If medications only yielded one specific action, prescribing drugs would be easy. In essence, a clinician would only need to monitor the patient for the desired effect and modify the dosage accordingly to achieve the preferred outcome.

In reality, however, every medication has an effect on a multitude of organ systems. In rare instances, there may be an unexpected and/or beneficial effect of medication use. But, in many cases, side effects are dangerous or even deadly.

Package inserts rarely help us understand the totality of these unwanted consequences because each medication includes a lengthy, exhaustive list of precautions that’s nearly impossible to memorize. Such extensive information may lead patients, and even practitioners, to believe that every drug can potentially be associated with every side effect imaginable.

With more than four billion prescriptions written in the US each year, we must familiarize ourselves with the ocular and non-ocular side effects of the most commonly prescribed systemic medications.1,2

Cholesterol Medications
Because nearly 40 million Americans (about one in eight) are considered to have elevated cholesterol levels, lipid-lowering agents, such as statins, remain the most frequently prescribed medications in the US.3,4

Additionally, statins may be prescribed in cases of atherosclerosis and/or elevated triglycerides and C-reactive protein levels. Clinical trials have documented the efficacy of statins in preventing coronary heart disease, stroke and death from hypercholesterolemia-related disease.5 The result: In 2010, 255.4 million prescriptions for lipid-lowering drugs were filled in the US.6

Clinical Pearls for Cholesterol Medications
• Eye care practitioners should be on the lookout for unexplained diplopia, extraocular muscle palsy and ptosis in patients with a history of statin use.16 Notify the prescribing physician so that a management plan, including medication discontinuation, can be considered. A subsequent modification of the patient’s health care treatment may be needed to prevent cardiovascular and cerebrovascular events in the absence of a lipid-controlling medication.

• Statins should not be given concomitantly with oral macrolide antibiotics, such as erythromycin, because of an increased risk for myopathy.17 Also, one rodent study showed an increased risk of rapidly developing cataract when systemic erythromycin was used concurrently with simvastatin.18
Lipitor (atorvastatin calcium, Pfizer), which became generic in 2011, was the 12th most commonly prescribed medication in 2010, with 51 million scripts.6 Additionally, Zocor (simvastatin, Merck) was prescribed 83 million times in 2011––the second overall most frequently prescribed medication that year.7,8 Other cholesterol medications include Mevacor (lovastatin, Merck), Pravachol (pravastatin sodium, Bristol-Myers Squibb), Lescol (fluvastatin sodium, Novartis) Vytorin (exetimibe/simvastatin, Merck) and Crestor (rosuvastatin calcium, AstraZeneca).

• Systemic side effects. Although considered somewhat rare, possible side effects of statin use include chronic fatigue and muscle pain, which may be significant signs of skeletal muscle breakdown (e.g., myopathy). Further, liver enzyme elevation is possible. Patients who use statin medications should avoid drinking grapefruit juice, because of an increased risk for liver and kidney damage secondary to excessive drug absorbtion.9

• Ocular side effects. Only one published case report has surfaced regarding myopathy-induced unilateral ptosis following atorvastatin use.10 The ptosis resolved upon medication discontinuation.



Patients on long-term statin therapy have an elevated risk of new-onset ptosis, as seen in this patient. Photo: Mary E. Boname, OD

In 2008, Fredrick T. Fraunfelder, MD, authored a report on eye disorders related to statin use.11 In this retrospective study, his research group reported 256 cases of new-onset diplopia, ptosis and ophthalmoplegia within eight months following statin administration. In all instances, the signs or symptoms resolved following drug cessation.

