Katherine Wang, OD, FAAO
Course List | Take This Exam | CE Home | Optometry's Home
Introduction
Many widely prescribed medications can result in serious, drug-induced ocular side-effects. Some side-effects may be transient and reversible; others can cause serious and irreversible visual loss. Due to possible adverse ocular complications, it is necessary to be aware of all the medications our patients are taking and their possible ocular consequences. This is especially important because patients often do not associate ocular and visual problems with medications being taken for conditions not directly related to their eyes.
In most cases, management of ocular side-effects involves careful patient monitoring and/or consulting with the prescribing practitioner about adjusting the drug dosage or discontinuing the offending medication.
The purpose of this course is to review common systemic medications, their uses, and their ocular side-effects. Although there are many medications that have ocular sequelae, this course will focus on medications that have a high frequency of side-effects, those that produce severe ocular problems, and those that are the most commonly prescribed (as determined by the top 200 generic and legend pharmaceutical drugs prescribed in 2002).
By convention, drugs will be listed by generic name first, then the most common brand/proprietary names will be given. In addition, some drugs will be followed by a number in brackets representing where it ranks in a list of the most commonly prescribed 200 medications.
You can navigate through this course by clicking any of the section titles listed below. At the end of each section, you can return to this list or continue on through the remainder of the course.
Loratadine (Claritin® [18], Claritin D 24 Hour® [56]), Cetirizine (Zyrtec® [30])
Fig. 1. OTC Claritin® packaging.
Claritin® and Zyrtec® are well known and commonly used for seasonal allergies. They are long-acting tricycline antihistamines with selective peripheral histamine H1 receptor antagonistic properties.(1,2) Visual side-effects are uncommon and frequently disappear even if drug use is continued. However, these drugs do have a weak atropine-like action that can produce pupillary changes. Long-term use can cause anisocoria, decreased accommodation, and blurred vision.(1) These side-effects should be considered when the drugs are prescribed for long periods of time or for pre-presbyopes who could experience near vision problems.
Claritin® and Zyrtec® can also cause decreased mucoid or lacrimal secretion resulting in contact lenses intolerance and dry eye symptoms.(2) Normal ocular moisture typically returns when the drugs are discontinued.
Large doses of Claritin® and Zyrtec® can cause facial dyskinesia or blepharospasms.
(Click here to return to Drug Category List)
Antiarrythmic: Amiodarone [46] (Cordarone®)
Amiodarone is a well-known benzofuran derivative that is used in the treatment of various cardiac arrythymias. Its half-life ranges from 26 to 160 days.(3) Ocular side-effects produced by this drug are common and are time and dose-dependent. Because of this, ophthalmic examinations should be conducted every 6 to 12 months, or more frequently depending on findings.
The cornea is the most commonly affected ocular structure with superficial punctuate opacities occurring in 69-100% of patients taking amiodarone. Decreased corneal sensation and a whorl-like keratopathy can also be produced.(4) According to Romero, the whorl-like keratopathy occurs because the lipophilic drug attaches to the basal stem cells at the limbus and is carried with them into the center of the cornea until the cells differentiate and then desquamate at the surface of the cornea. The whorl-like pattern traces the migratory pathway of these cells. It can take months for the corneal changes to disappear after stopping the drug.(3)
Fig. 2. Whorl-like pattern on the cornea.
Often the lids show a loss of eyelashes or eyebrows along with eyelid and periocular tissue photosensitivity.
Further, the conjunctiva may develop yellow-brown deposits. Lenticular changes can include anterior, subcapsular, small, yellow-white punctuate opacities and cortical changes.(1)
Fig. 3. Optic neuropathy resulting from amiodarone use.
One of the most severe side-effects of amiodarone use is optic neuropathy, which occurs in 1.8% of patients.(1) If optic neuropathy does develop, amiodarone should be discontinued by the prescribing doctor.
The optic neuropathy is considered a drug-induced lipid storage disease.(3) Ultrastructural changes in optic nerve tissue illustrate a primary lipidosis. There is a selective accumulation of intracytoplasmic lamellar inclusions in large optic nerve axons, and this may decrease axoplasmic flow biochemically or mechanically. The result is optic nerve head edema, which can persist as long as transport is compromised. A vascular event can occur at the posterior ciliary arteries and the peripapillary choroidal arterial system.(3)
The main predisposing risk factors for the occurrence of optic neuropathy caused by amiodarone are diabetes (25%) and hypertension (50%). Other predisposing risk factors include crowding of the optic nerve, nocturnal hypotension, cataract extraction, carotid diseases, atrial fibrillation, embolization, acute blood loss, uremia, hematologic abnormalities, trauma, herpes zoster, radiation, eclampsia, pseudoxanthoma elasticum, migraine, and G6PD deficit.(4-9)
An important aspect of optic neuropathy assessment involves determining whether the condition is a non-arteritic anterior ischemic optic neuropathy (AION) or an amiodarone-induced optic neuropathy. An amiodarone-induced neuropathy will differ from an AION in several ways. Amiodarone-induced neuropathy onset will be insidious (e.g., over a period of months), visual loss will be less significant (e.g., visual acuity loss to 20/200), disc edema will resolve over months for amiodarone-induced neuropathy versus weeks for an AION, and amiodarone-induced optic neuropathy typically occurs within weeks of initiation of drug therapy.(1)
Comparison of Amiodarone-Induced Optic Neuropathy to Non-Arteritic AION
|
Amiodarone-Induced Optic Neuropathy
|
Non-Arteritic AION
|
|
|
Onset of visual loss
|
Insidious (months)
|
Rapid (days to weeks)
|
|
Degree of vision loss
|
20/20 to 20/200
|
20/20 to NLP
|
|
Ocular involvement
|
Usually simultaneous
|
Rarely simultaneous
|
|
Resolution of disc edema
|
Within weeks
|
Within weeks/months
|
Sensory visual side-effects include photophobia reported by 57% of patients taking amiodarone, blue-green rings or halos around lights, and blurred vision.(4)
Visual field defects can also occur as a result of amiodarone use, but the incidence rate is unknown.
