drug toxicity eye

1. ADVERSE DRUG REACTIONS
Presenter : Dr. Mohit Garg
Moderator : Dr. Gayatri Bharali

2. ADVERSE DRUG REACTIONS
➤ WHO
Any response to a drug which is noxious and
unintended, and which occurs at doses normally used in
man for prophylaxis, diagnosis, or therapy of disease, or
for the modification of physiological function.
An unexpected ADR refers to a reaction, the nature or
severity of which is not consistent with domestic
labelling or market authorisation, or is unexpected from
characteristics of the medicine.

3. DOCTOR’S OBLIGATIONS
➤ To have complete insight to recognise and prevent threatening
complications from ADRs
➤ To elicit proper history with special attention to particular
medicine
➤ To be aware of certain oculotoxic drugs and their side effects.

4. PRE-TREATMENT EXAMINATION
➤ Required for drugs that
➤ Are to be administered for a long duration
➤ Have known severe side effects
➤ May consist of various parameters that have to be recorded
such as visual acuity, pupillary responses, ocular motility, IOP,
slit lamp examination and fungus examination.

5. CAUSES OF ADVERSE DRUG REACTIONS
➤ Exaggeration of intended pharmacological effects
➤ Concomitant administration of drugs with synergistic effects
➤ Immunological reactions
➤ Idiosyncratic reactions
➤ Cytotoxic reactions
➤ Genetically determined enzymatic defects
➤ Errors in self administration of drugs

6. ADVERSE DRUG
REACTIONS OF
OCULAR
THERAPEUTIC
AGENTS

7. TOPICAL ANTIMICROBIAL AGENTS
Systemic Complications
Even though topicals have minimal systemic absorption , certain idiosyncratic and
immunological reactions have been observed such as
➤ Aplastic Anaemia
Chloramphenicol is the most common cause of aplastic anaemia. Bacterial breakdown
product maybe responsible for this. Chloramphenicol has 2 known effects on bone marrow
1. Dose related suppression of bone marrow
2. Progressive marrow aplasia
➤ Stevens-Johnsons Syndrome
Acute dermatitis with severe mucous membrane involvement that most commonly occurs
in association with Mycoplasma pneumonia or as an adverse drug reaction.
Mild : symmetrical involvement with skin lesions involving extremities. Mucous membrane
involvement is mild and limited to one surface, resolves within 1-4 weeks
Severe : Lesions become confluent, bulla may form , and there maybe toxic epidermal
necrolysis.

8. ➤ Drug induced cases of SJS usually occur
within 7-14 days of therapy but may occur
within hours if previous exposure to drug is
there.
➤ Ocular involvement, which occurs in as many
as half of patients, varies from a mild
mucopurulent conjunctivitis to severe
perforating corneal ulcers.
➤ Blindness occasionally occurs in patients with
severe late-phase corneal complications, such
as ulceration, vascularisation, and perforation.
➤ Sulfonamides> Penicillin.
➤ History of previous exposure to be elicited
before prescribing.
➤ Management primarily consists of withdrawal
of the offending drug. Role of corticosteroids
is controversial.

9. Local Complications
➤ Contact Dermatoconjunctivits
Cell-mediated reaction in patients usually sensitised
to drug previously
Popularity of neomycin-polymyxinB-bacitracin
ointment sensitises individuals to neomycin, a
common cause of this ADR
Starts 24-72 hours following instillation
C/O itching, hyperpigmentation and thickening of skin
Conjunctiva : papillary conjunctivitis
Cutaneous patch testing
Drugs : Neomycin, tobramycin, idoxiuridine, natamycin, atropine, preservatives
like thiomersal, EDTA

10. ➤ Chronic Follicular Conjunctivitis
Due to long term application of the drug
Complains of chronic redness and mild discharge.
Diagnosis of exclusion
Follicular reaction involves both the upper and lower palpebral conjunctiva but more in
lower fornix
MC cause : Idoxiuridine, Sulphonamides
➤ Punctate Marginal Keratitis
MC cause : gentamicin
Atropine, mydriatics and epinephrine.
Discontinuation of the drug + topical steroids

