Methods for Assessing the Effects of Pharmacologic Agents on Aqueous Humor Dynamics
RACHEL PECK, MIEKO HAYASHI, MICHAEL E. YABLONSKI, JOEL S. MINDEL and DOUGLAS J. RHEE
Table Of Contents
STEADY-STATE ALTERATIONS OF INTRAOCULAR PRESSURE
NON-STEADY–STATE ALTERATIONS OF INTRAOCULAR PRESSURE
NON-STEADY–STATE ALTERATION OF INTRAOCULAR PRESSURE BYPHARMACOLOGIC AGENTS
|The steady-state intraocular pressure is determined by the rate of aqueous humor formation, the flow of fluid from the eye, and the episcleral venous pressure. All agents that affect the steady-state intraocular pressure must do so by affecting at least one of these three variables. Non-steady–state alterations can occur by transient changes in these variables as well as by a variety of other mechanisms.|
|STEADY-STATE ALTERATIONS OF INTRAOCULAR PRESSURE|
AQUEOUS HUMOR FORMATION
Active and Passive Mechanisms of Formation
Aqueous humor is secreted into the posterior chamber by the nonpigmented ciliary epithelium. Aqueous humor production requires an active sodium-potassium adenosine triphosphatase similar to that found in other secretory epithelial tissues throughout the body.1–4 In addition, the enzyme carbonic anhydrase is intimately involved in the secretory mechanism.5–8 Passive flow of aqueous humor into the posterior chamber has also been postulated to account for a significant fraction of aqueous humor formation9; however, this seems unlikely. Passive flow would result from hydrostatic and osmotic pressures acting as driving forces. If passive formation were significant, an appreciable decrease in the rate of aqueous humor formation should occur when the intraocular pressure was raised. However, the baseline rate of aqueous humor formation in the primate, approximately 2.0 μL/min, decreases only 0.02 μL/min per millimeter of mercury (mm Hg) as intraocular pressure is raised.10 As pointed out by Bill,11 the protein colloid osmotic pressure of the interstitial fluid is 14 mm Hg. This would draw fluid from the posterior chamber into the ciliary processes. For passive fluid flow to occur in the opposite direction, the ciliary process hydrostatic pressure would have to exceed the intraocular pressure by more than 14 mm Hg.
Measurement of the Rate of Aqueous Humor Formation
Goldmann12 calculated the rate of aqueous humor flow through the anterior chamber by measuring the relationship between aqueous humor fluorescein concentration and plasma fluorescein concentration after intravenous administration of the dye. Subsequently, oral administration of fluorescein was used for this purpose.13,14 The chief disadvantage of both methods is that knowledge of the fluorescein concentration in the posterior chamber is required. This is difficult to determine. In addition, frequent measurements of the unbound plasma fluorescein concentration are necessary.
Jones and Maurice15 showed that after application of fluorescein to the cornea by iontophoresis it was possible to measure aqueous humor flow by monitoring the changes of fluorescein concentration in the corneal stroma and anterior chamber. Topical administration using fluorescein eye drops has also been effective.16 The typical time course of the fluorescein concentration in the corneal stroma and anterior chamber after topical administration is shown in Figure 1. In method I of Jones and Maurice,15 aqueous humor flow was calculated from the magnitude of the peak anterior chamber concentration and the time required to reach this peak. Because the exact time of the peak fluorescein concentration in the anterior chamber was difficult to determine, owing to the relative flatness of the curve, this method was seldom used. Method II of Jones and Maurice15 used data from those portions of the cornea stroma and anterior chamber fluorescein decay curves that were parallel. The magnitude of the anterior chamber aqueous humor flow, Fa, is a function of the anterior chamber volume, Va, the slope of the decay curve, A, and the ratio of the mass of fluorescein in the cornea to that in the anterior chamber, Mc/Ma, as shown in equation 1.
Fa = VaA[1 + Mc/Ma]
Mc = Vc Cc , where Vc is the corneal stroma volume and Cc is the corneal stroma fluorescein concentration. Similarly, Ma = Va Ca, where Ca is the anterior chamber concentration of fluorescein. Making these substitutions
in equation 1 yields:
Fa = VaA[1 + VcCc/VaCa]
If the volumes of the cornea and anterior chamber are assumed to remain constant in the steady state, then Fa is a function of A, the steepness of the decay curve, and Cc/Ca, which is the ratio of fluorescein concentrations in the corneal stroma and aqueous humor. The logarithm of Cc/Ca is represented by the distance between the parallel decay curves (see Fig. 1). Equation 2 shows that the more rapid the rate of aqueous humor flow, Fa, the steeper will be the decay curves and the larger the magnitude of the distance between the two decay curves (i.e., Cc/Ca will increase). At the other extreme, if Fa becomes equal to zero, the fluorescein concentrations in the anterior chamber and corneal stroma will equalize by diffusion and decay curves will be flat (A = 0).
