Drugs for Glaucoma

Crisfel R. del Mundo, MSc, RPh

Topic Outline

I. Applied Anatomy and Physiology of

Aqueous Humor Dynamics

II. Glaucoma
III. Pathogenesis and Classifications
IV. Anti-glaucoma Agents
Applied Anatomy
Aqueous Humor
A clear, watery fluid formed from plasma by
epithelial cells of the ciliary processes
• fills the anterior and posterior chambers of the eyeball.
Functions:
• It plays an important metabolic role by providing
substrates and by removing metabolites from the
avascular cornea and lens
• It maintains a proper intraocular pressure
• It maintains optical transparency
• It takes the place of lymph that is absent within the
eyeball
Aqueous Humor Dynamics

Ocular structures concerned with the

aqueous humor dynamics:
1) Ciliary body – Contains ciliary processes
that produce the aqueous humor
2) Angle of the anterior chamber
3) Aqueous outflow system
 Angle of Anterior Chamber
• It is formed by root of
iris, anterior-most part
of ciliary body, scleral
spur, trabecular
meshwork and
Schwalbe’s line
• Plays an important role
in the process of
aqueous drainage
Aqueous Outflow System
Includes the following structures (3):
1. Trabecular meshwork – sieve-like structure which
aqueous humor leaves the eye
2. Schlemm’s Canal - endothelial lined oval channel
present circumferentially in the scleral sulcus
3. Collector Channels - also called intrascleral
aqueous vessels
• 25-35 in number
• leave the Schlemm’s canal at oblique angles to
terminate into episcleral veins in a laminated fashion
Aqueous Outflow System
Applied Physiology
Applied Physiology
Physiological processes
concerned with the aqueous
humor dynamics:
1. Production (Inflow)
2. Drainage (Outflow)
3. Maintenance of intraocular pressure
(IOP)
1) Production

• Aqueous humor is derived from plasma

within the capillary network of ciliary
processes

• The normal aqueous production rate is

2.3 μl/min.
1) Production
• Steps in Production:
1. Ultrafiltration à passage of plasma fluid
from the pigmented epithelium to the non-
pigmented epithelium of the ciliary
processes
2. Secretion à active transport via NAP and
CA systems
3. Diffusion
2) Drainage
• Aqueous humor flows from the posterior
chamber into the anterior chamber through
the pupil against slight physiologic
resistance.
Drainage

• Drained by two routes:

1. Trabecular (Conventional) Outflow
2. Uveoscleral (Unconventional)
Outflow
 Trabecular Outflow

• Trabecular meshwork is
the main outlet for
aqueous from the
anterior chamber (~90%)
• Trabecular Meshwork à
Schlemm’s Canal à
Episcleral Vein
 Uveoscleral Outflow

• It is responsible for about

10% of the total aqueous
outflow
• Goes to beyond the iris à
Uveoscleral Tissue à
Schlemm’s Canal
• Bypasses the Trabecular
Meshwork
Drainage
3) Maintenance of IOP
• The intraocular pressure (IOP) refers to
the pressure exerted by intraocular
fluids on the coats of the eyeball
• The normal IOP varies between 10 and
21 mm of Hg (mean 16 ± 2.5 mm of
Hg).
• Dynamic equilibrium between inflow
and outflow of aqueous humor.
Glaucoma
Glaucoma

• Progressive optic neuropathy with

corresponding visual field changes, as well as
optic disc changes.
• Second leading cause of blindness in the world
• IOP is the most common risk factor but NOT
the only risk factor for glaucoma development
Glaucoma
Pathogenesis and
Classifications
Pathogenesis
Etiological Factors

A. PRIMARY INSULTS
1. Raised IOP
• Increased IOP alters capillary blood flow
• Axonal deformation and ischemia
• Neurotophins (GFs) are not able to
reach the ganglion cell bodies in
sufficient amount needed for survival
Etiological Factors

A. PRIMARY INSULTS
2. Pressure independent Factors
a) Failure of Autoregulatory
Mechanism of Blood Flow
b) Vasospasm
c) Systemic hypotension
Etiological Factors

B. SECONDARY INSULTS
• Toxic Factors
• Glutamate (excitatory toxin)
• ROS
• Nitric oxide
Classifications
OPEN ANGLE
Trabecular meshwork is visible
Asymptomatic
No complaint of blurring of vision
Errors of Refraction: Myopia
Cataracts
Focal loss of vision
Pharmacologic intervention
CLOSED ANGLE
Iris is touching the cornea
Occluded trabecular meshwork
when seen
Errors of Refraction: Hyperopia
Surgical Intervention
Major Aim of Therapy

