Ординатура / Офтальмология / Английские материалы / Ophthalmic Drugs Diagnostic and Therapeutic Uses 5th edition_Hopkins, Pearson_2007
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MIOTICS ACTING ON THE PUPIL DILATOR MUSCLE
As the sympathetic innervation to the dilator muscle is stimulatory (motor), it is logical that alpha-receptors predominate. The effect of noradrenaline on this muscle can be blocked by an alpha-blocking agent. Many alpha-blocking agents are available for use in general medicine. They are used in the treatment of hypertension and peripheral vasospastic conditions, but only moxisylyte (thymoxamine) has been formulated as an eyedrop. Unfortunately, this is no longer available.
Studies have been carried out with a new alpha-blocking drug dapiprazole (Molinari et al 1994), which is available to eyecare practitioners in the USA and Canada under the Trade Name Rev-Eyes; it is not available in the UK.
PARASYMPATHOMIMETIC MIOTICS
Parasympathomimetic miotics can be grouped into choline esters, which are derivatives of acetylcholine, and cholinomimetic alkaloids, which include pilocarpine, arecoline and muscarine. By far the most commonly used parasympathomimetic miotic is pilocarpine.
PILOCARPINE
Obtained from the leaves of Pilocarpus microphyllus (the Jaborandi plant) and other species of Pilocarpus, pilocarpine is a colourless, syrupy, liquid alkaloid that is soluble in water. The hydrochloride salt, which is freely soluble in less than one part of water, is now preferred to the nitrate (previously used) in the preparation of the eyedrops, because it is compatible with a wide range of antimicrobial preservatives.
Mechanism of action Pilocarpine is a direct-acting parasympathomimetic agent (compare with the indirect-acting physostigmine). Like all such agents (including also such synthetic choline esters as carbachol and bethanecol), its primary action is the stimulation (or inhibition) of autonomic effector cells in a similar manner to that accomplished by the acetylcholine released by stimulation of postganglionic parasympathetic nerves, that is, it acts primarily at muscarinic receptors of autonomic effector cells. Koelle (1975) states that it also has some nicotinic ganglionic effects, but part of this secondary ganglionic action involves stimulation of muscarinic receptors, which are now known also to be present in varying proportions on autonomic ganglion cells. The nicotinic actions of parasympathomimetic drugs refer to their initial stimulation and, in higher dosage, to subsequent blockade (as with nicotine) of autonomic ganglion cells and neuromuscular junctions. All the actions of pilocarpine and other parasympathomimetic drugs (as well as ACh) can be blocked by atropine through competitive occupation of the cholinoceptive sites on
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autonomic effector cells, and on the secondary muscarinic receptors of autonomic ganglion cells.
Bowman & Rand (1980) consider the nicotinic action to be very weak; in this, pilocarpine resembles the endogenous mediator acetylcholine. However, it does not, like the latter, stimulate the motor endplates of skeletal muscle in normal doses. Its systemic effects are also similar to its fellow cholinomimetic alkaloid, muscarine: it slows the heart and pulse; increases peristalsis; constricts the bronchioles; and increases the secretions of the salivary, lacrimal, gastric, pancreatic and intestinal glands, and also of the mucous glands of the respiratory tract. Pilocarpine causes marked sweating, as a result of its direct stimulatory action on the sweat glands and vasodilatation of blood vessels in the skin, this latter effect producing flushing in man. As long ago as 1975, Langley described pilocarpine’s peripheral dilator actions. Large doses of pilocarpine at first stimulate then depress the CNS. It will have been noted that physostigmine, taken orally, produces all these effects, but in this case they are caused by this anticholinesterase prolonging the activity of acetylcholine and not, as with pilocarpine, by the direct excitatory (or inhibitory) action of the alkaloid itself on the cholinoceptive receptor sites.
Ophthalmic Applied locally to the eye as a 0.5–4% solution (the 1% strength is the preparations most commonly used by practitioners), pilocarpine hydrochloride (or nitrate) causes a miosis that, after commencing in about 10 min, is maximal within half an hour and gradually decreases over a period of 6 hours with the 1% solution (Lowenstein 1956). Although the spasm of the ciliary muscle can last for up to 2 hours, unlike the spasm following physostigmine, once it has worn off this spasm does not return if near
work is commenced.
