Article Date: 4/1/2003

systemic side effects
Get Side Effect Savvy
Learn about the common ocular side effects of frequently prescribed systemic drugs.
BY GARY A. LESHER, Ph.D., F.A.A.O., Chicago, Ill.

As optometrists, your ability to identify drug-induced ocular side effects is critical to efficient and effective patient care. Many drugs interfere with normal visual function, some causing minor transient discomfort or vision changes, others significantly impairing vision with possible permanent consequences. This article will briefly describe the ocular effects of some of the more frequently prescribed systemic agents as well as some popular drugs that are safe on the eyes.

Fortunately, the most frequently prescribed drugs don't often cause serious ocular toxicities. However, even the minor, transient problems seen with some of these agents will bring your patient into the office with specific complaints that they may not associate with the drugs they're taking. Therefore you need to become familiar with these side effects and know what to look for in patients who take these agents. In general, if you see any ocular side effects that are associated with a drug treatment, consult the prescribing practitioner before making any adjustment in dosage.

ILLUSTRATION BY MARK HEINE

Popularity has its risks

NDC Health, a provider of health information services, lists hydroco-done with acetaminophen (#1), an opiate/ non-opiate analgesic combination, as the most prescribed drug in the United States in 2001. The number in parentheses after each drug represents the drug's ranking based on 2001 pharmaceutical sales data. This group also includes agents such as propoxyphene HCl, codeine and oxycodone.

The opiates in these preparations can easily cause miosis. The clinical significance of this ocular side effect is decreased or dim vision related to the miosis, which is transient and completely reversible by discontinuing use of the drug.

The effects of the non-opiate component, usually aspirin or acetaminophen, are rare in the usual doses. Aspirin use has been associated with increased bleeding problems, including increased bleeding of conjunctival or retinal bleeds following surgery. This risk is minimal with the short-term use usually associated with acute pain management. However, continued, long-term use of aspirin or aspirin-like compounds will exaggerate this risk.

Continued use proves safe

Another group of frequently prescribed agents are the antihyperlipidemic agents that block cholesterol synthesis, commonly referred to as the "statins" (atorvastatin [#2] and simvastatin [#21]). While early research into the toxicities of this group of drugs indicated a possible risk for inducing cataracts, their continued use for many years has not supported the earlier findings and in fact these agents are unlikely to cause any serious ocular toxicities.

HRT linked to dry eye

Hormone replacement therapy (HRT) with estrogens (such as conjugated estrogens [#3]) alone or in combination with progestins (e.g., conjugated estrogens/med-roxyprogesterone acetate [#28]) is another treatment that doctors prescribe frequently. The use of estrogens has been linked with possible dry eye symptoms.

Although few scientific studies have clearly established this relationship, one recent report on more than 25,000 postmenopausal women provides evidence of a significant increased risk of dry eye syndrome and severity of dry eye symptoms in women taking estrogens. Because this risk has been shown to increase with longer durations of estrogen use, you should monitor patients who are on long-term HRT with estrogens for dry eye problems.

In addition to dry eye problems, there have been occasional reports of an association between estrogen use and retinal vascular disorders. One suggestion is not to give these medications to patients who have existing retinal vascular disorders and if retinal vascular disorders develop while on these agents, you should should ask the prescribing physician re-evaluate their use.

Safe on the Eyes

  • The antibacterial agent azithromycin (Zithromax) is the sixth most frequently prescribed drug in the United States and hasn't been reported to cause any significant ocular toxicities. Other agents in this same class include clarithromycin and erythromycin.
  • Physicians frequently use calcium channel blockers to treat patients who have hypertension or angina pectoris. Amlodipine (Norvasc, #9) is unlikely to cause serious ocular toxicity.
  • Newly released as an over-the-counter agent, Claritin was the twelfth most frequently prescribed agent in the United States in 2001. These newer, non-sedating antihistamines have provided excellent management of allergic disease with minimal toxicity. No serious ocular toxicities have been reported to the Registry.
  • Omeprazole (Prilosec, #14) and lansoprazole (Prevacid, #18) are agents that inhibit the production of gastric acid, which makes them useful in treating gastric and duodenal ulcers, gastroesophageal reflux disease and esphagitis. No serious ocular toxicities have been reported with the oral use of these anti-ulcer agents.
 

Consider thyroid levels

Physicians use another hormone replacement agent, levothyroxine (#5), to treat patients who have hypothyroidism. The actions of thyroid hormone are critically important to the health of the patient. However, excess thyroid hormone can cause some ocular toxicity, especially when initiating treatment or increasing the dose.

These toxicities could include symptoms of a myasthenia-like nature such as diplopia, ptosis and paralysis of the extraocular muscles. Visual hallucinations have also been reported. Pseudotumor cerebri has been seen in some hypothyroid children treated with thyroid hormone. These symptoms generally respond to a reduction in dose or short-term discontinuation of the thyroid hormone.

