Ocular Toxicology

1. Ocular Toxicology Preston H. Blomquist, MD Department of Ophthalmology University of Texas Southwestern Medical Center at Dallas

2. Tamsulosin (Flomax) Systemic alpha-1 antagonist Relaxes the smooth muscle in the bladder neck and prostate, improves urinary flow in benign prostatic hypertrophy (BPH) Tamsulosin is highly selective for the alpha-1A receptor subtype that predominates in the prostate, more uroselective compared to other alpha-1 blockers for BPH, such as Hytrin and Cardura

3. Tamsulosin (Flomax) Intraoperative Floppy Iris Syndrome (IFIS) Subnormal preoperative pupil dilation Repeated incisional prolapse of a billowing, floppy iris, causing progressive intraoperative miosis that is not prevented by sphincterotomies and mechanical pupil stretching.

4. Tamsulosin (Flomax) Intraoperative Floppy Iris Syndrome (IFIS) Stop Flomax 2 weeks preop Improves, but does not eliminate floppy iris behavior IFIS occurs as late as 1 year after stopping Flomax Iris hooks, pupil expansion rings Sphincterotomies, pupil stretching ineffective Pharmacologic aids Atropine (no!), phenylephrine/epinephrine

5. Erectile DysfunctionAgents Sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra) Inhibits phosphodiesterase-5 (PDE5) most dramatically Also has 10% effectiveness in inhibiting PDE6 (found in photoreceptors, mediates transduction) Visual symptoms include bluish tinge or haze to vision, increased light sensitivity (3% incidence at low dosages, 11% after 100 mg dose, near 50% after 200 mg)

6. Erectile DysfunctionAgents By summer 2005, FDA had received 43 reports of NAION in men using these drugs Due to decreased perfusion pressure from drug-induced hypotension? Viagra alone estimated to have 23 million habitual users

7. Erectile DysfunctionAgents FAA recommends that pilots not fly within 6 hours of taking the drug Unknown what long-term effects on eye are Caution advised in patients with retinal problems (do not exceed 50 mg) Macular degeneration Retinitis pigmentosa (don’t take in autosomal recessive RP due to genetic defect in PDE-6?) Diabetic retinopathy Definitely avoid if previously had NAION in one eye

8. Vigabatrin (Sabril) Recently approved by FDA Drug may control refractory seizures (inhibits GABA transaminase) GABA plays a role in horizontal cell coupling, amacrine and bipolar cells in retina High incidence of side effects (20-36%) Bilateral peripheral constriction of visual field Tunnel vision In children, can have peripheral retinal atrophy and secondary “inverse” (nasal) optic atrophy Visual field loss does not progress on withdrawal of drug, but may persist and be irreversible Baseline (within 4 wks of starting drug) exam, every 3 months while on drug, and exam 3 – 6 months after discontinuing Visual fields Indirect ophthalmoscopy

9. Phenytoin Nystagmus Fine nystagmus at therapeutic doses Coarse nystagmus in toxic states May persist for months after stopping drug

10. Topiramate Used to treat refractory epilepsy and, off label, to treat migraine headache or as a weight loss medication Can cause transient myopia or, more importantly, angle closure glaucoma Treat by stopping drug, use topical cycloplegic agents, consider topical beta-blocker and topical or oral CAI

11. Cancer Chemotherapy Imperia PS, et al. Surv Ophthalmol 34:209-230, 1989 Burns LJ. Seminars in Oncology 19:492-500, 1992 Al-Tweigeri T, et al. Cancer 78:1359-1373, 1996 Schmid KE, et al. Surv Ophthalmol 51:19-46, 2006

12. Alkylating Agents Busulfan — Polychromatic posterior subcapsular cataract (10 – 30%) Cisplatin — Neuroretinal (blurred vision and color blindness from retinal toxicity, optic neuritis, papilledema) Intracarotid injection may cause ipsilateral vision loss from retinal and optic nerve ischemia Cyclophosphamide — Blurred vision Nitrosoureas — Orbital and neuroretinal toxicity with intracarotid administration

13. Antimetabolites 5-Fluorouracil — Ocular surface toxicity, punctal stenosis Cytosine arabinoside — Photophobia and pain from keratoconjunctivitis (relieved with topical corticosteroids, resolves several weeks after completion of therapy) Vincristine — Cranial nerve palsies (50%), optic neuropathy, night blindness, cortical blindness Methotrexate — Ocular toxicity in 25% (periorbital edema, blepharitis, conjunctivitis — treat with artificial tears)

14. Taxanes Promote the assembly of tubulin micropolymers (abnormal microtubules) Paclitaxel Photopsia (flashing lights across the visual field), often described as “flies,” “shooting lights,” or “fireworks” (usually lasts 15 min to 3 hr after infusion) Decreased visual acuity Docetaxel Epiphora due to canalicular and nasolacrimal duct obstruction (early temporary silicone intubation in symptomatic patients recommended)

