Some unexpected side effects of ocular medications can be beneficial

Issue: November 1997

ByMichael J. Trad, OD

Interesting reports have surfaced recently in the ophthalmic literature regarding surprising ocular side effects purportedly attributed to various topical ophthalmic and oral systemic medications. The effects of these drugs vary considerably in that some are detrimental while others are relatively innocuous or, in some instances, potentially beneficial. Further research and publication in peer-reviewed form is necessary to substantiate these observations.

Corneal decompensation

Trusopt (dorzolamide HCl, Merck & Co.), like other carbonic anhydrase inhibitors (CAIs), decreases intraocular pressure (IOP) by inhibiting the carbonic anhydrase (CA) enzyme in the ciliary processes and subsequently decreasing aqueous production.

Upon its approval a few years ago as the first topical CAI, it was a welcome addition to the glaucoma therapeutic armamentarium because of significant systemic side effects associated with oral CAIs. However, during the past year, reports of irreversible and progressive corneal decompensation in patients treated with dorzolamide have arisen. Such cases have occurred in individuals who already had compromised endothelial function (Ophthalmology Times, June 15, 1997).

Although it is not certain whether CA is necessary in preserving the clarity of the cornea, CA activity has " ... been observed in both the cytoplasm and around the plasma membrane of the corneal endothelium," according to the Merck package insert. Therefore, until more definitive information is obtained, it is advisable for practitioners to exercise caution when considering treatment of this at-risk patient population with Trusopt.

Eyelash growth, CME

Xalatan (latanoprost, Pharmacia & Upjohn), an antiglaucoma agent, was approved by the Food and Drug Administration in June 1996. A prostaglandin analog, latanoprost is thought to loosen intercellular spaces on the ciliary body, thereby decreasing IOP by increasing uveoscleral outflow. It is approved as a second-line antiglaucoma agent and, in clinical studies, demonstrated similar efficacy to timolol in decreasing IOP.

Upon its initial release, most eye doctors were already aware of reports associating Xalatan with iris color changes in some individuals. Recent claims that the medication may stimulate eyelash growth and apparently cause cystoid macular edema (CME), however, were not anticipated. (Eyelash growth cited by Murray Johnstone, MD, in a presentation at the Association for Research in Vision and Ophthalmology [ARVO] meeting, May 1997; CME cited by Robert A. Schumer, MD, PhD, at ARVO, May 1997.)

Eyelash growth associated with latanoprost apparently is observed approximately 6 weeks after beginning the drug, and by 3 months is very noticeable. Lashes grow an additional 19% to 20% in length and, in 25% to 30% of cases, also appear thicker and curlier. Hair growth has also been observed in the medial and lateral canthal areas. It has been suggested that prostaglandin analogs are active mitogens that convert vellus hair into terminal follicles.

Another recent claim regarding Xalatan is that it may cause CME in susceptible individuals, that is, those who are pseudophakic or aphakic, have a history of surgery or CME in the involved eye or have previously been diagnosed with retinal venous occlusive disease.

The suggestion that latanoprost may cause CME is not surprising in light of studies claiming a prostaglandin-mediated inflammatory role in its pathogenesis. Lastly, as anticipated, Dr. Schumer reported that discontinuation of Xalatan led, in most cases, to CME resolution.

Neuro-, vasoprotective properties

Alphagan (brimonidine tartrate 0.2%, Allergan), another relatively new topical glaucoma drug, can be used as a first- or second-line medication. An alpha-2 adrenergic agonist, brimonidine decreases IOP through two mechanisms: reducing aqueous production by stimulating presynaptic alpha-2 receptors and blocking norepinephrine release, and enhancing uveoscleral outflow through dilation of spaces between ciliary muscle bundles.

Brimonidine may hold additional promise in minimizing optic nerve damage secondary to glaucoma and other optic neuropathies. Studies involving rats suggested that Alphagan increased both excitability and survival of optic nerves when subjected to crush injury. The mechanism of this neuroprotective effect, however, is not well understood.

Another potential benefit of brimonidine relates to its effect on the microvasculature of the optic nerve and posterior pole.

Because of its highly alpha-2 selective properties, Alphagan does not cause vasoconstriction of the aforementioned ocular structures (alpha-1 agonists control vasoconstriction). Therefore, it is theorized that these two additional properties of Alphagan - neuroprotection and increased vascular perfusion - may better address other factors contributing to or comprising the multifaceted disease process known as glaucoma.

Optic neuropathy, neuritis

Cordarone (amiodarone HCl, Wyeth-Ayerst), a class III antiarrhythmic agent, is used for treating severe, life-threatening ventricular arrhythmias that are unresponsive to other medications or when alternative drugs cannot be tolerated. Its use is extremely limited because of potentially serious (including fatal) side effects such as pulmonary and hepatic toxicity, as well as exacerbation of pre-existing arrhythmias. Amiodarone exerts its pharmacological effect by acting as an alpha- and beta-receptor antagonist with antiarrhythmic and vasodilatory properties.

Although Cordarone has long been known to cause ocular side effects, such as corneal epithelial verticillate pigmentary deposits and anterior subcapsular lenticular opacities, it is only recently that optic neuropathy or optic neuritis, disc edema and permanent blindness have been reported in association with its usage. At this time, however, an actual causal relationship between amiodarone and optic neuropathy/neuritis has not been established (according to a revised labeling alert for the Cordarone package insert sent by Wyeth-Ayerst Laboratories to health care professionals in 1997).

ACE inhibitors and retinopathy

Lisinopril is an oral angiotensin-converting enzyme (ACE) inhibitor used in the treatment of systemic hypertension, heart failure and acute myocardial infarction. Known by proprietary names such as Zestril (Stuart) and Prinivil (Merck & Co.), it exerts its systemic effect by suppressing the renin-angiotensin-aldosterone system.

Of present and pertinent interest, however, is the possibility that lisinopril may slow the progression of diabetic retinopathy in insulin-dependent diabetics. Results of a 2-year European study, presented in June at the American Society of Hypertension meeting in San Francisco, demonstrated that lisinopril decreased the progression of nonproliferative diabetic retinopathy 9% to 10% when compared to placebo, 22% to 26%, in normotensive (systemic) patients.

The study was initiated after a 1993 study revealed that ACE inhibitors effectively treated diabetic nephropathy in hypertensive patients. The mechanism by which lisinopril exerts its beneficial effects on renal and ocular function is not known.

For Your Information:

Michael J. Trad, OD, is responsible for primary care eye services at Medical Arts Center, Dixon, Ill. His primary interests are in posterior segment disease and neuro-ophthalmology. He may be contacted at 1620 Sauk Rd., Dixon, IL 61021; (815) 288-7711; fax: (815) 288-5077. Dr. Trad has no direct financial interest in any of the products mentioned in this article, nor is he a paid consultant for any company mentioned.

Pharmacology and the Eye is edited by Bruce E. Onofrey, OD, RPh, who is responsible for primary care eye services at Lovelace Medical Center, Montgomery Eye Clinic, in Albuquerque. He lectures on the management of ocular disease and the use of pharmaceutical agents, and is a charter member of the Editorial Advisory Board of Primary Care Optometry News. He may be contacted at 9101 Montgomery Blvd., NE, Albuquerque, NM 87111; (505) 275-4226; fax: (505) 275-4023. Dr. Onofrey has no direct financial interest in any of the products mentioned in this article, nor is he a paid consultant for any company mentioned.