Conjunctival yellowing may occur in cases of jaundice secondary to statin use, but ocular side effects are rare.12 Unexplained visual blur and non-specific eye irritation have been reported in patients who use using lovastatin.13 Cataract development also has been documented as a rare side effect of simvastatin use.13

Additionally, atorvastatin and simvastatin have been associated with pseudo-cystoid macular edema.14 So, patients on atorvastatin who experience unexplained reduced visual acuity should undergo OCT evaluation. Elevated IOP and an increased incidence of intraocular hemorrhages were reported infrequently in statin users.15

Psychogenic Medications

Clinical Pearl for Psychogenic Medications
• Today, antidepressants are being prescribed to an increasingly younger demographic. This may explain unexpected dry eye complaints in children and adolescents during the contact lens fitting process.
Antidepressants and antipsychotics are the second most commonly prescribed class of medications in the US, with more than 250 million scripts filled in 2010.6 Some of the more regularly prescribed antidepressants include Celexa (citalopram, Forest Laboratories), Cymbalta (duloxetine, Eli Lily), Effexor XR (venlafaxine, Pfizer), Lexapro (escitalopram, Forest Laboratories), Nardil (phenelzine, Pfizer), Paxil (paroxetine, GlaxoSmithKline), Prozac (fluoxetine, Eli Lilly), Pristiq (desfenlafaxine, Pfizer), Sinequan (doxepin, Pfizer), Wellbutrin (bupropion, GlaxoSmithKline) and Zoloft (sertraline, Pfizer).

In addition, the antipsychotic agents Abilify (aripiprazole, Bristol-Myers Squibb), Seroquel XR (quetiapine, AstraZeneca) Zyprexa (olanzapine, Eli Lilly), Mellaril (thioridazine, Novartis) and chlorpromazine often are used in combination with anti-depressants.

• Systemic side effects. Anti-psychotics have been associated with an increased incidence of suicidal thoughts in children, adolescents and young adults.19 Aripiprazole is associated with neuroleptic malignant syndrome, which is characterized by fever, convulsions, fast breathing, sweating and rapid

 
Vortex keratopathy often presents with a whorl-like pattern in some patients who are on long-term Nexterone (amiodarone, Baxter Healthcare Corporation) therapy. Photo: Jay S. Pepose, MD, PhD
heartbeat.20

Tardive dyskinesia is a group of severe side effects associated with all antipsychotic medications, and includes lip smacking, cheek puffing, worm-like tongue movements, and uncontrolled jaw, arm and leg motions.21 The use of antipsychotic medications is associated with an increased risk of diabetes, liver and kidney disease as well as a higher incidence of seizures.19-21

• Ocular side effects. The most common ocular side effects of psychogenic drugs are blurred vision and photophobia as well as nonspecific visual complaints.22 But, of particular concern is the association between antidepressant use and dry eye. Patients with unexplained dry eye symptoms, such ascomplaints of grittiness, foreign-body sensation, conjunctivitis and corneal epithelial staining, should be asked about antidepressant use.

Such drug-induced dry eye also may inhibit successful contact lens wear in some patients.

Thioridazine and chlorpromazine are both associated with night blindness, a “browning of vision,” cataract development and a salt-and-pepper pigmentation of the fundus. Also, selective serotonin reuptake inhibitors, including citalopram and escitalopram, have been implicated in angle- closure glaucoma––with attacks typically occurring within six months of therapeutic initation.22

Pain Medications

Clinical Pearl for Pain Medications
• Unexplained diplopia and blurred vision mandates a detailed history of prescription painkiller use.
Narcotic analgesics were the third most commonly prescribed medications in the US in 2011––with Vicodin (hydrocodone/acetaminophen, Abbott) being the country’s most frequently prescribed medication overall.23 In fact, of the more than 250 million pain medication prescriptions in 2011, almost half were written for Vicodin. Other commonly prescribed pain medications include OxyContin (oxycodone, Purdue Pharma), Percocet (oxycodone/ acetaminophen, Endo Pharmaceuticals) and Neurontin (gabapentin, Pfizer).

