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

first drop. Cyclopentolate is also a less effective mydriatic in whites with dark irides (Figure 9-3).

In whites maximum cycloplegia occurs 30 to 60 minutes after instillation of two drops of 0.5% solution or one drop of 1% solution.The residual accommodation measured subjectively ranges between 0.50 D and 1.75 D, with an average of 1.25 D. However, it was reported that in patients with light irides, clinically acceptable cycloplegia may occur as early as 10 minutes after instillation of one

drop of 1% cyclopentolate when cycloplegia is indexed by objective measures of residual accommodation. In a group of adults with light irides, residual accommodation measured 0.57 D at 10 minutes and 0.35 D at 40 minutes after instillation. In a small group of children with light irides, the residual accommodation measured 0.59 D at 10 minutes. In contrast, in individuals with dark irides, 30 to 40 minutes may be required before accommodation is at an acceptable level for cycloplegic refraction (Figure 9-4). Ten minutes

Optometer

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132 CHAPTER 9 Cycloplegics

after instillation of one drop of 1% cyclopentolate, 1.11 D of residual accommodation was present in individuals with dark irides, whereas 1.84 D of accommodation remained in blacks. Forty minutes after instillation, there was 0.52 D of residual accommodation in individuals with dark irides and 0.83 D in a small group of blacks. It was also shown that eyes with blue irides lose accommodation at a faster rate and also recover in less time than brown eyes. For all eyes the cycloplegic effect usually dissipates within 24 hours.

Among black patients ranging in age from 9 to 40 years, 1% cyclopentolate has been reported to produce satisfactory cycloplegia in 98% of patients. The 0.5% concentration was effective in only 66% of a group of 100 black patients aged 20 to 40 tested using subjective measures of accommodation. In those subjects who achieved less than 2.5 D of residual accommodation after the use of 0.5% cyclopentolate, the average residual accommodation was 1 D. However, 24% of the subjects showed no cycloplegia.

Clinical Uses

Cyclopentolate is the cycloplegic agent of choice for routine cycloplegic refractive procedures in nearly all age groups, especially infants and young children. Its cycloplegic effect is superior to that of homatropine and closely parallels that of atropine in older children and adults, but with a relatively faster onset and shorter duration (see Table 9-1). Pupils dilated with cyclopentolate do not constrict when exposed to intense light, such as that of the binocular indirect ophthalmoscope, or during fundus photography.Although full recovery from mydriasis and cycloplegia generally occurs within 24 hours, most patients have sufficient recovery of accommodative amplitude to permit reading in 6 to 12 hours. Unlike with atropine and homatropine, onset of maximum cycloplegia generally approximates the onset of maximum mydriasis.Thus, when the pupil is fully dilated, the cycloplegia is adequate for refraction. However, the time course of mydriasis and the time course of cycloplegia are not the same. Pupil dilation typically lags behind the loss of accommodation. Hence, if pupillary dilation is used to determine whether cycloplegia is at a level acceptable for refraction, the refraction may be unnecessarily delayed or additional drugs may be used unnecessarily.

Cyclopentolate is also useful in the treatment of anterior uveitis, particularly in patients sensitive to atropine. If the inflammation is severe, more frequent instillations may be necessary, because its duration of action is less than that of atropine.

Side Effects

Ocular Effects. The most common ocular side effect is transient stinging on initial instillation.The degree of irritation appears to be concentration dependent, with the 0.5% solution causing the least amount of burning and tearing.

Allergic reactions to cyclopentolate are quite rare and may go unrecognized by the practitioner. However, several cases of redness and discomfort in eyes of patients after in-office use of cyclopentolate have been reported. Symptoms consist of irritation and diffuse redness of the eyes and a facial rash that develops within minutes to hours of drug instillation. Lacrimation, a stringy white mucous discharge, and blurred vision are prominent.

