit their use in this population.

Brimonidine, an alpha-2-selective agonist, has been studied in pediatric populations. One study of 30 patients (mean age, 10 years) showed a small (7%) decrease in IOP, but had a high rate of central nervous system depression (two became transiently unarousable and five others experienced fatigue).33 In another study of 23 children (mean age, 8 years), the side effects were sufficient to merit discontinuation of therapy in 18%.34 Other published reports include somnolence in four children, and multiple "coma" episodes, with hypotension, hypothermia, hypotonia, and bradycardia.35,36 In one large study of 83 patients, brimonidine had only a modest effect on IOP (5mmHg) and a high rate (84%) of side effects, including lethargy (76%). There was an association between patient age and weight and the incidence of fatigue and lethargy. The researchers suggested caution in children younger than 6 years of age or weighing less than 20 kg.37

13.3.2.7 Osmotic agents. Glycerol (0.75 to 1.5 g/kg) in a 50% solution can be administered orally mixed with other fluids or over ice to partially mask the excessively sweet flavor. Glycerol is seldom used for the treatment of developmental glaucoma, but can be used in older children where an acute decrease in IOP is needed. Mannitol can be given intravenously (0.5 to 1.5 g/kg) and has the maximum effect within 20 to 30 minutes and lasting 4 to 10 hours. This can be useful for clearing the cornea prior to surgery. Patients must be carefully monitored during intravenous infusions of mannitol for cardiovascular and volume overload problems.

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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