A lesser known side-effect of amiodarone use is thyroid dysfunction.(2) Cordarone® inhibits peripheral conversion of thyroxine (T4) to T3 and thus may cause increased thyroxine levels, decreased T3 levels, and increased levels of inactive reserve T3 in euthyroid patients.(2)
Typically, the prescribing doctor will be monitoring patients on amiodarone by using a thyroid functional panel. (For more information on this and other blood tests, see the On-Line CE Course by Alan Kabat, OD, FAAO titled, "Using Blood Tests and Urinalysis to Assess Systemic Conditions with Ocular Consequences.")
Fig. 4. Thyroid hormone pathway.
Because of inorganic iodine release, or for other reasons, amiodarone can cause hypothyroidism or hyperthyroidism. Hypothyroidism has an incidence rate of about 2 to 4% (2) and is best managed by dose reduction or thyroid supplementation.
Hyperthyroidism has an incidence rate of about 2%, however the incidence may be higher among patients with prior inadequate dietary iodine intake. If a patient is somewhat proptotic and on amiodarone, hyperthyroidism should always be considered as a possible side-effect. Treatment involves a reduction in amiodarone dosage.
Anti-Anginal Agents: Diltiazem (Cardizem®), Nifedipine [30 and 77 for different generics] (Adalat®, Procardia®), Verapamil [19] (Calan®)
Fig. 5. Calan® sustained release 240 mg tablets.
These agents are used in the treatment of vasospastic and chronic stable angina, hypertension, and supraventricular tachyarrhythmias. Ocular side-effects include decreased vision, photosensitivity, and visual hallucinations. Periorbital edema and lacrimation can also occur. Eyelids and conjunctiva can demonstrate chemosis, erythema, non-specific conjunctivitis, angioneurotic edema, urticaria, purpura, erythema multiforme, and subconjunctival hemorrhages secondary to drug-induced anemia.(1) Retinal hemorrhages can also occur secondary to drug-induced anemia.
Nifedipine can cause ocular pain. Rotary nystagmus and non-specific ocular irritation can also occur with nifedipine and verapamil use.
Intraocular pressure does not appear to be affected by calcium channel blockers. However, glaucoma patients may be more difficult to control if they are taking these agents.
Nifedipine has been reported to attenuate the intraocular response to intubation following succinylcholine administration.(1)
Anti-Anginal Drugs: Nitroglycerin [74] (Minitrin®, Nitro-BID®, Nitro-DUR®, Nitrolingual®, Nitrostat®)
These anti-anginal agents are short-acting trinitrate vasodilators that are effective in the treatment of acute angina pectoris attacks, reduction of attacks, or hypertensive urgency. They are usually given by systemic or sublingual administration.
Fortunately, nitroglycerin rarely produces ocular side-effects. Oral administration produces few or no visual side-effects, but sublingual administration may cause transient visual blurring.(13) If side-effects do occur, they can include decreased vision, variable IOP, vasodilation of the conjunctiva or retina, colored haloes around lights, exfoliative dermatitis around the eyelids, papilledema secondary to pseudotumor cerebri, and hallucinations.
Digitalis Drugs: Digitalis Glycosides[13] (Digitoxin®, Digoxin®, Lanoxin®)
Fig. 6. Lanoxin® tablets.
Digitalis is the 13th most commonly prescribed drug in the US, and is used for congestive heart failure and certain arrhythmias. Ocular side-effects occur in 11 to 25% of patients.(1) They can include blue-yellow color vision defects, abnormal visual sensations, and scotomas.(13)
Digoxin® is well known to have a low safety profile with a therapeutic index of 5, so toxicity can commonly occur. One of the first signs of Digoxin® toxicity is yellow-blue axis color vision changes. In one study, 805 of patients on digitalis had generalized color vision disturbances.(4)
IOP can be decreased by Digitoxin®. The endothelial ion pump (sodium-potassium adenosine triphosphatase) is inhibited by Digoxin® and other cardiac glycosides. Thus, corneal edema may occur.
In addition to other side-effects, some patients taking digitalis may complain of pain on eye movement.
Nearly all the ocular side-effects caused by digitalis are reversible.
ACE Inhibitors: Captopril (Capoten®), Enalapril (Vasotec®)
Fig. 7. Vasotec® tablets.
ACE inhibitors are used for the management of hypertension, diabetic nephropathy, and congestive heart failure. Ocular side-effects may include decreased vision, conjunctivitis, photosensitivity, visual hallucinations, and subconjunctival or retinal hemorrhages secondary to drug-induced anemia. Eyelids also may have angioneurotic edema, brown discoloration, blepharoconjunctivitis, urticaria, lupoid syndrome, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, or pemphigoid lesion.(1)
ACE inhibitors a much higher probibility than most drugs of causing angioedema involving the eye and the orbit, but the incidence is still less than 1 to 2%.(2) Angioneurotic edema usually occurs within weeks of starting the drugs, but it can occur 3 to 4 years after initial drug exposure.
These drugs may or may not be associated with facial urticaria. Conjunctivitis has also been reported, but photosensitivity is rare.
Beta-blockers: Atenolol [7], Metaprolol [27] Lopressor® [43], and Propanolol [102] Inderal® [154])
Fig. 8. Inderal® tablets.
Beta-blockers are some of the most frequently prescribed medications. They are used for hypertension, reducing mortality in unstable patients after a myocardial infarction, long-term management of angina, arrhythemia (e.g., atrial fibrillation) reduction, symptomatic hyperthyroidism, and migraine prophylaxis. Ocular side-effects produced by beta-blockers can include reduced tear secretion producing a sicca-like syndrome, reduced perfusion of the optic nerve head causing possible progression of glaucoma, and decreased intraocular pressure.(1) Changes in vision are the 5th most common complaint associated with beta-blocker use.
Calcium Channel Blockers: Amlopidipine Besylate (Norvasc® [9])
Fig. 9. Norvasc® tablets.
