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
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
• No Financial Disclosures
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.
Systemic medication and their
ocular side effects
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.
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.
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
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.
• What are drugs used to prevent clot formation
in the disease associated with the EKG below?
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
• What are drugs to alleviate the following
symptoms?
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
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
• What are drugs to treat the condition?
ANTI-MIGRAINE AGENTS
• Topamax (topiramate)
– Indicated for migraines, seizures, mood
disorder
– Mechanism of action:
• blockage of voltage-dependent sodium
channels, an augmentation of gammaaminobutyric 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
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
ANTI-MIGRAINE AGENTS
• Serotonin receptor antagonist
– Imitrex
– Corneal opacity
• Beta Blockers
– Reduce tear lysozyme levels and
immunoglobulin IgA
– Dry eye, contact lens intolerance
• Name some medications to treat depression.
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
• Name some drugs to treat the following
symtpoms.
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
• What are some medications used for the
following associated with CHF?
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
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
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.
Starry Night
Van Gogh also suffered from glaucoma making him see haloes around lights
• What class of drugs would you use to treat the
following condition?
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
• Name some agents to treat a condition related
to the following picture.
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.
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
• Name some meds for glycemic control.
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
• What is a common drug to treat the following
process?
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”
• What drug is prescribed for breast cancer and
reducing the incidence of breast cancer
among high-risk women
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%)
• What is the effect of hormones?
HORMONES
•
Synthroid (Levothyroxine)
Ocular Side Effects
• Pseudotumor Cerebri (PTC)
• Visual Hallucinations
• Diplopia
• Ptosis
• Paralysis of EOM
• Hyperemia
• Side effects disappear with discontinuation
of drug
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
• What is common drug to treat this teenager?
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
DERMATOLOGIC AGENTS
Minocycline
– For severe acne vulgais
Ocular side effect
• Swollen optic disc, called "papilledema”
the result of increased intracranial
pressure.
• A patient travels back to the U.S. with night
sweats.
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.
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.
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.
• Name a drug that can be used to treat the
following pictures?
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
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.
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.
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.
• 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.
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
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
• What drugs are use for treatment/prevention
in men and women?
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
• What is the class of drugs to treat hepatitis
and multiple sclerosis?
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
• A man reports discoloration of vision after
taking a medication from his pill box last
night?
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 bluegreen, 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
ERECTILE DYSFUNCTION
•
The above ocular side effects are dosedependent 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.
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.
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
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
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
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
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.
Thank you for your attention!