THERAPEUTIC INSIGHTS
"Double-Edged Swords"
How to recognize the ocular side effects of systemic medications.
By Leonid Skorin Jr., O.D., D.O., Albert Lea, MN

Systemic drugs are the double-edged swords of pharmacology. On one hand, they can cure or mitigate your patient's particular ailment. But on the other hand, they can cause ocular problems ranging in severity from mildly annoying to visually devastating.

The most frequently used systemic medications I encounter fall under nine categories, according to their actions. I'll review these categories below, list some drug examples and discuss possible ocular complications associated with each.

Anti-arrhythmic drugs

Some of your patients who have advanced cardiovascular disease may be taking amiodarone HCl (Cordarone), a powerful anti-arrhythmic, to control atrial and ventricular heart arrhythmias. Amiodarone affects the cornea and the lens, so during your slit lamp exam, look for corneal micro-deposits. These changes resemble those of chloroquine toxicity (see section on anti-malarials, this page) and form a whorl-like pigment deposit in the subepithelial layers.

I recommend performing a regular ophthalmic exam, including fundoscopy and slit lamp examination, during administration of amiodarone.

Virtually all patients will demonstrate corneal changes after 3 months of treatment. Once amiodarone therapy is discontinued, the keratopathy gradually resolves within 6 to 18 months. Lenticular opacities usually cause no visual symptoms, but moderate to severe keratopathy can lead to complaints of blurred vision, glare and halos around lights or light sensitivity.

In advanced cases, the corneal epithelium may break down and form cysts. The crystalline lens may also be involved, but your patient will usually remain asymptomatic. Check for fine anterior subcapsular lens deposits (light brown to yellow-white) along the visual axis.

Your patient's vision will rarely be affected, but cases of optic neuropathy or optic neuritis, usually resulting in visual impairment, have occurred in patients treated with amiodarone. In some of these cases, visual impairment has progressed to permanent blindness.

Optic neuropathy and optic neuritis may occur any time after therapy begins. If symptoms of visual impairment appear, experts recommend prompt ophthalmic examination.

Anti-coagulants

Aspirin, of course, can aggravate any ocular bleeding, but a blood thinner such as warfarin sodium (Coumadin) can substantially increase the risk of severe conjunctival or retinal hemorrhaging. Consult with the patient's physician before referring him for ocular surgery.

Anti-malarials

Chloroquine (Aralen phosphate) and hydroxychloroquine (Plaquenil sulfate) were first used to treat malaria before doctors found that they were also effective agents for rheumatoid arthritis, lupus and other autoimmune diseases. Anti-malarials affect the cornea, lids and retina. These medications can produce poliosis, a whorl-pattern opacity in the cornea, as well as retinal pigmentary degeneration.

During the dilated fundus examination, search for early signs of retinopathy, such as stippling or mottling of the macular pigmented epithelium. Left untreated, this degeneration progresses to the classic "bull's-eye" maculopathy (a granular hyperpigmentation surrounded by a zone of depigmentation, which is surrounded by another ring of pigment [see image below]). Variations of pigmentary disturbances can occur, and some patients may show retinal changes resembling retinitis pigmentosa. To establish baseline informa-tion, perform the following tests:

• dilated fundus exam
• Amsler grid test
• color vision evaluation
• threshold central perimetry
• fundus photography.

Bull's eye maculopathy.

Anti-neoplastic drugs

Tamoxifen citrate (Nolvadex) is a nonsteroidal anti-estrogen agent used for long-term, preventative therapy after breast cancer surgery. Maculopathy is a risk (see the image below ). Monitor your patient for macular changes, particularly bilateral, superficial, yellow-white crystalline, ring-like deposits. Discontinuing the drug can at least partially reverse vision loss.

The patient may experience reduced visual acuity associated with the macular deposits, and her central visual fields may demonstrate abnormalities.

Anti-psychotics

Psychiatrists prescribe anti-psychotics and phenothiazines, such as chlorpromazine HCl (Thorazine) and thioridazine HCl (Mellaril) to manage psychiatric disorders. Phenothiazine therapy is a pharmacological Catch 22. These drugs work best in relatively large doses, and the ocular problems they trigger are typically dose-dependent.

Chlorpromazine usually causes pigmentary changes in the cornea and conjunctiva, but it can also cause anterior subcapsular cataracts. Chlorpromazine rarely affects the retina, but thioridazine may. Thioridazine can create pigmentary changes, which can affect visual acuity, color vision and dark adaptation.

