Ocular Side Effects of Systemic Drugs

14 Jan, 15

Introduction

Although therapeutically beneficial, most medications can cause various degrees of adverse effects. Among all body organs, it is aptly stated that the eye manifests drug toxicity second only to the liver.

Ocular disorders occur not only from topical drugs, but also from their systemic administration. There are thousands of prescription and non-prescription drugs that can cause ocular drug toxicity. Some of them are listed below.

Tamsulosin and Alpha-Adrenergic Antagonists

Indication

Used to treat benign prostatic hyperplasia and hypertension.

Clinical Concerns

Intraoperative floppy iris syndrome (IFIS) associated with tamsulosin(first reported in 2005)

IFIS diagnosis: fluttering and billowing of the flaccid iris stroma, a propensity for iris prolapse, and progressive constriction of the pupil during surgery. Additional characteristics include poor preoperative pupil dilation and elasticity of the pupil margin.
Alpha-1A blocking effect of tamsulosin may selectively block the receptors in the iris dilator muscle.
Long-term receptor blockade could result in a type of disuse atrophy of the iris dilator smooth muscle. This may explain why some patients have permanent IFIS, even after the medication is discontinued.

Management

Take patient history prior to cataract surgery- whether or not a patient is taking an alpha-adrenergic inhibitor like tamsulosin
Iris retractors or other pupil expansion devices will help enlarge the pupil size throughout surgery in IFIS patients.
Unfortunately, stopping the medicine does not always ensure IFIS prevention.

Topiramate

Indication

Used to treat patients with various types of epilepsy and migraine headaches. It is used off label as a “magic” weight reduction medication and in bipolar disorder and clinical depression.

Clinical Concerns

Acute angle closure glaucoma

Recent case reports have ballooned into almost 100 cases of a classic syndrome of acute angle closure glaucoma
Patients range in age from 3½ - 53 years of age
Time to onset of reaction ranges from 3 - 14 days after the start of oral therapy

Management

Patients should stop the medication
Hype
Cycloplegics
Topical anti-glaucoma medication

Bisphosphonates: Pamidronate Disodium, Alendronic Acid, Ibandronate, Zolendronate, Risedronate Sodium, Clodronate, Etidronate Disodium, Olpadronate

Indication

Pamidronate disodium inhibits bone resorption in the management of hypercalcemia of malignancy, osteolytic bone metastases of both breast cancer and multiple myeloma, and Paget’s disease of the bone

Clinical Concerns

Anterior uveitis, nonspecific conjunctivitis, episcleritis, nerve palsy, ptosis, retrobulbar neuritis, blurred vision, ocular pain and yellow vision.

The most studied drug in this class, pamidronate, has caused 17 cases of unilateral scleritis and one case of bilateral scleritis.
Onset is usually within 6-48 hours of intravenous drug administration

Management

Guidelines are as follows:

If persistent decrease in vision or ocular pain occurs, the patient should see an ophthalmologist.
Nonspecific conjunctivitis seldom requires treatment, and usually decreases in intensity or may be absent on subsequent pamidronate injections. In rare instances, a non-steroidal anti-inflammatory (NSAID) eye drop may be needed.
Bilateral anterior uveitis or, rarely, posterior or bilateral uveitis may occur and can vary markedly in severity. Many cases require intensive topical ocular or systemic medication. In some instances, the drug may need to be discontinued for the uveitis to resolve.
Episcleritis may require topical ocular medication; however, pamidronate may be continued.
For Scleritis, the intravenous pamidronatehas to be discontinued.

Ethambutol

Indication

For thetreatment of pulmonary tuberculosis.

Clinical Concerns

Optic neuropathy

55 case reports of optic neuropathy have been received at the National Registry of Drug-Induced Ocular Side Effects and the World Health Organization
Dose-related incidence of optic neuropathy: 50% of patients at a dose of 60-100 mg/kg/day, 5-6% at 25 mg/kg/day, and 1% with dosages at or below 15 mg/kg/day
Optic neuropathy may occur, on average, at 2-5 months after starting therapy.
The earliest ophthalmologic findings in toxic optic neuropathy from ethambutol may be loss of visual acuity, color vision loss or central scotomas.

