Glaucoma

Glaucoma

• Glaucoma is a group of diseases

that damage the eye’s optic
nerve - a leading cause of vision
loss and blindness.
• Usually associated with
increased intraocular pressure.
It is as a major risk factor for
optic nerve damage.
Control + click on the image to see a simulation of progressive vision
• Early detection and treatment loss of glaucoma from American Academy of Ophthalmology.
can often protect against https://www.aao.org/eye-health/drugs/glaucoma-vision-simulator

serious vision loss.

Please click on these links from National Eye Institute (NEI) to learn about glaucoma.
https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/glaucoma
https://www.youtube.com/watch?v=XlI_JXYMzbs Animation: Glaucoma
M7.A2: reading
Statistics of Glaucoma

Prevalence
• > 2.7 million Americans over age 40 have glaucoma.
• Estimated to more than double by 2050

Risk factors
• Age – rare < age 40, but affects 1 to 2% of the population above
40.
• A family history of glaucoma, eye injuries, nearsightedness, high
blood pressure, and ethnicity.
• Women are more likely to develop angle closure glaucoma.

Diagnosis
• Ophthalmologic examination of the optic nerve
• Examination of visual field
• Measurement of intraocular pressure
(>21 mm mercury)
M7.A2: reading Graphs retrieved in 2019 from National Eye Institute website
https://nei.nih.gov/health/glaucoma
Anatomy of Eye

Sympathetic Parasympathetic
Pupil size Mydriasis Miosis (myosis)
(iris smooth (pupil dilation) Pupil constriction
muscle)
Vision focus Far vision Near vision
Lens shape Lens less convex Lens more convex
(ciliary body) (ciliary relaxes) (ciliary contracts)

Images adapted from Figures 12-1 & 12-10 Barrett K, Brooks H, Boitano S, et al. eds.
Ganong’s Review of Medical Physiology, 23rd ed. McGraw Hill; 2010
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 Aqueous humor in the eye

• Aqueous humor is produced

by the ciliary epithelium and
flows around the iris through
the trabecular meshwork and
out the canal of Schlemm into
the blood stream.

• Intraocular pressure increases

due to excess aqueous humor
in the eye.
Image from National Eye Institute. M7.A3: Panopto video
https://www.nei.nih.gov/about/news-and-events/news/cataract-surgery-infancy-increases-glaucoma-risk
 Two types of glaucoma

• Closed angle (angle-closure)

• Open angle
– Less common.
– More common. Chronic condition.
Usually managed by drug therapy. – Obstruction of the outflow of aqueous humor.
– Drainage angle is “open”, the fluid passes – Acute angle-closure glaucoma is a medical
too slowly through the meshwork emergency. It is accompanied by eye pain, tearing,
visual defects and other signs and symptoms.
• In both types, intraocular pressure rises due to fluid builds up, leading to damage to the optic
nerve.
• The main goal to glaucoma therapy - to decrease pressure inside the eye
Images from the University of Iowa Ophthalmology and Visual Sciences M7.A3: Panopto video
Figure 5-2 A&B https://eyerounds.org/books/glaucoma_guide/chapter5.html
 Adrenergic and cholinergic receptors in the eye
a1 adrenoceptor activation
causes contraction of dilator muscle, M3 mAChR activation causes
resulting pupil dilation (mydriasis). contraction of sphincter
muscle, resulting in pupil
M3 mAChR activation
constriction (miosis).
causes contraction of ciliary
muscle, which:
1) puts tension on the
trabecular meshwork, mAChR
a1 b adrenoceptor activation
opening its pores and causes increased
facilitating outflow of the mAChR secretion of fluid.
aqueous humor into the
canal of Schlemm. a2 adrenoceptor activation
2) moves iris towards the b, a2 causes decreased
cornea.
secretion of fluid.
M7.A4: Panopto video

Figure 6-9. Katzung BG, Vanderah TW. eds. Basic & Clinical Pharmacology, 15e. McGraw Hill; 2021
Cholinergic and adrenergic drugs to decrease intraocular pressure

Decrease secretion of
aqueous humor
Adrenergic drugs –
administered topically
Increase outflow of
aqueous humor
mAChR b-adrenoceptor
Cholinomimetics –
blocking drugs
administered topically
•Timolol
•Betaxolol
mAChR agonists
•Pilocarpine
b, a2 adrenergic agonists
•Carbachol
a2 •Apraclonidine
•Brimonidine
AChE inhibitors
•Echothiophate iodide
•Physostigmine Nonselective agonists
•Epinephrine
Figure 6-9. Katzung BG, Vanderah TW. eds. Basic & Clinical Pharmacology, 15e. McGraw Hill; 2021 •Dipivefrin
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Adrenergic drugs for glaucoma

• Mechanism of action: reduce aqueous humor production

– All administered topically
• Alpha-2 adrenergic agonists
• b-adrenoceptor blocking drugs
– Apraclonidine
– Timolol (Timoptic®) non-selective
– Brimonidine
• What are side effects of beta-blockers?
– Betaxolol (Betoptic®) b1-selective
• What is the benefit of beta-1 selective • Nonselective adrenergic agonists
blocker? – Epinephrine
– Dipivefrin - a prodrug, rapidly converted to
epinephrine. It is longer-acting and better
tolerated with less systemic effects like
increased heart rate.