Toxic keratitis has also been reported after abuse of cyclopentolate. Instillation of 100 to 400 drops of the 1% solution over several months caused a diffuse epithelial punctate keratitis with marked conjunctival hyperemia. As expected, the pupils were widely dilated and unresponsive to light.

Topically applied cyclopentolate can increase IOP in patients with primary open-angle glaucoma, and it may precipitate an attack of acute glaucoma in patients with narrow angles. It was reported that approximately 1 of

4 eyes with open-angle glaucoma responded to topical 1% cyclopentolate with a significant elevation of IOP (6 mm Hg or more increase compared with the baseline IOP), whereas only 2 of 100 normal eyes responded in a similar manner. These two apparently normal eyes also responded with an IOP increase of 6 mm Hg or more with the application of 5% homatropine or an application of 1% atropine.

Systemic Effects. Systemic cyclopentolate toxicity is dose related and evolves in a manner similar to atropine toxicity. Compared with atropine, however, cyclopentolate causes more CNS effects.

The CNS disturbances are characterized by signs and symptoms of cerebellar dysfunction and visual and tactile hallucinations. These can include drowsiness, ataxia, disorientation, incoherent speech, restlessness, and emotional disturbances (Box 9-2). The CNS effects are particularly common in children with use of the 2% concentration, but multiple instillations of the 1% solution may also cause the same symptoms. Forty children were evaluated before and after use of the 2% solution. Of these children, five exhibited transient psychotic reactions within 30 to 45 minutes after instillation of the drops. The symptoms included restlessness with aimless

Box 9-2 Side Effects of Cyclopentolate

wandering, irrelevant talking, visual hallucinations, memory loss, and faulty orientation of time and place. Psychotic reactions have been reported with the 1% concentration after instillation of two drops in each eye in children and adults. In addition, adults have also complained of drowsiness, nausea, or weakness. All reactions usually subside within 2 hours in adults and within 4 to 6 hours in children without permanent sequelae. Cyclopentolate is not without possible serious toxic effects, however. Grand mal seizures were reported in isolated case reports of three children with use of both 1% and 2% solution.Two of the three children who experienced seizures were neurologically impaired. However, one child, an 11-month-old boy who received one drop of 2% cyclopentolate in each eye, had no neurologic impairments and was reported to be normal. Also, a grand mal seizure was reported in a child after receiving a drop of 1% cyclopentolate and a drop of 10% phenylephrine.The child had abnormally low serum sodium levels, which may have predisposed him for the seizure.

Peripheral effects typical of atropine, such as flushing or dryness of the skin or mucous membranes, have not been observed with cyclopentolate in children or adults. Moreover, temperature, pulse, blood pressure, and respiration are generally not affected. Treatment of cyclopentolate toxicity is the same as that for atropine toxicity. Because toxic reactions occur more commonly with the 2% solution or with multiple instillations of the 1% solution, the smallest possible dose should be used.

Contraindications

Because increased susceptibility to the side effects of cyclopentolate has been reported in infants, young children, and children with spastic paralysis or brain damage, use of concentrations higher than 0.5% is not recommended in these patients. The potential for systemic absorption of cyclopentolate, as of other topically applied ocular drugs, may be reduced with nasolacrimal occlusion.

Tropicamide

Pharmacology

A synthetic derivative of tropic acid, tropicamide became available for ocular use in 1959. Although tropicamide has been reported to be a nonselective muscarinic antagonist, tropicamide may have a moderate selectivity for M4 receptors.With a pKa of 5.37, it is only approximately 2.3% ionized at physiologic pH.The un-ionized molecules can readily penetrate the corneal epithelium, and thus a greater concentration of drug can reach the muscarinic receptor sites than is the case with atropine, homat-

The first English-language report of the effects of the 0.5% and 1% solutions of tropicamide in human eyes showed maximum mydriasis occurred in 20 to 40 minutes after instillation of either the 0.5% or the 1% solution. The 1% concentration produced an average increase of approximately 4.0 mm in pupil size at 30 minutes. Thereafter, the pupil diameter began to decrease, reaching preinstillation size in 6 hours. The effect of the 0.5% solution on mydriasis was only slightly less than that of the 1% concentration.

