1. Systemic medications and their ocular side effects Jennifer Tordilla-Wadia, M.D. Vitreoretinal Surgeon James A. Haley Veterans Hospital Tampa, Florida Assistant Professor Department of Ophthalmology University of South Florida Tampa, Florida Systemic medications and their ocular side effects

2. OBJECTIVES To review basic eye anatomy and physiology To educate clinicians on ocular side effects from common systemic medications To encourage providers to report ocular adverse effects to the National Registry of Drug-Induced Ocular Side Effects, Food and Drug Administration, World Health Organization, and the pharmaceutical industry

3. No Financial Disclosures

4. Anatomy of the Eye Drug molecules reach the eye through fenestrations in the choroid and retinal vessels then diffuse to avascular structures such as lens and cornea.

5. Systemic medication and their ocular side effects

6. WHO CLASSIFICATION SCHEME Certain: – A clinical event, including a laboratory test abnormality, occurring in a plausible time relationship to drug administration, and which cannot be explained by concurrent disease or by the presence of other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be clinically plausible. The event must be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if necessary. Probable/Likely: – A clinical event, including a laboratory test abnormality, occurring within a reasonable time from administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. Possible: – A clinical event, including a laboratory test abnormality, that occurs within a reasonable time from administration of the drug, but which could also be explained by concurrent disease or the presence of other drugs or chemicals. Information on drug withdrawal may be lacking or unclear.

7. WHO CLASSIFICATION SCHEME Unlikely: – A clinical event, including a laboratory test abnormality, with a temporal relationship to drug administration which makes a causal relationship improbable, and for which the presence of other drugs, chemicals or underlying disease provides a plausible explanation. Conditional/Unclassified: – A clinical event, including a laboratory test abnormality, reported as an adverse reaction but about which more data is essential for a proper assessment or for which the additional data are under examination. Unassessible/Unclassifiable: – A report, suggesting an adverse reaction, which cannot be judged because information is insufficient or contradictory, and which cannot be supplemented or verified.

8. Report an adverse ocular effect FDA MedWatch www.fda.gov/medwatch The World Health Organization Uppsala Monitoring Center www.who-umc.org Pharmaceutical industry phone numbers are listed in the current PDR for Ophthalmic Medicines. The National Registry of Drug-Induced Ocular Side effects www.eyedrugregistry.com www.eyedrugregistry.com

9. National Registry of Drug-Induced Ocular Side Effects Founded in 1976 and was initially funded by the Federal Food and Drug Administration. The Registry is supported by the Casey Eye Institute at Oregon Health and Science University and the American Academy of Ophthalmology. The goal is to maintain an international clearinghouse of information on adverse ocular events associated with drugs, chemicals and herbals. The Registry accumulates data from spontaneous reports sent to the World Health Organization's Uppsala Monitoring Center (Uppsala, Sweden), the Food and Drug Administration (Rockville, MD), pharmaceutical companies, and screening of the world's literature.

10. What are drugs used to prevent clot formation in the disease associated with the EKG below?

11. ANTICOAGULANTS Aspirin (salicylate) Coumadin (warfarin) Heparin (unfractionated heparin) Lovenox (enoxaparin sodium) Plavix (clopidogrel) Pradaxa (dabigatran etexilate mesylate) Ocular Side Effects Subconjunctival and retinal hemorrhage Recommend to be discontinued for a week prior to eye surgery INR > 5 prone to bleed Chronic use of ASA may cause yelllowing of vision

12. What are drugs to alleviate the following symptoms?

13. ANTI-ALLERGY AGENTS Claritin (Loratadine) Zyrtec (cetirizine) Allegra (fexofenadine) Singulair (Montelukast sodium) Benadryl (Diphenhydramine HCl) Sudafed (pseudoephedrine) Ocular Side Effects: Dry Eye, Keratitis sicca Contact lens intolerance Mydriasis Angle closure glaucoma or Narrow angle glaucoma

14. ANTI-ALLERGY AGENTS Claritin (Loratadine) Zyrtec (cetirizine) Allegra (fexofenadine) Benadryl (Diphenhydramine HCl) Sudafed (pseudoephedrine) Mechanism of Ocular Side Effects: Block Histamine-1 (H1) receptors Weak atropine action (cholinergic antagonist), causing mydiasis, anisocoria, decreased vision and blurred vision Inhibit glandular secretion and reduce mucous and tear secretion which aggrevate keratitis sicca and contact lens wear Anti-ulcer drugs also block histamine receptors