Whereas pilocarpine 1% adequately reconstricts the mydriasis produced by sympathomimetic agents, it appears unnecessary to use the more powerful but also more uncomfortable physostigmine, although the latter appears necessary to satisfactorily reverse the mydriasis following antimuscarinic eyedrops. This view coincides with that of Anastasi et al (1968), who found that pilocarpine 1% counteracted the effects of phenylephrine and hydroxyamphetamine (another sympathomimetic mydriatic) in concentrations usually used in ophthalmology within 30 min, but that after mydriasis with antiparasympathomimetic agents, such as tropicamide and homatropine, pilocarpine did not cause effective miosis.
Like physostigmine, pilocarpine is ineffective in the presence of atropine. Atropine competes successfully with pilocarpine for the effector cell receptor but, unlike pilocarpine, does not result in the excitation of these cells.
The miotic effect of pilocarpine produces rather marked individual differences in the latent period before miosis, in the rate, the degree and the duration of contraction and the time factor for redilatation (Lowenstein & Loewenfeld l953). Strength for strength it is only about
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half as powerful a drug as physostigmine and thus a 1% solution does not produce the extreme degree of miosis that the anticholinesterase agent does in this concentration. Neither is the spasm of accommodation nearly as marked or as painful as when physostigmine is used. However, for a patient with light-coloured irides, the amount of pseudomyopia could be sufficient to cause problems driving (Gilmartin et al 1995).
After pilocarpine has diffused out of the eye, the pupil on recovery remains slightly more dilated than normal, because of a diminished response of the sphincter pupillae to normal reflex stimulation after the direct action of the pilocarpine. The lack of recurring accommodative spasm on attempting close work, together with the absence of pain and discomfort, are advantages of pilocarpine over physostigmine, but the latter is a more reliable miotic in counteracting the dilatation of the pupil caused by the antimuscarinic mydriatics, as the effects of these might outlast those of the pilocarpine, in which case the pupils will redilate.
In addition to the effect of the drug on the ciliary and sphincter pupillae muscles, pilocarpine increases the flow of blood through the vasculature of the anterior uvea (Alm & Bill 1973).
CARBACHOL
Carbachol occurs as very hygroscopic colourless crystals or a white crystalline powder. It is used in general medicine to produce motility of the gut in postoperative paralytic ileus and contraction of the bladder in non-obstructive conditions of urinary retention. Carbachol, a quaternary ammonium parasympathomimetic drug (direct action), has muscarinic and nicotinic properties and is not rapidly inactivated by cholinesterase. It can be used as a miotic in a 3% solution in the treatment of glaucoma, and is a useful alternative to pilocarpine and to other miotics when resistance or intolerance has developed. However, it was not considered a suitable agent in the treatment of accommodative esotropia because of its irregular onset and short duration of action.
The British Pharmaceutical Codex (BPC; 1973) eyedrops contain up to 3% of carbachol but, as an alternative miotic for pilocarpine allergic patients, the optometrist should find a 0.5% strength adequate to reverse sympathomimetic mydriatics. As the only prepacked proprietary ophthalmic solution (Isopto Carbachol) is 3%, extemporaneous preparation of a 0.5% eyedrops by the pharmacist is required. As it is poorly absorbed through the cornea the drops include a wetting agent, such as benzalkonium chloride, which also performs the additional role of acting as a bactericide. It is a derivative of, but more stable than, acetylcholine.
ACETYLCHOLINE CHLORIDE + MANNITOL (MIOCHOL-E)
Synthetically manufactured acetylcholine chloride is a white, very hygroscopic crystalline powder. Very soluble in water, it is a powerful parasympathomimetic agent but, when injected, its action is very transient because it is so rapidly hydrolysed by cholinesterase. It has the
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same action as endogenous acetylcholine but has been largely replaced in medicine by the more stable synthetic parasympathomimetics discussed above. However, a freshly prepared 1% solution incorporating 5% mannitol, a white crystalline powder soluble 1 in 6 in water, acting as an osmotic agent in the combination, intensifies the effect of the acetylcholine. This preparation is used in intraocular surgery after cataract extraction to constrict the pupil in seconds. A solution of acetylcholine instilled into an intact eye will not cause miosis as this substance would be hydrolysed by acetylcholinesterase long before it could reach an effective concentration in the anterior chamber aqueous.
