Miotics General Statement (Monograph)

Drug class: Miotics
- Anticholinesterase Agents
ATC class: S01EB01
VA class: OP102

Introduction

Miotics are direct- or indirect-acting parasympathomimetic agents that cause contraction of the iris sphincter and the ciliary muscle, producing constriction of the pupil and spasm of accommodation.

Uses for Miotics General Statement

Open-Angle Glaucoma

Miotics are used topically on the eye principally to reduce elevated IOP in the treatment of primary open-angle glaucoma. The drugs are also useful in the treatment of some noninflammatory secondary glaucomas. Reduction in IOP may decrease or prevent glaucomatous visual field loss or optic nerve damage and obviate the need for surgery. Pilocarpine is usually the initial miotic of choice because it generally provides good control of IOP with relatively few adverse effects. Acetylcholine has little value in the treatment of glaucoma because of its rapid inactivation. Carbachol, although pharmacologically similar to pilocarpine, must be combined with a wetting agent to ensure corneal penetration and is used mainly in patients refractory or hypersensitive to pilocarpine. Physostigmine is not as well tolerated as pilocarpine or carbachol and is rarely used for long-term therapy. The long-acting anticholinesterases (demecarium, echothiophate [no longer commercially available in the US], isoflurophate [no longer commercially available in the US]) require less frequent administration, produce greater control of diurnal pressure variations, and cause more sustained myopia than do pilocarpine, carbachol, or physostigmine solutions. However, because of their adverse effects, long-acting anticholinesterases should be reserved for use in aphakic patients and other patients with open-angle glaucoma not satisfactorily controlled with pilocarpine or other miotics. Choice of a long-acting anticholinesterase depends on individual response; some patients refractory to or intolerant of one drug may respond to or tolerate another. Unresponsiveness to the IOP-reducing effects, but not to miosis, may develop during prolonged use of miotics, although this effect usually occurs less rapidly with the anticholinesterases than with other miotics. The response may be restored by changing to another miotic, timolol, epinephrine (after confirming the angle of the eye is open), or a carbonic anhydrase inhibitor for a short time and then returning to the original drug.

In the treatment of open-angle glaucoma, a miotic may be used in conjunction with a carbonic anhydrase inhibitor, epinephrine, and/or timolol. When used in conjunction with these agents, the effect of the miotic in lowering IOP may be additive. Reduction in miotic dosage may thus be possible so that the patient experiences less miosis or ciliary spasm. Concomitant administration of two miotics is generally not recommended because there may be antagonism between the drugs (see Drug Interactions: Miotics), and unresponsiveness may develop to both drugs, making selection of an alternative miotic more difficult. In addition, there may be an increased risk of allergic reactions and toxicity. In some patients, concomitant instillation of a 10% solution of phenylephrine hydrochloride or a 1–2% solution of epinephrine hydrochloride with a miotic may improve visual acuity by dilating the miotic-treated eye without increasing IOP, provided the angle of the eye is open. Simultaneous administration of phenylephrine with miotics, especially long-acting anticholinesterases, may prevent development of iris cysts, although the mechanism is unknown. (See Ocular Effects in Cautions: Adverse Effects.) Use of combinations of drugs in a single preparation is generally not recommended because of the improper dosage that may result from the different durations of action.

Angle-Closure Glaucoma

Pilocarpine (or occasionally carbachol) is used to lower IOP in the emergency treatment of acute (congestive) angle-closure glaucoma prior to surgery. Because it may preclude successful surgery, the drug should not be used for long periods prior to surgical treatment of angle-closure glaucoma. Lack of response to pilocarpine in acute angle-closure glaucoma may be caused by paralysis of the iris sphincter by the extremely high IOP and may require systemic administration of acetazolamide or hyperosmotic solutions (e.g., glycerin or mannitol). Long-acting anticholinesterases should not be used in patients with acute or chronic angle-closure glaucoma prior to surgery because of the risk of further angle narrowing. (See Cautions: Precautions and Contraindications.)

Ocular Surgery

Pilocarpine is used to reduce IOP and to protect the lens by causing miosis prior to goniotomy or iridectomy including laser iridectomy. Miotics may be used to control glaucoma which persists after surgery. Following cyclodialysis, the drugs are used to keep the cleft open.

