effects side ocular induced-Drug • 7 Part
Proprietary names: 1. Femiron, Feostat, Ferretts, Hemaspan, Hemocyte, Nephro-Fer, Vitron-C; 2. Fergon; 3. Ed- in-sol, Feosol, Fer-gen-sol, Fe-Iron, Feratab, Fero-Grad, Isospran, Slow-Fe; 4. Dexferrum, Infed, Proferdex; 5. Venofer; 6. Fe-Tinic, Ferrex, Ferrex Plus, Hytinic, Niferex, Nu-Iron, Poly-Iron.
Primary use
These iron preparations are effective in the prophylaxis and treatment of iron-deficiency anemias.
Ocular side effects
Systemic administration (toxic levels)
Certain
1. Decreased vision (iron dextran)
2. Yellow-brown discoloration
a.Sclera
b.Choroid
3. Eyelids or conjunctiva (iron dextran)
a.Erythema
b.Edema
c.Angioneurotic edema
d.Urticaria
e.Photosensitivity reactions
Probable
1. Retinal degeneration – overdosage
Inadvertent ocular exposure
Certain
1. Irritation
a. Hyperemia b Photophobia c. Edema
2. Yellow-brown discoloration or deposits
a.Eyelids
b.Conjunctiva
c.Cornea
d.Sclera
Probable
1. Ulceration
a.Eyelids
b.Conjunctiva
c.Cornea
Clinical significance
Systemically administered iron preparations seldom cause ocular side effects. Adverse ocular reactions have been reported after multiple blood transfusions (over 100), with unusually large amounts of iron in the diet or markedly prolonged iron therapy. A few cases of retinitis pigmentosa-like fundal degeneration have been reported. Hodgkins et al (1992) described a case of pigment epitheliopathy with an overlying serous retinal detachment following an infusion of iron dextran. Newer iron preparations make retinal degenerations less likely. Kawada et al (1996) described photosensitivity reactions due to sodium ferrous citrate.
Direct ocular exposure to acidic ferrous salts can cause ocular irritation, but significant ocular side effects rarely occur.
References And Further Reading
Appel I, Barishak YR. Histopathologic changes in siderosis bulbi. Ophthalmologica 176: 205, 1978.
Brunette JR, Wagdi S, Lafond G. Electroretinographic alterations in retinal metallosis. Can J Ophthalmol 15: 176, 1980.
Declercq SS. Desferrioxamine in ocular siderosis. Br J Ophthalmol 64: 626, 1980.
Hodgkins PR, Morrell AJ, Luff AJ, et al. Pigment epitheliopathy with serous detachment of the retina following intravenous iron dextran. Eye 6(Pt 4): 414–415, 1992.
Kawada A, Hiruma M, Noguchi H, et al. Photosensitivity due to sodium ferrous citrate. Contact Dermatitis 34(1): 77, 1996.
Kearns M, McDonald R. Generalized siderosis from an iris foreign body. Aust J Ophthalmol 8: 311, 1980.
Salminen L, Paasio P, Ekfors T. Epibulbar siderosis induced by iron tablets. Am J Ophthalmol 93: 660, 1982.
Syversen K. Intramuscular iron therapy and tapetoretinal degeneration. Acta Ophthalmol 57: 358, 1979.
Wolter JR. The lens as a barrier against foreign body reaction. Ophthalmic Surg 12: 42, 1981.
Generic name: Methylthioninium chloride (methylene blue).
Proprietary name: Urolene Blue.
Primary use
Systemic
Methylthioninium is a weak germicidal agent used as a urinary or gastrointestinal antiseptic. It is also given intravenously in the treatment of methemoglobinemia and ‘cyanosis anemia’. It is also used as a dye to demonstrate cerebrospinal fluid fistulae or blocks.
Ophthalmic
Methylthioninium is used as a tissue marker during ocular or lacrimal surgery and has been applied to the conjunctiva to decrease glare during microsurgery.
