Download Ocular Adverse Effects Of Common Systemic Medications

Major Review
N. Sandhya MS
Ocular Adverse Effects Of Common
Systemic Medications
Introduction
Many of the commonly used systemic medications affect the
eye to varying degrees. It is important to be aware of this to
recognize ocular involvement early. Diagnosis is suspected
when there is temporal association with a drug known to
cause ocular involvement.
Drugs Affecting Conjunctiva and Eyelids
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Address for correspondence: Giridhar Eye Institute, Kochi
Vol. XXIV, No.1, Mar. 2012
Kerala Journal of Ophthalmology
Drugs affecting cornea
Systemic drugs and their metabolites reach cornea and lens
via the tear film, limbal vasculature and the aqueous humor.
Although corneal opacities secondary to drug therapy do
not produce much of visual impairment, these opacities
may signal more permanent deposit of drugs in the lens and
more importantly in the retina.
Chloroquine and hydroxychloroquine
Chloroquine and hydroxychloroquine are used for the
chronic management of rheumatoid arthritis, discoid and
systemic lupus erythematosus and other collagen diseases.
Chloroquine and hydroxychloroquine in the early stages
produce fine diffuse deposits in the corneal epithelium.
Later they aggregate into curved lines that converge and
coalesce just below the centre of cornea. Finally greenyellow pigment spots appear as concentric lines in a whorl
like pattern. The corneal deposits can be observed as early as
2-6 weeks of initiation of therapy. Compared to chloroquine
(upto 95%) incidence of keratopathy is less with hydroxy
chloroquine . Generally doses of less than 400mg/day of
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hydroxy chloroquine do not show keratopathy. At higher
doses(800mg/day) upto 6% develop keratopathy within 6
months. Those who have corneal deposits mostly complain
of haloes around light, glare and photophobia whereas visual
acuity remains unchanged. On drug discontinuation both
subjective symptoms and objective corneal signs disappear.
There is no relationship between the development of corneal
deposits and the occurrence of retinopathy. Development
of keratopathy does not contraindicate continued use of
the drug. However if symptoms of haloes and glare bother
the patient reduction of drug dose may be considered in
consultation with physician.
Amiodarone
Amiodarone is used to treat various cardiac arrhythmias like
atrial fibrillation and ventricular tachycardia.
Keratopathy is the most common ocular adverse effect of
amiodarone found in almost all patients (70-100%). It most
commonly appears after 1-4 months of therapy. Involvement
is bilateral but is often asymmetric.
Sandhya - Adverse effects of common medications
Grade-1
Grades of Amiodarone keratopathy
Grade-2
Grade-3
Irregular round clumps of deposits are seen in grade IV
amiodarone keratopathy
Severity of keratopathy appears to significantly correlate
with total drug dosage and duration of therapy. Patients
taking higher doses >400mg/day demonstrate more
advanced keratopathy depending on the duration of
treatment. Once the keratopathy becomes fully developed,
it remains relatively stationary until the drug dosage is
reduced. Keratopathy gradually resolves within 3-20 months
of discontinuation of the medication. Corneal changes
associated with amiodarone therapy are benign and special
follow up of affected patients is not needed.
A case of Amiodarone keratopathy
Drugs Affecting the Lens
Amiodarone
Fine anterior subcapsular lens deposits occur in approximately
50% of patients taking Amiodarone for 6-18months. These
do not cause any visual symptoms. Like corneal deposits,
lenticular changes are benign, special follow up of patients
is not required.
is cataract. The use of systemic, ophthalmic, dermatologic,
Corticosteroids
including age-related PSC cataracts. The incidence of steroid
One of the most common ocular side effect of corticosteroids
induced cataract is 6.4%-38.7%.
nasal, aerosol or inhalation steroids all have been implicated
in causing posterior subcapsular cataracts which are clinically
indistinguishable from that produced by other causes
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Vol. XXIV, No.1, Mar. 2012
Kerala Journal of Ophthalmology
Cataract
Drugs Affecting Episclera, Sclera And Uvea
Topical ocular medications such as beta-blockers, latanoprost
and many others are known to produce uveitis. Some systemic
medications like cidofovir, sulfonamides, rifabutin and oral
contraceptives also produce uveitis. Drug-induced uveitis is
almost always reversible within weeks of discontinuation of
the drug and treatment of the inflammation.
Tamsulosin
Tamsulosin, the α1a adrenoceptor antagonist produce
an interesting syndrome called intraoperative floppy iris
syndrome(IFIS) characterized by
1. Flaccid iris stroma that billows on ocular irrigation.
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Cataract
2. Tendency of the iris to prolapse towards the side-port
incisions and phaco probe.
3. Progressive intra operative miosis despite conventional
pharmacologic measures to maintain pupillary dilatation.