Although topical pilocarpine or intraocular carbachol has also been used, intraocular acetylcholine is probably the most useful drug for producing miosis during surgery on the anterior chamber of the eye such as cataract extraction, keratoplasty, peripheral iridectomy, or cyclodialysis. Because of its extremely short duration of action, acetylcholine is less likely to cause postoperative pain than are other miotics. In cataract surgery, acetylcholine should be used only after delivery of the lens. Miosis will occur to a lesser extent in acute angle-closure glaucoma or in eyes which demonstrate posterior synechiae or atrophy of the iris. For rapid and complete miosis with acetylcholine, obstructions such as synechiae may require surgery. Following lens extraction, the rapid miosis produced by acetylcholine protects the vitreous face and facilitates the placement of corneal sutures by reducing the hazard of incarceration of iris tissue during the closure of the wound. The taut, easily accessible iris permits a precisely located peripheral iridectomy. Following iridectomy, the traction produced by acetylcholine upon the released iris helps to reposit it toward its original position within the anterior chamber and in this taut condition there is less danger of iris prolapse. Following surgery, miosis must be augmented by longer acting topical miotics such as pilocarpine or physostigmine.

Convergent Strabismus

Long-acting anticholinesterases are the preferred miotics for the diagnosis and treatment of convergent strabismus (accommodative squint or esotropia) uncomplicated by amblyopia or anisometropia because of their greater effect on the accommodation/convergence ratio and longer duration of action than the direct-acting miotics; the drugs may be used alone or combined with corrective lenses. These drugs are especially useful preoperatively in young children and patients with hypermetropic refractive error. In spite of anticholinesterase treatment, the nonaccommodative portion of squint persists.

Ophthalmologic Examinations

Miotics may counteract the mydriatic effects of sympathomimetic agents such as hydroxyamphetamine and phenylephrine and have been used for this effect after ophthalmoscopic examinations. Administration of a miotic, particularly the long-acting anticholinesterases, may cause accommodative spasm and myopia once the effects of the mydriatic have worn off. For this reason, some clinicians recommend that a miotic be used after a mydriatic only in glaucoma patients and that pilocarpine should be the miotic used. Miotics have little effect on mydriasis produced by parasympatholytic agents such as homatropine or tropicamide.

Other Uses

Demecarium may be used for its miotic effect in certain conditions which obstruct aqueous humor outflow such as synechial formation.

Miotics General Statement Dosage and Administration

Administration

In the management of glaucoma, miotic ophthalmic solutions, ointment, or gel is applied topically to the conjunctival sac. Patients should be supine during administration of long-acting anticholinesterases. Finger pressure should be applied on the lacrimal sac for 1–2 minutes following topical instillation of miotic ophthalmic solutions to minimize drainage into the nose and throat and reduce the risk of absorption and systemic reactions. Excess solution around the eye should be removed with a tissue and any medication on the hands should be rinsed off immediately.

For miosis during ophthalmic surgery, acetylcholine or carbachol may be administered intracamerally (into the anterior chamber of the eye) using a suitable atraumatic cannula.

Dosage

The concentration and dosage of the miotic must be adjusted to the requirements and response of individual patients as determined by tonometric readings before and during therapy. Whenever possible, the daily dose or one of the daily doses should be applied at bedtime to minimize adverse ocular effects.

Cautions for Miotics General Statement

Adverse Effects

Adverse effects of topically applied miotics are similar, although they are generally most severe and prolonged with the long-acting anticholinesterases. Topical pilocarpine is generally better tolerated than are other miotics. Adverse effects of miotics are reduced if therapy is started with a low concentration of the drug, the concentration is increased gradually, and the daily dose or one of the daily doses is instilled in the eye at bedtime. Adverse effects often subside after the first few days of therapy or if treatment with the miotic is temporarily discontinued.

