Clinically Relevant Toxicology and Patient n Valerie Q. Wren, O.D.
Manycommonsystemicmedi- Oneofthemostimportantaspectsof
the patient intake is obtaining a thorough sues and visual function. Adverse effects Abstract
Many systemic drugs have reported ocu- tions. The optometrist is in the ideal posi- treatment. Some drugs have a greater pro- lar and visual side effects that impact pa- tient management. It is important to be occurrences. In order to appropriately ed- drug is used. Others tend to affect the eyes familiar with the associated side effects ucate patients, prevent and minimize seri- more if used in higher dosages. In general, which can be mild and transient or may it is a good idea to identify the condition deals briefly with the mechanisms and temic drugs. While this is true for all op- tiple approved and off-label uses. For in- reasons that account for the effects that tometrists, it is particularly important for systemic drugs can exert on the visual sys- those with special interest and expertise in hypertension, arrhythmia, angina, and mi- the diagnosis and treatment of functional cover major drug classes and serve as a guide to familiarize clinicians with impor- practitioners are most apt to treat patients tant ocular and visual implications. side effects, advising patients, plus collab- Key Words
Melanin binding, photosensitizer, sys- temic drugs, ocular toxicity, ocular and prescribed for patients. Another is being able to correlate a particular side effect ministration). It can be a formidable task with a suspected drug. It is the vision care practitioner’s responsibility for eye care well as those already on the market. There practitioners to maintain current pharma- cologic knowledge. This article will deal in terms of their ability to affect the eye.
can affect the eyes. The remainder of the serve as a guide to familiarize clinicians prescribed drugs in each class, while Ap- pendix B can serve as a clinically relevant MELANIN BINDING
summary of the ocular and visual side ef- molecules has been postulated as a precur- (IgA).5 This causes a reduction in tear se- sor to ocular toxicity.2 It is possible that cretion, and patients complain of ocular ir- The total area of the globe is relatively from the free-radical nature of melanin in small compared to the rest of the body.
structures such as the uveal tract and the clude artificial tear supplementation and treat another part of the body, the eyes fre- refitting the patient with lower water con- cule enters the systemic circulation, it can a high affinity to melanin and tend to af- reach ocular tissues through uveal or reti- intraocular pressure (IOP) by blocking the fect ocular tissues. Drugs binding to mel- nal circulations.2 The choroid, sclera and ciliary body have thin, fenestrated walls adjacent, non-pigmented ocular tissues by the ciliary body. Topical B2 blockers pro- duce little additional IOP reduction with sues. The melanin theory is still being de- into avascular structures such as the lens, c o n c o m i t a n t a d m i n i s t r a t i o n o f a bated, and is not completely explained.
At the ocular level, the ability of a drug DRUG METABOLISM
to penetrate the major barriers determines its likelihood to affect ocular tissues and drug directly correlates with toxicity. In visual function. The first barricade is the duced, appearing within normal limits.
blood-brain barrier where tight junctions Patients should continue taking their med- ication, and the clinician should contact cells in the retinal blood vessels prevent late to toxic levels.3 Also, toxic metabo- includes changing the dosage or the medi- lites formed elsewhere like the liver, can reach the eye through systemic circulation whose fenestrations sort by molecular size or can be produced locally in ocular tis- and lipid solubility. The blood-retinal bar- (ACE) inhibitors and alpha adrenergic an- tagonists. These rarely cause ocular side PHOTOSENSITIZERS
the zonular occludens of the retinal pig- Diuretics
ters most ultra-violet ( UV) radiation, so there is minimal risk of UV affecting the treat congestive heart failure. Hydrochlo- the uveal circulation exit the eye from the tially bind.1 UV radiation does affect an- tures. Drugs from the retinal circulation can reenter the systemic circulation, dif- structures, or get actively transported out.