BETHANECOL CHLORIDE (URECHOLINE, MECOTHANE)
Bethanecol chloride occurs as white hygroscopic crystals or a crystalline powder, soluble 1 in 1 in water. It has the same uses in general medicine as carbachol. A quaternary ammonium parasympathomimetic agent that is not inactivated by cholinesterase (Martindale 1977), it has a muscarinic but – unlike carbachol – no nicotinic, action (Koelle 1975). Bethanecol is used in a 1% solution as a miotic and, like carbachol, also needs a wetting agent to help it penetrate the cornea.
As there are no official or proprietary ophthalmic preparations available, eyedrops have to be prepared extemporaneously by the pharmacist if required and, indeed, if the basic compound can be obtained. In reality, this particular miotic must at this stage be considered as part of history and is included here only for completeness.
METHACHOLINE CHLORIDE
Methacholine chloride occurs as deliquescent colourless or white crystals or a white crystalline powder, soluble in less than one part of water. It has the muscarinic action of acetylcholine but is more stable, and was used in general medicine to terminate attacks of atrial paroxysmal tachycardia when simpler methods have failed.
Although the two synthetic parasympathomimetic drugs – carbachol and methacholine – generally possess the same muscarinic actions as acetylcholine (slowing of the heart, increased peristalsis, dilatation of peripheral blood vessels and increased salivary, sweat and bronchial secretion) there is some selectivity on particular structures. For example, carbachol is relatively more effective on the gastrointestinal tract and bladder, whereas methacholine is relatively more effective on the cardiovascular system. Normal pupils require a 10–20% solution to produce miosis and this drug has also been used in these strengths for the treatment of simple glaucoma, although other miotics are now generally preferred, principally because of availability. Contraindications and precautions are similar to those appertaining to pilocarpine. Methacholine is hydrolysed by acetylcholinesterase, but even alone in an adequate concentration it is successful in producing a marked miosis (and spasm of accommodation and lid twitching) by its direct action, as it has some resistance to this enzyme.
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ANTICHOLINESTERASES
Anticholinesterase agents can be divided into reversible and irreversible agents, depending on their duration of action. Anticholinesterases and acetylcholine are taken up by cholinesterase in the same way. There then follows a series of reactions in which the anticholinesterase or acetylcholine is broken down and the enzyme regenerated. The difference is that the reactions when acetylcholine is the substrate are very fast, whereas for anticholinesterase they are very slow. If the anticholinesterase is an irreversible one, the regenerating reactions are thought to take place at such a slow rate that – effectively – they do not take place and the body manufactures new enzyme.
Anticholinesterases are sometimes erroneously referred to as indirectacting parasympathomimetics, which patently they are not. An indirect parasympathomimetic would have an action on the nerve terminal (cf indirect sympathomimetics), which these drugs do not have. Additionally, their use in the treatment of myasthenia gravis has nothing to do with the parasympathetic system. Such terms are misleading and should be avoided.
REVERSIBLE ANTICHOLINESTERASES
The principal agents in this group are physostigmine (eserine) and neostigmine.
Physostigmine (eserine) Physostigmine is an alkaloid obtained from the seeds of Physostigma venenosum (Calabar beans) and can also be prepared synthetically. It forms large, colourless crystals, which are sparingly soluble in water (1 in 75) but the official salt, the sulphate, is deliquescent and has a solubility in less than 1 part of water, and the salicylate (which stings rather less when used in the eyedrops) is soluble 1 in 90 parts water. Because of the greater solubility of the sulphate and its compatibility with a wider range of preservatives, it is now preferred to the salicylate for the preparation of eyedrops.