Ocular Effects

The most common adverse effects of miotic therapy are painful ciliary or accommodative spasm, blurred vision or myopia, and poor vision in dim light. Ophthalmic ointments interfere with vision more than do solutions. Miotic-induced spasm and myopia may respond to use of a clip-on minus lens, but may necessitate withdrawal of miotic therapy in some patients; epinephrine or timolol may be a useful substitute for miotic therapy, but only if the angle is confirmed by gonioscopy to be open. Miosis may reduce the background illumination of the eye enough in some patients to make glaucomatous field defects appear to enlarge. If a visual defect worsens in a patient receiving miotic therapy, the field should be retested after the pupil is dilated. Rarely, retinal detachment may occur and may be precipitated by ciliary spasm in patients with peripheral retinal degenerative changes receiving miotics, especially anticholinesterases, although the exact cause is not clear. A macular hole occurred in one patient treated with pilocarpine.

Other adverse ocular effects of the miotics include ciliary or conjunctival congestion, lacrimal passage stenosis, twitching of the eyelids, stinging, burning, lacrimation, ocular or brow pain, headache, photophobia, and increased visibility of floaters. Pain is usually relieved by analgesics such as salicylates.

Nodular excrescences of the iris pigment epithelium (“iris cysts”) may form at the pupillary margin, enlarge, and obscure vision following prolonged use of long-acting anticholinesterases, especially in children; iris cysts occur rarely with the other miotics. Appearance of these cysts appears to be related to the frequency of administration of the drug. Cysts usually shrink and disappear upon reduction in dosage or withdrawal of the drug; rarely, a cyst may rupture or break free into the aqueous humor. Simultaneous administration of 2.5–10% phenylephrine hydrochloride ophthalmic solution may prevent development of iris cysts. Phenylephrine will not prevent iris cysts caused by long-acting anticholinesterase therapy if the two drugs are administered several hours apart.

Anterior chamber flare or hyperemia may occur, especially with the anticholinesterases, because of increased blood-aqueous permeability and vasodilation in the conjunctiva and iris. Long-acting anticholinesterases may increase the frequency of hemorrhage (hyphema) during ocular surgery. Acute fibrinous iritis has occurred rarely within a few days after initiation of anticholinesterase therapy, although a direct causal relationship with the drugs has not been established. Activation of latent iritis or uveitis may occur with long-term use of miotics. Aggravation of inflammatory processes such as iritis, acute iridocyclitis, or inflammation after ocular surgery may lead to development of posterior synechiae; this effect occurs most frequently in patients receiving long-acting anticholinesterases and is rare in children.

Lens opacities have been reported in patients receiving miotic therapy, possibly because of a change in lens metabolism. Anterior subcapsular lens vacuoles and mossy opacities are the first changes observed. The incidence of cataracts appears to be highest in patients treated with long-acting anticholinesterases and seems to be related to age of the patient (higher in patients older than 60 years of age), drug concentration, frequency, and duration of therapy (6 months or longer). Lens opacities usually regress if miotic therapy is discontinued early in their development; however, once established, cataracts are often progressive despite discontinuation of miotic therapy.

Hypersensitivity reactions such as allergic conjunctivitis, dermatitis, or keratitis occur frequently with physostigmine and occasionally with the other miotics. These reactions are usually alleviated by changing to another miotic. In some instances, allergic reactions may be caused by preservatives in the preparations.

Prolonged use of anticholinesterases (months to years) may result in loss of tone of the dilator muscle fiber and formation of fine synechiae, leading to a persistent miosis following withdrawal of the drug. Follicular conjunctival hypertrophy may occur from prolonged use of pilocarpine or physostigmine and rarely with isoflurophate (no longer commercially available in the US). Long-term administration of physostigmine or isoflurophate may cause slowly reversible depigmentation of the lid margins in blacks.

Systemic Effects

Systemic toxicity may occur, especially with frequent or prolonged topical instillation of a miotic. Toxicity occurs most commonly with the long-acting anticholinesterases as a result of reduction of tissue cholinesterases; however, isoflurophate ointment seldom caused systemic toxicity, except in high doses, because of its slow systemic absorption and rapid hydrolysis. Systemic reactions after chronic topical application of other miotics to the eye or intraocular injection of acetylcholine or carbachol are rare and usually occur only with very frequent administration of the drug (e.g., in the treatment of acute angle-closure glaucoma). Systemic miotic toxicity occurs less frequently and tends to be milder and of shorter duration in children than in adults.

