effects side ocular induced-Drug • 7 Part
Fig. 7. 7c Dense hemorrhage of the disc with vitreous hemorrhage. Photo courtesy of Higa A et al: Vitreous haemorrhage in a 19-year- old Japanese woman using an oral contraceptive. Acta Ophthalmol Scand 82(2): 244-246, 2004.
Stowe CC, III, Zakov ZN, Albert DM. Central retinal vascular occlusion associated with oral contraceptives. Am J Ophthalmol 86: 798, 1978.
Tagawa H, Yoshida A, Takahashi M. A case of bilateral branch vein occlu sion due to long-standing use of oral contraceptives. Folia Ophthalmol Jpn 32: 1951, 1981.
Takahashi H, Sakai F, Sakuragi S. A case of retinal branch vein occlusion associated with oral contraceptives. Folia Ophthalmol Jpn 34: 2670, 1983.
Tomlinson A, Pearce EI, Simmons PA, et al. Effect of oral contraceptives on tear physiology. Ophthal Physiol Opt 21: 9–16, 2001.
Vandenbroucke JP, Rosing J, Bloemenkamp KWM, et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 344: 1527–1535, 2001.
Vessey MP, et al. Oral contraception and eye disease: findings in two large cohort studies. Br J Ophthalmol 82: 538-542, 1998.
4. Problems with color vision
a.Color vision defect – red-green or yellow-blue defect
b.Objects have blue tinge
c.Colored haloes around lights – mainly blue
5. Eyelids or conjunctiva
a.Allergic reactions
b.Edema
c.Hyperpigmentation
d.Photosensitivity
e.Angioneurotic edema
f.Urticaria
g.Ptosis
Possible
1. Retinal vascular disorders
a.Occlusion
b.Thrombosis
c.Hemorrhage
d.Retinal or macular edema
e.Spasms
f.Acute macular neuroretinopathy
g.Periphlebitis
2. Papilledema secondary to intracranial hypertension
3. Eyelids or conjunctiva
a.Lupoid syndrome
b.Erythema multiforme
Clinical significance
This female hormone is largely responsible for the changes that take place at puberty in females and also provides their second ary sexual characteristics. These agents are infrequently given orally because of extensive first-pass hepatic metabolism and the resulting failure to produce high enough therapeutic blood levels. However, slow, sustained release from dermal patches or creams can produce systemic effects. Most ocular side effects are the same as those listed in Combination Products of Estrogens and Progestogens. Reports of fluctuation of corneal curvature, steepening of the cornea and intolerance of contact lens wear are probably real.
Generic name: Estradiol.
Proprietary names: Alora, Climara, Delestrogen, Estrace, Estraderm, Estrasorb, Estring, Estrogel, Femring, Femtrace, Gynodiol, Inofem, Menostar, Vagifem, Vivelle, Vivelle-Dot.
Primary use
This naturally occurring estrogen is administered in tablets, transdermal patches and vaginal creams, and used in the man agement of menopause, vulval and vaginal atrophy, ovarian failure, uterine bleeding, and prevention of osteoperosis.
Ocular side effects
Systemic administration – oral, transdermal patch or creams
Probable
1. Decreased vision
2. Decreased tolerance to contact lenses
3. Cornea
a.Fluctuation of corneal curvature
b.Increased steeping of cornea
References And Further Reading
Gurwood AS, Gurwood I, Gubman DT, Brzezicki LJ. Idiosyncratic ocular symptoms associated with the estradiol transdermal estrogen replace ment patch system. Optom Vis Sci 72(1): 29–33, 1995.
Physicians’ Desk Reference, 60th edn, Thomson PDR, Montvale NJ, pp 795–800, 805–810, 2288–2293, 2340–2343, 3200–3205, 2006.
See also references of previous section, Combination Products of Estrogens and Progestogens.
Generic name: 1. Levonorgestrel; 2. norgestrel.
Proprietary names: 1. Mirena, Norplant II, Plan B; 2. multi-ingredient preparations only.
Primary use
Synthetic progestin given as an intradermal implant that acts as a long-term contraceptive agent.
