DRY EYE REPORT

Are Medications the Culprit?

Many patients are taking systemic medications that cause or exacerbate dry eye. Here's what you need to know.

By William Townsend, OD, FAAO

If you're not taking medications, you're part of an evershrinking minority. Overall, Americans are becoming older, heavier, more anxious and depressed, and less physically active than ever before.¹ Our intake of medications has increased accordingly; approximately nine out of ten older Americans take one or more prescription drugs daily. It is estimated that in any given week, four out of five U.S. adults will use prescription medicines, OTC drugs or dietary supplements, and nearly one-third of adults will take five or more different medications.² Many of these drugs may impact the occurrence or severity of dry eye in our patients. It is therefore essential that we maintain a current medications list for all of our patients, update it at every visit and know which categories of medications carry the potential for causing or exacerbating ocular side effects.

Dry eye syndrome affects an estimated 25-30 million individuals in the United States. The condition is more common in those over 40 years old.¹ This segment of the population is projected to grow during the upcoming decades, increasing the likelihood of patients with significant dry eye presenting in our practices. The age-related increase in dry eye is related to several causative factors including declining androgen levels³ and medications.^4,5 In this article, we will evaluate how prescription and non-prescription medications impact the occurrence and severity of dry eye syndrome.

Beta-adrenergic antagonists (β-blockers)

The geriatric population is growing and the incidence of hypertension increases with aging. Pathogenic mechanisms that elevate blood pressure in the elderly include increasing arterial stiffness, high dietary sodium intake and increasing obesity.⁶ Several classes of medications are used in the treatment of hypertension.

β-blockers are commonly prescribed for hypertension as well as arrhythmias and migraine.⁷ They exert their effects by blocking the binding of norepinephrine and epinephrine to receptors in various tissues. Blocking beta-1 (β1) receptors cause the heart muscle to relax and beat more slowly thereby reducing the amount of blood that the heart pumps and lowering blood pressure. Beta-2 blockade relaxes vascular smooth muscle lowering resistance to blood flow and reducing blood pressure. It also impairs respiratory flow and may exacerbate asthma or chronic obstructive pulmonary disease.⁸ Systemic beta blockers have substantial anticholinergic effects and may cause significant reduction in lacrimation causing or exacerbating dry eye. Topical beta blockers also reduce tear production — but to a lesser extent than their systemic counterparts.

Diuretics

Diuretics increase urinary output thus reducing blood volume and ultimately lowering blood pressure and reducing edema. They may exert forced diuresis at several locations in the kidneys. Loop diuretics, such as furosemide, inhibit the body's ability to reabsorb sodium at the ascending loop. Thiazide-type diuretics, such as hydrochlorothiazide, act on the distal convoluted tubule reducing reabsorption of electrolytes from the renal tubules.⁹ This results in increased excretion of water and electrolytes, including sodium, potassium, chloride and magnesium. Diuretics reduce the amount of fluid available for tear production and can cause ocular dryness and discomfort.¹⁰

Anxiolytics, Antidepressants & Antipsychotics

Depression and anxiety are closely linked and are prevalent in our society.¹¹ Evidence suggests that they are caused by alterations in the neurotransmitters in the brain. The benzodiazepines and selective serotonin reuptake inhibitors (SSRIs) are two very common classes of medications used to treat these conditions; they are also used to treat seizures. Benzodiazepines work by binding to receptors sites on the GABA (gammaamino-butyric acid). Examples of this include alprazolam (Xanax, Pfizer), clonazepam (Klonapin, Roche), and diazepam (Valium). SSRIs block the reuptake of serotonin and elevate the amount of extracellular neurotransmitter in the presynaptic cleft. Examples include paroxetine (Paxil) and sertraline (Zoloft, Pfizer). Schaumberg et al¹² reported an almost two-fold incidence of dry eye in individuals taking antidepressants.

Antipsychotic agents are used to treat psychoses, which are defined as “radical changes in personality, impaired functioning, and a distorted or nonexistent sense of objective reality.” These medications are used to treat schizophrenia, bipolar disorder and other forms of psychosis. Haloperidol (Haldol) and ripiprazole (Abilify, Bristol-Myers Squibb) are examples of antipsychotics, which often cause anticholinergic side effects, such as dry mouth.^13,14 Dry eyes often occur in conjunction with this.