The calcium channel blocker Norvasc® is very commonly used to treat hypertension and angina. It is number 9 on the list of most commonly prescribed legend medications. Ocular side-effects can include decreased vision, conjunctivitis, photosensitivity reactions, visual hallucinations, and subconjunctival and retinal hemorrhages. Fortunately, these side-effects occur in less than 1% of patients taking calcium channel blockers.(2)
Anticoagulants: Warfarin [24] (Coumadin® [99])
Fig. 10. Coumadin® tablets.
Warfarin is the 24th most commonly prescribed generic drug in the United States. This drug is indicated for prevention of clot formation including in patients with atrial fibrillation and for treatment of thrombosis. It has a low safety profile so toxicity is very possible.(13)
Ocular side-effects are uncommon, however massive retinal hemorrhages have been reported. These hemorrhages are more likely to occur in patients with diseased tissue and capillary fragility such as macular disciform degeneration in age-related macular degeneration.(1)
Hypolipidemia Agents: Atorvastin calcium (Lipitor® [1])
Lipitor® is currently the most commonly prescribed brand name drug in the United States. It is used as a lipid-lowering agent. Ocular side-effects occur in less than 2% of patients taking Lipitor®(2) but include dry eye, blurred vision, hemorrhages, and increased intraocular pressure. Early research suggested a possible cataract induction risk with Lipitor®, but this risk has not been substantiated.(2-15)
Peripheral Vasodilators: Niacin (Advicor®, Niaspan® [177])
Fig. 11. Time release OTC niacin.
This medication is used in the treatment of hyperlipidemia.
It has been known to cause cystoid macular edema (CME) in patients taking at least 3 g/day, but this condition has also been reported in patients taking as little as 1.5 g/day.(16) Drug-induced CME occurs most commonly in men in between 30 to 50 years of age and usually disappears when the drug is discontinued. Transient visual loss can also occur and is more common in males.(1) The visual loss usually disappears within 24 to 48 hours after the medication is discontinued. There are reports of vision loss occurring within 1 to 2 hours after taking niacin. This side-effect appears to be dose-related.
Niacin is secreted in the tears, and it sometimes aggravates patients with sicca like problems.(1)
(Click here to return to Drug Category List)
Psychotropic Drugs: Chlorpromazine (Thorazine®), Fluphenazine (Prolixin®), Thioridazine (Mellaril®), Prochlorperazine (Compazine®)
Fig. 12. Mellaril® tablets.
These medications are used to treat various forms of psychosis as well as various forms of schizophrenia.(13) Prochlorperazine is also used and an antiemetic. They can cause a variety of ocular side-effects including decreased vision, accommodation problems, color vision changes, corneal deposits, pupil size changes, retinal defects, visual field loss, lenticular changes, visual hallucinations, lacrimal problems, eyelid or conjunctival changes, and extraocular muscle difficulties.
Chlorpromazine is probably the most well known drug in this category and is cited in over 10,000 literature publications. The overall rate of side-effects for chlorpromazine is 3% with the most common problem being decreased vision, probably due to anticholinergic effect on the accommodative system.
Chlorpromazine is the phenothiazine most likely to cause pigmentary deposits in or on the eye. Deposits are often first seen on the lens surface of the pupillary aperture and later near Descemet’s membrane. Pigmentary changes on the cornea are reversible, but lens deposits may be permanent.
Retinal pigmentary changes are most frequently associated with Mellaril® use. This side-effect is considered dose-related and is seldom seen at recommended dosages.(1) Typically, patients taking this medication are told to avoid bright lights.
Anticonvulsants: Gabapentin (Neurontin® [11]), Topiramate (Topamax® [46]), Lamotrigine (Lamictal® [71])
Fig. 13. Neurontin® capsules.
Neurontin® is commonly prescribed for epilepsy, neuropathic pain, and post-herpetic neuralgia. The exact mechanism of action for this drug is open to debate.
Visual disturbances may occur as a side-effect within a few days of starting Neurontin®, but patients often improve within 7-10 days while still on the usual dosage.
Eight to 11% of patients taking Neurontin® complain of nystagmus and 6% report diplopia. There are also reports of macular edema, optic neuritis and visual field changes associated with this drug, however field changes have not been confirmed.(1)
Topamax® is a relatively new medication that can be used as an anti-epileptic agent. It apparently enhances the action of GABA, an inhibitory neurotransmitter that normally blocks transmission of neural impulses from one cell to another.(14) The mechanism of action is thought to be chemically similar to the function of carbonic anhydrase inhibitors (CAIs).
CAIs have been associated with an acute onset of myopia presumably due to ciliary body edema, which causes zonule relaxation and an induced myopic shift.(17)
Kambi, et al. noted in the Archives of Ophthalmology that a group of 19 patients who reported ocular side-effects while taking Topamax® experienced headaches, eye pain, and decrease acuity, most of which occurred within one month of starting the medication.(23)
Topamax® can also affect intraocular pressure. Ultrasonography has shown choroidal effusion, ciliochoroidal detachments and ciliary body edema in some patients. This could lead to an anterior displacement of the lens and iris causing a shallow anterior chamber and blocking intraocular fluid drainage. Angle closures episodes occurring in patients taking Topamax® do not appear to be related to pupillary block and therefore may not be responsive to laser iridotomy. Treatment for patients with high IOPs should include promptly discontinuing Topamax®. Use of cycloplegia and topical steroids along with IOP lowering medications may be necessary.
Lamictal® is an antiepileptic drug thought to suppress seizures by inhibiting the release of excitatory neurotransmitters. This drug is often used as an add-on when the initially prescribed anti-epileptic drug is not effective enough. Clinical trials have shown that at least 40% of the side-effects caused by Lamictal® were ocular.(18) Diplopia comprised 22% of the complaints, 15% of patients had blurred vision, and about 5% reported nystagmus. A few patients also had ptosis, hallucinations, and pigmentary retinal defects.(1)
Antidepressants: Fluoxetine hydrochloride [1] (Prozac® [79], Sertraline (Zoloft® [6])
Fig. 14. Prozac® capsules.
Fluoxetine hydrochloride is the most commonly prescribed generic medication in the United States. It is a selective inhibitor of serotonin re-uptake and is commonly used as an antidepressant. It is also prescribed for obsessive-compulsive disorders, pre-menstrual syndrome, and bulimia nervosa.