Physostigmine eyedrops are not now available prepacked by pharmaceutical manufacturers in the UK but can be prepared extemporaneously, if necessary, by the pharmacist – a costly process. Like the alkaloid itself, on exposure to light and air solutions of physostigmine salts become pink, especially the sulphate, due to oxidation. This results in the formation of rubreserine, which is more irritating to the eye than eserine, even though the miotic effect is maintained. Physostigmine eyedrops, usually contain an antioxidant to retard formation of this degradation product. Roger & Smith (1973) have brought this problem into perspective by their investigations into the stability of physostigmine eyedrops. They found that the 0.25%, 0.5% and 1% eyedrops, prepared in accordance with the BPC, 1973 formula (pH 3.6–3.8) and sterilized by heating or filtration, retained more than 99% of their activity
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after storage at 25°C for 1 year. A faint pink colour appeared after sterilization by heat and was also present in all samples after storage for this time. It would appear from these researches that filtration might be the method of choice to obtain colourless eyedrops from the date of manufacture. However, despite a faint pink coloration, as long as the date of manufacture is within a year, and the interval after first opening the container not more than a month, it would appear to be in order to use these drops.
Mechanism of action Physostigmine is an anticholinesterase (anti-AChE) drug. The role of this enzyme in terminating the action of the transmitter acetylcholine, liberated by cholinergic nerve impulses at junctions with their effector organs, and at synaptic sites, was discussed in Chapter 2. Thus physostigmine allows the acetylcholine to accumulate at sites of cholinergic transmission and, as the action of the acetylcholinesterase on the acetylcholine is being inhibited, the effect will be similar to continuous stimulation of these cholinergic fibres. Physostigmine is an excellent example of this class of drug but because the chemical complex of drug and acetylcholinesterase is only temporary and finally dissociates, its effects are limited to about 12 hours or so and it is termed a reversible anticholinesterase. This is in contrast to the effects of very much more potent organophosphate compounds, which also act in this manner, but for very prolonged periods (from days to weeks); these are called irreversible anticholinesterase drugs, for example Dyflos (see later). The latter are extremely toxic compounds and are never used by optometrists. The irreversible anticholinesterases form extremely stable complexes with the enzyme (acetylcholinesterase) and, in the case of the physostigmine–enzyme complex, slow hydrolysis eventually results in regeneration of the cholinesterase.
Physostigmine, when topically applied to the eye, therefore permits a prolonged stimulation by acetylcholine of the ciliary and sphincter pupillae muscles, which result in spasm of accommodation and miosis, respectively. Conjunctival hyperaemia also occurs due to the peripheral vasodilatory effects of this miotic.
In the body, the cholinergic fibres of the parasympathetic system slow the heart and pulse rate, increase peristalsis, salivary, bronchial and gastric secretions and dilate peripheral blood vessels. Taken orally, physostigmine therefore enhances these cholinergic effects. It is not surprising that this drug in toxic doses causes slow pulse, vomiting, diarrhoea, intestinal colic and flushing.
Ophthalmic preparations Physostigmine is little used today as a miotic. Ophthalmic aqueous solutions of 0.25%, 0.5% and 1% (or even 2% in an acute attack of glaucoma) of either the official sulphate or salicylate, and the alkaloid itself in similar strengths in a castor oil vehicle (although the latter is no longer official), are the usual forms in which it is administered.
Strength for strength, physostigmine is about twice as active as pilocarpine, that other most useful miotic. On instillation of eyedrops of this anticholinesterase drug, constriction of the pupil commences in
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between 5 and 10 min and miosis is maximal in about 30 min. The effects last up to 12 hours or more with a 0.5% solution, and somewhat less with the 0.25% solution.
Physostigmine ointment 0.5% (the BPC 1973 eye ointment was 0.125%) causes an intense miosis continuing for 12–36 hours (Havener 1978) but this is no longer available.
The physostigmine 1% eyedrops should not be used by optometrists, even in the emergency produced by a sudden attack of acute glaucoma. Because of the pain and discomfort this concentration causes, this strength is unsuitable for constricting the dilated pupil of the normal eye after mydriatic examination. The marked pupillary contraction resulting from instillation of a 1% solution, the pupil diameter being less than 2 mm, persists for more than 12 hours, and its normal size might not be regained for a few days. Eyedrops of this concentration should be reserved for the medical treatment of the later stages of simple glaucoma, when weaker strengths and weaker miotics (e.g. pilocarpine) no longer control the rise in tension.
