Ocular side effects of systemic drugs

OCULAR SIDE EFFECTS OF
SYSTEMIC DRUGS
PRESENTER- ANJU NAGAR
DATE : 15-4-2013

Introduction
• After a drug molecule enters the systemic circulation, it can reach ocular
tissues through uveal or retinal circulations.
• The choroid, sclera and ciliary body have thin, fenestrated walls for drug
molecules to pass.
• Small, lipid soluble molecules pass freely into the aqueous humor, and
can further diffuse into avascular structures such as the lens, cornea, and
trabecular meshwork

Introduction
Drug molecules that enter by means of the uveal circulation exit the eye from
the Canal of Schlemm, ciliary body or may diffuse into adjacent anatomical
structures.
Drugs from the retinal circulation can re-enter the systemic circulation,
diffuse into the vitreous and anatomical structures, or get actively
transported out.

Ocular Accumulation Sites
 Three major accumulation sites- cornea, lens and vitreous. The duration
of drug in the eye is prolonged if deposited, increasing chances for toxicity.
 The cornea has a permeable endothelium, and the stromal
glycosaminoglycans (GAGs) can bind drug molecules, leading to edema
and decreased transparency.
 Drug molecules can also bind to lens protein, and photosensitize the
lens to ultraviolet (UV) radiation.
 Lastly, drug molecules tend to accumulate in the vitreous due to the
slow rate of fluid exchange.

MELANIN BINDING
• Melanin absorbs light and damage results from the free-
radical nature of melanin in structures such as the uveal tract
and the RPE.
• Chloroquine and chlorpromazine have a high affinity to
melanin and tend to affect ocular tissues

DRUG METABOLISM
• The body’s ability to metabolize a drug directly correlates with toxicity.
• In patients with hepatic and renal disease, there is a decreased rate of
excretion, which allows drug molecules to accumulate to toxic levels.
• Also, toxic metabolites formed elsewhere like the liver, can reach the eye
through systemic circulation or can be produced locally in ocular tissues.

PHOTOSENSITIZERS
 The adult crystalline lens normally filters most ultra-violet ( UV) radiation,
so there is minimal risk of UV affecting the retina, where drug molecules
can potentially bind.
 UV radiation does affect anterior tissues like the cornea and lens when
photosensitized by bound drug molecules.
 Exposed lens proteins, when UV photosensitized by bound drug
molecules, may denature, opacify and accumulate leading to cataract
formation.

PHOTOSENSITIZERS
 UV radiation can potentially affect the retina in aphakic and
pseudophakic patients, because UV can penetrate without the normal
absorptive lens barrier.
 Well-known photosensitizers that cause anterior subcapsular lens
changes –
 allopurinol,
 phenothiazine,
 amiodarone, and
 chloroquine

Possible basis of ocular side effects of
systemic drugs
1. Specific biochemical basis known:
Antimuscarinic drugs
Tamsulosin(alpha adrenergic blocker)
Sildenafil (Block hyperpolarisation of photoreceptors)
2. Altered metabolism – increased drug concentration
Therapeutic window
Metabolism by liver/ kidney-
ethambutol toxicity in renal impairment;
digoxin.
Different metabolism in young age
Possibility of drug transfer
Drug interaction

systemic drugs
3. Predisposition to allergy in atopic individuals- Steven Johnson
4. Toxicity due to overdose
quinine,
Chloroquine
5. Teratogenecity
6. Idiopathic & idiosyncratic- side effects even at correct dose
Diplopia- Glitazone, ethambutol, steroid, topiramate
Floroquinolone.
BIH- vitamin A
Red tears- rifampicin in leprosy

systemic drugs
7. Recreational drugs
Canthaxanthin-gold dust retinopathy
LSD
Ayahuasca tea(hallucinogen)
8. Adverse new side effects

Drugs Affecting Cornea
Vortex keratopathy/ cornea verticillata:
characterized by whorl-like corneal epithelial
deposits.
1. Signs:
• Bilateral, fine greyish or golden-brown opacities
in the inferior corneal epithelium.
• Arborizing horizontal lines

