The cholinergic drugs are the oldest effective medical treatment for glaucoma. More than 100 years ago, Laqueur used physostigmine (eserine), an extract from the Calabar or ordeal bean, for the treatment of glaucoma, and Weber described the effects of pilocarpine, an extract from the leaf of a South American plant, on the pupil. The cholinergic drugs mimic the effects of acetylcholine, which is a transmitter at postganglionic parasympathetic junctions, some postganglionic sympathetic endings (e.g., sweat glands), autonomic ganglia, somatic motor nerve endings (i.e., skeletal muscle), and some central nervous system synapses. Acetylcholine is synthesized by the enzyme choline acetyltransferase and produces its effects by binding to cholinergic receptors in various tissues. Cholinergic drugs are applied topically for the treatment of glaucoma because of their effect on parasympathetic receptors in the iris and ciliary body. However, topical miotics absorbed systemically can produce side effects by stimulating cholinergic receptors in other sites.
Drugs that mimic the effects of acetylcholine act at muscarinic and/or nicotinic receptors, the latter being subdivided into N 1 and N 2 types. This classification system is based on the relative potency of various agonists and antagonists at the different receptor sites. As a rule, muscarinic receptors are found in smooth muscle and glands, stimulated by muscarine and inhibited by atropine. N 1 nicotinic receptors are found in autonomic ganglia, stimulated by dimethylphenylpiperazine and inhibited by hexamethonium and d -tubocurarine. N 2 receptors are found in striated muscle, stimulated by paratrimethylammonium and inhibited by decamethonium or d -tubocurarine. Nicotine stimulates N 1 and N 2 receptors at low doses and inhibits them at high doses.
Acetylcholine is released from vesicles in nerve terminals and then hydrolyzed within a few milliseconds by acetylcholinesterase. The rapid destruction of acetylcholine permits the cholinergic receptors to repolarize and prepare for the next stimulation. Cholinergic drugs act either directly by stimulating cholinergic receptors or indirectly by inhibiting the enzyme cholinesterase, thereby potentiating and prolonging the effects of endogenous acetylcholine.
Strictly speaking, the words cholinergic , parasympathomimetic , and miotic are not synonymous; cholinergic refers to acetylcholine, parasympathomimetic refers to the parasympathetic nervous system, and miotic refers to a constricted pupil. However, we will follow common ophthalmic usage in this text and use the three words interchangeably to refer to this entire class of drugs.
MECHANISMS OF ACTION
ANGLE-CLOSURE GLAUCOMA
Cholinergic drugs are useful for the short-term management of angle-closure glaucoma associated with pupillary block. Miotic agents help prepare an eye for iridotomy and are not a substitute for it in pupillary block angle-closure glaucoma. Cholinergic drugs constrict the pupillary sphincter, tighten the iris, decrease the volume of iris tissue in the angle, and pull the peripheral iris away from the trabecular meshwork. These changes reduce intraocular pressure (IOP) by allowing aqueous humor to reach the outflow channels. If the IOP is quite elevated (i.e., above 45 or 50 mmHg), the pupillary sphincter may be ischemic and may not respond to cholinergic stimulation. In this situation, other drugs (i.e., a topical α-adrenergic antagonist, topical apraclonidine or brimonidine, possibly a topical or systemic carbonic anhydrase inhibitor, and, if necessary, a systemic hyperosmotic agent) are used to reduce IOP sufficiently so that a parasympathomimetic agent can produce miosis.
While tradition and over a century of experience have confirmed the utility of pilocarpine use in acute angle-closure attacks, recent evidence suggests that our understanding of how the drug accomplishes what it does and under what circumstances is incomplete. For example, Chinese with acute angle-closure attacks in one eye show less opening of the angle after topical pilocarpine in the fellow eye. Certainly, caution is warranted when considering the use of these agents chronically in narrow-angle eyes without iridotomy.
It is important to emphasize that miotic agents are capable of narrowing the angle in some eyes, especially in eyes with shallow anterior chambers or spherophakia. Constricting the pupil increases the area of contact between the iris and the lens and may augment pupillary block and iris bombé. Furthermore, contraction of the ciliary muscle loosens the zonules, allowing the lens to move forward and become more spheric in shape. Usually the net effect of direct-acting cholinergic drugs such as pilocarpine and carbachol is to open narrow angles. Occasionally, standard miotic agents in high concentrations or cholinesterase inhibitors such as demecarium and echothiophate can produce sufficient miosis, forward movement of the lens, and vascular congestion to precipitate or aggravate angle-closure glaucoma. Cholinesterase inhibitors are difficult to reverse and are rarely indicated in unoperated cases of angle-closure glaucoma with pupillary block. Following a laser or standard iridectomy, cholinesterase inhibitors may be useful in controlling residual glaucoma.
