Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

120 CHAPTER 8 Mydriatics and Mydriolytics

Dapiprazole

Pharmacology

Dapiprazole was specifically developed for ocular use. After topical instillation it produces miosis and a reduction in IOP. Like thymoxamine, dapiprazole reverses mydriasis by blocking α receptors in the iris dilator muscle. Concentrations ranging from 0.12% to 1.5% significantly reduce pupil size in both normal and glaucomatous eyes. The miotic effect is concentration dependent and can last up to 6 hours after instillation. IOP can be reduced for up to 6 hours. In patients with decreased amplitude of accommodation associated with tro- picamide-induced cycloplegia, dapiprazole may partially increase the accommodative amplitude (Figure 8-5). This restoration of near vision seems to come from a combination of increasing depth of field due to pupillary recovery and an actual increase in accommodative amplitude independent of pupillary size.

Clinical Uses

Unlike pilocarpine, dapiprazole appears to be a safe miotic for reversing phenylephrine-induced mydriasis. Moreover, the miosis is maintained long after the phenylephrine effect has dissipated.When instilled according to the manufacturer’s recommendation of two drops followed 5 minutes later by two drops, dapiprazole can produce nearly complete reversal of phenylephrineinduced pupillary dilation. Studies reported that a single drop of dapiprazole has a clinical effect equivalent to the multiple-drop regimen. Dapiprazole was shown to increase the recovery rate of adequate pupillary dilation and accommodative function with the use of Paremyd more rapidly in mainly white subjects with light brown irides than in mainly black subjects with dark brown

TIME (hr)

Figure 8-5 Amplitude of accommodation after instillation of 0.5% dapiprazole (0 hour) in eyes dilated with 0.5% tropicamide. (Reprinted with permission from Nyman N, Reich L.The effect of dapiprazole on accommodative amplitude in eyes dilated with 0.5% tropicamide. J Am Optom Assoc 1993;64:625–628.)

Figure 8-6 Mean pupil diameter after dilation in subjects with either light or dark irides. Subjects were treated with either Paremyd and dapiprazole or Paremyd only. (Reprinted with permission from Anicho UM, Cooper J, Feldman J, et al. Optom vis Sci 1999;76:94–101.)

irides (Figure 8-6). However, the observed difference in pupillary diameters was probably too small to produce any clinically significant change in the patient’s visual perception. This was verified by the observation that no significant difference was seen in visual acuity with and without the use of dapiprazole after dilation. Partial reversal of pupillary dilation induced with tropicamide has been reported as well. A tropicamide-dilated pupil returns to within 0.5 mm to 1.0 mm of its premydriatic diameter in less than 2 hours. Pupillary dilation with combinations of phenylephrine and tropicamide or hydroxyamphetamine and tropicamide was studied, and partial reversal of pupillary dilation occurred within 2 hours, with a significant reduction in pupil size after 1 hour (Figure 8-7). In addition, one drop of 0.5% dapiprazole is as effective in reversing mydriasis induced by 2.5% phenylephrine followed by tropicamide 0.5% or by Paremyd than is the recommended dosage of two drops followed 5 minutes later by an additional two drops.

Despite the reduction in pupil size,however,dapiprazole may have only limited usefulness in the pre-presbyopic population, because the drug may induce little improvement in functional vision as measured by changes in accommodation and near visual acuity.The effect seems to depend on the type of agent used for pupillary dilation.

The miosis produced by 0.5% dapiprazole begins 10 minutes after instillation and results in a significant reduction in pupil size, compared with that in the contralateral eye treated with 1% tropicamide alone.

Figure 8-7 Reversal of mydriasis with two drops followed 5 minutes later with an additional two drops of 0.5% dapiprazole after pupillary dilation induced by a combination of 2.5% phenylephrine and 1% tropicamide. (Reprinted with permission from Allinson RW, Gerber DS, Bieber S, Hodes BL. Reversal of mydriasis by dapiprazole. Ann Ophthalmol 1990;22:131–138.)

Because the miosis is due to α-receptor blockade in the iris dilator muscle, no shifting of the iris–lens diaphragm occurs with subsequent shallowing of the anterior chamber. As with thymoxamine, eye color can affect the rate of pupillary constriction. The rate of pupillary constriction may be slower in patients with brown irides than in individuals with blue or green irides.