the eye, contact various ocular tissues, and potentially affect the retina in aphakic and eventually accumulate in ocular tissues or exit the eye. There are three major accu- mulation sites including the cornea, lens lens barrier. Well-known photosensitizers and vitreous. The duration of drug in the eye is prolonged if deposited, increasing tendency towards lipid storage in the cor- CARDIOVASCULAR AGENTS
tion is used when standard digitalis ther- can also bind to lens protein, and photo- “heart problem,” it is important to deter- sensitize the lens to ultraviolet (UV) radi- corneal deposits in as early as six days of mine the particular condition(s) for which they are being treated, e.g, hypertension, accumulate in the vitreous due to the slow congestive heart failure, angina, arrhyth- appear whorl-like because epithelial cells migrate centripetally from the limbus.
ten treated with antihyperlipidemic drugs.
they experience TIAs due to the increased son-Stahle lines should be ruled out.
posterior subcapsular lens changes since it frequently start estrogen replacement.
is a photosensitizing agent. As a preven- Similar to oral contraception, steepening of corneal curvature and contact lens in- cebo groups.8 Niacin (B3) is another drug is not usually affected, but can be mildly that lowers triglycerides and low-density include glare, halos, and foggy vision.
rience dry eye and several cases of cystoid CENTRAL NERVOUS SYSTEM
drug, where toxicity increases with higher dition, symptoms of lid edema and blurred doses and longer therapy. Fortunately, the side effects usually regress as amiodarone HYPERGLYCEMICS
scribed class of medication in the world.
cases of optic neuropathy with vision loss In general, visual acuity may be inexplica- as well as reports of pseudotumor cerebri, glyburides are used to treat diabetes.3 For some patients, subcutaneous insulin treat- ment is necessary. Side effects from these drugs are rare and it may be difficult to dif- Antipsychotic
test should be performed, and consultation is recommended with the patient’s inter- a g e s c h i z o p h r e n i a . T h i o r i d a z i n e nist or cardiologist to consider alternative (Mellaril) has almost completely replaced previous chlorpromazine (Thorazine) use.
diac arrhythmia is digitalis (Digoxin).
ties causing blurred vision, decreased ac- 11-25% of patients using this drug experi- prescribed for replacement therapy. In pa- in color vision, visual sensation, or flick- retrobulbar optic neuritis toxicity.5 Later, found in the retina and choroid. Thus, the tions with the use of this drug.10 Other side retina instead of the optic nerve is thought e ff e c t s a r e e y e l i d h y p e r e m i a a n d to be the site of digitalis toxicity. In partic- longed periods have a higher incidence of ular, cone dysfunction is caused by inhibi- irreversible corneal and lenticular depos- The patient’s internist or endocrinologist its.8 Pigment deposits can occur on areas ATPase, which plays a vital role in main- of the bulbar conjunctiva that are exposed balancing adequate T-level control and re- and these patients should simply be moni- effect is reduction of IOP in glaucomatous tored on a yearly basis. More importantly, lens intolerance from reduced tear secre- g l y c o s i d e s l i k e D i g o x i n i n h i b i t tion. The exact cause has not been proven, ported in higher doses.6 This can lead to the corneal curvature, corneal edema from sponsible for the active transport of so- some of these changes may be reversible if dium, necessary for aqueous secretion.
Thus, its inhibition leads to reduced aque- ous secretion and IOP. Along with the oc- tions like artery and venous occlusions re- bipolar affective disorders, e.g., manic de- ported in the past. These may be related to systemic side effects associated with this drug precluding its use in glaucoma treat- the drug is stopped.2 Blurred vision some- s i d e e ff e c t s i n c l u d e m i g r a i n e s , times occurs due to cortical involvement.
diplopia, keratitis sicca and contact lens scribed for gout and rheumatoid arthritis.
Aside from irritation of the gastric lining, Antianxiety
should not be used in patients with trau- extreme tension. Ocular side effects like are sometimes used to treat migraines.
of rebleed. In contrast to blood thinners, it rare and reversible.10 Mydriasis can result (Imitrex) is a serotonin receptor antago- panretinal hemes in diabetics.4 It should conjunctivitis may onset after 30 minutes nist. Not many side effects have been re- due to antigenic factors in this drug class.
porting of side effects may not be current “dirty” drugs in that they produce many or accessible. Thus, it is best to take a Corticosteroids
anticholinergic side effects. Symptoms of careful history and monitor any changes.