Ocular side-effects include blurred vision (3%), mydriasis, photophobia, keratitis sicca, conjunctivitis, diplopia, unilateral ptosis, eyelid changes, and increased eye movements during sleep. These eye movements can persist for up to 19 months after the drug is discontinued (1) and can be disturbing to the patient.
Fig. 15. Zoloft® tablets.
Zoloft® is a very commonly prescribed antidepressant used for obsessive-compulsive disorder, depression, and pre-menstrual syndrome. Ocular side-effects include eye pain, conjunctivitis, and accommodation problems.(2)
Anti-anxiety Agents: Alprozolam (Xanax® [43])
Fig. 16. Xanax® tablets.
Xanax® is indicated for treatment of anxiety and panic disorder. Ocular side-effects include decreased corneal reflex, conjunctivitis, decreased accommodation, reduced depth perception, abnormal extraocular muscle movements, diplopia, and increased phorias.(1) Other side-effects include blurred vision, burning, tearing, and foreign body sensation. These side-effects seldom have clinical importance, and all seem to be reversible.
A significant number of patients with diplopia have been noted, possibly due to an increase in phorias beyond the point at which the patients could sustain single vision.
Xanax® and the other anti-anxiety agents can produce conjunctivitis because they have a common metabolite, desmethyldiazepam. This substance can act as a primary antigen and probably causes an allergic conjunctivitis, type I hypersensitivity reaction. If it occurs, the conjunctivitis usually begins about 30 minutes after taking the drug, peaks within 4 hours, and subsides in 1 to 2 days.
(Click here to return to Drug Category List)
Acne Agents: Accutane®
Fig. 17. Accutane®.
Accutane® is used to treat severe, recalcitrant nodular acne that is unresponsive to conventional therapy, which typically includes systemic antibiotics.
Ocular side-effects of Accutane® are dose related and include blepharoconjunctivitis, dry eyes, and transient blurred vision. Acute transient refractive changes, generally toward myopia, have also been reported.
Accutane® is secreted in the tears via the lacrimal gland, and this often causes irritation including a drug-induced conjunctivitis with corneal irritation. This side-effect may be related to isotrentinoin's ability to decrease meibomian gland function, which results in increased tear evaporation and osmolarity.(1) Approximately 20% of previously successful contact lens wearers who start taking Accutane® will be affected; some may need to discontinue contact lens wear, others can have decreased lens wearing times, and still others will need additional preservative-free lubricating eye drops while wearing their lenses.
Retinal dysfunction can occur, probably due to competition for binding sites between retinoic acid and retinol (vitamin A). The risk that photosensitizing drugs such as Accutane® can enhance the deleterious effects of light on the macular and other retinal areas is uncertain but of concern.
There are also well-documented cases of decreased ability to see at night occurring as early as a few weeks or as late as 1 to 2 years after beginning Accutane® use. This may be a permanent effect.(1)
Optic neuritis has also been reported in patients shortly after starting isotrentinoin therapy.(14) This is possibly related to concomitant tetracycline use, which should be avoided.
If papilledema or visual disturbances along with headaches, nausea, and vomiting occur, the patient should be referred to a neurologist and Accutane® therapy discontinued.(14)
(Click here to return to Drug Category List)
Synthetic thyroid hormones: Levothyroxin (Synthryoid® [42], Levoxyl®, Levothyroid®)
Fig. 18. Synthroid® tablets.
Synthetic thyroid hormones are used in replacement therapy for thyroid deficiencies such as hypothyroidism and simple goiter.
Dry eyes are a very common side-effect of synthetic thyroid use.(15) Serious adverse central nervous system (CNS) effects including psychosis with hallucinations have also occurred soon after initiation of thyroid replacement therapy in patients with underlying psychiatric disorders.
Pre-puberty and peripuberty hypothyroid children may be susceptible to pseudotumor cerebri when given this class of drugs.(14) Generally, all symptoms resolve within a few months after discontinuing the medication.
With excess thyroid hormone intake, symptoms of a myasthenia-like nature including diplopia, ptosis, and paralysis of extraocular muscles may emerge.(15)
Adrenal Corticosteroids: Beclomethasone (Beclomethasone®), Hydrocortisone (Acticort®), Methylprednisolone [76] (Solu-Medrol®), Prednisone (Deltasone® [4])
Systemic corticosteroids are used in replacement therapy for adrenocortical insufficiency as well as in the treatment of inflammatory and allergic disorders.
Ocular side-effects of systemic steroid use include posterior subcapsular cataracts, increased intraocular pressure, decreased resistance to infection, mydriasis, possible precipitation of narrow-angle glaucoma, papilledema secondary to pseudotumor cerebri, and delayed corneal wound healing.
One large study of the elderly showed that oral and nasal spray steroid use caused a statistically significant increase in the rate of cataract surgeries.
(Click here to return to Drug Category List)
Omeprazole [122] (Prilosec® [3])
Fig. 19. Prilosec® OTC.
Prilosec is the 3rd most commonly prescribed brand name medication in the United States and was recently released as an over-the-counter drug. This medication is used for the short-term treatment of active benign gastric ulcers, active duodenal ulcers, erosive esophagitis, symptomatic gastric esophageal reflux disease (GERD), pathological hypersecretion states, prevention of stress-related gastris, and for triple therapy in combination with amoxicillin and clarithyromycin for H. pylori eradication in duodenal ulcer disease.(2)
Ocular side-effects include visual hallucinations and vertigo, which occur in less than 1% of patients.(14)
(Click here to return to Drug Category List)
Chloroquine (Aralens®), Hydroxychloroquine [69] (Plaquenil®)
Fig. 20. Plaquenil® tablets.
These aminoquinolines are used in the treatment of malaria and extraintestinal amebiasis. They are also commonly used in the treatment of rheumatoid arthritis and lupus erythematosus.
