Systemic Medications and Their Effects on the Retina and Choroid: An Updated Review Systemic Drugs and Retinal–Choroidal Effects
Article Sidebar
Main Article Content
Abstract
This review provides a comprehensive analysis of systemic medications and illicit substances that can lead to various forms of retinal and choroidal toxicity. Accurate diagnosis requires a detailed medication history and the identification of characteristic retinal changes using multimodal imaging techniques. The discussion includes drugs associated with retinal pigment epithelial disruption, vascular alterations, cystoid macular edema, crystalline deposits, drug-induced retinal folds, and uveitis. The ocular effects of emerging chemotherapeutic and immunotherapeutic agents are also examined. Key mechanisms of action, preventive strategies, and available treatment options are explored in detail. The focus is on medications frequently encountered in ophthalmic practice and important considerations for eye care professionals. Many drug-induced retinal toxicities are reversible with discontinuation of the medication, especially when detected early before causing significant visual impairment. However, certain agents may lead to permanent and progressive retinal damage. Close monitoring and timely intervention by ophthalmologists are essential. This review highlights the importance of early detection and proper management of medication-induced retinal and choroidal toxicity to reduce the risk of vision loss and related complications.
Downloads
Article Details
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Articles in this journal are copyrighted by the x may be read and used for academic purposes, such as teaching, research, or citation, with proper credit given to the author and the journal.use or modification of the articles is prohibited without permission.
statements expressed in the articles are solely the opinions of the authors.
authors are fully responsible for the content and accuracy of their articles.
other reuse or republication requires permission from the journal."
References
Stokkermans TJ, Falkowitz DM, Trichonas G. Chloroquine and hydroxychloroquine toxicity. In: StatPearls, editor. StatPearls Publishing; 2024.
Bernstein H, Zvaifler N, Rubin M, Mansour AM. The ocular deposition of chloroquine. Invest Ophthalmol 1963;2(4):384-92.
Ivanina TA, Zueva MV, Lebedeva MN, Bogoslovsky AI, Bunin AJ. Ultrastructural alterations in rat and cat retina and pigment epithelium induced by chloroquine. Graefes Arch Clin Exp Ophthalmol 1983;220(1):32-8. doi: 10.1007/BF02307013.
Pasadhika S, Fishman GA, Choi D, Shahidi M. Selective thinning of the perifoveal inner retina as an early sign of hydroxychloroquine retinal toxicity. Eye (Lond) 2010;24(5):756-62. doi: 10.1038/eye.2010.21.
Xu C, Zhu L, Chan T, Lu X, Shen W, Madigan MC, et al. Chloroquine and hydroxychloroquine are novel inhibitors of human organic anion transporting polypeptide 1A2. J Pharm Sci 2016;105(2):884-90. doi: 10.1002/jps.24663.
Somisetty S, Santina A, Sarraf D, Mieler WF. The impact of systemic medications on retinal function. Asia Pac J Ophthalmol (Phila) 2023;12(2):115-57. doi: 10.1097/APO.0000000000000605.
Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 Revision). Ophthalmology 2016;123(6):1386-94. doi: 10.1016/j.ophtha.2016.01.058.
Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol 2014;132(12):1453-60. doi: 10.1001/jamaophthal-mol.2014.3459.
Kellner U, Renner AB, Tillack H. Fundus autofluorescence and mfERG for early detection of retinal alterations in patients using chloroquine/hydroxychloroquine. Invest Ophthalmol Vis Sci 2006;47(8):3531-8. doi: 10.1167/iovs.05-1290.
Maturi RK, Yu M, Weleber RG. Multifocal electroretinographic evaluation of long-term hydroxychloroquine users. Arch Ophthalmol 2004;122(7):973-81. doi: 10.1001/archopht.122.7.973.
Lyons JS, Severns ML. Detection of early hydroxychloroquine retinal toxicity enhanced by ring ratio analysis of multifocal electroretinography. Am J Ophthalmol 2007;143(5):801-9. doi: 10.1016/j.ajo.2006.12.042.
Wolfe F, Marmor MF. Rates and predictors of hydroxy-chloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res (Hoboken) 2010;62(6):775-84. doi: 10.1002/acr.20133.
