Systemic medications and their ocular side effects

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Systemic medications and their ocular side effects
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

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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

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• No Financial Disclosures

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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.
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Systemic medication and their ocular side effects

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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.

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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.

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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

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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.

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

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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 gt 5 prone to bleed
• Chronic use of ASA may cause yelllowing of vision
  

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• What are drugs to alleviate the following
  symptoms?

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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

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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

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• What are drugs to treat the condition?

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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

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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

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ANTI-MIGRAINE AGENTS

• Serotonin receptor antagonist
• Imitrex
• Corneal opacity
• Beta Blockers
• Reduce tear lysozyme levels and immunoglobulin
  IgA
• Dry eye, contact lens intolerance

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• Name some medications to treat depression.

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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

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• Name some drugs to treat the following symtpoms.

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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

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

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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
• lt10 bothered by blurred vision or haloes
• Anterior and posterior subcapsular lens changes
• Optic neuropathy

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Antiarrhythmics

• Digoxin (Digitek)
• Inhibition of NaK 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

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Ever wonder why there is a predominance of the
color yellow in most of Van Goghs 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.

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Starry Night
Van Gogh also suffered from glaucoma making him
see haloes around lights
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• What class of drugs would you use to treat the
  following condition?

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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

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

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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.

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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

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• Name some meds for glycemic control.

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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

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• What is a common drug to treat the following
  process?

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Flomax (tamsulosin)

• 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

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

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Tamoxifen citrate

• 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)

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• What is the effect of hormones?

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HORMONES

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

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Estrogen or Progesterone

• 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

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• What is common drug to treat this teenager?

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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

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DERMATOLOGIC AGENTS

• Minocycline
• For severe acne vulgais
• Ocular side effect
• Swollen optic disc, called "papilledema the
  result of increased intracranial pressure.

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

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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.

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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.

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

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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
• Bulls-eye maculopathy
• This bulls-eye maculopathy starts as fine
  pigmentary mottling within the macular area.
• The end result can range from reduced vision to
  blindness

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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.

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Antimalarials

• Age lt40 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.

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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.

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• 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.

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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

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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

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

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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

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

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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

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

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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 tingesusually 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

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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.

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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.

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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

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Herbal Medicines and Nutrional Supplementation

• Datura angels trumpet
• Mydriasis from tropane alkaloids,
  atropine/scopolamine properties
• poison
• Echinacea purpurea
• Conjunctivitis
• Used for URI, yeast infection, and many other
  ailments

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Herbal Medicines and Nutrional Supplementation

• Ginkgo biloba
• Spontaneous hyphema, retinal hemorrhage
• Dementia, Alzheimers, memory
• Licorice
• visual loss associated with migraine-like
  symptoms
• Vasospasm
• hypertension

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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

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Summary

• A careful and detailed case history is important
  to reveal a patients medication history.
• The ocular and visual side effects from a
  patients 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.

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Thank you for your attention!