Causes:
a. Antimalarial
Chloroquine (Nivaquine, Avlocor)
Hydroxychloroquine (Plaquenil)
• INDICATIONS: malaria; certain rheumatological disorders
• Unlike retinopathy, keratopathy bears no relationship to dosage or duration
of treatment.
• reversible on cessation of therapy.

b. Amiodarone
• INDICATIONS: atrial fibrillation; ventricular
tachycardia
• keratopathy - slowly reversible on
discontinuation of medication.
• Higher dose/ longer duration of
administration more advanced the
corneal deposits.
• keratopathy does not affect vision-
discontinuation not indicated.
• Other toxic effects-
 anterior subcapsular lens deposits
 optic neuropathy

CHLORPROMAZINE:
INDICATIONS- sedative; psychotic illnesses
SIGNS-
 innocuous, subtle, diffuse yellowish-brown
granular deposits in the endothelium,
Descemet membrane and deep stroma
occurring only in exposed cornea of the
interpalpebral fissure
 anterior lens capsule deposits
 retinopathy
Doses greater than 500 mg/day given for
prolonged periods have a higher incidence
of irreversible corneal and lenticular
deposits.

ARGYROSIS:
discoloration of ocular tissues secondary
to silver deposits, and may be iatrogenic
or from occupational exposure.
Keratopathy is characterized by greyish
brown granular deposits in Descemet
membrane.
The conjunctiva may also be affected.

CHRYSIASIS:
• Deposition of gold in living tissue, occurring after prolonged administration.
• treatment of rheumatoid arthritis.
SIGNS:
• Corneal chrysiasis :
– characterized by dust-like or glittering purple granules scattered throughout
the epithelium and stroma, more concentrated in the deep layers and the
periphery.
– total dose of gold compound >1500 mg develop corneal deposits.
– not an indication for cessation of therapy.
• innocuous lens deposits
• marginal keratitis.

AMANTADINE:
INDICATIONS: Parkinson disease.
SIGNS:
• Diffuse white punctate opacities that may be associated with epithelial
edema, 1–2 weeks after commencement of therapy (dose 200-400 mg/d).
• Resolve with discontinuation of treatment.

Drugs Affecting Lens
STEROIDS: cataractogenic; topical
/systemic/nasal.
• lens opacities:
• PSC
• later the anterior subcapsular
– relationship between weekly systemic
dose, duration of administration, total
dose and cataract formation is unclear.
– patients on less than 10 mg
prednisolone (or equivalent), or
treated for less than 4 years may be
immune.

– children- more susceptible to the
cataractogenic effects of systemic
steroids, individual (genetic) susceptibility
may also be of relevance.
– Early opacities may regress if therapy is
discontinued; alternatively progression
may occur despite withdrawal and
warrant surgical intervention.
– The etiology is unknown, the drug may
react with amino groups of crystalline lens
fibers causing protein complexes to
aggregate

CHLORPROMAZINE:
• Deposition of innocuous, fine, stellate,
yellowish-brown granules on the
anterior lens capsule within the
pupillary area
• 50% of patients who have received a
cumulative dose of 1000g.
• The deposits persist despite
discontinuation of the drug.

BUSULPHAN (MYLERAN):
INDICATIONS: Treatment of chronic myeloid leukemia.
SIGNS: Occasionally cause lens opacities.
GOLD:
INDICATIONS:
used in the treatment of rheumatoid arthritis
SIGNS:
Causes innocuous anterior capsular deposits in about 50% of patients on
treatment for longer than 3 years.

 ALLOPURINOL:
INDICATIONS: hyperuricaemia and chronic gout
SIGNS:
Increases the risk of cataract formation in elderly patients, if the
cumulative dose exceeds 400 g or duration of administration exceeds 3
years.
 DESFERRIOXAMINE: can cause cataract

Drugs causing uveitis
RIFABUTIN:
INDICATIONS: Tuberculosis in combination
with other drugs in immunocompetent
patients.
• Drugs that inhibit metabolism of
rifabutin through the cytochrome
p-450 pathway (clarithromycin
and fluconazole), increase the risk
of uveitis.
SIGNS:
ACUTE ANTERIOR UVEITIS (AAU)
U/L; assoc with hypopyon;
Treatment involves withdrawal of
the drug or reduction of dose.