Management

Following is recommended by AAO:

Obtain informed consent prior to assuming care for patients taking ethambutol explaining that optic neuropathy can occur at any dose despite regular ophthalmic exams and that the vision loss can be severe and irreversible.
Obtain a baseline exam to include a visual field test, color vision test, dilated fundus and optic nerve exam, and visual acuity.
If any visual symptoms occur, patients should discontinue the medication and see an ophthalmologist.
Frequency of examination is monthly for doses greater than 15mg/kg/day (PDR),
Monthly exams at lower doses may be necessary for patients at increased risk (mentioned below) for toxicity:
- Diabetes mellitus
- Chronic renal failure
- Alcoholism
- Elderly
- Children
- Other ocular defects
- Ethambutol-induced peripheral neuropathy
- Dose greater than 15mg/kg/day
Consider optical coherence tomography or contrast sensitivity testing as these tests could pick up early ethambutol toxicity not detected with the baseline exam.

Sildenafil, Tadalafil, Vardenafil

Indication

Management of erectile dysfunction

Clinical Concerns

Changes in color perception (objects have colored tinges, usually blue or blue/green, may also be pink or yellow; diminished color vision; and dark colors may appear darker), blurred vision (central haze and transitory decreased vision), changes in light perception, (increased perception of brightness and/or a sensation of seeing flashing lights), conjunctivalhyperemia, ocular pain, photophobia

Side effects with Sildenafil

Incidence: 3% with 50mg, 10% with 100mg, 40-50% with 200mg
The side effects based on dosage with sildenafil start 15-30 minutes after ingestion of the drug, and usually peak 60 minutes after ingestion
To date, the literature contains 14 case reports Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION) with sildenafil
86 cases of visual disturbances have been reported to be associated with sildenafil therapy
11 cases of macular edemahave also been reported (including chronic macular edema and positive rechallenge of serous macular edema cases)

Management

The only patients who should not take phosphodiesterase type 5 inhibitors (sildenafil, vardenafil, and tadalfil) are those who have previously suffered NAION in one eye or anyone who experiences transitory visual loss while on these medications.
These patients may be more prone to developing NAION in the same or fellow eye if sildenafil or other medicines in this class are ingested.
The subset of patients who take phosphodiesterase type 5 inhibitors may have the highest risk of developing NAION, independent of an adverse effect, but this is not proven.

Herbal Medicines And Nutritional Supplements

Indication

Used to treat a variety of systemic and ocular conditions

Clinical Concerns

From 263 spontaneous reports received at the National Registry and from an additional 60 case reports in the literature, canthaxanthine, chamomile, datura, Echinacea purpurea, ginkgo biloba, licorice, niacin and vitamin A are all associated with clinically significant ocular side effects.

Canthaxanthine- Certain: Crystalline retinopathy
Chamomile- Certain: Allergic conjunctivitis
Datura- Certain: Mydriasis
Echinacea purpurea- Probable: Conjunctivitis
Ginkgo biloba- Possible: Spontaneous hyphema, retinal hemorrhage
Licorice- Possible: Vasospasm, visual loss associated with migraine-like symptoms
Niacin-

Probable: Cystoid macular edema
Possible: Decreased vision, dry eyes, discoloration of the eyelids, eyelid edema, proptosis, loss of eyebrows and eyelashes, and superficial punctate keratitis

Vitamin A- Certain: Intracranial hypertension when taken in large doses

Management

Clinicians should remain vigilant in recognizing adverse ocular reactions as well as inquiring whether these alternative treatments are being used by the patients
If the clinician recognizes an ocular or systemic side effect from one of these agents, the symptoms are usually reversible.