15. Antibiotics Doxorubicin (adriamycin) — conjunctivitis, increased tearing (25%) Mitomycin C — Blurred vision

16. Interferon Interferon-α used for hairy cell leukemia, Kaposi’s sarcoma, CML, non-Hodgkin’s lymphoma, malignant melanoma, renal cell carcinoma Retinopathy common Cotton wool spots, retinal capillary non-perfusion, vascular occlusions, leakage, hemorrhages, retina edema Likely due to autoimmune mechanism (complement dependent)

17. Tamoxifen (Nolvadex) Estrogen antagonist Ocular toxicity at high doses (≥ 180 mg/d) Keratopathy — bilateral white whorl-like subepithelial opacities Retinopathy — white refractile opacities associated with cystoid macular edema Optic neuritis (reported at total dosage of only 2 to 3 grams)

18. Tamoxifen Probably little ocular risk at low dose (10-20 mg bid-tid) Baseline eye exam and repeated eye exams every two years recommended Tamoxifen may also increase the risk of posterior subcapsular cataracts

19. Corticosteroids Ocular side effects include: Cataract (posterior subcapsular) Increased intraocular pressure (secondary open angle glaucoma) Immunosuppression leading to infectious complications

20. Steroid-Induced Glaucoma More common with topical administration Steroid-induced intraocular pressure (IOP) increases occur more frequently, more severely, and more rapidly with topical dexamethasone in children than adults Even inhaled and intranasal steroids can cause IOP rise, especially if positive family history

21. Steroids and Infection Cancer patients Candida endophthalmitis Cytomegalovirus retinitis Ocular toxoplasmosis Topical steroids can potentiate infections Herpes simplex keratitis Fungal keratitis

22. Phenothiazines Thioridazine (Mellaril) may cause a pigmentary retinopathy Drug binds to melanin in RPE Rare if daily dose ≤ 800 mg Early sxs include blurred vision and decreased night vision ERG and EOG abnormal Complicating exam is that patients on thioridazine often have significant psychiatric disease

23. Phenothiazines Unlike thioridazine, chlorpromazine does not cause similar retinopathy Chlorpromazine (Thorazine) can cause heavy deposits on the lens and cornea Only other phenothiazine that produces retinopathy is experimental drug NP 207 (reported in 1956)

24. Lithium Myriad ocular side effects Photophobia Extraocular muscle abnormalities Exophthalmos Pseudotumor cerebri

25. Amiodarone One of the most effective antiarrhythmic agents available Up to 40% of patients report seeing colored (blue-green) rings or haloes around lights Keratopathy in almost 100% of patients Golden-brown verticillate whorl-like pattern Asymptomatic

26. Amiodarone and AION Anterior ischemic optic neuropathy has been reported Because patients taking amiodarone have serious cardiovascular disease, unknown if AION is due to drug or systemic blood vessel disease

27. Amiodarone and AION In 1997, an Oregon county court awarded a $20,000,000 judgment against Wyeth-Ayerst Laboratories. Plaintiff developed bilateral AION 6 weeks after starting drug. Even if causal relationship exists, how can one withhold drug when indication is for “life-threatening recurrent ventricular arrhythmias” not controlled by other meds PDR since suit calls for “regular ophthalmic examinations”

28. Amiodarone Optic Neuropathy • Unlike AION, amiodarone optic neuroapthy usually presents bilaterally • Initially mildly decreased vision, visual field defects, optic disc swelling • Upon discontinuing amiodarone, optic disc swelling and visual function may slowly improve Nagra PK, Foroozan R, Savino PJ, Castillo I, Sergott RC. Amiodarone induced optic neuropathy. Br J Ophthalmol 2003; 87:420-422

29. Digitalis 11 – 25% ocular side effects at toxic dosages Color vision abnormality (yellow-blue) Reversible Toxicity may be made worse with concomitant quinidine therapy

30. Antimalarials Chloroquine (CQ) and hydroxychloroquine (HCQ) are both aminoquinolones CQ first used in the treatment of rheumatologic disease in 1950’s Hobbs, 1959 — association of CQ and retinopathy (paracentral scotomas with macular pigmentary disturbance, progresses to permanent central retina damage (“bull’s eye maculopathy”) Less likely at ≤ 3.5 mg/kg/day (250 mg/day for small patients)

31. Hydroxychloroquine Unlike CQ, HCQ does not cause a breakdown of blood-retinal barrier Less toxicity with HCQ Retinopathy unlikely if daily dose < 6.5 mg/kg/day for < 6 years in patients with normal renal function Incidence of corneal deposits < 10% (as compared to 95% of patients on CQ)

32. Hydroxychloroquine PDR recommends quarterly ophthalmologic exams Royal College of Ophthalmologists recommends annual check by prescribing physician with referral to ophthalmologist only if abnormality noted What to do?

