Cholinergic agents all lower intraocular pressure (IOP) by improving aqueous outflow. These medications differ, however, by the manner in which they stimulate ciliary muscle contraction. The most commonly used cholinergic agent is pilocarpine, which directly stimulates the cholinergic receptor. Cholinesterase inhibitors, such as echothiophate and physostigmine, work indirectly by inhibiting the enzyme acetylcholinesterase and thus prolonging the duration of action of endogenous acetylcholine. Carbachol has both a direct and an indirect effect. The most notable side effects of miotics (myopia, brow ache, and miosis) limit the widespread use of these agents for treating chronic glaucoma. However, they remain effective pressure-lowering agents and still can play an important role in managing specific glaucoma situations.

BACKGROUND

The cholinergic agents are our oldest glaucoma medications. In 1876, Laquer introduced the cholinesterase inhibitor, physostigmine, which was isolated from the calobar bean, the seed of the plant Physostigma venenosum.1 One year later, Weber first treated glaucoma with pilocarpine, a derivative from the leaf of the South American shrub Pilocarpus microphyllus.2 These two medications were the only successful glaucoma agents available until the turn of the 20th cen- tury.3–5 Although we now have many effective glaucoma medications, cholinergic agonists have a proven track record and are still helpful in selected glaucoma patients.

MECHANISM OF ACTION

PHARMACOLOGY

The term cholinergic agents refers to medications that mimic the effect of acetylcholine. Acetylcholine is a neurotransmitter at postganglionic parasympathetic junctions, some

postganglionic sympathetic endings, autonomic ganglia, somatic nerve endings, and in the central nervous system. It is synthesized by the enzyme choline acetyltransferase and activates the cell by binding to cholinergic receptors.

Acetylcholinesterase, strategically present in the endplate region, rapidly hydrolyzes acetylcholine to limit its duration of action. The cholinergic drugs act either directly, by mimicking acetylcholine at the neuromuscular junctions (direct-acting cholinergic agonists), or indirectly, by inhibiting cholinesterase, thereby retarding acetylcholine degradation and potentiating its effect (cholinesterase inhibitors).

Cholinergic receptors are either muscarinic or nicotinic. Muscarinic receptors reside in the smooth muscle (e.g., ciliary body) and glands, and are stimulated by muscarine and inhibited by atropine. Nicotinic receptors exist in skeletal muscle and autonomic ganglia, and are antagonized by decamethonium and hexamethonium, respectively.

The effect of a cholinergic medication depends, in part, on its selectivity to preferentially interact with one receptor over another. The effect of a medication also depends on the location of its receptor. In the eye, the parasympathetic nervous system innervates the ciliary body and iris sphincter. Thus, while a cholinergic agent contracts the longitudinal muscle of the ciliary body and increases aqueous outflow, it will also stimulate the circular muscle of the ciliary body and the iris sphincter, producing accommodation and pupillary constriction.

Outside the eye, the parasympathetic nervous system controls many important functions of the body. In contrast to the adrenergic nervous system, which regulates the fight or flight response of the body and prepares the body for strenuous muscular activity; the parasympathetic nervous system modulates certain actions of the cardiovascular and digestive system and is principally involved in accumulation, storage, and preservation of body resources (Table 34–1).

MECHANISM OF INTRAOCULAR

PRESSURE REDUCTION

Cholinergic medications lower IOP by increasing aqueous humor outflow, a result of muscarinic receptor-mediated contraction of the ciliary muscle. Ciliary muscle activation can have two opposing effects on aqueous outflow. First, because the anterior portion of the ciliary muscle inserts into the scleral spur, trabecular meshwork, and Schlemm’s canal, contraction widens the spaces within the trabecular meshwork and Schlemm’s canal. This decreases resistance and facilitates aqueous outflow via

the conventional route (Fig. 34–1A,B). However, aqueous humor also leaves the eye via uveoscleral outflow, following a pressure gradient between the ciliary muscle bundles and into the suprachoroidal space. Contraction of the muscle diminishes the space between muscle bundles and obstructs this pathway.6 Although initial work showed that the uveoscleral route accounts for only 10 to 20% of normal outflow in humans,7 more recent studies demonstrate that it accounts for as much as 50% of total outflow, particularly in younger individuals (Chapter 4). In spite of this, miotics still produce a net reduction in IOP,8 suggesting that the positive effect of ciliary muscle

contraction on conventional outflow is significantly greater than the negative effect on uveoscleral outflow.