Hydroxychloroquine/Chloroquine

Indication

Hydroxychloroquine is used for the treatment of rheumatoid arthritis and lupus erythematosis, dermatologic conditions, and various inflammatory disorders. Chloroquine is no longer available except for malaria treatment and is primarily used in the military.

Clinical Concerns

Approximately 1 million patients have used hydroxychloroquine or chloroquine
Yet only 20 cases of toxicity have been reported in the low dose range (<6.5mg/kg.day).
Patients at greatest risk are those on hydroxychloroquine for longer than 5 years and those with renal or liver disease
Retinal toxicity-can be devastating and guidelines need to be available for screening. A recent preliminary paper suggested that individuals with Stargardt’s disease may be predisposed to develop retinal toxicity when exposed to chloroquine/hydroxychloroquine.
Hydroxychloroquine crystals have been found in the tear film, which may aggravate sicca or be bothersome to contact lens wearers. If hydroxychloroquine is found to have caused skin, eyelid, corneal or hair changes, the clinician should suspect retinal changes.
Maculopathy bilateral and reproducible by Amsler grid and visual field testing. Transient or unilateral defects are not sufficient reasons to implicate the drug, and are not necessarily an indication to stop therapy.

Management

Find early changes, i.e., relative scotomas.
Later findings include retinal changes, color vision loss, absolute scotoma or decreased vision.
Even if the drug is stopped, once these changes occur they are irreversible, and many patients may continue to lose some vision and/or peripheral fields.
informed consent and explanation of risk/benefit ratios is necessary
Baseline Examination for patients with hydroxychloroquine–
Within the first year after starting this drug, patients should have a complete, dilated ophthalmic examination, including the informed consent, warning of possible permanent visual problems in rare instances.
The baseline exam should include visual acuity, Amsler grids, and optional color vision testing.
If macular abnormalities are evident, it would be ideal to obtain fundus photographs.
If any progressive ocular abnormality is suspected, consider a baseline Humphrey 10-2 or other automated perimetry. Multifocal ERG is optional
Follow-up Examinations
Annual eye examinations should be considered if patients have been on hydrochloroxyquine therapy for longer than 5 years, if they are obese, or lean and small (especially in the case of elderly patients), or if they have progressive macular disease of any type, significant renal or liver disease, or their dosage exceeds 6.5 mg/kg.
Recommendation for follow-up of patients on hydroxychloroquine: aged 20-29- one examination; ages 30-39- two examinations; 40-64- every 2 to 4 years, and patients aged 65 and over should be seen every 1 to 2 years.
For patients taking chloroquine- See patients at least annually if dosage is less than 3.0 mg/kg of ideal body weight. See every 6 months if dosage is greater than 3.0 mg/kg body weight, or if patients are short, obese, or have renal and/or liver impairment.
Follow-up examination procedures- Repeat baseline examination, Fundus photography if any macular abnormality noted, Automated central visual fields (optional), Multifocal ERG (selected cases), Consider fluorescein angiography only in the presence of suspicious pigmentary changes

Fluoroquinolones

This class of antibiotic is considered broad spectrum and is associated with specific side-effects not seen in other classes of antibiotics.

Clinical Concerns

Peripheral neuropathy (rarely), diplopia

171 case reports of diplopia are associated with fluoroquinolones in the National Registry.
There were 75 case reports associated with ciprofloxacin, 40 with ofloxacin, 20 with levofloxacin, 16 with moxifloxacin, 11 with norfloxacin, and 9 with gatifloxacin.

Management

In 53 instances when the drug was reportedly withdrawn, the diplopia resolved. There is also a possible mechanism for these ADRs: localized tendinitis in the extraocular muscles. Perhaps most compelling are the 5 positive rechallenge case reports.

HMG-CoA Reductase Inhibitors (Statins)

Indication

3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) are a class of hypolipidemic drugs used to lower cholesterol levels in patients at risk of cardiovascular disease.

