ocular adverse effects of common systemic · pdf file27 ocular adverse effects of common...

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Ocular Adverse Effects Of Common Systemic Medications

Address for correspondence: Giridhar Eye Institute, Kochi

N. Sandhya MS

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

Major Review

Vol. XXIV, No.1, Mar. 2012

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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 green-yellow 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

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.

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Grades of Amiodarone keratopathyGrade-1 Grade-2 Grade-3

A case of Amiodarone keratopathy

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.

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.

Corticosteroids

One of the most common ocular side effect of corticosteroids

Drugs Affecting the Lens

is cataract. The use of systemic, ophthalmic, dermatologic,

nasal, aerosol or inhalation steroids all have been implicated

in causing posterior subcapsular cataracts which are clinically

indistinguishable from that produced by other causes

including age-related PSC cataracts. The incidence of steroid

induced cataract is 6.4%-38.7%.

Sandhya - Adverse effects of common medications


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Drugs Affecting Episclera, Sclera And UveaCataract Cataract

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.

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

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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

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 PupilSympathetics 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.

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

edema and rotation or peripheral choroidal detachment which produce forward displacement and thickening of lens-iris 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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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 PressureSeveral 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 steroid-

specific receptors on the trabecular meshwork activate TM

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.

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Chloroquine and Hydroxychloroquine

A fine pigmentary mottling within the macular area with or without loss of foveal reflex is the first visible evidence of chloroquine retinopathy. Even before visible ophthalmoscopic changes are detectable, a ‘pre maculopathy’ state can exist in which the drug interferes with metabolism of the macular tissues causing subtle visual field defects. As macular changes progress, a classic pattern pathognomonic of chloroquine toxicity referred to as “bull’s eye maculopathy” develops consisting of an area of granular hyper pigmentation surrounded by a zone of depigmentation which in turn is surrounded by another ring of pigment. In 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.

Some patients can have changes resembling retinitis pigmentosa (RP). Chloroquine retinopathy does exhibit RPE hyperplasia but unlike RP the pigments do not accumulate

around the retinal veins. Peripheral lesions can occur with or without simultaneous macular involvement. Other changes include attenuated retinal vessels, optic atrophy, peripheral visual field loss, abnormal color vision, and a subnormal electro-retinogram. Unlike retinitis pigmentosa, the dark adaptation is normal or only minimally abnormal. Visual field loss correlates well with retinal damage. Typical visual field defects consist of central or paracentral scotoma, which may become confluent and form a complete ring. Advanced cases of retinopathy exhibit markedly abnormal or even extinguished ERGs. These changes produce symptoms of metamorphopsia, decreased visual acuity and impaired color vision.

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 minimal if the daily dose of hydroxychloroquine is less than 6.5mg/kg and the duration of treatment is less than 5 years and the renal function is normal.



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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

and MF ERG at baseline and at each visit is recommended for

screening patients on hydroxychloroquine. Other tests like

fundus color photo, FFA, time domain OCT, Amsler charting,

color vision tests and EOG are not of much use for screening.

Digoxin

Digoxin is widely used in patients with congestive heart

failure and in cardiac arrhythmias like atrial fibrillation.

Approximately 80% of patients with digoxin toxicity

demonstrate generalized color vision deficiencies. But

detectable color vision impairment or other visual symptoms

can occur even at therapeutic drug levels.

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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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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

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.

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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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Characteristics of optic neuropathy due to ethambutol

Color vision deficiencies are the most sensitive indicator of ethambutol optic neuropathy, which can occur even 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 peripheral neuropathy may indicate early toxicity and should serve as a warning sign of impending optic neuropathy. If 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.

Chloramphenicol

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.

Drugs affecting extra ocular muscles

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.

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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.

References1. Srikantia N, Mukesh S, Krishnaswamy M. Crystalline maculopathy : A rare complication of tamoxifen therapy: J Can Res Ther 2011; 6: 313-5. 2. Drenser K, Sarraf D, Atul Jain. Crystalline Retinopathies: Surv Ophthalmol 2006; 51:535-5493. Blain P. Paques M, Massin P, Erginay A, Santiago P, Gaudric A. Acute transient myopia induced by indapamide. Am J Ophthalmol 2000;129:538-40. 4. Debra A. Schwinn, Natalie A. Afshari.a1-Adrenergic Receptor Antagonists and the Iris: New mechanistic insights into Floppy Iris Syndrome. Surv Opthalmol 2006;51(5):501-512.

5. Pradeep Sharma,Reena Sharma.Toxic optic neuropathy. Indian J ophthalmol 2011;59: 137-141.6. Cynthia A. Carvalho-Recchia, Lawrence A. Cortico- steroids and Central Serous Chorioretinopathy Ophthalmology. 2008;109:1834–1837.7. Esther kim, Howard F Fine, Michael D. Retinal and Uveal Drug Toxicity.Retinal Physician. January 2008;8. Michael F. Marmor, Ronald E. Carr, Michael Easterbrook. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy. Ophthalmology. 2002;109(7)1377-81.9. C. Lisa Prokopich, Jimmy D. Bartlett, and Siret D Jaanus. Chapter 35, Ocular adverse drug reactions to systemic medications.10. Song M K, Azen S P, Buley A. Effect of anti-cytomegalovirus therapy on the incidence of immune recovery uveitis in AIDS patients with healed cytomegalovirus retinitis. Am J Ophthalmol 2003;136:696-702.


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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