Clinical significance

agents Gastrointestinal • 5 Section

Local ophthalmic use or exposure

Probable 

1. Eyelids or conjunctiva – contact dermatitis

Clinical significance

Class: Antiemetics

Generic name: Metoclopramide.

Proprietary name: Reglan.

Primary use

This orthopramide is used as adjunctive therapy in roentgen-ray examination of the stomach and duodenum, for the prevention and treatment of irradiation sickness, and as an antiemetic.

Ocular side effects

Systemic administration

Certain

1. Extraocular muscles a. Oculogyric crises b. Diplopia

c. Paralysis d. Nystagmus e. Strabismus

2. Eyelids or conjunctiva

a.Edema

b.Angioneurotic edema

c.Urticaria

Probable

1. Decreased vision

2. Problems with color vision-color vision defect

Possible

1. Mydriasis – may precipitate narrow-angle glaucoma

2. Photophobia

Clinical significance

Ocular side effects secondary to metoclopramide are rare, but the drug can produce acute dystonic reactions, particularly in children.

140 This includes transitory oculogyric crises, inability to close the

eyes, nystagmus, and various extraocular muscle abnormalities. These dystonic reactions usually occur within 36 hours of starting treatment and subside within 24 hours of stopping the drug.

References And Further Reading

Berkman N, Frossard C, Moury F. Oculogyric crises and metoclopramide. Bull Soc Ophthalmol Fr 81: 153, 1981.

Bui NB, Marit G, Noerni B. High-dose metoclopramide in cancer chemotherapyinduced nausea and vomiting. Cancer Treat Rep 66: 2107, 1982.

Hyser CL, Drake ME, Jr. Myoclonus induced by metoclopramide therapy. Arch Intern Med 143: 2201, 1983.

Kofoed P-E, Kamper J. Extrapyramidal reactions caused by antiemetics ­during cancer chemotherapy. J Pediatr 105: 852, 1984.

Laroche J, Laroche C. Etude de l’action d’un 4e groupe de medicaments sur la discrimination des couleurs et recapitulation des resultats acquis. Ann Pharm Fr 38: 323, 1980.

Terrin BN, McWilliams NB, Maurer HM. Side effects of metoclopramide as an antiemetic in childhood cancer chemotherapy. J Pediatr 104: 138, 1984.

Class: Antilipidemic Agents

Generic names: 1. Atorvastatin calcium; 2. fluvastatin sodium; 3. lovastatin; 4. pravastatin sodium; 5. rosuvastatin calcium; 6. simvastatin.

Proprietary names: 1. Lipitor; 2. Lescol; 3. Altoprev, Mevacor;­ 4. Pracachol; 5. Crestor; 6. Zocor.

Primary use

These inhibitors of 3-hydroxy-3-methylglutaryl-coenxyme A (HMG-CoA) reductase are used to treat patients with hypercholesterolemia­ by lowering total cholesterol and LDL cholesterol, and increasing HDL cholesterol. Fluvastatin and lovastatin are also indicated for preventing coronary atherosclerosis­ .

Ocular side effects

Systemic administration

Probable 

1. Decreased rate of choroidal neovascularization

2. Type II diabetes retinopathy

a.Reduces severity of hard exudates

b.Reduces subfoveal lipid migration

c.Reduces clinically significant macula edema 3. Retina

a.Increases blood velocity and blood flow in arteries and veins

b.Increases plasma in veins 4. Intraocular pressure

a.Decreases

b.Reduced risk of open-angle glaucoma 5. Diplopia

Possible 

1.Myasthenia gravis

a.Diplopia

b.Ptosis

c.Paresis of extraocular muscles

2.Blurred vision

3.Eyelids or conjunctiva

a.Steven-Johnson syndrome

b.Toxic epidermal necrolysis

c.Erythema multiforme

d.Xanthelasma decreases

4. External ophthalmoplegia (reversible)

5. Ptosis

Conditional/Unclassified

1.Lens opacities

a.Improves

b.Worsens

c.Increase risk if taken with erythromycin

2.Keratitis sicca

3.Macular degeneration

a.Impedes

b.Increase

Clinical significance

This group of medications, commonly called the statins, is one of the largest groups of prescription drugs in the world. While there are millions of patients on long-term therapy with these agents and multiple peer review articles on their effects on the eye, little concrete data are available. There are no CERTAIN visual side effects, although some patients may complain of a decrease in vision from an unknown cause. This is not statistically significant compared to a placebo in phase III trials (Physicians’ Desk Reference 2006). The side effects more likely, although still only POSSIBLE, are ptosis, diplopia and muscle paralysis. Fraunfelder and Fraunfelder (1999) described 71 cases of possible diplopia associated with the use of HMG-CoA reductase inhibitors, with 31 having positive dechallenge tests and two positive rechallenge. The National Registry has 60 additional cases of diplopia and eight of ptosis. Ertas et al (2006) described a case of unilateral ptosis possibly due to atorvastatin. The above may be related to the statins effect on muscle tissue by yet another mechanism. Purvin et al (2006) and Cartwright et al (2004) showed that statins can also exacerbate myasthenia gravis. Cases in the National Registry describe the statins associated with reversible external ophthalmoloplegia with a mechanism unknown.