• BISPHOSPHONATES: osteoporosis.
– FOSAMAX
– AREDIA
– ACTONEL
Bisphosphonate molecules preferentially "stick" to
calcium and bind to it.
They accumulate to a high concentration in bones,
resulting in maintained or increased bone density and
strength
Ocular Side Effects
• Scleritis/Episcleritis
• Blurred vision
• Hyperemia
• Anterior uveitis

Cidofovir
INDICATION: CMV retinitis in AIDS
patients.
SIGNS:
AAU- Vitritis is common and
hypopyon may occur with long-
term administration.
Treatment- topical steroids and
mydriatics.

Drugs affecting retina
ANTIMALARIALS:
Drugs
Antimalarials- melanotropic drugs.
 Chloroquine retinotoxicity- related to the total cumulative dose(>300g),
Rx duration > 3y
 Hydroxychloroquine - much safer than chloroquine
The risk of toxicity is increased if a daily dose over 6.5 mg/kg is
administered for longer than 5 years, although even then the risk is
still very small.

CHLOROQUINE RETINOPATHY
Chloroquine retinopathy can be divided into the following stages:
1. Premaculopathy
– normal visual acuity and a scotoma to a red target located
between 4° and 9° from fixation.
– Amsler grid testing may also show a defect.
– colour vision assessed- mild blue-yellow and protan red-green
defects. (Adams Desaturation-15 test and the Hardy-Rand-
Rittler test).
– If the drug is discontinued, visual function usually returns to
normal.

2. Early maculopathy
 modest reduction of visual acuity (6/9–
6/12).
 Fundus examination- subtle ‘bull’s eye’
macular lesion (central foveolar island of
pigment surrounded by a depigmented
zone of RPE atrophy, which is itself
encircled by a hyperpigmented ring).
 may progress even if the drug is stopped.

3. Moderate maculopathy
– characterized by moderate
reduction of visual acuity
(6/18–6/24)
– Obvious ‘bull’s eye’ macular
lesion.
4. Severe maculopathy
– characterized by marked
(6/36–6/60)
– Widespread RPE atrophy
surrounding the fovea.

5. End-stage maculopathy
– Characterized by severe
– Marked atrophy of the RPE
with unmasking of the larger
choroidal blood vessels.
– retinal arterioles may also
become attenuated and
pigment clumps develop in the
peripheral retina.

DRUGS AFFECTING RETINA
PHENOTHIAZINES:
1. Thioridazine: schizophrenia and related
psychoses.
– normal daily dose is 150– 600 mg.
– Doses> 800 mg/day: cause reduced visual
acuity and impairment of dark adaptation.
The clinical signs of progressive retinotoxicity are :
•‘Salt and pepper’ pigmentary disturbance
involving the mid-periphery and posterior pole.
Pigmented plaques and focal
loss of the RPE and
choriocapillaris

DRUGS AFFECTING RETINA
• Plaque-like pigmentation and focal loss of
the RPE and choriocapillaris.
• Diffuse loss of the RPE and
choriocapillaris.
2. Chlorpromazine: Normal daily dose is
75–300 mg.
Retinotoxicity ( larger doses over a
prolonged period)
It is characterized by nonspecific
pigmentary granularity and clumping.
diffuse atrophy of the RPE
and choriocapillaris

DRUG-INDUCED CRYSTALLINE
MACULOPATHIES:
1. TAMOXIFEN : specific anti-oestrogen -breast
carcinoma.
Normal daily dose is 20–40 mg.
SIGNS:
 Retinopathy- bilateral, superficial, fine, yellow,
crystalline deposits in the inner layers of the
retina and punctate grey lesions in the outer
retina and RPE
 Visual impairment- caused by maculopathy
associated with foveolar cyst formation.
 Optic neuritis- reversible on cessation of
therapy.