Watch out for beta blockers

The oral administration of beta blockers (atenolol [#4] and metoprolol [#36]) for the treatment of hypertension, myocardial infarction and angina pectoris have been reported to cause several ocular side effects. Visual disturbances and vivid visual hallucinations have been reported frequently to the National Registry of Drug-Induced Ocular Side Effects and tend to disappear with a decrease in dose.

Patients who have myasthenia gravis may report a worsening of symptoms with the use of the beta blockers and this could cause them to present in your office with diplopia, ptosis and paralysis of the extraocular muscles. Most of the beta blockers are also believed to decrease tear secretion and may worsen dry eye symptoms.

In addition, as with the actions of topical beta blockers, the systemic beta blockers also decrease intraocular pressure (IOP). While this side effect may seem innocuous, you could misdiagnose patients who have glaucomatous changes as having normal tension glaucoma. If a patient in this scenario discontinues the systemic beta blocker, you may note a significant rise in his IOP.

Dealing with diuretics

Physicians also frequently prescribe diuretic agents to treat hypertension and various edematous states. furosemide (#7), hydrochlorothiazide (#13) and the combination product of triamterene with hydrochlorothiazide (#17) are classic agents in this group.

The most frequent ocular side effect seen with these agents seems to be transient drug-induced myopia, sometimes as much as 4.00D. This transient myopia seems to be caused by ciliary body edema, which relaxes the zonule fibers and allows the lens to thicken, causing a myopic shift in the refractive error. This effect may be related to a sensitivity reaction to the drug, and most sulfonamides (including many of the diuretics, antibacterials and carbonic anhydrase inhibitors) will cause this effect. Once the patient discontinues use of this drug, his refractive error returns to pre-drug levels within a few days to several weeks.

Remember the least harmful

Amoxicillin (#8), in its many formulations, is the eighth most frequently prescribed drug in the country. Ocular effects with amoxicillin -- or with any of the penicillin class of antibiotics -- are rare and transient, with the exception of allergic reactions to these drugs, which isn't uncommon. One rare ocular effect is the risk of unmasking or aggravating the signs of myasthenia gravis.

Another popular antibiotic, cephalexin (#22), works in a manner similar to the penicillins and is closely related chemically. Allergic reactions to this drug, as well as cross-allergic hypersensitivity with the penicillins, are responsible for most of the ocular effects reported with its use.

The anti-anxiety benzodiazepines are also frequently prescribed, as represented on the list by alprozolam (#10). Ocular toxicities with this group of drugs are generally minor and transient but could include decreases in the corneal reflex, accommodation, depth perception and extraocular muscle abnormalities that lead to diplopia. These effects are also additive with other central nervous system depressants.

Keep a low guard with inhalers

Physicians usually prescribe the beta agonist albuterol aerosal (#11) to treat acute broncho-spasm in reversible airway disease. This drug will only occasionally cause ocular toxicities, but reports to the Registry have included visual hallucinations, mydriasis (with a possible risk of angle closure in narrow-angle glaucoma patients) and possible ocular allergic symptoms. Some cases of mydriasis were seen after inadvertent ocular exposure to the aerosolized product.

Safe SSRIs

The selective serotonin reuptake inhibitors (SSRIs) have become the most frequently prescribed antidepressants. Sertraline HCl (#15) and paroxetine (#16) head the list of these useful drugs. Even with the millions of prescriptions for these drugs worldwide, reports of ocular toxicities (e.g., nystagmus and diplopia) are rare. Blurred vision, along with numerous other central nervous system toxicities, have been reported after rapid withdrawal of the SSRIs, and practitioners should avoid this practice.

Watch out for NSAID effects

Although ibuprofen (#19) is available "over the counter," it's still widely prescribed in a higher dosage tablet (up to 800 mg). In this form, it's most often used to treat osteo- and rheumatoid arthritis. Ibuprofen can cause refractive error changes, diplopia, photophobia, dry eyes and color vision abnormalities. When a patient stops taking ibuprofen, his vision returns to normal. Going back on ibuprofen causes the vision problems to return.

Ibuprofen, and the other non-steroidal anti-inflammatory agents (NSAIDs), have numerous other ocular toxicities that include optic neuritis, papilledema and visual field changes. Retinal hemorrhage has also been seen with this class of drugs.

Because of these serious but infrequent risks, practitioners should warn their patients to stop these medications if a sudden or unexplained decrease in vision occurs while taking one of these drugs and to have a complete eye exam to determine the actual cause of the vision problem.

The new group of selective COX-2 inhibitors, including celecoxib (#20) and rofecoxib (#24), are also considered NSAIDs, and may well have similar ocular toxicities. In fact, reports of blurred vision, conjunctivitis, ocular pain, increased IOP and cataract, have occurred with the use of these selective COX-2 inhibitors. Even though practitioners frequently prescribe these compounds, they don't yet have the track record of the older compounds.

For that reason, although there are few reports of severe or sudden vision loss, until we have much more data, these agents should also carry the same warning as the non-selective COX inhibitors, such as ibuprofen and aspirin.