The only U.S. Food and Drug Administration–approved use for dapiprazole at present is the reversal of iatrogenically induced mydriasis produced by adrenergic agents (phenylephrine or hydroxyamphetamine) or anticholinergic agents (tropicamide). An alternative use for dapiprazole is as a weak miotic agent to reduce peripheral distortion after refractive surgery. Another interesting, although theoretical,use for dapiprazole is in the treatment of pigment dispersion glaucoma. Since this α-adrenergic blocking agent causes miosis and iridoplegia, a decrease in the shedding of pigment from the posterior iris may occur, causing less obstruction of aqueous outflow.

Dapiprazole in 0.25% and 0.5% solutions is effective in cases of angle-closure glaucoma. In patients with gonioscopically narrow angles, the drug has been effective in preventing angle-closure glaucoma.

Intraocular dapiprazole has been shown to be clinically effective for reversing mydriasis during extracapsular cataract extraction with IOL implantation. A study compared intraocular dapiprazole 0.25% with acetylcholine 1% and found that after extracapsular cataract extraction with posterior chamber intraocular lens implantation, 0.25% dapiprazole was effective in producing a more persistent miosis without side effects. The drug also reduced the transient postoperative IOP increase.

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Dapiprazole is commercially available as Rev-Eyes in a kit consisting of one vial of the drug (25 mg), one vial of diluent (5 ml),and a dropper for dispensing. Once the solution has been mixed, the eyedrops are clear, colorless, and slightly viscous and can be stored at room temperature

Figure 8-8 Right ptosis,miosis,and conjunctival hyperemia induced by 0.5% dapiprazole instilled into right eye after bilateral pupillary dilation with 2.5% phenylephrine.

for 21 days. The recommended dosage per eye is two drops followed 5 minutes later by an additional two drops.

Side Effects

Transient burning and conjunctival hyperemia after topical ocular application of dapiprazole are common. Other mild to moderate ocular side effects include superficial punctate keratitis, corneal edema, chemosis, ptosis, lid erythema and edema, itching, dry eye, and browache. Many of these are the result of the dilation of conjunctival blood vessels,which is a pharmacologic action of α-receptor antagonists. Ptosis (Figure 8-8) can also be attributed to α-receptor blockade in Müller’s muscle. Blood pressure and pulse rate are not significantly affected by topical use of dapiprazole. One study concluded that topical application of dapiprazole produces no corneal endothelial toxicity, but intracameral use postsurgically may result in adverse corneal endothelial effects.

Contraindications

Dapiprazole is contraindicated in circumstances in which pupillary constriction is undesirable, such as acute anterior uveitis,and for patients having hypersensitivity to any component of the preparation.

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Cycloplegic agents are useful for diagnosis and management in eye care because of their effect on pupil size and accommodation. Cycloplegics inhibit the actions of acetylcholine on muscarinic sites innervated by autonomic fibers and on smooth muscle cells that lack cholinergic autonomic innervation. These drugs are also called anticholinergics, antimuscarinics, and cholinergic antagonists.

and acetylcholinesterase. Experimental evidence indicates that the cholinergic system may play a role in the transmission of tactile perception and corneal hydration involving epithelial ionic transport. The lens capsule exhibits cholinesterase activity. Cholinergic neurons have also been demonstrated in the human retina. Muscarinic receptors in the retina are believed to be involved in the control of refractive development in humans and other mammals.

CHOLINERGIC INNERVATION

TO THE EYE

In the eye the ciliary body, the iris sphincter muscle, and the lacrimal gland receive cholinergic innervation. The innervation for the ciliary body and the iris sphincter muscle originates in the Edinger-Westphal nucleus. From the Edinger-Westphal nucleus preganglionic parasympathetic fibers travel through the third cranial nerve (oculomotor) and proceed to the ciliary ganglion. There they synapse with postganglionic fibers, enter the globe through the short ciliary nerves, and pass to and terminate on the muscarinic receptors in the iris sphincter muscle and ciliary body (Figure 9-1).

Pupil size is determined by varying degrees of parasympathetic innervation to the sphincter muscle, which contracts accordingly and produces a corresponding degree of pupillary constriction. Sympathetic innervation, which is secondary, maintains a persistent tone in the dilator muscle, aiding relaxation of the sphincter and resulting in dilation.

