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Drug toxicity of posterior segment of eye


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Drug toxicity of posterior segment of eye

  2. 2.  A variety of systemic medications can cause retinal toxicities.  Majority of cases, loss of visual function is minimal or reversible.
  3. 3. Classification  Pigmentary retinopathies  Crystalline retinopathies,  Retinal vasculopathies  Retinal folds  CME
  4. 4. Classification  Disruption of retina and RPE /Pigmentary retinopathies  Thioridazine  Quinolines  Deferoxamine  Phenothiazine  Clofazimine  Chlorpromazine  Corticosteroid  Cisplatin
  5. 5. Quinolines  Antimalarial agents now used in the treatment of autoimmune diseases, (RA) and (SLE).  Both medications have been shown to bind melanin and to concentrate in the iris, ciliary body and retinal pigment epithelium, altering normal physiologic function.  Early: asymptomatic, with only blunting of the foveal reflex and RPE granular pigmentary changes.  With progression, symptoms can include blurred vision, scotomas and photopsias.  Bilateral bulls-eye maculopathy .
  6. 6.  In late-stage disease, optic disc pallor.  Retinal toxicity has been shown in patients taking greater than 3 mg/kg/day of chloroquine or 6.5 mg/kg/day of hydroxychloroquine.  Patients should be monitored annually, as toxicity can be irreversible and even progress after drug cessation.
  7. 7. Chloroquine retinopathy. bone-spicule Early chloroquine toxicity. Hydroxychloroquine toxicity
  8. 8. Thioridazine  Thioridazine (Mellaril) is a piperadine antipsychotic agent  Ocular toxicity was first described in 1980 and has been shown in both short- and long-term treatment.  Bind to melanin in RPE and alter retinal enzyme kinetics loss of photoreceptor ,RPE and CC.  Symptoms of toxicity include decreased vision and dyschromatopsia.  Macular pigmentary changes can develop into a "salt-andpepper" pattern.  Long-term use can cause significant optic nerve atrophy and destruction of both the RPE and choriocapillaris.
  9. 9. Intermediate thioridazine toxicity. Pigmentary changes With choriocapillary atrophy. End-stage thioridazine toxicity. Diffuse pigmentary and choriocapillary atrophy, optic atrophy
  10. 10. Chlorpromazine  Similar to thioridazine  Binds to melanin and can cause hyperpigentation of skin , conjunctiva, cornea, lens and retina.  Dose : 40-75 mg/day  2400 mg/day for 12 months: pigmentary changes, retinal vessel attenuation, optic nerve pallor.
  11. 11. Granular pigment changes
  12. 12. Deferoxamine  Deferoxamine is an iron-chelating agent used to treat conditions with excessive serum iron levels, including hemochromatosis.  1g IM initially and then 500mg Q4hr for 2 doses Maximum dose: 6g in 24 hours  MO toxicity : due to removal of cu from RPE( crucial for the normal functioning of antioxidant enzymes)  Vision loss, scotomas, dyschromatopsia, and nyctalopia.  RPE mottling may develop over time.  May cause diminished ERG amplitudes and late-phase vascular leakage on FA.  Deferoxamine toxicity is reversible with drug cessation, with full recovery of visual function.
  13. 13. Clofazimine  Red phenazine dye antimycobacterial agent Capsule 50 mg, 100 mg  Used for leprosy, psoriasis, pyoderma gangrenosum, DLE , mycobact.avium complex infection in HIV pt.  50 mg daily for at least 2 years  Clofazimine crystal deposition in cornea.  Bulls eye maculopathy.  Retinopathy with 200-300 mg/day and irreversible.
  14. 14. Cisplatin  Used in Malignant glioma ,metastatic breast cancer, testicular cancer.  1st change: Pigmentary retinopathy in macula with abnomal ERG  2nd : CWS, hemorrhages , macular exudates , optic neuropathy with disc swelling.  3rd : Arterial occlusion , vasculitis , papilitis  MO toxicity: Due to platinum toxicity to retina  Begins 6 weeks after drug initiation.  Others : pain, chemosis,secondary glaucoma, internal ophthalmoplegia,cavernos sinus syndrome.  Progressive treatment.
  15. 15. Quinine sulphate  Treatment for Nocturnal muscle cramps or restless leg syndrome  Recommended dose : less than 2 g/day.  Toxicity wt >4 g and fatal dose is 8 gm.  Mechanism of toxicity is not known: disruption of cholinergic transmission and it is vascular in origin.  Cinchonism ( syndrome due to overdose): nausea, vomiting ,headache, tremor, LOC, blindness.  Fundus : venous dilatation with retinal oedema  VA returns with field defect and optic disc pallor after few weeks to months.