11. ➤ Keratitis Medicamentosa
Refers to corneal epitheliopathy related to use of topical medications.
Milder form usually affect only lower cornea
Severe form entire corneal epithelium affected
Sloughing, superficial corneal edema, necrosis leading to scarring and vascularisation.
MC cause : topical antivirals
Antibiotics : ahminoglycosides, neomycin, gentamicin, tobramycin
Preservative : benzalkonium
Rx : discontinuation of topicals, use of preservative free tear substitute, use of bandage
contact lens to relieve pain.
Extensive superficial punctate staining; this could be caused by benzalkonium chloride-
exacerbated dry eye syndrome.
Okoro, Chiemela & Amiebenomo, Onyekachukwu & Aruotu, Nwakuso. (2016).
Medicamentosa keratoconjunctivitis: A case report. African Vision and Eye Health. 75.
10.4102/aveh.v75i1.20.

12. ➤ Inhibition of Epithelial wound healing
Anti-microbials exert their effects by either :
1. Disruption of cell wall
2. Inhibition of intracellular metabolic process
In order to heal an epithelium, the bordering epithelial cells must replicate and slide to
fill any defect. And antimicrobials might have a deleterious effect on this mechanism by
inhibiting intracellular metabolism.
Rx: Discontinue the anti-microbial in cases where the epithelial healing is getting
delayed (resolved infiltrates but persisting epithelial defect with rolled out irregular
margins).

13. SPECIFIC ADR
➤ Sulphonamides
Calcific band shaped keratopathy has been reported with topical sulphonamides
➤ Amphotericin B
Salmon coloured subconjunctival nodules following s/c injection of amphotericin B in doses
greater than 5 mg. ( numerous histiocytes with fibrosis + lymphocytic infiltration)
➤ Idoxuridine
Punctual or canalicular stenosis due to cicatricial changes

14. STEROIDS
➤ Complications are related to dose and the duration of
administration.
➤ Must consider all known complications while counselling and
treating the patient.
➤ In general, lower the maintenance dosage, lower are the side
effects noted.

15. TOPICAL STEROIDS
➤ Dermatitis : Should not be confused with allergic dermatitis.
➤ Infection and ulceration : Inappropriate use can lead to
infectious keratitis, esp. Herpetic.
Reactivation of herpetic keratitis in a patient who has
undergone penetrating keratoplasty has been previously
treated with antibiotic-steroid combination is fairly
common.
➤ Delayed Wound Healing

16. ➤ Cataract Formation
Specially posterior sub-capsular cataract.
Exact mechanism unknown but related to glucocorticoid dependant cell
proliferation, suppressed differentiation, a reduced susceptibility to apoptosis,
altered transmembrane transport, and enhancement of reactive oxygen species
activity.

17. ➤ Elevated IOP
Prolonged use can lead to raised IOP.
Also abuse by patient for treatment of minor inflammation of the eye.
More common in patients with myopia or a family history of glaucoma.
Due to steroid receptors in trabecular meshwork - decreased outflow.
Also decreased phagocytosis leads to increased debris at the angles
leading to obstruction in outflow.
Mostly responds to stopping steroid administration n matter of days to
weeks.

18. SYSTEMIC STEROIDS

19. GLAUCOMA MEDICATIONS
Beta-adrenergic Blockers
Befall, timolol, cartelol, metipranalol
Generally well tolerated topically but occasionally may cause systemic side effects severe enough to
discontinue treatment.
Not to be used in :
Reactive airway disease
HR < 55 bpm
History of heart failure
Use of anti-depressants
Impotence
➤ CVS : Arrythmia, bradycardia, cardiac arrest, CVS accident,
CHF, heart block, hypotension,palpitaion, syncope
➤ CNS : Asthenia, ataxia, depression, dizziness, fatigue,
lethargy
➤ Dermatological : Alopecia, pruritus, urticaria
➤ GIT : Diarrhoea, Nausea
➤ Endocrine : Glucose imbalance, potassium imbalance
➤ Respiratory Effects : Asthma, bronchospasm, Dyspnea,
Respiratory failure
➤ Urogenital Effects : Sexual dysfunction