Innervation to the lacrimal gland originates near the superior salivary nucleus in the pons where preganglionic fibers become part of the seventh nerve until they join and synapse with the sphenopalatine ganglion. The postganglionic fibers become part of the fifth nerve and pass to the lacrimal gland through the lacrimal nerve (see Figure 9-1).

Other potential targets of cholinergic stimulation or blockade by drugs include the cornea, lens, and retina. The corneal epithelium contains the neurotransmitter acetylcholine and the enzymes choline acetylase

Cholinergic Receptors

Cholinergic receptors in iris sphincter tissue and ciliary body have been shown to be of the muscarinic type. Five muscarinic receptor subtypes (M1–M5) have been identified. Sixty percent to 75% of the muscarinic receptors in the human iris sphincter and ciliary body are M3, and 5% to 10% are M2 and M4.Approximately 7% of receptors in the ciliary processes and iris sphincter are of the M1 subtype. Approximately 5% of receptors present in the iris sphincter are M5. Inhibition of these receptors by cholinergic antagonists induces pupillary dilation (mydriasis) and paralysis of accommodation (cycloplegia) and may elevate intraocular pressure (IOP), particularly in patients with predisposing risk factors.

CHOLINERGIC ANTAGONISTS

Five mydriatic–cycloplegic cholinergic antagonists are currently available for topical use in the eye: atropine sulfate, homatropine hydrobromide, scopolamine hydrobromide, cyclopentolate hydrochloride, and tropicamide. Atropine and scopolamine are believed to be nonspecific in their binding to the various muscarinic receptors, whereas tropicamide may have a moderate selectivity for M4 receptors. Several subtypes of neuronal nicotinic acetylcholine receptors have been shown to be sensitive to atropine, which suggests that atropine may exert its effects through several different mechanisms. The efficacy of all these agents is influenced by the amount of iris pigmentation.

The heterogeneity of the muscarinic receptor subtypes in the iris and ciliary body suggests that subtypeselective antagonist drugs could be developed that might have a different action from the currently available muscarinic antagonists. There is investigative work being done to develop other anticholinergic agents with more specific selectivity for the types of muscarinic receptors and with less systemic toxicity. More selective muscarinic antagonists could be useful not only for cycloplegia, but also for the effect they may have in other ocular tissues. For example, ophthalmic pirenzepine hydrochloride, a muscarinic receptor antagonist with M1 selectivity, has been evaluated for slowing of myopia progression.

The reported cycloplegic effect of these drugs is also influenced by the methods used to assess the loss of accommodative function. Most early studies used subjective clinical measures of accommodation (push-up or minus lens blur), which require the subject to report when letters appeared blurred. Recently, objective methods (autorefractors, optometers) have been used to revisit the effectiveness of some of the shorter acting agents. Because selection of the most appropriate agent requires consideration of the risks and benefits associated with each drug on a case-by-case basis, patient characteristics and the ability of the agent to produce the desired outcome are fundamental to the selection process.

Atropine

Pharmacology

Atropine, a naturally occurring alkaloid, was first isolated from the belladonna plant, Atropa belladonna, in its pure form in 1831.Atropine is a nonselective muscarinic antagonist.The stability of atropine is both pH and temperature dependent. At 20° C, the half-life of atropine is 2.7 years in a pH 7 solution and 27 years at pH 6.At 30° C its stability is reduced to 0.61 years at pH 7 and 6.1 years at pH 6.At the physiologic pH, atropine with a pKa of 9.8 is primarily ionized.The ionized state makes corneal penetration difficult, and thus small concentrations of the drug are available at the muscarinic receptor sites. However, atropine is the most potent mydriatic and cycloplegic agent presently available. Depending on the concentration used, mydriasis may last up to 10 days and cycloplegia, 7 to 12 days (Table 9-1).Atropine is available commercially as a sulfate derivative in a 1% solution and in a 1% ointment formulation (Table 9-2).

Feddersen is credited with the first extended study of the ocular effects of atropine sulfate after topical application of a 1% solution.After the instillation of one drop, the mydriatic effect began at 12 minutes and reached maximum in 26 minutes.The pupil began to return to normal in 2 days and reached preinstillation size by the tenth day.