Equation 2 rests on the assumptions that (i) all fluorescein in the corneal stroma leaves by diffusion into the anterior chamber, (ii) the anterior chamber is a well-mixed compartment, and (iii) all anterior chamber fluorescein is removed by convective flow.15–17 These assumptions have been shown to be reasonably accurate.15,18 In addition, there is close agreement between the empirically measured changes in fluorescein concentration and the theoretical values predicted by the model.15–18
The chief advantage of the fluorophotometric method is that aqueous humor flow can be measured without invasive procedures. The normal physiology is altered in only two ways: (i) fluorescein is present in the eye and (ii) the eye is intermittently exposed to blue light. The blue light causes the dye in the corneal stroma and aqueous humor to fluoresce. This fluorescence is measured by the fluorophotometer and is directly proportional to the fluorescein concentration.
Invasive methods have been used to measure aqueous humor flow in experimental animals.10,19–21 These methods suffered from the obvious disadvantage that they could not be carried out without an obligatory insult to the eye.22 They usually measured the rate of change in the concentration of a tracer substance injected into the aqueous humor or measured the rate of flow from a reservoir into the cannulated anterior chamber as the infusion pressure was changed.11,20 Tracer molecules can also be used to determine the routes of flow from the anterior chamber; in this manner uveoscleral flow was first discovered.23
Tonography has been used to measure anterior chamber aqueous humor flow. The
method is noninvasive. However, at best, tonography can only reveal
the rate of flow across the trabecular meshwork (i.e., the pressure-dependent flow). Because tonography measures
the change in aqueous humor flow caused by an increase in intraocular
pressure, it yields no information regarding the magnitude of the pressure-independent
flow of aqueous humor, usually referred to as
uveoscleral outflow, Fu. Therefore, it is not possible to determine the rate of aqueous humor
formation on the basis of tonography alone. As shown in equation 3, in
the steady state, the rate of anterior chamber aqueous flow, Fa, equals the sum of trabecular outflow, Ftr, and uveoscleral outflow, Fu.
Fa = Ftr + Fu
AQUEOUS HUMOR OUTFLOW
Trabecular Meshwork Outflow
The inner wall of the canal of Schlemm and the juxtacanalicular tissue seem to be the sites of the major resistance to flow through the trabecular meshwork.24 Tonography is used to measure this resistance to the flow of aqueous humor. In its simplest form, tonography is accomplished by placing the Schiøtz tonometer on the cornea of the supine patient for 4 minutes and observing the change in intraocular pressure over the test period. Electronic tonography machines allow a continuous recording of the intraocular pressure.
The flow of aqueous humor into the canal of Schlemm seems to be a passive
process and therefore obeys the general physical law relating passive
flow, F, the hydrostatic pressure driving force, Δp, and the resistance
to flow, R (equation 4).
ΔP = FR
When applied to the trabecular flow, it yields
IOP-PCS = FtrRtr
where the driving force is IOP − Pcs, the difference between the hydrostatic pressure of the anterior chamber, IOP, and
that of the canal of Schlemm, Pcs. Ftr is the transtrabecular flow of aqueous humor, and Rtr is the resistance to flow between the anterior chamber and the canal of
Schlemm. The inverse of Rtr is Ctr, the trabecular outflow facility.
Ctr = 1/Rtr
Combining equations 5 and 6 yields:
Ftr = Ctr(IOP–Pcs)
If in equation 7 IOP is changed by ΔIOP, while Ctr and Pcs remain constant, the trabecular meshwork flow will change by ΔFtr, as shown in equation 8.
Ctr = ΔFtr/ΔIOP
Thus, in order to measure the trabecular outflow facility, Ctr, one must only measure ΔFtr and ΔIOP.
In conventional tonography, ΔIOP is equal to the mean increase above the baseline intraocular pressure produced by the tonometer. Measurement of ΔFtr is based on the change in the volume of the globe during tonography. This change in volume of the globe is indirectly derived from the change in intraocular pressure that occurs during the 4-minute tonography period. The relationship between the volume of the globe and the intraocular pressure, although somewhat controversial, has been reasonably well worked out.25,26 The intraocular volume decrease determined by tonography is assumed to be equal to the magnitude of the flow of aqueous humor across the trabecular meshwork in excess of the normal rate of flow.
