Dry eye disease (DED), also known as dry eye syndrome or keratoconjunctivitis sicca, is a common ophthalmic disorder that affects the quality of life for millions of people around the world.6,8 In addition to the discussion of DED in this chapter, nonprescription therapies for the condition are detailed in Chapter e10, “Minor Ophthalmic Disorders (Conjunctivitis, Xerosis, Corneal Abrasions, Bacterial Keratitis).”
The prevalence of DED ranges from 5% to 50% due to a lack of a standardized definition and consistent diagnostic criteria.6 DED is estimated to account for $3.8 billion annually in healthcare expenditures in the United States, with quality-of-life impact estimated at approximately $55 billion.9
DED is defined by the Tear Film & Ocular Surface Society International Dry Eye Workshop II (TFOS DEWS II) Definition and Classification Subcommittee as follows: “Dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.”6
This definition classifies DED as a condition with multiple contributing factors. The eye depends on a healthy tear film composed of mucus, aqueous, and mucin to maintain lubrication, provide nutrients, and remove waste.2,3,10 DED can occur when any aspect of the tear film is compromised. This may be due to evaporation of the tear film, an imbalance in tear film composition, or decreased production of tears.6,8,9 This pathophysiologic mechanism leads to patient reports of light sensitivity, pain, blurry vision, and a feeling of grittiness in the eye.8,9
DED is common in the older population because of polypharmacy and age-related changes. It is also common in women due to sex hormone effects on meibomian gland function and tear secretion.6,9,10 Other risk factors for DED include anatomic disorders (floppy eyelid syndrome), autoimmune diseases (rheumatoid arthritis, Sjogren’s disease), diabetes, graft versus host disease, meibomian gland dysfunction, neural dysfunction (neuropathic pain), low sex hormone levels, prolonged computer screen time, systemic lupus erythematosus, and medications.8,9
Numerous systemic and topical medications can cause DED. These include alpha-1 antagonists, alpha-2 agonists, anticholinergics, anticonvulsants, antihistamines, antimalarials, antineoplastics, antipsychotics, anxiolytics, beta agonists and antagonists, bisphosphonates, cannabinoids, systemic and topical decongestants, diuretics, retinoids, oral contraceptives, and tricyclic antidepressants.8–12 Preservatives present in topical ophthalmic products, such as benzalkonium chloride, may cause DED by disrupting tear film homeostasis and causing inflammation.8 A thorough patient history and examination should be collected to determine risk factors present and likely type of tear film issue at hand.
Several strategies are used to treat DED. Interventions aim to increase liquid on the ocular surface, decrease the amount of evaporation of eye fluids, and restore balance to tear film components.6,8,13 Many of these medications must be used chronically; their benefits are viewed as outweighing any risks of long-term therapy. Agents include topical lubricants, anti-inflammatory ophthalmic drops such as 0.05% cyclosporine, and lymphocyte function–associated antigen 1 (LFA-1) antagonists.
Additionally, discontinuation of the causative agent, if possible, or switching to preservative-free ophthalmic drops and products can help alleviate DED symptoms. A summary of common causative agents and treatment options is available in Table e112-2.
TABLE e112-2Strategies to Prevent Drug-Induced Ophthalmic Disorders |Favorite Table|Download (.pdf) TABLE e112-2 Strategies to Prevent Drug-Induced Ophthalmic Disorders
Educate patients on the signs and symptoms of common ophthalmic side effects related to prescribed medication
Schedule regular ophthalmic examinations
Use nonpharmacologic management when appropriate
Prescribe prophylactic medication therapy when appropriate
Avoid exceeding recommended daily dose, cumulative lifetime doses, or duration of therapy
Assess for predisposing conditions or risk factors prior to use of medication
Monitor drug levels as appropriate
Stress importance of adherence to scheduled follow-up visits and monitoring
Encourage communication of any new or discontinued prescription, natural medicine, or OTC products.