20. CARBONIC ANHYDRASE INHIBITORS
➤ Most common constellation of symptoms - malaise, fatigue,
anorexia, depression.
GI discomfort , nausea, diarrhoea, metallic taste
Metabolic acidosis in patients with hepatic or renal
disease. May also lead to worsening of sickle cell disease
Parasthesia of extremities, tremors, numbness, vertigo
Blood dyscrasias
Crystalluria, glycosuria, hematuria, polyuria, renal
calculi, renal colic

21. ALPHA-ADRENERGIC
➤ Brimonidine, apraclonidine
➤ Chronic use of apraclonidie is limited due to allergic reaction.
Brimonidine is better tolerated.
➤ Side effects : dry mouth, fatigue, drowsiness
➤ Stinging/burning sensation
Brimonidine is contraindicated in children below 2 years because of
observed side effects such as bradycardia, hypotension, hypothermia,
hypotony, lethargy and apnoea

22. PARASYMPATHOMIMETICS
➤ Pilocarpine, physostigmine
➤ Adverse effects are reduced if the miotics are started with low
concentration of the drug and bed time instillation.
➤ Usually subside if the treatment is discontinued
➤ Abdominal pain, Nausea, Vomitting
➤ Asthma, bronchospasm, dyspnoea, pulmonary edema
➤ Asthenia, headache, tremor
➤ Sweating and vasodilation

23. PROSTAGLANDIN ANALOGUES
➤ Latanoprost : conjunctival hyperaemia, burning ans stinging,
blurred vision, headache, itching, tearing and eye pain.
Can lead to increased iris pigmentation
PG related orbitopathy : posterior migration of lash
line, periocular erythema, MGD and cantonal
deformities
➤ Travoprost : greater chance of hyperaemia but a lesser chance
of iris pigmentation as compared to latanoprost.

24. TOPICAL OCULAR ANAESTHETICS
➤ Direct corneal effects
➤ Alteration of lacrimation : decreased stability of tear film
(disrupting surface microvilli) and reflex tear secretion.
➤ Epithelial toxicity : slow down healing process by disrupting
epithelial cell motility complexes.
➤ Endothelial toxicity : in case where trans corneal portal of
entry is present (perforating injury).
➤ Microbial contamination : possibility of multi dose vial
contamination.
➤ Systemic and Non corneal
➤ Allergy and idiosyncratic reaction : contact dermatitis

25. ➤ Secondary adverse effects
➤ Interference in diagnostic tests :
➤ decrease in fluorescence of sodium fluorescein. Use
of artificial tears as vehicle avoids this
➤ Variability in schirmer's testing
➤ Reduction in microbial recovery
➤ Distort result of tests such as corneal sensitivity
testing.
➤ Surface keratopathy
➤ Punctate keratitis : hypersensitivity reaction.

26. ➤ Alteration of ocular response to other topical agents
➤ Changes in epithelial permeability : loosening of
desmosomal cell to cell adhesions
➤ Prolonged surface contact : decrease in reflex tearing
➤ Topical aesthetic abuse : serious disorder causing persistent
epithelial defect and stromal infiltration
https://www.aao.org/diagnose-this/diagnose-this-topical-anesthetic-abuse

27. TOXICITY OF SURGICAL SOLUTIONS
➤ They include
➤ Antiseptic solutions
➤ Irrigating solutions
➤ Visco-elastic substances

28. ➤ Antiseptic solutions :
➤ Chlorhexidine : Keratitis if solution is allowed to enter
conjunctival sac has been reported. Epithelial defect,
punctate keratitis, stromal edema, bullies keratopathy.
➤ Also adverse effects ( de-epithelisation, chemises,
stromal edema) have been reported with tincture of
iodine, hexachlorophene with detergent and 7.5 %
providing iodine with detergent (betadine).

29. ➤ Irrigating solutions
➤ Potential cause for damage : chemical composition, pH
and osmolality affecting the endothelial barrier and
aqueous pump.
➤ Most physiological solution is one which matches the
chemical composition of aqueous humour.
➤ BSS : physiological bicarbonate buffer and presence of
glucose and glutathione.
➤ Also toxicity might result from microbial contamination,
inadequate packaging and improper packaging.
➤ Patients at risk : low endothelial cell densities and poor
endothelial morphology.

