What causes ocular toxicity?: A Comprehensive Look at Medication and Other Causes

October 10, 2025 •

5 min read

Did you know that the eye is the second most common organ to show drug toxicities, after the liver? Understanding what causes ocular toxicity is crucial for medication safety, as adverse effects can range from minor irritations to permanent vision loss, making early detection vital.

Quick Summary

An exploration of the pharmacological mechanisms and specific drugs that lead to ocular toxicity, detailing how various systemic and topical medications affect different parts of the eye and outlining key risk factors for adverse reactions.

Key Points

Diverse Mechanisms: Ocular toxicity is caused by various pharmacological mechanisms, including drug accumulation, mitochondrial dysfunction, oxidative stress, and vascular disruption.
Melanin Binding: Drugs like hydroxychloroquine and phenothiazines bind to melanin in the RPE, leading to metabolic disruption and retinal damage over time.
Mitochondrial Vulnerability: High-energy tissues like the optic nerve are susceptible to drugs that interfere with mitochondrial function, such as ethambutol, causing optic neuropathy.
Risk Factors are Varied: The risk of ocular toxicity depends on the drug's cumulative dose and treatment duration, as well as individual patient factors like age, genetics, and co-existing renal or liver disease.
Irreversible Damage: While some effects like corneal deposits are reversible, retinal and optic nerve damage can be permanent, sometimes progressing even after the medication is discontinued.
Early Detection is Crucial: Proactive monitoring with advanced imaging techniques like SD-OCT and visual field testing is the best strategy for high-risk patients to detect toxicity early and mitigate vision loss.

The intricate structure of the eye makes it a potential target for systemic medications and environmental toxins. While the blood-ocular barriers typically offer protection, some compounds can cross these barriers and accumulate in ocular tissues, leading to adverse effects. The resulting damage can manifest in different parts of the eye, from the cornea and lens to the retina and optic nerve, and can result from various pharmacological mechanisms.

Pharmacological Mechanisms of Ocular Toxicity

Understanding the specific ways drugs cause harm is key to preventing and managing ocular toxicity. Several pathways contribute to drug-induced damage in the eye.

Accumulation in Melanin-Rich Tissues

One prominent mechanism involves drugs with a high affinity for melanin, the pigment found in the retinal pigment epithelium (RPE) and the uveal tract. This is a major factor in the toxicity caused by antimalarial drugs like hydroxychloroquine and psychiatric medications like phenothiazines.

Binding to Melanin: Medications bind to the melanin pigment, leading to their concentration and prolonged retention in the RPE.
Metabolic Disruption: The accumulated drugs interfere with the RPE's metabolic functions, including its ability to process waste products from photoreceptors.
Cell Damage: Over time, this disruption leads to RPE cell damage and migration, followed by degeneration of the nearby photoreceptor cells.

Mitochondrial Dysfunction

Some drugs can damage the mitochondria, the powerhouses of cells, which is particularly detrimental to high-energy-demand tissues like the optic nerve and retinal ganglion cells.

Energy Depletion: Interference with mitochondrial oxidative phosphorylation can cause energy depletion and dysfunction, especially in the sensitive papillomacular bundle of the optic nerve.
Optic Neuropathy: This mechanism is primarily responsible for the optic neuropathy caused by medications such as ethambutol, linezolid, and chloramphenicol.

Oxidative Stress and Cellular Disruption

Certain medications can induce oxidative stress, where the production of free radicals overwhelms the eye's antioxidant defenses, causing cellular damage. This mechanism can disrupt critical cellular barriers, like the blood-aqueous and blood-retinal barriers, allowing more drug to enter the eye and potentiating toxicity.

Vascular Damage and Fluid Accumulation

Vascular changes caused by medications can lead to fluid accumulation in the retina. Some cancer therapies, like MEK inhibitors, can cause serous retinal detachments due to dysfunction in the RPE, which normally pumps fluid out of the subretinal space. Other drugs, such as sildenafil, can affect retinal vasculature and lead to macular detachment.

Specific Medications and Ocular Effects

An awareness of common culprits is essential for all healthcare providers and patients.

Antimalarials (Hydroxychloroquine, Chloroquine): These drugs cause retinopathy, often presenting as characteristic "bull's-eye" maculopathy. They can also cause reversible corneal deposits (vortex keratopathy).
Ethambutol: This anti-tuberculosis agent can cause optic neuropathy, leading to decreased visual acuity and color vision loss.
Tamoxifen: Used in breast cancer treatment, it can cause crystalline retinopathy, macular edema, and cataracts, with risks linked to high dosage and long-term use.
Amiodarone: An antiarrhythmic drug, it is well-known for causing vortex keratopathy and, in rarer cases, optic neuropathy.
Phenothiazines (e.g., Thioridazine): These psychiatric drugs can cause a dose-dependent retinopathy by accumulating in the RPE.
Corticosteroids: Extended use, whether topical or systemic, can lead to posterior subcapsular cataracts and elevated intraocular pressure, which can cause glaucoma.
MEK Inhibitors: These targeted cancer drugs have been linked to serous retinal detachments.

