Nonselective Agonists

Some brands of the nonselective agonists epinephrine and dipivefrin are listed in table 4.2.

4.3.1 Epinephrine. Epinephrine, a mixed alpha- and beta-adrenergic agonist, was the first topical adrenergic agent used to lower IOP in patients with open-angle glaucoma. Topical administration of epinephrine causes alpha-1-adrenoreceptor-induced conjunctival vasoconstriction, which manifests as blanching, and slight mydriasis. The mydriatic effect can be used to advantage during cataract surgery, where epi-nephrine added to the intraocular irrigating solution may retard the development of intraoperative miosis and enhance visualization. Epinephrine is employed routinely in ophthalmic plastic surgery to minimize bleeding and slow absorption of local anesthetics. However, it is strictly avoided in the correction of blepharoptosis, because epinephrine (like apraclonidine, clonidine, and brimonidine) induces upper eyelid retraction by stimulation of Muller's muscle and can lead to inadequate surgical correction. Similarly, epinephrine is not used in retrobulbar anesthesia because of the risk of vasospasm and occlusion of the ophthalmic or central retinal artery, along with systemic absorption resulting in tachyarrhythmias with reported fatalities.

Table 4.2 Nonselective Alpha- and Beta-Adrenergic Agonists

Epinephrine

Glaucon, Epifrin 0.5%, 2% HCl salt Eppy N, Epinal 0.5%, 1%, 2% borate Epitrate, 2% bitartrate salt E Pilo, P1E1, P2E1, P3E1, P4E1, P6E1 Mixtures of 1% epinephrine bitartrate and pilocarpine HCl 1%, 2%, 3%, 4%, 6%

Dipivefrin Propine, 0.1%

The effect of epinephrine on IOP varies over time, initially raising IOP slightly, followed by reduction lasting 12 to 24 hours.3 Epinephrine penetrates the cornea rather poorly; thus, while concentrations less than 0.5% lower IOP slightly, concentrations of 0.5% and 1% have greater efficacy. The effect of epinephrine is additive to long-term treatment with pilocarpine and oral acetazolamide.15 Although awkward conceptually, the combination of epinephrine, a mixed alpha and beta agonist, with timolol, a nonselective beta blocker, has been common practice in the recent past. The additivity of these two agents, however, has been variable and short-lived,16 and as medical options in glaucoma have expanded, the need to combine these agents has diminished.

Epinephrine may cause tachycardia, extra systoles, systemic hypertension, palpitation, and anxiety. Topical use can be uncomfortable, causing tearing and stinging. Long-term use leads to allergic blepharoconjunctivitis in a significant subset of patients, which resolves when the drug is discontinued. Epinephrine is contraindi-cated in patients with narrow anterior chamber angles, because the induced my-driasis can precipitate pupillary block, inciting a pupillary-block glaucoma attack. Epinephrine is also contraindicated in aphakic patients, because topical use is associated with symptomatic, usually reversible, cystoid macular edema (CME) in roughly 13% to 30%.17,18 Of note, epinephrine-related CME has been described in aphakic, but not pseudophakic, patients. This may therefore be a problem seen only if the anterior hyaloid is disrupted following traumatic extracapsular cataract surgery. Finally, epinephrine can cause black adrenochrome deposits in the palpebral conjunctiva, on contact lenses, and on the cornea.

4.3.2 Dipivefrin. Dipivefrin is a derivative prodrug of epinephrine, made less hy-drophilic by the diesterification of epinephrine and pivalic acid. Dipivefrin is converted to epinephrine inside the eye by esterases in the cornea, iris, and ciliary body, which cleave the pivalic acid moiety. Dipivefrin is less potent than most beta blockers, except perhaps for betaxolol 0.25%.19

Dipivefrin penetrates the corneal epithelium much more readily than epinephrine, allowing 10- to 20-fold lower concentrations to be used20 with only slightly less efficacy.21,22 While topical side effects, stinging and irritation, are less than those experienced with epinephrine, the intraocular effects are identical, including my-driasis and aphakic CME. Therefore, like epinephrine, dipivefrin is contraindicated in patients who are aphakic or have narrow anterior chamber angles. Also, like epi-nephrine, dipivefrin can cause a severe acute allergic blepharoconjunctivitis.

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