Cycloplegia began within 12 to 18 minutes, reaching maximum by 106 minutes. Accommodation began to

Figure 9-2 Changes of accommodation and pupil size after administration of 1% solution of atropine sulfate and 1% solution of homatropine hydrobromide. (Modified from Wolf AV, Hodge HC. Effects of atropine sulfate, methylatropine nitrate [Metropine], and homatropine hydrobromide on adult human eyes.Arch Ophthalmol 1946;36:293–301.)

return in 42 hours, with full accommodative ability usually attained within 8 days.

A similar time course of action was observed for 1% atropine sulfate in a series of 16 eyes (Figure 9-2). In addition, wide variations were reported in individual responses to topical ocular atropine.

Clinical Uses

Refraction. Since publication of Risley’s essay on cycloplegics in 1881, atropine has become the standard to which all other cycloplegic agents have been compared. Because atropine is the most potent cycloplegic agent currently available, it is often used for cycloplegic refractions in young actively accommodating children with suspected latent hyperopia or accommodative esotropia.

Because of prolonged paralysis of accommodation that renders patients visually handicapped in near vision, atropine is not typically used for routine cycloplegic refractions in school-aged children or adults. Other shorter acting agents are becoming more widely used for refraction in almost all patients when a cycloplegic refraction is deemed necessary, so that the inconvenience of a prolonged accommodative loss is avoided. Use of atropine often reveals more hyperopia, however, and thus may be warranted in cases of esotropia with a suspected accommodative component.

Treatment of Uveitis. Atropine is extremely useful in the treatment of anterior uveal inflammation. Atropine relieves the pain associated with the inflammatory process by relaxing the ciliary muscle spasm and helps prevent posterior synechiae by dilating the pupil.

With the pupil dilated, the area of posterior iris surface in contact with the anterior lens capsule decreases. Moreover, the cycloplegia produced by atropine is of additional value in reducing both the thickness and convexity of the lens. If posterior synechiae should develop even when the pupil is dilated, there is less chance of iris bombé. Atropine may also help decrease the excessive permeability of the inflamed vessels and thereby reduce cells and protein in the anterior chamber (aqueous flare).

Treatment of Myopia. It has been suggested that topical ocular use of atropine may prevent or slow the progression of myopia. By placing the ciliary muscle at rest accommodation is relaxed, and the tension that produces elongation of the eye may be reduced. With administration of 1% atropine for 1 to 8 years, the decrease in myopia in treated eyes of children has usually been less than 0.5 D; the nontreated eye showed an increase in myopia that averaged approximately 0.91 D per year.

A study showed significant reduction in myopia progression with atropine in patients who presented good compliance. Another uncontrolled study reported that topical instillation of 1% atropine for 6 to 12 months in children 7 to 14 years of age seemed to prevent the progression of myopia, but on discontinuation of the drops only 12% of children maintained improvement for more than 6 months. In a more recent study, 20 children with 6.00 D or more of myopia were treated with 0.5% atropine once at bedtime and followed for up to 5 years. The myopic progression that occurred under atropine treatment was significantly slower than the progression observed before atropine treatment was initiated or under treatment with tropicamide. Although the results from these and other studies appear to be encouraging, dropout rates can be high, and side effects such as glare, photophobia, and increased exposure to ultraviolet radiation appear troublesome. Clearly, a controlled clinical trial is needed to determine the efficacy of atropine in myopia control.

Treatment of Amblyopia. Atropine can be used as an alternative to direct occlusion in the treatment of amblyopia. This form of amblyopia therapy is referred to as “penalization” and is often combined with optical overcorrection or undercorrection to blur the better eye for distance or near vision or both.The resultant cycloplegic blur in the eye with normal vision often forces the patient to use the amblyopic eye when the vision in the good eye is rendered poorer than that of the amblyopic eye.Thus this treatment is often reserved for moderate and mild amblyopia (acuity better than 20/100 in the amblyopic eye). Renewed interest in this form of therapy has been expressed because of its potential for improved compliance and stimulation of binocular function. Although pharmacologic occlusion can improve visual acuity in amblyopic eyes, care is needed because penalization can result in amblyopia in eyes with normal acuity.

Side Effects

Ocular Effects. Ocular reactions include direct irritation from the drug preparation itself, allergic contact dermatitis, risk of angle-closure glaucoma, and elevation of IOP in patients with open angles. The allergic reaction to atropine generally involves the eyelids and manifests itself as an erythema, with pruritus and edema. Allergic papillary conjunctivitis and keratitis have also been reported.

