Generic name: Heparin.

Proprietary names: Hepflush-10, Hep-lock, Hep-lock U/P.

Primary use

This complex organic acid inhibits the blood-clotting mechanism and is used in the prophylaxis and treatment of venous thrombosis.

Ocular side effects

Systemic administration

Certain

1. Subconjunctival, anterior chamber or retinal hemorrhages

a.Secondary to drug-induced anticoagulation

b.Secondary to drug-induced anemia

2. Eyelids or conjunctiva

a.Allergic reactions

b.Conjunctivitis – non-specific

c.Angioneurotic edema

d.Urticaria

e.Necrosis

Probable

1. Lacrimation

Possible

1. Eyelids or conjunctiva – Lyell’s syndrome

Local ophthalmic use or exposure – subconjunctival injection

Certain

1. Subconjunctival or periocular hemorrhages

Probable

1. Subconjunctival scarring

2. Decreased intraocular pressure (minimal)

Possible

1. Exacerbation of primary disease

Clinical significance

Ocular side effects due to systemic heparin are few and usually of little consequence. Ocular hemorrhage is the most serious adverse reaction and is probably more common in conditions with increased capillary fragility such as diabetes (Levartovsky et al 2003). Subconjunctival or periocular hemorrhage is the most common adverse reaction with subconjunctival heparin injections. It is more common after the third or fourth injection and seldom prevents continuous injections of heparin. Chang et al (1996) described two pregnant women who developed spontaneous orbital hemorrhages following treatment with subcutaneous heparin. Both women developed severe unilateral visual loss. Heparin-induced antiheparin platelet antibody leads to the thrombosis of ocular circulation (Nguyen et al 2003). Slusher et al (1975) reported hyphema in an otherwise normal eye seen 1 hour after 10 000 units of heparin were administered intravenously. The National Registry has received a single case each of sudden onset of severe keratoconjunctivitis sicca associated with the use of intravenous or subcutaneous heparin injections.

References And Further Reading

Aronson SB, Elliott JH. Ocular Inflammation. Mosby, St Louis, pp 91–92, 1972.

Chang WJ, Nowinski TS, Repke CS, et al. Spontaneous orbital hemorrhage in pregnant women treated with subcutaneous heparin. Am J Ophthalmol 122(6): 907–908, 1996.

Leung A. Toxic epidermal necrolysis associated with maternal use of heparin. JAMA 253: 201, 1985.

Levartovsky S, Reisin I, Reisin I, et al. Bilateral posterior segment intraocular hemorrhage in a diabetic patient after therapy with heparin. Isr Med Assoc J 5: 605, 2003.

Levine LE, et al. Heparin-induced cutaneous necrosis unrelated to injection sites. Arch Dermatol 119: 400, 1983.

Lipson ML. Toxicity of systemic agents. Int Ophthalmol Clin 11(2): 159, 1971. Nguyen QD, Van DV, Feke GT, et al. Heparin-induced antiheparin-platelet antibody associated with retinal venous thrombosis. Ophthalmology

110: 600–603, 2003.

Slusher MM, Hamilon RW. Spontaneous hyphema during hemodialysis. N Engl J Med 293: 561, 1975.

Zurcher K, Krebs A. Cutaneous Side Effects of Systemic Drugs, S. Karger, Basel, pp 18–19, 300-303, 1980.

Generic name: Streptokinase.

Proprietary name: Streptase.

Primary use

This protein is used to dissolve thrombi in patients with myocardial infarction, pulmonary embolism and other thromboembolic occlusions of veins and arteries.