30. ➤ Viscoelastic substances
➤ Increased intraocular pressure : Due to decreased
outflow facility. usually peaks within 12 hours of
administration.
➤ Intraocular inflammation : Commercially available
formulations are highly purified and non-antigenic but in
some cases inflammation might be due to protein
impurities or endotoxins.
➤ Corneal edema and corneal decompensation.

31. DRUG INDUCED OCULAR CICATRISATION
➤ Occurs secondary to long term use of topical ocular
medications.
➤ Drugs reported :
➤ Epinephrine
➤ Pilocarpine
➤ Idoxuridine
➤ Timolol
➤ Preservatives in eye drops

32. ➤ Disease stages
➤ Stage 1 : conjunctival inflammation, mucoid discharge, rose
Bengal staining of conjunctival epithelium and sub epithelial
fibrosis
➤ Stage 2 : conjunctival shrinkage and shortening of fornix
➤ Stage 3 : Frank symblepharon, keratopathy, corneal
neovascularisation, trichiasis and tear insufficiency.
➤ Stage 4 : end stage disease marked by severe sick syndrome,
ocular surface keratinisation and ankyloblepharon.

33. ➤ Management
➤ Primary stoppage of all topical medications
➤ Rule out any other cause ( chemical/irradiation burs/
membranous conjunctivitis/ SJS/ sjogrens syndrome/
sarcoidosis etc.)
➤ Artificial tear substitutes (preservative free) with mild
topical steroids for mild disease
➤ Soft bandage contact lens to prevent cornea from drying up
➤ Secondary bacterial infection if develops needs to be
treated.
➤ Blepharitis, if developed due to discharge to be managed.
➤ Trichiasis to be managed by electrolysis/cryotherapy.

36. OCULAR SIDE
EFFECTS OF
SYSTEMIC
MEDICATIONS

37. OCULAR EFFECTS OF SYSTEMIC MEDICATIONS
➤ cAfter a drug molecule enters the systemic circulation, it can
reach ocular tissues through uveal or retinal circulations.
➤ The choroid, sclera and ciliary body have thin, fenestrated
walls for drug molecules to pass.
➤ Small, lipid soluble molecules pass freely into the aqueous
humor, and can further diffuse into avascular structures such
as the lens, cornea, and trabecular meshwork

38. OCULAR ACCUMULATION SITES
➤ The cornea has a permeable endothelium, and the stromal
glycosaminoglycans (GAGs) can bind drug molecules, leading
to edema and decreased transparency.
➤ Drug molecules can also bind to lens protein, and
photosensitize the lens to ultraviolet (UV) radiation.
➤ Lastly, drug molecules tend to accumulate in the vitreous due
to the slow rate of fluid exchange.

39. DRUGS AFFECTING CORNEA
➤ Causes :
➤ Antimalarial : Chloroquine, Hydroxychloroquine; no
relationship to dose or duration, reversible
➤ Amiodarone : Used in Atrial fibrillation, V. tachy. ; slowly
reversible but does not affect vision so discontinuation
not warranted. Also causes ASC, optic neuropathy
➤ Vortex keratopathy/ cornea verticillata:
characterized by whorl-like corneal
epithelial deposits

40. ➤ Chlorpromazine
➤ Sedative/psychotic illnesses
➤ Fine granular yellowish brown deposits in the
endothelium,
➤ Anterior lens capsule deposits
➤ retinopathy

41. ➤ Agyrosis : Discoloration of tissue due to
silver deposits. Greyish brown deposits in
DM.
➤ Chrysiasis : deposition of gold in living
tissue. Corneal chyrsiasis- dust like
granules throughout the cornea.

42. DRUGS AFFECTING LENS
➤ Steroids
➤ Lens opacities : PSC, ASC
➤ Children more susceptible
➤ Early opacity might regress if treatment discontinued

43. ➤ CHLORPROMAZINE:
➤ Schizophrenia, mania,
➤ Deposition of innocuous, fine, stellate, yellowish-brown
granules on the anterior lens capsule within the
pupillary area
➤ The deposits persist despite discontinuation of the drug.