Adverse systemic effects of miotics result from parasympathetic stimulation and the most common effects, especially in children, include nausea, vomiting, diarrhea, epigastric distress, abdominal and/or intestinal pain or cramps. With the long-acting anticholinesterases, these adverse GI effects may be severe and may be mistaken for acute gastroenteritis. In addition, frequent urination, tightness of the urinary bladder, excessive salivation, lacrimation, sweating, flushing, headache, pallor, cyanosis, bronchoconstriction or increased secretion, nasal congestion, and rhinorrhea may occur. Systemically absorbed miotics may precipitate an attack in asthmatics. There is a risk of cardiac arrest after vagal stimulation during surgery in patients receiving anticholinesterases. One patient treated with a high dose of pilocarpine for glaucoma experienced disturbances in the middle ear and eustachian tube, which improved on reduction of dosage. Vertigo, tremors, muscle weakness, paresthesia, bradycardia, cardiac arrhythmias, hypotension, syncope, increased systemic vascular resistance, and CNS excitation followed by depression, confusion, ataxia, seizures, and coma occur with severe miotic toxicity. Echothiophate has been reported to cause hyperactivity in children with Down’s syndrome in spite of normal serum cholinesterase concentrations. In acute miotic poisoning, death may result from respiratory or, less commonly, cardiovascular (impaired atrioventricular conduction, heart block, decreased atrial contractility) collapse. Alcoholic beverages may increase the severity of systemic toxicity of the anticholinesterases.

Miotics should be discontinued, at least temporarily, if systemic symptoms occur. In the treatment of severe systemic miotic toxicity, maintaining adequate respiration is of primary importance. Tracheostomy, bronchial aspiration, and postural drainage may be required to maintain an adequate airway; respiration can be assisted mechanically or with oxygen, if necessary. Some manufacturers of miotics suggest that 0.4–2 mg of atropine sulfate be administered IV or IM, but many clinicians recommend 1–4 mg of atropine sulfate IV, IM or subcutaneously. Additional doses of atropine may be given every 3–60 minutes as needed to control muscarinic symptoms, and then as needed for 24–48 hours; as much as 50 mg of atropine sulfate may be required in the first 24 hours. The dose of atropine sulfate in children is 0.04–0.08 mg/kg up to 4 mg IM or IV; the IV dose may be repeated every 5 minutes and the IM dose every 15 minutes. Atropine should be administered with caution if the patient is cyanotic because of the risk of ventricular fibrillation. It should be kept in mind that, unlike muscarinic effects, the skeletal muscle effects and consequent respiratory paralysis that can occur following parasympathomimetic overdosage are not alleviated by atropine. IV pralidoxime chloride may be used as an adjunct to atropine therapy to reverse the muscle paralysis resulting from nicotinic effects of the anticholinesterases. A short-acting barbiturate may control seizures not relieved by atropine; dosage should be carefully adjusted to avoid respiratory depression. Accidental ingestion of an overdose of the miotics requires the same treatment; a 0.02% solution of potassium permanganate may be employed for gastric lavage to detoxify alkaloids such as physostigmine or pilocarpine.

Precautions and Contraindications

Although withdrawal of the iris from the angle by miosis reduces the tendency for angle closure, a transient increase in IOP may occur even when the angle is open. In some patients with angle-closure glaucoma receiving miotics, IOP may be increased and acute attacks may be precipitated; the risk is much higher with long-acting anticholinesterases than with other miotics. For this reason, long-acting anticholinesterases are contraindicated in most patients with angle-closure glaucoma prior to surgery and should be avoided in other forms of glaucoma due to unrelieved pupillary block. Prior to therapy with long-acting anticholinesterases, gonioscopic examination should confirm that the angle of the eye is open. Miotics appear to reduce ocular rigidity, so that Schiotz readings of IOP are inaccurate; applanation tonometry should be used in patients receiving these drugs. Tonometric measurements should be done at least hourly for the first 3–4 hours after the initial instillation of long-acting anticholinesterases to detect an unexpected rise in IOP. If angle closure occurs, the angle usually opens slowly after discontinuance of miotic therapy.

Because of the spasm of accommodation and poor vision in dim light, patients receiving miotic therapy, particularly geriatric patients or those with lens opacities, should avoid driving at night.