Overestimations of the trabecular meshwork flow, Ftr, could result if (i) part of the intraocular volume decrease
during tonography were caused by increased flow of fluid leaving the
eye by nontrabecular meshwork routes (e.g., if blood and extracellular fluid were squeezed out of the choroid) and (ii) the
rate of aqueous humor secretion were decreased
during tonography. These and possibly other sources of overestimation
seem to occur. Overestimation errors are collectively referred to as
pseudofacility. As shown by equation 9, the difference between the total
outflow facility measured by tonography, Ctot, and the trabecular outflow facility, Ctr, equals the pseudofacility, Cps.27
Cps = Ctot – Ctr
Changes in outflow facility determined by tonography could be caused by either a change in Ctr, as is usually assumed, or a change in Cps, or both.
Attempts have been made to measure Cps in humans by measuring the relationship between an induced increase in episcleral venous pressure and the resultant increase in intraocular pressure.28,29 However, this method is fraught with potential artifacts and therefore is of limited usefulness.
An attempt to determine human Ctr noninvasively has been made by Yablonski and co-workers.30,31 They used fluorophotometry to measure ΔFtr after administration of a β-blocker and/or a carbonic anhydrase inhibitor. With the measurement of the concomitant ΔIOP, assumed to be entirely caused by decreased aqueous humor formation, Ctr was determined using equation 8. This method avoids the confounding influence of Cps and ocular rigidity; however, because of inherent variability, its main use is in studies of many subjects rather than of individuals.
Invasive methods of tonography have been used in experimental animals.22,32,33 These methods involve cannulation of the anterior chamber and thereby permit direct measurement of ΔFtr caused by ΔIOP without having to deduce volume changes from intraocular pressure changes. These methods also permit the injection of tracers into the anterior chamber and thus increase the capabilities of these studies; however, the invasive techniques also create artifacts caused by anesthesia, a variable inflammatory response, and penetration of the globe, that are not present in noninvasive procedures.22,34
The value of (IOP − Pcs) in equation 7 is the outflow pressure, the driving force for fluid flow into the canal of Schlemn. The value of Pcs is assumed to be nearly equal to the value of the episcleral venous pressure, which is approximately 10 mm Hg; therefore, a change in intraocular pressure from 16 mm Hg to 12 mm Hg represents a 25% decrease in intraocular pressure but a 67% decrease in outflow pressure. On the other hand, a decrease in intraocular pressure from 40 mm Hg to 30 mm Hg is also a 25% decrease in intraocular pressure but only a 33% decrease in outflow pressure. When studying drugs that affect the trabecular outflow, it is more meaningful to express changes in the steady-state condition as percent changes in outflow pressure rather than as percent changes in intraocular pressure.
In 1937, after the injection of indigo carmine dye into the anterior chambers of rabbits, von-Seidel noted staining in the sclera and uvea.35 Thirty years later in an experimental primate model, Bill36,37 identified the alternate (uveoscleral) outflow pathway with a description of the consecutive progression of radiolabeled aqueous humor from the anterior chamber through the interstitial spaces of the ciliary body muscle to the suprachoroidal space and though the sclera. Some fluid is removed by the ciliary body capillaries38 and a strong case has been made by Yablonski39 for the final route of uveoscleral flow to be largely into the uveal blood rather than entirely across the sclera. The basis for this hypothesis is the large protein colloid osmotic pressure difference between the uveal blood and aqueous humor which would act as a strong driving force for aqueous humor flow into the uveal capillaries. According to this hypothesis the term uveoscleral flow is a misnomer because most of the flow is not across the sclera. It has similarly been suggested that pressure-insensitive outflow is a better term.40 Nevertheless, we will continue to use the term uveoscleral outflow in this chapter in order to be consistent with the rest of the literature. Direct measurement of uveoscleral outflow involves the use of radiolabeled tracers, is invasive and requires a disturbance to the eye. Uveoscleral flow of tracer molecules injected into primate eyes accounted for 30% to 50% of the total aqueous humor egress.41 Bill42 identified twelve human eyes that were to undergo medically necessary enucleation for suspected and/or confirmed malignant melanoma. Prior to enucleation, Bill injected 131I-albumin into the eyes and, at carefully measured intervals, quantified the amount of radioactive tracer identified in the ocular tissues. The average amount of uveoscleral outflow was approximately 10%.