Ocular side effects
Subdermal implantation
Probable
1. Decreased vision
178
Possible
1. Papilledema secondary to intracranial hypertension
2. Diplopia
3. Myasthenia gravis
a.Diplopia
b.Ptosis
c.Paresis of extraocular muscles 4. Ocular porphyria
Clinical significance
Levonorgestrel is twice as potent as, and more commonly used than, norgestrel. Primarily, the documented side effects men tioned here are all for levonorgestrel. Alder et al (1995) reported 57 cases of intracranial hypertension or papilledema from a spontaneous reporting system and there are an additional 70 cases known to the manufacturer (Weber et al 1995), all pos sibly due to levonorgestrel. Alder’s series of patients were female with a mean age of 23 years (range 16–34 years), with a mean levonorgestrel treatment of 175 days (range 9–616 days) before the onset of intracranial hypertension. Visual field defects were present in at least 12 cases, which were primarily enlarged blind spots. Diplopia, usually due to 6th nerve paresis, was present in 16 cases. However, there were at least 140 cases of blurred vision reported with patients taking this agent. The problem, of course, with this type of data is that intracranial hypertension occurs in this age group of persons without obesity at a rate of approxi mately 3.3 per 100 000 a year, therefore a report of 57 cases, with much of the data being incomplete, is suspect for causality. The drug first came on the market in 1991, and in 1994 the manufacturer first released the possible association of this drug with intracranial hypertension. They stated that in patients who have vision disturbances or headaches, especially headaches that change in frequency, pattern, severity or persistence, it is par ticularly important to view the optic nerves. Also, they suggest that patients who develop papilledema or intracranial hyper tension have the implants removed. While not a proven asso ciation, one should probably remove the implants if optic nerve findings occur. Brittain and Lange (1995) reported myasthenia gravis occurring after insertion of a levonorgestrel implant and improving after its removal. Levonorgestrel has been associated with acute attacks of pophyria with various ocular and acute ocular findings. These include retinal edema, cotton wool spots, hemorrhages and scleral ulcers. Partial third nerve palsey, ptosis and mydriasis can occur.
References And Further Reading
Alder JB, Fraunfelder FT, Buchhalter JR. Levonorgestrel implants and intra cranial hypertension. N Engl J Med 332(25): 1720–1721, 1995.
Brittain J, Lange LS. Myasthenia gravis and levonorgestrel implant. Lancet 346: 1556, 1995.
Physicians’ Desk Reference, 60th edn, Thomson PDR, Montvale, NJ, pp 810–815, 2006.
Weber ME, et al. Levonorgestrel implants and intracranial hypertension. N Engl J Med 332: 1721, 1995.
Class: Ovulatory Agents
Generic name: Clomifene citrate.
Proprietary names: Clomid, Milophene, Serophene.
Primary use
This synthetic non-steroidal agent is effective in the treatment of anovulation.
Ocular side effects
Systemic administration
Certain
1. Visual sensations
a.Flashing lights
b.Scintillating scotomas
c.Distortion of images secondary to sensations of waves or glare
d.Various colored lights – mainly silver
e.Phosphene stimulation
f.Prolongation of after image
g.Entoptic phenomenon
2. Decreased vision
3. Mydriasis
4. Visual fields
a.Scotomas – central, paracentral, centrocecal
b.Constriction
5. Photophobia
6. Eyelids or conjunctiva
a.Allergic reactions
b.Urticaria
c.Loss of eyelashes or eyebrows
Probable
1. Decreased tolerance to contact lenses
Possible
1. Diplopia
2. Optic neuritis
Conditional/Unclassified
1. Cataracts
2. Retina
a.Phebilitis
b.Spasms
3. Increased intraocular pressure
Ocular teratogenic effects
Probable
1. Retinal aplasia
2. Cyclopia
3. Nystagmus
Clinical significance
