Ocular Side Effects of Systemic Drugs

Cynthia Heard, O.D., F.A.A.O.

Southern College of Optometry
Associate Professor
901.722.3265
cheard@sco.edu

Commonly Reported Side Effects

 Abnormal vision
 Blurred vision
 Poor focusing ability
 Dry/irritated eyes
 Color perception changes
 Altered pupil size

How Do Systemic Drugs Enter the Eye?

 The eye, because of its rich blood supply and relatively small mass, exhibits an unusually high susceptibility
to toxic substances
 Drug molecules present in systemic circulation can reach the ocular structures by way of the uveal or retinal
vasculature

Determinants of Drug Reactions

 Amount of drug administered
 Nature of drug
 Route of administration
 Pathophysiologic variables
 Age and gender
 Multiple drug therapy – drug interactions
 History of allergies to drugs
 Individual idiosyncrasy

DRUGS WITH OCULAR SIDE EFFECTS

Digoxin (Cardiac Glycoside)
 Marketed as Lanoxin, Digoxin, Lanoxicaps, Digitex
 Prescribed for congestive heart failure and certain cardiac arrhythmias
 Visual symptoms
o Flickering or flashes of light or colored spots
o Snowy, hazy, or dimming of vision
o Reduction of IOP and decrease of aqueous humor
 Visual change is reversible

Amiodarone
 Marketed as Cordarone and Pacerone
 Benzofurane derivative used to treat variety of cardiac abnormalities (atrial, ventricular arrhymias and
Wolff-Parkinson-White syndrome
 Drug has amphiphilic properties that bind to polar lipids and accumulate within lysosomes. The presence
of these complex lipid deposits are thought to be a drug-induced lipid storage disease
 Can cause keratopathy (corneal verticillata) and anterior subcapsular lens opacities as early as 6 days
after drug initiation, but typically appears after 1-3 months of treatment
 Keratopathy resolves within 6-8 months after d/c of drug
 Severity of keratopathy appears to be dose related (100 –200 - mg/d minimal effect; 400 - 1,400 mg/d -
more advanced keratopathy)
 Amiodarone-induced lens deposits occur within the pupillary area and limited to the superficial anterior
subcapsular area
 Amiodarone-Induced Optic Neuropathy
o Most severe ocular SE occurring in 1.8% of patients

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 o Selective accumulation of inclusions in large optic nerve axons; may decrease axoplasmic flow
biochemically or mechanically resulting in optic nerve head edema
o Ocular SEs
 Photophobia in 57%, blue-green rings around lights, blurred vision, VF defects
o Other SEs
 Thyroid dysfunction by causing increased T4 levels and decreased T3 levels

Four stages of keratopathy

Grade I – Faint horizontal line appears in interpalpebral fissure at junction of middle and lower third of cornea.
It consists of golden brown microdeposits in the epithelium just anterior to Bowman’s layer
Grade II – Transition occurs by 6 months, during which time the deposits become aligned in more linear
pattern and extend toward limbus
Grade III – Deposits increase in number and density, and lines extend superiorly to produce a whorl-like
pattern into visual axis
Grade IV – Irregular, round clumps of deposits characterize this grade
Keratopathy resolves within 6-8 months after d/c of drug. Amiodarone-induced lens deposits occur within the
pupillary area and limited to the superficial anterior subcapsular area

Corticosteroids
 Many trade names—more common ones are Deltasone, Kenalog, Decadron, Dexasone, Pred-Pak
 Commonly prescribed for rheumatoid arthritis, lupus, and other immune-mediated diseases
 Taken at high doses (25-80 mg/d) for more than two years can lead to posterior subcapsular and nuclear
cataract formation (irreversible, but stable after discontinuation)
 Inhaled steroids have been associated with development of central serous choroidopathy. Macular
detachment can occur in susceptible individual