Incidence of IFIS is 86% in patients taking tamsulosin. IFIS
is also reported with other α1 adrenoceptor antagonists.
45% of patients taking doxazocin and 15% of those taking
alfazocin also demonstrate IFIS.
Pupillary miosis occurs because tamsulosin blocks the iris
dilator muscle. This constant blockade is postulated to cause
a form of disuse atrophy of the dilator smooth muscle. This
Sandhya - Adverse effects of common medications
may explain why some patients can still have this syndrome
even after stopping the medication. Though poor pupillary
dilatation is common in other conditions pupillary miosis
associated with tamsulosin is different in that the pupillary
margin remains elastic and hence normal mechanical
stretching of the iris is ineffective.
Pre operative history of tamsulosin intake, anticipation of
complications and appropriate interventions to deal with it
will avoid unwanted post operative outcome.
Cidofovir
The use of Cidofovir for the treatment of CMV retinitis is a
primary risk factor in the subsequent development of immune
Drugs Causing Myopia and Cycloplegia
Commonly prescribed medications that are known to induce
myopia are sulfonamides, diuretics and carbonic anhydrase
inhibitors. In most cases the myopia was immediate in
onset and subsided within days of discontinuation of the
medication. In most cases the amount of drug induced
myopia was slight (<5.0D) .There is allergic ciliary body
recovery uveitis which has evolved with the widespread use
of highly active retroviral therapy (HAART). Patients who
have responded to HAART have increased CD4+ counts
allowing withdrawal of CMV maintenance therapy. Upto 40%
of immune recovered patients may have immune recovery
uveitis which consists of iritis, vitritis and macular edema.
Large CMV lesion is a risk factors for the development of
immune recovery uveitis.
Drugs Affecting Pupil
Sympathetics
supply
the
dilator
pupillae
and
parasympathetics supply the sphincter pupillae muscles of
the iris. Drugs affecting the autonomic pathway can hence
affect the size and activity of the pupil.
edema and rotation or peripheral choroidal detachment
which produce forward displacement and thickening of lensiris diaphragm and shallowing of anterior chamber which
lead to myopia.
Phenothaizines, antihistaminics, anti anxiety agents and
tricyclic antidepressants produce cycloplegia through their
anticholinergic effects.
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Vol. XXIV, No.1, Mar. 2012
Kerala Journal of Ophthalmology
Case example of a patient who had transient Chlorthalidone
induced myopia. There were ILM folds at macula and
peripheral choroidal elevation as shown in the color photo
and ultrasonogram.
Drugs Affecting Intraocular Pressure
Several drugs ( β- blockers and cardiac glycosides like
digoxin) reduce IOP by decreasing the aqueous production.
Antihistaminics and antipsychotic agents (phenothiazines)
because of their anticholinergic effect produce pupillary
dilatation and produce narrow angle glaucoma.
Corticosteroids
Steroids by systemic, topical, inhalational and even nasal
routes can cause rise in intra ocular pressure. In patients who
are steroid responders, oral steroids produce approximately
60% of the increase in IOP as compared with topical agents
because of differences in anterior chamber concentrations of
the drug. Those with primary open angle glaucoma respond
to steroids at a rate of 46-92% compared to 18-36% of normal
population. Patients noted to be at greater risk include those
with increasing age, diabetes, high myopia, connective
tissue disorders and first degree relatives with open angle
glaucoma . The onset of IOP rise is usually after 2 weeks,
however it can occur after many weeks and the time onset
of IOP rise is usually longer for systemic steroids compared
to topical steroids. When activated by steroids, the steroidspecific receptors on the trabecular meshwork activate TM
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cells and cause accumulation of amorphous material in the
extracellular matrix, thickening of trabecular beams and
juxta canalicular tissue and there by decrease the out flow
space. The risk of developing steroid induced glaucoma can
be moderated with the judicious use of steroids and careful
monitoring. The IOP usually returns to normal levels within
2-4 weeks of steroid taper or discontinuation but in some
cases the IOP remains high for long time. The use of low to
medium dose inhaled steroids and nasal steroids have little
associated risk.
Drugs affecting retina
Numerous drugs have been associated with retinal toxicity.
Drugs like Indomethacin, tamoxifen, thioridazine and
chloroquine produce retinopathies by a common ocular
oxidative pathway.
