PHYSIOLOGY OF AQUEOUS HUMOR

& FACTORS MAINTAINING

NORMAL IOP

PRESENTED By Dr Rohit Rao

References

Becker-Shaffer’s diagnosis & therapy of glaucoma

Shields Textbook of Glaucoma

Adlers Physiology of the Eye

AQUEOUS HUMOR

• Clear, colorless fluid that fills the anterior and posterior chambers of the eye.

Physiological properties • Volume 0.31ml

• Refractive index 1.333

• PH 7.2

• Hyper osmotic

• Rate of formation 1.5 to 4.5 µl/min

Composition• Water constitutes 99.9% of Normal Aqueous • Proteins (5-16mg/100ml) concentration in

Aqueous is less than 1% of its plasma concentration

• Glucose – 75% of the plasma concentration.• Electrolytes:

– Na+ similar in plasma and aqueous – Bicarbonate ion: Concentration in PC &

in AC– Cl ion concentration than plasma and

phosphate concentration than plasma • Ascorbic acid concentration is very high in

aqueous.• Various components of the coagulation and

anticoagulation pathways may be present in human aqueous humor.

Functions of aqueous humor

• Brings oxygen and nutrients to cells of lens, cornea, iris

• Removes products of metabolism and toxic substances from those structures

• Provides optically clear medium for vision

• Inflates globe and provides mechanism for maintaining IOP

• High ascorbate levels protect against ultraviolet-induced oxidative products, e.g., free radicals

• Facilitates cellular and humoral responses of eye to inflammation and infection

The blood–aqueous barrier• Barriers to the movement of substances from the

plasma to the aqueous humor.

• In the ciliary body the barriers include – Vascular endothelium– Stroma – Basement membrane– Pigmented and non-pigmented epithelium.

Zona occludens

• The blood–aqueous barrier is responsible for differences in chemical composition between the plasma and the aqueous humor.

• Breakdown of blood aqueous barrier– In some situations (e.g., intraocular

infection), a breakdown of the blood–aqueous barrier is clearly therapeutic

– In other situations (e.g., some forms of uveitis and following trauma), the breakdown of the barrier leads to complications.

Stimuli that break blood–aqueous barrier

Aqueous humor dynamics• Secreted by ciliary epithelium lining the ciliary

processes

• Enters the posterior chamber.

• It then flows around the lens and through the pupil into the AC.

• There is convection flow of aqueous in the AC due to temperature gradiant.

• It leaves the eye by two pathways at the anterior chamber angle:

– Through the TM, across the inner wall of Schlemm's canal into its lumen, and thence into collector channels, aqueous veins, and the episcleral venous circulation – the trabecular or conventional route

– Across the iris root, uveal meshwork, and the anterior face of the ciliary muscle, through the connective tissue between the muscle bundles, the suprachoroidal space, and out through the sclera – the uveoscleral or unconventional route.

Aqueous humor formation

• Aqueous humor is produced from pars plicata along the crests of the ciliary processes.

• Aqueous humor is derived from plasma within the capillary network of the ciliary processes.

• Three physiologic processes contribute to the formation and chemical composition of the aqueous humor:– Diffusion

– Ultrafiltration

– Active secretion.

Lens

Pars plicata

Diffusion• Diffusion is the movement of substance

across a membrane along concentration gradient.

• As aqueous humor passes from the PC to Schlemm’s canal, it is in contact with ciliary body, iris, lens, vitreous, cornea, and trabecular meshwork.

• There is diffusional exchange, so that the AC aqueous humor resembles plasma.

Ultrafiltration• The process by which fluid and its solutes

cross semipermeable membrane under pressure gradient is called ultrafiltration.

• As blood passes through capillaries of the ciliary processes, about 4% of the plasma filters through capillary wall into the interstitial spaces between the capillaries and the ciliary epithelium.