  16. 16. Retinal vasculopathies  Quinine sulphate  Cisplatin  Talc  Oral contraceptive  Aminoglycoside  Interferon
  17. 17. Talc  Talc, an inert filler used in oral powdered medications.  Talc retinopathy inevitably indicates a history of intravenous drug abuse.  The talc deposits range from 5 to 10 µm.  Refractile yellow opacities in the macula.  Lodge in the macular arterial vasculature, causing a granulomatous reaction with focal occlusion, leading to eventual macular ischemia.  Ischemic sequelae include peripheral retinal or optic disk neovascularization, vitreous hemorrhage and arteriovenous anastomosis.  FA imaging will show capillary nonperfusion, enlargement of the foveal avascular zone and vascular leakage.
  18. 18. Perifoveal yellow-white glistening crystals.
  19. 19. Ischemic talc retinopathy
  20. 20. Oral contraceptive  The synthetic estrogen and progesteron effect coagulation factors hypercoagulable state theomembolic CRVO, CRAO.
  21. 21. Aminoglycoside  Gentamicin, tobramycin, amiikacin  Massive doses :retinal hemorrhages,retinal oedema,CWS, arteriolar narrowing, venous beading.  Rubiosis iridis, NVG,pigmentary retinopathy, optic atrophy.  FFA: severe vascular nonperfusion in acute stage  Preservative ( methylparaben, propylparaben,edetate disodium) play an additive role in its toxicity.
  22. 22.  Retinal toxicity enhanced by : a) Intravitreal injection bevel end pointing towards retina b) Increased rate of injection  100 -400 ug can still produce toxicity  Gentamicin small doses cause formation of abnormal lamellar lysosomal inclusions in the RPE.  large doses cause retinal necrosis.  Pt should be placed upright as soon as possible after surgery as gravity produces toxicity to the macula.
  23. 23. Intraocular gentamicin injection with acute macular necrosis
  24. 24. Interferon  Interferon (Betaseron) is a recombinant DNA-based protein used in the treatment of hepatitis C, leukemia, lymphoma and multiple sclerosis.  Toxicity is due to deposition of immune complex, activated complement C5a wt leukocyte infiltration.  Retinopathy : Cotton-wool spots, intraretinal and pre-retinal hemorrhage, and macular edema.  Signs develop within two weeks to three months of treatment onset.  High risk for diabetic and/or hypertensive patirnts.  Disc oedema, CRVO, BRVO, AION, CME.  Resolve spontaneously when discontinued,
  25. 25. CME  Epinephrine  Latanoprost  Nicotinic acid  Pactitaxel /docetaxel
  26. 26. Epinephrine  Sympathomimetic agent  It acts to lower IOP by decreasing aqueous production  Patients complain of blurred or decreased vision within weeks to months of initiating therapy.  Topical epinephrine may produce cystoid changes by reducing blood flow in the retina and choroid.  Two points : one is the stimulation of PG synthesis ,the other is the dysfunction, in some aphakic eyes, of the active transport system which is responsible for the removal of PGs from intraocular fluids  CME will resolve with drug cessation.
  27. 27. Latanoprost (Xalatan)  Latanoprost (Xalatan) is a prostaglandin analog used to lower IOP by increasing uveoscleral outflow.  Should not exceed once daily.  Toxicity occures if used > 6 months.  Conjunctival hyperemia, darkening of eyelashes and iris heterochromia ,reversible cystoid macular edema  As a PG analog, latanaprost is thought to contribute to the disruption of the blood–aqueous barrier and angiographic CME formation in early postoperative pseudophakes.  The CME is reversible on discontinuation of the latanoprost
  28. 28. Cystoid macular edema with latanoprost use
  29. 29. Petalloid pattern of foveal hyperfluorescence on fluorescein angiography.
  30. 30. Niacin  Niacin, or vitamin B3, is used to treat pellagra, hyperlipidemia and hypercholesterolemia.  Initial dose: 100 mg orally 3 times a day,. Maintenance dose: 1 to 2 g orally 3 times a day The maximum recommended dose is 6 g/day.  Niacin has direct toxic effects on Müller cells, without disruption of the blood-retinal-barrier.  Systemic side effect: facial flushing  Visual complaints: blurred vision/decreased vision and metamorphopsia.
  31. 31.  Macula appears edematous  FA is silent without leakage, which is thought to indicate that the edema is secondary to fluid accumulation inside retinal cells, as opposed to an extracellular location.  While OCT imaging exhibits classic cystic space in the inner nuclear and outer plexiform layers.  The discontinuation of niacin will gradually reduce CME and improve visual acuity.
  32. 32. Pactitaxel /docetaxel  Antineoplastic agent /antimicrotubule agent  Treats different kinds of cancer, including cancer in the lungs, ovary, or breast.  Also may be used to treat Kaposi's sarcoma.  Angiographically negative CME.  Toxic dose:135mg/m2 infusion every 3 wks
  33. 33. Crystalline Retinopathy  Tamoxifen  Canthaxanthine  Talc  Nitrofurantoin Miscellaneous Medications  Digoxin  Sildenafil  Interferon
  34. 34. Tamoxifen  Tamoxifen is a selective estrogen receptor modulator used in the management of breast cancer.  It is an amphiphilic agent that can accumulate in lysosomes and cause oxidative damage.  The mechanism of ocular toxicity : has been postulated that the cationic amphiphilic nature of tamoxifen allows binding with polar lipids, interfering with their catabolism.  Patients may be asymptomatic at onset but may complain of decreased vision and dyschromatopsia.  Ocular symptoms: doses greater than 60-100 mg/day over 1 year.  Clinically, fundus examination will show refractile intraretinal crystalline deposits concentrated primarily in the perifoveal macula,Optic neuropathy,CME.