Data obtained using noninvasive indirect measurements suggest that uveoscleral outflow can vary significantly with changes in the pathophysiologic condition of the eye. In young, healthy human subjects, Townsend and Brubaker43 used tonography to determine that 36% of outflow occurred through the uveoscleral pathway. In a fluorophotometry study comparing the rates of uveoscleral outflow in young and elderly nonglaucomatous people, Toris et al44 calculated that the uveoscleral outflow accounts for 54% of the total outflow in the young, and 46% of the total outflow in elderly. The 54% of outflow that is uveoscleral in young humans (n = 51) is consistent with earlier data from tracer experiments in young monkeys.45 In contrast, fluorophotometry showed 23% of the aqueous passed through the uveoscleral pathway of ocular hypertensive patients.46
Eyes with primary open-angle glaucoma (n = 15) treated with maximally tolerated medical therapy have fluorophotometry measured uveoscleral flow rates that are 73% of total outflow,30 which suggests high resistance in the trabecular meshwork may result in the therapeutic redirection of aqueous to the uveoscleral pathway.
Episcleral Venous Pressure
In 1901 scientists postulated that the aqueous humor drains into the episcleral veins.47 This theory was substantiated 20 years later by Uribe-Troncoso48 and von Seidel49 with their independent descriptions of the movement of aqueous humor from the anterior chamber to the episcleral veins in rabbits. Aqueous humor was identified in the episcleral veins by Ascher.50–52
Although there are different methods to measure the episcleral venous pressure (Pev), all are rooted in the principle introduced by von Seidel53 that the intravascular pressure of the vein will be equal to the amount of external pressure necessary to elicit a change in the caliber of that vein. This theory assumes that vein walls have negligible rigidity and tension, and therefore, the vein will not become reduced in caliber until the extravascular pressure exceeds the intravascular pressure. Brubaker54 corroborated this assumption with the observation that episcleral venous pressures measured by external compression of the vein correlated with the venous pressures measured by vessel cannulation. Episcleral venous pressure may vary up to 1 mm Hg with changes in posture.55,56 Regardless, most studies conclude that Pev is normally 8 to 12 mm Hg in humans.57 In most forms of glaucoma, the episcleral venous pressure remains relatively stable.55,58,59
The factors influence obtaining accurate measurements of episcleral venous pressure in humans: (i) identifying the correct vessel, (ii) applying the measurement device at an appropriate position over the vessel, and (ii) the determination of the end point. To obtain the most accurate representation of the pressure of the canal of Schlemm, the episcleral venous pressure should be measured in an aqueous- containing vein. Aqueous veins originate at the limbus and are paler than the blood filled episcleral veins. Zeimer60 suggests placing the measurement device slightly distal to the junction of the aqueous and episcleral vein. If these vessels are difficult to visualize, the device can be placed 3 mm distal to the limbus. Proposed end points60–63 range from the first visible change in the vessel,55,64,65 either in color or shape, to the complete occlusion of the vessel.54 The controversy centers on how much of a change in vein appearance best represents just exceeding the episcleral venous pressure. In the same eye, different endpoints produce different results. The excess increase in external pressure required to reach the first detectible change in caliber of the vein has been reported to be 0.25 to 2 mm Hg.55,62 As much as 7 mm Hg64 more may be required to fully collapse the vein. The end point measured as either a 50% reduction in the color or width of the vessel is generally accepted as an appropriate choice.57
The pressure chamber technique, first described by von-Seidel53in 1923, is generally accepted as the most reliable and accurate method to measure episcleral venous pressure.66 Although the instrument has been modified over the years to improve accuracy and ease of use, the principle underlying this technique is unchanged. A transparent distensible membrane covers one end of the chamber and the other end enables the observer to view the vessel. The observer applies external pressure by placing the membrane end of the chamber on the conjunctiva overlying the vein. Pressure is applied until a change in the caliber of the vessel, the end point, is noted. The pressure of the chamber at the end point is measured by a manometer connected to the apparatus. Zeimer et al60 made a significant contribution to the pressure chamber method in 1983 with the development of the episcleral venomanometer. This device has many advantages: it can be operated by a single observer, it is compact, and it can easily be attached to a slit-lamp biomicroscope to provide a stereoscopic view. The episcleral venomanometer has been demonstrated to have both intraobserver and interobserver reproducibility.60 Calibration of this instrument is not necessary, and an end point of half-balancing of the selected vein is recommended.
