Pratap Challa, MD, MS and David L. Epstein, MD, MMM
Miotics, or more appropriately termed muscarinic (cholinergic-acting) agonists, have been used in the treatment of the glaucomas for more than 100 years. This is the first class of medications used to treat glaucoma, and they remain an important glaucoma therapy for both open-angle and angle-closure glaucomas. It is noteworthy that our understanding and discrimination between open-angle and angle-closure glaucomas have been widely recognized for only the past 60 or 70 years. (Paul Chandler was an important voice in teaching this differentiation.) Cholinergic-acting agonists are miotics, but this effect on the pupil is of significance only in the acute treatment of angle-closure glaucoma due to pupillary block. For the chronic treatment of primary open-angle glaucoma (POAG), the side effects of pupillary miosis and accommodation can be bothersome for many patients and can lead to discontinuation of these medications. Some of the discussion in this chapter is of more historical than clinical relevance because the practice patterns of medical care have shifted over time. It is intrinsic, however, to understand the history of miotics as it relates to glaucoma therapy and to recognize the continuing role that this group of medications has in patient care.
Miotics are classified as weak (eg, pilocarpine or carbachol) or strong (eg, echothiophate iodide). The former refers to direct-acting acetylcholine-mimicking drugs that bind directly to the receptor site, whereas the latter refer to indirect-acting (acetylcholinesterase) enzyme inhibitor drugs that allow the endogenous normal transmitter, acetylcholine, to accumulate at the receptor site.
In acute angle-closure glaucoma, the miotic effect of pilocarpine, the most commonly used agent, may decrease pupillary block at the level of the pupil by this miotic action on the usually semidilated pupil. But probably just as important is the drug acting to constrict the iris out of the angle and to increase iris tension that in turn helps resist the increased pressure in the posterior chamber found in pupillary block. At the level of the pupil, these cholinergic drugs may increase pupillary block if there is excessive miosis (the pupil is more closely apposed to the convex forward crystalline lens) and if the cholinergic effect on the ciliary muscle results in ciliary muscle contraction and release of zonular tension that can allow the crystalline lens to move forward to the pupil and thus actually increase pupillary block. On occasion, patients with underlying POAG thus can develop a superimposed angle-closure component from the use of miotic therapy. Hence, gonioscopy should be repeated in patients who have POAG and are taking miotic therapy.
In patients with POAG or with chronic forms of (noninflammatory) secondary open-angle glaucoma, such as exfoliation, the mechanism of intraocular pressure (IOP) lowering by miotics has nothing to do with the pupillary effect. It is due to the contraction of the longitudinal portion of the ciliary muscle that inserts on the scleral spur. The latter is adjacent to, and receives also the insertion of, the trabecular meshwork (TM). The IOP-lowering effect of miotics is due almost exclusively to the outflow effect produced by mechanical traction by the longitudinal ciliary muscle onto the scleral spur. Anatomically, cholinergic therapy alters the spaces within the TM and makes them more open or wide and increases the number of pores in the inner wall of Schlemm’s canal.1 Experimentally, when the ciliary muscle is disinserted from the scleral spur, cholinergic drugs do not improve outflow.2 (The latter observation also might have potential relevance to the clinical conditions of cyclodialysis or angle recession, although likely the overall circumferential extent of these conditions might be an important determinant of cholinergic drug efficacy.)