Ocular side-effects can be numerous including an enhanced Hudson-Stahli line, transient edema, decreased sensitivity, retina parafoveal granularity of RPE (early), Bull’s-eye appearance of the macula (late), attenuation of the vascular tree, peripheral fine granular pigmentary changes, prominent choroidal pattern filing defects (late phase), and other angiography changes.(1) Patients may have abnormal sensory testing responses and distorted color vision (late phase) with a yellow, green, or blue tinge to objects, and colored haloes around lights.
The drugs are found excreted in the tear film and can aggravate dry eye along with possibly decreasing contact lens tolerance. They can also cause decreased accommodation and visual field defects.
For patients taking antimalarial drugs, the American Academy of Ophthalmology (2002) recommends baseline dilated fundus exams and testing the central visual field by Amsler grid or a central 10 degree field using automated field testing. Ideally, these tests should be done before starting the antimalarial mediations (or at the latest within one year after starting the medications). Low risk patients are considered to be those taking less than 6.5 mg/kg/day for less than 5 years. These patients should have a follow up exam every 5 years. Higher risk patients, such as those taking over 6.5 mg/kg/day for more than 5 years should be examined more frequently. Risk factors such being over 60 years of age, or having a high body fat level, concomitant kidney or liver disease, and/or concomitant retinal disease also justify more frequent exams.(19)
Quinine [154] (Quindan®)
Quinine is used to treat nocturnal leg cramps, and, less commonly, as an anti-malarial agent. Side-effects are being reported more frequently because quinine is often used in diluents for street drugs and as a method to terminate pregnancy. These non-medical uses seldom cause ocular side-effects, except when toxic states are reached.
Ocular side-effects can include decreased vision, retinal changes, and optic nerve damage. The etiology of retinal changes involves not only an early effect on the outer layers of the retina and pigment epithelium, but also probably involves a direct effect on retinal ganglion cells and optic nerve fibers.(1) Low doses of quinine rarely cause hypersensitivity reactions, even when given long-term.
With massive doses, vision loss may be sudden or progress over a number of hours to days. The worst overdose cases have involved retinal arteriolar constriction, venous congestion, along with pronounced retinal and papillary edema. Although it rarely occurs, irreversible vision loss may occur.(1) Most patients have some return of vision, even in the most severe cases of drug overdose.
(Click here to return to Drug Category List)
Didanosine [Videx®]
Fig. 21. Videx tablets.
Videx is a purine analogue anti-retrovirus agent that is a used to treat HIV-related infections. Ocular side-effects include retinal changes such as RPE mottling and atrophy, night blindness, and optic neuritis.(1)
Whitcup, et al. reported retinal toxicity associated with didanosine in 43 children.(20) Three children developed peripheral retinal pigment epithelial atrophy. The ocular side-effects appeared to be dose related and are generally not found in adults. However, one-third of patients have been found to have systemic peripheral neuropathy, which tends to occur within a few weeks of beginning therapy.(1) Treatment involves discontinuing drug use.
Zidovudine (Retrovir®), Abacavir/lamivudine/zidovudine (Trizivir® [103]), Lamivudine/zidovudine (Combivir® [63])
Zidovudine and the HIV combination drugs have been known to cause cystoid macular edema, hypertrichosis, and color vision abnormalities, along with urticaria, rashes, and vasculitis of the eyelids. Overdoses can cause eyelid and conjunctival hyperpigmentation, diplopia, visual hallucinations, and nystagmus.(21)
(Click here to return to Drug Category List)
Ethambutol (Myambutol®)
Ethambutol is an effective treatment for tuberculosis. It can cause a multitude of dose- and time-dependent ocular side-effects including color vision changes, visual field defects, and either unilateral or bilateral optic neuritis.(13)
The incidence of side-effects is about 1% at normal dosages and 18% after 2 months on 35 mg/kg/day.(1) A 5 to 6% side-effect incidence occurs with a dose level of 25 mg/kg/day. The side-effect incidence is higher in patients with renal disease, diabetes, drug-induced peripheral neuropathy, low plasma zinc levels, and in very young or very old patients. Onset of side-effects usually occurs about 2 months after the onset of therapy. However, rare idiosyncratic toxicity has occurred at low dosages within 6 days of starting therapy.
A gradual decrease in central visual acuity and a green-red color vision problem (or less commonly blue-yellow color vision defects) have been reported. These defects continue to progress for 1 to 2 months after the drug is discontinued. Over 200 well-documented cases of permanent vision loss caused by ethambutol exist in the registry of drug-induced side-effects.(1)
Isoniazid (INH®)
Isoniazid appears to be quite effective against M. tuberculosis and is considered the drug of choice for initial treatment. However, INH® can induce optic neuropathies.(24)
Honegger and Gene found that one-third of patients on isoniazid had some sort of accommodation impairment that was transient and reversible(25). Side-effects caused by INH® tend to be less severe than those produced by ethambutol.(1)
(Click here to return to Drug Category List)
Indomethacin [Indocin®]
Fig. 22. Indocin® capsules.
Indocin® is used for moderate to severe rheumatoid arthritis, osteoarthritis, anklyosing spondylitis, acute painful shoulder, and gouty arthritis. Indocin® is also used for muscle inflammation, joint pain, and menstrual cramps.
Indocin® can cause numerous ocular side-effects including transient blurred vision, corneal toxicity (11 to 16% of patients), optic neuritis and pseudotumor cerebri.(1) Since this medication can also be a photosensitizer with an adverse effect on the macula, UV protection is recommended for patients taking Indocin®.
(Click here to return to Drug Category List)
Aledronate (Fosamax® [23]), Pamidronate sodium (Aredia®)
Fig. 23. Fosamax® tablets.
These are commonly prescribed medications for osteoporosis and for management of hypercalcemia of malignancy, metastatic bone pain, and Paget’s bone disease.(13) Ocular side-effects include blurred vision, conjunctival irritation with a burning sensation or gritty sensation and/or increased lacrimation, hyperemia, ocular pain, anterior uveitis, episcleritis, and scleritis.
In the drug side-effects registry, there are reports that anterior uveitis occurred within 24 to 48 hours of exposure to Fosamax®, with 6 out of 7 cases being bilateral.(1) Five cases were re-challenged and in four cases bilateral uveitis recurred.