MACULOPATHIES
2. CANTHAXANTHIN:
– carotenoid used to enhance sun
tanning.
– deposition of innocuous glistening
yellow inner retinal deposits arranged
symmetrically in a doughnut shape at
the posterior poles- GOLD DUST
RETINOPTHY
– deposits are slowly reversible.

MACULOPATHIES:
3. METHOXYFLURANE:
– Inhalant general anaesthetic.
– metabolized to oxalic acid which combines
with calcium to form an insoluble salt which
is deposited in tissues including the RPE.
– Prolonged administration may lead to renal
failure and secondary hyperoxalosis.
Ocular involvement is characterized by-
mild visual impairment associated with
calcium oxalate crystals scattered
throughout the retina that may later be
associated with RPE hyperplasia at the
posterior pole.

MACULOPATHIES
Interferon-alpha: chemotherapeutic
Delayed type hypersensitivity reaction
OCULAR SIGNS:
• Retinopathy –
– characterized by cotton wool spots and intraretinal haemorrhages (particularly
high-dose therapy).
– usually resolves spontaneously with cessation of therapy and in the
majority of patients the visual prognosis is good.
• Less common ocular side-effects
– oculomotor nerve palsy,
– optic disc edema
– retinal vein occlusion.

MACULOPATHIES
Desferrioxamine:
• Iron chelating agent used in the Rx of
chronic iron overload(hemosiderosis)
• subcutaneous infusion.
• Presentation is with rapid visual loss
although the fundi may be normal or
show only mild macular greying.
• Within several weeks mottled pigmentary
changes develop
• FA shows punctate hyperfluorescence.

MACULOPATHIES
Nicotinic acid: Cholesterol-lowering agent.
OCULAR SIGNS:
– cystoid maculopathy suggestive of cystoid
macular edema .
– occur when doses greater than 1.5 g daily
are used
– resolve with discontinuation of the drug.

DRUGS AFFECTING OPTIC NERVE:
ETHAMBUTOL
 used in combination with INH and
rifampicin in the treatment of tuberculosis.
 Chelates copper, so the decreased levels
impair mitochondrial activity of axonal
transport in optic nerve leading to optic
neuropathy
 Ocular toxic effects include:
– optic neuritis: normal or slightly
swollen optic discs with splinter-shaped
haemorrhages
– colour vision abnormalities: blue-yellow

ETHAMBUTOL
– visual field defects: two types
• Central type- involves the
maculopapular bundle
and results in decreased
visual acuity, central or
centrocaecal scotomas
and impairment of blue-
yellow color vision.
• Peripheral type- causes
peripheral visual field
constriction and red-
green dyschromatopsia.
Visual field test results obtained 3 months
after onset of visual symptoms. Both the left
(A) and right (B) visual fields show central
scotoma with inferior temporal quadrant
defects.

ETHAMBUTOL
• Toxicity is dose- and duration-
dependent;
• the incidence is up to 6% at
a daily dose of 25 mg/kg
and rare with a daily dose
not exceeding 15 mg/kg.
• Toxicity typically occurs
within 3–6 months of
starting treatment.
• Isoniazid may also rarely cause
toxic optic neuropathy, particularly
when given in combination with
ethambutol.

AMIODARONE
 Antiarrythmic
 Optic neuropathy: rare and not dose-related.
Presentation is with insidious unilateral or bilateral visual impairment.
Signs are bilateral optic disc swelling that may persist for a few months
after medication is stopped.
Visual field defects may be mild and reversible or severe and permanent.
Cessation of the drug may not inevitably bring about improvement.

VIGABATRIN
• Second-line antiepileptic drug for the treatment of
uncontrolled complex partial seizures
• first line monotherapy for infantile spasms (West syndrome).
• Presentation-
– months or years after starting treatment
– bilateral concentric or binasal visual field defects.
– The defects persist if treatment is stopped but do not
progress if medication is continued. This suggests that the
defects are idiosyncratic rather than a dose-related effect.