Tropicamide has been reported to provide sufficient mydriasis for routine ophthalmoscopy at concentrations as low as 0.25% in some individuals. One drop of 0.25% tropicamide was reported to provide a 5-mm or greater dilation in most subjects.

The maximum cycloplegic effect also occurs at

30 minutes after instillation. Unlike the mydriatic effects, which appear less dependent on the concentration of tropicamide in white individuals, the inhibition of accommodation is dose related. The cycloplegic effects of 0.25%, 0.5%, 0.75%, and 1% tropicamide were studied (Figure 9-5). Some inhibition of accommodation occurred with each concentration, and the effects were dose related. The maximum residual accommodation ranged from 3.17 D for the 0.25% concentration to 1.3 D for the 1% concentration when assessed by the subjective pushup method. For all subjects maximum cycloplegia occurred 30 to 35 minutes after instillation. Significant differences in cycloplegic effects were found between the 0.25% and 1% solutions but not among the 0.5%, 0.75%, or 1% concentrations. Figure 9-6 illustrates the residual accommodation (measured subjectively using

Figure 9-5 Mean mydriatic dose–response curves for tropicamide 0.25%, 0.5%, 0.75%, and 1% under normal and bright illuminance. (SD = standard deviation.) (Reprinted with permission from Pollack SL, Hunt JS, Polse KA. Dose-response effects of tropicamide HCl. Am J Optom Physiol Opt 1981;58:361–366.)

134 CHAPTER 9 Cycloplegics

Figure 9-6 Mean residual accommodation after tropicamide instillation over the period of maximum cycloplegia. (Reprinted with permission from Pollack SL, Hunt JS, Polse KA. Dose-response effects of tropicamide HCl. Am J Optom Physiol Opt 1981;58:361–366.)

the push-up method) during the period of maximum cycloplegia for all concentrations of tropicamide tested. Two diopters or less of residual accommodation were present for at least 40 minutes with the 0.75% and 1% concentrations and for approximately 15 minutes with the 0.5% concentration.A mean residual accommodation of 2.2 D was present after the application of 0.25% tropicamide. This effect was sufficient to incapacitate the subjects for most near vision tasks for 40 to 60 minutes.

The cycloplegic effect of 1% tropicamide was studied and found to be clinically effective (less than 2.5 D with the subjective minus-to-blur technique) in 90% of the eyes tested, provided that a second drop was instilled 5 to 25 minutes after the first and provided that the examination was performed 20 to 35 minutes after instillation. Accommodation returned to preinstillation values within 6 hours.

In myopic children two drops of 1% tropicamide instilled 5 minutes apart was demonstrated to be a very effective cycloplegic agent. The effectiveness of tropicamide as a cycloplegic had previously been compared with that of cyclopentolate and homatropine. The maximum cycloplegic effect of 1% tropicamide at 30 minutes was observed to be greater than that obtained from 1% cyclopentolate or 5% homatropine. However, the clinically effective cycloplegia produced by tropicamide was only maintained for approximately 35 minutes after instillation of a single drop.The effects of 1% tropicamide, 1% cyclopentolate, and 4% homatropine combined with 1% hydroxyamphetamine were compared. In one eye, two drops of tropicamide were given 5 minutes apart. The other eye received either one drop of 1% cyclopentolate or two instillations of 4% homatropine combined with hydroxyamphetamine. Subjective measurements of accommodation were performed 20 to 40 minutes after

Time (Min)

Figure 9-7 Average residual accommodation (measured subjectively) after instillation of 1% tropicamide, 1% cyclopentolate, or 4% homatropine in adult patients. (Reprinted with permission from Gettes BC, Belmont O. Tropicamide: comparative cycloplegic effects. Arch Ophthalmol 1961;66:336–340. Copyright 1961, American Medical Association.)