Additional methods have been proposed to measure episcleral venous pressure but none have been able to achieve the accuracy and reproducibility of the episcleral venomanometer and/or pressure chamber technique. The force method, developed by Goldmann,67 involves the application of a variable force to a constant area over the episcleral vein. Pressure is calculated, as the force required, to reach the endpoint divided by the area of the applanation tip. The reproducibility of this method is controversial: Brubaker54 demonstrated that the end point is difficult to reproduce with the force method. However, Podos et al59 reported a reproducibility of ±1.2 mm Hg. The size and shape of the applanation tip are factors that influence the calculation of pressure; if the flat tip does not completely conform to the curved globe, the force will not be evenly distributed.54,59,68 The air jet method, like the pressure chamber method, is based on the theory that the pressure of the vein will be equal to the pressure from a jet of air that elicits a change in the caliber of the vein. This device must be calibrated to account for the loss of pressure due to resistance as the air travels from the manometer toward the eye. The accuracy of this method is decreased if the jet of air does not hit the vein directly.61 An indirect tonographic method69 has also been proposed, but it was found to provide reliable information only in normal eyes.70
Alternative Model for Aqueous Humor Dynamics
The preceding discussion and equations are derived from the traditional two-compartment model of aqueous humor dynamics. The two-compartment model describes the passage of fluorescein between the systemic circulation, the anterior chamber, and the cornea. In recent years, McLaren et al71 have proposed that the mathematical calculations of aqueous humor dynamics should be routed in a three-compartment model. This theory arose as a result of the observation that the existing (two-compartment) equations do not accurately predict the time in which fluorescein enters the anterior chamber from the systemic circulation. The three-compartment model adds an additional transfer coefficient that takes into account the diffusion of the fluorescein through a tissue component, the iris, prior to its appearance in the anterior chamber. Although the three-compartment model has yet to gain wide acceptance, there are convincing arguments on its behalf.
|NON-STEADY–STATE ALTERATIONS OF INTRAOCULAR PRESSURE|
|Intraocular pressure can be altered transiently by a variety of means. However, if
no alteration occurs in any of the factors that determine
the steady-state level of intraocular pressure, the intraocular
pressure will eventually return to its prealteration level.|
The eye may be thought of as an elastic sphere of sclera and cornea, inflated
by a liquid at a pressure equal to the intraocular pressure. Alterations
in intraocular volume will transiently change intraocular pressure. Equation 10 gives
the change in the value of the log of the intraocular
pressure as the product of ΔV, the change in intraocular
volume, and E, the ocular rigidity coefficient.25
Δlog (IOP)= EΔV
Equation 11 expresses this relationship using the natural logarithm and
assumes that the normal value for E is 0.0215/μL
Δln (IOP)=2.303 Δlog(IOP)=(2.303)(0.0215) (ΔV)
For small changes in V, dV, equation 11 becomes
dln (IOP)=d(IOP)/IOP =(2.303)(0.0215) (dV)=0.05 (dV)
There is an approximate 5% change in intraocular pressure for every microliter change in volume.25,26 Equations 10 to 12 apply only when intraocular volume is changing. Changes in intraocular volume cannot be sustained unless there is a coincident change in the rate of aqueous humor secretion, the outflow facility, the uveoscleral flow, or the episcleral venous pressure. For example, if 1 μL of fluid were somehow removed from the globe, the intraocular pressure would decrease by 5%, however, the globe's volume and intraocular pressure would soon return to their prealtered level if the factors that determine the steady-state level of intraocular pressure were unchanged.
A sphere is the geometric configuration with the smallest surface area per unit volume or, stated differently, it has the largest volume per unit surface area. Any alteration in its shape results in smaller volume. Deformation of a sphere without a decrease in volume results in its being overinflated. Hence, deformation of the eye results in an increase in intraocular pressure.
Tonography and ophthalmodynamometry deform the eye. During tonography, because none of the steady-state determinants of intraocular pressure has been altered, the pressure decreases exponentially toward its pretonography level. When the extraocular muscles rotate the globe, the eye is deformed by their pull. Usually, the resultant change in intraocular pressure is minimal,72 however, when a muscle is mechanically restricted, the pull of the antagonist muscle may result in considerable deforming force. Thus, in a case of extraocular muscle entrapment after orbital floor fracture, or of an extraocular muscle adhesion due to endocrine ophthalmopathy,73 attempts to rotate the globe away from the direction of action of the restricted muscle will result in an elevation of the intraocular pressure. With each heart beat a slight increase in the intraocular vascular volume occurs; hence, there is a transient increase in intraocular pressure.