Aminoquinolines
 Chloroquine (Aralen) and hydroxychloroquine (Plaquenil) are used to treat rheumatoid arthritis, discoid
and systemic lupus erythematosus, other collagen diseases, and as an antimalarial
 Corneal opacities appear to represent binding of drug to intracellular nucleoproteins (limited to corneal
epithelium)
 Decrease in corneal sensation has been reported in 50% of those taking chloroquine
 Chloroquine may decrease accommodation
 Chloroquine may cause white, flakelike posterior subcapsular lens opacity
 State can exist in which the drug interferes with metabolism of macular tissues, causing relative VF
defects with normal-looking macula
 These drugs bind to melanin in the retina. This binding leads to degenerative changes (pigment
clumping) of the RPE and migration of pigment-laden cells from the RPE to the outer nuclear and outer
plexiform layers. Foveal cones are often spared leading to the “bull’s eye” appearance and
arteriole attenuation (late signs)
 Management should include monitor for fundus changes every 6-12 months (esp. age 65+). VF
(threshold) is the most sensitive way to monitor for retinal damage. Contrast sensitivity testing (esp.
<40 years) can be used to assess macular function. Color vision should also be assessed. Patient
should be instructed in use of Amsler grid for monthly self monitor
 In the US
o Incidence of retinopathy increased with both increased dose and duration of treatment
o Incidence of 10% in unmonitored patients taking 250mg/d of chloroquine
o Incidence of 3-4% in unmonitored patients taking 400mg/d of hydroxychloroquine
 Internationally incidence from 1-28%
 Recommended safe threshold dose
o 3.5 mg.kg/d of chloroquine
o 6.5 mg/kg/d of hydroxychloroquine

Isotretinoin (Accutane)
 Accutane Information Page
o http://www.fda.gov/cder/drug/infopage/accutane/default.htm

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 o Fraunfelder, FT, Fraunfelder, FW, Edwards, R: Ocular side effects possibly associated with
isotretinoin usage. Am J Ophthal. 2001;132 (3):299-305
 An analog of vitamin A (13-cis-retinoic acid) is used for control of severe recalcitrant cystic acne and
keratinizing dermatoses
 Average dose is 1-2 mg/kg body wt. Daily suppression of sebaceous gland activity, changes surface
lipid composition of the skin and inhibits keratinization
 Ocular side effects include meibomian gland dysfunction and atrophy, blepharoconjunctivitis, corneal
opacities, decreased dark adaptation, decreased tolerance to CL, decreased vision, increased tear
osmolarity, keratitis, myopia, ocular discomfort, ocular sicca, photophobia, teratogenic ocular
abnormalities, and possibly decreased color vision (reversible)

Phenothiazines
 Thioridazine (Mellaril) and Chlorpromazine (Thorazine) are psychotropic agents used to manage
depression with anxiety and other behavioral conditions
 Dose-dependent toxicity - 800 mg/d considered at risk
 Ocular side effects may include:
o Nyctalopia
o “Brown vision”
o Decreased vision
o Salt/pepper fundus leading to widespread loss of RPE and choriocapillaris

Tamoxifen Citrate (Nolvadex)

 Nonsteroidal antiestrogen agent is one of the most effective antitumor treatments of metastatic breast
carcinoma in postmenopausal women
 Normal dosage levels (20 mg/d) are unlikely to induce retinopathy. High dosages (90-120 mg bid) can
cause toxic effects in 17-27 months (total cumulative dose >90 g)
 Causes crystalline retinopathy

Agents for Erectile Dysfunction

Sildenafil Citrate (Viagra), Vardenafil (Levitra), & Tadalafil (Cialis)
 Potent inhibitors of cyclic guanosine monophosphate (cGMP)—phosphodiesterase type 5 (PDE 5).
 Effective treatment for erectile dysfunction. The drug enhances the effect of nitric oxide by inhibiting
PDE 5, which is responsible for degradation of cGMP in the corpus cavernosum. Increased levels of
cGMP result in smooth muscle relaxation and inflow of blood.
o These drug types have an affinity for PDE 6, enzyme found in retina (involved in retinal
phototransduction)
 Visual side effects
o Bluish color tinge to vision
o Increased light sensitivity
o Blurred vision
o Last several minutes to a few hours
o Some patients with retinitis pigmentosa (RP) have genetic disorders of retinal phosphodiesterases,
sildenafil should be used with caution
o Occur in 11% of men taking 100-mg doses
 All have been associated w/40+ cases of nonarteritic ischemic optic neuropathy (NAION)
 Leads to permanent vision loss
 All patients had at least one arteriosclerotic risk factor: HTN, DM, hypercholesterolemia, hyperlipidemia
 All patients had low cup-to-disk ratio
 “Disks at risk” are full disks with little to no cupping
Journal of Neuro-ophthalmology, Mar 2005

