Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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 27 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 28 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 29 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. 30 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. 31 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 32 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. 33 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. 34 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 35 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 36 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. 37 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. 38 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 References 7. Esther kim, Howard F Fine, Michael D. Retinal and Uveal Drug 1. 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; 51:535-549 3. Blain P. Paques M, Massin P, Erginay A, Santiago P, Gaudric A. Acute transient myopia induced by indapamide. Am J Ophthalmol ophthalmol 2011;59: 137-141. 6. Cynthia A. Carvalho-Recchia, Lawrence A. Cortico- steroids and Central Serous Chorioretinopathy Ophthalmology. 2008;109:1834– 1837. 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)137781. 9. C. Lisa Prokopich, Jimmy D. Bartlett, and Siret D Jaanus. Chapter 35, Ocular adverse drug reactions to systemic medications. 2000;129:538-40. 10. Song M K, Azen S P, Buley A. Effect of anti-cytomegalovirus 4. Debra A. Schwinn, Natalie A. Afshari.a1-Adrenergic Receptor therapy on the incidence of immune recovery uveitis in AIDS Antagonists and the Iris: New mechanistic insights into Floppy Iris patients with healed cytomegalovirus retinitis. Am J Ophthalmol Syndrome. Surv Opthalmol 2006;51(5):501-512. 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 39