ALTERATION OF STEADY STATE DETERMINANTS OF INTRAOCULAR PRESSURE BY PHARMACOLOGIC AGENTS
The goal of pharmacologic glaucoma therapy is to prevent visual field loss. The only proven method is to lower the intraocular pressure.74–78 In order for a drug to be effective, it must alter one or more of the factors that maintain the steady-state intraocular pressure: the rate of aqueous humor formation, the rate of aqueous humor outflow (trabecular meshwork and uveoscleral pathways), and the episcleral venous pressure. None of the commonly used eye medications seem to significantly affect the episcleral venous pressure.79
α-Agonists were first noted to have an ocular hypotensive effect in 1966 with the observation that oral clonidine, an α2-agonist, decreased intraocular pressure in humans.80 Topical clonidine was found to have potent systemic side effects which included systolic and diastolic hypotension, bradycardia, and sedation.81–83 The dose-dependent systemic hypotension resulted in a decrease in ophthalmic artery pressure, which may put the optic nerve at increase risk for ischemic damage.84 In 1978, apraclonidine, a clonidine analogue, was the first α2-agonist approved in the United States for treating ocular hypertension. Apraclonidine, compared to clonidine, had decreased blood-aqueous and blood–brain permeabilities, and therefore had a safer systemic side effect profile.85 Brimonidine, introduced subsequently, was 23-fold to 32-fold more α2-adrenoceptor selective than apraclonidine, so much so that it is considered a reference compound.86–88
In vivo fluorophotometry data in rabbits, monkeys, and humans indicate suppression of aqueous humor formation following administration of clonidine, apraclonidine, and brimomidine.89–91 In humans it has been suggested that, with long-term therapy, brimomidine might lower intraocular pressure by another mechanism (i.e., not by a reduction in aqueous formation). Toris et al89 observed with fluorophotometry that, acutely, both brimomidine and apraclonidine decrease aqueous humor formation.92,93 By day 8 of treatment, the magnitude of the inhibition of aqueous flow decreased for both drugs and the outflow facility in apraclonidine treated eyes increased, thereby sustaining the decrease in intraocular pressure.93 After 8 days of treatment with brimomidine, fluorophotometry measured aqueous humor flow was reduced by 0.44 μL/min, compared to that on day 1, 0.70 μL/min. By day 29 the rate of aqueous flow had returned to pretreatment levels,92 yet the pressure-lowering effect remained stable. Toris and co-workers92 explanation was that uveoscleral outflow was presumed to have increased by 60% above baseline by day 8, and remained at this elevated level through day 29. Trabecular outflow facility and episcleral venous pressure were unchanged by brimomidine. The mechanism by which brimomidine may cause such an increase in uveoscleral outflow is unknown. Some suggest that stimulation of α2-adrenergic receptors by brimomidine may result in the release of endogenous prostaglandins.92 It is widely believed that prostaglandins enhance uveoscleral outflow.94,95
Epinephrine is an α1-, α2-, β1-, and β2-adrenergic agonist. It is believed to act as an ocular hypotensive agent primarily through its β2-agonist activity, because selective β2-agonists such as salbutamol can mimic epinephrine's hypotensive action.96 α1-Agonists, such as phenylephrine,97 have no significant hypotensive effect.
Based on earlier tonographic studies,98,99 and even some early fluorometric studies,13,100 it was erroneously concluded that topical epinephrine lowered intraocular pressure primarily by decreasing the rate of aqueous humor formation. This was based on the observation that the increase in Ctot produced by epinephrine was not sufficient to account for the decrease in intraocular pressure. Because epinephrine did not significantly affect the episcleral venous pressure66 and the concept of uveoscleral flow had not been fully appreciated, it was assumed that the decrease in intraocular pressure was primarily because of a decrease in aqueous humor secretion. Subsequent fluorometric studies have found that epinephrine actually increases, by approximately 20%, aqueous humor formation.17,38,43
Topical epinephrine, and other β2-agonists, seem to act primarily by increasing uveoscleral flow,17,43 with the increase in trabecular outflow facility being of secondary importance. However, the literature is not consistent. Of those parameters (intraocular pressure, episcleral venous pressure, rate of aqueous humor secretion, outflow facility, and uveoscleral flow) evaluated, human uveoscleral flow is the most indirectly and possibly the least accurately, calculated. Conflicting findings exist. For example, Wang et al101 investigated the effects in 26 human volunteers of twice-daily doses of topical epinephrine hydrochloride 2% on aqueous humor dynamics after 1 week of use. Their results contradicted almost all of the preceding statements. Fluorophotometry was used to measure both aqueous humor formation and trabecular outflow facility. The trabecular outflow facility was calculated as the ratio of the change in aqueous humor flow to the change in IOP (equation 8). Aqueous formation decreased by 12% after epinephrine treatment, and trabecular outflow facility increased approximately 44%. Episcleral venous pressure was determined with an episcleral venomanometer and was not significantly affected by treatment with epinephrine. Measurement of uveoscleral outflow with indirect mathematical methods suggested that epinephrine did not alter Fu.