Episcleritis or scleritis have been reported to occur within 3 to 6 days of exposure to Fosamax®. Conjunctivitis that occurred as a result of Fosamax® use was non-specific and transient. The mechanism of action is unknown, but biphosphonates are high molecular weight drugs that can cause a potential immune complex formation. The drugs may be secreted by the lacrimal gland, thus causing transient irritation to mucus membranes.(1)
Patients with conjunctivitis, episcleritis, and uveitis were able to continue the drug(21), but scleritis only resolved with discontinuation of the drug.(22) Check patients taking Fosamax® for ocular side-effects every six months or possibly more frequently.
(Click here to return to Drug Category List)
Orphenadrine (Norflex®), Benztropine (Cogentin® [194]), Baclofen® [104]
These agents are used in the treatment of skeletal muscle spasms and associated Parkinsonian pain. The ocular side-effects include mydriasis, decreased vision, decrease or paralysis of accommodation, diplopia, visual hallucinations, subconjunctival or retinal hemorrhages secondary to drug-induced anemia, and decreased tolerance to contact lenses.(1) These effects are transient, probably resulting from weak anticholinergic effects of the drugs. They are seldom a significant clinical problem. However, taking these medications could force a pre-presbyope into needing an add. The drugs can also precipitate narrow angle glaucoma.(13)
(Click here to return to Drug Category List)
Tamoxifen [13] (Novaldex®), Methotrexate [50] (Mexate®)
Tamoxifen is an anti-estrogen agent primarily used in the treatment of estrogen-receptive positive breast cancer, ovarian cancer, pancreatic cancer, and malignant melanoma. Dose-dependent ocular side-effects include corneal opacities (whorl-like subepithelial calcium map-dot changes), and retinal or macular yellow or white refractile opacities, edema, degeneration, pigmentary changes and hemorrhages.(1)
Retinal and corneal findings were more common at dosages of 180 mg/day. The standard dosage is now 20 mg/day or less, and the ocular side-effect incidence levels are around 1 to 2%.
Ocular side-effects seem to take two forms, one acute and the other chronic. The acute form is not well defined and usually occurs within a few weeks after therapy is instituted. Symptoms include vision loss, retinal edema, retinal hemorrhage, and optic disc swelling. It is thought to result from tamoxifen estrogenic activity, which may cause venous thromboembolism.
Typical tamoxifen retinopathy most commonly occurs after more than one year of therapy when a total of more than 100 grams of the drug have been taken. The retinopathy can include cystoid macular edema, punctuate macular retinal pigment epithelial changes, parafoveal hemorrhages, and peripheral RPE changes. Refractile bodies are located in the inner retina histologically may be the products of axonal degeneration. These lesions do not appear to regress if the drug is discontinued.
Visual acuity loss in the chronic side-effect form is often progressive, dose dependent and irreversible unless cystoid macular edema or hemorrhages are the cause of vision loss. Corneal deposits are seldom clinically significant and are usually reversible.
When retinal crystals are present, the patient should be evaluated every three months and should see their oncologist on a regular basis. Significant color vision loss may provide valid grounds to consider discontinuing the drug. If the medication is stopped for 3 months and color vision returns to normal, Tamoxifen may be re-started. If there is no rebound or if the visual side-effects continue to progress, a substitute for Tamoxifen may need to be considered.
Fig. 24. Methotrexate tablets.
Methotrexate is a folic acid antagonist used in the treatment of diseases such as rheumatoid arthritis, psoriasis, and uveitis. The drug is commonly found to cause ocular side-effects in up to 25% of patients.(1) Many of the patients taking this drug will develop one or more of the following ocular problems: blepharitis, periorbital edema, conjunctival hyperemia, and increased tearing or photophobia. The drug is found in the tears and may cause ocular irritation, thus interfering with corneal and conjunctival epithelial metabolism.(1)
Interferon [Intron A®]
This medication is used for a variety of diseases, especially hepatitis C and malignancies. Ocular side-effects potentially include decreased vision, ocular pain, conjunctivitis, retinal changes and optic neuritis. These side-effects can be significantly increased in diabetics and hypertensives, especially when higher dosages are used.
Side-effects may occur within 15 minutes of the first exposure or may not appear for many months. Transiently decreased vision can occur after each exposure. Patients may often be subjectively aware of this and should be informed in advance about this potential side-effect. Some patients experience intense ocular or orbital pain, but the cause it unknown.
Conjunctivitis is a well-documented side-effect occurring about 4% of patients taking interferon.(14) Eyelash growth from 2.0 to 6.5 cm in length can also occur.
If they are going to occur, retinal changes characteristically are found between 2 weeks and 3 months after drug therapy is started. They may spontaneously regress while the patient is still on the drug or may require discontinuation of the drug. Retinal ischemic changes in both large vessels and in capillaries can occur in normal patients as shown by fluorescein angiography.(1)
Retinal capillary non-perfusion and/or cotton wool spots due to vascular occlusions may occur, but surprisingly good central vision remains. Only a small percentage of patients have permanent changes. The mechanism of action is unknown.
It is generally recommended that a retinal exam be performed prior to starting interferon therapy. The patient should be followed on a monthly basis if retinal problems occur. There have been 11 documented cases of optic neuritis in patients taking interferon.(1)
Cyclophosphamide [Cytoxan®]
Cytoxan® is used as a chemotherapeutic agent used for cancer patients and as an anti-rejection medication for organ transplant recipients.(27) This is a lesser known medication but notorious for causing dry eye. Therapy can include artificial tears, punctual plugs, and nutritional therapy as well as alteration of the patient’s environment.
Radiation
Radiation is indicated for treatment for malignancy as a primary or adjuvant therapy. Radiation impairs cells’ ability to survive by targeting their DNA. Many different ocular side-effects can occur as result of radiation therapy including trichiasis, epiphora, ectropion, nasolacrimal duct obstruction, dry eye (61% of patients), iritis, cataract, and radiation retinopathy.(26) Radiation retinopathy clinically appears as capillary nonperfusion, telangectasias, intraretinal hemorrhages, microaneurysms, retinal NFL infarcts, exudates, retinal and optic nerve head neovascularization, iris, and angle neovascularization.(26) Clinically significant macular edema and radiation optic neuropathy also can occur.