There are numerous peer review papers on both sides on whether or not these drugs are cataractogenic. It has been suggested that they are possibly weakly cataractogenic, but Cumming and Mitchell (1998), along with others, have shown no clear association of a cataractogenic effect. Klein et al have reported that these drugs decrease the incidence of nucular sclerosis of aging. Another debate is if these drugs impede the development of age-related maculopathy. Several authors feel there is a plausible explanation to support a potential role of anticholesterol drugs, especially the statins, to protect against age-related maculopathy. A recent study by McGwin et al feels statins may increase the risk of age-related maculopathy. Wilson et al (2004) have shown a decreased rate of chorodial neovascularization in agerelated maculopathy when patients are on statins. Klein and Klein pooled these findings in a perspective editorial. Nagaoka et al (2006) have shown an increase in blood velocity and blood flow in retinal arteries and veins, an increase in plasma nitrites/­ nitrates, and a decrease in intraocular pressure probably due to an increase in nitric oxide. Gupta et al (2004) have reported in patients on atorvastatin with type II diabetes and dyslipidema that statins reduced the severity of hard exudates and subfoveal lipid migration in clinically significant macular edema. McGwin et al suggest that long-term use of statins may be associated with a reduced risk of open-angle glaucoma, especially in patients with cardiovascular disease and lipid disease. The questions of the effect of statins on cataracts, age-related maculopathy, type II diabetes retinopathy, and glaucoma need additional confirmation to determine causation.

References And Further Reading

Cartwright MS, Jeffery DR, Nuss GR, et al. Statin-associated exacerbation of myasthenia gravis. Neurology 63: 2188, 2004.

Cumming RG, Mitchell P. Medications and cataract: The blue mountains eye study. Ophthalmology 105: 1751–1758, 1998.

Ertas FS, Ertas NM, Gulec S, et al. Unrecognized side effect of statin treatment: Unilateral blepharoptosis. Ophthal Plast Reconstr Surg 22: 222–224, 2006.

Fraunfelder FW, Fraunfelder FT, Edwards R. Diplopia and HMG-CoA ­reductase inhibitors. J Toxicol Cut Ocular Toxicol 18: 319–321, 1999.

Gupta A, Gupta V, Thapar S, et al. Lipid-lowering drug atorvastatin as an adjunct in the management of diabetic macular edema. Am J Ophthalmol 137: 675–682, 2004.

Hall NF, Gale CR, Syddall H, et al. Risk of macular degeneration in users of statins: Cross sectional study. BMJ 323: 375–376, 2001.

Klein R, Klein BEK. Do statins prevent age-related macular degeneration? Am J Ophthalmol 137: 747–749, 2004.

Klein R, Klein BEK, Tomany SC, et al. Relation of statin use to the 5-year incidence and progression of age-related maculopathy. Arch Ophthalmol 121: 1151–1155, 2003.

Klein BEK, Klein R, Lee KE, et al. Statin use and incident nuclear cataract. JAMA 295: 2752–2758, 2006.

McCarty CA, Mukesh BN, Guymer RH, et al. Cholesterol-lowering medication reduces the risk of age-related maculopathy progression. Let Med J Aust 175: 340, 2001.

McGwin G, Jr, Owsley C, Curcio CA, et al. The association between statin use and age related maculopathy. Br J Ophthalmol 87: 1121–1125, 2003.

McGwin G, Jr, McNeal S, Owsley C, et al. Statins and other cholesterollowering medication and the presence of glaucoma. Arch Ophthalmol 122: 822–826, 2004.

McGwin G, Jr, Modjarrad K, Hall TA, et al. 3-Hydroxy-3-methylglutaryl coen­ zyme a reductase inhibitors and the presence of age-related macular degeneration in the cardiovascular health study. Arch Ophthalmol 124: 33–37, 2006.

Nagaoka T, Takahashi A, Sato E, et al. Effect of systemic administration of simvastatin on retinal circulation. Arch Ophthalmol 124: 665–670, 2006.

Physicians’ Desk Reference, 60th edn, Thomson PDR, Montevale NJ, pp 943–948, 2006.

Purvin V, Kawasaki A, Smith KH, et al. Statin-associated myasthenia gravis: Report of 4 cases and review of the literature. Medicine 85: 82–85, 2006. van Leeuwen R, Vingerling JR, Hofman A, et al. Cholesterol lowering drugs

and risk of age related maculopathy: Prospective cohort study with cumulative exposure measurement. BMJ 363: 255–256, 2003.

Wilson HL, Schwartz DM, Bhatt HRF, et al. Statin and aspirin therapy are associated with decreased rates of choroidal neovascularization amoung patients with age-related macular degeneration. Am J Ophthalmol 137: 615–624, 2004.