Comparison of Common Drug-Induced Ocular Toxicities


Drug/Class	Ocular Effect	Primary Mechanism	Key Risk Factors	Reversibility
Hydroxychloroquine	Retinopathy ('bull's-eye' maculopathy), Vortex Keratopathy	Melanin binding, RPE disruption, lysosomal damage	Cumulative dose, duration >5 years, renal disease, genetics	Keratopathy is reversible; retinopathy often irreversible, can progress after cessation
Ethambutol	Optic Neuropathy (bilateral, painless vision loss)	Mitochondrial dysfunction, disrupting metal-containing enzymes	High dose, renal dysfunction, prolonged use	Often irreversible, but early discontinuation can lead to some recovery
Tamoxifen	Crystalline Retinopathy, Macular Edema, Cataracts	Not fully understood; possibly related to cellular lipid disruption	High cumulative dose, duration of use	Retinopathy often irreversible; macular edema may improve with cessation
Amiodarone	Vortex Keratopathy, Optic Neuropathy	Accumulation of drug in cellular lipids; unknown for optic nerve	Dose-dependent	Keratopathy reversible; optic neuropathy may or may not improve with cessation
Corticosteroids	Cataracts, Glaucoma (raised IOP)	Multiple mechanisms (e.g., disrupting lens proteins, altering aqueous humor outflow)	Cumulative dose, duration, age, pre-existing conditions	Cataracts irreversible; glaucoma reversible with cessation

Risk Factors and Prevention

Several factors increase an individual's susceptibility to ocular toxicity. Awareness of these risks is critical for proactive care.

Dose and Duration: For many medications, like hydroxychloroquine and tamoxifen, the risk of toxicity increases with the total cumulative dose and the duration of use.
Patient Physiology: Factors such as age, genetics, and pre-existing conditions like renal or liver disease can affect how drugs are metabolized and excreted, influencing their concentration and toxicity. Some genetic variations (e.g., in the cytochrome P450 system) can alter a drug's metabolism and toxicity risk.
Concurrent Medications: Certain drug combinations, such as hydroxychloroquine with tamoxifen, can increase the risk of adverse ocular effects.

Preventing ocular toxicity requires a collaborative effort between patients and healthcare providers.

Pre-treatment Assessment: A baseline ophthalmological exam is often recommended before starting a medication with known ocular risks.
Regular Monitoring: High-risk patients should undergo regular eye screenings, including specific tests like Spectral-Domain Optical Coherence Tomography (SD-OCT) and automated visual fields (e.g., 10-2 HVF).
Symptom Reporting: Patients must be educated on potential ocular side effects and instructed to report any visual changes immediately.

Conclusion

Ocular toxicity is a significant and sometimes irreversible consequence of medication use, with numerous systemic and topical drugs capable of causing damage to various parts of the eye. The specific causes of ocular toxicity are rooted in diverse pharmacological mechanisms, including accumulation in pigmented tissues, mitochondrial damage, and oxidative stress. Risk factors like cumulative dose, treatment duration, and individual patient factors must be carefully considered. For many medications, especially those causing retinal or optic nerve damage, early detection through regular monitoring is the most effective strategy to preserve vision, as some damage may not reverse even after the offending medication is stopped. All individuals on potentially toxic medications should be vigilant for visual symptoms and maintain open communication with their eye care specialist and prescribing doctor.

For more detailed information on drug-related side effects, including ocular ones, the National Registry of Drug-Induced Ocular Side Effects can be a valuable resource.

Frequently Asked Questions

Ocular toxicity refers to adverse effects on the eye caused by systemic or topical medications, or other toxic substances. These effects can impact any part of the eye, from the cornea to the retina and optic nerve.

Common culprits include antimalarials like hydroxychloroquine, anti-tuberculosis drugs such as ethambutol, breast cancer therapies like tamoxifen, corticosteroids, and certain psychiatric and cardiac medications.

Yes, topical eye drops can cause ocular toxicity. This can be due to the active ingredient or preservatives, such as benzalkonium chloride, which can cause irritation or damage to the corneal surface.

No, not always. Some adverse effects, like corneal deposits from amiodarone, are often reversible upon drug cessation. However, damage to the retina or optic nerve from medications like hydroxychloroquine or ethambutol is often irreversible.

Initial symptoms vary by drug but can include blurred vision, color desaturation, night vision problems, central or paracentral blind spots (scotomas), and light sensitivity. Early signs are often subtle and may be detected only through specialized eye exams.

Bull's-eye maculopathy is a characteristic pattern of retinopathy seen in advanced hydroxychloroquine toxicity. It is caused by drug accumulation in the RPE, leading to a concentric ring of retinal depigmentation surrounding the central fovea.

For patients on high-risk medications, monitoring typically involves a baseline eye exam followed by regular screenings. Recommended tests include Spectral-Domain Optical Coherence Tomography (SD-OCT), visual field testing, and fundus autofluorescence.