Antihistamines

Oral antihistamines exert their effects by reversibly blinding to histamine receptors throughout the body. Type 1 receptors are associated with allergy and systemic antihistamines are commonly used to treat this condition. Antihistamines are classified by their sedating characteristics. Common minimally sedating antihistamines include loratdine (Claritin, Schering-Plough) and ceterazine (Zyrtec, McNeil-PPC, Inc.). Diphenhydramine (Benadryl, McNeil-PPC, Inc.) is an example of a strongly sedating antihistamine. All antihistamines exert some degree of anticholinergic activity and therefore may cause reduced lacrimation and ocular dryness.¹⁵

Decongestants

Systemic decongestants stimulate α-adrenergic receptors causing constriction of blood vessels leading to reduced mucous membrane congestion. They are used in treating allergy and the symptoms of upper respiratory infection, such as the common cold. Pseudoephedrine (Sudafed, McNeil-PPC, Inc.) is a very commonly prescribed decongestant that is sometimes combined with an antihistamine. Decongestants cause decreased tear production leading to ocular dryness.¹⁵

Antispasmodics

Atropine, scopolomine and homatropine are antispasmodic agents commonly used to treat gastrointestinal tract spasticity to reduce symptoms seasickness. They are competitive antagonists for the muscarinic acetylcholine receptor and exert very strong anticholinergic properties. Antispasmodics commonly cause ocular dryness by reducing lacrimation.¹⁶

Narcotic Analgesics

Narcotic analgesics are frequently used in the management of severe or chronic pain. Nausea, constipation, slow and/or irregular breathing, and urinary hesitancy are only a few of the side effects associated with these medications.¹⁶ They reduce the perception of pain by binding to opioid receptors in the brain and spinal cord. Oxycodone and hydrocodone are commonly prescribed narcotic analgesics. Dry eye, one of the common side effects of these medications, is caused by their anticholinergic properties.

Hormone Therapies

In the past decade, we've seen an increase in research evaluating the effects of sex hormones on tear and lipid production. In a recently published study, Sullivan et al reported that androgens have a stimulatory effect on tear production, especially meibomian gland secretions, while estrogens.¹⁷ Conversely, estrogens reduce the size, activity and lipid output of sebaceous glands and have been known to decrease sebaceous gland function.¹⁸ The exact mechanism by which down regulation of secretion is accomplished is still undetermined, but the clinician should be aware that estrogens may contribute to the development of dry eye.

Incontinence Medications

Incontinence, the inability to control the evacuative functions of urination or defecation, is increasing in prevalence as our population ages.^19,20 Women have higher rates of urinary incontinence than men.²¹ Prevalence increases with age; one half of women older than 65 have some degree of incontinence.²² In addition to exercises to strengthen the pelvic muscles, antimuscarinic agents are used to treat incontinence. Common examples include oxybutynin (ditropan; oxytrol) and tolterodine (Detrol, Pfizer), dry mouth, constipation, blurred vision (accommodation abnormalities), urinary retention and dry eyes are common side effects attributed to these medications.²³

Chemotherapeutic Agents & Radiation

Rapid replication of the cells allows tumors to grow. Chemotherapeutic agents work principally by damaging the DNA of the affected cancer cells, inhibiting synthesis of new DNA strands or stopping mitosis of the original cell into two new cells. These agents can impact normal cells such as the lacrimal glands. A number of chemotherapeutic agents cause ocular dryness.²⁴ Radiation is also been widely used in treating malignant lesions and has been identified as a cause of cataracts and dry eye syndrome.²⁵

The number of medications available worldwide is climbing and many more are in the pipeline. Eyecare providers should be aware that many of these compounds have the potential to cause or exacerbate ocular dryness. As we obtain patient histories, we should proactively ask patients taking these medications if they are experiencing symptoms characteristic of dry eye.

