OCULAR SIDE EFFECTS OF SYSTEMIC DRUGS

PRESENTER- ANJU NAGARDATE : 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

IntroductionDrug 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 drugsTamsulosin(alpha adrenergic blocker)Sildenafil (Block hyperpolarisation of photoreceptors)

2. Altered metabolism – increased drug concentrationTherapeutic windowMetabolism by liver/ kidney-

ethambutol toxicity in renal impairment; digoxin.

Different metabolism in young agePossibility of drug transferDrug interaction

Possible basis of ocular side effects of systemic drugs

3. Predisposition to allergy in atopic individuals- Steven Johnson

4. Toxicity due to overdosequinine, Chloroquine

5. Teratogenecity

6. Idiopathic & idiosyncratic- side effects even at correct doseDiplopia- Glitazone, ethambutol, steroid, topiramate Floroquinolone.BIH- vitamin ARed tears- rifampicin in leprosy

Possible basis of ocular side effects of systemic drugs

7. Recreational drugsCanthaxanthin-gold dust retinopathyLSDAyahuasca tea(hallucinogen)

8. Adverse new side effects

Drugs Affecting CorneaVortex 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

Drugs Affecting Cornea

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.

Drugs Affecting Cornea

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

Drugs Affecting CorneaCHLORPROMAZINE:INDICATIONS- sedative; psychotic illnessesSIGNS- 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.

Drugs Affecting CorneaARGYROSIS:

discoloration of ocular tissues secondary to silver deposits, and may be iatrogenic or from occupational exposure.

Keratopathy is characterized by greyishbrown granular deposits in Descemet

membrane.

The conjunctiva may also be affected.

Drugs Affecting CorneaCHRYSIASIS:• 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.

Drugs Affecting CorneaAMANTADINE: 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 LensSTEROIDS: 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 equiva lent), or treated for less than 4 years may be immune.

Drugs Affecting Lens– 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

Drugs Affecting LensCHLORPROMAZINE:• 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.

Drugs Affecting LensBUSULPHAN (MYLERAN): INDICATIONS: Treatment of chronic myeloid leukemia. SIGNS: Occasionally cause lens opacities. GOLD: INDICATIONS:used in the treatment of rheumatoid arthritisSIGNS:Causes innocuous anterior capsular deposits in about 50% of patients on

treatment for longer than 3 years.

Drugs Affecting Lens 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 uveitisRIFABUTIN:INDICATIONS: Tuberculosis in combination

with other drugs in immuno competent 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.

Drugs causing uveitis• 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

Drugs causing uveitisCidofovir

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 retinaANTIMALARIALS: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 RETINOPATHYChloroquine 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.

CHLOROQUINE RETINOPATHY2. 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.

CHLOROQUINE RETINOPATHY3. 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 reduction of visual acuity (6/36–6/60)

– Wide spread RPE atrophy surrounding the fovea.

CHLOROQUINE RETINOPATHY5. End-stage maculopathy

– Characterized by severe reduction of visual acuity

– 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 RETINAPHENOTHIAZINES: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.

DRUG-INDUCED CRYSTALLINE 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.

DRUG-INDUCED CRYSTALLINE 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.

DRUG-INDUCED CRYSTALLINE MACULOPATHIES

Interferon-alpha: chemotherapeutic Delayed type hypersensitivity reactionOCULAR 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.

DRUG-INDUCED CRYSTALLINE 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.

DRUG-INDUCED CRYSTALLINE 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

DRUGS AFFECTING OPTIC NERVE: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 con striction 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.

DRUGS AFFECTING OPTIC NERVE: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.

DRUGS AFFECTING OPTIC NERVE: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.

DRUGS AFFECTING OPTIC NERVE: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.

DRUGS AFFECTING OPTIC NERVE: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.

DRUGS AFFECTING OPTIC NERVE: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 EYE1. Beta blockers2. Diuretics(change the tear film)3. Niacin 4. Oral contraceptives5. 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 PUPILDRUGS- 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 IOPINCREASE 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. Barbiturate3. Oculomotor nerve palsy- interferon alpha

Visual sensation: • Digitalis

RARE OCULAR SIDE EFFECTS Visual hallucinations:1. Levothyroxine2. Cimetidine/ranitidine(H2 receptor blocker)

Nystagmus: 1. Lithium2. Barbiturate3. Phenytoin4. Carbamazepine Diplopia:1. Lithium2. Antianxiety3. NSAIDs4. Tetracycline

RARE OCULAR SIDE EFFECTS Eyelid hyperemia:1. Levothyroxine.

Ptosis:1. Barbiturate 2. Chloroquine

Visual field changes:1. Vigabatrin2. Paracentral scotoma: Chloroquine

Pseudotumor cerebri:1. Amiodarone2. Levothyroxine3. OCPs4. NSAIDs5. Isotretinoin6. 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”

SILDENAFILinhibits 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.

STEVEN-JOHNSON SYNDROMEThe ophthalmic pathology mainly involves:• conjunctiva, both bulbar and palpebral, • cornea, • lid margins and skin• eyelashes.

STEVEN-JOHNSON SYNDROMEConjunctiva:• 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.

STEVEN-JOHNSON SYNDROMEEyelids:• 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.

STEVEN-JOHNSON SYNDROMECornea: • 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

STEVEN-JOHNSON SYNDROMEManagement: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

SUMMARYA 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.