|Secondary angle-closure glaucomas||Worsens angle closure by shallowing anterior chamber (miotics produce forward movement of lens-iris diaphragm)|
|Status post-vitreoretinal surgery|
|Status post-panretinal photocoagulation or retinal cryopexy|
|Status post-central retinal vein occlusion (acute)|
|Secondary to sulfa drugs|
|Associated with ciliary body swelling|
|Uveitic glaucoma||Increases inflammation, may paradoxically increase IOP|
|Neovascular glaucoma||Increases inflammation, may produce hyphema, ineffective|
|Trauma (recent, with inflammation)||Increases inflammation, increases ciliary spasm and pain|
Some have described small effects of cholinergic-acting drugs on reducing aqueous humor formation or a potential direct effect on the TM. These proposed alternative actions deserve further evaluation, but the existing data strongly indicate that the effects of these muscarinic drugs on outflow are mainly mechanical from longitudinal ciliary muscle contraction. The latter action likely produces few adverse effects, except perhaps for the risk of mechanical traction on attachments to the ora serrata potentially leading to detachment of the retina. Macular hole formation has also been associated with cholinergic therapy, and therefore, all patients should have a careful retinal examination both before and after initiation of these medications. Unfortunately, it is not (yet) possible to have drugs that exert cholinergic effects on only this longitudinal portion of the ciliary muscle (although some have argued that aceclidine exerts a preferential effect on the longitudinal muscle).3 Furthermore, the necessary accompanying contraction of the circular and other portions of the ciliary muscle from cholinergic-acting drugs leads to relaxation of zonular tension, increased axial lens diameter, and forward movement of the lens-iris diaphragm. This then produces accommodation and the commonly unacceptable symptoms of visual blurring and myopia. In young patients, myopia-producing effects are frequently intolerable.
On the other hand, many presbyopic patients achieve a reestablishment of their near point, and if the accompanying miosis does not adversely affect their visual function (by cutting down light entering the eye, especially at night) and there are not excessive problems with the required frequency of drug administration or ocular irritation, many patients accept this therapy. Like miosis, the effect on accommodation is not part of the IOP-lowering mechanism (and, therefore, is not necessary for efficacy). The therapeutic efficacy is due to the contraction of the longitudinal portion of the ciliary muscle, which is mechanically connected to the TM via the scleral spur.
Another effect of this class of medications is that contraction of the ciliary muscle may obliterate some of the extracellular spaces available for uveoscleral outflow and thus cause a decrease in outflow by this unconventional outflow pathway.4,5 In general, this effect is of little importance when treating glaucoma in most patients, except in rare individuals who are primarily dependent on the unconventional outflow pathway. Such individuals have exhibited a paradoxical rise in IOP.6 However, pilocarpine does not appear to inhibit the increased uveoscleral outflow effects produced by prostaglandin analogs, suggesting that the biochemical changes induced by them are not affected by the mechanical effects of miotics.7
Considering the effect of miotics on anterior chamber depth and its mechanism of action, it does not come as a surprise that there are several forms of glaucoma that are not amenable to miotic therapy or are worsened by it (Table 13-1). Forms of angle-closure glaucoma in which axial shallowing, such as malignant glaucoma or that following an acute central retinal vein occlusion, are worsened by miotics. Additionally, neovascular and inflammatory forms of secondary angle-closure glaucoma are not amenable to miotic treatment.
Miotics have many ocular side effects that should be considered before and after initiating therapy (Table 13-2).
VISUAL SIDE EFFECTS OF MIOTICS
In patients with early cataractous lens changes, especially those close to the visual axis, miotic therapy can be visually disabling. In such patients who are well controlled on miotic therapy but have visual disability, the substitution by other medications or laser trabeculoplasty should be considered. The patient’s objective and subjective vision should be assessed when miotic therapy has been stopped for a few days, if possible. Less desirable is to assess this after pupillary dilation (which unfortunately itself, likely due to light scattering and spherical aberration, may make cataract symptoms worse). It is useful to ask patients about their visual function in the morning before putting their miotic drops in, for this may offer a clue as to the role of the miotics in the visual disability. In patients with early cataract formation, a substitution strategy for miotic therapy is often effective in delaying the need for cataract surgery and thus allowing longer time for the glaucoma status to be evaluated (eg, time often can help answer the question whether cataract surgery alone or, in fact, combined cataract and filtration surgery is required).
OCULAR SIDE EFFECTS OF MIOTICS
In addition to the effects of miosis and accommodation (which by allowing the crystalline lens to move forward might have adverse effects beyond the visual, eg, pupillary block and susceptibility to malignant glaucoma-type syndromes), cholinergic-acting drugs appear to increase vascular permeability and perhaps thereby induce some type of proinflammatory predisposition in certain eyes. These drugs should not be used in inflammatory glaucoma and, in fact, may cause paradoxical effects on IOP. One of the rules discussed previously is that if a patient with presumed POAG is placed on a miotic and demonstrates an increase in IOP, gonioscopy should be repeated (as always when there is an increase in IOP) with the suspicion of an induced angle-closure component or an accentuated occult inflammatory trabeculitis. Furthermore, chronic miotic therapy can influence surgical considerations by creating small pupil problems and suspected increased iris rigidity. These eyes are also more injected and frequently have a greater propensity for postoperative inflammation and sustained breakdown of the blood-aqueous barrier. Filtration surgery patients often have greater subconjunctival inflammation and potential scarring at the filtration site. Thus, there is this clinical sense, that perhaps has been somewhat overstated, that chronic miotic therapy is not good for the eye.