OPEN-ANGLE GLAUCOMA
In open-angle glaucoma, the cholinergic agents reduce IOP by increasing the facility of outflow. Parasympathomimetic drugs stimulate the ciliary muscle, putting traction on the scleral spur and the trabecular meshwork, which separates the trabecular sheets and prevents Schlemm’s canal from collapsing. This mechanical change in the configuration of the meshwork increases fluid conductivity. The cholinergic drugs do not cure the basic outflow disorder of glaucoma (i.e., primary open-angle glaucoma is not caused by cholinergic insufficiency), but they do reduce the obstruction to outflow, thereby lowering IOP and preventing or reducing optic nerve damage. Several lines of evidence support this proposed mechanism of action of the cholinergic drugs:
- 1.
A number of experimental conditions that pull on the scleral spur or contract the ciliary muscle reduce resistance to outflow, including voluntary accommodation, electrical stimulation of the oculomotor nerve, posterior depression of the lens, tension on the choroid, and traction on the iris root with a suture.
- 2.
Histologic studies indicate that cholinergic agents widen the intertrabecular spaces, distend the juxtacanalicular tissue, and increase the number of giant vacuoles in the endothelium of Schlemm’s canal, implying an increased flow through the meshwork. Some of these changes are also seen in tissue culture.
- 3.
Topical, intracameral, and systemic cholinergic drugs reduce outflow resistance in animal eyes. Conversely, ganglionic blocking agents and cholinergic antagonists increase resistance to outflow.
- 4.
Intravenous injection of pilocarpine produces an almost instantaneous increase in outflow facility in monkey eyes. This implies that the effect is mediated by an arterially perfused structure (i.e., the ciliary muscle as opposed to Schlemm’s canal).
- 5.
Detaching the ciliary muscle from the scleral spur in monkey eyes almost abolishes the facility-increasing effect of miotic agents. This indicates that cholinergic drugs do not have a major direct action on the trabecular meshwork or Schlemm’s canal, as had been proposed in the past. However, some improvement in outflow with the use of miotics persists even when the ciliary muscle has been disinserted, suggesting that other mechanisms may be at work as well; furthermore, although ciliary muscle function declines with age, the effect of cholinergic stimulation does not appear to be affected by age. The residual effect on outflow facility may be mediated by cyclic AMP.
Cholinergic agents reduce unconventional or uveoscleral outflow. Thus the net decrease in IOP produced by miotic drugs represents a predominance of the trabecular effect over the uveoscleral effect.
The effect of cholinergic agents on outflow facility does not depend on pupil size. Parasympathomimetic drugs increase outflow facility in the presence of a bound-down pupil, a sector iridectomy, or multiple sphincterotomies. Dilating the pupil with phenylephrine does not inhibit the effect of cholinergic agents on outflow facility. In monkeys, totally removing the iris has no effect on IOP, aqueous outflow, or the response of outflow resistance to pilocarpine.
A number of studies using tonography have detected an apparent pilocarpine-induced reduction in aqueous humor formation. It has been postulated that cholinergic agents alter aqueous humor formation by constricting afferent arterioles in the ciliary body. However, other studies, including direct measurements of aqueous formation by fluorophotometry, fail to confirm this. Miotic agents are reported to produce a slight but clinically insignificant increase in episcleral venous pressure.
Continuous exposure to high levels of one cholinergic agonist produces subsensitivity to stimulation by another agonist in a number of animal models. The induced subsensitivity appears to be more profound after treatment with cholinesterase inhibitors or constant-release preparations of direct cholinergic agents. In part, this process may be caused by a decrease in the number of cholinergic receptors on the ciliary muscle cell membranes (i.e., ‘downregulation of receptors’). However, there is also experimental evidence in animals suggesting a direct or indirect toxic effect of miotic agents on the trabecular meshwork and ciliary epithelium, muscle, and stroma. The clinical significance of these findings is unclear at present. It is unknown whether these processes explain the loss of therapeutic responsiveness to cholinergic agents seen in some patients.
Cholinergic agents are additive to virtually all other classes of IOP-lowering agents including the prostaglandin-like ones. Fixed combinations such as timolol/pilocarpine have the advantage of convenience and therefore may enhance compliance. In addition, the fixed combinations reduce the amount of preservative to which the eye is exposed. However, the combinations have the disadvantage of non-optimal dosing. For example, timolol/pilocarpine combines a once or twice a day medication with a four times a day medication, raising the issue of either overdosing with one or underdosing with the other. Pilocarpine does seem to block some of the IOP-lowering effect of latanoprost when used in combination (at least in monkey eyes) but the net effect is synergistic with lowering that is greater than either agent alone.