Aqueous humor flow measurements, determined by fluorophotometry, show that after either a single dose of 0.5% timolol,16,102 or 1 week of twice-daily topical administration,17 a 50% reduction in the rate of aqueous humor formation results. One drop of timolol maleate reduced flow from 2.24 μL/min to 1.17 μL/min. The intraocular pressure fell from 26.8 mm Hg to 18.7 mm Hg. Based on the assumption that the episcleral venous pressure was 10 mm Hg, this decrease in intraocular pressure represented a 50% decrease in outflow pressure (IOP − Pev) from 16.8 mm Hg to 8.7 mm Hg. The 50% decreases in aqueous humor flow and outflow pressure suggested that the entire intraocular pressure effect of timolol maleate was caused by the reduction in aqueous humor production. These assumptions were substantiated by the absence of significant alteration of the episcleral venous pressure,103 outflow facility,17,103 and uveoscleral flow.17
CARBONIC ANHYDRASE INHIBITORS
For over 40 years, carbonic anhydrase inhibitors have been important agents used in the treatment of glaucoma. The intraocular pressure-lowering effects of carbonic anhydrase inhibitors in humans were first noted by Becker,104 shortly after acetazolamide was introduced as a diuretic. Oral carbonic anhydrase inhibitors have a high frequency of adverse effects, and often are not tolerated by patients. Attempts to produce a topical carbonic anhydrase inhibitor were initially unsuccessful because of difficulty achieving the 99% inhibition of carbonic anhydrase needed to elicit a significant psysiologic response.105,106 In 1983, Maren et al107 demonstrated that topical trifluoromethazolamide lowered the intraocular pressure of rabbits. Eventually, a safe and effective topical carbonic anhydrase inhibitors for use in humans was developed.
Acetazolamide, methazolamide, and dichlorphenamide are oral carbonic anhydrase inhibitors approved for use in the United States. These drugs lower intraocular pressure by decreasing the rate of aqueous humor secretion as evidenced by fluorophotometry108,109 and tonography data.6,103,110,111 The initial decrease in acetazolamide treatment has been found to be as much as 75% in dogs, determined by radioactive tracer anterior chamber dilation.20 Tonographic data based on equation 7 has been shown to reduce aqueous humor formation by approximately 50% in most studies of animals112 and humans.110,113 Fluorophotometry in humans has also shown a 50% decrease in the steady-state rate of aqueous humor formation.108,109
Using fluorophotometry, 2% topical dorzolamide was shown to induce a 38% decrease in aqueous humor secretion in monkeys.114 In humans, a 20% fluorophotometric reduction of aqueous secretion was measured within 2 to 5 hours of topical dorzolamide administration.115 The effect of carbonic anhydrase inhibitors on uveoscleral outflow is not known; however, it seems unlikely that a change occurs in this parameter since the reduction in aqueous humor formation is sufficient to explain the entire effect on intraocular pressure.
Fluorophotometry has been utilized in studies investigating the effects of topical dorzolamide and oral acetazolamide used in combination. While both treatments result in a statistically significant reduction in aqueous humor flow,115,116 oral acetazolamide produces a greater effect: acetazolamide, 30%;dorzolamide, 17%.116,117 Most data suggest that, used concurrently, topical and oral carbonic anhydrase inhibitors are not additive.116,118,119 However, Maus et al117 found that the addition of oral acetazolamide to patients already receiving topical dorzolamide reduced aqueous humor formation by an additional 16%. Adding dorzolamide to patient's already receiving acetazolamide did not result in further aqueous flow reduction.
Topical carbonic anhydrase inhibitors are less potent than β-blockers when used as monotherapies.118 In combination, timolol and dorzolamide produce additive lowering effects on both aqueous humor formation and intraocular pressure. Their additive effects have been shown to reduce aqueous flow by approximately 55%.119
Direct-acting cholinergic agents such as pilocarpine and carbachol, and indirect-acting cholinergic agents, such as physostigmine (Eserine) and echothiophate iodide appear to lower the intraocular pressure entirely on the basis of their effects on Ctr.33 Fluorophotometry has shown no effect of echothiophate iodide on the rate of human aqueous humor formation.120 These agents also have no significant effect on Pev.79 In vivo studies in humans121 and primates122 indicate that pilocarpine decreases the magnitude of Fu. Presumably, the contraction of the ciliary body musculature decreases the ease with which aqueous humor can penetrate the ciliary body. The increase in Ctot, determined tonographically, is often larger than appears appropriate for the decrease in intraocular pressure. This may be due to the decrease in Fu, which would tend by itself to raise the intraocular pressure.