• Systemic side effects. The most common side effects of patients who use hydrocodone include lightheadedness, nausea, vomiting and increased sweating.31 Less common side effects include weakness, tiredness, headache, dizziness, dry mouth, constipation and rapid heartbeat.24,25

• Ocular side effects. Infrequently, hydrocodone users report nonspecific visual distortions, minor hallucinations and conjunctival yellowing.26 Double vision and transient blur are commonly reported in patients using gaba-pentin.25

Antihypertensive Medications

Clinical Pearl for Antihypertensive Drugs
• Patients with chronic dry eye secondary to beta blocker and diuretic use may benefit from nasolacrimal plugs.
The risk of systemic hypertension increases with age, eventually affecting 66% of Americans older than 60 years of age.27 Because 77 million Americans will turn 65 this year, it is no surprise that antihypertensive drugs are some of the most frequently prescribed medications in the US.

Systemic beta blockers, angiotensin-converting enzyme (ACE) inhibitors and the calcium-channel blockers were respectively the fourth, fifth and 13th most commonly prescribed drugs in 2010.6

Beta blockers are used in the treatment of heart disease and, in particular, high blood pressure. Commonly prescribed systemic beta blockers include Coreg (carvedilol, GlaxoSmithKline), Inderal (propranolol, AstraZeneca), Lopressor (metoprolol, Novartis), Toprol-XL (metoprolol, AstraZeneca) and Tenormin (atenolol, AstraZeneca).



Lupus patients who use Plaquenil (Sanofi-Aventis) should be monitored for the development of hydroxychloroquine maculopathy, as seen in this individual. Photo: Lloyd Pate, OD

Common ACE inhibitors include Lotensin (benazepril, Novartis), Capoten (captopril, Bristol-Myers Squibb), Vasotec (enalapril, Biovail Pharmaceuticals Inc.), Prinivil (lisinopril, Merck), Zestril (lisinopril, AstraZeneca), Accupril (quinapril, Pfizer) and Altace (ramipril, King Pharmaceuticals).

Norvasc (amlodipine besylate, Pfizer) is the most commonly prescribed calcium-channel blocker, with 57 million scripts written in 2010.6

Additionally, diuretics––such as Esidrex (hydrochlorthiazide, Novartis) and Lasix (furosemide, Sanofi-Aventis)––are often prescribed for systemic hypertension.6

• Systemic side effects. Side effects of beta blockers include central nervous system depression, impotence, hypoglycemia, lipidemia and alopecia.28

• Ocular side effects. The most significant side effects of systemic beta blocker and diuretic use are dry eye, conjunctivitis, corneal epithelial damage and staining secondary to decreased tear production. Furthermore, patients on beta blockers and diuretics may experience difficulty wearing contact lenses due to significant ocular surface dryness.

Ocular side effects of ACE inhibitors include decreased vision, photophobia and conjunctivitis. Further, the anemia associated with ACE inhibitors can cause retinal hemorrhaging.29

Thyroid Medications

Clinical Pearl for Thyroid Medications
• A patient who presents with unexplained diplopia, ptosis or extraocular motility issues requires a detailed history, including levothyroxine use.
The thyroid preparation Synthroid (levothyroxine sodium, Abbott) was the fourth overall most commonly prescribed medication of 2010, with 70 million scripts.6 Levothyroxine is used as hormonal replacement therapy (HRT) in cases of hypothyroidism caused by an underactive thyroid gland.

Use of thyroid replacement hormone increases metabolism, but may worsen the symptoms of diabetes.

• Systemic side effects. Within the first month of hypothyroidism treatment initiation, HRT may rarely cause heart palpitations, rapid heartbeat, weight loss, tremor, headache, diarrhea, nervousness, hair loss and sweating.30

• Ocular side effects. Although ocular side effects associated with levothyroxine use are extremely rare, ptosis, diplopia and ophthalmoplegia have been reported.31 Thyroid hormone toxicity may mimic the symptoms of myasthenia gravis, including ptosis and diplopia. Be aware that the use of topical beta blockers may interfere with the body’s response to thyroid replacement hormones. If you start a patient on a topical beta blocker, be sure to contact his or her primary care physician for a thyroid hormone level evaluation. The dose of levothyroxine may have to be adjusted once the blood serum levels of the beta blocking agent are stabilized.31

Antibiotics

Clinical Pearl for Antibiotic

• A new onset of unexplained diplopia mandates a detailed history, including systemic antibiotic use.