Cannabinoids
 Derivatives of marijuana plant, Cannabis sativa
 Smoking and ingesting marijuana reduces IOP (maximum effect 60-90 minutes after inhalation)
 Systemic side effects (postural hypotension, anxiety, drowsiness, euphoria, and hunger) make this
treatment unacceptable for glaucoma management

Antiseizure Agents
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 Anti-seizure/mood stabilizing indications
o Topiramate (Topamax) - Also prescribed off label for migraine headaches
 Enhances action of GABA, which is an inhibitory neurotransmitter. Mechanism of action thought
to be similar to carbonic anhydrase inhibitors
 Syndrome observed
 Acute myopia
 Secondary angle closure glaucoma due to anterior chamber shallowing
 Reported side effects are headaches, eye pain, and decreased acuity
 Ultrasonography has shown choroidal effusion, choroidal detachment, ciliary body edema,
which can cause anterior displacement of lens and iris leading to shallow anterior
chamber=angle closure=IOP increase
o Gabapentin (Neurontin) – also used for post-herpetic neuralgia and neuropathic pain
 Nystagmus in 8% to 11%
 Diplopia in 6%
 Also reports of macular edema, optic neuritis and VF defects
o Lamotrigine (Lamictal)
 Thought to inhibit release of excitatory neurotransmitters
 Clinical trials show that 40% of SEs are ocular
 Diplopia occurred in 22%
 Blurred vision in 15%
 Nystagmus in 5%

Bisphosphonates
 Osteoporosis treatment/prevention, hypercalcemia of malignancy, Paget’s disease, and metastatic bone
pain
 Bind permanently to the surfaces of the bones and slow down the osteoclasts (bone-eroding cells). This
allows the osteoblasts (bone-building cells) to work more effectively
 Drug brands
o Alendronate (Fosamax), risedronate (Actonel), zoledronic acid (Zometa), etidronate (Didronel),
tiludronate (Skelid), pamidronate (Aredia), ibandorate (Boniva)
 Ocular SEs
o Blurred vision
o Conjunctival irritation w/burning or grittiness
o Hyperemia
o Ocular pain, anterior uveitis, episcleritis, scleritis

Allergy Medications
 Long-acting tricyclic antihistamine & selective peripheral histamine H1 receptor antagonist
 Has weak atropine-like action; SEs are anisocoria, decreased accommodation, blurred vision,
decreased mucoid and lacrimal secretion
 Can induce mydriasis and provoke IOP elevation
 Large doses can cause facial dyskinesia or blepharospasm
o Certirizine (Zyrtec)
o Loratadine (Claritin/Claritin D) OTC
o Desloratadine (Clarinex)

Intraoperative Floppy Iris Syndrome (IFIS)

 Flomax (tamsulosin hydrochloride) – selective systemic alpha-1A antagonist
o Used for benign prostate hypertrophy. Alpha-1A receptor subtype which predominates in prostate
gland
 Ocular SE
o Loss of tone in iris dilator smooth muscle causing poor pupil dilation during cataract surgery
 Changes in patient management
o Ask patient to stop Flomax treatment 2 weeks before surgery
o Smaller incision site to prevent iris prolapse
o Avoid excessive injection of fluid through incision site
o Recommend iris hooks or iris expansion ring to maintain large enough pupil during surgery

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Perspectives in Lens & IOL Surgery Surgeons report—a new small pupil syndrome caused by Flomax accessed Feb 10, 2005 at
http://www.eyeworld.org/printarticle.php?id=2299

Anti-Coagulants
 Coumadin (Warfarin)
 Used to prevent clot formation in atrial fibrillation and treat thrombosis
o Low safety profile
 Ocular SEs (uncommon)
 Retinal heme
 More likely w/capillary fragility; AMD