15. What are drugs to treat the condition?

16. ANTI-MIGRAINE AGENTS Topamax (topiramate) – Indicated for migraines, seizures, mood disorder – Mechanism of action: blockage of voltage-dependent sodium channels, an augmentation of gamma- aminobutyric acid activity at some subtypes of the GABA- A receptors, antagonism of AMPA/kainate subtype of the glutamate receptor, and inhibition of the carbonic anhydrase enzyme, particularly isozymes II and IV

17. ANTI-MIGRAINE AGENTS Ocular side effects Acute Closed Angle Glaucoma Diplopia Acute Myopia 6-8 diopters Suprachoroidal Effusion Dry Eyes Sulfa Allergy Symptoms within 2-4 weeks

18. ANTI-MIGRAINE AGENTS Serotonin receptor antagonist – Imitrex – Corneal opacity Beta Blockers – Reduce tear lysozyme levels and immunoglobulin IgA – Dry eye, contact lens intolerance

19. Name some medications to treat depression.

20. ANTI-DEPRESSANTS Prozac (fluoxetine) Zoloft (sertraline) Paxil (paroxetine) Celexa (citalopram) Effexor (venlafaxine hydrochloride) Anticholinergic effects blocking the binding of the neurotransmitter acetylcholine to its receptor in nerve cells Ocular Side Effects Blurred vision Cycloplegia Photophobia Dry eye

21. Name some drugs to treat the following symtpoms.

22. Anxiolytics Xanax (Alprazolam) Valium (Diazepam) – Binds to the benzodiazepine receptor site on the GABA receptor and modulates function Ocular Side Effects Blurred Vision Diplopia Mydriasis Conjunctivitis

23. What are some medications used for the following associated with CHF?

24. Antiarrhythmics Amiodarone (Cordarone) Photosensitizer, tendecy towards lipid storage in the cornea and lens Dose and duration dependent, usually reversible Ocular side effects Vortex Keratopathy – Nearly 100% pts treated greater than 6 months – <10% bothered by blurred vision or haloes Anterior and posterior subcapsular lens changes Optic neuropathy

25. Antiarrhythmics Digoxin (Digitek ) Inhibition of Na+K+ ATPase which plays a vital role in maintaining normal cone receptor funtion and ciliary epithelium responsive for active transport of sodium necessary for aqueous secretton Ocular Side Effects Affects cone receptor function 11-25% of patients red-green color defects Yellow tinged vision (xanthopsia) Snowy, hazy, or dimming vision Flickering or flashes of light, and colored spots Reduces acqueous secretion and IOP

26. Ever wonder why there is a predominance of the color yellow in most of Van Gogh’s works? In the 19th century, Digitalis was widely used; its uses went beyond treating edema, including epilepsy, mania, asthma, and among others. Vincent van Gogh was diagnosed as having Epilepsy and Mania He was said to have been prescribed Digitalis by his attending physician, who was interestingly enough, painted by Van Gogh beside a Foxglove plant, where Digitalis is derived Digitalis was widely used and plasma level controls were non-existent. One can, therefore imagine how easy it was to prescribe an overdose of digitalis at the time. Van Gogh suffered from Xanthopsia, a distortion in color vision, in which objects appear more yellow than they truly are; a usual sign of Digitalis Toxicity.

27. Starry Night Van Gogh also suffered from glaucoma making him see haloes around lights

28. What class of drugs would you use to treat the following condition?

29. Diuretics Thiazides or diuretics are often used to treat congestive heart failure and HTN Hydrochlorothiazide (HCTZ) Furosemide (Lasix) Changes the tear film Ocular Side Effects: Dry eye Myopic shift Band keratopathy

30. Name some agents to treat a condition related to the following picture.

31. Antihyperlipidemics Mevacor (lovastatin) Lipitor (atorvastatin) Zocor (simvastatin) The enzyme HMG-CoA reductase is inhibited, thereby preventing the rate-limiting step in the mevalonate pathway of cholesterol synthesis.