Punctal occlusion, a procedure in which the puncta—the small openings in the corner of the eye—are blocked, can benefit those with DED by decreasing tear drainage when other options have failed.6 This provides the eye with tear availability to continually bathe the eye and decrease symptoms of DED.6,10 If left untreated, severe DED may lead to corneal ulcers (Fig. e112-2), vascularization, and permanent vision impairment.14
Corneal ulcer caused by dry eye syndrome. (Reproduced, with permission, from Reference 14.)
Drug-induced cataracts may occur with use of corticosteroids, phenothiazines, alkylating agents, and statins.5,15 Patients presenting with cloudiness in specific parts of the lens can provide clues as to the route of administration of the causative agent.5 Table e112-3 summarizes the location of lens changes observed by route of administration for medication classes known to cause cataracts. In general, systemically administered drugs cause changes along the equator of the lens, while topically administered drugs cause central anterior lens changes. Posterior subscapular and cortical changes may also occur irrespective of the route of administration.5
TABLE e112-3Location of Lens Changes Observed by Route of Administration for Common Causative Agents that Induce Cataracts |Favorite Table|Download (.pdf) TABLE e112-3 Location of Lens Changes Observed by Route of Administration for Common Causative Agents that Induce Cataracts
Route of Administration
Lens Change Location
Alkylating agents (busulfan)
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Corticosteroids may cause cataracts on any portion of the lens when used for an extended period of time (Fig. e112-3).5,14 The incidence of cataract formation secondary to corticosteroid therapy is 22% to 58%.14 Risk factors for adverse effects of corticosteroid therapy include young age, condition of the skin, extent of disease, location on the body, dose and duration of therapy, and use of occlusive dressings.14 Topical application of corticosteroids to distal areas of the body and in limited doses has demonstrated minimal risk of cataract formation.14 Discontinuation of corticosteroid therapy does not reverse the cataract.5,14
Steroid-induced cataract. (Reproduced, with permission, from Reference 14.)
Phenothiazines, specifically chlorpromazine and thioridazine, cause cataract formation in a dose- and duration-dependent manner.5 Fine granules that are white to brown in color form and accumulate in the anterior cortex over time, forming a cataract. Ophthalmic side effects are rare at standard thioridazine doses less than 800 mg/day.5,16
Alkylating agents, such as busulfan, causes a posterior subscapular cataract by interfering with production of nucleic acid during mitosis.5
Statins are associated with an increased risk of cataracts, although for quite some time statin therapy was associated with a protective effect.15,17,18 Clinicians must weigh the benefits and risks of statins in all cases prior to initiation of therapy.
In most cases, drug-induced cataracts remain relatively stable and will not reverse once formed, irrespective of type of causative agent exposure. Surgical removal of the lens may be necessary to restore vision.5,14
Intraoperative Floppy Iris Syndrome
Intraoperative Floppy Iris Syndrome (IFIS) occurs in approximately 0.5% to 3.7% of patients undergoing cataract surgery worldwide, with a rate of approximately 2% in the United States.19,20 It is characterized by presentation of one or more intraoperative events: floppiness and billowing of the iris, progressive intraoperative constriction of the pupil despite pharmacologic intervention to maintain dilatation, and prolapse of the iris through the surgical wound(s).19 IFIS complicates the surgical procedure and may lead to endophthalmitis, pupil deformity, retinal detachment, and vitreous loss.19–22
Use of alpha-1 antagonists (tamsulosin, silodosin, alfuzosin, doxazosin, terazosin, and prazosin) is a major risk factor for development of IFIS.23 IFIS is most commonly seen in men; however, women prescribed alpha-1 antagonist therapy for urinary stone passage, hypertension, or chronic urinary retention have also experienced IFIS.20 Patients taking tamsulosin are 30 times more likely to experience IFIS, with a rate of approximately 60% to 89% in those undergoing cataract surgery.23,24 Tamsulosin is highly selective for alpha-1A receptors located in the bladder neck, prostate, and urethra. These receptors are also present in the smooth muscle of the iris. Binding of tamsulosin to these receptors inhibits dilatation and may lead to IFIS. Discontinuing alpha-1 antagonist therapy prior to cataract surgery has not been shown to decrease the risk of IFIS.20,24,25 The evidence suggests that patients with a prior history of alpha-1 antagonist use are still at risk for IFIS, attributed to atrophy of the dilator muscle of the iris due to disuse.26,27
