Aqueous Humor Drainage Regulation and the Goldmann Equation

What drugs are used in the cholinergic activation of AH outflow?

Pilocarpine and Echothiophate

What is Pilocarpine?

A muscarinic agonist

Where are muscarinic receptors found on outflow structures?

Present in ciliary muscle cells, trabecular meshwork, JCT, and collector channel cells

What does pilocarpine do?

Stimulates ciliary muscle contraction, which pulls on trabecular meshwork (thins ECM), and decreases resistance to conventional outflow

What may Pilocarpine also cause?

Retraction of trabecular meshwork cells to decrease resistance to conventional outflow

What is Echothiophate?

An acetylcholinesterase inhibitor

What is acetylcholine?

A ligand for muscarinic receptors

What does acetylcholinesterase do?

Breaks down acetylcholine and function to prevent reuptake of the ligand

What does the prevention of break down of acetycholine by acetylcholinesterases inhibitors (Echothiophate) do?

Causes indirect stimulation of muscarinic reeptors

What is the effect of uveoscleral outflow due to muscarinic receptor agonists? Is this beneficial?

Although muscarinic receptor agonists activate ciliary muscle and would inhibit uveoscleral outflow, the benefit of increased facility of the trabecular meshwork outweighs the reduction of uveoscleral outflow

What type of adrenergic receptors are found in trabecular meshwork cells?

B2 receptors

What can adrenergic agonists (ie. beta 2 agonists) do?

Lower IOP

How do adrenergic agonists lower IOP? Is ciliary muscle involved?

Bind to Beta 2 receptors/activate them and increase AH outflow; independent of ciliary muscle

What is the lower IOP by adrenergic agonists attributed to?

Increased facility of trabecular meshwork

What are examples of topically applied adrenergic agonist drugs?

Epinephrine, Norepinephrine, Isoproterenol

Adrenergic agonists outflow mechanism of action (Pharmacologic regulation of outflow):

1. Bind to Beta 2 receptors

2. Activate cAMP signaling cascade in trabecular meshwork cells

3. A reduction in trabecular meshwork cell cytoskeleton function

4. Focal adhesion break-down

5. Trabecular meshwork cell retraction (due to focal adhesion breakdown)

6. Cell degeneration

7. Shrinkage of tissue volume is suggested to increase facility (decrease resistance)

What is the adrenergic physiological regulation of AH secretion mechanism? (recall)

1. Binding of agonists to B-adrenergic receptors in the ciliary epithelium triggers formation of cAMP which in turn indirectly activates chloride channels

2. Activation of chloride channels increases aqueous humor formation and increases IOP

Why do beta adrenergic agonist drugs lower IOP if the physiological regulation of secretion increases IOP due to B-adrenergic receptors?

Because the increase in outflow from the drugs outweighs the increase in secretion and overall net lowers IOP

What is the contraction of intracellular actin cytoskeleton (in TM cells) regulated by?

Contractile proteins (non-muscle myosins)

What specific protein is identified to activate contraction of the actin cytoskeleton (in TM cells)?

Rho-kinase (similar to beta-adrenergic agonists)

What is the contraction of the actin cytoskeleton in TM cells important for?

Important for focal adhesions and ability of cells to stretch out

What happens if we inhibit rho-kinase?

1. Disrupts focal adhesions

2. Reduces contractility

3. Increases facility (cells round up)

What are the drugs that target rho-kinase?

Netarsudil/Rhopressa

What are prostaglandins?

Hormone-like lipid compounds with many activities

What do prostaglandins do in the eye?

Decrease IOP

What are examples of drugs that are prostaglandin analogs that act on endogenous receptors?

Latanoprost (Xaltan), Travoprost (Travatan), Unoprostone (Rescula), Bimatoprost (Lumigan)

What do prostaglandin analogs (ie. Latanoprost) do to AH outflow?

Increases uveoscleral outflow

How do prostaglandin analogs increase uveoscleral outflow?

1. Relaxes ciliary muscles (minor)

2. Cause an increase of Matrix metalloproteinases which leads to degradation of collagen (ECM) which reorganizes scleral tissue and increases its permeability (Major) (remodels uveoscleral tissue)

What is the most common glaucoma medication used?

Prostaglandin analogs (Latanoprost)

What are Glucocorticoid drugs often used for?

Immunosuppression or anti-inflammation

Where are glucocorticoid receptors found in the eye?