Garrity ST, Jung JY, Zambrowski O, Pichi F, Su D, Arya M, et al. Early hydroxychloroquine retinopathy: optical coherence tomography abnormalities preceding Humphrey visual field defects. Br J Ophthalmol 2019;103(11):1600-4. doi: 10.1136/bjophthalmol-2018-313350.
Santina A, Fogel-Levin M, Abraham N, Sarraf D. Nine-year progression of pentosan maculopathy with multimodal retinal imaging. Retin Cases Brief Rep 2023;17(6):664-7. doi: 10.1097/ICB.0000000000001276.
Barnett JM, Jain N. Potential new-onset clinically detectable pentosan polysulfate maculopathy years after drug cessation. Retin Cases Brief Rep 2022;16(6):724-6. doi: 10.1097/ICB.0000000000001090.
Somisetty S, Santina A, Abraham N, Lu A, Morales VR, Sarraf D. Rapid pentosan polysulfate sodium maculopathy progression. Retin Cases Brief Rep 2023;17(6):660-3. doi: 10.1097/ICB.0000000000001273.
Somisetty S, Santina A, Au A, Romero-Morales V, Bousquet E, Sarraf D. Progression of pentosan polysulfate sodium maculopathy in a prospective cohort. Am J Ophthalmol 2023;255:57-67. doi: 10.1016/j.ajo.2023.05.021.
Kinross-Wright V. Clinical trial of a new phenothiazine compound: NP-207. Psychiat Res Rep 1956(4):89-94.
Meredith TA, Aaberg TM, Willerson WD. Progressive chorioretinopathy after receiving thioridazine. Arch Ophthalmol 1978;96(7):1172-6. doi: 10.1001/archopht.1978. 03910060006002.
Miyata M, Imai H, Ishikawa S, Nakajima S. Change in human electroretinography associated with thioridazine administration. Ophthalmologica 1980;181(3-4):175-80. doi: 10.1159/000309049.
Miller FS 3rd, Bunt-Milam AH, Kalina RE. Clinical-ultrastructural study of thioridazine retinopathy. Ophthalmology 1982;89(12):1478-88. doi: 10.1016/s0161-6420(82)34613-8.
Siddall JR. The ocular toxic findings with prolonged and high dosage chlorpromazine intake. Arch Ophthalmol 1965;74(4):460-4. doi: 10.1001/archopht.1965.00970040462005.
Wu CH, Yang CP, Lai CC, Wu WC, Chen YH. Deferoxamine retinopathy: spectral domain-optical coherence tomography findings. BMC ophthalmol 2014;14:1-3. doi: 10.1186/1471-2415-14-88.
Viola F, Barteselli G, Dell’arti L, Vezzola D, Villani E, Mapelli C, et al. Abnormal fundus autofluorescence results of patients REVIEW ARTICLE in long-term treatment with deferoxamine. Ophthalmology 2012;119(8):1693-700. doi: 10.1016/j.ophtha.2012.01.039
Vahdani K, Makrygiannis G, Kaneshyogan H, Sian IS, Giasin O. Bilateral central serous retinopathy in a patient with paroxysmal nocturnal hemoglobinuria treated with deferoxamine. Eur J Ophthalmol 2016;26(6):e152-4. doi: 10.5301/ejo.5000840.
Brittenham GM. Iron-chelating therapy for transfusional iron overload. N Engl J Med 2011;364(2):146-56. doi: 10.1056/NEJMct1004810.
Booth AEC, Hopkins AM, Rowland A, Kichenadasse G, Smith JR, Sorich MJ. Risk factors for MEK-associated retinopathy in patients with advanced melanoma treated with combination BRAF and MEK inhibitor therapy. Ther Adv Med Oncol 2020;12:1758835920944359. doi: 10.1177/1758835920944359.