These mechanisms have been well documented. Severing the anterior tendon of the ciliary muscle from the scleral spur in cynomolgus monkeys abolishes the effect of pilocarpine on outflow.9 Cholinergic drugs do not directly affect the trabecular meshwork, nor do they significantly alter aqueous production.10 Pilocarpine primarily reaches the ciliary body through the cornea,11 where the drug is largely metabolized, allowing only a small percentage to enter the eye.12

SIDE EFFECTS

OCULAR

Ocular side effects related to contraction of the iris and ciliary body are common with cholinergic agents and frequently lead to discontinuation of the medication (Table 34–2). Miosis can degrade vision, particularly in elderly patients with cataracts. In patients with a posterior subcapsular cataract, the miosis exaggerates the effect of a central media opacity, whereas patients with nuclear cataracts may become more symptomatic in conditions of low illumination.

Ciliary muscle contraction, particularly in young patients, can produce a severe headache and accommodative myopia. The headaches, a result of the muscle spasm, are worse at the onset of therapy and can be less troublesome if the physician warns the patient of this potential and begins therapy at a low concentration and frequency (e.g., pilocarpine 0.5% at bedtime). The induced

TABLE 34–2 SIDE EFFECTS OF TOPICAL CHOLINERGIC

MEDICATIONS

Ocular

Miosis

Accommodative spasm, headache Induced myopia

Increased permeability of the blood–aqueous barrier Retinal detachment

Pupillary border cysts* Anterior subcapsular cataracts*

Systemic

Depression of serum cholinesterase activity**

Nausea

Diarrhea

Sweating

Salivation

Bronchoconstriction

Decreased blood pressure

*More likely with indirect-acting agents. **Specific to indirect-acting agents.

CHAPTER 34 CHOLINERGIC AGENTS • 385

myopia, which can exceed 5 diopters, results from axial thickening and forward displacement of the lens. This effect begins 15 minutes after instillation of 2% pilocarpine, peaks at 45 minutes, and lasts for 1 to 2 hours, making it difficult to provide stable vision for a young patient using a single spectacle correction.13 To date, efforts have failed to dissociate the accommodative and miotic response of cholinergic agents from their beneficial effect on outflow facility.

PEARL... To improve acceptance and compliance, the physician should warn the patient of expected side effects prior to starting cholinergic medications. Acetaminophen, 30 minutes before instilling pilocarpine, may help palliate the ciliary spasm discomfort.

Cholinergic agents can also increase the permeability of the blood–aqueous barrier14 and aggravate ocular inflammation. This effect is dose related and is more likely with the indirect-acting agents.15 Chronic inflammation from long-term miotic use encourages posterior synechiae and can produce an adherent and miotic pupil, both of which can complicate cataract surgery. Because these agents can also increase postoperative inflammation, patients should discontinue an indirect-acting agent, or at least switch to a weaker miotic, 2 weeks prior to intraocular surgery. Cholinergic agents are also relatively contraindicated in the treatment of glaucoma associated with uveitis.

Miotics have also been implicated in causing rhegmatogenous retinal detachments, possibly by vitreoretinal traction due to ciliary body contraction. Although the evidence for this is indirect,16–18 the peripheral retina should be examined prior to beginning miotics, and higherstrength, direct-acting agents should be used cautiously in patients with high myopia and lattice degeneration, while avoiding indirect agents altogether.

Miotic cysts most commonly result from indirectacting cholinergic medications, although they can also follow long-term use of pilocarpine (Fig. 34–2A,B). These cysts result from the proliferation of iris pigment epithelium near the pupillary margin and generally decrease in size after discontinuation of therapy.19 Phenylephrine may decrease the incidence and size of these cysts.

In general, the frequency and severity of ocular and systemic side effects from indirect-acting cholinergics exceed that of the direct agents. For example, although pilocarpine has been suggested to produce cataracts,20 the evidence for this effect is more conclusive with the anti- cholinesterases.21–23 Typically, anticholinesterase cataracts begin with anterior subcapsular vacuoles.22 The prevalence of cataract formation increases with longer treatment duration, higher drug concentration, greater application frequency, and in older patients, particularly those with preexisting cataractous changes.