Ocular side effects
Intrathecal and intraventricular injections
Certain
1. Decreased vision
2. Blue-gray discoloration
a.Vitreous and retina
b.Eyelids
3. Problems with color vision – objects have blue tinge
Probable
1. Decreased accommodation (intravenous)
2. Mydriasis (intravenous)
Possible
1. Papilledema
2. Diplopia
3. Paresis of extraocular muscles
4. Accommodative spasm
5. Optic atrophy
6. Subconjunctival or retinal hemorrhages secondary to drug-induced anemia
Intracameral injection
Certain
1. Cytotoxicity
a.Corneal endothelium
b.Iris
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Local ophthalmic use or exposure
Certain
1. Irritation
a.Lacrimation
b.Edema
c.Burning sensation
d.Photosensitivity
2. Blue discoloration or staining
a.Eyelid margins
b.Conjunctiva
c.Corneal nerves and epithelium 3. Cornea – endothelial toxicity
Clinical significance
Significant ocular side effects due to methylthioninium have only been reported with intrathecal or intraventricular injections and with intracameral injections at high concentrations. The most common ocular side effects after intravenous administration other than cyanopsia or blue-gray discoloration of ocular tissue are decreased vision, mydriasis and decreased accommodation. Porat et al (1996) have shown that this drug can be a photosensitizer, causing significant skin reactions with blue staining of tissues.
Infrequent use of topical ocular application of methylthioninium in low concentrations (1%) is almost free of ocular side effects. However, irritation and pain may be so severe that a local anesthetic may be required for the patient’s comfort. Kushner (1993) reports a case in which this agent was used to irrigate the lacrimal system in a 2-year-old. The solution broke through to the periocular tissue, causing subcutaneous necrosis and marked edema along with bluish discoloration. Edema persisted for up to 2 years and amblyopia treatment was necessary. Staining of ocular and periocular tissue may be permanent if the dye is applied daily for years. Intracameral use appears safe if used in low concentration. Brouzas et al (2006) reported that inadvertent intracameral injection of 1% methylthioninium chloride may possibly cause extreme cytotoxicity of the corneal endothelium. Low concentrations may possibly aggravate already diseased endothelium, but this is theoretical.
Proprietary names: 1. Activase, Cathflo activase; 2. Retavase; 3. TNKase.
Primary use
Systemic
These tissue plasminogen activators (t-PA) are produced by recombinant DNA technology and are primarily indicated for the management of acute myocardial infarctions. Alteplase is also used in the management of acute ischemic stroke and pulmonary embolism.
Ophthalmic
Used to treat submacular hemorrhages, post vitrectomy fibrin syndrome, fibrin lysis, lysis of blood clots, intravitreal t-PA and pneumatic displacement for submacular hemorrhages, central retinal artery occlusion.
Ocular side effects
Systemic administration – intravenous injections
Certain
1. Hemorrhages
a.Hyphema
b.Retinal
c.Orbital
d.Choroidal
e.Vitreous
f.Retrobulbar
g.Subretinal
Probable
1. Eyelids or conjunctiva
a.Allergic reactions
b.Angioneurotic edema
c.Rashes
d.Urticaria
References And Further Reading
Brouzas D, Droutsas S, Charakidas A. Severe toxic effect of methylene blue 1% on iris epithelium and corneal endothelium. Cornea 25: 470–471, 2006.
Chang YS, Tseng SY, Tseng SH, et al. Comparison of eyes for cataract surgery. Part 1: cytotoxicity to corneal endothelial cells in a rabbit model. J Cataract Refract Surg 31: 792–798, 2005.
Evans JP, Keegan HR. Danger in the use of intrathecal methylene blue. JAMA 174: 856, 1560.
Kushner BJ. Solutions can be hazardous for lacrimal system irrigation. Arch Ophthalmol 111: 904–905, 1993.
Lubeck MJ. Effects of drugs on ocular muscles. Int Ophthalmol Clin 11(2): 35, 1971.
Morax S, Limon S, Forest A. Exogenous conjunctival pigmentation by methylene blues. Arch Ophthalmol 37: 708A, 1977.
Norn MS. Methylene blue (Methylthionine) vital staining of the cornea and conjunctiva. Acta Ophthalmol 45: 347, 1967.
Pasticier-Florquin B, et al. Ocular tattooing from abuse of methylene blue collyrium. Bull Soc Ophtalmol Fr 77: 147, 1977.
Perry PM, Meinhard E. Necrotic subcutaneous abscesses following injections of methylene blue. Br J Clin Pract 8: 289–291, 1974.