Ocular side effects

Systemic administration – intravenous

Certain

1. Bleeding

a.Periocular

b.Tenon’s capsule

c.Intraocular hemorrhage

d.Total hyphema

e.Choroidal hematoma

f.Vitreous hemorrhage

g.Postoperative ocular bleeding 2. Anterior uveitis

3. Eyelids and orbit

a.Urticaria

b.Rash

c.Angioneurotic edema

Conditional/Unclassified

1. Central retinal artery occlusion

Clinical significance

There are a number of reports of streptokinase causing intra­ ocular bleeding, hyphemas, vitreous hemorrhages or choroidal hematomas. Cahane et al (1990) reported a total hyphema secondary to streptokinase after cataract surgery. Marcus and Frederick (1994) described a case of streptokinase-induced tenon’s capsule hemorrhage following retinal detachment surgery. The patient received intravenous streptokinase 2 hours after surgery when he developed a myocardial infarct. Potdar et al (2001) reported a case of unilateral central retinal artery occlusion following intravenous streptokinase, possibly due to an emboli leading to optic atrophy and blindness. There are a number of cases (Kinshuck 1992; Birnbaum et al 1993; Gray and Lazarus 1994; Proctor and Joondeph 1994; Fraunfelder and Rosenbaum 1997) of primarily bilateral anterior uveitis. Streptokinase-induced serum sickness,

coagulability and formation blood affecting Agents • 8 Section

effects side ocular induced-Drug • 7 Part

which Proctor and Joondeph (1994) felt occurs about 6% of the time, may occasionally exhibit a uveitis. Streptokinaseinduced uveitis is most likely a result of an immune complex reaction, like serum sickness, and not due to any specific toxicity to the eye (Fraunfelder and Rosenbaum 1997). Anterior chamber injections of this agent for dissolution of fibrin exudates have had no detectable adverse intraocular effects (Cherfan et al 1991). Berger (1962) stated that there was intraocular irritation secondary to streptokinase, but it is possible that the drug used was not in as purified a form as is available now. Up to one-third of patients who have received repeat injections of this drug have become hypersensitive to it. This may present by periorbital swelling or angioneurotic edema.

References And Further Reading

Battershill PE, Benfield P, Goa KL. Streptokinse: a review of its pharmacology and therapeutic efficacy in acute myocardial infarction in older patients. Drugs & Aging 4(1): 63–86, 1994.

Beare N. ‘Hyperacute’ unilateral anterior uveitis and secondary glaucoma following streptokinase infusion. Eye 18: 111, 2004.

Bec P, Arne JL, et al. Choroidal and vitreous hemorrhage in the course of treatment of a thrombosis of the central retinal vein with streptokinase. Bull Soc Ophthalmol France 80: 607–609, 1980.

Berger B. The effect of streptokinase irrigation on experimentally clotted blood in the anterior chamber of human eyes. Acta Ophthalmol 40: 373–378, 1962.

Birnbaum T, et al. Acute iritis and transient renal impairment following thrombolytic therapy for acute myocardial infarction (letter). Ann Pharmacother 27(12): 1539–1540, 1993.

Boyer HK, et al. Studies on simulated vitreous hemorrhages. Arch Ophthalmol 59: 333–336, 1958.

Cahane M, et al. Total hyphaema following streptokinase administration eight days after cataract extraction. Br J Ophthalmol 74: 447, 1990.

Caramelli B, et al. Retinal haemorrhage after thrombolytic therapy. Lancet 337: 1356–1357, 1991.

Cherfan GM, et al. Dissolution of intraocular fibrinous exudate by streptokinase. Ophthalmology 98(6): 870–874, 1991.

Fraunfelder FW, Rosenbaum JT. Drug-induced uveitis: incidence, prevention, and treatment. Drug Safety 17(3): 197–207, 1997.

Glikson M, et al. Thrombolytic therapy for acute myocardial infarction following recent cataract surgery. Am Heart J 121: 1542–1543, 1991.

Gray MY, Lazarus JH. Iritis after treatment with streptokinase. Drug Points. BMJ 309: 97, 1994.

Kinshuck D. Bilateral hypopyon and streptokinase. Drug Points. BMJ 305(6865): 1332, 1992.

Lundgren B, Ocklind A, Holst A, Harfstrand A. Inflammatory response in the rabbit eye after intraocular implantation with poly(methyl methacrylate) and heparin surface modified intraocular lenses. J Cat Refract Surg 18(1): 65–70, 1992.

Manners TD, Turner DPJ, Galloway PH, Glenn AM. Heparinised intraocular infusion and bacterial contamination in cataract surgery. Br J Ophthalmol 81: 949–952, 1997.