Since retinal detachment may rarely occur (see Ocular Effects in Cautions: Adverse Effects), miotics should be used with extreme caution, if at all, in patients with a history or risk of retinal detachment, especially the young and those who are aphakic. Careful examination of the retinal periphery of patients treated with miotics should be done at least annually to detect an impending detachment; a sudden drop in IOP may indicate that retinal detachment has occurred.

Miotics are contraindicated in patients in whom pupillary constriction is undesirable, such as in those with glaucomas associated with acute inflammatory processes, especially where posterior synechiae may occur.

Slit-lamp examinations should be performed regularly, and miotic therapy should be discontinued, at least temporarily, if iris cysts, iritis, synechiae, or lens opacities occur.

Some commercially available preparations of physostigmine contain sodium bisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.

A miotic should be discontinued if sensitivity develops or if the original irritation persists or increases. Miotics are contraindicated in patients hypersensitive to any component of the preparation.

Although no studies have been published, the possibility that miotics may be absorbed by soft contact lenses should be considered. In addition, preservatives used in miotic preparations may have a deleterious effect on soft lenses. Therefore, it is probably advisable to remove soft contact lenses from the eye before applying miotics. Although epithelial roughening caused by hard contact lenses may increase ocular penetration of the miotic, this effect probably is not clinically important.

Miotics should be used with caution in patients with corneal abrasion to avoid excessive penetration and systemic toxicity.

Serum cholinesterase concentrations are not entirely reliable in predicting which patients will experience adverse systemic effects with anticholinesterases; some patients with low concentrations experience no toxicity. With the anticholinesterases, toxicity is usually cumulative and symptoms, which may not appear for weeks or months, may not be recognized as toxicity.

There are no known contraindications to intraocular acetylcholine or carbachol therapy. Topical miotics, particularly long-acting anticholinesterases, should be used with extreme caution, if at all, in patients with marked vagotonia, bronchial asthma, spastic GI conditions, urinary tract obstruction, peptic ulcer, severe bradycardia, hypotension, vascular hypertension, hyperthyroidism, acute cardiac failure, recent myocardial infarction, epilepsy, marked vasomotor instability, or parkinsonism. If possible, therapy with long-acting anticholinesterases should be discontinued 2–6 weeks prior to surgery, and pilocarpine should be substituted.

Bacterial keratitis has been reported with the use of multidose containers of topical ophthalmic preparations. These containers had been contaminated inadvertently by patients who, in most cases, had a concurrent corneal disease or disruption of the ocular epithelial surface. Patients should be informed that improper handling of ocular solutions can result in contamination of the solution by common bacteria known to cause ocular infections and should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures. Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic solutions. Patients also should be advised to seek their physician’s advice immediately regarding the continued use of the present multidose container if an intercurrent ocular condition (e.g., trauma, ocular surgery or infection) occurs.

Pediatric Precautions

Safety and efficacy of carbachol in pediatric patients have not been established.

Pregnancy and Lactation

Pregnancy

Safe use of miotics in pregnancy has not been established. Because of the potential risks of cholinesterase inhibition in general, the manufacturers of some anticholinesterases (e.g., demecarium, isofluophate [no longer commercially available in the US]) state that the drugs are contraindicated in women who are or may become pregnant, and that women who receive the drug inadvertently during pregnancy or who become pregnant while receiving the drug should be apprised of the potential hazard to the fetus.

The manufacturers of carbachol state that carbachol should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Lactation

Since it is not known if carbachol is distributed into milk, the drug should be used with caution in nursing women.

Drug Interactions

Ocular Hypotensive Agents

When used in conjunction with topical epinephrine, topical timolol, and/or systemically administered carbonic anhydrase inhibitors, the effect of miotics in lowering IOP may be additive. This effect may be used to therapeutic advantage in the treatment of glaucoma.

Miotics

Although low doses (those not producing maximal miosis) of pilocarpine and an anticholinesterase may produce additive miosis, the miotic effect and presumably the IOP-lowering effect of the anticholinesterases is competitively inhibited by pilocarpine in doses used in glaucoma treatment. To minimize adverse reactions of long-acting anticholinesterases, some clinicians recommend that pilocarpine be administered at the onset of long-acting anticholinesterase therapy and tapered off gradually so that the antagonism between the drugs allows the full effects of the anticholinesterase to be obtained gradually. The short-acting anticholinesterase, physostigmine, blocks the binding to receptors and the pharmacologic effects of subsequently administered long-acting anticholinesterases.