Clinical trials have documented the efficacy of statins in preventing coronary heart disease, cerebrovascular accidents, and death from hypercholesterolemia-related disease.
Although side effects are rare, myopathies are a well-known adverse reaction to statin therapy

Clinical Concerns

Diplopia and ptosis

256 cases of diplopia, ptosis, or ophthalmoplegia associated with statins have been reported.
The average time from the start of statin therapy to the appearance of the ADR was 8.3 months +/- 1.5 months (range 1 day to 84 months).
A total of 23 case reports described total ophthalmoplegia.
Ptosis was reported alone 20 times and in conjunction with diplopia 13 times.

Patients taking atorvastatin: 55 case reports of diplopia, 5 cases of ptosis, 3 cases of diplopia with ptosis, and 3 cases of ophthalmoplegia.
Patients taking cerivastitin: 15 cases of diplopia, 1 case of ptosis, 1 case of diplopia with ptosis and 1 case of ophthalmoplegia.
patients taking fluvastatin: 8 case reports of diplopia and 2 cases of ophthalmolplegia.
For lovastatin: 34 case reports of diplopia, 2 cases of ptosis, 2 cases of diplopia with ptosis, and 6 cases of ophthalmoplegia.
patients taking pravastatin: 38 reported cases of diplopia, 4 cases of ptosis, 4 cases of diplopia with ptosis, and 5 cases of ophthalmoplegia.
Patients taking rosuvastatin: 5 cases of diplopia and one case of ptosis.
For simvastatin: 59 cases of diplopia, 7 cases of ptosis, 3 cases of diplopia with ptosis, and 6 cases of ophthalmoplegia

Management

Statin-associated diplopia, ptosis, and ophthalmoplegia are completely reversible on discontinuation of the statin.

Hepatitis B Vaccine

Indication

Hepatitis B vaccine was approved by the FDA in November 1981 and is currently recommended in the prevention of hepatitis B for all children aged 0-18 years.

In addition, the vaccine is recommended for some adults such as homosexual men, subjects incarcerated for long periods of time, and for health care workers.
The dosage is usually administered in 2 or 3 separate vaccinations.

Clinical Concerns

Uveitis

There are multiple case reports of uveitis occurring in association with vaccines like Bacillus Calmette-Guerin (BCG) vaccine, diptheria, tetanus, and pertussis (DPT) vaccines, influenza vaccine, measles, mumps, and rubella vaccines (MMR), varicella vaccine, and smallpox vaccine.
Thirty-two case reports of uveitis occuring after hepatitis B vaccine were reported to the National Registry

Others

Conclusion

All drugs used in the treatment of ocular and systemic disorders have the potential to induce adverse effects in the eye. Careful and detailed case history is important to reveal a patient’s medication history. The ocular and visual side effects from a patient’s systemic medication can range from mild to severe. Recognition of ocular and visual side effects is important for prompt management to prevent and minimize serious complications.

Discontinuing the use of the drug could lead to resolution or reversal of the toxic manifestations, but a number of iatrogenic diseases, especially glaucoma and cataract, may be irreversible and warrant appropriate medical and/or surgical intervention to prevent or slow the loss of vision.

Clinicians should be cognizant of drug-induced disorders of the eye, be watchful for their manifestation and seek consultation with an ophthalmologist when instituting therapy.

References

American Academy of Ophthalmology November 2012. Drug?Related Adverse Effects of Clinical Importance to the Ophthalmologist: 1-21.
Drug Safety 2008; 31 (2): 127-141.
http://www.google.co.in/url?sa=t&rct=j&q=potential+ocular+side+effects+of+select+systemic+drugs&source=web&cd=1&cad=rja&ved=0CC0QFjAA&url=http%3A%2F%2Fcommons.pacificu.edu%2Fcgi%2Fviewcontent.cgi%3Farticle%3D1002%26context%3Dcoofac&ei=M2J_Uf8zw5euB4TKgagG&usg=AFQjCNEtZKHT1BBfeyssnQM3dbOLsLKGOg&bvm=bv.45921128,d.bmk Last accessed on 26^th May 2013.
Journal of Behavioral Optometry 2000;11(6): 149-157