Generic name: Clofibrate.

Proprietary names: Generic only.

Ocular side effects

Systemic administration

Certain 

1. Decreased vision

2. Eyelids or conjunctiva

a.Erythema

b.Conjunctivitis – non-specific

c.Edema

d.Urticaria

e.Purpura

f.Blepharoclonus

g.Loss of eyelashes or eyebrows

h.Pruritis

Possible 

1.Subconjunctival or retinal hemorrhages secondary to drug-induced anemia

agents Gastrointestinal • 5 Section

effects side ocular induced-Drug • 7 Part

2. Hypermetropia

3. Decreased intraocular pressure

4. Myokymia

5. Eyelids or conjunctiva

a.Lupoid syndrome

b.Erythema multiforme

Clinical significance

Ocular side effects due to clofibrate are quite rare and seldom of major clinical significance. All reactions seem to clear on cessation of the drug. There are two reports that suggest this agent, by decreasing blood viscosity, has made glaucoma more easily managed. However, this has not been proven. Regression of xanthomas and diabetic retinopathy has been claimed as well. The drug can make hair more brittle, and alopecia may occur. One case in the National Registry documents a +2.50 refractive change, lasting for 6 weeks after cessation of the drug. Clements et al (1968) did a clinical study using this drug to treat retinal vein occlusions, but the drug was unsuccessful. Teravainen and ­Makitie (1976) described myokymia as a side effect of clofibrate.

References And Further Reading

Arif MA, Vahrman J. Skin eruption due to clofibrate. Lancet 2: 1202, 1975. Clements DB, Elsby JM, Smith WD. Retinal vein occlusion. A comparative study of factors affecting the prognosis, including a therapeutic trial of

Atromid S in this condition. Br J Ophthalmol 52: 111, 1968. Cullen JF. Clofibrate in glaucoma. Lancet 2: 892, 1967.

Orban T. Clofibrate in glaucoma. Lancet 1: 47, 1968.

Teravainen H, Makitie J. Myokymia, unusual side-effect of clofibrate. Lancet 2: 1298, 1976.

Class: Antispasmodics

Generic names: 1. Atropine; 2. homatropine.

Proprietary names: 1. Atropen, Atropine sulfate ansyr plastic syringe; 2. topical ocular multi-ingredient preparations only.

Primary use

Systemic

These anticholinergic agents are used in the management of gastrointestinal tract spasticity, peptic ulcers, hyperactive carotid sinus reflex, Parkinson’s disease, in the treatment of dysmenorrhea and to decrease secretions of the respiratory tract.

Ophthalmic

These topical anticholinergic mydriatic and cycloplegic agents are used in refractions, semiocclusive therapy, accommodative spasms and uveitis.

Ocular side effects

Systemic administration

Certain

1. Decreased vision

2. Mydriasis – may precipitate angle-closure glaucoma 3. Decrease or paralysis of accommodation

4. Photophobia

5. Micropsia

6. Decreased lacrimation

7. Visual hallucinations

8. Problems with color vision

a.Color vision defect

b.Objects have red tinge

Local ophthalmic use or exposure – topical ocular application­

Certain

1. Decreased vision

2. Decrease or paralysis of accommodation

3. Irritation

a.Hyperemia

b.Photophobia

c.Ocular pain

d.Edema

4. Mydriasis

a.May precipitate angle-closure glaucoma

b.May elevate intraocular pressure

5. Eyelids or conjunctiva

a.Allergic reactions

b.Blepharoconjunctivitis – follicular and/or papillary 6. Micropsia

7. Decreased lacrimation

8. Visual hallucinations

Local ophthalmic use or exposure – subconjunctival injection

Probable

1. Brawny scleritis

2. Conjunctival and/or necrosis (Fig. 7.5b)

Systemic side effects

Local ophthalmic use or exposure – topical application

Certain

 1. Agitation

 2. Confusion

 3. Psychosis

 4. Delirium

 5. Hallucinations

 6. Ataxia

 7. Hostility

 8. Fever

 9. Dry mouth

10.Vasodilation

11.Dysarthria

12.Tachycardia

13.Convulsion

14.Cardiac dysrhythmias

Clinical significance

Atropine and homatropine have essentially the same ocular side effects whether they are administered systemically, via aerosols, or by topical ocular application. Systemic administration causes fewer and less severe ocular side effects because significantly smaller amounts of the drug reach the eye. Mydriasis is of greatest ocular concern from systemic anticholinergics. Data in the National Registry support the fact that acute glaucoma occurs much more commonly unilaterally and only very rarely is it precipitated bilaterally.

Topical ocular atropine and homatropine have the same ocular effects. The action of homatropine’s cycloplegic and mydriatic actions are more rapid and of shorter duration than those of ­atropine. Irritation or allergic reactions of the eyelids or conjunctiva are the most frequent occurrences, followed by increased light sensitivity. Conjunctival papillary hypertrophy usually suggests