Nti AA, Serrano LW, Sandhu HS, Uyhazi KE, Edelstein ID, Zhou EJ, et al. Frequent subclinical macular changes in combined BRAF/MEK inhibition with high-dose hydroxy-chloroquine as treatment for advanced metastatic BRAF mutant melanoma: preliminary results from a phase I/II clinical treatment trial. Retina 2019;39(3):502-13. doi: 10.1097/IAE.0000000000002027
Francis JH, Habib LA, Abramson DH, Yannuzzi LA, Heinemann M, Gounder MM, et al. Clinical and morphologic characteristics of MEK inhibitor–associated retinopathy: differences from central serous chorioretinopathy. Ophthalmology 2017;124(12):1788-98. doi: 10.1016/j.ophtha.2017.05.038.
Mozo Cuadrado M, Tabuenca Del Barrio L, Compains Silva E. Bilateral drug-induced uveitis and epiretinal membrane during the treatment of a metastatic cutaneous melanoma. Ocul Immunol Inflamm 2021;29(3):543-5. doi: 10.1080/09273948.2019.1685111.
Ramtohul P, Denis D, Comet A. Pseudovitelliform maculopa-thy associated with FGFR inhibitor therapy. Ophthalmol Retina 2021;5(2):140. doi: 10.1016/j.oret.2020.10.005.
Alekseev O, Ojuok E, Cousins S. Multifocal serous retinopathy with pemigatinib therapy for metastatic colon adenocarcinoma. Int J Retina Vitreous 2021;7(1):34. doi: 10.1186/s40942-021-00305-9.
Fraunfelder FW, Fraunfelder FT, Illingworth DR. Adverse ocular effects associated with niacin therapy. Br J Ophthalmol 1995;79(1):54-6. doi: 10.1136/bjo.79.1.54.
Freisberg L, Rolle TJ, Ip MS. Diffuse macular edema in niacin-induced maculopathy may resolve with dosage decrease. Retin Cases Brief Rep 2011;5(3):227-8. doi: 10.1097/ICB.0b013e3181e180c0.
Joshi MM, Garretson BR. Paclitaxel maculopathy. Arch Ophthalmol 2007 May;125(5):709-10. doi: 10.1001/archopht.125.5.709.
Telander DG, Sarraf D. Cystoid macular edema with docetaxel chemotherapy and the fluid retention syndrome. Semin Ophthalmol 2007;22(3):151-3. doi: 10.1080/08820530701457373.
Dwivedi R, Tiroumal S. Possible efficacy of topical dorzolamide in the treatment of paclitaxel-related cystoid macular edema. Retin Cases Brief Rep 2018;12(1):75-79. doi: 10.1097/ICB.0000000000000433.
Pul R, Osmanovic A, Schmalstieg H, Pielen A, Pars K, Schwenkenbecher P, et al. Fingolimod associated bilateral cystoid macular edema-wait and see? Int J Mol Sci 2016;17(12):2106. doi: 10.3390/ijms17122106.
Afshar AR, Fernandes JK, Patel RD, Ksiazek SM, Sheth VS, Reder AT, et al. Cystoid macular edema associated with fingolimod use for multiple sclerosis. JAMA Ophthalmol 2013;131(1):103-7. doi: 10.1001/jamaophthalmol.2013.570.
Chui J, Herkes GK, Chang A. Management of fingolimod-associated macular edema. JAMA Ophthalmol 2013;131(5):694-6. doi: 10.1001/jamaophthalmol.2013.47.
Schröder K, Finis D, Harmel J, Ringelstein M, Hartung HP, Geerling G, et al. Acetazolamide therapy in a case of fingolimod-associated macular edema: early benefits and long-term limitations. Mult Scler Relat Disord 2015;4(5):406-8. doi: 10.1016/j.msard.2015.06.015.
Thoo S, Cugati S, Lee A, Chen C. Successful treatment of fingolimod-associated macular edema with intravitreal triamcinolone with continued fingolimod use. Mult Scler 2015;21(2):249-51. doi: 10.1177/1352458514528759.
Friberg TR, Gragoudas ES, Regan CD. Talc emboli and macular ischemia in intravenous drug abuse. Arch Ophthalmol 1979;97(6):1089-91. doi: 10.1001/archopht.1979.01020010543006.