Follow diabetes closely

Metformin (#23) has become the most frequently prescribed oral agent for patients who have type-2 diabetes mellitus. While it has only been used in the United States for about eight years, it has been widely used throughout the world for many more years. The risks of serious ocular side effects with this agent are minimal. However, any patient taking this drug or other antidiabetic agents needs careful monitoring of their vision to try and catch diabetic changes as quickly as possible.

Be mindful of ACE inhibitor dosing

The last drug on the top 25 list is lisinopril, an angiotensin converting enzyme (ACE) inhibitor. This is just one of the many ACE inhibitors available in the United States. They are useful in treating hypertension, congestive heart failure and acute myocardial infarction.

The ACE inhibitors have caused angioedema of the lids and orbit, which isn't always associated with angioedema or allergic-like phenomenon in other areas. The mechanism for these effects may relate to an increase in kinins caused by ACE inhibition. This type of reaction may subside with continued use of the drug, but usually requires a decrease in dose or discontinuance of the drug. Oral antihistamines may also help relieve the symptoms. There are also reports of conjunctivitis related to the use of this drug.

Know your side effects

In the end, only a few of these frequently prescribed drugs cause serious ocular toxicity. But even in the case of drugs that only cause minor, transient ocular effects, with this information, you'll be able to better manage each patient's visual complaints.

Dr. Lescher is professor of pharmacology and toxicology and is chairman of the department of basic and health science at the Illinois College of Optometry. He is also a fellow in the American Academy of Optometry.

 

Make the Connection

This guide lists ocular side effects and the popular systemic drugs most commonly associated with them.

Allergic Reaction

  • cephalexin (Biocef, Keflex, Keftab)
  • amoxicillin (Amoxil, Biomox, Polymox)
  • albuterol aerosal (Ventolin, Volmax)

Blurred Vision

  • celecoxib (Celebrex)
  • rofecoxib (Vioxx)

Transient Myopia

  • furosemide (Lasix)
  • hydrochlorothiazide (Esidrix, Hydrodiurnal)
  • triamterene with hydrochloro- thiazide (Maxide, Dyazide)

Nystagmus

  • sertraline HCl (Zoloft)
  • paroxetine (Paxil)

Changes in Refractive Error

  • ibuprofen (Advil, Motrin, Nuprin)

Ocular Pain

  • celecoxib (Celebrex)
  • rofecoxib (Vioxx)

Angioedema of the Lids and Orbit

  • lisinopril (Zestril, Prinivil)

Decrease/Increase in Intraocular Pressure

  • decrease, atenolol (Tenormin)
  • decrease, metoprolol (Lopressor, Toprol XL)
  • increase, celecoxib (Celebrex)
  • increase, rofecoxib (Vioxx)

Photophobia

  • ibuprofen (Advil, Motrin, Nuprin)

Pseudotumor Cerebri

  • levothyroxine (Synthroid)

Cataracts

  • celecoxib (Celebrex)
  • rofecoxib (Vioxx)

Dry Eye

  • ibuprofen (Advil, Motrin, Nuprin)
  • atenolol (Tenormin)
  • conjugated estrogen (Premarin)
  • conjugated estrogen/medroxy- progesterone acetate (Prempro)

Increased Bleeding

  • acetylsalicylic acid (Aspirin)
  • ibuprofen (Advil, Motrin, Nuprin)

Miosis

  • hydrocodone with acetamino- phen (Vicoden, Zydone)

Optic Neuritis

  • ibuprofen (Advil, Motrin, Nuprin)

Color-Vision Abnormalities

  • ibuprofen (Advil, Motrin, Nuprin)

Retinal Vascular Disorders

  • conjugated estrogen (Premarin)
  • conjugated estrogen/medroxy- progesterone acetate (Prempro)

Visual Hallucinations/ Disturbances

  • levothyroxine (Synthroid)
  • atenolol (Tenormin)
  • metoprolol (Lopressor, Toprol XL)
  • unmasking/aggravating symptoms, amoxicillin (Amoxil)

Conjunctivitis

  • celecoxib (Celebrex)
  • rofecoxib (Vioxx)

Myasthenia-Like Symptoms

  • levothyroxine (Synthroid)
  • atenolol (Tenormin)
  • metoprolol (Lopressor, Toprol XL)
  • unmasking or aggravating signs, amoxicillin (Amoxil)

Mydriasis

  • albuterol aerosal (Ventolin, Volmax)

Decreases in Corneal Reflex, Accommodation, Depth Perception and Extraocular Muscle Abnormalities Leading to Diplopia

  • alprozolam (Xanax, Alxam, Alzor)
  • diplopia, sertraline HCl (Zoloft)
  • diplopia, paroxetine (Paxil)
  • diplopia, ibuprofen (Advil, Motrin, Nuprin)

Note: Sources of data for this chart include NDC Health and www.rxlist.com/top200.html.

 

 


Optometric Management, Issue: April 2003