Peripheral Vascular Dilators

 Lovastatin and niacin (Advicor), niacin (Niaspan)
 Used to treat hyperlipidemia
 1.5 to 6 g/day
 Ocular SEs
o Pseudo-Cystoid macular edema
o Occurs most in men between 30-50 years old
o Vision loss is reversible in 1-2 days after D/C
o Eye irritation
o Secreted in the tears

Antidepressant Agents
 Fluoxetine hydrochloride (Prozac) is used to treat depression, OCD, PMS, bulimia
o Selective serotonin re-uptake inhibitors
o Most commonly prescribed generic drug in US
 Sertraline (Zoloft) has same indications
 Ocular SEs
o Blurred vision in 3%, mydriasis, photophobia, K sicca, conjunctivitis, diplopia, ptosis, increased eye
movements during sleep, accommodation problems

Synthetic Thyroid Agents

 Levothyroxin (Synthroid, Levoxyl, Levothyroid)
 Replaces thyroxin not produced by thyroid gland
 Ocular SEs
o Pseudotumor cerebri in pre- & peripuberty hypothyroid children
o Excess hormone can lead to myasthenia-like symptoms
o Diplopia, ptosis, paralysis of EOMs

Neoplastic Agents
 Interferon (Intron A) – used to treat hepatitis C and malignancies
 Ocular SEs
o Decreased vision, ocular pain, conjunctivitis (in 4%), retinal changes (ischemia, nonperfusion) and
optic neuritis
 Cyclophosphomide (Cytoxan)
 Ocular SEs
o Dry eye (pronounced)

Radiation for malignancy therapy

 Targets cellular DNA-kills abnormal and normal cells
 Ocular SEs
o Trichiasis, epiphora, ectropion, nasolacrimal duct obstruction, dry eye (61% of patients)
o Iritis, cataract, iris/angle neovascularization
o Radiation retinopathy (clinically appears as capillary nonperfusion, telangectasias, intraretinal
hemorrhages, microaneurysms, retinal NFL infarcts, exudates, retinal and optic nerve head
neovascularization), clinically significant macular edema and radiation optic neuropathy

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Drugs That Can Affect Cornea
Drug Side Effect
Chloroquine/ Whorl-like epithelial opacities
Hydroxychloroquine
Chlorpromazine Pigmentation of endothelium and Descemet’s membrane
Indomethacin Stromal opacities or whorl-like epithelial opacities
Amiodarone Whorl-like epithelial opacities
Isotretinoin Corneal opacities, neovascularization
Crack cocaine Ulceration, epithelial defects

Drugs That Can Affect Lens

Drug Side Effect
Chlorpromazine Anterior subcapsular; stellate-shaped cataract
Corticosteroids Posterior subcapsular cataract
Amiodarone Anterior subcapsular opacities

Drugs That Can Affect Conjunctiva, Lids, and Sclera

Drug Side Effect
Isotretinoin Blepharoconjunctivitis, dry eye, CL intolerance
Chlorpromazine Slate-blue discoloration of conjunctiva and dermis of lids
Niacin Lid edema
Sulfonamides Lid edema, conjunctivitis, chemosis
Tetracyclines Pigmented conjunctival inclusion cysts

Drugs That Can Affect Aqueous Tear Secretion

Drug Side Effect
Anticholinergics (atropine, scopolamine) Decrease aqueous tears
Antihistamines (chlorpheniramine) Decrease aqueous tears
Vitamin A analogs (isotretinoin) Decrease aqueous tears
Vitamins (niacin) Decrease aqueous tears
Beta-Adrenergic blockers (timolol, propranolol) Decrease aqueous tears
Phenothiazines (Chlorpromazine, thioridazine) Decrease aqueous tears
Antianxiety agents (diazepam) Decrease aqueous tears
Tricyclic antidepressants (amitrityline, doxepin) Decrease aqueous tears
Adrenergic agonists (ephedrine) Increase aqueous tears
Antihypertensives (reserpine, hydralazine) Increase aqueous tears
Cholinergic agonists (neostigmine, pilocarpine) Increase aqueous tears