32. Antihyperlipidemics Ocular Side Effects: localized myositis in the extraocular muscles or levator palpebrae superioris muscles Diplopia – reversible on discontinuation of the statin as evidenced by the 62 positive rechallenge case reports. Ptosis Lid edema Lens opacities Dry eye Blurred vision Pseudo-cystoid macular edema

33. Name some meds for glycemic control.

34. Avandia/Actos Avandia (rosiglitazone) Actos (pioglitizone) Thiazolidinedione class – Thiazolidinediones act as insulin sensitizers. They reduce glucose, fatty acid, and insulin blood concentrations. Ocular Side Effect Macular edema

35. What is a common drug to treat the following process?

36. Flomax (tamsulosin) alpha-adrenergic blockers, relaxes the muscles in the prostate and bladder neck, making it easier to urinate Ocular Side Effects Loss of tone in iris dilator smooth muscle causing poor pupil dilation Iris prolapse during cataract surgery “Floppy Iris Syndrome”

37. What drug is prescribed for breast cancer and reducing the incidence of breast cancer among high-risk women

38. Tamoxifen citrate – Tamoxifen competitively binds to estrogen receptors on tumor cells and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects Ocular Side Effects: Crystalline retinopathy Treatment involves withdrawal of the drug as it is reversible Ocular complications are rare (0.6%)

39. What is the effect of hormones?

40. HORMONES Synthroid (Levothyroxine) Ocular Side Effects Pseudotumor Cerebri (PTC) Visual Hallucinations Diplopia Ptosis Paralysis of EOM Hyperemia Side effects disappear with discontinuation of drug

41. Estrogen or Progesterone Decreased aqueous production, microvacular occlusions from enhanced platelet adhesiveness, or increase in fibrinogen and clotting factors. Ocular Side Effects Microvascular complications like artery and venous occlusions Dry Eye Contact Lens Intolerance Optic neuritis Macular Edema TIA (Transischemic attacks) Pseudotumor cerebri

42. What is common drug to treat this teenager?

43. DERMATOLOGIC AGENTS Accutane (isoretinoin) This retinoid (a form of vitamin A) is used to treat psoriasis, cystic acne, and various other skin conditions. Deficiency of the normal lipid layer in the tear film Ocular Side Effects: Swollen optic disc, called "papilledema” the result of increased intracranial pressure (pseudotumor cerebri). Symptoms are headache and transient black-outs of vision upon assuming the upright posture. The visual black-outs are caused by postural drops in blood pressure and secondary compromise of blood flow to the retina through the tightly packed optic disc. Night blindness Retinotoxicity Keratitis

44. DERMATOLOGIC AGENTS Minocycline – For severe acne vulgais Ocular side effect Swollen optic disc, called "papilledema” the result of increased intracranial pressure.

45. A patient travels back to the U.S. with night sweats.

46. Anti-tuberculosis drugs Ethambutol HCL (Myambutol), Isoniazid (Laniazid) Rifampin (Rimactane) Chelates copper, so the decreased levels impair mitochondrial activity of axonal transport in optic nerve leading to optic neuropathy Ocular side effects Optic neuritis/neuropathy and blindness. Change tears, sweat, saliva,urine, feces and contact lenses a red-orange color.

47. Anti-tuberculosis drugs Ophthalmic examinations are recommended by the PDR every month for doses of ethambutol greater than 15mg/kg/day. No official standard of care exists in dosages less than 15 mg/kg/day. 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.

48. Visual field test results obtained 3 months after onset of visual symptoms. Both the left (A) and right (B) visual fields show central scotoma with inferior temporal quadrant defects.

49. Name a drug that can be used to treat the following pictures?

50. Antimalarials Plaquenil (hydroxychloroquine) Aralen phosphate (chloroquine) – Treats malaria, rheumatoid arthritis, and lupus erythematosis High affinity to melanin, toxic to the retinal pigment epithelium Ocular Side Effects: Bull’s-eye maculopathy This bull’s-eye maculopathy starts as fine pigmentary mottling within the macular area. The end result can range from reduced vision to blindness

51. Antimalarials Patients at greatest risk are those on hydroxychloroquine for longer than 5 years and those with renal or liver Elderly, thin patients may also be overdosed, as may obese patients. Dosing regimens are based on body weight, but hydroxychloroquine is primarily absorbed by cellular tissue. Since adipose tissue is relatively acellular, obese patients may be overdosed. Dosage exceeds 6.5 mg/kg Examination – A baseline exam should be performed before the patient starts treatment. – Eye exam including Fundus Photos, HVF-10 (red-white), OCT, Amsler grid, and color vision.

52. Antimalarials Age <40 who are not higher risk follow-up every 2-4 years Patients between 40 and 64 years: follow-up every 2-4 years Age 64 and older: follow-up(every 1-2 years 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.