Zithromax (azithromycin, Pfizer), Amoxil (amoxicillin, GlaxoSmithKline) and several systemic fluoroquinolones are being prescribed with greater frequency for the treatment of various colds and infections.32 Fluoroquinolones are broad-spectrum antibiotics that have a side effect profile that isn’t seen in other antibiotics.

• Systemic side effects. Reports of new-onset myasthenia gravis, including symptoms of muscle weakness and difficulty swallowing, have surfaced in patients who use Zithromax.33 Other common side effects of Zithromax include diarrhea, nausea, vomiting, heart palpitations and headache.33
Additionally, one report indicated that systemic fluroquinolone use might be associated with tendinitis and tendon rupture.34

• Ocular side effects. Patients on Zithromax may, on rare occasion, develop photophobia or conjunctival yellowing secondary to jaundice. In one study, diplopia was reported in 171 patients.35 In most of these cases, the diplopia resolved following drug discontinuation. However, subsequent dosing of Zithromax caused diplopia to reoccur in five individuals.35

Tetracycline has been associated with non-pupillary block angle-closure glaucoma, most likely due to an allergic response to the sulpha molecule.36 This reaction may trigger edema and swelling of the ciliary body, causing the anterior chamber to shallow.36

Diabetes Drugs

Clinical Pearl for Diabetes Drugs
• Any large, bilateral, unexplained refractive shift warrants referral for a diabetes work-up. Consider asking the patient if he or she has experienced a recent increase in hunger, thirst or urination—three of the most common symptoms of diabetes.
The type 2 diabetes medication Glucophage (metformin, Merck) was the ninth most commonly prescribed drug in 2010, with 52 million scripts written.6 Metformin lowers the amount of glucose produced by the liver, reduces the amount of sugar absorbed from food and helps cells utilize glucose.

• Systemic side effects. Gastrointestinal issues are the most common side effects of metformin.37

• Ocular side effects. Patients on metformin therapy may experience transient refractive shifts while serum glucose levels stabilize.38

Respiratory Medications

Clinical Pearl for Respiratory Medications

• All asthmatic and pulmonary patients on inhaled steroids must be followed regularly for the development of cataract and glaucoma.

The two most common types of asthma medications are inhaled steroids and bronchodilators.6 The most popular and useful way to deliver asthma medication is via inhaler. Steroids are the single most important treatment for asthma. They are used to decrease the airway’s sensitivity to asthma triggers, and to reduce swelling and mucus production within the airways. Following a serious asthma attack, oral steroids may be prescribed; however, the longer the steroid is used, the greater the risk of serious and permanent side effects.39
Significant retinal hemorrhage is one potential side effect of Coumadin (warfarin, Bristol-Myers Squibb) use. Photo: Mark T. Dunbar, OD

Bronchodilators can help make breathing easier by relaxing the muscles that tighten the airway in asthma patients. Inhaled agents can be used to promptly rescue a patient in an asthmatic attack, or can be used prophylactically to prevent exercise-induced asthma.40

Inhaled steroids and bronchodilators are also useful in the treatment of chronic obstructive pulmonary disease (COPD). The three types of bronchodilating agents include beta2-agonists (both short- and long-acting), short-acting anticholinergics and long-acting theophylline.

Beta2-agonists are emergency medications that act quickly to give rapid, temporary relief of acute asthmatic episodes. Albutarol can relieve bronchospasm and may yield fewer systemic and cardiac side effects than epinephrine. Short-acting anticholinergics include Spiriva (tiotropium, Pfizer), which is used to treat bronchospasm associated with COPD.41

• Systemic side effects. Inhaled steroid use can cause dry mouth, fungal infections of the mouth and depression as well as increase the risk of respiratory infections.6 Spiriva is associated with upper respiratory infection and headache; albuterol is associated with those symptoms and stuffy nose as well.41,42

