The normal tear volume is 8 to 10 μL. Evaporation accounts for 25% of tear film loss, with 75% discharged into the lacrimal system. The tear turnover rate is about 16%. The volume of most topical preparations is 10 to 25 μL. Excess drug often spills in the nasolacrimal system. It is estimated that only 40% of the medication retained within the lids is present after 1 minute (4). Given the limited amount of drug retained after drop placement and the high washout rate, it is estimated that only 8% of the original medication in the drop is retained after 5 minutes (4).

There are several natural barriers to topically applied drug penetration. The tear film has natural buffers in proteins and bicarbonates. Tears contain approximately 0.7% protein, mostly albumin. The mean pH of the tear films is 7.5, and tears are most effective against acidic compounds (5). The corneal epithelium is five cell layers thick. Cell lipid membranes are hydrophobic. The corneal stroma has a lipid content of about 1% and is hydrophilic. The endothelium is only one cell layer thick and is less significant as a barrier.

Lipophilic drugs are absorbed more readily by the nasal mucosa. Up to 80% of the drug may diffuse into the systemic circulation if it drains into the lacrimal system (6). Methods for decreasing the systemic absorption include punctal occlusion, dilution of drops, and use of microdrops (7). Punctal plugs have improved the efficacy of glaucoma drops in patients with lacrimal insufficiency (8). Local tolerance of topical medication is variable. Ocular concerns include pain on instillation, allergic reactions, delayed healing, punctate keratopathy, disturbances of lacrimal secretion, and disturbances of accommodation (9). Patient comfort is best at a pH of 7.4 (tear film pH). Stability for many topical drugs is a pH as low as 5.0. Thus, choice of the proper pH and buffer capacity is a compromise between drug stability and patient comfort (3).

Periocular injection allows for greater intraocular penetration. This is especially true for penetration into the vitreous and the retina. In rabbits, the intraocular concentration was 41 times greater with a retrobulbar application compared with systemic administration. This ratio doubled if the eye was inflamed (10). The eye is supplied by the retinal and choroidal circulation. Systemic access to the vitreous and the retina is restricted by a blood–retina barrier with endothelial tight junctions. The vessels of the choroid allow larger molecules to pass into the choroidal space, but the retinal pigment epithelium, under the retina, and the ciliary nonpigmented epithelium have tight junctions.

Pupil size is determined by sympathetic and parasympathetic influence. The pupil dilator is sympathetic and the constrictor is parasympathetic. The primary sympathetic mydriatic agent is phenylephrine. Phenylephrine is fast
acting and of short duration. The 10% solution can cause hypertension, tachycardia, cerebral vascular accidents, and ruptured aneurysms (11,12). Use of topical phenylephrine intraoperatively to effect pupil dilation for surgery has been associated with the development of pulmonary edema (13). A 2.5% preparation is considered safe in the pediatric age group.

Anticholinergic agents such as tropicamide, atropine, and cyclopentolate induce dilation by inhibiting the parasympathetic constrictor muscle and inducing cycloplegia. Tropicamide 0.5% or 1.0% is a short-acting agent with little adverse effect (14). Atropine and cyclopentolate directly inhibit the action of acetylcholine on the smooth muscles in the iris and the ciliary body. They are used to dilate the pupil and to block the accommodative effect of the ciliary muscle. This allows an intraocular examination without pupillary constriction. It also allows determination of the refractive state of the eye without interference from accommodation.

Reported side effects to anticholinergics include angle-closure glaucoma, cardiopulmonary problems, and central nervous system effects. Premature infants and those with neurologic impairments and seizure disorders have a greater risk of systemic side effects. Premature infants are prone to apnea and bradycardia with cyclopentolate. Judicious use in neonates and infants has been recommended. Women, fair children, and children with Down syndrome may be prone to atropine toxicity (15). Systemic anticholinergic toxicity include dry mouth, decreased sweating, hyperthermia, rash, tachycardia, urinary retention, and behavioral changes. Fatal complications have been reported with topical doses no longer available (16). The risk of an adverse effect is greater with the 2% cyclopentolate solution (17). However, a seizure was reported in a 4.5-year-old boy with cerebral palsy and no seizure history with a standard topical instillation of cyclopentolate 1% (18). Topical use of atropine 1% increased the frequency of seizures in a 3-year-old boy (19). A survey of 57 pediatric ophthalmology facilities estimated the risk of severe (monitored in the office a few hours) or very severe (hospital admission) as 2 to 10 episodes per 1.6 million exposures (20).

Preservatives have been added to drops to prevent microbial contamination. Benzalkonium chloride is the most common. The preservative destabilizes the lipid layer of the tear film and increases the evaporation of the tear film (21). Ocular signs of toxicity can be twice as common with preservative compared with without preservative (22). Ocular signs include stinging, foreign body sensation, tearing, and itching. Superficial punctuate keratitis can occur indicative of epithelial damage. There have been no specific reports of pediatric sensitivity.

Myopia is a refractive condition of the eye affecting 80 million children worldwide. Atropine has been suggested to decrease progression of myopia but with significant side effects of hypoaccommodation and photosensitivity. Pirenzepine is an M1-receptor antagonist used to treat dyspepsia in Europe. In United States, a 2-year study of 174 children aged 8 to 12 years treated with topical pirenzepine against placebo showed a 40% reduction in the progression of myopia (23).

Ocular allergy can be treated with vasoconstrictors, antihistamines, mast cell stabilizers, nonsteroidal preparations, and steroids. Routine allergic conjunctivitis can be treated with over-the-counter preparations. Over-the-counter eye drops contain sympathomimetic agents for α-adrenergic vasoconstriction. Accidental oral ingestion of 2 to 3 mL of imidazole in a 2-year-old child resulted in hypothermia, hypoglycemia, central nervous system depression, and respiratory depression (24). Toxicity has been limited to surface discomfort with topical use similar to adults (25).

Many topical agents are multimodal in effect. Ketotifen fumarate 0.025% (Zaditor) and olopatadine HCl 0.1% (Patanol) combine an antihistamine and a mast cell stabilizer effect. Many of these are approved by the FDA for children 3 years and older. The primary complication is surface irritation. No other systemic complications have been reported in the pediatric age group. Finally, topical steroids are used for short times in conjunction with a nonsteroidal anti-inflammatory, antihistamine, or mast cell stabilizer. Long-term use of steroids is problematic, as described in the next subsection.

Vernal conjunctivitis is a less common form of ocular allergy in children and young adults requiring prescription therapy. It presents with severe itching, photophobia, injection of the conjunctiva, and corneal foreign body sensation. Obliteration of the ductules of the lacrimal gland can lead to severe keratitis sicca and corneal ulcer. However, Tabbara reported that the most common cause of loss of sight was steroid related in a small series (26). Twenty-five percent of patients had steroid-induced cataracts and 12% had steroid-induced glaucoma. Topical cyclosporine has been used effectively in pediatric patients with vernal conjunctivitis without complication (27).