Systemic Cholinesterase Inhibitors

Systemic cholinesterase inhibitors (e.g., neostigmine, physostigmine, pyridostigmine) may produce additive systemic effects with ophthalmic anticholinesterases and vice versa, and the drugs should be administered together with extreme caution. The effects of an anticholinesterase miotic that has been absorbed systemically are additive or possibly synergistic with systemically absorbed anticholinesterase pesticides; therefore, patients who receive anticholinesterase miotics and who may be exposed to anticholinesterase pesticides should wear respiratory masks, wash frequently, and change clothing frequently.

Anesthetic Agents and Adjuncts to Anesthesia

Cholinesterase inhibitors may potentiate the effects of some general anesthetics and caution must be observed if patients receiving an anticholinesterase must undergo general anesthesia with cyclopropane or halothane. Extreme caution should be exercised in patients receiving anticholinesterases who subsequently receive succinylcholine prior to general anesthesia; the reduced pseudocholinesterase concentrations prevent hydrolysis of the neuromuscular blocking agent, which may cause prolonged apnea, cardiovascular collapse, and death. Determination of pseudocholinesterase concentrations before succinylcholine administration may indicate which patients are susceptible to this reaction. Although the clinical importance has not been established, severe systemic effects, resulting from inhibition of hydrolysis of the local anesthetic by pseudocholinesterase, reportedly may occur with usual doses of ester-type local anesthetics (e.g., procaine [no longer commercially available in the US]) in patients receiving prolonged topical anticholinesterase therapy; carbocaine and lidocaine are not affected.

Other Drugs

Although the clinical importance has not been established, the miotic and/or ocular hypotensive effects of some miotics reportedly may be antagonized by long-term topical or systemic corticosteroid therapy, topical nonsteroidal anti-inflammatory agents, systemic anticholinergics, antihistamines, meperidine, sympathomimetics, and tricyclic antidepressants, and the miotic effects of anticholinesterases may be potentiated by pantothenic acid and clofibrate (no longer commercially available in the US).

Pharmacology

Miotics are direct-acting (acetylcholine, carbachol, pilocarpine) or indirect-acting (demecarium, echothiophate [no longer commercially available in the US], isoflurophate [no longer commercially available in the US], physostigmine) parasympathomimetic agents. Methacholine, which is commercially available only in combination products, is also a direct-acting parasympathomimetic. The pharmacologic effects of all the miotics are similar; they differ primarily in ocular and systemic absorption, duration of action, and degree of effects.

Acetylcholine, an endogenous mediator of nerve impulses, stimulates cholinergic receptors, resulting in muscarinic and nicotinic effects. The action of acetylcholine is transient; the drug is rapidly hydrolyzed by cholinesterases (acetylcholinesterase and pseudocholinesterase) to choline and acetic acid. Pilocarpine, carbachol, and methacholine also directly stimulate cholinergic receptors; however, these drugs have a more prolonged duration of action (several hours) than does acetylcholine. There is some evidence that carbachol also has a weak anticholinesterase effect; it may also increase the release of acetylcholine following nerve stimulation.

The indirect-acting miotics (anticholinesterases) bind with and inactivate postsynaptic cholinesterases, thus inhibiting hydrolysis of acetylcholine. As a result, acetylcholine accumulates at cholinergic synapses and its effects are prolonged and exaggerated. The organophosphates (echothiophate [no longer commercially available in the US] and isoflurophate) phosphorylate cholinesterase and their effects are relatively “irreversible,” except by the cholinesterase reactivator pralidoxime. The effects of the organophosphates persist for days or even weeks until new cholinesterase is synthesized. Physostigmine and demecarium inactivate cholinesterases by carbamylation. Physostigmine is gradually destroyed, liberating cholinesterase; therefore, its effects are “reversible” and persist only a few hours longer than those of the direct-acting miotics. Although demecarium is also a “reversible” anticholinesterase, it is more resistant to hydrolysis by cholinesterase than is physostigmine and, therefore, has a duration of action similar to the organophosphates.

