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Ocular Toxicology. Preston H. Blomquist, MD Department of Ophthalmology University of Texas Southwestern Medical Center at Dallas. Tamsulosin (Flomax). Systemic alpha-1 antagonist

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ocular toxicology

Ocular Toxicology

Preston H. Blomquist, MD

Department of Ophthalmology

University of Texas Southwestern Medical Center at Dallas

tamsulosin flomax
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

tamsulosin flomax3
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.

tamsulosin flomax4
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

erectile dysfunction agents
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)

erectile dysfunction agents6
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

erectile dysfunction agents7
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

vigabatrin sabril
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

phenytoin
Phenytoin

Nystagmus

Fine nystagmus at therapeutic doses

Coarse nystagmus in toxic states

May persist for months after stopping drug

topiramate
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

cancer chemotherapy
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

alkylating agents
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

antimetabolites
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)

taxanes
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)

antibiotics
Antibiotics

Doxorubicin (adriamycin) — conjunctivitis, increased tearing (25%)

Mitomycin C — Blurred vision

interferon
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)

tamoxifen nolvadex
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)

tamoxifen
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

corticosteroids
Corticosteroids

Ocular side effects include:

Cataract (posterior subcapsular)

Increased intraocular pressure (secondary open angle glaucoma)

Immunosuppression leading to infectious complications

steroid induced glaucoma
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

steroids and infection
Steroids and Infection

Cancer patients

Candida endophthalmitis

Cytomegalovirus retinitis

Ocular toxoplasmosis

Topical steroids can potentiate infections

Herpes simplex keratitis

Fungal keratitis

phenothiazines
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

phenothiazines23
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)

lithium
Lithium

Myriad ocular side effects

Photophobia

Extraocular muscle abnormalities

Exophthalmos

Pseudotumor cerebri

amiodarone
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

amiodarone and aion
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

amiodarone and aion27
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”

amiodarone optic neuropathy
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

digitalis
Digitalis

11 – 25% ocular side effects at toxic dosages

Color vision abnormality (yellow-blue)

Reversible

Toxicity may be made worse with concomitant quinidine therapy

antimalarials
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)

hydroxychloroquine
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)

hydroxychloroquine32
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?

screening for hcq toxicity
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

toxic optic neuropathy
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

alcohols
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

antitubercular drugs
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

screening for toxic optic neuropathy
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
quinine
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

nutritional optic neuropathy
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

pseudotumor cerebri
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

drug induced uveitis
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)

drug induced uveitis42
Drug-Induced Uveitis

Topical

Metipranolol (< 0.5% incidence)

Intravitreal

Cidofovir (incidence decreased from 53% to 19% if oral probenecid given before injection)

3 hydroxy 3 methyl glutaryl coa reductase inhibitors statins
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

niacin nicotinic acid
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

ddx of cme without leakage on fa
Ddx of CME without leakage on FA

Niacin maculopathy

Congenital X-linked retinoschisis

Goldmann-Favre syndrome

Paclitaxel/docetaxel maculopathy

herbal supplements
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

potpourri
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)

over the counter eye drops
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

topical anesthetic abuse
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!