the second drop. Figure 9-7 summarizes these subjective measures of accommodation. Although the initial intensity of the cycloplegic effect of tropicamide was nearly equal to that of cyclopentolate, accommodation rapidly returned after approximately 35 minutes. Cyclopentolate remained effective 35 minutes after instillation and for the duration of the measurements (55 minutes after instillation). The homatropine–hydroxyamphetamine combination exhibited a slower onset, reaching clinically effective levels of cycloplegia for refraction at 45 to 55 minutes. Similar studies using 1% tropicamide, 1% cyclopentolate, or 5% homatropine, two drops to each eye, found that cyclopentolate was superior to tropicamide in 92% of patients and homatropine was superior to tropicamide in 80% of patients. Moreover, the magnitude of residual accommodation (assessed subjectively) was inversely related to age and was greater than 2.5 D with tropicamide in patients under 40 years of age (Table 9-3).

The time course of cycloplegia for tropicamide and cyclopentolate in adult subjects aged 20 to 30 years was studied.The data indicated that one drop of 0.5% or 1.0% tropicamide leaves as much as 28% to 40% of baseline accommodation active at 20 minutes after drug instillation when residual accommodation is determined by subjective methods. In contrast, cyclopentolate 0.5% or 1.0% induced a deeper and more stable level of cycloplegia within the same period when the same measurement methods were used.

Prior application of a topical anesthetic appears to prolong the mydriatic and cycloplegic actions of tropicamide. It was reported that prior instillation of proparacaine 0.5% in blue-green eyes prolonged both the time required for 50% recovery to normal pupil size and the time during which mydriasis was maintained within

90% of maximum. In brown-hazel eyes the time for recovery to 50% was lengthened by 30 minutes, but the time during which mydriasis remained 90% of maximum was not lengthened by prior application of the anesthetic.The time during which cycloplegia was maintained within 90% of maximum was extended by 3 to 4 minutes in all eyes, regardless of degree of pigmentation. The effect of the prior instillation of 0.5% proparacaine on pupil dilation obtained with 0.5% tropicamide was investigated. In persons with light irides, when the instillation of 0.5% tropicamide was preceded by the instillation of 0.5% proparacaine, a statistically significant difference in pupil diameter was obtained compared with the fellow eye, in which tropicamide instillation was preceded by the instillation of saline; however, the effect was small (0.6 mm) and not clinically significant. Proparacaine preinstillation had no effect in the dark iris group. In addition, the rate of pupillary dilation over the first 20 minutes after drug application was not significantly different in the test and control eyes for either iris group. Therefore, the application of proparacaine before the application of tropicamide is not recommended in routine clinical practice. The depth of cycloplegia as assessed by subjective techniques 20 minutes after instillation of 0.5% or 1.0% tropicamide is greater in eyes pretreated with 0.5% proparacaine than in eyes receiving tropicamide alone. However, the difference did not reach statistical significance at the 5% level.

Clinical Uses

Because of its relatively fast onset, short duration, and sufficient intensity of action, tropicamide is considered the drug of choice for ophthalmoscopy and other procedures in which mydriasis is desirable. Moreover, unlike with atropine, homatropine, or cyclopentolate, pupillary dilation with tropicamide appears to be less dependent on iris pigmentation.

In clinical situations in which only mydriasis is necessary, a pupillary dilation with minimum paralysis of accommodation is desirable so as not to interfere with

near vision tasks.To achieve clinically useful mydriasis with minimal accommodative paralysis, various combinations of drugs have been investigated.