Ruys J, de Smet MD, Van de Sompel W. Bilateral talc maculopathy and fibrovascular proliferation in a drug abuser. Retin Cases Brief Rep 2010;4(2):123-4. doi: 10.1097/ICB.0b013e31819bfa57.
Martidis A, Yung CW, Ciulla TA. Talc embolism: a static retinopathy. Am J Ophthalmol 1997;124(6):841-3. doi: 10.1016/s0002-9394(14)71704-0.
Niazi S, Gnesin F, Jawad BN, Niazi Z, Løkkegaard E, Mørch L, et al. Hormonal contraception and retinal vascular occlusion risk. Am J Ophthalmol 2025;277:286-94. doi: 10.1016/j.ajo.2025.05.027.
Gombos GM, Moreno DH, Bedrossian PB. Retinal vascular occlussion induced by oral contraceptives. Ann Ophthalmol 1975;7(2):215-7.
Perry HD, Mallen FJ. Cilioretinal artery occlusion associated with oral contraceptives. Am J Ophthalmol 1977;84(1):56-8. doi: 10.1016/0002-9394(77)90323-3.
Varga M. Recent experiences on the ophthalmologic complications of oral contraceptives. Ann Ophthalmol 1976;8(8):925-34.
Vessey MP, Hannaford P, Mant J, Painter R, Frith P, Chappel D. Oral contraception and eye disease: findings in two large cohort studies. Br J Ophthalmol 1998;82(5):538-42. doi: 10.1136/bjo.82.5.538.
Schulman JA, Liang C, Kooragayala LM, King J. Posterior segment complications in patients with hepatitis C treated with interferon and ribavirin. Ophthalmology 2003;110(2):437-42. doi: 10.1016/S0161-6420(02)01741-4.
Tokai R, Ikeda T, Miyaura T, Sato K. Interferon-associated retinopathy and cystoid macular edema. Arch Ophthalmol 2001;119(7):1077-9. doi: 10.1001/archopht.119.7.1077.
Hejny C, Sternberg P, Lawson DH, Greiner K, Aaberg TM Jr. Retinopathy associated with high-dose interferon alfa-2b therapy. Am J Ophthalmol 2001;131(6):782-7. doi: 10.1016/s0002-9394(01)00836-4
Fraunfelder FW, Fraunfelder FT. Interferon alfa-associated anterior ischemic optic neuropathy. Ophthalmology 2011;118(2):408-11.e1-2. doi: 10.1016/j.ophtha.2010.03.063.
Nishiwaki H, Ogura Y, Miyamoto K, Matsuda N, Honda Y. Interferon alfa induces leukocyte capillary trapping in rat retinal microcirculation. Arch Ophthalmol 1996;114(6):726-30. doi: 10.1001/archopht.1996.01100130718014.
Willson RL, Ross RD, Willson LM, Cohen G, Redfield TL, Gitter KA. Interferon-associated retinopathy in a young, insulin-dependent diabetic patient. Retina 2000;20(4):413-5. doi: 10.1097/00006982-200004000-00023.
Mindel JS, Rubenstein AE, Franklin B. Ocular ergotamine tartrate toxicity during treatment of Vacor-induced orthostatic hypotension. Am J Ophthalmol 1981;92(4):492-6. doi: 10.1016/0002-9394(81)90641-3.
Kaiser-Kupfer MI, Kupfer C, Rodrigues MM. Tamoxifen retinopathy. A clinicopathologic report. Ophthalmology 1981;88(1):89-93. doi: 10.1016/s0161-6420(81)35071-4.
Heier JS, Dragoo RA, Enzenauer RW, Waterhouse WJ. Screening for ocular toxicity in asymptomatic patients treated with tamoxifen. Am J Ophthalmol 1994;117(6):772-5. doi: 10.1016/s0002-9394(14)70321-6.
Bazvand F, Mahdizad Z, Mohammadi N, Shahi F, Mirghorbani M, Riazi-Esfahani H, et al. Tamoxifen retinopathy. Surv Ophthalmol 2023;68(4):628-40. doi: 10.1016/j.survoph- thal.2023.02.003.