Pilocarpine may be used to prevent IOP spikes after argon laser trabeculoplasty; it is at least as effective as apraclonidine although with more visual side effects. Pilocarpine may be especially useful in this regard in patients who are already using apraclonidine or brimonidine.
DRUGS IN CLINICAL USE
All cholinergic agents increase the facility of outflow, constrict the pupil, and reduce IOP. The various drugs differ in their duration of action and their potential for producing side effects. At one time, the miotics were the most commonly prescribed type of antiglaucoma agent. However, with the advent of antiglaucoma agents whose side effects are less likely to interfere with visual function, the use of the miotics as antiglaucoma medications has declined. Because they are still potent IOP-lowering drugs, improve outflow facility rather than reduce aqueous formation, and work well in concert with the other agents, they should still have a place in the armamentarium as third-line drugs.
Miotics either stimulate cholinergic receptors directly or inhibit the enzyme cholinesterase, thereby potentiating the effects of endogenous acetylcholine ( Table 27-1 ). Based on which of these two mechanisms of action they exhibit, cholinergic agents are divided into direct-acting and indirect-acting agents.
| Drug | Major mechanism of action | Concentration (formulation) | Usual dosage in glaucoma | Duration of hypotensive effect |
|---|---|---|---|---|
| Pilocarpine | Direct | 0.5–10% (solution) | 4 times daily | 4–8 hours |
| Carbachol | Strong direct; weak indirect | 0.75–3% | 3 or 4 times daily | 6–12 hours |
| Methacholine (Mecholyl) | Direct | 2–20% (solution) | Every 2–12 hours | 1–12 hours |
| Aceclidine (Glaucostat) | Direct; weak indirect | 0.5–4% (solution) | 4 times daily | 4–8 hours |
| Echothiophate iodide (Phospholine Iodide, Echodide) | Strong indirect | 0.03–0.25% (solution) | Every 12 to 24 hours | 0.5–7 days |
| Demecarium bromide (Humorsol, Tosmilen) | Strong indirect | 0.125–0.25% (solution) | Every 12 to 24 hours | 0.5–7 days |
| Physostigmine (Eserine) | Weak indirect | 0.25–1% (solution) 0.25–0.5% (ointment) | 4 times daily at bedtime | 4–6 hours |
| Neostigmine (Prostigmine) | Weak indirect | 3–5% (solution) | 4 times daily | 4–6 hours |
| Isoflurophate (DFP, Floropryl) | Strong indirect | 0.25% (ointment) | Every 12 hours, at bedtime | 0.5–7 days |
DIRECT-ACTING CHOLINERGIC AGENTS
Acetylcholine
Acetylcholine is the prototype direct-acting cholinergic drug. When injected into the anterior chamber, acetylcholine stimulates parasympathetic end organs in the iris and ciliary body. Acetylcholine is not used for the treatment of glaucoma because it penetrates the cornea poorly and is destroyed rapidly by cholinesterase.
Intracameral acetylcholine is used almost exclusively during ocular surgery to constrict the pupil. Intracameral acetylcholine causes rapid pupil contraction and reduces the risk of immediate postoperative IOP rise after extracapsular cataract extraction. Intracameral carbachol produces a slower miosis but extends protection from IOP elevation to over 24 hours and is more effective at lowering IOP in the immediate postoperative period than placebo, pilocarpine gel, or acetylcholine.
Pilocarpine
Pilocarpine is still the most widely prescribed miotic agent. It is more potent at muscarinic than at nicotinic receptor sites. Pilocarpine is manufactured as a water-soluble hydrochloride or nitrate in solutions ranging from 0.25–10% ( Fig. 27-1 ). The aqueous solutions are stable at slightly acidic pH levels. Pilocarpine penetrates the cornea well and produces a low incidence of allergic reactions. Animal studies indicate that the cornea absorbs pilocarpine rapidly and then releases it slowly to the aqueous humor (i.e., the cornea serves as a drug reservoir). The usual vehicles for pilocarpine are hydroxypropyl methylcellulose and polyvinyl alcohol. Benzalkonium chloride and sodium ethylenediamine tetra-acetic acid (EDTA) are added to prevent microbial growth and to facilitate penetration.