Clomifene appears to have a unique effect on the retina that may occur in up to 10% of patients. This consists of any or all of the following: flashing lights, glare, various colored lines (often silver), multiple images, prolonged after images, ‘like look ing through heat waves’, objects have ‘comet’ tails, phosphene stimulation and scintillating scotomas identical to migraine. These may occur as early as 48 hours after taking this agent and are reversible after stopping the medication. Transitory and prolonged decreased vision have also been reported. With pro longed use after years, vision loss in the 20/40 to 60 range may occur (etiology unknown), which may be slow to recover. Purvin reported three cases of irreversible prolonged visual disturbances (palinopsia), as described above. Cases in the National Registry support this. Bilateral acute reversible loss of vision, even in the light perception range, is a rare event. Mydriasis is common, but
mechanisms hormonal affecting agents and Hormones • 7 Section
179
effects side ocular induced-Drug • 7 Part
of a mild degree and reversible. Of major clinical significance are the unilateral or bilateral scotomas, and visual field constriction. It is of interest that classic scintillating scotoma seems to occur secondary to clomifene. In general, these side effects required discontinuing the medication. The causes of these are unclear but Padron Rivas et al (1994) and several cases in the National Registry suggest the possibility of an optic neuritis for some of these effects. These are in females in the multiple sclerosis age group and a cause-and-effect relationship is conjecture. Usually, the patient refuses to take further medication, and the long-term sequalae, if the drug is continued, are unclear. Decreased contact lens wear may be due to clomifene’s ability to inhibit mucus pro duction. Monocular and binocular diplopia have been reported but are not well documented. While the literature contains refer ences to the cataractogenic potential of this agent, a drug-related cause has not been proven. There is one well-documented case in the National Registry of this agent causing bilateral elevat ed intraocular pressure. Lawton (1994) reported a case sugges tive of anterior ischemic optic neuropathy on the basis that the drug may cause increased blood viscosity. If this were true, retinal vasular occlusions could also occur. This drug also has ocular teratogenic effects. It has been reported that about 1% of patients are forced to stop taking it secondary to ocular side effects.
References And Further Reading
Asch RH, Greenblatt RB. Update on the safety and efficacy of clomiphene citrate as a therapeutic agent. J Reprod Med 17: 175, 1976.
Kistner RW. The use of clomiphene citrate in the treatment of anovulation. Semin Drug Treatment 3(2): 159, 1973.
Kurachi K, Aono T, Minagawa J, Miyake A. Congenital maliformations of newborn infants after clomiphene-induced ovulation. Fertil Steril 40(2): 187–189, 1983.
Laing IA et al. Clomiphene and congenital retinopathy. Lancet 2: 1107, 1981.
Lawton AW. Optic neuropathy associated with clomiphene citrate therapy. Fertil Steril 61(2): 390–391, 1994.
Padron Rivas VF, Sanchez Sanchez A, Lerida Arias MT et al. Optic neuritis appearing during treatment of clomiphene (letter). Atencion Primaria 14(7): 912–913, 1994.
Piskazeck VK, Leitsmann H. Uber die Behandlung derfunktionellen Sterili tat mit Clostylbegyt. Zentralbl Gynaekol 98: 904, 1976.
Purvin VA. Visual disturbance secondary to clomiphene citrate. Arch Ophthalmol 113(4): 482–484, 1995.
Roch LM, II et al: Visual changes associated with clomiphene citrate therapy. Arch Ophthalmol 77: 14, 1967.
Rock T, Dinar Y, Romen M. Retinal periphlebitis after hormonal treatment. Ann Ophthalmol 21: 75–76, 1989.
Van Der Merwe JV. The effect of clomiphene and conjugated oestrogens on cervical mucus. South Afr Med J 60(9): 347–349, 1981.
Class: Thyroid Hormones
Generic names: 1. Levothyroxine sodium; 2. liothyronine sodium; 3. thyroid.
Proprietary names: 1. Levolet, Levo-T, Levothroid, Lev oxyl, Novothyrox, Synthroid, Unithroid; 2. Cytomel, Triostat; 3. Nature Throid.
Primary use
These thyroid hormones are effective in the replacement ther apy of thyroid deficiencies such as hypothyroidism and simple goiter.