Other investigators have tested various concentrations of tropicamide with adrenergic agonists. A combination of 0.1% tropicamide and 1% hydroxyamphetamine was effective for routine ophthalmoscopic examinations. Various concentrations of tropicamide combined with 1% hydroxyamphetamine were evaluated to find a clinically useful mydriatic with minimal accommodative effects. When combined with 1% hydroxyamphetamine, 0.05%, 0.1%, 0.25%, or 0.5% tropicamide produced mean pupillary diameters 3.5 to 3.8 mm greater than baseline values (Figure 9-8).The differences in pupillary diameter among the concentrations tested were not statistically significant in this group of 16 predominately light iris subjects. However, inhibition of the pupillary response to light was directly related to the concentration of tropicamide. The effect on accommodation was also directly related to the concentration of tropicamide (Figure 9-9).The mean loss of accommodation was 3.8 D for 0.05% tropicamide and 5.5 D for the 0.5% concentration. Most eyes returned to baseline values at 6 hours. By 24 hours both pupil size and accommodation were at predrug levels. The ideal combination was recommended as 0.25% tropicamide combined with 1% hydroxyamphetamine for dilation and inhibition of the light response without reducing accommodation to the point of interfering with near vision. A study compared the mydriatic and cycloplegic effect of 0.25% tropicamide combined with 1% hydroxyamphetamine (Paremyd) to one drop of 0.5% tropicamide combined with 2.5% phenylephrine. Results found that both Paremyd and the 0.5% tropicamide and 2.5% phenylephrine combination produced adequate pupil dilation and that the mydriasis was not affected by iris color. However, the dilation was not challenged with a bright light stimulus such as that needed for a dilated fundus examination. It was observed that dilation with Paremyd was faster in mainly white subjects with light brown irides than in black subjects with dark brown irides.

Mean Pupil Size (mm)

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0.05 % Tropicamide

0.10 % Tropicamide

0.25 % Tropicamide

0.50 % Tropicamide

Similarly, subjects with light irides recovered accommodative function more rapidly. Overall, Paremyd provided adequate dilation for the intense illumination of the binocular indirect ophthalmoscope in all study subjects, irrespective of iris pigmentation. Subjects also reported that Paremyd was more comfortable on initial instillation than the 0.5% tropicamide and 2.5% phenylephrine combination. Paremyd is currently only available through compounding pharmacies.

The advantage of tropicamide compared with other mydriatic–cycloplegic agents is its fast onset and relatively short duration of action. Practitioners should note that, clinically, tropicamide has a greater mydriatic than cycloplegic effect. Although tropicamide is not the drug

of choice for cycloplegic refractions in patients with suspected latent hyperopia, tropicamide can stabilize fluctuations in accommodation and thus aid in the refraction of children. One percent tropicamide compared favorably with 1% cyclopentolate as a useful agent for measuring distance refractive error in school-aged children with low to moderate hyperopia. Tropicamide 1% also produces a significant decrease in accommodation when measured both objectively and subjectively and has proved useful in the measurement of ocular components.

Pupil dilation with tropicamide 0.01% is being evaluated as a diagnostic tool for Alzheimer’s and Parkinson’s disease. However, the dependability of this test is still very controversial.

Side Effects

Tropicamide, particularly the 1% concentration, may produce transient stinging on instillation. As with the other mydriatic–cycloplegics, it can raise IOP in eyes with open-angle glaucoma. In most patients the increase in IOP is small and may be related to a decrease in aqueous outflow. In some patients, however, dilation can result in a significant increase in IOP. Dilation with 1.0% tropicamide and 2.5% phenylephrine has resulted in pressure elevations of 5 mm Hg or more in 32% and of 10 mm Hg or more in 12% of patients with open-angle glaucoma. The incidence of pressure elevations appears to be highest in eyes receiving miotic therapy.Thus to reduce the risk associated with iatrogenic pressure elevations, it seems prudent to recheck IOP after dilation with tropicamide in glaucoma patients.

Tropicamide, like atropine, cyclopentolate, and scopolamine, enters the systemic circulation rapidly.After applying two 40-ml drops of 0.5% tropicamide to one eye in eight patients, peak plasma concentrations were reached in 5 to 30 minutes but were variable (1.3 to 5.2 ng/ml). A mean peak concentration of 2.8 ng/ml was measured at 5 minutes. Despite the rapid systemic absorption, tropicamide has a low affinity for systemic muscarinic receptors.Thus adverse systemic reactions to tropicamide are quite rare. Two studies observed no significant adverse reactions associated with the use of tropicamide in 3,851 drug applications in patients undergoing ophthalmoscopy with either 0.5% or 1% tropicamide.The only reported effects were mild and transient; transient changes in IOP on the order of 4 to 12 mm occurred in seven patients, and one individual experienced a transient intermittent esotropia.