Topical pilocarpine administration produces a reduction in IOP that begins in an hour and lasts for 4 to 8 hours. Pilocarpine is prescribed for use four times daily (i.e., as close to every 6 hours as possible) to ensure good IOP control. Pilocarpine (as well as its other miotic cousins) works well with other antiglaucoma agents. Specifically, miotics have been shown to work well with β-blocking agents, carbonic anhydrase inhibitors, adrenergic agonists, and latanoprost. When used in conjunction with other antiglaucoma medications, control can sometimes be obtained with administration three times (or even twice) daily. Several formulations containing both pilocarpine and a β-blocking agent have been reported to be synergistic and have the convenience of a twice-daily dosage with a single drop. These studies encompass most of the available topical β-blockers. One study even suggests that combination therapy may work better than the individual agents used alone.
Because pilocarpine binds to melanin in the iris and ciliary body, iris color may influence IOP response. Studies indicate that 2% pilocarpine often yields the maximum IOP reduction in blue-eyed patients. Eyes with darkly pigmented irides may require 4% pilocarpine for maximum effect. Some darkly-pigmented patients (e.g., those of black African ancestry) may obtain additional therapeutic effect from 6% or even 8% solutions. When the top of the dose–response curve is reached, higher concentrations of pilocarpine often extend the duration of action without increasing the maximum effect. The increased duration of effect, however, must be weighed against the increased incidence of side effects produced by the stronger solutions. It is important to emphasize that the dose–response characteristics and duration of drug effect for a given patient can only be determined in a therapeutic trial.
Alternative drug delivery systems
Because of the inconvenient dosage schedule and variable visual side effects mandated by the relatively short duration of action of pilocarpine, a variety of delivery systems have been used to prolong drug retention in the cul-de-sac and enhance drug penetration through the cornea. These systems have been used in hopes of reducing the frequency of drug administrations, improving convenience and patient compliance, minimizing side effects, and increasing therapeutic effect. The simplest of these systems is a viscous vehicle capable of prolonging drug–corneal contact time. Pilocarpine in 1.6% polyvinylpyrrolidone (Adsorbocarpine) was reported to produce good IOP control with twice-daily administrations. However, this was not confirmed by subsequent studies.
Soft contact lenses
The hydrophilic soft contact lens is capable of taking up medication and serving as a drug reservoir (i.e., releasing medication over a period of time to the tear film). If a soft contact lens is soaked for 2 minutes in 0.5% pilocarpine and then placed on the eye for 60 minutes, IOP may be reduced for 24 hours. Administration of 1% pilocarpine over a soft contact lens has a greater effect on IOP than instillation of 8% pilocarpine drops without the lens. Although this system is too cumbersome for general use, a few patients with difficult conditions have been treated successfully in this manner.
Membrane-controlled delivery (Ocusert)
Pilocarpine can be sealed within a multilayered polymer envelope to form the Ocusert delivery system ( Fig. 27-2 ). The system is manufactured in two forms that release the drug continuously into the tear film at either 20 μg per hour or 40 μg per hour. The lower rate gives an IOP reduction comparable to 1% pilocarpine eyedrops administered four times daily, whereas the higher rate gives a reduction comparable to 2–4% pilocarpine. A single Ocusert generally reduces IOP for 1 week. However, the ophthalmologist must determine the duration of the IOP reduction in each patient. The advantages of the system include less miosis, a more constant and less pronounced myopic shift, and better diurnal pressure control as compared with eyedrops. The disadvantages of the system include increased cost, difficulty in insertion and removal, loss from the cul-de-sac, and foreign body sensation.
The Ocusert system releases more medication during the first several hours after insertion. Patients tolerate this best if the new Ocusert is inserted Saturday night before retiring, assuming a standard Monday to Friday work week. Occasionally an Ocusert bursts, causing intense miosis and myopic refractive shift. Also, the Ocusert may fall out unnoticed by the patient, or it may twist and become ineffective. Given proper introduction, education, and encouragement, many patients are helped by Ocuserts. These devices were particularly helpful in younger patients with glaucoma. To a lesser degree, they may be useful in older patients with lens opacities. Unfortunately, because of the relatively small market, they are no longer being manufactured as of the current date.
Pilocarpine gel (Pilopine HS gel)
Pilocarpine is now formulated in a high-viscosity gel. The gel prolongs contact time between the drug and the tear film, enhances drug penetration, and reduces the frequency of drug administration. A single dose of 4% pilocarpine gel applied at bed time is approximately equal in effect to 4% pilocarpine eyedrops applied four times daily. Some patients prefer the gel because it is more convenient, whereas others prefer it because of lessened side effects. However, it is not clear whether the gel applied once daily can control IOP for 24 hours in all patients. Some studies suggest a diminishing effect of the gel after 18 hours. In addition, in one study, 20% of the patients treated with pilocarpine gel for several months developed reversible anterior stromal haze of the cornea.