Fig. 25. Trichiasis.
Fig. 26. Ectropion.
Radiation side-effects tend to be progressive and may occur years after treatment. Incidence increases with total radiation dosage. Routine examinations are imperative for patients with radiation therapy treatment histories.
(Click here to return to Drug Category List)
Hormone replacement therapy: Premarin® (28), Prempro® (48)
Fig. 27. Premarin®.
Hormone replacement therapy (HRT) usually involves an estrogen-type drug combined with a progesterone-type drug. In some cases an estrogen-type drug alone is prescribed. These drugs are used to reduce hot flashes, vaginal dryness, and possibly osteoporosis. Hormone receptor sites are located on meibomian glands(27), and physiologic or chemical variations in hormones can affect these glands. Thus, the tear film can be altered, often contributing to dry eye. Corneal steepening and intolerance to contact lenses are also some of the more common adverse symptoms of hormone replacement therapy. In rare cases, pseudotumor cerebri can also occur as a result of HRT.
Fig. 28. Pseudotumor cerebri as a side-effect of HRT.
Approximately 8% of women in the US over age over the age of 50 years suffer from dry eye syndrome.(27) In addition, Hispanic and Asian women are more likely to experience severe symptoms, but are less likely to be clinical diagnosed with dry eye.(28) Researchers from Brigham and Women’s Hospital in Boston found a 69% increase in dry eye symptoms among patients taking estrogen versus patients not on HRT.(28) Treatment of dry eye symptoms includes artificial tears, punctual plugs, and increasing daily water intake.
Estrogen and progestrogens: Orthocyclen® [162], Orthonovum® [157], Mircette® [196], Medroxy progesterone [94] (Provera®)
These hormones are commonly used for birth control, treatment of amenorrhea, and premenstrual tension. The ocular side-effects are very similar to those for HRT. They consist of decreased vision, retinal vascular disorders, pseudotumor cerebri, and decreased tolerance to contact lenses.(14)
(Click here to return to Drug Category List)
Ibuprofen [31] (Advil®)
Fig. 29. Advil®.
Advil® is used for the treatment of rheumatoid arthritis, osteoarthritis, aches, pains, and fevers. The most common side-effect associated with this medication is transient blurred vision. In a drug re-challenge test, there were also documented reports of refractive error changes, diplopia, photophobia, dry eyes, visual field changes, and altered color vision.(1) Dry eye symptoms probably occur because the drug is secreted in the tears and aggravates previously existing dry eyes. If they occur, vision changes usually resolve after 1-3 months, but color vision problems can take up to 8 months to resolve.
Corneal vortex keratopathy, which generally resolves within 3 weeks, has been documented(1), and reversible toxic amblyopia is rare but a real side-effect.
There are also a few reports of a rare, idiosyncratic, unilateral or bilateral optic nerve response that can reduce acuity to between 20/80 and 20/200.(1) This usually occurrs within a few months of starting therapy.
There are rare cases of CNS changes, such as aseptic meningitis, with secondary effects on the visual system. Three cases of macular edema from long-term ibuprofen use have been documented.(1) Advil®, like other anti-inflammatory medications, can also cause pseudotumor cerebri. In these cases, the drug must be discontinued because permanent vision loss can occur.
Hydrocodone [2] (Tussionex® [184], Vicoprofin® [198])
Hydrocodone is a powerful pain reduction medication that can cause miosis.(15) The effect is transient and completely reversible when the drug is discontinued.
(Click here to return to Drug Category List)
Aspirin [Bufferin®]
Fig. 30. Bufferin®.
Ocular side-effects associated with aspirin use are rare. However, this drug is secreted in tears so transient blurred vision can occur along with aggravation of dry eyes and keratitis. These symptoms can be idiosyncratic or hypersensitive. Also, aspirin can increase bleeding problems including subconjunctival hemorrhages or retinal bleeds following surgery.(15)
(Click here to return to Drug Category List)
Methadone [Dolophine®]
Fig. 31. Methadone.
Methadone can be used for the treatment of chronic pain conditions and as maintenance therapy for narcotic addicts. Methadone seldom causes significant ocular side-effects, but rare side-effects could include decreased vision, pupillary changes (miosis in toxic states and mydriasis in withdrawal states), and talc retinopathy caused by contamination of methodone used by addicts who intravenously inject their oral medications.(1)
(Click here to return to Drug Category List)
Albuterol [4] (Albuterol nebulizer® [13], Combivent® [93], Proventil®, Ventolin®)
Fig. 32. Albuterol inhaler.
These medications are used for bronchodilation and symptomatic relief of bronchospasm. Ocular side-effects rarely occur but could include decreased vision and mydriasis. There have been reports of vivid visual hallucinations lasting approximately one hour caused by these drugs.(1)
The drugs can also cause chronic conjunctival hyperemia and chemosis due to blood vessel dilation. Patients often have petechial conjunctival hemorrhages due to inhaler use.
Sildenafil citrate (Viagra® [32])
Fig. 33. Viagra® tablets.
Used in the treatment of erectile dysfunction, Viagra® inhibits phosphodiesterase-5 (PDE-5), which is responsible for the degradation of cyclic GMP in the corpus cavernosum.(14) By increasing levels of cGMP, smooth muscles in the corpus cavernosum are relaxed, allowing blood inflow.
The occurance of ocular side-effects may be due to the fact that PDE-5 is involved in light excitation of visual cells. Ocular side-effects include a bluish tinge to the visual field, hypersensitivity to light, and hazy vision. These effects are reversible and may last only a few minutes or hours. It has been reported that only 3% of patients have visual side-effects with the standard 50 milligram dose.(29)
Sponsel, et al. found a 29% increase in pulsatile ocular blood flow and a 34% increase in contrast sensitivity occurred approximately 110 minutes after Viagra® ingestion.(29) Retinal microcirculation also increased 8% in about 80% of patients. The authors attributed these findings to choroidal vessel dilation.