Ocular side effects
Systemic Administration
Certain
1. Decreased vision
2. Eyelids or conjunctiva
a.Hyperemia
b.Edema
3. Photophobia
4. Exophthalmos
5. Visual hallucinations
Probable
1. Eyelids or conjunctiva – angioneurotic edema
2. Papilledema secondary to intracranial hypertension
Possible
1. Myasthenia gravis
a.Diplopia
b.Ptosis
c.Paresis of extraocular muscles
2. Open-angle glaucoma (levothyroxine)
3. Blepharospasm
Clinical significance
Lee et al (2004) found a possible association of glaucoma and thy roid disease in the Blue Mountains Eye Study. This was particularly true in patients currently treated with levothyroxine. They stated, however, that further evaluation of this potential association is war ranted. There are numerous articles suggesting that this group of drugs can cause intracranial hypertension. Prepubertal and peripu bertal hypothyroid children may be the most susceptible to intrac ranial hypertension when beginning this group of drugs. Sundaram et al (1985) reported petit mal status epilepticus with rapid rhyth mic eyelid fluttering and blinking occurring in a patient approxi mately 1 week after starting levothyroxine therapy. Lledo Carreres et al (1992) reported a case of toxic internuclear ophthalmoplegia after the use of these agents for weight loss. Visual hallucinations have appeared soon after initiation of thyroid replacement therapy in hypothyroid patients, usually in patients with an underlying psy chiatric disorder. Other than the CNS changes, most ocular find ings clear within a few months of discontinuing the medication.
References And Further Reading
Hymes LC, Warshaw BL, Schwartz JF. Pseudotumor cerebri and thyroid- replacement therapy. N Engl J Med 309: 732, 1983.
Josephson AM, MacKensie TP. Thyroid-induced mania in hypothyroid patients. Br J Psychiatry 137: 222, 1980.
Kaeser HE. Drug-induced myasthenic syndromes. Acta Neurol Scand 70(Suppl. 100): 39, 1984.
Lee AJ, Rochtchina E, Wang JJ, et al. Open-angle glaucoma and systemic thyroid disease in an older population: the Blue Mountains Eye Study. Eye 28: 600–608, 2004.
Lledo Carreres M, Lajo Garrido JL, Gonzalez Rico M, et al. Toxic inter nuclear ophthalmoplegia related to antiobesity treatment. Ann Pharm 26(11): 1457–1458, 1992.
McVie R. Pseudotumor cerebri and thyroid-replacement therapy. N Engl J Med 309: 731, 1983.
Misra M, Khan GM, Rath S. Eltroxin induced pseudotumor cerebri? A case report. Indian J Ophthalmol 40(4): 117, 1992.
Raghavan S, DiMartino-Nardi J, Saenger P, Linder B. Pseudotumor cerebri in an infant after L-thyroxine therapy for transient neonatal hypo thyroidism. J Ped 130(3): 478–480, 1997.
Sundaram MBM, Hill A, Lowry N. Thyroxine-induced petit mal status epilepticus. Neurology 35: 1792, 1985.
Van Dop C, et al. Pseudotumor cerebri associated with initiation of levothyro xine therapy for juvenile hypothyroidism. N Engl J Med 308:1076, 1983.
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SECTION 8
Agents Affecting Blood
Formation and Coagulability
Class: Agents Used to Treat Deficiency Anemias
Generic name: Cobalt.
Proprietary names: None.
Primary use
This agent is used in the treatment of iron-deficiency anemia.
Ocular side effects
Systemic administration
Probable
1. Eyelids or conjunctiva
a.Allergic reactions
b.Photosensitivity
c.Urticaria
2. Uveitis (skin tattoo)
Possible
1. Decreased vision
2. Optic atrophy
Clinical significance
Cobalt is now only occasionally used since significant systemic side effects occur and safer drugs are available. Only rarely are ocular side effects due to cobalt therapy seen, and decreased vision is the most common complaint. Rorsman et al (1969) reported three cases of uveitis associated with cobalt skin tattooing. Each time a reaction at the tattoo site occurred, the uveitis exacerbated. Fraunfelder and Rosenbaum (1997) speculated that this is a type IV hypersensitivity reaction. There are two well-described cases of long-term cobalt treatment causing bilateral optic atrophy (Licht et al 1972; Meecham and Humphrey 1991).