The authors share this gestalt. It also must be stated that glaucoma itself is probably not good for the eye and that nearly all medications (and their preservatives) increase ocular injection. If miotics can reasonably control the IOP in patients with various forms of open-angle glaucoma, then the risk/benefit considerations indicate that this therapy should not be avoided. We are dealing again with the humbling realization that all of our treatments for glaucoma are nonspecific and have potential downsides. Many patients appreciate the induced near point visual side effects and the pinhole effect on overall visual acuity from the miosis (except at night). Yet, there is legitimacy to the dissatisfaction that clinicians feel with the use of long-term cholinergic therapy.
David L. Epstein, MD, MMM
Acetylcholine, which is commonly released at cholinergic nerve terminals in the eye, is normally inactivated by the enzyme acetylcholinesterase. Inhibitors of the latter enzyme allow acetylcholine to accumulate at the receptor site and thus produce a cholinergic miotic effect of long duration. Such acetylcholinesterase enzyme inhibitors have been used as systemic nerve gases or insecticides (where presumably they are lethal as a result of sustained cholinergic stimulation).1 It is remarkable that such agents in dilute concentrations have found use topically as anti-glaucoma agents. With respect for the ocular cholinergic side effects, such cholinesterase inhibitor therapy can be very effective, particularly in pseudophakic or aphakic eyes. This observation, on the one hand, makes one wonder whether all of our current glaucoma therapy is not, in fact, applied toxicology, but on the other hand teaches us the importance of dose-response relationships and therapeutic indexes in the development of all new glaucoma medications (or for any disease). Any drug at a high-enough dosage can have substantial side effects. When we screen for new drugs, we commonly use high concentrations, looking for large effects because they are easier to detect initially.
One wonders how many potentially useful drugs may have been missed because of such screening techniques. The first attempts to study topical cholinesterase inhibitor therapy to the eyes of rabbits produced a lethal result!
1. Rengstorff RH. Vision and ocular changes following accidental exposure to organophosphates. J Appl Toxicol. 1994;14:115-118.
Systemic Side Effects
Systemic side effects from cholinergic agents (except for the use of cholinesterase inhibitors; see the following section “Cholinesterase Inhibitors”) are uncommon. The most frequently seen systemic side effects are gastrointestinal, which seem to be a direct cholinergic effect and likely result from the drug reaching the alimentary channels directly through luminal connections from the throat. The latter derives from the topical drug reaching the nasolacrimal duct. Often, this symptom responds well to punctal occlusion (or gentle eyelid closure). Theoretically, this cholinergic symptom could result also from systemic absorption (that would obviously not be responsive to punctal occlusion strategies), and despite the efficacy of punctal occlusion diminishing this symptom, such systemic absorption might be more involved than first appreciated. Rarely, cholinergic bladder symptoms have been observed from topical miotic therapy and cerebral influences that are frequently viewed positively by the rare patient who believes that they are so affected. The latter has been observed more with the use of cholinesterase inhibitors than with short-acting miotics in our experience. Certain cholinergic therapies may positively slightly influence mental function in Alzheimer’s disease.8 Regardless, the bottom line for the clinician is that one should be alert to the possibility of systemic cholinergic symptoms in patients on topical cholinergic therapy to the eye, especially the cholinesterase inhibitors, although these are decidedly uncommon.
The short-acting miotics are cholinergic-acting drugs that mimic and theoretically might compete at the receptor with endogenously released acetylcholine, which is the usual transmitter at cholinergic sites in the eye. Such potential competition of cholinergic drugs with acetylcholine for the receptor, while theoretically possible, does not occur from a practical clinical point of view. Cholinesterase inhibitors and cholinergic drugs are not negatively interactive on IOP9; in fact, in some small minority of patients, there is slight additivity.
