Ocular Toxicology Preston H. Blomquist, MD Department of

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Ocular Toxicology

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

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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

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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.

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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

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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)

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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

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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 (dont take in autosomal
  recessive RP due to genetic defect in PDE-6?)
• Diabetic retinopathy
• Definitely avoid if previously had NAION in one
  eye

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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

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Phenytoin

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

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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

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Cancer Chemotherapy

• Imperia PS, et al. Surv Ophthalmol 34209-230,
  1989
• Burns LJ. Seminars in Oncology 19492-500, 1992
• Al-Tweigeri T, et al. Cancer 781359-1373, 1996
• Schmid KE, et al. Surv Ophthalmol 5119-46, 2006

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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

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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)

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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)

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Antibiotics

• Doxorubicin (adriamycin) conjunctivitis,
  increased tearing (25)
• Mitomycin C Blurred vision

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Interferon

• Interferon-a used for hairy cell leukemia,
  Kaposis sarcoma, CML, non-Hodgkins 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)

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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)

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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

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Corticosteroids

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

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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

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Steroids and Infection

• Cancer patients
• Candida endophthalmitis
• Cytomegalovirus retinitis
• Ocular toxoplasmosis
• Topical steroids can potentiate infections
• Herpes simplex keratitis
• Fungal keratitis

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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

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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)

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Lithium

• Myriad ocular side effects
• Photophobia
• Extraocular muscle abnormalities
• Exophthalmos
• Pseudotumor cerebri

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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

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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

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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

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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 87420-422
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Digitalis

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

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Antimalarials

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

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Hydroxychloroquine

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

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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?

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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 gt 6.5 mg/kg/day (use lean body
  weight)
• Duration of treatment gt 6 years
• Renal disease
• Age gt 65 years

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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

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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

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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

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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

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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

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Nutritional Optic Neuropathy

• Tobacco-alcohol amblyopia
• Thought to be due to dietary deficiency of
  B-complex vitamins, especially thiamine (B1)
• Some patients may have Lebers hereditary optic
  neuropathy
• Treatment
• Vitamin supplementation
• Discontinue smoking, drinking

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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

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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-sulfamethoxa
  zole)

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Drug-Induced Uveitis

• Topical
• Metipranolol (lt 0.5 incidence)
• Intravitreal
• Cidofovir (incidence decreased from 53 to 19
  if oral probenecid given before injection)

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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
  20081152282-5

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Niacin (Nicotinic acid)

• Used to treat hyperlipidemia
• Causes reversible toxic cystoid maculopathy in
  approximately 0.67 of patients taking high
  dosages (gt 1.5 g/day)
• Absence of leakage on fluorescein angiography
• Refer symptomatic patients for exam

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Ddx of CME without leakage on FA

• Niacin maculopathy
• Congenital X-linked retinoschisis
• Goldmann-Favre syndrome
• Paclitaxel/docetaxel maculopathy

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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. Johns 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

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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)

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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

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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!