Pilocarpine polymer (Piloplex)
Piloplex represents another attempt to obtain a prolonged drug effect from a single administration of pilocarpine. Piloplex is an aqueous emulsion consisting of a polymeric material to which pilocarpine base is chemically bound. The drug is released over a period of hours as the polymer is hydrolyzed. Piloplex appears to be effective in preliminary trials and may provide better control of IOP when administered twice daily than pilocarpine eyedrops do when administered four times daily. Despite the positive reports, Piloplex has failed to make any inroads in the United States.
Methacholine (Mecholyl)
Methacholine chloride is a synthetic derivative of acetylcholine. In the past, 10–20% methacholine was administered every 5–10 minutes to treat angle-closure glaucoma, and 2–10% methacholine was given alone or combined with neostigmine to treat open-angle glaucoma. The drug is rarely used anymore because it is unstable in solution and is short acting, and it penetrates the cornea poorly. Its major use today is in the diagnosis of Adie’s pupil.
Carbachol
Carbachol, a synthetic derivative of choline, acts primarily by stimulating muscarinic receptors. It also releases acetylcholine at certain neuroeffector junctions and ganglia. Carbachol is manufactured in aqueous solutions of 0.75–3% and is administered 3–4 times daily (i.e., every 6–8 hours). It is more powerful than pilocarpine on a concentration basis (e.g., 1.5% carbachol has the same ocular effect as 2% pilocarpine) and has a more prolonged effect. However, carbachol penetrates the cornea poorly and must be combined with a wetting agent or a preservative such as benzalkonium chloride to reach an effective intraocular concentration. Like pilocarpine, carbachol is not destroyed by cholinesterase.
Carbachol is an excellent miotic agent that could be used more frequently for the treatment of glaucoma. It can be used to initiate cholinergic treatment or to substitute for pilocarpine and other miotics when the patient develops resistance or intolerance. Carbachol has a greater tendency than pilocarpine to produce headache and accommodative spasm, especially during the first few days of treatment. It is also a more potent miotic that can cause more interference with vision than pilocarpine for those patients with lens opacities.
The use of carbachol has declined with the general decline in the use of miotics. Today, it finds its widest use intracamerally to reduce the risk of a postoperative IOP spike in glaucoma patients whose optic nerves might be further damaged.
Aceclidine (Glaucostat)
Aceclidine, a synthetic cholinergic drug, is used extensively in Europe for the treatment of glaucoma. Aceclidine stimulates muscarinic receptors directly and inhibits cholinesterase weakly. It is less effective than pilocarpine on a concentration basis (e.g., 4% aceclidine has the same ocular hypotensive effect as 2% pilocarpine). Aceclidine is thought to induce less ciliary muscle spasm and accommodation than pilocarpine.
INDIRECT (ANTICHOLINESTERASE) AGENTS
Anticholinesterase drugs inhibit the enzyme acetylcholinesterase, thereby potentiating the effects of endogenous acetylcholine. In general, these agents produce more side effects than the direct-acting cholinergic drugs, including hyperemia, irritation, vascular congestion, and spasm of the orbicularis, ciliary, and iris sphincter muscles. Cholinesterase inhibitors are rarely administered to eyes with narrow angles before iridectomy; the drug-induced miosis, forward movement of the lens, and vascular congestion can precipitate or aggravate angle closure. In the past, anticholinesterase drugs were classified as reversible (e.g., physostigmine, neostigmine) or irreversible (e.g., isoflurophate, echothiophate) enzyme inhibitors. It is probably more accurate to classify these drugs as weak/short-acting or strong/long-acting inhibitors of cholinesterase.
Echothiophate iodide (phospholine iodide)
Echothiophate, a potent inhibitor of both true cholinesterase and pseudocholinesterase, is manufactured as a white crystalline solid that is mixed with a diluent at the time of dispensing. Because of limited stability, solutions of the drug should be refrigerated. Echothiophate is administered as an aqueous solution in concentrations of 0.03–0.25% every 12–48 hours ( Fig. 27-3 ). The 0.06% concentration produces the maximum IOP reduction in most patients and is roughly equivalent in peak effect to 4% pilocarpine. Echothiophate, however, has a much longer duration of action than pilocarpine and controls IOP in some eyes that have not responded adequately to direct-acting cholinergic agents. However, the benefits of echothiophate are offset by the systemic and ocular side effects, particularly cataract formation. Because of these side effects, echothiophate and the other strong inhibitors of cholinesterase are used mostly in adult aphakic and pseudophakic eyes and in eyes that have not responded adequately to standard medical and surgical treatment for glaucoma.Manufacture of echothiophate has been episodic in the last several years.