References And Further Reading
Camarasa JG, Alomar A. Photosensitization to cobalt in a bricklayer. Contact Dermatitis 7: 154, 1981.
Fraunfelder FW, Rosenbaum JT. Drug-induced uveitis: incidence, prevention, and treatment. Drug Safety 17(3): 197–207, 1997.
gilman AG, Goodman LS, Gilman A. (eds). The Pharmacological Basis of Therapeutics, 6th edn. Macmillan, New York, p 1326–1327, 1980.
Hjorth N. Contact dermatitis in children. Acta Derm Venereal 95(Suppl): 36, 1981.
Licht A, Oliver M, Rachmilewitz EA. Optic atrophy following treatment with cobalt chloride in a patient with pancytopenia and hypercellular marrow. Isr J Med Sci 8: 61–66, 1972.
Meecham HM, Humphrey P. Industrial exposure to cobalt causing optic atrophy and nerve deafness: a case report. J Neurol Neruosurg Psychiat 54: 374–375, 1991.
Rorsman H, et al. Tattoo granuloma and uveitis. Lancet 2: 27–28, 1969. Smith JD, Odom RB, Maibach HI. Contact urticaria from cobalt chloride.
Arch Dermatol 111: 1610, 1975.
Walsh FB, Hoyt WF. Clinical Neuro-Ophthalmology, Vol. III, 3rd edn, Williams & Wilkins, Baltimore, pp 2686–2687, 1969.
Generic name: Epoetin (erythropoietin).
Proprietary names: Epogen, Procrit.
Primary use
Recombinant human epoetin is used in the treatment of anemia in chronic renal failure in dialysis patients.
Ocular side effects
Systemic administration
Probable
1. Decreased vision
2. Iritis-like reaction
3. Retina
a.Induces retinal angiogenesis
b.Enhances retinopathy of prematurity 4. Conjunctiva – hyperemia
Possible
1. Visual hallucinations
Conditional/Unclassified
1. Recurrent post-operative lens capsule opacity
Clinical significance
Low birth weight premature infants are at higher risk for retinitis of prematurity and may undergo treatment with epoetin to prevent anemia of prematurity. Manzoni et al (2005) have reported this drug as an additional independent predictor of severe threshold retinopathy of prematurity, requiring urgent ablative surgery. This occurred in 31% of infants on this drug compared to 19.6% of those not receiving this agent. Kelley (2002) reported proliferation of lens capsular debris that may be due to epoetin. Beiran et al (1996) described 13 patients with an iritis-like reaction associated with the use of epoetin. They feel this may be related to epoetin’s ability to alter prostaglandin levels, which may break the tight junctions of the iris and ciliary epithelium. Watanabe et al (2005) reported epoetin as a factor in inducing retinal angiogenesis in proliferative diabetic retinopathy. Patients on hemodialysis receiving epoetin may develop visual hallucinations.
References And Further Reading
Beiran I, Krasnitz I, Mezer E, et al. Erythropoietin induced iritis-like reaction. Eur J Ophthalmol 6(1): 14–16, 1996.
Kelley JS. Recurrent capsular opacity and erythropoietin. American Ophthalmological Society Meeting, 2002.
Manzoni P, Maestri A, Gomirato G. Erythropoietin as a retinal angiogenic factor. N Engl J Med 353: 782–792, 2005.
Stead R. Erythropoietin and visual hallucinations (reply). N Engl J Med 325(July 25): 285, 1991.
Steinberg H. Erythropoietin and visual hallucinations (letter). N Engl J Med 325: 285, 1991.
Steinberg H, Saravay SM, Wadhwa N, et al. Erythropoietin and visual hallucinations in patients on dialysis. Psychosomatics 37(6): 556–563, 1996.
Watanabe D, Suzuma K, Matsui S, et al. Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N Engl J Med 353: 782–792, 2005.
Generic names: 1. Ferrous fumarate; 2. ferrous gluconate; 3. ferrous sulfate; 4. iron dextran; 5. iron sucrose; 6. polysaccharideiron complex.
coagulability and formation blood affecting Agents • 8 Section
181