In general, topical atropine, as well as other cholinergic antagonists, increases patients’ risk for angle-closure glaucoma. However, the risk of inducing angle closure in eyes without a previous history of attack is remote. Patients with open-angle glaucoma may experience an elevation of IOP with topical application. The effect is unpredictable, because not all patients respond to cholinergic antagonists with IOP elevations. The mechanisms involved in the pressure rise are not completely understood.The pressure elevation appears to be related not to the degree of mydriasis attained but rather to a decrease in facility of aqueous outflow.

Systemically administered atropine may also cause mydriasis and raise IOP in patients with open-angle glaucoma. After intramuscular injection of 0.6 mg atropine, three of eight patients developed 0.5- to 1.5-mm mydriasis.A mean increase of 0.8 cm in the near point of accommodation after atropine administration was also reported.

Systemic Effects. A large portion of topically applied atropine rapidly enters the systemic circulation, primarily from the conjunctival vessels and the nasal mucosa. Plasma concentrations peak at approximately 10 minutes after application of the drug.Therefore it is not surprising that systemic reactions from the topical administration of atropine have been reported (Box 9-1). Adverse systemic reactions appear to be dose dependent, although patients vary in susceptibility. Systemic peripheral effects occur with low doses, which generally do not produce central symptomatology. Depression of salivation and drying of the mouth are usually the first signs of toxicity.

Box 9-1 Systemic Reactions to Atropine in Children

Diffuse cutaneous flush

Depressed salivation/thirst

Fever

Urinary retention

Tachycardia

Somnolence

Excitement/restlessness and hallucinations

Speech disturbances

Ataxia

Convulsions

Slightly higher dosages produce facial flushing and inhibit sweating. Adverse systemic symptoms and central nervous system (CNS) manifestations generally occur at 20 times the minimum dose. Convulsions have been associated with topical ocular atropine instillation, particularly in children. The elderly are more susceptible to anticholinergic toxicity, including cognitive impairments and delirium.

Deaths have been attributed to topical ocular atropine. Six reported cases in the literature have occurred in children 3 years of age and younger. The dosages applied ranged from 1.6 to 18 mg, but the cases are rather poorly documented. Most of the children either were ill or had motor and mental retardation. What these cases imply, however, is that care must be taken not to overdose small children.Two drops of a 1% solution contain 1 mg of the drug or approximately twice the usual preoperative injectable dose. Caution must be exercised particularly with children who are lightly pigmented and individuals who have spastic paralysis or brain damage. White males with Down’s syndrome have been shown to have an enhanced cardioacceleratory response to intravenous administration of atropine sulfate. Although the mechanism for this presumed increase in sensitivity to the vagolytic action of atropine is not clear, the rapid systemic absorption of topically applied agents in general warrants caution in this population.

The treatment of atropine overdosage is largely supportive, with prevention of hyperpyrexia and dehydration. Only in cases of severe or life-threatening toxicity should physostigmine be considered. Two milligrams given intramuscularly or a single intravenous dose of 1 to 2 mg, administered very slowly over 5 to 10 minutes, is recommended for adults. However, the short duration of action of physostigmine may require repeated doses of 1 to 2 mg every 30 minutes if life-threatening signs persist. Children are given 0.02 mg/kg intramuscularly or by slow intravenous injection up to a maximum of 0.5 mg per minute. The dosage may be repeated every 5 to

10 minutes up to a maximum dose of 2 mg or until the therapeutic effect is achieved.

Contraindications

Atropine is contraindicated for patients who are hypersensitive to the belladonna alkaloids, have open-angle or angle-closure glaucoma, or have a tendency toward IOP elevations. Manufacturers’ recommended dosages should not be exceeded, particularly in infants, small children, and the elderly. Children with Down’s syndrome demonstrate a hyperreactive pupillary response to topical atropine.

Homatropine

Pharmacology

Homatropine is approximately one-tenth as potent as atropine and has a shorter duration of mydriatic and

130 CHAPTER 9 Cycloplegics

cycloplegic action (see Table 9-1). Homatropine is partly synthetic and partly derived, like atropine, from the plants of the Solanaceae family. It is quite stable in solution. At physiologic pH, homatropine with a pKa of 9.88 is approximately 0.32% un-ionized. Homatropine is commercially available as the hydrobromide salt in concentrations of 2% and 5% (see Table 9-2).