Sandhya - Adverse effects of common medications
around the retinal veins. Peripheral lesions can occur with or
Chloroquine and Hydroxychloroquine
without simultaneous macular involvement. Other changes
A fine pigmentary mottling within the macular area
include attenuated retinal vessels, optic atrophy, peripheral
with or without loss of foveal reflex is the first visible
visual field loss, abnormal color vision, and a subnormal
evidence
before
electro-retinogram. Unlike retinitis pigmentosa, the dark
visible ophthalmoscopic changes are detectable, a ‘pre
adaptation is normal or only minimally abnormal. Visual
maculopathy’ state can exist in which the drug interferes
field loss correlates well with retinal damage. Typical visual
with metabolism of the macular tissues causing subtle visual
field defects consist of central or paracentral scotoma, which
field defects. As macular changes progress, a classic pattern
may become confluent and form a complete ring. Advanced
pathognomonic of chloroquine toxicity referred to as “bull’s
cases of retinopathy exhibit markedly abnormal or even
eye maculopathy” develops consisting of an area of granular
extinguished ERGs. These changes produce symptoms of
hyper pigmentation surrounded by a zone of depigmentation
metamorphopsia, decreased visual acuity and impaired color
which in turn is surrounded by another ring of pigment. In
vision.
of
chloroquine
retinopathy.
Even
advanced stages well circumscribed area of RPE atrophy in
the macular area may resemble a macular hole. High degree
of bilateral symmetry is noted but occasionally one eye can
be affected more than the other.
Incidence of retinopathy increases with age and in older
patients retinal toxicity is correlated with total drug dosage.
Despite early diagnosis and drug withdrawal permanent
visual field defects can occur. The risk of retinal toxicity is
Some patients can have changes resembling retinitis
minimal if the daily dose of hydroxychloroquine is less than
pigmentosa (RP). Chloroquine retinopathy does exhibit RPE
6.5mg/kg and the duration of treatment is less than 5 years
hyperplasia but unlike RP the pigments do not accumulate
and the renal function is normal.
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Vol. XXIV, No.1, Mar. 2012
Kerala Journal of Ophthalmology
Color photo and fundus fluorescein angiogram of a patient with chloroquine retinopathy
Recommendations for screening for Chloroquine and Hydroxychloroquine Retinopathy
Multi focal ERG is said to be the most sensitive test for
screening patients on hydroxy chloroquine. According to
the newer guidelines 10-2 perimetry + one of SD OCT, FAF
Digoxin
Digoxin is widely used in patients with congestive heart
failure and
in cardiac arrhythmias like atrial fibrillation.
and MF ERG at baseline and at each visit is recommended for
Approximately 80% of patients with digoxin toxicity
screening patients on hydroxychloroquine. Other tests like
demonstrate generalized color vision deficiencies. But
fundus color photo, FFA, time domain OCT, Amsler charting,
detectable color vision impairment or other visual symptoms
color vision tests and EOG are not of much use for screening.
can occur even at therapeutic drug levels.
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Sandhya - Adverse effects of common medications
Farnsworth Munsell 100-hue test is particularly sensitive for
detecting digoxin induced color vision deficiencies. Visual
symptoms often occur within 2 weeks of initiation of therapy.
Once the serum level is decreased visual symptoms quickly
subside, usually within weeks.
Sildenafil
Sildenafil, tadalafil and vardenafil are cyclic GMP specific
phosphodiesterase type V (PDE 5) inhibitors used for erectile
dysfunction. Though highly selective for PDE-5, they retain
some affinity for PDE-6, an enzyme found in the retina.
Inhibition of this is the basis for ocular side effects. Visual
side effects which are mild and transient occur in 3-10% of
patients taking sildenafil. Tadalafil is more specific to PDE-5
and so may produce less ocular side effects. Ocular adverse
drug reactions considered certain by WHO for sidenafil
include bluish tinged or occasionally yellowish or pinkish
tinged vision and other color vision disturbances, blurred
vision and light sensitivity, conjunctival hyperemia, ocular
pain and transient ERG changes. Other adverse reactions
considered “possible” include non arteritic ischemic optic
neuropathy, mydriasis, retinal vascular accidents and
subconjunctival hemorrhage. Most symptoms last several
minutes to a few hours.
Oral contraceptives
Oral contraceptive users have an increased risk of retinal
vascular lesions (relative risk of 2-2.4). This includes
retinal vascular occlusions, vein thrombosis and retinal
hemorrhages. Continuation of treatment should be based on
risk to benefit ratio.
Tamoxifen
Tamoxifen is an anti-estrogen drug used most commonly in
the management of hormone receptor positive breast cancer.
Ocular complications are rare and occur in 0.6% of patients
and include cataract, vortex keratopathy, optic neuritis
and retinopathy. In the literature, patients with tamoxifen
retinopathy had a cumulative dose ranging from 6-81g.
However more recent reports demonstrate maculopathies
occurring at much lower cumulative doses(less than 10
gms). Up to 12% of patients taking 20mg/day of tamoxifen
develop retinal toxicity. The pathogenesis is thought to be
increased accumulation of glutamate which leads to axonal
degeneration. The crystals seen on fundus examination
correspond to the degenerative products. Extensive deposits
may result in macular edema and impaired visual acuity.
Visual acuity may improve with tamoxifen withdrawal along
with resolution of macular edema, but retinal deposits often
do not regress .