44. ➤ Cataract Formation
➤ Busulphan : CML
➤ Allopurinol : hyperuricaemia and gout
➤ Desferrioxamine

45. DRUGS CAUSING UVEITIS
➤ Exact mechanism unknown
➤ Direct mechanism seen soon after medication
instillation
➤ Indirect mechanism include immune complex
deposition, immune reaction against antigens releases
from antibiotic induced microbe death or an
alteration of melanin’s ability to scavenge free
radicals.

46. ➤ Rifabutin
➤ Used for Rx and prophylaxis of Mycobacterium avian
complex in HIV
➤ Drugs that inhibit metabolism of rifabutin through
the cytochrome p-450 pathway (clarithromycin and
fluconazole), increase the risk of uveitis.
➤ ACUTE ANTERIOR UVEITIS (AAU); U/L; assoc with
hypopyon

47. ➤ Cidofovir
➤ INDICATION: CMV retinitis in AIDS patients.
➤ SIGNS: AAU- Vitritis is common and hypopyon may
occur with long- term administration.
➤ Bisphosphonates
➤ Alandronic acid, Palmindronic Acid ; osteoporosis
➤ Ocular Side Effects : Scleritis/Episcleritis, Blurred
vision, Hyperemia, Anterior uveitis.

48. DRUGS AFFECTING RETINA
➤ ANTIMALARIAL Drugs
➤ melanotropic drugs.
➤ Chloroquine retinotoxicity- related to the total
cumulative dose(>300g), Rx duration > 3y
➤ Hydroxychloroquine - much safer than chloroquine
➤ The risk of toxicity is increased if a daily dose over
6.5 mg/kg is administered for longer than 5 years,
although even then the risk is still very small.

49. ➤ PHENOTHIAZINES:
➤ Thioridazine: schizophrenia and related psychoses.
➤ – normal daily dose is 150– 600 mg.
– Doses> 800 mg/day: cause reduced visual acuity and
impairment of dark adaptation.
➤ The clinical signs of progressive retinotoxicity are : ‘Salt and
pepper’ pigmentary disturbance involving the mid-
periphery and posterior pole.Plaque-like pigmentation and
focal loss of the RPE and choriocapillaris.
➤ Chlorpromazine: Normal daily dose is 75–300 mg.
➤ Retinotoxicity ( larger doses over a prolonged period)
➤ It is characterized by nonspecific pigmentary granularity
and clumping.

50. ➤ CRYSTALLINE MACULOPATHIES
➤ crystalline deposits in the inner layers of the retina
Tamoxifen

51. ➤ Canthaxanthin : Gold dust retinopathy
➤ Methoxyflurane : inhalation GA; metabolised to oxalic acid

52. ➤ Desferrioxamine : Iron chelation , mottled pigmentary
changes

53. DRUGS AFFECTING OPTIC NERVE
➤ Ethambutol
➤ Chelates copper, decreased level impair mitochondrial
transport in optic nerve, optic neuritis progressing to
optic atrophy
➤ Blue-yellow colour vision abnormalities

54. ➤ Amiodarone : optic atrophy is a rare but known adverse effect.
➤ Vigabatrin : anti-epileptic, bilateral concentric or binasal
visual field defects
➤ Topiramate : anticonvulsant ; causes acute-angle closure
glaucoma with ciliochoroidal effusion leading to myopia.

55. DRUGS CAUSING DRY EYES
➤ Beta blockers
➤ Diuretics(change the tear film)
➤ Niacin
➤ Oral contraceptives
➤ Antipsychotics (phenothiazines: thioridazine,
chlorpromazine,), tricyclic antidepressant,
anticholinergics(atropine, scoploamine) -anticholinergic
properties.
➤ Isotretinoin(decreased meibomian gland function-
deficiency of normal lipid layer in tear film)

56. CONCLUSION
➤ 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.
➤ These side effects may or may not be serious enough to
warrant discontinuing treatment.
➤ Recognition of ocular and visual side effects is important for
prompt management to prevent and minimize serious
complications
➤ Familiarity with medications improves by routinely paying
attention to concomitant medications.

57. THANK YOU