Marcus DM, Frederick AR Jr. Streptokinase-induced tenon’s hemorrhage after retinal detachment surgery. Am J Ophthalmol 118(6): 815–816, 1994.

Oliveira DC, Coelho OR, Paraschin K, et al. Angioedema related to the use of streptokinase. Arq Br Cardiol 85: 131–134, 2005.

Ortega-Carnicer J, Porras-Leal L, Fernandez-Ruiz A. Intraocular hemorrhage after intravenous streptokinase. Med Clin 115: 718–719, 2000.

Pick R, et al. Acute renal failure following repeated streptokinase therapy for pulmonary embolism. West J Med 138: 878–880, 1983.

Potdar NA, Shinde CA, Murthy GG, et al. Unilateral central retinal artery occlusion following intravenous streptokinase. J Postgrad Med 47: 262–263, 2001.

Proctor BD, Joondeph BC. Bilateral anterior uveitis. A feature of streptokinase-induced serum sickness. N Engl J Med 330: 576, 1994.

Steinemann T, et al. Acute closed-angle glaucoma complicating hemorrhagic choroidal detachment associated with parenteral thrombolytic agents. Am J Ophthalmol 106: 752–753, 1988.

Sunderraj P. Intraocular hemorrhage associated with intravenously administered streptokinase. Am J Ophthalmol 112(6): 734–735, 1991.

Van den Berg E, Lohmann N, Friedburg D, Rabe F. Report of general temporary anticoagulation in the treatment of acute cerebral and retinal ischaemia. Vasa 26(3): 222–227, 1997.

Winther-Nielson A, Johansen J, Pedersen GK, Corydon L. Posterior capsule opacification and neodymium: YAG capsulotomy with heparin- surface-modified intraocular lenses. J Cat Refract Surg 24(7): 940-944, 1998.

Generic name: Tranexamic acid.

Proprietary name: Cyklokapron.

Primary use

An antifibrinolytic agent used primarily for treatment of excessive fibrinolysis. It has been used to control uterine and gastrointestinal bleeding as well as traumatic hyphemas.

Ocular side effects

Systemic administration

Possible

1. Decreased vision

2. Abnormal color vision – transient

3. Retinal artery or venous occlusion

4. Decreased corneal thickness

a.Post intraocular surgery

b.Bullous keratopathy

Conditional/Unclassified

1. Conjunctivitis – ligneous

2. Retinal pigment epithelium disturbances

Clinical significance

This agent is not available in the USA, but is in Asia and Europe. Clinical trials have been done in the USA, and occasionally US ophthalmologists have used this drug. It is, however, not FDA approved. Its actions are similar to aminocaproic acid, but much more potent. In animals, at three to seven times human dosages, retinal degenerations were seen in a matter of days. These changes were both central and peripheral (Theil 1981). To date this has not been seen in humans. However, Kitamura et al (2003) with rechallenge data, showed that large dosages of tranexamic acid caused reversible decreased vision, probably due to malfunction of the pigment epithelium of the retina. The authors felt that reduction of renal function (where the drug is metabolized) was a factor. Pharmacia and UpJohn (unpublished) reported no retinal degenerative change in patients on therapeutic dosages for periods ranging from 15 months to 8 years. However, occasional cases of transient disturbances of color vision were seen. Theil (1981) confirmed this. Possible ocular side effects include arterial or venous occlusion, including venous stasis retinopathy (Snir et al 1990). Their two patients had venous stasis with disc edema, engorged veins, cotton-wool spots and hemorrhages. Findings resolved after stopping the drug with resultant 20/20 vision OU. Parsons et al (1988) described a case of branch retinal artery occlusion. There are six cases of central or branch venous occlusion associated with the use of this agent in the National Registry.

Bramsen et al (1978) found that this agent decreases corneal edema in both bullous keratopathy and post intraocular surgery in humans. Hull et al (1979) could not confirm this in rabbits. Diamond et al (1991) reported a possible case of ligneous conjunctivitis after exposure to this drug. Reports to the National Registry of decreased color vision, both transitory and possibly permanent, have come from Sweden.