The 0.25–0.5% solutions of physostigmine, particularly the former, are the more usual concentrations of this miotic, and the 0.25% proves to be quite adequate in constricting the pupil in about half an hour, following the dilatation produced by the mydriatic concentrations of such antimuscarinic eyedrops as cyclopentolate hydrochloride 0.1%, homatropine hydrobromide 0.25–0.5%, eucatropine 2–5% and tropicamide 0.5%.
IRREVERSIBLE ANTICHOLINESTERASES
Many agents in this group are chemically related to the organophosphorus compounds. They were originally developed as nerve gases and insecticides but some have found medical uses, e.g. di-isopropyl fluorophosphonate (Dyflos; now unavailable) and ecothiopate, which has a restricted supply.
Ecothiopate iodide Ecothiopate iodide is an irreversible, organophosphorous, anticholinesterase miotic, used in 0.06–0.25% solution mainly in the treatment of open-angle glaucoma. It considerably improves the facility of outflow in these glaucomatous eyes (Drance & Carr 1960) but is not without some adverse effects. These include such systemic toxic effects in some patients (frequency of dosage is an important factor here) as diarrhoea, nausea, abdominal cramps and general weakness and fatigue (Humphreys & Holmes 1963) and – locally – iris cysts. It is also used on occasion in the treatment of accommodative esotropia in children. The iris cysts (which also occur with prolonged Dyflos therapy) disappear when the miotics are discontinued, or can usually be prevented from forming by the simultaneous use of phenylephrine (2.5–10.0%), which does not impair the therapeutic effect of the ecothiopate (Abraham 1964).
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Ecothiopate eyedrops must be freshly prepared by the pharmacist in a diluent supplied by the manufacturers, the drops only remaining stable if the solution is kept refrigerated. Ecothiopate iodide is not available for use by optometrists.
ALPHA-BLOCKING AGENTS (ALPHA-1 ANTAGONISTS)
MOXISYLYTE (THYMOXAMINE)
The principal agent in this group is moxisylyte, which is purely an alphablocker and has little beta-blocking activity. Many other alpha-blockers have been isolated (e.g. tolazoline, phentolamine and ergotoxine) but only moxisylyte was used ophthalmically. Unfortunately, it is no longer available commercially. It causes miosis by relaxing the pupil dilator muscle. Its main indication is the reversal of mydriasis caused by sympathomimetic agents. When a 0.1% solution was used to reverse the mydriasis caused by 2.5% phenylephrine, the pupil returned to normal in about 2 hours, compared with 5 hours for the control eye that received only the mydriatic (Wright et al 1990). It also would appear to have some activity in overcoming the mydriasis caused by tropicamide. Moxisylyte can be used intraocularly (Grehn et al 1986). It produces no endothelial damage when used in very dilute concentration (e.g. 0.02%) and is potentially useful in cataract surgery and penetrating keratoplasty. Its miotic effects are modified by iris pigmentation to such an extent that it is poorly effective on dark brown irides (Diehl et al 1991).
In addition to its miotic action, moxisylyte paralyses the smooth muscle of the upper lid, causing a slight ptosis. For this effect it has been used in the treatment of exophthalmos. These effects are most notable in patients with thyroid problems. There would appear to be little effect on normal patients (Dixon et al 1979). Its effects last for about 5 hours.
There appears to be little effect on ciliary muscle or on intraocular pressure in eyes with deep anterior chambers. The latter is surprising as phenylephrine, which moxisylyte antagonizes, lowers intraocular pressure and thus a small rise would have been expected. However, the mydriatic and ocular hypotensive effects of sympathomimetics have separate time courses and probably involve different receptors. Conversely, in closed-angle glaucoma, moxisylyte does, for several reasons, appear to have a role in reducing pressure (Halasa & Rutkowski 1973). First, it is thought that during such attacks the sphincter becomes less effective than the dilator and the latter muscle dominates. Second, a relaxed sphincter reduces the possibility of pupil block; Halasa & Rutckowski (1973) explain this by the use of a mathematical model. In pupil block, forces trying to pull the iris back towards the anterior lens capsule should be avoided. If both muscles are relaxed there are no posterior vector forces. Third, it might have an overall synergistic effect with other miotics.