  35. 35. Crystalline retinopathy with tamoxifen use Perifoveal leakage on fluorescein angiography Foveal cystic changes
  36. 36. Canthaxanthine  Canthaxanthine is a vitamin A derivative used in the treatment of psoriasis, eczema, vitiligo.  Toxicity has been shown after high-dose oral therapy of greater than 0.5 mg/kg/day over 2 years.  Patients are primarily asymptomatic  On fundus exam, a doughnut-shaped ring of golden intraretinal deposits surrounds the fovea.  FA, ERG and color vision are typically normal; however OCT demonstrates crystalline deposition within the inner retinal layers.  Visual field testing shows a dose-dependent decrease in retinal sensitivity
  37. 37.  Patients should be monitored with regular ophthalmologic examination.  With drug cessation, the retinal crystals may take years to disappear, while patients often remain asymptomatic.  Canthaxanthine crystals are localised in the degeneration neutrophil and associated with atrophy of muller cells.  Vacuolization of RPE and disruption of phagolysosome.
  38. 38. Perifoveal punctate yellow deposits in a doughnutshaped ring surrounding the macula
  39. 39. Methoxyflurane  Inhalational anaesthetic agente  Specially used in patients with renal insufficiency,  Biodegradation product inorganic flouride and dichloroacetic acid is responsible for the toxicity. Metabolized to oxalic acid combine with Ca Ca oxalate salt deposited in RPE  Each 3 milliliter dose lasts approximately 30 minutes  Pain relief begins after 6–8 breaths and continues for several minutes after stopping inhalation.  The maximum recommended dose is 6 milliliters per day or 15 milliliters per week.  Yellow white punctate lesion in posterior pole and periarterially.
  40. 40. Periarterial crystals throughout the posterior pole
  41. 41. Retinal fold  Acetazolamide  Chlorthalidone  Ethoxyzolamide  Hydrochlorothiazide  Metronidazole  Sulfa antibiotic  Triamteren
  42. 42.  Cause a syndrome of transient acute myopia and anterior chamber shallowing.  This is due to ciliary body swelling, choroidal effusion or lens swelling with forward rotation of lens iris diaphragm.  Folds develop due to vitreous traction on the macula that is caused by forward shift of the lens and iris. Chlorthalidone-induced retinal folds
  43. 43. Miscellaneous Medications  Sildenafil: Sildenafil (Viagra) is a selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5) that causes smooth muscle relaxation.  Sildenafil also acts on the retina to alter cGMP levels by inhibiting retina-specific PDE6 depolarization of the rod cell & influences the phototransduction cascade and increased light sensitivity.  Patients may present with visual disturbances, complaining of cyanopsia, photophobia and blurred vision.  Typically, visual acuity is unchanged and there are no fundus changes.  Case reports have also described NAAION, CSR, cilioretinal arterial occlusion et.  Symptoms resolve over four to six hours after medication ingestion.
  44. 44. Digoxin       Digoxin (Lanoxin) is a cardiac glycoside: used in atrial fibrillation, atrial flutter and congestive heart failure. Systemic toxicity is rare when plasma digoxin concentration is less than 0.8 µg/L. Ocular side effects are common with high doses, Decreased vision to photopsias, xanthopsia and scotomas. Digoxin acts on retinal cells by inhibiting the sodium-potassium ATPase pump and altering potassium levels. When digoxin is stopped, both the visual symptoms and prolonged ERG b-wave will resolve over weeks as the medication is metabolized
  45. 45. Methanol  Visual blurring and field defect within 18 hrs.  Toxicity is mediated by formic acid which affects the inner retina and optic nerve.  Vision loss is thought to be caused by interruption of mitochondrial function in the optic nerve.  Optic nerve demyelination has been reported to be due to formic acid destruction of myelin resulting in hyperemia, edema, and optic nerve atrophy.
  46. 46. Carbamazepine  Carbamazepine is an anticonvulsant  200 mg orally twice a day.  Maintenance dose: 800 to 1200 mg/day  Dosage generally should not exceed 1200 mg/day  Might cause damage of the retinal pigment epithelium in long-term treatment.  Fundus : Extensive lesions of the retinal pigment epithelium in the posterior poles of the eyes including the macular regions.  Discontinuation of carbamazepine lead to improvement of visual function.
  47. 47. Conclusion  The exact mechanisms of pathogenesis for many of these drugs remain unknown.  Early detection and prompt treatment are often crucial in reversing these adverse ocular effects.  The associated clinical presentations, colour vision, contrast sensitivity, FFA, OCT, perimetry , Electrophysiological tests are important aids for diagnosis.