This drug may be delivered to the eye via finger from the liquid, aerosol or spray formulation, which may confuse reactions from systemic exposure. Blurred vision, decreased accommodation and mydriasis are the most common ocular side effects seen. Anisocoria is clinically the most disturbing side effect because it is an early sign of an impending neurological emergency. A unilateral exposure to ipratropium is more often seen in the pediatric age group due to an ill-fitting face mask (Woelfle et al 2000), in an intensive-care setting (Bisquerra et al 2005) or self-administered nebulizers (Weir et al 1853). There are reports of ipratropium-induced angle-closure glaucoma (Ortiz-Rambla et al 2005; de Saint-Jean et al 2000; Lellouche et al 1999), but these are rare. This agent dries all mucous membranes, including the eye. Direct conjunctival drug contact may result in irritation and hypersensitivity reactions. Other than angle-closure glaucoma, all ocular side effects are transitory and reversible.

Generic Name:

Salbutamol (albuterol).

Proprietary Names:

Accuneb, Proventil, Proair, Ventolin, Vospire.

Primary use

This sympathomimetic amine is primarily used as a bronchodilator in the symptomatic relief of bronchospasm.

Oral salbutamol has no reported adverse ocular effects. This beta-agonist only has significant ocular side effects if delivered via a nebulizer with the drug coming into direct contact with the eye. Methods to prevent ocular contact will completely prevent all ocular effects. Salbutamol can cause mydriasis and may increase intraocular pressure in predisposed narrow angles. This drug is often given also in nebulized form with ipratropium and will induce angle-closure glaucoma by its parasympathetic inhibitory effect. In a study by Kalra et al (1988), both salbutamol and ipratropium were administered simultaneously via nebulizers without eye protection, and all patients with narrow angles had an increase in intraocular pressure. Transient angle closure occurred in 50% of them. This effect was completely prevented when protective eye goggles were worn. Contact of this drug with the eye and eyelids may occasionally cause transitory irritation and/or ocular pain. Visual hallucinations have been reported only in children.

Sami et al (2007) point out that this drug can cause chronic eyelid edema.

Ocular side effects due to these diuretics occur only occasionally and are usually transitory. It appears that most of these agents can cause transitory myopia. There are many different possible mechanisms involved in causing myopia. One is a change directly related to the crystalline lens and ciliary body, i.e. spasm of accommodation, altered sodium-chloride metabolism, ciliary body edema, inhibition of fluid by the lens or change in lenticular index of refraction. The second mechanism is related to changes in the media or sclera, i.e. changes in the refractive index of the media or stretching of the sclera (Jampolsky et al 1953). Blain et al (2000), using angiography, showed diffuse choroidal thickening during indapamide induced myopia. Some of the mechanisms proposed for inducing myopia are probably causes of inducing angle-closure glaucoma. There are well-documented cases of unilateral or bilateral ciliary body edema or effusions, which produce anterior rotation of the ciliary body at the scleral spur, allowing laxity of the lens zonule and forward displacement of the iris lens diaphragm. This increases the anterioposterior diameter of the lens, allowing for a shallowing of the anterior chamber with a resultant narrow angle. The cause of the ciliary body edema is unknown; however, Geanon et al (1995) described a case they felt was due to a hypersensitivity reaction. Krieg et al (1996) showed that prostaglandins and eicosanoids are involved. The management of this type of glaucoma is the same as with topiramate. Sponsel et al (1992) reported a posterior subcapsular cataract after indapamide therapy but made no statement as to causation. Miller et al (1979) described a case of transient oculomotor nerve palsy associated with thiazide-induced glucose intolerance. Thiazide diuretics can also cause hypercalcemia, which may result in band keratopathy.

When thiazide diuretics are used in combination with carbonic anhydrase inhibitors, one should be alert for signs of hypokalemia. These diuretics are photosensitizers and Hartzer et al (1993) showed that in tissue culture hydrochlorothiazide will interact with UV-A radiation to produce toxic synergistic effects on human RPE cells. In a case control study, de la Mamierre et al (2003) concluded that drug-induced phototoxicity (thiazide diuretics in long-term treatment) may be involved in causing more severe neovascularization in age-related macular degeneration. Costaglioloa et al (2008) reported a case of suspected retinal phototoxicity caused by UV tanning booth in a patient on hydrochlorothiazide. Iacono et al (2011) reported macular edema secondary to hydrochlorothiazide treatment.

Generic Name:

Furosemide.

Proprietary Name:

Lasix.

Primary use

This potent sulfonamide diuretic is effective primarily in the treatment of hypertension complicated by congestive heart failure or renal impairment.

Furosemide has potent systemic side effects and is not commonly used. Ocular side effects are rare and seldom of significance. One instance of a baby born blind after the mother took 40 mg of furosemide three times daily during her second trimester has been reported. Lee et al (2004) found little clinical or pharmacologic evidence of sulfa allergy causing life-threatening cross-reaction with furosemide.