SYSTEMIC SIDE EFFECTS

Frequently instilled direct-acting cholinergics, and the stronger, indirect-acting compounds, can produce systemic side effects of parasympathetic overstimulation (Table 34–2). Most of these correspond to the known distribution and actions of cholinergic receptors (Table 34–1). Nausea, diarrhea, sweating, salivation, bronchoconstriction, and a fall in blood pressure have all been reported with physostigmine.

The indirect-acting agents can also depress serum cholinesterase, or pseudocholinesterase, in addition to acetylcholinesterase, which can occur in almost all patients using as little as 0.06% echothiophate. This presents an important, adverse drug interaction when succinyl choline, which is hydrolyzed by pseudocholinesterase, is used during induction of general anesthesia. Because this inhibition can also prolong the action of succinylcholine and can produce sustained apnea, patients using these drugs should be warned of this potentially life-threatening side effect and switched to a direct-acting cholinergic drug at least 2 weeks prior to any anticipated surgery and general anesthesia.

PITFALL... Patients using cholinesterase inhibitors are at risk for prolonged apnea following use of succinylcholine and should switch to an indirect agent prior to undergoing any elective surgery.

CURRENT FORMULATIONS

DIRECT-ACTING AGENTS

Pilocarpine

Pilocarpine is our most commonly used miotic. Today, it is rarely used as first-line therapy because other medications have either fewer ocular side effects or a more convenient dosing schedule. Its efficacy, cost, and lack of systemic effects, however, make pilocarpine attractive as a second-line agent in many patients.

Chronic use studies demonstrate that the response correlates with dosages ranging from 0.5 to 4% concentration, with an IOP reduction of approximately 20%.24–26 Higher concentrations may provide added effect in patients with dark irides.27 The maximum IOP reduction occurs within 2 hours of instillation and lasts for at least 8 hours with a 10 to 15% reduction in IOP still present at 12 to 15 hours.26 Although most patients use pilocarpine three or four times daily, twice-daily instillation of 2% pilocarpine can lower IOP to a similar degree if combined with forced eyelid closure or nasolacrimal occlusion.28 Because this may not apply to everyone, however, pressures should still be checked 8 to 12 hours after drug instillation in any patient using pilocarpine less than every 6 hours to insure adequate IOP control.

Younger patients, as well as some older patients with cataracts, tolerate pilocarpine poorly because of ciliary muscle spasm and induced myopia. Various pilocarpine delivery systems have been developed to decrease these side effects, as well as reduce the frequency of administration.

Pilocarpine Gel (Pilopine)

All cholinergic medications have the same basic effect on aqueous humor dynamics. They differ primarily in their duration of action and the severity of their side effects.

Pilocarpine gel, the equivalent of 4% pilocarpine hydrochloride in a high-viscosity acrylic gel, reduces IOP for up to 24 hours when applied at bedtime.29 Although

this produces fewer ocular side effects,30 the IOP can rise significantly after 12 hours. In addition, 25% of patients develop a superficial corneal haze that can decrease vision and may persist even after the gel is discontinued.31

Membrane-Controlled Delivery

System (Ocusert)

The Ocusert Pilo-20 and Pilo-40 are diffusion-controlled inserts using ethylene vinyl acetate polymeric membranes that release pilocarpine at either 20 g/hr (Ocusert 20) or 40 g/hr (Ocusert 40) for approximately 1 week, producing pressure-lowering effects equivalent to 1 to 2%, and 4% pilocarpine, respectively.32–35 The insert is placed in the superior cul-de-sac and can be effective for 7 days, although individual patients may respond for less than 1 week.30,36 Because the controlled delivery minimizes the total amount of drug needed to lower IOP, this preparation limits ocular side effects. However, some patients find the membrane uncomfortable and difficult to keep in place. In addition, the Ocusert can periodically release increased amounts of drug and produce intense symptoms, especially when it is first inserted. The Ocusert is no longer commercially available.

Aceclidine

Aceclidine is a synthetic cholinergic drug that acts directly on muscarinic receptors in a manner similar to pilocarpine. The IOP lowering of 4% aceclidine is comparable to 2% pilocarpine, but produces less accommodative spasm.15,37 This drug is currently unavailable in the United States.