To lower intraocular pressure (IOP) to a level

where (further) visual loss does not occur
• Decrease production of aqueous humor
(decrease inflow)
• Enhancement of aqueous humor drainage
(increase outflow)
Antiglaucoma Agents
Anti-glaucoma Agents

Decrease Inflow of Aqueous Humor:

• Inhibit production of aqueous humor

1. Alpha-2 Agonists

2. Beta Blockers

3. Diuretics
a) Carbonic Anhydrase Inhibitors
b) Mannitol
Anti-glaucoma Agents

Enhance Outflow of Aqueous Humor:

1. Parasympathomimetics

2. Epinephrine & Dipivefrin

3. Prostaglandin Analogs
Inhibitors of Aqueous Humor
Production
1) Alpha-2 Agonists:
Apraclonidine
• Central alpha-2 agonist

• Produces a significant fall in IOP in patients

following cataract surgery

• Single dose à tx or prevention of the postsurgical

rise in IOP following anterior segment laser surgery

• Multiple dose à adjunct for open-angle glaucoma

• Adverse Effect: Tachyphylaxis

 1) Alpha-2 Agonists:
Brimonidine
• Highly selective alpha-2 adrenoceptor stimulant (1000
times more effective on the alpha-2 receptor than the
alpha-1 receptor)

• Produces no mydriasis or vasoconstriction and has

little effect on the cardiovascular system

• Reduces secretion and enhances uveoscleral outflow

• Safe in long-term treatment and appears to have

neuroprotective properties
2) Beta Blockers

• Reduction of IOP is due to Beta receptor

antagonism à reduced secretion of Cl-

• No effect in outflow resistance

• BID therapy (morning and night)

• Classifications (?)
2) Beta Blockers

• Commonly used beta blockers:

• Timolol à non-selective; BID regimen (usual);
Timoptic LA (OD only)
• Betaxolol à cardioselective
• Others: Carteolol, Levobunolol, Metipranolol
3) Diuretics

• Carbonic Anhydrase Inhibitors

• Acetazolamide and Dichlorphenamide
(systemic) à high incidence of
adverse effects
ØAs topicals à ineffective
• Applicable CAIs (topical) à
Dorzolamide, Brinzolamide
3) Diuretics
• Mannitol (Intravenous)
• Lowers vitreous volume (during very
high IOP à Acute Angle Closure
Glaucoma)
• Adverse Effects
• Dehydration
• Cardiac Arrest
Aqueous Humor Drainage
Enhancers
1) Parasympathomimetics

• Through Muscarinic-3 receptor activation in the

ciliary bodies à MIOSIS
• Pupillary Constriction à Opens trabecular
meshwork = increased outflow – lower IOP
• Adverse Effects
• Systemicà DUMBBELS
• Ocular à vision impairment, central lens
opacities, constriction of the visual field
1) Parasympathomimetics

Pilocarpine
• Only parasympathomimetic in routine use

• Problems:
• Expensive
• Erratic supply (natural source)
• High risk of hypersensitivity
Parasympathomimetics
Alternative Presentations of Pilocarpine
1. Viscolized solutions à addition of viscolizers (HEC,
PVA) to make the preparation more viscous
2. Gels à slow release of Pilocarpine
3. Oily solutions
4. Soft contact lenses
5. Ocusert à lasts for up to 9 days
• Constant level of Pilocarpine à smaller incidence
of A/E
Parasympathomimetics
Alternative MIOTICS:
1. Aceclidine

2. Metachol

3. Carbachol

4. Short- & Intermediate-acting

Anticholinesterases

5. Long-acting Anticholinesterase
2) Epinephrine
• Aka Adrenaline

• NO LONGER USED

• Pharmacodynamics
• Beta stimulation à cAMP synthesis à
enhanced uveoscleral outflow
• Alpha stimulation à mydriasis
• Lowers IOP in open-angle glaucoma, BUT
increases in acute angle-closure glaucoma
2) Epinephrine

• Combined with Guanethedine

• Adverse Effects
• Reactive hyperemia à red eyes
• Black deposits in cornea

• Maculopathy
2) Dipivefrin

• Pivalic acid ester of EPI

• With enhanced lipid solubility

• Adverse Effects:
• Reactive hyperemia
• Endothelial damage
• Follicular conjunctivitis
2) Prostaglandin Analogs

• Open Schlemm’s Canal

• Examples: Latanoprost, Travoprost,

Bimatoprost

• Long duration of action (OD hs)

• Adverse effect:
• Increased pigmentation of the iris and eyelashes
Thank you for listening! J
“You become what you think about.”