IFIS has also developed in patients with hypertension or those receiving therapy with other medications (finasteride, duloxetine, donepezil, quetiapine, and benzodiazepines).23,28–33 Additional studies are needed to determine if the risk associated with hypertension is due to medication use or a disease process.23,24 It remains unclear if use of these medications represents an actual causative risk factor in the development of IFIS. More research is necessary to fully elucidate the iris smooth muscle relaxation activity of these agents.23,28–31
IFIS may be avoided by conducting a complete preoperative screening of a patient’s medication regimen prior to cataract surgery. Intracameral administration of preservative-free epinephrine or phenylephrine at the beginning of surgery helps reduce IFIS and dilates the pupil.20,28 Use of ophthalmic viscosurgical devices (OVDs), iris retractors, and pupil expanders are additional techniques that may be employed in conjunction with intracameral epinephrine or phenylephrine. Mechanical pupil stretching and partial sphincterotomy are not useful and may exacerbate IFIS.20
Drug-induced optic neuropathy (DION) is a subset of toxic optic neuropathy (TON), a disorder in which the optic nerve degenerates due to toxic exposure to medication therapy. Mitochondrial injury, blood flow disruption, and free radical exposure are possible pathophysiologic mechanisms leading to this condition.5,34 DION is characterized by bilateral vision loss, decreased visual acuity, decreased color vision, and afferent pupillary defect.5,34 Symptoms occur slowly over time and do not cause pain. TON is more common in developing countries due to exposure to toxins and drugs in the environment.34 Epidemiological studies have not elucidated any age-, gender-, or race-related risk factors associated with TON or DION.34
DION has occurred most often with use of amiodarone, ethambutol, linezolid, and PDE-5 inhibitors. Vision issues associated with these agents are dose and duration dependent. Discontinuation of the causative agent generally leads to reversal of symptoms.5,14 It is critical to educate patients about this potential side effect of therapy to ensure prompt notification and discontinuation of therapy prior to development of permanent damage.
Optic neuropathy is thought to occur due to accumulation of amiodarone in the axon, interfering with normal neural function and leading to vision loss.5,16 The incidence of amiodarone-induced optic neuropathy is estimated to be 1.79%.16 Optic neuropathy occurs slowly over an average of 9 months due to the 160-day half-life of amiodarone, resulting in bilateral vision loss and optic disc edema.4,16,34 Upon discontinuation of amiodarone, it may take months for vision loss to reverse. Ophthalmic examinations every 6 to 12 months are important, given the dose and time dependent nature of visual side effects related to amiodarone use.
Optic neuropathy has been well documented in 6% of patients receiving ethambutol for treatment and prevention of tuberculosis.34 The average time to development is 235 days of therapy.5,16,34 Renal dysfunction may lead to diminished excretion of ethambutol and higher levels, lowering the time to development of optic neuropathy. Patients present with bilateral vision loss peripheral constriction, and color vision loss.5,16,34 Symptoms occur due to chelation of copper present in retinal cells. Chelation depletes copper available for mitochondrial activity, stunting the ability to acquire energy required for normal axonal transport.5,16 If symptoms occur, the clinician should explore discontinuation of ethambutol as clinically appropriate.5 Baseline eye examinations and ophthalmologic consultation is recommended to prevent vision loss and subsequent diminished quality of life.34 Education on the risk of optic neuropathy and obtaining informed consent are also recommended as best practices for use of ethambutol.16
Linezolid-induced optic neuropathy is thought to be caused by mitochondrial injury.5 Patients have generally experienced visual side effects after approximately 5 to 10 months of therapy, although a few cases have been reported in which loss of vision occurred after only 2 weeks of therapy.5,34 Vision has improved after discontinuation of linezolid in most patients; some patients experience lasting visual acuity issues.34 Patients on linezolid therapy need regular ophthalmic examinations.