• In the ciliary body, fluid movement is favored by the hydrostatic pressure difference between the capillary pressure and the interstitial fluid pressure and is resisted by the difference between the oncotic pressure of the plasma and the aqueous humor.

Active transport• Active transport is energy-dependent

process that selectively moves substance against its electrochemical gradient across a cell membrane.

• It is postulated that majority of aqueous humor formation depends on active transport.

• It is done by non-pigmented epithelial cells

Basic Physiologic Processes• Accumulation of Plasma Reservoir

– Most plasma substances pass easily from the capillaries of the ciliary processes, across the stroma, and between the pigmented epithelial cells before accumulating behind the tight junctions of the nonpigmented epithelium.

– This movement takes place primarily by diffusion and ultrafiltration.

• Transport across Blood-Aqueous Barrier

– Active secretion is a major contributor to aqueous humor formation.

– Selective transcellular movement of certain cations, anions, and other substances across the blood-aqueous barrier formed by the tight junctions between the nonpigmented epithelium.

– Aqueous humor secretion is mediated by transferring NaCl from ciliary body stroma to PC with water passively following.

– Carbonic anhydrase mediates the transport of bicarbonate across the ciliary epithelium through a rapid interconversion between HCO-

3 and CO2.

– Other transported substances include ascorbic acid, which is secreted against a large concentration gradient by the sodium-dependent vitamin C transporter 2.

• Osmotic Flow – The osmotic gradient across ciliary

epithelium, results from active transport

– It favors the movement of other plasma constituents by ultrafiltration and diffusion.

• The structural basis for aqueous humor secretion is the bilayered ciliary epithelium.(pigmented epithelium & non-pigmented epithelium )

• The active process of aqueous secretion is mediated by two enzymes present in the NPE: Na+-K+-ATPase and carbonic anhydrase

Biochemistry of aqueous humor formation

AQUEOUS HUMOR OUTFLOW

• The aqueous humor leaves the eye at the anterior chamber angle through trabecular meshwork, the Schlemm’s canal, intrascleral channels, and episcleral and conjunctival veins.

• This pathway is referred to as the conventional or trabecular outflow.

• In the unconventional or uveoscleral outflow, aqueous humor exits through the root of iris, between the ciliary muscle bundles, then through the suprachoroidal - scleral tissues.

• Trabecular outflow accounts for 70% to 95% of the aqueous outflow .

• And remaining 5% to 30% by uveoscleral outflow.

Cellular Organization of the Trabecular Outflow Pathway• Scleral Spur The posterior wall of the scleral sulcus

formed by a group of fibers, the scleral roll, which run parallel to the limbus and project inward to form the scleral spur.

• Schwalbe Line Anterior to the apical portion of the trabecular meshwork is a smooth area called as zone S. The posterior border is demarcated by a discontinuous elevation, called the Schwalbe line

• Trabecular Meshwork The scleral sulcus is converted into a circular channel, called the Schlemm canal, by the trabecular meshwork. It may be divided into three portions: (a) uveal meshwork; (b) corneoscleral meshwork; and (c) juxtacanalicular tissue

– Uveal Meshwork This innermost portion is adjacent to aqueous humor in the AC and is arranged in ropelike trabeculae that extend from iris root and ciliary body to peripheral cornea.

– Corneoscleral Meshwork This portion extends from the scleral spur to the anterior wall of the scleral sulcus .

– Juxtacanalicular Tissue This structure has three layers. The inner trabecular endothelial layer is continuous with the endothelium of corneoscleral meshwork. The central connective tissue layer & outermost portion is the inner wall endothelium of the Schlemm canal.

• Episcleral and Conjunctival Veins The Schlemm canal is connected to episcleral and conjunctival veins by a complex system of intrascleral channels.

• Two systems of intrascleral channels have been identified:– A direct system of large caliber vessels, with short

intrascleral course, drain into episcleral venous system

– An indirect system of more numerous, finer channels, which form an intrascleral plexus before draining into episcleral venous system.