Drugs That Can Affect Mydriasis or Miosis

Drug Side Effect
Anticholinergics Mydriasis
CNS Stimulants (amphetamines, cocaine) Mydriasis
CNS Depressants (barbiturates, antianxiety) Mydriasis
Antihistamines Mydriasis
Phenothiazines Mydriasis
Opiates (heroin, codeine, morphine) Myosis
Anticholinesterases (neostigmine) Myosis

Drugs That Can Cause Myopia or Cycloplegia

Drug Side Effect
Sulfonamides Myopia
Diuretics Myopia
Carbonic anhydrase inhibitors Myopia
Isotretinoin Myopia
Topiramate Acute myopia
Chloroquine Cycloplegia
Phenothiazines Cycloplegia
Anticholinergics Cycloplegia
Anticholinergic side effects
Antihistamines Cycloplegia
Antianxiety Cycloplegia
Tricyclic antidepressants Cycloplegia

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Drugs That Alter Intraocular Pressure (IOP)
Drug Side Effect
Antimuscarinic agents Increase IOP
Antihistamines Increase IOP
Phenothiazines Increase IOP
Tricyclic antidepressants Increase IOP
Corticosteroids Increase IOP
Topiramate Increase IOP
Beta blockers Decrease IOP
Cannabinoids Decrease IOP
Cardiac Glycosides Decrease IOP
Ethyl alcohol Decrease IOP

Drugs That Can Affect Retinal Function

Drug Side Effect
Chloroquine and Hydroxychloroquine Retinal pigmentary changes, VF defects, color vision loss
Thioridazine Retinal pigmentary changes, VF defects, color vision loss, disturbances of dark
adaptation
Quinine Impairment of dark adaptation, VF defects, vascular attenuation
Talc Intraarteriolar talc particles, retinal nonperfusion, neovascularization
Cardiac Glycosides Color vision disturbances, entoptic phenomena
Sildenafil/Vardenafil/tadalafil Color vision disturbancesl
Nonsteroidal anti-inflammatory agents Retinal hemorrhage, pigmentary changes, color vision loss, VF defects
Salicylates, indomethacin
Antineoplastic agents Refractile opacities in posterior pole, retinal vascular disease
Tamoxifen, Carmustine
Isotretinoin Impairment of dark adaptation
Niacin Cystoid macular edema

Drugs That Can Affect the Optic Nerve

Drug Side Effect
Ethambutol Retrobulbar neuritis
Chloramphenical Optic neuritis, Retrobulbar neuritis
Isoniazid Optic neuritis
Nonsteroidal anti-inflammatory Optic neuritis, papillitis
Oral contraceptive Pseudotumor cerebri (PTC), Optic neuritis
Tamoxifen (PTC)
Corticosteroids (PTC)
Amiodarone Papillitis
Nitrofurantoin (PTC)
Vitamin A (PTC)
Tetracyclines (PTC)
Sildenafil & others NAION

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References
1. Bartlett J, Jaanus S, eds. Ocular Effects of Systemic Drugs. Clinical Ocular Pharmacology 4th Ed. Woburn, MA: Butterworth-
Heinemann, 2001:903-48. 37.
2. NEI Statement: Glaucoma and Marijuana Use, Feb 18, 1997. Accessed 11/12/04 at http://www.nei.nih.gov/news/statements/marij.asp
3. Schwartz S, Chavis P. Dietary Supplements and the Ophthalmologist, Comp Ophthalmol Update. 2005;6(3):153-159. Accessed 8/8/05
at http://www.medscape.com/viewarticle/508287
4. Gupta D. Systemic Drugs and the Eye, Optometric Study Center: Jan 2002. Accessed 11/8/2002 at
http://www.revoptom.com/print.asp?page=osc/jan02/lesson_0102.htm
5. Wang K. Adverse Ocular Side Effects of Commonly Prescribed Systemic Medications. Accessed 3/29/05 at
http://opt.pacificu.edu/ce/catalog/11466-PH/WangDrugs.html