Following topical application to the conjunctival sac or intraocular injection, miotics cause contraction of the iris sphincter and the ciliary muscle, which produces constriction of the pupil (miosis) and spasm of accommodation, respectively. Unlike direct-acting miotics, the anticholinesterases have no effect on denervated structures and will not constrict the pupil during retrobulbar anesthesia.

Miotics reduce intraocular pressure (IOP) in normal and glaucomatous eyes. The mechanism of action of the drugs in lowering IOP has not been precisely determined. In patients with open-angle (chronic simple, noncongestive) glaucoma, the drugs facilitate aqueous humor outflow, apparently by causing contraction of the ciliary muscle and widening of the trabecular meshwork. Reduction of IOP in angle-closure (closed-angle, narrow-angle, obstructive) glaucoma is thought to result from constriction of the pupil and stretching of the iris which relieves blockage of the trabecular meshwork by the peripheral iris. Miotics are less effective in producing miosis and reducing IOP in dark (black, brown, or hazel) than in light-colored eyes because of absorption of the drug by the pigment. Miosis, ciliary spasm, and vascular congestion produced by the miotics cause progressive shallowing of the anterior chamber, increased contact of the lens with the iris, and increased physiologic iris bombé, possibly resulting in angle closure and increased IOP. Angle closure is most likely to occur in patients with narrow angles receiving long-acting anticholinesterases.

Miotics decrease activity of extraocular muscles of convergence. The drugs also cause vasodilation of blood vessels of the conjunctiva, iris, and ciliary body and increased permeability of the blood-aqueous barrier, which may lead to vascular congestion and ocular inflammation; these effects are most common with the long-acting anticholinesterases.

Systemically absorbed miotics produce parasympathomimetic effects on various body systems. (See Systemic Effects in Cautions: Adverse Effects.)

Miotics General Statement Pharmacokinetics

Absorption

Following topical instillation into the conjunctival sac, penetration of miotics into ocular tissues occurs through the cornea and varies with the drug, dosage form, concentration, volume and frequency of application, tear production, loss through the lacrimal drainage system, and absorption by ocular tissues. After topical application to the eye, acetylcholine is almost immediately destroyed by cholinesterases. Topical carbachol penetrates intact corneal epithelium very poorly; combination with a wetting agent such as benzalkonium chloride 0.03% greatly improves corneal penetration by the drug. Demecarium, echothiophate (no longer commercially available in the US), isoflurophate [no longer commercially available in the US], physostigmine, and pilocarpine reportedly penetrate the cornea rapidly; the penetration of these drugs is not greatly enhanced by wetting agents.

Occasionally, enough miotic may be absorbed through the conjunctiva and lacrimal drainage system to cause systemic parasympathomimetic effects, especially with frequent or prolonged use of ophthalmic solutions. The anticholinesterases and carbachol are also absorbed through intact skin. Because systemic absorption from ointment bases is minimal and isoflurophate undergoes hydrolysis in the circulation almost immediately, isoflurophate ophthalmic ointment produces limited systemic effects. Systemic anticholinesterase activity is detectable within a few minutes after ocular application of demecarium or echothiophate solutions. Following long-term topical application, these anticholinesterases reduce red blood cell, serum, and tissue cholinesterase concentrations in most patients; reduced concentrations may persist several weeks after the drugs are discontinued.

Distribution

Pilocarpine is bound to serum and ocular tissues. The organophosphates (echothiophate [no longer commercially available in the US] and isoflurophate) or their metabolites may be bound to proteins in the blood and tissues.

Elimination

Acetylcholine, demecarium, and physostigmine are hydrolyzed by cholinesterases, although hydrolysis of demecarium and physostigmine occurs much more slowly than that of acetylcholine. The mechanism by which pilocarpine is inactivated in the body is unclear. The organophosphates (echothiophate [no longer commercially available in the US] and isoflurophate) are oxidized and hydrolyzed in the tissues by phosphorylphosphatases. The organophosphates are excreted almost entirely as metabolites in urine.

Related Monographs

For specific information on dosages and additional information on the miotics available as single entities, see the individual monographs in 52:40.20.

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