One reaction was reported in a 10-year-old white boy. Immediately after instillation of one drop of 0.5% tropicamide into each eye, the patient fell from the chair to the floor unconscious. Generalized muscular rigidity, pallor, and cyanosis followed. Within a few minutes the patient became flaccid and regained consciousness, but he remained in a state of generalized weakness and drowsiness. Approximately 1 hour after the onset of the episode, his vital signs were normal but he remained drowsy. This reaction was classified as acute hypersensitivity manifested by anaphylactic shock.The spontaneous recovery, however, argues against an anaphylactic mechanism. Others suggested that psychomotor factors may have played a role in this reaction or that the child fainted.

Because tropicamide is reported to be devoid of vasopressor effects in adults, it is one of the safest mydriatic agents for use in patients with systemic hypertension, angina, or other cardiovascular disease. Tropicamide has also been shown to be the safest agent (as indexed by changes in blood pressure and heart rate) for dilated retinal examinations in neonates. Additional information on pupil dilation in infants may be found in Chapter 8.

Contraindications

Patients with hypersensitivity to belladonna alkaloids may also exhibit cross-sensitivity to topical ocular tropicamide. Tropicamide is also contraindicated in patients with narrow anterior chamber angles in whom angleclosure glaucoma may be iatrogenically induced, but the reported risk is small. The eyes of 6,679 nonselected white adults aged 55 years or older were dilated with 0.5% tropicamide and 5% phenylephrine. Although the prevalence of narrow anterior chamber angles was 2.2% (Van Herick method), only two participants (0.03%) developed an acute angle-closure glaucoma.Theoretically, tropicamide is not very likely to cause angle closure because it is moderately selective for M4 receptors, and it was demonstrated that the muscarinic receptors in the trabecular meshwork are primarily of the M2 and M3 kind. In a multiracial population of adults over age 40 years, a 0.8% prevalence of narrow angles by penlight examination was reported. The risk of inducing an acute angle-closure glaucoma with 1% tropicamide and 2.5% phenylephrine was estimated to be approximately 0.3% if patients who have shallow anterior chamber angles via penlight examination or who have a history of glaucoma are excluded from dilation because of these risk factors.

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Glaucoma can often lead to visual impairment and even blindness. Although great progress has been made in defining the spectrum of diseases known collectively as glaucoma, their etiopathogenesis is still poorly understood. Management of these disorders is almost always directed at lowering the existing intraocular pressure (IOP).This can be accomplished either pharmacologically or surgically by decreasing aqueous production or by increasing aqueous outflow.

Many pharmacologic agents are available to decrease IOP through distinctly different mechanisms. Because of their unique mechanisms of action, these drugs are used either alone or in combination in attempts to reduce IOP to acceptable levels that forestall further damage to retinal ganglion cells. This chapter considers the most clinically useful ocular hypotensive agents (Box 10-1). Chapter 34 addresses how these drugs are used in the context of specific glaucomatous conditions.

PROSTAGLANDIN ANALOGUES

Because of their convenient use (once daily) in the treatment of glaucoma, their superior efficacy as ocular hypotensive agents, and good safety profile, the prostaglandin analogues are the first-line treatment for most patients with ocular hypertension and open-angle glaucoma. These agents represent a novel class of topically active drug with demonstrated long-term clinical usefulness. Latanoprost was the first commercially successful prostaglandin for clinical use in the treatment of glaucoma.

Latanoprost (Xalatan)

Pharmacology

Prostaglandins were originally discovered in the eye as mediators of the ocular inflammatory response, and most of the preliminary research focused on their potential role in uveitis and other inflammatory diseases. More recent studies, however, have demonstrated additional roles for prostaglandins in several physiologic processes.