OCT findings in tamoxifen retinopathy include hyper
reflective intra retinal crystalline deposits mainly in the inner
retinal layers, intra retinal cystoids spaces, IS-OS junction
abnormalities, photoreceptive atrophy and retinal thinning.
Color photo of a patient with tamoxifen retinopathy
Right Eye
Left Eye
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Vol. XXIV, No.1, Mar. 2012
Kerala Journal of Ophthalmology
Fundus autoflurescence of the same patient
Right Eye
Left Eye
Spectral domain optical coherence tomography of the right and left eye of the same patient showing intra
retinal hyper reflective crystalline deposits
Recommendations
Yearly ophthalmologic evaluations with retinal examination
are recommended. OCT analysis is especially helpful in
determining the presence and severity of macular edema as
well as for following up its resolution. 3D-OCT is very effective
in detecting early subtle changes in tamoxifen maculopathy
that can occur in asymptomatic patients. Consideration
should be given to discontinuation of the drug at the first
sign of retinal deposits. Cessation is strongly recommended
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if numerous deposits are present or if macular edema is
noted, in consultation with the oncologist.
Corticosteroids
Use of steroids in any form including inhaled steroids
has been associated with the development of central
serous chorioretinopathy and rarely acute bullous retinal
detachment and serous detachment with exudative deposits
& subretinal fibrosis.
Sandhya - Adverse effects of common medications
Color photo and fluorescein angiogram of a patient with steroid induced CSR.
The classic smoke stack and ink blot patterns can be seen
Drugs affecting optic nerve
The most important drugs affecting optic nerve are
ethambutol, chloramphenicol and amiodarone. So in any
patient with optic neuropathy a careful history of drug intake
should be obtained. Maternal use of drugs like phenytoin,
quinine, alcohol and cocaine may lead to optic nerve
hypoplasia in children.
Ethambutol
The most important ocular side effect of ethambutol is
retrobulbar neuritis but fortunately its incidence is rare.
Clinical course can be acute or chronic and is typically
progressive. Incidence is 5-6% with a dose of 25mg/kg/day
and <1% with a dose of 15mg/kg/day when taken for more
than 2months.
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Vol. XXIV, No.1, Mar. 2012
Kerala Journal of Ophthalmology
Characteristics of optic neuropathy due to ethambutol
Color vision deficiencies are the most sensitive indicator
of ethambutol optic neuropathy, which can occur even
Chloramphenicol
peripheral neuropathy may indicate early toxicity and should
Chloramphenicol is used for the treatment of typhoid fever,
bacterial meningitis and certain anaerobic infections. It
mainly produces retrobulbar neuritis but papillitis can also
occur. Visual impairment associated with chloramphenicol
therapy usually recovers after the drug is discontinued but
pretreatment visual acuity is often not regained and visual
field defects may persist.
serve as a warning sign of impending optic neuropathy. If
Drugs affecting extra ocular muscles
before visual acuity and visual fields are affected. Sometimes
contrast sensitivity can be affected even before color
vision becomes impaired. Ethambutol therapy must be
discontinued in patients who develop reduced visual acuity,
color vision deficiency or visual field defects. Symptoms of
discontinuation of drug therapy alone does not result in
visual improvement hydroxycobalamine injections may help
in visual recovery. This vitamin may act by neutralizing the
chelating action of ethambutol on optic nerve.
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Drugs affecting the autonomic nervous system or central
vestibular system or causing extrapyramidal effects have been
associated with ocular manifestations such as nystagmus,
diplopia, extra ocular muscle palsy and oculogyric crisis.
Sandhya - Adverse effects of common medications
Drug induced intracranial hypertension
Two main groups of drugs which produce intracranial
hypertension are the tetracyclines and retinoids. Drug
induced intracranial hypertension is especially of concern
because it may be asymptomatic for a long time. However
the general presenting symptoms and signs are same as for
the idiopathic form. The rise in intracranial pressure is related
to the decreased absorption of cerebrospinal fluid via the
effect on c GMP on the arachnoid villi. Patients who take
retinoids especially along with tetracyclines should promptly
report if they develop blurred vision, double vision or head
aches which may indicate the development of intracranial
hypertension. Discontinuation of treatment usually results in
resolution of intracranial pressure and disc edema but other
interventions may be undertaken if warranted.
Conclusion
Many commonly used drugs affect different segments of the
eye in varied severity ranging from minor and insignificant to
major and vision threatening. It is crucial to recognize early
and appropriately intervene before irreversible damage sets
in by modification of dosage or use of alternative drugs.
5. Pradeep Sharma,Reena Sharma.Toxic optic neuropathy. Indian J
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Dr N. Sandhya MS,DO, DNB,MNAMS is currently a consultant in cataract, glaucoma and uvea
services in the Giridhar Eye Institute, Kochi
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