References

1. Niskanen L, Laaksonen DE, Nyyssönen K, et al. Inflammation, abdominal obesity, and smoking as predictors of hypertension. Hypertension. 2004;44(6):859-865.
2. Nichols KK, Foulks GN. The New Dry Eye: A Global Perspective A review of how dry eye has changed in the two years since the International Dry Eye Workshop report. Contact Lens Spectrum, May 2009.
3. Sullivan DA, Sullivan BD, Evans JE, Schirra F, Yamagami H, Liu M, Richards SM, Suzuki T, Schaumberg DA, Sullivan RM, Dana MR. Androgen deficiency, meibomian gland dysfunction, and evaporative dry eye. Ann N Y Acad Sci. 2002;966:211-222.
4. Moss SE, Klein R, Klein BE Incidence of dry eye in an older population. Arch Ophthalmol. 2004;122(3):369-373.
5. Rogowski J, Lillard LA, Kington R. The financial burden of prescription drug use among elderly persons. Gerontologist. 1997;37(4):475-482.
6. Cohen DL, Townsend RR. Update on pathophysiology and treatment of hypertension in the elderly. Curr Hypertens Rep. E-pub ahead of print: June 18, 2011.
7. Gbemudu A, Marks JW. Beta Blockers Drug Information. Available at: http://www.rxlist.com/script/main/art.asp?articlekey=90349; accessed August 3, 2011.
8. Witte KK, Clark AL. Beta-blockers and inspiratory pulmonary function in chronic heart failure. J Card Fail. 2005;11(2):112-116.
9. Reddy P, Mooradian AD. Diuretics: An update on the pharmacology and clinical uses. Am J Ther. E-pub: January 8, 2009.
10. Jaanus SD. Ocular side effects of selected systemic drugs. Optom Clin. 1992;2(4):73-96.
11. Major Depressive Disorder Among Adults. National Institute of Mental Health website. Available at: http://www.nimh.nih.gov/statistics/1MDD_ADULT.shtml; last accessed August 2, 2011.
12. Schaumberg DA, Dana R, Buring JE, Sullivan DA. Prevalence of dry eye disease among US men: estimates from the Physicians' Health Studies. Arch Ophthalmol. 2009;127(6):763-768.
13. Abilify (aripiprazole) Prescribing Information. Bristol-Myers Squibb; 2011.
14. Davis CP. Haldol Drug Center. Available at: http://www.rxlist.com/haldol-drug-center.htm; accessed August 2, 2011.
15. Jaanus SD, Hegeman SL, Swanson MW Antiallergy drugs and decongestants. In: Bartlett JD, Jaanus SD eds; Clincal ocular pharmacology. Boston Butterworth-Heinemann.
16. Drugs.com. Atropine ophthalmic Side Effects in Side Effects by Body System: for Healthcare Professionals. 2011
17. Sullivan DA, Jensen RV, Suzuki T, Richards SM.Do sex steroids exert sex-specific and/or opposite effects on gene expression in lacrimal and meibomian glands? Mol Vis. 2009;15:1553-1572.
18. Porola P, Laine M, Virkki L, Poduval P, Konttinen YT. The influence of sex steroids on Sjögren's syndrome. Ann NY Acad Sci. 2007;1108:426-432.
19. Markland AD, Goode PS, Redden DT, Borrud LG, Burgio KL. Prevalence of urinary incontinence in men: results from the national health and nutrition examination survey. J Urol. 2010;184(3):1022- 1027.
20. Vecchioli-Scaldazza C, Morosetti C. Effect of aging on urinary incontinence in woman. Arch Ital Urol Androl. 2010;82(3):167-171.
21. Lee AH, Hirayama F. Physical activity and urinary incontinence in older adults: A community-based study. Curr Aging Sci. E-pub ahead of print; July 15, 2011.
22. Sampselle CM, Harlow SD, Skurnick J, Brubaker L, Bondarenko I. Urinary incontinence predictors and life impact in ethnically diverse perimenopausal women. Obstet Gynecol. 2002;100(6):1230-1238.
23. Weiss BD. Selecting medications for the treatment of urinary incontinence. Am Fam Physician. 2005;71(2):315-322.
24. Maino DM, Tran S, Mehta F. Side effects of chemotherapeutic oculo-toxic agents: a review. Clin Eye Vis Care. 2000;12(3-4):113-117.
25. Sanders JE. Late effects in children receiving total body irradiation for bone marrow transplantation. Radiother Oncol.1990;1:82-87.

---

Dr. Townsend practices in Canyon, Texas and is an adjunct professor at UHCO. He is president of the Ocular Surface Society of Optometry. E-mail him at drbilltownsend@gmail.com.