Significant systemic absorption of a topical ocular drug can occur. Therefore, it is not surprising that this happens also with cholinesterase inhibitors. The clinician should be alert to the potential for gastrointestinal, urological, or cerebral cholinergic side effects, although these are uncommon. However, what is common with the use of topical acetylcholinesterase inhibitors is the inhibition of cholinesterase activity in the blood.10 For some forms of general anesthesia, certain agents such as succinylcholine are used and require the blood enzyme for inactivation. Therefore, anesthesiology consultation should be obtained preoperatively, and the anesthesiologist should be informed ahead of time to flag the chart as to the use of topical cholinesterase inhibitors. It may require several months of cessation of such ocular therapy for blood levels of cholinesterase to return to normal. Fortunately, many alternatives exist in the choice of general anesthesia, but the anesthesiologist needs to know ahead of time about the use of this type of medication in patients who have glaucoma.
Potential Retinal Complications
Presumably because the ciliary muscle sends extensions of its tendon to the ora serrata, there is the potential for retinal complications with use of these cholinergic agents as a result of mechanical tension from the muscle’s contraction.
As part of the routine of a full ophthalmologic evaluation of the glaucoma patient, indirect ophthalmoscopy should be performed, with special attention to the retinal periphery looking for preexisting retinal pathology that might be adversely affected by the mechanical actions of miotics. As part of the routine follow-up of patients with glaucoma, the pupil is periodically dilated not only to examine the optic nerve head but also to reexamine the retina.
Patients receiving miotics are told of potential symptoms including flashes, floaters, and curtains. Although rare, retinal tears can occur with weak miotic therapy (eg, pilocarpine).11 In fact, posterior vitreous detachment may occur more commonly after even weak miotic therapy than is often appreciated. It would make sense, and clinically seems to be the case, that the risk goes up with increasing concentration of miotic and, therefore, with use of the stronger miotics (ie, cholinesterase inhibitors).
The potential for such rare side effects is perhaps another reason why the miotics are no longer the drug of first choice for POAG. But, as discussed, even with these general cholinergic effects on the eye, these agents are still effective medications. As with all glaucoma medications, they have risk/benefit considerations that need to be appreciated by the clinician and discussed with the patient ahead of time.
Whether patients with previous retinal detachment and successful repair should be treated with strong miotics is an interesting question that requires retina specialist consultation. Retina specialists have given their approval provided they are satisfied with the result of the retinal surgery. Thus, although these strong miotics should still be a drug of last resort, we have used them effectively in such patients. Such patients need continuing evaluation by a retina colleague.
For patients with a predisposition to retinal detachment, whether due to significant myopia or identified retinal thinning, avoid these stronger miotics unless absolutely necessary. Again, retinal consultation is strongly advised, and only the weakest effective solution should be used.
STRATEGIES IN CHOICE/USE OF MIOTICS
Pilocarpine is the usual first choice of cholinergic eye drop therapy. Several preparations differ only in the choice of salt, buffer, preservatives, or other constituents added for comfort. Strengths of pilocarpine range from 0.5% to 6%. Some glaucoma clinicians have argued that the maximally effective concentration may occur at concentrations less than 4%, whereas others have argued that 6% is probably the top of the dose-response curve. There is individual variability, but we believe that for most patients, except those with heavily pigmented irides, 4% is likely the clinically meaningful top of the dose-response curve and that lesser concentrations are not. Also, although 6% concentration may be slightly more effective in certain heavily pigmented non-White eyes, for practical purposes, 4% pilocarpine is still the highest concentration used, except perhaps for individuals with severe glaucoma.
Even in patients in whom it is anticipated that higher strengths of pilocarpine will be required, one should still start with low strengths of 0.5% or 1% to allow the patient to adapt to the anticipated initial ciliary spasm. Headaches and brow aches due to miotics are common, and the clinician should spend time explaining this to the patient (eg, the drug makes the muscle next to the drain contract and open the spaces, and like any muscle that has not been used fully, some initial cramping [“Charlie horse”] is to be anticipated). These symptoms should abate after the first few days. The patient should be told to call if they do not or if there are any other symptoms, such as flashes and floaters.