In trabecular meshwork cells

What do long term treatments of the eye with corticosteroids do to outflow of AH?

Can decrease facility due to build up of ECM in trabecular meshwork and rearrangement of cytoskeleton in TM cells

Is the build up of ECM in trabecular meshwork similar or distinct from what is seen in POAG?

Distinct but we see an increase in the expression of a POAG associated protein Myocilin

What are the fluid mechanics of aqueous humor at steady state (normal physiological conditions)?

Any flux in aqueous humor production is balanced by a corresponding flux in outflow

(F = F_in = F_out)

Tissues of the filtration angle normally offer blank, but that blank has the capacity to change.

Resistance to fluid outflow; resistance

What are the primary suspects as the major site of outflow resistance in the Trabecular meshwork?

JCT and surrounding ECM

What is the Goldmann equation?

Formula used to describe the relationship between physiological measurements (relating to AH outflow)

What does the goldmann equation assume?

Assumes that the resistance to inflow and uveoscleral outflow are negligible

Is the uveoscleral outflow rate usually measured or calculated?

Usually calculated rather than measured

What does P_i stand for in the Goldmann Equation?

IOP

What does P_e stand for in the Goldmann Equation?

Episcleral Pressure

What does F_in stand for in the Goldmann Equation?

Inflow rate

What does F_u stand for in the Goldmann Equation?

Uveoscleral outflow

What does C_trab stand for in the Goldmann Equation?

Facility of outflow of the Trabecular meshwork

What is the average IOP (P_i)?

15 mmHg

What is the average episcleral pressure (P_e)?

9mmHg

What is the average inflow rate (F_in)?

2.5 ul/min

What is the Goldmann equation formula?

P_i = P_e + (F_in - F_out )/ C_trab

What is the Goldmann equation with the average values added?

15 = 9 + (2.5-1.25)/0.21

There is a blank relationship between IOP and the episcleral pressure

1:1 (direct) (increasing one increases the other)

What are the three main categories of causes of increased episcleral pressure?

1. Posture

2. Pulse

3. Eyelid closure

How does posture increase episcleral pressure (and therefore IOP)?

Laying down and head below level of heart heart can increase IOP

How does pulse increase episcleral pressure (and therefore IOP)?

1. Fluctuates 1-2mmHg with each cardiac cycle

2. Exercise will increase IOP

How does eyelid closure increase episcleral pressure (and therefore IOP)?

1. Transient increase in IOP (during attempted closure)

2. Blepharospasm which can raise the IOP to 40mmHg (no confirmed risk of POAG)

3. Widely opening eyes can incrase IOP

What happens to the Goldmann equation if you’re taking glucocorticoids for a porlonged time, (which builds up ECM)?

IOP will increase because there is more resistance to outflow and trabecular facility decreases (decrease C_trab)

(Pi =Pe + (Fin-Fu)/Ctrab)

(24.6 = 9 + (2.5-1.25)/ 0.08)

What is considered ocular hypertension?

When IOP is > 20mmHg

What are pharmacologic treatments aimed at in terms of the goldmann equation in patients with high IOP?

Reducing inflow rate (F_in) or by increasing facility of outflow of Trabecular Meshwork (C_trab)

(P_i = P_e + (F_in - F_out )/ C_trab)

What are the effects of age on the Goldmann equation?

1. Age decreases uveoscleral ouflow (F_u)

2. Age decreases Inflow rate (F_in)

3. Age decreases facility

(15 = 9 + (2.0-1.1)/ 0.15)

Is there a change in IOP with age as demonstrated by the Goldmann Equation?

No change in IOP

What is there a loss of in advanced age (recall)? What can that cause? (recall)

Loss of TM cells which can cause the inner uveal and corneascleral meshwork tissue to become “glued” together

What is there an increase of in advanced age? (recall)

ECM around elastic fibers which may cause come increased resistance but no consistent IOP changes noted with age

When is the Goldmann Equation not useful in measuring fluid mechanics? Why?

During sleep becuase sleep decreases F_in (aqueous secretion) but data suggests a rise in IOP at night

(22 ≠ 9 + (2.0-1.25)/ 0.21)

What type of drug is not useful at night? What is an example of that type of drug?

Beta adrenergic antagonists such as Timolol (used to treat glaucoma)

Why is the fact that some adrenergic drugs cannot further lower IOP at night concerning?

Concerning for glaucoma patients because risk at night may be greater