Rahimy E, Sarraf D. Bevacizumab therapy for tamoxifen-induced crystalline retinopathy and severe cystoid macular edema. Arch Ophthalmol 2012;130(7):931-2. doi: 10.1001/archoph- thalmol.2011.2741.
Jeng KW, Wheatley HM. Intravitreal triamcinolone acetonide treatment of tamoxifen maculopathy with associated cystoid macular edema. Retin Cases Brief Rep 2015;9(1):64-6. doi: 10.1097/ICB.0000000000000093.
Chan A, Ko TH, Duker JS. Ultrahigh-resolution optical coherence tomography of canthaxanthine retinal crystals. Ophthalmic Surg Lasers Imaging 2006;37(2):138-9. doi: 10.3928/1542-8877-20060301-09.
Weber U, Goerz G, Baseler H, Michaelis L. Canthaxanthin-retinopathie. Follow-up of over 6 years. Klin Monbl Augenheilkd 1992;201(3):174-7. doi: 10.1055/s-2008-1045888.
Novak MA, Roth AS, Levine MR. Calcium oxalate retinopathy associated with methoxyflurane abuse. Retina 1988;8(4):230-6. doi: 10.1097/00006982-198808040-00002.
Dalvin LA, Shields CL, Orloff M, Sato T, Shields JA. Checkpoint inhibitor immune therapy: systemic indications and ophthalmic side effects. Retina 2018;38(6):1063-78. doi: 10.1097/IAE.0000000000002181.
Thomas S, Bae C, Joy-Ann T, Traverse W. Behcet’s-like syndrome following pembrolizumab: an immune-related adverse event associated with programmed death receptor-1 inhibitor therapy. J Oncol Pharm Pract 2020;26(4):995-9. doi: 10.1177/1078155219877219.
Fusumae T, Kamiya K, Maekawa T, Komine M, Murata S, Inoda S, et al. Vogt-Koyanagi-Harada disease-like uveitis induced by vemurafenib for metastatic cutaneous malignant melanoma. J Dermatol 2018;45(6):e159-60. doi: 10.1111/1346-8138.14200.
Agemy SA, Mehta AN, Pachydaki SI, Tewari A. Bilateral panuveitis in a patient on vemurafenib BRAF inhibitor therapy for stage IV melanoma. Eur J Ophthalmol 2014;24(4):629-32. doi: 10.5301/ejo.5000423.
Fraunfelder FW, Fraunfelder FT, Keates EU. Topiramate-associated acute, bilateral, secondary angle-closure glaucoma. Ophthalmology 2004;111(1):109-11. doi: 10.1016/j.ophtha.2003.04.004.
Yan H, Yu W. Retinal toxicity of long term overdose of sildenafil citrate: a case report. Am J Ophthalmol Case Rep 2022;29:101761. doi: 10.1016/j.ajoc.2022.101761.
Vignal-Clermont C, Audo I, Sahel JA, Paques M. Poppers-associated retinal toxicity. N Engl J Med 2010;363(16):1583-5. doi: 10.1056/NEJMc1005118.
Ali A, Shah AA, Jeang LJ, Fallgatter KS, George TJ, DeRemer DL. Emergence of ocular toxicities associated with novel anticancer therapeutics: what the oncologist needs to know. Cancer Treat Rev 2022;105:102376. doi: 10.1016/j.ctrv.2022.102376.
Bhavsar KV, Lin S, Rahimy E, Joseph A, Freund KB, Sarraf D, Cunningham ET Jr. Acute macular neuroretinopathy: a comprehensive review of the literature. Surv Ophthalmol 2016;61(5):538-65. doi: 10.1016/j.survophthal.2016.03.003.
Guo J, Tang W, Liu W, Zhang Y, Wang L, Wang W. Bilateral methamphetamine-induced ischemic retinopathy. Am J Ophthalmol Case Rep 2019;15:100473. doi: 10.1016/j.ajoc.2019.100473.
Aktaş S, Tetikoğlu M, İnan S, Aktaş H, Özcura F. Unilateral hemorrhagic macular infarction associated with m arijuana, alcohol and antiepileptic drug intake. Cutan Ocul Toxicol 2017;36(1):88-95. doi: 10.3109/15569527.2016.1141420.