Systemic glycerin causes decreased intraocular pressure, which is an intended ocular response, and has surprisingly few other ocular effects. However, severe vitreal dehydration with resultant shrinkage of the vitreous body may possibly cause traction on the adjacent retina, resulting in a tear. This principle has been described with cerebral dehydration as causing intracranial hemorrhages. Severe dehydration from systemic or topical ocular administration can rupture fine vessels, causing local bleeds. In addition, visual hallucinations are thought to occur, probably due to cerebral dehydration. There have been reports of expulsive hemorrhages occurring during intraocular surgery due to strong osmotic agents. The postulated mechanism is that a sudden drop in intraocular pressure may rupture sclerotic posterior ciliary arteries. Patients with renal, cardiovascular or diabetic disease are more susceptible to serious systemic side effects, particularly if they are elderly and already somewhat dehydrated. Kalin et al (1993) reported percutaneous retrogasserian glycerol injection to control intractable pain, where inadvertent orbital injection caused proptosis and vision loss. Mizuta et al (2000) reported a case of possible glycerol-induced asymmetry response to the inner ear, causing vertigo and a resultant vertical nystagmus.

Generic Name:

Mannitol.

Proprietary Names:

Osmitrol, Resectisol.

Primary use

This hyperosmotic agent is used to decrease intraocular pressure in various acute glaucomas and in preoperative intraocular procedures. It is also used in the management of oliguria and anuria.

Probably all visual side effects are secondary to dehydration. An increase in aqueous flare but not cells has been caused by mannitol, especially in the elderly. Severe vitreal dehydration with resultant shrinkage of the vitreous body may cause traction on the adjacent retina, resulting in a tear. This principle has also been described with cerebral dehydration causing intracranial hemorrhage. Expulsive hemorrhages have been reported to occur during surgery in which strong osmotic agents were used. The postulated mechanism is the sudden decrease in intraocular pressure, which may rupture sclerotic posterior ciliary arteries. Isosorbide does not adversely affect blood glucose levels and is preferred in diabetics. Hasegawa et al (2012) described a case of temporary indented corneas at surgery after 900 mL of mannitol for cardiovascular surgery under general anesthesia. Cardiovascular or renal disease may contraindicate use of isosorbide or mannitol. It has been suggested that these agents open the blood-retinal barrier and may give drugs or chemicals greater access to the retina and CNS.

James et al (2011) described a unique case in which they felt phenoxybenzamine decreased auto-regulation of vessels which predisposed to venous engorgement causing edema of the optic nerve and surrounding tissue. This, along with a prolonged prone position during surgery, may put patients on this drug at risk for developing posterior ischemic optic neuropathy.

Ocular side effects from systemic administration of ephedrine are rare. O’Brien et al (1989) described an acute macular neuroretinopathy, possibly due to ephedrine. Dark red, outer retinal wedge-shaped lesions surrounding all or part of the central macula, with normal vision but permanent paracentral scotomas developed. This may be due to a direct retinal effect of the drug or an acute hypertensive effect. Lee et al (2007) described a case of -8.0 diopter with ciliochoroidal effusion in a 28 year old on ephedrine and phendimetrazine for weight loss. There was positive dechallenge without complication.

Topical ocular ephedrine is not currently used by most ophthalmologists. The currently used concentration is rarely sufficient to cause significant side effects other than the intended response of vasoconstriction. Repeated use of topical ocular ephedrine, however, may cause rebound conjunctival hyperemia or loss of the drug’s vasoconstrictive effect. The FDA gave a warning for drugs containing ephedrine: “Pupils may become dilated. If you have narrow-angle glaucoma, do not use this product.”

Generic Names:

1. Epinephrine; 2. norepinephrine (levaterenol).

Proprietary Names:

1. Adrenaclick, Epipen, Epipen Jr., Twinject, Twinject 0.3; 2. Levophed.

Adverse events from systemic administration are heavily dose dependent or additive dependent on associated drug use. All events are rare because dosages used have been tested to be safe over time. O’Brien et al (1989) and Desai et al (1993) have reported cases of intravenous epinephrine causing acute macular neuroretinopathy. Savino et al (1990) described four patients with severe visual loss after intranasal anesthetic with epinephrine injections. The causes of the visual loss included retinal arterial occlusion and optic nerve ischemia, both of which the authors felt were due to secondary vasospasm induced by epinephrine. Patients undergoing ocular surgery with halothane anesthesia may experience tachycardia and arrhythmia from supplemental injection of local anesthetics containing epinephrine, from topical ophthalmic administration or intracameral injection of epinephrine.

Norepinephrine causes few ocular side effects from systemic exposure, and those are transitory and reversible except in overdose situations. Jandrasits et al (2002) reported that high levels of circulating norepinephrine have little impact on retinal vascular tone or retinal blood flow.