After topical instillation of a 1% solution, maximum mydriasis occurs by 40 minutes. The pupil requires 1 to 3 days to recover. The amount of cycloplegia produced by homatropine is significantly less than that produced by comparable doses of atropine (see Figure 9-2) and cyclopentolate. The duration of cycloplegia obtained is longer with homatropine than with cyclopentolate.

Clinical Uses

Because of its prolonged mydriatic and cycloplegic effect and relatively weak cycloplegic action, particularly in darkly pigmented irides, homatropine is not a drug of choice for fundus examination or cycloplegic refraction. Homatropine is primarily used in the treatment of anterior uveitis, in which its effects are similar to those of atropine.

Side Effects

The toxic effects of homatropine are indistinguishable from those of atropine, and the treatment is the same.

Contraindications

Contraindications for homatropine are essentially the same as for atropine. As with atropine, very small amounts of homatropine have been detected in breast milk. According to the American Academy of Pediatrics, however, homatropine use is compatible with breast-feeding, but caution should be exercised when administering homatropine to nursing women. As with topical administration of atropine, homatropine can also induce CNS toxicity in the elderly.

Scopolamine (Hyoscine)

Pharmacology

Scopolamine is a nonselective antagonist. The alkaloid scopolamine (hyoscine) is found chiefly in the shrub

Hyoscyamus niger (henbane) and Scopolia carniolica. The antimuscarinic potency of scopolamine on a weight basis is greater than that of atropine. Except for a shorter duration of mydriatic and cycloplegic action at the dosage levels used clinically, its effects are similar to those of atropine (see Table 9-1). Although previously available in both ointment and solution, scopolamine is currently available as the hydrobromide salt in solution at a 0.25% concentration (see Table 9-2). The mydriatic and cycloplegic effects of 0.5% solution of scopolamine were studied in subjects ranging from 15 to 37 years of age. The maximum cycloplegic effect occurred at 40 minutes, with residual amplitude of accommodation of 1.6 D

measured subjectively. This effect lasted for at least 90 minutes, and by the third day accommodation gradually returned to a level at which the average patient could read.

Clinical Uses

In low dosages scopolamine can produce effects on the CNS, presumably due to its ability to penetrate the blood–brain barrier. Drowsiness and confusion are frequently reported. Patients also tend to exhibit a higher incidence of idiosyncratic reactions to scopolamine than to other anticholinergic agents, and, hence, it is not the drug of first choice for cycloplegic refraction or treatment of anterior uveal inflammations. Its use is reserved primarily for patients who exhibit sensitivity to atropine.

Side Effects

Systemic reactions from the topical administration of scopolamine are quite similar to those of atropine. However, CNS toxicity appears to be more common with scopolamine than with atropine. In a series of several hundred patients whose pupils were dilated with 1% scopolamine, seven cases of confusional psychosis were observed. The reactions included restlessness, confusion, hallucinations, incoherence, violence, amnesia, unconsciousness, spastic extremities, vomiting, and urinary incontinence. Others have reported similar acute psychotic reactions in children receiving from 0.6 to 1.8 mg of topically administered scopolamine. However, no deaths have been reported from topical ocular use of scopolamine. Treatment of toxic reactions is the same as that for atropine toxicity.

Scopolamine is available as a transdermal drug delivery system for prevention of motion sickness. When placed behind the ear the system delivers 0.5 mg of scopolamine for 3 days. Mydriasis and blurred vision can occur if scopolamine from the patch comes in contact with the eyes.

Contraindications

The contraindications for scopolamine are the same as for atropine.

Cyclopentolate

Pharmacology

Cyclopentolate was introduced into clinical practice in 1951. A stable water-soluble ester with a pKa of 8.4, cyclopentolate is primarily in an ionized state at physiologic pH. It is commercially available in 0.5%, 1%, and 2% solutions (see Table 9-2).

In whites one drop of 0.5% cyclopentolate or two drops of 0.5% cyclopentolate instilled 5 minutes apart or one drop of 1% solution produces maximum mydriasis within 20 to 30 minutes.The average pupil size is usually 6.5 to 7.5 mm. In blacks two instillations of 0.5% cyclopentolate produce a 6.0-mm pupil at 30 minutes and a 7.0-mm pupil at 60 minutes after instillation of the