blurred vision, cycloplegia and dry eye are ANTIULCER AGENTS
are very effective for acute disease states tors. It is important to correlate the pa- from steroid use are well known and occur tient’s medication with the time frame of peptic ulcer and gastritis.3,10 Cimetidine with topical, systemic, and nasal adminis- of crystalline lens fibers causing protein blurred vision, photophobia, conjunctivi- subcapsular lens opacity is the most fre- systemic side effects are the selective se- tis and color change.4 However, these side quent and critical side effect, especially in r o t o n i n r e - u p t a k e i n h i b i t o r s l i k e effects are usually rare and reversible.
children since it is irreversible and ambly- fluoxetine (Prozac), sertraline (Zoloft), ANTICOAGULANTS
each patient, regardless of duration or dos- (Celexa).11 These do not have any signifi- Barbiturate
should be informed to weigh the risk ver- sus benefit of steroid treatment. Another significant side effect from steroid use is their blood thinning effect.4 This is a par- keted heavily and can be easily purchased.
ticular concern in patients with diabetic retinopathy or age-related macular degen- eration. It is important to closely follow diabetic patients for proliferative retinal Anticonvulsant
t r e a t m e n t . E x c e s s i v e a m o u n t s o f for chronic epilepsy but for pain as well.
ous outflow by hydrating the trabeculum.
(Tegretol) are very commonly prescribed.
This results in resistance to aqueous out- before ocular surgery in diabetic and hy- lowering drugs, as well as changing or ta- CNS Stimulant
pertensive patients. This may not be nec- pering the steroid medication. Other side effects include iris microcysts, exacerba- cortical stimulant with CNS actions simi- tion of herpetic keratitis, papilledema, and ANALGESICS
agonists. In adults, this drug stimulates therapeutic uses. Not only is it effective for pain and fever reduction, but aspirin has a paradoxical effect on children, and is also works well as a platelet inhibitor.
sociated with nonsteroidal anti-inflamma- frequently used to calm children with At- This anticoagulant property is helpful in ANTICHOLINERGICS
sion, refractive changes, diplopia, color Tetracyclines
use, permanent vision and visual field loss such as sedatives, sleep aids, cold prepara- have been reported.4 The patient’s inter- tions, antidiarrheals and nasal deconges- bacteriostatic drug against gram-positive nist should be notified, and a neurological secretions in a dose-dependent manner.
s u a l f i e l d c h a n g e s . I n d o m e t h a c i n Ocular effects include dry eye, mydriasis (Indocin) is a prescription medication that occur in the palpebral conjunctiva. Tetra- plain of light sensitivity, and RPE or reti- patches contain an antiemetic used to pre- improve with discontinuation of the drug.
tween 12 hours and four days after begin- dispensed on cruise lines. Passengers may directly contaminate their eyes after ap- ported side effects include transient myo- ANTIRHEUMATICS
to anisocoria or mydriasis. Practitioners can easily rule out any neurological asso- Antimalarials
there is no extraocular palsy and the di- cornea and lens by circulation through the aqueous in the anterior chamber. This can lead to numerous, minute colored deposits DERMATOLOGIC AGENTS
6 . 0 - 6 . 5 m g / k g / d a y f o r h y d r o x y - vary from yellow-brown to violet or red.
medication is a Vitamin A analog and fre- These deposits are benign, so there is no chloroquine. The risk of irreversible reti- need to discontinue or reduce the dosage.
nal damage is dose-dependent. The likeli- If the patient stops taking this medication, the deposits usually disappear in three to This bull’s-eye maculopathy starts as fine ciency of the normal lipid layer in the tear tors, Celebrex and Vioxx, to treat rheuma- area, with or without the loss of the foveal film. Along with artificial tears, treatment reflex. The end result can range from re- includes decreasing the dosage or discon- duced vision to possible blindness. Differ- chronic users as compared to NSAIDs.