Phosphodiesterase Type 5 Inhibitors
Phosphodiesterase type 5 (PDE-5) inhibitors (avanafil, sildenafil, tadalafil, and vardenafil) can cause DION, which manifests as blurriness, color discrimination deficits (particularly in the blue-green and blue-purple spectrum), and light sensitivity.34 The color-related symptoms are thought to result from drug effects on phosphodiesterase type 6 (PDE-6) receptors present on the rods and cones of the eye.35 These symptoms are dose dependent and reverse upon discontinuation of the drug.5
Chloroquine and hydroxychloroquine use is associated with retinal issues. Risk for toxicity depends on total dose and duration of therapy. Patients receiving hydroxychloroquine doses greater than 5 mg/kg/day and chloroquine doses greater than 2.3 mg/kg/day are at greatest risk for retinopathy.4,14,37 Aminoquinoline therapy for more than 5 years also increases the risk of toxicity.14 Advanced age, extremes of body weight, liver disease, and renal disease are also risk factors for development of retinopathy due to hydroxychloroquine or chloroquine use.5,16
Amioquinolines have a high affinity for melanin within the retinal pigment epithelium, allowing accumulation and prolonged effect. This ultimately contributes to toxicity seen with this class of medications. The retinal issue associated with aminoquinoline therapy is a maculopathy, in which the macula of the retina appears as a bull’s eye or ring in most patients.5,14 Ideally, conducting regular ophthalmic screenings, as described below, should make development of this bull’s eye maculopathy a rarity.37
Patients typically present with complaints of color vision disturbance, central visual field defect, and loss of night vision.4,14,16 To positively attribute maculopathy to hydroxychloroquine use, the maculopathy must be bilateral. It can be detected using visual field testing and Amsler grid.5,16
The American Academy of Ophthalmology recommends a dilated fundus exam and visual field test at baseline. A color vision test is also recommended but optional. Clinicians must conduct ongoing monitoring and regular ophthalmic examinations, with consideration for discontinuation of therapy if medically appropriate.14 If patients continue use of the medication beyond 5 years, follow-up examinations are recommended every 12 months.37 Once bull’s eye maculopathy occurs, reversal of vision is not possible, leading to permanent vision loss.5,14,16
The mechanism of toxicity for phenothiazines is similar to that of aminoquinolines, whereas drug binds to melanin in the retinal pigment epithelium, causing degeneration of the retina.5 At high doses, chlorpromazine retinal disorder causes conjunctival lesions, pigmentation of the eyelid, while high-dose thioridazine causes a rapid, severe retinopathy with a few weeks or months of use.5 Patients present with diminished visual field and night vision loss.
Tamoxifen is known to cause retinopathy and loss of color vision. Retinopathies manifest as retinal edema, hemorrhage, swelling of the optic disc, and yellow deposits around the macula.5 As seen with other therapies, these effects depend on dose and duration and can occur within a few weeks after initiation of therapy.
Retinal effects are generally reversible when tamoxifen is discontinued. To prevent retinopathy associated with tamoxifen use, it is recommended that baseline ophthalmic examination with a color vision test and slit lamp biomicroscopy be performed, with follow-up examinations completed every 2 years thereafter.
Patients on high-dose isotretinoin therapy are at high risk for night vision loss, blurry vision, dry eye, and blepharoconjunctivitis. The mechanism of toxicity is thought to occur due to binding site competition between retinoid acid and retinol.5