Pumping model for trabecular outflow

• The aqueous outflow pump receives power from transient increases in IOP such as occur in systole of the cardiac cycle, during blinking and during eye movement.

The biomechanical pump model. Powered by transient increases in IOP, caused by cardiac cycle, blinking & eye movements. As pressure increases, fluid is forced into one-way collector valves (C) that span across Schlemm’s canal. At the same time, the increase in IOP pushes the endothelium of the inner wall of Schlemm’s canal (A, B) outward and forces aqueous in the canal to move circumferentially into collector channels and aqueous veins. As the pressure drops, the tissues rebound, causing a pressure drop inside Schlemm’s canal, moving fluid from the one-way valves (C) into the canal.

• Active involvement of the TM in regulating outflow– The cellular component of the conventional outflow

pathway: Schlemm’s canal endothelia, juxtacanalicular cells, endothelium lining the lumen of Schlemm’s canal valves, and endothelium lining trabecular lamellae.

• The TM is suspended between two fluid compartments (anterior chamber and Schlemm’s canal) at different pressures.

• The TM can “sense” the pressure differential and strives to maintain these parameters within a homeostatic range.

Theory of transcellular aqueous transport in which a series of pores and giant vacuoles opens (probably in response to transendothelial hydrostatic pressure) on the connective tissue side of the juxtacanalicular meshwork (2–4). Fusion of basal and apical cell plasmalemma creates a temporary transcellular channel (5) that allows bulk flow of aqueous into Schlemm’s canal.

Cellular Organization of the Uveoscleral Pathway• Two unconventional pathways have been discriminated: (a)

through the anterior uvea at the iris root, uveoscleral pathway, and (b) through transfer of fluid into the iris vessels and vortex veins, which has been described as uveovortex outflow.

•  Uveoscleral Outflow– Studies have shown aqueous humor passes through the root of the

iris and interstitial spaces of the ciliary muscle to reach the suprachoroidal space. From there it passes to episcleral tissue via scleral pores surrounding ciliary blood vessels and nerves, vessels of optic nerve membranes, or directly through the collagen substance of the sclera.

• Uveovortex Outflow– Tracer studies in primates have also demonstrated unidirectional flow

into the lumen of iris vessel by vesicular transport, which is not energy dependent. The tracer can penetrate vessels of the iris, ciliary muscle, and anterior choroid to eventually reach the vortex veins

• The uveoscleral pathway is characterized as “pressure independent,”

• It is reduced by cholinergic agonists, aging, and is enhanced by prostaglandin drugs.

• A potential explanation for the observed decline in uveoscleral outflow with aging is thickening of elastic fibers in the ciliary muscles.

FACTORS EXERTING LONG-TERM INFLUENCE ON IOP

• Genetics

• Age

• Gender

• Refractive Error

• Ethnicity

Genetics

• The IOP is under hereditary influence.

• IOP tends to be higher in individuals with enlarged CDR & in those who have relatives with open-angle glaucoma.

• IOP increases with age.

• Studies indicate that children have lower pressures than the rest of the normal population,

• But tonometric measurements may be influenced by the level of cooperation of the child, tonometer used, use of general anesthesia or a hypnotic agent.

• There may be a positive independent correlation between IOP and age & may be related to reduced facility of aqueous outflow & decreased aqueous production.

Age

• Gender – IOP is equal between the sexes in ages 20 to 40 years.

– In older age groups, the apparent increase in mean IOP with age is more in women.

• Refractive Error– A positive correlation between IOP and both axial length of

the globe and increasing degrees of myopia

– Myopes also have a higher incidence of COAG

EthnicityBlacks have been reported to have slightly higher pressures than whites.

FACTORS EXERTING SHORT-TERM INFLUENCE ON IOP

• Diurnal

• Postural Variation

• Exertional Influences

• Lid and Eye Movement

• Intraocular Conditions

• Systemic Conditions

• Environmental Conditions

• General Anesthesia

• Foods and Drugs

Diurnal Variation

• IOP shows cyclic fluctuations throughout the day.