With increased dosage, the ocular side-effect incidence rate significantly increases. There is a 40% incidence rate reported for a 200 mg dosage (this is double the recommended maximum 100 mg dose). Retinitis pigmentosa patients may also have increased side-effects caused by Viagra® use.
Five cases of anterior ischemic optic neuropathy (AION) have been associated with Viagra®.(30) They have not been proven to be drug related, however Viagra® may be associated with NAION. A small cup-to disc ratio may be a risk factor for the development of NAION in association with the use of sildenafil.(30)
(Click here to return to Drug Category List)
In conclusion, it is important to be aware of the potentially vision and ocular damaging side-effects associated with commonly prescribed systemic medications. When side-effects do occur, it is necessary to pursue appropriate treatment or medication discontinuation through the patient's primary care provider. In this way, the best and most comprehensive eye care possible can be provided for each patient.
1. Fraunfelder, FT, Fraunfelder FW. Drug-Induced Ocular Side effects. Fifth edition. Butterworth Heinemann. Boston: 2001.
2. Up-To-Date online reference. www.uptodate.com.
3. Romero, JM. Amiodarone Optic neuropathy. NY eye and ear infirmary case presentation. 9-17-1999.
4. Castells, DD, Teitelbaum, BA, Tresley DJ. Visual changes secondary to initiation of amiodarone: a case report and review involving ocular management in cardiac polypharmacy. Optometry. 2002 Feb; 73 (2): 113-21. Review.
5. Mindel JM. Editorial: amiodarone and optic neuropathy - a medicolegal issue. Surv Ophthalmol 1998;42(4):358-9.
6. Latini R, Tognoni G, Kates RE. Clinical pharmacokinetics of amiodarone. Clin Pharmacokinet 1984;9:136-56.
7. Feiner LA, Younge BR, Kazmier FJ, Stricker BH, Fraunfelder FT. Optic neuropathy and amiodarone therapy. Mayo Clin Proc 1987;62:702-17.
8. Mindel JS. Ocular side effects of amiodarone. Surv Ophthalmol 1998;42:360-6.
9. Borruat F, Regli F. Pseudotumor cerebri as a complication of amiodarone therapy. Am J Ophthalmol 1993;116:776-7.
10. Seemongal-Dass RR, Spencer SR. Bilateral optic neuropathy linked with amiodarone. Eye 1998;12(Pt 3a):474-7.
11. Gittinger JW, Asdourian GK. Papillopathy caused by amiodarone. Arch Ophthalmol 1987;105:349-51.
12. Macaluso DC, Shults WT, Fraunfelder FT. Features of amiodarone-induced optic neuropathy. Am J Ophthalmol 1999;127(5):610-2.
13. PDR: Pocket guide to prescription Drugs. 6th edition. Pocket Books. New York. 2003.
14. Monthly Prescribing Reference. Jeanette Murphy et al. (editor). Prescribing Reference, Inc. 2002. www.prescribingreference.com.
15. Lesher, G. Get side effect savvy. Optometric Management April 2003: 45-52.
16. Callahan, D. Niacin and Cystoid macular edema. JAMA 1998: 21:1702.
17. Angle-closure glaucoma associated with ciliary body detachment in patients using topiramate. Arch Ophthalmol. 2003 Feb;121(2):282-5.
18. Schacter, SD: A multicenter, placebo-controlled evaluation of the safety of lamotrigine (Lamictal) as an add-on therapy in outpatients with partial seizures. Presented at the 1992 Annual Meeting of the American Epilepsy Society, Seattle, December 4-10, 1992.
19. Arthritis & Rheumatism, Vol 48 No 6 June 2003 pg 1764
20. Whitcup, SM, et al: Retinal toxicity in human immunodeficiency virus-infected children treated with 2’,3’-dideoxyinosine. Am. J. Ophthalmol. 113:1-7, 1992.
21. Fraunfelder FW, Fraunfelder FT, Jensvold B. Scleritis and other ocular side effects associated with pamidrone disodium. Am J Ophthalmol 2003 Feb; 135 (2): 219-22.
22. Fraunfelder FW, Fraunfelder FT. Bisphosphonates and ocular inflammation. N Engl J Med. 2003 Mar 20; 348-(12):1187-8.
23. Kambi L, Kapcala LP, Chambers W, Mourjah P, Beitz J, Chen M, Lu S. Topiramate-associated secondary angle-closure glaucoma: A case series. Arch Ophthalmol 2002 Aug; 120 (8):1108.
24. Karmon, G, et al: Bilateral optiac neuropathy due to combined ethambutol and isoniazid treatment. Ann. Ophthalmology 11:1013, 1979.
25. Hongegger, H, Genee, E: Disturbances of accommodation in association with treatment with tuberculostatics. Klin. Monastbl. Augenheikld 155:361-380, 1969.]
26. Than, Tammy P. Ocular complications of cancer treatment: diagnosis and management. AAO lecture 2001.
27. Hoscheit, A. Patients’ meds affect comfort. Review of Optometry. Feb. 2003: 102-103.
28. Schaumberg DA, Buring JE, Sullivan DA, Dana MR. Hormone replacement therapy and dry eye syndrome. JAMA 2001 Nov 7: 286 (17):2114-9.
29. Sponsel W., Paris G, Sandoval S. etal. Sildenafil and ocular perfusion (letter), N Engl J Med 2000: 343:1680.
30. Pomeranz, Ha, Smith, KH, Hart, WM, Egan, RA. Sildenafil-associated nonarteritic anterior ischemic optic neuropathy. Ophthalmology 2002. 109:584-587.
Contact the Author:
Pacific University College of Optometry provides On-Line CE as a service to optometrists. The college does not endorse or recommend any products, equipment, or services that might be discussed in the courses. Courses are prepared by individuals believed to be experts in their areas of specialization who are compensated for their efforts. The College relies on their expertise to produce accurate and timely courses. Questions or concerns about courses should be directed to the individual authors and/or the Continuing Education Department at the College of Optometry at kundart@pacificu.edu .
© Copyright 2006,