It is also very useful for the clinician to assess the IOP-lowering efficacy of 1% pilocarpine. Sometimes, there is a surprisingly large IOP effect. In fact, many years ago, a pilocarpine drop test for glaucoma was described in which a large decrease in IOP was anticipated in patients with true glaucoma. It is not certain in the era of this pilocarpine drop test whether all forms of chronic angle closure were well differentiated from open-angle glaucoma, and there is likely great individual variability, regardless, in IOP reduction in POAG patients from miotics. The clinical point is that some patients with POAG are very responsive to lower strengths of pilocarpine. It is not possible to predict what strength of pilocarpine will be required in the individual patient. In some cases of POAG, perhaps just a slight mechanical widening of whatever the critical space is in the outflow pathway is enough,1 at least initially, to substantially improve the outflow of aqueous humor from the eye. One of the major problems with pilocarpine and short-acting cholinergic-acting agonists is the short duration of drug effect. This necessitates a need for frequent instillation, usually 4 times a day for pilocarpine, which represents medication every 6 hours. Patients do not have to wake up at night after 6 hours of sleep to instill the drop, but it is surprising how many patients, in fact, do this due to inadequate initial instruction! However, while the patient is awake, the drops should be spaced as far apart as possible, approximately every 6 hours. There is the possibility of an IOP spike after 6 hours of sleep. Patients should administer the morning drop soon after awakening.
Clinically, some patients behave as if the maximum IOP effect from pilocarpine lasts only 4 hours, and we have seen some clinicians with good documentation therefore prescribe pilocarpine drops 6 times a day! We as clinicians need to appreciate how disruptive frequent drop regimens are to a patient’s lifestyle. In fact, most patients do not adhere to a 4-times-daily dosage regimen.12,13 For such patients with an apparent shorter time of clinical efficacy from cholinergic therapy, one should consider a higher strength of the drug—up to 6%, or perhaps, more reasonably, the use of pilocarpine ointment at night supplemented with pilocarpine drops during the day.
David L. Epstein, MD, MMM
Compliance is a real issue for the frequent dosing regimen required with weak miotic therapy. Kass and others have documented the surprising magnitude of this problem in glaucoma therapy with the use of a special electronic monitoring eye bottle.1–4 But the clinician, by simple means, can also sometimes gain insight into this issue in patients who are using miotics. Examination and recording of pupil size is an important part of the eye examination. For example, although the degree of miosis induced by these agents may be variable among different individuals, it should be consistent within the same patient. One often finds that the pupil is somewhat larger at a subsequent visit, and it takes specific physician probing to uncover the fact that the patient (who usually wants to actually please the glaucoma clinician) failed to take the medication, at least on the day of the visit. One patient told us that she did not want to hurt her physician’s feelings by telling him that she could not take her medication routinely! It goes without saying that, given the short duration of IOP effect from such therapy, failure to take the medication on the day of examination will cause an unexpectedly higher IOP. Some patients, unless counseled otherwise, routinely will omit their drops on the day of examination for a variety of reasons that reflect miscommunication (eg, “the doctor puts in his own drops at the visit” or “it interferes with the examination”).
Patients on miotic therapy (truly, all patients with glaucoma) need specific instructions about these issues and about inquiry into actual medication usage. Poor compliance is a common cause of fluctuating IOP. We are aware of cases in which the clinician prescribed a miotic, but the patient, due to confusion, did not take it, and this was not picked up by the office personnel until a referral consultation was arranged, at which time it was observed that the pupil was not miotic! Thus, the recording of the pupil size is an important part of the glaucoma examination.
1. Kass MA, Meltzer DW, Gordon M, Cooper D, Goldberg J. Compliance with topical pilocarpine treatment. Am J Ophthalmol. 1986;101:515-523.
2. Kass MA, Gordon M, Meltzer DW. Can ophthalmologists correctly identify patients defaulting from pilocarpine therapy? Am J Ophthalmol. 1986;101:524-530.
3. Kass MA, Gordon M, Morley RE Jr, Meltzer DW, Goldberg JJ. Compliance with topical timolol treatment. Am J Ophthalmol. 1987;103:188-193.
4. Budenz DL. A clinician’s guide to the assessment and management of nonadherence in glaucoma. Ophthalmology. 2009;116(suppl 11):S43-S47.