If a patient reports vision changes, perform visual field evaluations looking for a concentric contraction or irregular paracentral or ring scotomas. Once you discontinue the medication, your patient's vision will usually stabilize or improve.

Anti-tuberculosis drugs

Tuberculosis is aggressively treated with a regimen of drugs that includes ethambutol HCl (Myambutol), isoniazid (Laniazid) and rifampin (Rimactane). Ethambutol is the most dangerous because it affects the optic nerve. It can trigger optic neuritis and blindness secondary to optic neuritis. Be on the alert for ocular symptoms or nerve head changes. Signs of ocular toxicity can appear several weeks following initial therapy, but the onset of ocular complications usually occurs several months after treatment is begun. The primary ocular manifestation of ethambutol toxicity is retrobulbar neuritis.

If your patient complains of changes in central vision, such as decreased visual acuity and color vision disturbances, suspect an axial form of optic neuritis.

Advise patients not to wear contact lenses while taking rifampin. This medication may turn tears, sweat, saliva, urine, feces and contact lenses a red-orange color. The rifampin may permanently discolor lenses.

Cardiac glycosides

Digoxin (Lanoxin) and digitoxin (Crystodigin) can affect your patient's overall health as well as his vision, depending on the concentration of the drugs in his bloodstream. These derivatives of digitalis are used to treat congestive heart failure and certain atrial arrhythmias. They're tricky drugs to administer because the therapeutic or effective dose is often close to the toxic level.

Patients with digitalis intoxication may complain of color vision disturbance, flickering or flashing lights, colored spots, snowy, hazy or blurred vision, dimming vision and heightened sensitivity to glare. Color vision testing may reveal a reduction in both red-green and blue-yellow discrimination.

If your patient develops ocular symptoms, realize that he's facing life-threatening cardiac consequences. Call his physician or cardiologist.

Your promptness in alerting the physician or heart specialist will greatly benefit your patient. Once the prescribing doctor decreases the medication dosage, nearly all of the ocular side effects should subside.

Steroid-induced posterior subcapsular cataract.

Corticosteroids

Primarily used to treat systemic inflammation, corticosteroids such as prednisone and cortisone acetate produce secondary complications including hypertension secondary to salt and water retention, peptic ulcers, osteoporosis and diabetes. Corticosteroids also affect the lens and elevate intraocular pressure. In addition, they can cause extraocular muscle palsy, periorbital chemosis and ptosis. Prolonged use of corticosteroids may induce glaucoma and increase the risk of secondary ocular infections due to fungi or viruses.

The most common ocular side effect of systemic corticosteroids is a posterior subcapsular cataract, which is often indistinguishable from an age-related posterior subcapsular cataract (see image below). We know that posterior capsular lens changes depend on dosage and duration of steroid therapy, but individual susceptibility may also play a major role or have an impact on their development.

Even if the steroid dosage is reduced or discontinued, the cataract usually remains un-changed. Severe visual impairment is rare in patients with steroid-induced posterior subcapsular cataracts. In fact, most patients retain visual acuity of 20/40 or better but may report light sensitivity, frank photophobia, reading difficulty or glare.

Oral contraceptives

Women not only use oral contraceptives to regulate their fertility cycles, but also for amenorrhea, dysmenorrhea, dysfunctional uterine bleeding and premenstrual tension.

Unfortunately, these drugs can also affect the vascular system, particularly in women who are older, are obese or smoke. Watch out for retinal or cerebral vascular occlusion, retinal migraines, periphlebitis, optic neuritis and pseudotumor cerebri (see image below).

Raise your awareness

You can see that awareness of drug-induced complications is essential in helping to make a differential diagnosis for your patients. Knowing the effects that certain drugs can have on your patient's ocular health could save their sight.

Make sure you're aware of complications associated with the common drugs your patients may be taking -- they'll thank you for your knowledge and concern.

Dr. Skorin is adjunct professor of neuro-ophthalmology at Midwestern University in Chicago. He is a staff ophthalmologist at the Albert Lea Eye Clinic -- Mayo Health System.

Dr. Christensen has a partnership practice in Midwest City, Okla. He's a diplomate in the Cornea and Contact Lens Section of the American Academy of Optometry. He's also a member of National Academies of Practice.