• Ocular side effects. The ocular side effects of inhaled steroid use are well known and include the development of posterior subcapsular cataract and glaucoma as well as reduced corneal wound healing time.6 Epinephrine may be used in a severe asthmatic attack, and this has been linked to angle-closure glaucoma.6 The use of albuterol is associated with non-specific visual changes.41 Because Spiriva is related to atropine, a common ocular side effect is photophobia due to pupil mydriasis.43  

Common Ocular Side Effects of Less Frequently Prescribed Systemic Drugs

• Flomax (tamsulosin, Boehringer Ingelheim) is used to treat benign prostatic hyperplasia (BPH). However, it is extremely well known that patients who use Flomax are at increased risk for floppy iris syndrome.44 Always notify the ophthalmic surgeon if a patient is on Flomax or an alpha-adrenergic agonist.

• Viagra (sildenafil, Pfizer), Cialis (tadalafil, Ely Lilly) and Levitra (vardenafil, Bayer Healthcare Pharmaceuticals) are used for the management of erectile dysfunction. In 2012, Fredrick T. Fraunfelder, MD, concluded that, “to date, there is no proof of any permanent damage from any of these agents on the visual system.”11,45

Further, he suggested that rare vascular effects cannot be distinguished from those that would ordinarily occur from the increased blood pressure and pulse rate associated with normal sexual activity.

Color perception problems, blurred vision, central haze and decreased vision were reported infrequently.11,45 There is a possible association between Viagra use and non-arteritic ischemic optic neuropathy (NAION) in patients with a history of unilateral optic neuropathy.11,45 Take note that there is no association between Viagra and an increased risk for glaucoma.11,45

• Plaquenil (hydroxychloroquine, Sanofi-Aventis) is used to treat rheumatoid arthritis and lupus erythematosis. Plaquenil enters the tear film and may contribute to corneal deposits, dry eye and contact lens intolerance. Retinal changes also may occur, including bull’s eye maculopathy.46 Further, Plaquenil use should be avoided in patients with Stargardt’s disease.46

• Hormonal contraceptives used to prevent unwanted pregnancy carry a range of side effects. The ocular side effects of such estrogen- and/or progesterone-based agents include optic neuritis, pseudotumor cerebri, dry eye and retinal thrombosis.47 These medications also may increase the risk of cardiovascular and cerebrovascular events.47

• Coumadin (warfarin, Bristol-Myers Squibb) is an oral anticoagulant that is used to prevent blood clot formation and reduce the risk of recurrent heart attack or stroke. It is often associated with subconjunctival and retinal hemorrhage.48

• Topamax (topiramate, Janssen Pharmaceuticals) is prescribed to treat patients with epilepsy and migraine headaches. Additionally, the medication is used off label to manage obesity, bipolar disorder and clinical depression. By 2012, there were almost 100 reported cases of acute angle-closure glaucoma associated with Topamax use.49

• Qsymia (phentermine/topiramate extended-release, Vivus), a new prescription obesity medication, received FDA approval in July 2012. Patients who use Qsymia are at an increased risk for drug-induced myopia and angle-closure glaucoma.50

• Fosamax (alendroinic acid, Merck) inhibits bone reabsorption in the management of hypercalcemia of malignancy, bone metastasis in cancer patients, and Paget’s disease of the bone. Anterior uveitis and conjunctivitis are the most common ocular side effects.51 Further, one study indicated an association with scleritis and retrobulbar neuritis.51

• Myambutol (ethambutol, Stat-Trade, Inc.) is used in the treatment of pulmonary tuberculosis. Its ocular side effects include bilateral retrobulbar optic neuropathy, which typically manifests within two to five months of dosing initiation.52

• Nexterone (amiodarone, Baxter Healthcare Corporation) can produce a whorl-shaped keratopathy and optic neuropathy.53 The keratopathy typically resolves within one year of medication discontinuation. Nexterone also may cause loss of eyelash and eyebrow follicles as well as photophobia.53

Dr. Muchnick is chief of optometry at the Coatesville Veterans Affairs Medical Center in Pennsylvania. He is the author of “Clinical Medicine in Optometric Practice, 2nd Edition.”

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