TOPIRAMATE
• anticonvulsant
• Also used in the treatment of
migraine.
• It can cause acute angle-closure
glaucoma with associated myopia
due to ciliochoroidal effusion.
• Presentation is usually within a
month of starting treatment with
blurred vision, and sometimes
haloes, ocular pain and redness.

TOPIRAMATE
• Signs include shallowing of
the anterior chamber and
raised intraocular pressure.
• Treatment consists of
reducing the intraocular
pressure and stopping the
drug.
• Prognosis is usually good
provided the complication is
recognized.

DRUGS CAUSING DRY EYE
1. Beta blockers
2. Diuretics(change the tear film)
3. Niacin
4. Oral contraceptives
5. Antipsychotics (phenothiazines:
thioridazine, chlorpromazine,), tricyclic
antidepressant, anticholinergics(atropine,
scoploamine) -anticholinergic properties.
6. Isotretinoin(decreased meibomian gland
function- deficiency of normal lipid layer
in tear film)

DRUGS AFFECTING PUPIL
DRUGS- MYDRIASIS DRUGS - MIOSIS
Anticholinergic agents Opiates, heroin, codeine, morphine
CNS stimulants Anticholinesterases: neostigmine
CNS depressants
Antihistamines
Phenothiazines

DRUGS CAUSING MYOPIA AND
CYCLOPLEGIA
MYOPIA CYCLOPLEGIA
Sulfonamides Chloroquine
Diuretics (chlorthalidone) Phenothiazine
Carbonic anhydrase inhibitor anticholinergis
Isotretinoin antihistamines
Topiramate Anti-anxiety agents
Tricyclic antidepressants

DRUGS AFFECTING IOP
INCREASE IN IOP DECREASE IN IOP
Antimuscarinic agents Beta-blockers
Antihistamines Cannabinoids
Phenothiazines Cardiac glycosides
TCA Ethyl alcohol
Corticosteroids

ANTICOAGULANTS
• Aspirin (salicylate)
• Coumadin (warfarin)
• Heparin (unfractionated heparin)
• Lovenox (enoxaparin sodium)
• Plavix (clopidogrel)
• Pradaxa (dabigatran etexilate mesylate)
Ocular Side Effects
• Subconjunctival and retinal hemorrhage
• Recommend to be discontinued for a week prior
to eye surgery
• INR > 5 prone to bleed
• Chronic use of ASA may cause yelllowing of vision

Estrogen or Progesterone
Estrogen or Progesterone
Decreased aqueous production, microvacular
occlusions from enhanced platelet
adhesiveness, or increase in fibrinogen and
clotting factors.
Ocular Side Effects
• Microvascular complications like artery and
venous occlusions
• Dry Eye
• Contact Lens Intolerance
• Optic neuritis
• Macular Edema
• TIA (Transischemic attacks)
• Pseudotumor cerebri

RARE OCULAR SIDE EFFECTS
 Conjunctivitis:
1. Antianxiety (diazepam; alprazolam)
2. Phenytoin; carbamazepine
 Extraocular muscle paresis:
1. Sufonylureas- glipizide, glyburide.
2. Barbiturate
3. Oculomotor nerve palsy- interferon alpha
 Visual sensation:
• Digitalis

 Visual hallucinations:
1. Levothyroxine
2. Cimetidine/ranitidine(H2 receptor blocker)
 Nystagmus:
1. Lithium
2. Barbiturate
3. Phenytoin
4. Carbamazepine
 Diplopia:
1. Lithium
2. Antianxiety
3. NSAIDs
4. Tetracycline

 Eyelid hyperemia:
1. Levothyroxine.
 Ptosis:
1. Barbiturate
2. Chloroquine
 Visual field changes:
1. Vigabatrin
2. Paracentral scotoma:
Chloroquine
 Pseudotumor cerebri:
1. Amiodarone
2. Levothyroxine
3. OCPs
4. NSAIDs
5. Isotretinoin
6. Tetracycline.