M7.A5: Panopto video

Cholinergic drugs for glaucoma

• Mechanism of action: increase outflow of aqueous humor

– All administered topically
– The contraction of the ciliary muscle widens the trabecular mesh to increase the outflow of
aqueous humor through the canal of Schlemm.
• mAChR agonists: pilocarpine and carbachol • Adverse effects: Visual problems, eyelid
• AChE inhibitors: physostigmine and muscle twitching and other local effects
echothiophate. Indirect acting to increase may occur with cholinomimetics.
concentration of ACh. Occasional systemic parasympathetic
effects like diarrhea or urinary incontinence
may occur. Chronic use of echothiophate
has been associated with the development
Duration of action of cataracts. Echothiophate is a potent,
Physostigmine 0.5–2 hours irreversible organophosphate inhibitor of
Echothiophate 100 hours acetylcholinesterase.
M7.A6: Panopto video
Prostaglandin analogs for glaucoma

• Latanoprost, travoprost ,
bimatoprost – topical
Convenient with once a day, usually at
night, dosing. They are well tolerated
but may cause change of color of the
iris.

• MOA: The drugs are stable analogs of

prostaglandin F2a. By stimulating the
prostaglandin F receptor, they enhance
the outflow of aqueous humor through
the uveoscleral tract.
Image from:
Weinreb RN, Realini T, Verma R. US Ophthalmic Review, 2016;9(2):80–7 DOI: https://doi.org/10.17925/USOR.2016.09.02.80.c
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Nitric oxide for glaucoma

Uveoscleral pathway
20-30% outflow

Trabecular pathway
70-80% outflow

• Latanoprostene bunod – new, dual action

prodrug approved in 2017.

It produces active metabolites:

1) Nitric oxide promotes outflow via
trabecular meshwork.
2) Latanoprost acid, a prostaglandin analog
that increase outflow via uveoscleral pathway

Image from:
Weinreb RN, Realini T, Verma R. US Ophthalmic Review, 2016;9(2):80–7 DOI: https://doi.org/10.17925/USOR.2016.09.02.80.c
M7.A7: Panopto video
Carbonic anhydrase inhibitors

•Brinzolamide, dorzolamide – topical solutions

•Acetazolamide, methazolamide – oral tablets

• MOA: the enzyme carbonic anhydrase is present in the ciliary body and
its inhibition by drugs diminishes the production of aqueous humor.

• The systemic carbonic anhydrase inhibitors cause fatigue, nausea,

unpleasant metallic taste and other unpleasant systemic effects. The
topical preparations sometimes cause local irritation and bad taste in
mouth.

M7.A8: Reading
Netarsudil (Rhopressa®)

• New drug approved by FDA in 2017

0.02% netarsudil ophthalmic solution
– A pro-drug – esterase cleavage
– Netarsudil is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma
or ocular hypertension.

• Main mechanism - an inhibitor of Rho kinase

- Reduces cell contraction and stiffness in the trabecular meshwork
- Increases trabecular outflow
• Minor mechanism – an inhibitor of the norepinephrine transporter
– extends action duration of endogenous NE at a2 receptor
– decreases aqueous humor production from ciliary epithelium

• New combination drug approved by FDA in 2019

Rocklatan®: Netarsudil + latanoprost
M7.A9: Panopto video
Closed angle glaucoma

Acute angle-closure glaucoma is a medical emergency

Initial therapy often consists of a combination of a

direct muscarinic agonist and a cholinesterase inhibitor
(eg, pilocarpine plus physostigmine) as well as other drugs.
Intravenous mannitol (a hyperosmotic agent can
rapidly reduce intraocular pressure by decrease vitreous
volume.
Once the intraocular pressure is controlled and the
danger of vision loss is diminished, the patient can be
prepared for corrective surgery
- iridectomy or iridotomy

Angle-closure glaucoma
Images from:
generally affects one eye but
persons are at elevated risk
• The of an
University attack
of Iowa in the
Ophthalmology andother eye.Figure 5-2B
Visual Sciences
https://eyerounds.org/books/glaucoma_guide/chapter5.html
M7.A10: reading
• Columbia University Edward S. Harkness Eye Institute
 Drugs used in open-angle glaucoma
Mechanism Formula
Prostaglandins Topical
Latanoprost Increase outflow via uveoscleral pathway
Travoprost
Most popular Bimatoprost
•Convenience Latanoprostene bunod Increase outflow via uveoscleral and trabecular meshwork
1-2 daily
dosing Beta blockers Decrease aqueous secretion from the ciliary epithelium Topical
•Less adverse Timolol
Betaxolol beta1-selective. Better for patients with asthma & COPD
effects
Netarsudil Promote outflow via trabecular meshwork. Rho kinase Topical
inhibitor and norepinephrine transporter inhibitor 1 drop/day

Alpha agonists Decrease aqueous secretion

Apraclonidine Alpha2-selective Topical
Brimonidine
Epinephrine, Nonselective Topical
Dipivefrin (prodrug)

M7.A11: Panopto video

Drugs used in open-angle glaucoma (cont’d)

Mechanism Formula
Cholinomimetics Ciliary muscle contraction, opening of trabecular Topical drops or gel
meshwork; increased outflow
Pilocarpine, Carbachol mAChR agonists
Physostigmine, Echothiophate AChE inhibitors

Carbonic anhydrase inhibitors Decreased aqueous secretion

Brinzolamide, Dorzolamide Topical
Acetazolamide, Methazolamide Oral

Combinations Need to know MOAs of each drug below Topical

Timolol - dorzolamide
Epinephrine - pilocarpine
Timolol – latanoprost
Timolol - brimonidine
Latanoprost - netarsudil

M7.A11: Panopto video