Ocular side effects are rare. Only blurred hold the drug for a prolonged period after ANTIALLERGY AGENTS
to the melanin binding theory. This leads Sulfonamides
alleviates allergic conditions of rhinitis, dermopathies, urticaria, and systemic al- isms. Conjunctivitis and optic neuritis are rare, but myopic shifts commonly occur.
of dose reduction or cessation. The mech- corneal epithelium can occur from revers- causes contact lens intolerance.11 Antihis- ible binding of the drug to intracellular anticholinergic effects where the ciliary tamines have weak atropine action, acting nucleoproteins in the corneal epithelium.7 as cholinergic antagonists. This can cause tic nerve pallor, cycloplegia and ptosis can lens. A major hypersensitivity reaction to formed before the patient starts treatment.
Amsler grid to detect paracentral scotomas, color vision, contrast sensitiv- they are particularly important for those ity and central red-white visual field can who are increasingly called upon to diag- be used to follow the patient for changes.7 nose and treat the functional visual prob- REFERENCES
1. Jaanus SD, Bartlett JD, Hiett, JA. Ocular effects Antitubercular
of systemic drugs. In: Bartlett JDand Jaanus SD, eds. Clinical Ocular Pharmacology, 3rd ed.
mycobacterial diseases like tuberculosis.6 Boston: Butterworth-Heinemann, 1995:957-1006.
It is less toxic than other drugs such as Oculotoxicities of systemically administered the drug of choice. Patients with renal in- drugs. J Ocular Pharm 1886;2(4):385-399.
sufficiency, or impaired ability to excrete 3. M y c e k M J , H a r v e y R A , C h a m p e P C .
Lippincott’s Illustrated Reviews: Pharmacol- the drug, may be at greater risk for devel- ogy, 2nd ed. Philadelphia: Lippincott-Raven, 4. Muchnick BG. The ocular manifestations of sys- temic drugs. Optom Today 1998 May:44-52.
5. Bartlett JD. Ophthalmic toxicity by systemic drugs. In: GCY Chiou, ed. Ophthalmic Toxicol- retrobulbar optic neuritis, but most cases ogy, 2nd ed. Michigan: Taylor and Francis, 6. To HT, Townsend JC. Ocular toxicity of sys- ERECTILE DYSFUNCTION
7. Moorthy RS, Valluri S. Ocular toxicity associ- cation to treat males with erectile dysfunc- ated with systemic drug therapy. Curr Opin 8. Woodard DR, Woodard RB. Drugs in Primary Eyecare, 2nd ed. Connecticut: Appleton and a common side effect of this medication.
9. Fraunfelder FT, Herrin S. A practical guide to d r u g i n d u c e d o c u l a r s i d e e ff e c t s . R e v 10. Levine L. Optometrically-relevant side effects of the systemic drugs most frequently prescribed in 1991. J Behav Optome 1992;3(5):115-119.
may cause difficulty in distinguishing be- 11. Hom M. Is it the medication? Optom Mg, 2000; 12. Patel M. Ocular side-effects of systemic drugs: Part 2. Optom Today UK 1999;39(7):43-47.
13. Trachtman JN. The efficacy of ritalin for hyper- 14. Novack GD. Ocular toxicology. Curr Opin hours of taking the drug.18 Caution should 15. Ajamian PC. When systemic drugs cause trou- 16. Jaanus SD. Ocular side effects of selected sys- temic drugs. Optom Clin 1992;2(4):73-96.
17. Bright DC. What you may not know about over-the-counter drugs. Optom Mgt 1992;27(1): important to reveal a patient’s medication 18. Marmor MF, Kessler R. Sildenafil (Viagra) and history. The ocular and visual side effects from a patient’s systemic medication can range from mild to severe. These side ef- fects may or may not be serious enough to nition of ocular and visual side effects is vent and minimize serious complications.
routinely paying attention to concomitantmedications. While these considerationsshould be in the minds of all optometrists, Appendix A. Common Systemic Medications and Uses
Ace inhibitor
Coumadin derived
Alpha agonist
Platelet inhibitor
Manic Depressives
Ca++Channel Blocker
Cardiac Glycosides
Serotonin inhibitor
Serotonin agonist
and Visual Side Effects of Drugs

Source: http://www.oepf.org/sites/default/files/journals/jbo-volume-11-issue-6/11-6%20Valeriewren.pdf

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