33. Screening for HCQ Toxicity Baseline and annual ophthalmologic exams Best-corrected visual acuity Red Amsler grid Color plates Fundus exam Amsler grid to take home and check monthly Consider HVF 10-2 (white target) periodically More frequent exams if: Daily dose > 6.5 mg/kg/day (use lean body weight) Duration of treatment > 6 years Renal disease Age > 65 years

34. Toxic Optic Neuropathy Symptoms Gradual onset of visual impairment (vision hand motion or better) Painless vision loss Bilateral Centrocecal scotomas Dyschromatopsia Optic discs may look normal early on, pale (especially temporally) late

35. Alcohols Methanol and ethylene glycol Anion-gap metabolic acidosis Treatment Correct acidosis Hemodialysis Ethanol blocking of alcohol dehydrogenase Sterno = 71% ethyl alcohol, 3.6% methanol

36. Antitubercular Drugs Ethambutol Chelates metal ions involved in prokaryotic ribosomes (inhibits arabinosyl transferase, an enzyme in mycobacterial cell wall synthesis) Bilateral retrobulbar optic neuropathy Even at “safe” dosage (≤ 15 mg/kg/d) incidence of toxicity is 1 – 2 % Risk increased with impaired renal function or diabetes Usually noted at 3 – 6 months Usually reversible if promptly discontinued Isoniazid Optic neuropathy rare

37. Screening for Toxic Optic Neuropathy • Measure papillomacular bundle function • Visual acuity • Color vision • Contrast senstivitity • Central visual fields • Amsler grid (red) • HVF 10-2 or 10-1 • pVEP

38. Quinine Alkaloid from cinchona bark Used for muscle cramps, abortion, suicide Quinidine is an isomer of quinine Cinchonism Tinnitus, vertigo Headache, nausea, vomiting Diarrhea Hot, flushed skin, sweating Delirium, ventricular tachycardia Optic atrophy (ganglion cell damage), congenital blindness in unsuccessful abortions

39. Nutritional Optic Neuropathy “Tobacco-alcohol amblyopia” Thought to be due to dietary deficiency of B-complex vitamins, especially thiamine (B1) Some patients may have Leber’s hereditary optic neuropathy Treatment Vitamin supplementation Discontinue smoking, drinking

40. Pseudotumor Cerebri Idiopathic intracranial hypertension Increased intracranial pressure Normal or small ventricles on neuroimaging Normal CSF Papilledema Exogenous causes Heavy metals (lead, arsenic) Vitamin A / retinoids Tetracycline Nalidixic acid Prolonged corticosteroid therapy (or withdrawal) Lithium

41. Drug-Induced Uveitis Systemic drugs Rifabutin — semisynthetic derivative of rifamycin and rifampin, particularly effective against M. avium intracellulare Biphosphonates (pamidronate, etidronate, clodronate, risedronate) Sulfonamides (including trimethoprim-sulfamethoxazole)

42. Drug-Induced Uveitis Topical Metipranolol (< 0.5% incidence) Intravitreal Cidofovir (incidence decreased from 53% to 19% if oral probenecid given before injection)

43. 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitors (statins) Although initial concern for increased cataracts in patients, no evidence that lovastatin is cataractogenic Possible association of diplopia, blepharoptosis, and ophthalmoplegia with statin use Fraunfelder FW, Richards AB. Ophthalmology 2008;115:2282-5

44. Niacin (Nicotinic acid) Used to treat hyperlipidemia Causes reversible toxic cystoid maculopathy in approximately 0.67% of patients taking high dosages (> 1.5 g/day) Absence of leakage on fluorescein angiography Refer symptomatic patients for exam

45. Ddx of CME without leakage on FA Niacin maculopathy Congenital X-linked retinoschisis Goldmann-Favre syndrome Paclitaxel/docetaxel maculopathy

46. Herbal Supplements Eyebright looks like an eye, so must be good for the eye, right? Bilberry (for stabilizing microcirculation) pretty safe Gingko biloba acts as a blood thinner (stop 24 hours prior to surgery) St. John’s wort (natural antidepressant) may contribute to cataracts, especially in combination with bright-light therapy Canthexanthine (carotenoid) may cause crystalline-like retinopathy Licorice can cause transient vision loss similar to migraine aura

47. Potpourri Minocycline — pseudotumor cerebri, scleral pigmentation Ciprofloxacin — optic neuropathy similar to other quinolones (CQ, quinine) Clomiphene — palinopsia (prolonged afterimages), shimmering of peripheral field, photophobia Trazadone — palinopsia Didanosine — retinal lesions, constriction of peripheral visual field Cetirizine (Zyrtec) — oculogyric crisis Biphosphonates — scleritis Thiazolidinediones — macular edema (in patients also on insulin with peripheral edema)

48. Over-The-Counter Eye Drops Preserved eye drops Preservatives can cause toxic or allergic reactions Ocular decongestants Rebound vasodilatation Punctate epithelial keratitis May precipitate acute angle closure glaucoma attack in susceptible individuals

49. Topical Anesthetic Abuse Topical anesthetic eye drops are toxic to cornea Prolonged use leads to epithelial loss, stromal edema, corneal opacities Typical patient works in medical field with easy access to drops May have to search purse, pockets to make the diagnosis Never prescribe a patient a topical anesthetic drop!