When delivered in adequate doses, prostaglandins can either mediate inflammation or lower IOP. The therapeutic index of various prostaglandin analogues has been explored, and latanoprost demonstrates sufficient ocular hypotensive activity with minimal side effects. Latanoprost is an analogue of the prodrug prostaglandin F2a (PGF2a)-isopropyl ester. When instilled topically into the human eye, latanoprost is converted by corneal esterases into latanoprost acid, which exerts its biologic activity at the FP receptor on the ciliary muscle. The primary ocular hypotensive effect appears to be mediated by activation of FP receptors (receptors for PGF2a). Although the prostanoid FP receptors are known to be present in the eye, their specific localization and cellular functions are not well defined. These FP receptors are found in the ciliary muscle and iris sphincter muscle of the human eye. In the late 1990s, these receptors were also discovered in human trabecular meshwork cells, which may play a role in mediating some of the ocular hypotensive effects of PGF2a in the eye.

As a selective FP receptor agonist, latanoprost appears to exert its ocular hypotensive effects exclusively by increasing uveoscleral outflow. This effect is mediated by a substantial remodeling of extracellular matrix adjacent to the ciliary muscle cells. Topically applied prostaglandins have been demonstrated to reduce collagen levels in the ciliary muscle and adjacent sclera, and these changes may explain, at least in part, reduced hydraulic resistance to aqueous flow through these tissues. Although the specific mechanisms underlying reduction of collagen are obscure, exposure to PGF2a has been shown to increase production of matrix metalloproteinases, which are capable of degrading ciliary muscle extracellular matrix, which could in turn lead to the reduction of hydraulic resistance to uveoscleral flow.

In long-term clinical trials, latanoprost has been shown to be at least as effective as timolol maleate, a β-blocker, in reducing IOP. The ocular hypotensive effect of latanoprost is approximately 27% to 30%, whereas timolol reduces IOP approximately 20% (Figure 10-1). These results are of clinical significance because they reflect

140 CHAPTER 10 Ocular Hypotensive Drugs

Box 10-1 Ocular Hypotensive Drugs Used to Treat Glaucoma

Prostaglandin analogues

Latanoprost

Travoprost

Bimatoprost

b-Adrenergic antagonists (b-blockers)

Timolol Levobunolol Betaxolol Metipranolol Carteolol

Adrenergic agonists

Apraclonidine

Brimonidine

Carbonic anhydrase inhibitors

Acetazolamide

Methazolamide

Dorzolamide

Brinzolamide

Cholinergic agonist (miotic)

Pilocarpine

once-daily dosing of latanoprost 0.005% compared with twice-daily dosing of timolol 0.5% in patients with ocular hypertension or early primary open-angle glaucoma. Moreover, in patients with pigmentary and other forms of secondary glaucoma, latanoprost 0.005% dosed once daily has been shown to have a greater hypotensive effect than does timolol 0.5%.

The exact peak ocular hypotensive effect of latanoprost is unknown, but it is probably at least 8 hours after drug administration. Although administration of latanoprost once daily provides relatively uniform circadian (around-the-clock) reduction of IOP by itself or in combination with timolol, latanoprost seems to be most effective in the 12to 24-hour period after administration. As a result, IOP readings are generally lower during the daytime after drug administration during the preceding evening or at bedtime. Compared with the ocular hypotensive effect of twice-daily timolol, latanoprost applied once daily in the evening seems to provide better diurnal IOP control. In addition to increasing the peak IOP effect during the daytime, evening dosing of latanoprost also reduces the range of diurnal curve compared with morning administration.

The ocular hypotensive effect of latanoprost appears to be independent of race, gender, age, iris color, type of glaucoma, or previous glaucoma therapy.

Clinical Uses

Latanoprost and other prostaglandin analogues have supplanted the β-blockers as the drugs of first choice