Topical corticosteroids raise intraocular pressure without affecting aqueous humor flow.123–125 There is a reasonably consistent tonographic finding of reduced outflow facility,126,127 suggesting that the increase in intraocular pressure is due to a negative but reversible effect on the trabecular structure.
The ocular hypotensive effect of intracameral prostaglandins was noted in 1971.128 Camras et al129 showed a similar hypotensive effect from topically applied prostaglandins in 1977. Prostaglandin Fα2 analogues, latanoprost, bimatoprost, unoprostone isopropyl, and travoprost have emerged as effective therapies for the treatment of glaucoma.
Prostaglandins lower the intraocular pressure in large part by increasing the uveoscleral outflow. The exact mechanism in which this occurs is not known. One theory is that prostaglandins initiate a remodeling of the extracellular matrix of the ciliary body that results in improved drainage of aqueous humor through the ciliary body face. Experimental evidene exists that, in primates, prostaglandin Fα2 analogues decrease the extracellular matrix surrounding the ciliary body smooth muscle cells after 4 to 8 days of treatment.130,131 This finding corresponds to the observation that a larger intraocular pressure reduction was observed in monkeys after 4 to 5 days of daily latanoprost dosing.132,133 Bimatoprost was also found to increase tonographic outflow facility, Ctot.40 Similar, but not quite statistically significant increases in outflow facility were found, by fluorophotometry, for latanoprost.93
Initially, based on data from primate experimental models, there was concern that pilocarpine might inhibit prostaglandin induced enhancement of uveoscleral outflow.134,135 However, in humans, fluorophotometry data indicate that pilocarpine does not have this effect136–138; prostaglandin derivatives and pilocarpine are effective in lowering intraocular pressure when used together.
|NON-STEADY–STATE ALTERATION OF INTRAOCULAR PRESSURE BYPHARMACOLOGIC AGENTS|
|Agents that affect the tonus of the extraocular muscles will cause transient
changes in intraocular pressure. Succinylcholine, which is used
to paralyze the singly innervated muscle fibers found in voluntary muscles, causes
a sustained contraction of the multiply innervated fibers
in the extraocular muscles.139,140 Simultaneous contraction of the extraocular muscles can produce large
elevations in intraocular pressure. Curare, which produces a paralysis
of all the extraocular muscle fibers, not surprisingly yields a transient
decrease in intraocular pressure.141|
Hyperosmotic agents (e.g., urea, mannitol, and glycerol) decrease the intraocular pressure by reducing the intraocular volume. They increase the osmotic pressure exerted by the blood and drive intraocular fluid into the capillaries. As a result, fluid is drawn out of the vitreous and the extracellular spaces.142,143 The exact route of the fluid escape is not clear. Perhaps uveoscleral flow is increased, since there is some evidence that this flow is a function of the magnitude of the blood osmotic pressure.36,38,39
Vasoactive agents that reduce the intraocular blood volume can cause a transient decrease in intraocular pressure. For example, oxygen administration has been shown to lower the intraocular pressure144 and to cause a decrease in choroidal blood volume.145 However, the basis of the more sustained lowering of intraocular pressure during oxygen administration is a reduced episcleral venous pressure. On the other hand, intravenous administration of vasodilators such as amyl nitrite causes an increase in intraocular pressure that is assumed to be caused by increased uveal blood volume.146
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21. Obenberger J, Babický A: Alkali and acid burns of the rabbit eye: Measurement of aqueous flow by means of intravenously injected Na 125I and Na 131I. Graefes Arch Klin Exp Ophthalmol 193:253, 1975
49. Von Seidel E: Weitere experimentelle Untersuchungen uber die Quelle und den Verlauf der intraokularen Saftstromung. IX. Mitteilung. Uber den Abflu? des vorderen Augenkammer. Graefes Arch Clin Exp Ophthalmol 104:357, 1921
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83. Kaufman PL, Barany EH: Loss of acute pilocarpine effect on outflow facility following surgical disinsertion and retrodisplacement of the ciliary muscle from the scleral spur in the cynomolgus monkey. Invest Ophthalmol 15:793, 1976
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122. Bárány EH: Relative importance of autonomic nervous tone and structure as determinants of outflow resistance in normal monkey eyes (Cercopithecus ethiops and Macaca irus). In Rohen JW, (ed.): The Structure of the Eye: II. Symposium. Stuttgart. 1965:223–236
131. Lutjen-Drescoll E, Tamm E: The effects of ocular hypotensive doses of PGF F2?-1-isopropylester on anterior segment morphology. In Bito LZ, Stjernschantz J, eds. The Ocular Effects of Prostaglandins and Other Eicosanoids. Alan R. Liss: New York, 1989:737–776
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