• Ranges from approximately 3 mm Hg to 6 mm Hg.

• Higher lOP is associated with greater fluctuation, and a diurnal fluctuation of greater than 10 mm Hg is suggestive of glaucoma.

• The peak IOP is in the morning hours

• Primary clinical value of measuring diurnal IOP variation is to avoid the risk of missing a pressure elevation with single readings.

Postural Variation• The IOP increases when changing from the

sitting to the supine position, average pressure differences of 0.3 to 6.0 mm Hg.

• The postural influence on IOP is greater in eyes with glaucoma and persists even after a successful trabeculectomy.

• Patients with systemic hypertension have greater IOP increase after 15 minutes in supine

Exertional Influences• Exertion may lead to either a lowering or an

elevation of the IOP, depending on the nature of the activity.

• Prolonged exercise, such as running or bicycling, has been reported to lower the IOP.

• The magnitude of this pressure response is greater in glaucoma patients than in normal individuals.

• Straining, as associated with the Valsalva maneuver, electroshock therapy, or playing a wind instrument, has been reported to elevate the IOP.

• May be due to elevated episcleral venous pressure and increased orbicularis tone.

Lid and Eye Movement• Blinking has been shown to rise the IOP 10

mm Hg, while hard lid squeezing may raise it as high as 90 mm Hg.

• Contraction of extraocular muscles also influences the IOP.

• There is an increase in IOP on up-gaze in normal individuals, which is augmented by Graves' infiltrative ophthalmopathy.

Intraocular Conditions

• Elevated IOP is with associated glaucoma

• IOP may be reduced in Anterior uveitis, Rhegmatogenous retinal detachment

Systemic Conditions• Positive correlation between systemic hypertension,

• Systemic hyperthermia has been shown to cause an increased IOP.

• IOP may increase in response to ACTH, glucocorticoids, and growth hormone and it may decrease in response to progesterone, estrogen, chorionic gonadotropin, and relaxin.

• It is significantly reduced during pregnancy, may be due excess progesterone.

• IOP is lower in hyperthyroidism and higher in hypothyroidism.

• In myotonic dystrophy, the IOP is very low, which may be due to reduced aqueous production & increased outflow.

• Diabetic patients have higher pressures than the general population, while a fall in IOP is seen during acute hypoglycemia.

• Patients with HIV have lower than normal mean IOPs

• Environmental Conditions

– Exposure to cold air reduces IOP, apparently because episcleral venous pressure is decreased. Reduced gravity causes a sudden, marked increase in IOP.

• General Anesthesia – General anesthesia reduces the IOP,

– Exceptions are trichloroethylene and ketamine which elevate the ocular pressure.

– In infants and children GA can mask a pathologic pressure elevation.

– Hypnotics that are used to produce unconsciousness, such as 4-hydroxybutyrate and barbiturates and tranquilizers reduce the IOP

– Depolarizing muscle relaxants, such as succinylcholine and suxamethonium cause a transient increase in IOP, possibly due to a combination of extraocular muscle contraction and intraocular vasodilation.

– Tracheal intubation may also cause an IOP rise.

– Elevated pCO2causes an increase in IOP, whereas reduced pCO2 or increased concentration of O2 is associated with an IOP reduction.

Foods and Drugs• Alcohol has been shown to lower the IOP,

more so in patients with glaucoma.

• Caffeine may cause a slight, transient rise in IOP.

• A fat-free diet has been shown to reduce IOP, which may be related to a concomitant reduction in plasma prostaglandin levels.

• Tobacco smoking may cause a transient rise in the IOP, and smokers have higher mean IOPs than nonsmokers

• Heroin and marijuana lower the IOP, while LSD(lysergic acid diethylamide) causes an IOP elevation.

• Corticosteroids may also cause IOP elevation.

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