INTRODUCTION

Medications are employed with the intent of providing a specific benefit for their usage. In a select number of cases, however, there are unintended consequences in organs or systems, far beyond the initial target. This chapter will review the use of systemic medications (along with select topical agents) which can lead to unwanted retinal consequences.

KEY CONCEPTS AND FUNDAMENTALS

A wide variety of systemic medications are capable of inducing retinal toxicity. Fortunately, in the majority of cases the loss of visual function is minimal or reversible following discontinuation of the inciting drug. Nevertheless, permanent or progressive visual loss may occur in some instances. We present only those medications known to produce a welldescribed change. The medications can be grouped according to the type of retinal toxicities they produce: disruption of the retina and retinal pigment epithelium (RPE), vascular damage or occlusion, retinopathies characterized by macular edema and/or macular folds, crystalline retinopathies, induction of uveitis and/or hypotony, and functional toxicities without specific, visible retinal changes. The medications are listed in Table 16.1, and the most prominently encountered agents will be discussed throughout the course of this chapter. Also briefly discussed is the retinal toxicity of several topical ocular medications.

PHARMACOLOGY, BIOCHEMISTRY, AND TYPE OF IMPACT ON THE RETINA

DISRUPTION OF THE RETINA AND RETINAL PIGMENT EPITHELIUM

Phenothiazines

Thioridazine

Thioridazine is a piperidine antipsychotic drug that was previously widely used in the treatment of schizophrenia and psychosis. Due to concerns about cardiotoxicity and retinopathy at high doses, this drug is now prescribed less than previously and is mostly used for refractory cases.

Blurred vision, dyschromatopsia (reddish or brownish discoloration of vision), and nyctalopia characterize acute toxicity with thioridazine.1 In the earliest stages the retinal appearance may be normal or display only mild granular pigment stippling (Figure 16.1). An intermediate stage is characterized by circumscribed nummular areas of RPE loss from the posterior pole to the midperiphery2 (Figure 16.2). In late stages of thioridazine toxicity, widespread areas of depigmentation alternat-

ing with hyperpigmented plaques, vascular attenuation, and optic atrophy are seen3 (Figure 16.3).

Photography and fluorescein angiography (FA), visual field testing, and electrophysiologic testing are useful ancillary tests in screening and monitoring for possible thioridazine toxicity. FA highlights disruption of the choriocapillaris and zones of pigment rarefaction (Figures 16.2 and 16.3). Visual field testing can reveal mild constriction, paracentral scotomas, or ring scotomas. Electroretinography (ERG) is either normal or shows decreased oscillatory potentials in early stages of toxicity. In the later stages, both the rod and cone functions of the ERG, as well as the electro-oculography (EOG), are markedly abnormal.4 Multifocal ERG (mfERG) may provide an even better means of detecting early change and monitoring such patients, though such data are currently lacking.

Retinal toxicity from thioridazine is dependent more on the total daily dose than on the cumulative amount of drug received. With higher daily doses, toxicity can occur rapidly, even within the first 2 weeks of therapy.5 Toxicity is rare at dosages less than 800 mg/day. Nonetheless, a few cases have been reported with lower doses given over several years. As a result, any patient taking thioridazine, regardless of the daily dose, should be monitored for the development of visual symptoms or retinal changes.

At the earliest sign of toxicity, thioridazine should be discontinued. However, the early retinal changes associated with thioridazine often progress despite discontinuation of therapy. It is unclear whether this degeneration represents continued toxicity of the drug or a delayed expansion of chorioretinal scarring secondary to areas of subclinical, preexisting damage. Visual function, in contrast to retinal appearance, usually improves over the first year after drug cessation. In addition, if the drug is stopped early, ERG testing may actually improve over the first year6; this undoubtedly would not occur if thioridazine caused persistent toxicity.

The mechanism of thioridazine-mediated retinal toxicity probably involves damage to both the RPE and the retina. Many phenothiazines bind melanin granules of the RPE and uveal tissue, but not all commonly instigate retinal toxicity.7–9

Historically, the compound piperidyl-chlorophenothiazine hydrochloride (NP-207) had a similar chemical structure to thioridazine, including the same piperidyl side chain. NP-207 was never marketed however, because of the pronounced pigmentary retinopathy that developed during early clinical trials.10 This piperidyl side chain is not present in other phenothiazines, which in general exhibit much less evidence of retinal toxicity. Experimental studies demonstrate that phenothiazines alter enzyme kinetics and inhibit oxidative phosphorylation with subsequent abnormalities in rhodopsin synthesis.11–13 Other studies suggest that thioridazine toxicity may be due to direct effects on the retina rather than the RPE. For instance, histopathologic studies indicate that atrophy and disorganization of photoreceptor outer segments occur primarily, with a secondary loss of the RPE and choriocapillaris.14

Given the many antipsychotic medications available today, thioridazine is no longer widely employed. If one encounters a patient on this medication, and there is any degree of retinal pigmentary alternation, a discussion regarding the use of alternative agents should be entertained with the patient’s psychologist or psychiatrist.

delivery drug retinal for routes and models Animal • 2 section

Figure 16.4  Color photograph depicting pigment deposition in the anterior lens capsule in a patient on chlorpromazine. The patient was visually asymptomatic.

Figure 16.5  Color photograph of left eye of a patient on chlorpromazine. Mild disc pallor is seen along with slight vascular attenuation and diffuse pigment mottling.