Porat R, Gilbert S, Magilner D. Methylene blue-induced phototoxicity: an unrecognized complication. Pediatrics 97(5): 717–721, 1996.
Raimer SS, Quevedo EM, Johnston RV. Dye rashes. Cutis 63(2): 103–106, 1999.
Uttley SA. Methylene blue-associated corneal decompensation. Poster. AAO.
Class: Anticoagulants
Generic names: 1. Alteplase; 2. reteplase; 3. tenecteplase.
Intracrameral injections
Certain
1. Hemorrhages
a.Subconjunctival
b.Hyphemia
2. Cornea
a.Band keratopahty
b.Calcium phosphate precipitates 3. Retina – vitreous hemorrhage
Intravitreal injections
Certain
1. Retina toxicity (high dosages)
a.Diffuse pigmentary changes
b.Exudative retinal detachment
c.Granular hyperfluorescent lesion (flourscein
angiography) (Fig. 7.8a)
2. ERG (high dosage) – reduce scotopic and photoic a and b waves 3. Vitreous hemorrhages
Clinical significance
The major toxicity of tissue plasminogen activators (t-PAs) is hemorrhage. This results either from lysis of fibrin at the sites of vascular injury or a systemic lytic state from the formation of systemic plasmin, which produces fibrinogenolysis and the destruction of other coagulation factors.
coagulability and formation blood affecting Agents • 8 Section
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effects side ocular induced-Drug • 7 Part
Fig. 7.8a Fluorescein angiography of diffuse granular hyperfluorescence. Photo courtesy of Chen S-N, et al. Retinal toxicity of intravitreal tissue plasminogen activator. Ophthalmology 110: 704–708, 2003.
Systemically administered t-PA for various illnesses can cause bleeding anywhere within the eye or periorbital tissues. This may occur in sites of recent ocular surgery (Khawly et al 1996; Roaf et al 1997) or be associated with the presence of exudative macular degeneration or retinal vascular diseases (Kaba et al 2005). Visual outcomes vary from no complications to blindness, or loss of the eye. Chorich et al (1998) emphasized that the onset of eye pain or vision loss after systemic t-PA should alert physicians to the possibility of an ocular or adnexal hemorrhage.
Intracameral injection complications are much more frequent in single dosage over 25 μg and/or multiple t-PA intracameral injections. Hyphemas (Tripathi et al 1991; Lundy et al 1996; Loffler et al 1997), subconjunctival hemorrhage (Lee et al 1995) and vitreous hemorrhages (Kim et al 1998) have all been reported. Rehfeldt and Hoh (1999), in their series of 185 intracameral t-PA injections, had a 5.4% incidence of hypema and a 3.2% incidence of transient corneal edema. This included one case of Fuch’s dystrophy, which had irreversible corneal endothelial decompensation. Hesse et al (1999a) confirmed the temporary endothelial toxicity of t-PA. Damage to the corneal endothelium allows phosphate (buffer of t-PA) and calcium from the aqueous humour to distribute within the corneal stroma. The insoluble calcium phosphate may then be precipitated within the stroma. This results in irreversible corneal opacification. While this side effect is rare, it is easily produced in experimental animal models when the cornea endothelium is disturbed (Hesse et al 1999b).
Intravitreal injection complications increase with single dosages exceeding 50 μg and/or with repeat injections. Frequently, intravitreal t-PA is used along with pneumatic displacement, which adds a mechanical variable for possible ocular complications. Hesse et al (1999b) described four patients given 100 μg intravitreal t-PA who developed exudative retinal detachment followed by hyperpigmentation of the retinal pigment epithelium in the area of the detachment. Chen et al (2003) reported a case similar to the above after two successive injections of 50 μg intravitreal t-PA, 3 days apart with a minimal recovery of visual acuity. Because of numerous reports of retinal toxicity in animals and humans (Hrach et al 2000), Chen et al (2003) advocate not using an injection over 25 μg. Hassan et al (1999) varied
this by recommending 25–100 μg and Hesse et al (1999b) felt higher dosages were indicated. Intravitreal t-PA can cause sudden severe vitreous hemorrhages as an immediate complication (Kokame 2000).