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Because moxisylyte reduces the pressure in closed-angle but not openangle glaucoma, it can form the basis of a useful differential test. It is effective in concentrations between 0.01% and 1.3% (Lee et al 1983).
DAPIPRAZOLE
Molinari et al (1994) investigated the clinical effectiveness of dapiprazole (an alpha-blocking drug) in reversing the effects of 1% tropicamide. Pupillary recovery was faster following the application of the miotic, as was the return of accommodation. The latter effect could have been due to an increased depth of field. However, a later experiment (Molinari et al 1995) found that a true improvement in accommodation was achieved with dapiprazole. All patients exhibited conjunctival hyperaemia, which would be expected because the agent would cause a vasodilation of the conjunctival blood vessels. Dapiprazole has been instilled directly into the anterior chamber experimentally in rabbits where it was found to be effective and no more damaging than the saline controls (Bonomi et al 1989).
CHOICE OF MIOTIC
In the past, optometrists had a choice of three miotics – pilocarpine (a parasympathetic), physostigmine (an anticholinesterase) and moxisylyte (an alpha-blocker) – and would have based their choice on the mydriatic used and the circumstances under which the patient would be placed while the mydriatic was reversed naturally. Today, optometrists have to choose between pilocarpine and nothing; with new legislation even pilocarpine will not be available. Because of the short duration of the action of mydriatics and the recognition of the rarity of the incidence of closed-angle glaucoma, most patients can be safely spared the discomfort of a miotic.
MIXED MIOTICS
Just as it was the practice in the past to use mixed mydriatics containing agents with different modes of action to produce synergy, mixtures of miotics have also been employed. Whereas mixed mydriatics always contain an agent acting on the pupil dilator muscle and an agent acting on the pupil sphincter muscle, mixed miotics have tended to contain a parasympathomimetic and an anticholinesterase (e.g. pilocarpine and physostigmine), both of which are active on the sphincter. Their use has been based on empiricism rather than pharmacological evidence.
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MIOTICS IN THE TREATMENT OF SQUINT
According to Revell (1971), it was Green of St Louis who first suggested, in 1870, the use of eserine in cases of subnormal accommodation and later advocated the use of pilocarpine in esotropia. Hiatt (1983) found that miotics were no better than, and often not as good as, glasses in correcting the deviation and enhancing binocularity in accommodative esotropia and they are little used for this purpose today. A further problem is that the long-term use of miotics can be associated with side-effects.
The possible benefit of post-operative administration of echothiophate iodide following surgery for congenital esotropia has been investigated but it was not found to improve the surgical results during the first postoperative year (Spierer & Zeeli 1997).
MIOTICS FOR ADIE’S PUPIL
Adie’s pupil is the parasympathomimetic counterpart of Horner’s syndrome. In the differential diagnosis of anisocoria, a weak solution of a direct-acting miotic can be used (e.g. 0.125% pilocarpine). Because the sphincter muscle is parasympathetically denervated, it is supersensitive to acetylcholine and other parasympathomimetrics. Because there is no natural release of acetylcholine, anticholinesterases will have no effect.
Bourzon et al (1978) compared 2.5% methacholine and 0.125% pilocarpine in the diagnosis of Adie’s pupil. They found methacholine effective in 64% of patients, whereas pilocarpine was effective in 80%, so that the latter can be considered to be the better drug for this differential test.
Highly diluted concentrations of pilocarpine were evaluated by Leavitt et al (2002), who found that whereas normal pupils responded to 0.25% or 0.125%, they constricted insignificantly to concentrations of 0.0313% or 0.0625%. Accordingly, the 0.0625% concentration of pilocarpine was proposed to be appropriate to distinguish an Adie’s pupil from a normal one.
ADVERSE REACTIONS TO MIOTICS
In the main, the most serious side-effects from miotics arise from their chronic use in glaucoma or from possible overdosage during acute glaucoma treatment rather than the single application used to reverse mydriatics. However, miotics can cause transient effects that trouble some patients and might therefore discourage the optometrist from using them.
Moxisylyte (thymoxamine) is irritant on instillation, as are some other miotics. Miotics whose principal action is on the sphincter pupillae might also cause a spasm of accommodation even in some apparently presbyopic patients.