In over 20% of patients, topical ocular epinephrine must be stopped after prolonged use because of ocular discomfort and rebound conjunctival hyperemia. Over 50% of patients develop reactive hyperemia with long-term use. Concomitant use of timolol and epinephrine therapy occasionally has an additive effect on reactive hyperemia, cardiac arrhythmia or elevated blood pressure. Long-term topical ocular epinephrine preparations can cause cicatrizing conjunctivitis, which clinically or pathologically may be difficult to distinguish from ocular pemphigoid. This may include shortening of the fornices. Most epinephrine-induced macular edema is reversible, but lack of early detection may cause irreversible cystoid macular changes. Cystoid maculopathy may require more than six months to clear once the medication is discontinued. These changes occur more frequently in aphakic patients. This drug can cause conjunctival epidermalization, loss of eyelashes, blepharitis and meibomianitis. Most ocular adverse reactions due to epinephrine resolve or significantly improve with discontinuation of the drug. However, adrenochrome deposits in the cornea or conjunctiva may be exceedingly slow to absorb. Adrenochrome deposits in the lacrimal ducts may cause obstruction with epiphora. There are data to suggest that long-term topical ocular or intracameral epinephrine may cause significant corneal edema. This primarily occurs in corneas with damaged epithelium, which allows for increased penetration of this drug to reach the endothelium.

Norepinephrine is seldom given topically because epinephrine is much more effective and potent. Ocular side effects from norepinephrine are transitory and minimal. Systemic side effects are less potent then epinephrine, but norepinephrine may have a greater effect on the elevation of blood pressure.

Generic Name:

Phenylephrine.

Proprietary Names:

AH-chew D, Ak-Dilate, Children’s nostril, Children’s Sudafed PE, Mydfrin, Neo-Synephrine, Neofrin, Nostil, Ocu-Phrin, PediaCare Children’s Decongestant, Phenoptic, Prefin, Rectacaine, Relief, Rhinall, Sinex, Sudafed PE.

Ocular side effects due to topical ocular phenylephrine are usually of little significance unless the drug is used for prolonged periods of time. Phenylephrine used topically is one of the more toxic commercial drugs to the conjunctival and corneal epithelium. Soparkar et al (1997) have pointed out that even in low concentration in over-the-counter ophthalmic decongestants, acute and chronic conjunctivitis can go unrecognized. Unfortunately, signs and symptoms of these adverse effects of the drug may take 1–24 weeks to resolve. While the drug is used for pupillary dilation it may have a varied response on intraocular pressure. Initially, there may be a transitory decrease, later a transitory increase even with open angles. There may be no pressure change; or, in very rare instances, angle-closure glaucoma may be precipitated. Pupillary dilatation lasting for prolonged periods has been reported, especially in patients on guanethidine. Mydriasis varies with iris pigmentation and depth of the anterior chamber. Blue irides and shallow anterior chambers produce the greatest mydriasis, and dark irides or deep chambers produce the least. A diminished mydriatic response has been seen after repeated use of phenylephrine. A 10% concentration of phenylephrine can cause significant keratitis and a reduction in the conjunctival PO₂ , which may result in delayed wound healing by reducing aerobic metabolism of rapidly dividing cells. Blanching of the skin, particularly the lower eyelid, may occur secondary to topical ocular phenylephrine. Following ophthalmic examination with a combination of phenylephrine and cyclopentolate in neonates, an increased risk of feeding intolerance may result, which could be due to the mydriatic drugs, the physical stress applying eye medication or a combination of these factors. Pless et al (2003) described four patients with nonarteritic ischemic optic neuropathy who experienced acute worsening of visual function after instillation of phenylephrine for a dilated fundus exam. Morrison et al (2006) pointed out the effects of topical ocular phenylephrine on hydrogel keratoprosthesis, promoting hydrogel cloudiness and surface deposits. Chronic use of this drug may be one of the more common causes of contact dermatitis of the eyelids as per incidence of use. In fact, Villarreal (1998) reported that 93.5% of acute dermatitis from all eye drops was due to topical mydriatic drugs, primarily phenylephrine.

Over 100 plus articles support the finding that topical ocular phenylephrine can cause, in rare instances, severe stress on the cardiovascular system and marked elevation of blood pressure. This was first reported by Fraunfelder et al (1978), who reported 11 deaths. Numerous additional terminal cases have been reported to the National Registry. Phenylephrine 10% should be used with caution or not at all in patients with cardiac disease, significant hypertension, aneurysms and advanced arteriosclerosis. It also should be used with caution in the elderly and in patients on monoamine oxidase inhibitors, tricyclic antidepressants or atropine. Similar findings were reported in 11 patients (Fraunfelder et al 2002) to whom 10% phenylephrine was applied to the eye in pledget form.

There have been a few reports of topical ocular phenylephrine in concentrations of 10%, 5% and 2.5% causing hypertension with pulmonary edema primarily in infants, but even in young children (Baldwin et al 2002; Venkatakrishnan et al 2011).

Numerous reports in the National Registry and in the literature have associated unilateral and bilateral acute glaucoma, secondary to nasal drops containing phenylephrine (Khan et al 2002; Zenzen et al 2004). In a preterm infant, Berman et al (1994) postulate that 2.5% phenylephrine may have triggered a series of events to cause bilateral spontaneous pigment epithelial detachments. Also in infants, phenylephrine eye drops have been implicated in paralytic ileus (Lim et al 2003) and renal failure (Shinomiya et al 2003).