Carbachol

Carbachol is a synthetic combination of portions of the molecules of acetylcholine and physostigmine and is considered a combination directand indirect-acting cholinergic agent. Although it principally stimulates muscarinic receptors, it also inhibits acetylcholinesterase. Because carbachol is not lipid soluble at any pH, it penetrates the intact corneal epithelium poorly and must be formulated with an adjuvant, such as benzalkonium chloride, to help it reach effective intraocular concentrations.38

Carbachol is available in 0.75, 1.5, and 3% strengths and is usually administered three times a day. Although the 1.5% concentration three times daily lowers IOP similar to 2% pilocarpine four times daily,39 carbachol produces more brow ache and accommodative spasm, probably due to its indirect cholinergic properties.40 These same properties make carbachol an effective intraoperative agent for producing miosis and guarding against postoperative IOP elevation; its intracameral formulation (Miostat) provides better protection against postcataract surgery IOP rise than either acetylcholine (Miochol) or topical levobunolol.41,42

CHAPTER 34 CHOLINERGIC AGENTS • 387

INDIRECT-ACTING AGENTS

Echothiophate Iodide

Echothiophate iodide (Phospholine iodide) is a potent inhibitor of both true cholinesterase and pseudocholinesterase. This agent, available in concentrations of 0.03 to 0.25% and administered every 12 to 48 hours, has a peak IOP effect of 4 to 6 hours and can act for at least 24 hours.43 Due to limited stability, the solution should be refrigerated. Echothiophate, however, has a much longer duration of action than pilocarpine; the 0.06% solution lowers IOP comparable to 2% pilocarpine.44 Although 0.06% echothiophate is at the top of the dose response curve for most patients, 0.125% may further lower IOP in patients with dark irides.

Unfortunately, the significant side effects of this drug offset its advantages of efficacy and duration of action. Because echothiophate, like other indirect-acting cholinergic agents, can induce dose-related, anterior subcapsular cataracts,45 it is used primarily in aphakic and pseudophakic individuals. In addition, the indirectacting agents are more likely than pilocarpine to disrupt the blood–aqueous barrier, which can cause increased inflammation after intraocular surgery, as well as aggravate uveitis. Therefore, most practitioners will switch a patient from echothiophate to pilocarpine several weeks prior to intraocular surgery and avoid its use in patients with uveitis.

Systemic toxicity is more common with the anticholinesterases. Echothiophate iodide depletes both true cholinesterase (acetylcholinesterase) and serum cholinesterase (pseudocholinesterase). Pseudocholinesterase hydrolyzes succinnylcholine, and prolonged respiratory paralysis can occur after general anesthesia if succynylcholine is used on a patient with a depleted supply of pseudocholinesterase. Parasympathomimetic toxicity can also occur with these agents, producing diarrhea, nausea, and bronchospasm.

Physostigmine

Physostigmine (Eserine) is a short-acting inhibitor of cholinesterase. It is administered as a 0.5% ointment twice daily and has a longer duration of action than pilocarpine. The pressure reduction begins within 10 to 30 minutes of instillation, with maximal effect in 1 to 2 hours.46 Aqueous solutions of physostigmine are unstable. Ocular allergy and irritation limit its longterm use.

Demecarium

Demecarium bromide (Humorsol) is a long-acting cholinesterase inhibitor similar to echothiophate in efficacy and side effects. It is administered in a solution of 0.12 to 0.25% every 12 to 48 hours. After a single dose of

388 • SECTION V MEDICAL THERAPY OF GLAUCOMA

demecarium, reduction of IOP occurs in half an hour, is maximal at 24 hours, and can persist for several days.47 It is water soluble and stable at room temperature but is no longer available in the United States.

CURRENT USE OF

CHOLINERGIC AGENTS

Newer, better-tolerated agents have supplanted miotics for the treatment of chronic glaucoma. However, these remain effective pressure-lowering agents and they are still useful in specific clinical situations.

ADJUNCTIVE THERAPY

Many glaucoma patients require more than one glaucoma medication to control their IOP. In these patients, the cholinergic agents can be effective as adjunctive therapy. The cholinergic agents are particularly useful as adjuncts in pseudophakic or aphakic patients because these patients tend to have fewer ocular side effects from either miosis or induced myopia.