Tamsulosin
alpha-adrenergic blockers
 Indications:
• Benign prostate hypertrophy
 Ocular Side Effects:
• Loss of tone in iris dilator smooth
muscle causing poor pupil
dilation/prolapse during cataract
surgery
• “Floppy Iris Syndrome”

SILDENAFIL
inhibits phosophodiesterase-5 (PDE-5) which results
in vasodilation of smooth muscle.
Ocular Side Effects
• Objects have color tinges—usually blue or blue-
green, may be pink or yellow
• 11% of patients on 100mg perceive a blue haze
up to four hours
• Dark colors appear darker
• Visual disturbances

SILDENAFIL
• The above ocular side effects are
dose-dependent .
– For sildenafil side effects occur
at the following incidences:
– 50mg 3%
– 100mg 10%
– 200mg 40-50%
• The side effects based on dosage
with sildenafil start 15-30 minutes
after ingestion of the drug, and
usually peak 60 minutes after
ingestion.

STEVEN-JOHNSON SYNDROME
• Immune complex mediated hypersensitivity reaction
• Involves skin and mucosa
 Pathophysiology:
• SJS involves massive apoptosis of keratinocytes within epidermis.
• Intermediate drug metabolites initiate an immune response in
susceptible individuals- increase in release of Fas-ligand- binds to
and activates Fas, which is a keratinocyte cell surface receptor that
initiates apoptosis.
• In large retrospective studies, Power et al and Chang et al reported
ocular involvement in 69% and 81%, respectively, of patients with
SJS.

The ophthalmic pathology mainly involves:
• conjunctiva, both bulbar and palpebral,
• cornea,
• lid margins and skin
• eyelashes.

Conjunctiva:
• Mild cases- conjunctivitis- minimal
ocular discomfort and photophobia.
• Severe cases- pseudomembranous and
membranous conjunctivitis. Discomfort
and photophobia more pronounced.
• The raw surfaces can lead to adhesion
formation between the palpebral and
bulbar conjunctiva, known as
symblepharon.

Eyelids:
• Contracture of the palpebral conjunctiva can yield cicatricial entropion.
• Lid margin inflammation can cause widespread destruction of meibomian
gland orifices and the glands themselves.
• Eyelash architecture can also be affected, resulting in trichiasis and
distichiasis.
• Keratinization of the lid margins and palpebral conjunctiva further
contributes to discomfort and corneal damage via blink-related
microtrauma to the corneal epithelium.

Cornea:
• The abnormally directed lashes can abrade the
compromised ocular surface and lead to
discomfort, corneal abrasions, and corneal
ulceration.
• Destruction of the corneal limbal stem cells
can lead to vascularization and thickening of
the corneal epithelium.
• This “conjunctivalization” of the cornea,
accompanied by the abnormal tear film,
produces severe visual loss. Additionally, it
creates a poor prognosis for any future
corneal transplantation

Management:
1. Acute cases
• Non-surgical:
– Preservative free topical lubricant,
antibiotic, steroid
– Fornicial swiping with lubricating
ointment (to prevent symblepheron)
– Symblepheron rings: oval-shaped rings
with a round window cut out over the
cornea.

STEVEN JOHNSON SYNDROME
• Surgical:
Amniotic membrane: minimize the
destructive inflammation during the
acute phase of SJS
Indication-
– membranous conjunctivitis, early
symblepharon formation, and
intense lid margin inflammation with
lash loss

SUMMARY
A careful and detailed case history is important to reveal
a patient’s medication history
The ocular and visual side effects from a patient’s
systemic medication can range from mild to severe.
 These side effects may or may not be serious enough to
warrant discontinuing treatment.
 Recognition of ocular and visual side effects is important
for prompt management to prevent and minimize serious
complications
 Familiarity with medications improves by routinely
paying attention to concomitant medications.

Ocular side effects of systemic drugs

Ocular side effects of systemic drugs

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Ocular side effects of systemic drugs