53. Antimalarials Aralen phosphate (chloroquine) Obtain tests as plaquenil exam. 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.

54. Edward Calvin Kendall was awarded the 1950 Nobel Prize for Physiology or Medicine for discovery of this molecule. First produced commercially by Merck & Company on September 30, 1949.

55. Corticosteroids Prednisone To treat inflammatory and allergic conditions. They are very effective for acute disease states as well as chronic conditions Ocular Side Effects Posterior subcapsular cataract Elevated intraocular pressure Papilledema Exacerbation of herpetic keratitis

56. Corticosteroids Cataracts resulting from steroid use are well known and occur with topical, systemic, and nasal administration. The development of cataract is related to the cumulative dose of prednisone; 25% of patients who use 15 mg/day for 1 year or more will get cataracts that interfere enough with vision to require surgical removal The etiology is unknown, the drug may react with amino groups of crystalline lens fibers causing protein complexes to aggregate

57. What drugs are use for treatment/prevention in men and women?

58. Bisphophonates FOSAMAX AREDIA ACTONEL ZOMETA BONEFOS DIDROCAL Bisphosphonate molecules preferentially "stick" to calcium and bind to it. They accumulate to a high concentration in bones, resulting in maintained or increased bone density and strength Ocular Side Effects Scleritis/Episcleritis Blurred vision Hyperemia Anterior uveitis

59. What is the class of drugs to treat hepatitis and multiple sclerosis?

60. Interferons (Intron A/Avonex/Pegasys) Interferons Delayed type hypersensitivity reaction. In many infectious and systemic diseases, the deposition of immune complexes with subsequent complement activation is a major pathogenic mechanism for the devolopment of uveitis Ocular Side Effects: Cotton wool spots Optic neuritis Ocular pain Conjunctivitis Pronounced dry eye Dilated Eye exam prior to treatment and 2-4 weeks after treatments

61. A man reports discoloration of vision after taking a medication from his pill box last night?

62. ERECTILE DYSFUNCTION Viagra (sildenafil citrate) Cialis (tadalafi) Levitra(vardenafil) Staxyn( vardenafil HCl) Stendra (avanafil) inhibits phosophodiesterase-5 (PDE-5) which results in vasodilation of smooth muscle. Ocular Side Effects Objects have color tinges—usually blue or blue- green, may be pink or yellow 11% of patients on 100mg perceive a blue haze up to four hours Dark colors appear darker Visual disturbances NAION

63. ERECTILE DYSFUNCTION The above ocular side effects are dose- dependent with all three drugs. – For sildenafil side effects occur at the following incidences: – 50mg 3% – 100mg 10% – 200mg 40-50% The side effects based on dosage with sildenafil start 15-30 minutes after ingestion of the drug, and usually peak 60 minutes after ingestion.

64. ERECTILE DYSFUNCTION Patients who should not take phosphodiesterase type 5 inhibitors are those who have previously suffered ischemic optic neuropathy (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.

65. Herbal Medicines and Nutrional Supplementation Canthaxanthine – Tanning – crystalline retinopathy Chamomile – Allergic conjunctivitis – one of the most ancient medicinal herbs known to mankind. – terpenoids and flavonoids – human ailments such as hay fever, inflammation, muscle spasms, menstrual disorders, insomnia, ulcers, wounds, gastrointestinal disorders, rheumatic pain, and hemorrhoids. – Essential oils of chamomile are used extensively in cosmetics and aromatherapy

66. Herbal Medicines and Nutrional Supplementation Datura “angel’s trumpet” – Mydriasis from tropane alkaloids, atropine/scopolamine properties – poison Echinacea purpurea – Conjunctivitis – Used for URI, yeast infection, and many other ailments

67. Herbal Medicines and Nutrional Supplementation Ginkgo biloba – Spontaneous hyphema, retinal hemorrhage – Dementia, Alzheimer’s, memory Licorice – visual loss associated with migraine-like symptoms – Vasospasm – hypertension

68. Herbal Medicines and Nutrional Supplementation Niacin – Cystoid macular edema – Dry eyes, discoloration of the eyelids, eyelid edema, – proptosis, loss of eyebrows and eyelashes – superficial punctate keratitis Vitamin A – Intracranial hypertension when taken in large doses, cause papilledema

69. Summary A 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. There are four resources to report ocular adverse events: National Registry of Drug-Induced Ocular Side Effects, Food and Drug Administration, World Health Organization, and the pharmaceutical industry.

70. Thank you for your attention!