PEARL... Cholinergic agents are usually better tolerated by pseudophakic or aphakic patients, who are less likely to be affected by miosis and ciliary muscle spasm.

The effect of the cholinergic agents on IOP is generally additive to the other glaucoma medications. Of the possible adjunctive uses for the cholinergic drugs, the beta-blockers provide one rational combination. Because the beta-blockers lower IOP by decreasing aqueous production, it is not surprising that the action of the cholinergic agents to increase outflow would be synergistic. The addition of pilocarpine 2% to timolol results in an additional 10% decrease in IOP in patients with ocular hypertension, whereas the addition of pilocarpine 4% decreases IOP an additional 15 to 20% in a similar group of patients.48 The cholinergic medications can also be useful in combination with the carbonic anhydrase inhibitors, the alpha2 agonists, and epinephrine.49–51

Because prostaglandins lower IOP by increasing uveoscleral outflow, and the cholinergic medications decrease uveoscleral outflow, one would expect that these drugs would counteract each other when used in combination. Although the additivity of physostigmine to latanoprost is less than predicted by the full effect of the individual drugs, using the two agents together can produce some additional IOP lowering in certain cases (Chapter 35).52

ACUTE ANGLE-CLOSURE GLAUCOMA

Topical pilocarpine can effectively treat acute angle-closure glaucoma (Chapter 16). Several drops of 1 to 2% pilocarpine can cause miosis, help break pupillary block, and facilitate laser iridotomy. However, in some patients, elevated IOP can render the iris sphincter ischemic and unable to respond to the pilocarpine. After the first 30 minutes of the attack, using pilocarpine more than every 2 to 3 hours provides no additional benefits and can result in systemic toxicity. Stronger miotics are contraindicated because they can displace the lens–iris diaphragm forward and aggravate the angle closure. Although prophylactic miotics have been advocated in the contralateral eye, acute angle closure can still occur despite this treatment.53 Therefore, prompt iridotomy constitutes the preferred treatment for both the affected eye and the contralateral eye.

LASER IRIDOTOMY

Pilocarpine 1 to 2 % can be administered 20 minutes prior to laser iridotomy with the 2% concentration reserved for dark irides. The miotic pupil and thinner iris facilitates the laser procedure. Patients should be warned of the probable ciliary spasm and can be pretreated for this with acetaminophen to minimize discomfort.

PLATEAU IRIS SYNDROME

In certain phakic patients, the iris and cornea remain apposed despite a patent iridotomy. In these patients with plateau configuration, pilocarpine can open the angle, prevent the formation of peripheral anterior synechiae, and lower IOP.

PIGMENTARY GLAUCOMA

The miosis induced by pilocarpine can increase relative pupillary block, thus changing the iris contour from concave to flat or convex. This minimizes contact of the iris with lens zonules and thus can prevent iris pigment release (Chapter 19). Unfortunately, most patients with pigment dispersion are young and tolerate the accommodative spasm poorly. An alternative is the Ocusert, which gradually releases the medication and can improve tolerance. A more serious concern is the risk of retinal detachment from the use of miotics because patients with pigment dispersion are usually myopic and already at increased risk for this complication.54 A careful peripheral retinal exam is recommended prior to initiating therapy.

INITIATING THERAPY

To improve patient acceptance, therapy with cholinergic agonists medications should be started at a low concentration and frequency, such as pilocarpine 0.5% at bedtime.

The physician should instruct the patient on eyelid closure following instillation, which can increase the duration of action of the medication and allow twice daily dosing in many patients. The patient should also be warned of expected side effects prior to initiating therapy. For the first week, acetominophen taken 30 minutes before each pilocarpine dose can diminish the headache and improve acceptance and compliance. The IOP should also be checked immediately prior to a scheduled dose to help assure adequate IOP control throughout the dosing interval. Patients receiving long-term cholinergic agents should undergo repeat gonioscopy to detect insidious, progressive angle narrowing due to forward movement of the lens–iris diaphragm and pupillary block.

PITFALL... After initiating therapy with a cholinergic medication, gonioscopy should be repeated to detect cholinergic-induced angle narrowing.

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