Adverse reactions to medicines used for ocular disease can occur both in the eye itself and in other organ systems. Whether the drug is administered locally or systemically, side effects are varied and often difficult to diagnose. Clinicians must base their diagnoses and decision-making on many factors, including their own experience, published data, and confounding variables (i.e., multidrug therapy). Much of the accumulated literature on adverse drug reactions is of limited value because of difficulty in proving a cause-and-effect relationship between the side effect and the possible inciting agent. One of the most reliable ways to prove cause-and-effect is to assess rechallenge data. If the side effect disappears on removal of the drug (positive dechallenge) and recurs when it is restarted, strong evidence exists for a cause-and-effect relationship. In practice, however, it is not practical or even ethical to subject patients to a rechallenge of a drug to which they may have had an adverse reaction.

Ocular changes may be of minor importance with no apparent adverse sequelae. Iris color change secondary to latanoprost therapy or mild mydriasis caused by antidepressant medications are of this nature. Conversely, toxic ocular reactions, such as glaucoma from corticosteroid therapy, retinopathy of chloroquine therapy, or optic neuropathy of ethambutol therapy, can threaten sight. Ocular toxicity can also be part of a more widespread toxic reaction. Examples of this include Stevens-Johnson syndrome from a wide variety of drugs and fetal alcohol syndrome seen in offspring of alcoholic mothers. In certain cases, it may be beneficial to use mild toxic ocular reactions as an indicator of more serious systemic toxicity, such as abnormal color vision seen with digitalis toxicity.

The onset of a drug-induced ocular event may occur within minutes or it may take years, such as systemic hypertension occurring within 10 to 20 minutes after topical use of ocular 10% phenylephrine or permanent ocular sicca after years of oral isotretinoin use. The adverse ocular event may be dose dependent, as with phenothiazine or hydroxychloroquine. The reaction can be reversible, as with corneal deposits from amiodarone, or irreversible, as with amiodarone neuropathy. Other reactions can be idiosyncratic, such as aplastic anemia caused by topical ocular chloramphenicol or optic neuritis from ibuprofen use.

Recently recognized adverse ocular events caused by medications include the following: topiramate can induce acute angle closure glaucoma; bisphosphonates can cause uveitis and scleritis; herbal medicines can cause multiple eye side effects; sildenafil is associated with anterior ischemic optic neuropathy; and peripheral ulcerative keratitis can be caused by filgrastim.

In this chapter are reviewed toxic effects of topical ocular therapy and ocular toxicity of systemic drugs. The list of adverse effects is not comprehensive and the intent is to provide information on adverse drug effects of medications commonly used by ophthalmologists. Much of the data collected here come from the National Registry of Drug-Induced Ocular Side Effects, a clearinghouse for drug information on adverse ocular effects. Health care professionals suspecting a possible drug-induced ocular change are encouraged to send reports to the registry. Cases of greatest interest include previously unsuspected, rare, severe, or unusual drug-related ocular side-effects. Data can be forwarded to F.W. Fraunfelder, MD, Casey Eye Institute, Oregon Health Sciences University, 3375 SW Terwilliger Boulevard, Portland, OR 97201; fax: (503) 494–4286 or online at www.eyedrugregistry.com