References And Further Reading
Berry C, Weir C, Hammer H. A case of intraocular haemorrhage secondary to thrombolytic therapy. Acta Ophthalmol Scand 80: 561–562, 2002.
Chen S-N, Yang T-C, Cheng-Lien H, et al. Retinal toxicity of intravitreal tissue plasminogen activator: case report and literature review. Ophthalmology 110: 704–708, 2003.
Chorich LJ, Derick RJ, Chambers RB, et al. Hemorrhagic ocular complications associated with the use of systemic thrombolytic agents. Ophthalmology 105: 428–431, 1998.
Djalilian AR, Cantril HC, Samuelson TW. Intraocular hemorrhage after systemic thrombolytic therapy in a patient with exudative macular degeneration. Eur J Ophthalmol 13: 96–98, 2003.
Hassan AS, Johnson MW, Schneiderman TE, et al. Management of submacular hemorrhage with intravitreous tissue plasminogen activator injection and pneumatic displacement. Ophthalmology 106: 1900–1907, 1999.
Hesse L. Treating subretinal hemorrhage with tissue plasminogen activator. Arch Ophthalmol 120: 102–103, 2002.
Hesse L, Nebelin B, Kauffmann T. Etiology of corneal opacities after plasminogen activator-induced fibrinolysis of the anterior chamber. Ophthalmology 96: 448–452, 1999a.
Hesse L, Schmidt J, Kroll P. Management of acute submacular hemorrhage using recombinant tissue plasminogen activator and gas. Graefes Arch Clin Exp Ophthalmol 237: 273–277, 1999b.
Hrach CJ, Johson MW, Hassan AS, et al. Retinal toxicity of commercial intravitreal tissue plasminogen activator solution in cat eyes. Arch Ophthalmol 118: 659–663, 2000.
Kaba RA, Lewis A, Bloom P, et al. Intraocular haemorrhage after thrombolysis. Lancet 365: 330, 2005.
Khawly JA, Ferrone PJ, Holck DEE. Choroidal hemorrhage associated with systemic tissue plasminogen activator. Am J Ophthalmol 121: 577–578, 1996.
Kim MH, Koo TH, Sah WJ, et al. Treatment of total hyphema with relatively low dose tissue plasminogen activator. Ophthalmic Surg Laser 29: 762–766, 1998.
Kokame GT. Vitreous hemorrhage after intravitreal tissue plasminogen activator (t-PA) and pneumatic displacement of submacular hemorrhage. Am J Ophthalmol 129: 546–547, 2000.
Lee PF, Myers KS, Hsieh MM, et al. Treatment of failing glaucoma filtering cystic blebs with tissue plasminogen activator (t-PA). J Ocul Pharmacol Ther 11: 227–232, 1995.
Leong JK, Ghabrial R, McCluskey PJ. Orbital haemorrhage complication following postoperative thrombolysis. Br J Ophthalmol 87: 655–656, 2003.
Loffler KV, Meyer JH, Wollensak G, et al. Success and complications of rTPA treatment of the anterior eye segment. Opthalmologe 94: 50–52, 1997.
Lundy DL, Sidoti P, Winarko T, et al. Intracameral tissue plasmino gen activator after glaucoma surgery. Ophthalmology 103: 274–282, 1996.
Rehfeldt K, Hoh H. Therapeutic and prophylactic application of TPA (recombinant tissue plasminogen activator) into the anterior chamber of the eye. Ophthalmologe 96: 587–593, 1999.
Roaf E, DaSilva C, Tsao K, et al. Orbital hemorrhage after thrombolytic therapy. Arch Intern Med 157: 2670–2671, 1997.
Skolnick CA, Fiscella RG, Tessles HH, et al. Tissue plasminogen activator to treat impending papillary block glaucoma in patients with acute fibrinous HLA-B27 positive iridocyclitis. Am J Ophthalmol 129: 363–366, 2000.
Smith MF, Doyle JW. Use of tissue plasminogen activator to
revive blebs following intraocular surgery. Arch Ophthalmol 119: 809–812, 2001.
Tripathi RC, Tripathi BJ, Park JK, et al. Intracameral tissue plasminogen activator for resolution of fibrin clots after glaucoma filtering procedures. Am J Ophthalmol 111: 247–248, 1991.
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