new drugs, potential targets, recent trends for glaucoma treatment. important new target have been discussed along with current therapies. good enough for post graduate teaching and undergraduate classes.
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recent advances in pharmacotherapy of Glaucoma
1. 1
RECENT ADVANCES IN PHARMACOTHERAPY
Presented by: Dr. Shrey Bhatia
Junior Resident, Dept. of Pharmacology
Govt. Medical College, Patiala
2. 2
Optic neuropathy involving a
characteristic atrophy of the
optic nerve head, which
may or may not be
accompanied by elevated
intraocular pressure (IOP)
GLAUCOMA
global glaucoma burden to be 76.0 million in 2020 and 111.8 million in
2040, largely affecting people in Asia and Africa.
Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY, et al. Global prevalence of glaucoma and projections of glaucoma burden
through 2040: A systematic review and meta-analysis. Ophthalmology 2014;121:2081-90
10. 10
Currently, the only known modifiable risk factor for glaucoma is intraocular
pressure (IOP). Hence, it forms the mainstay target in contemporary
glaucoma practice
11. β -2
blockers
CURRENT THERAPIES
11
Abolishing Vasodilation by B2, blood reaching in the ciliary body reduced
AH secretion reduced
• Stinging, aching, or redness in the eyes
Dry eyes and foreign body sensation
• bradycardia.
• bronchospasm in asthma.
• Fatigue, dizziness, and inability to
tolerate exercise.
• c/i- diabetes, asthma, CHF
ADRsAdvantages
• No change in pupil size
• No induced myopia
• No headache / brow pain due to persistent
spasm of iris and ciliary muscle
• No fluctuation in IOP as occur with
pilocarpine drops.
• Convenient 1 or 2 daily application
12. α
agonists
12
• Potent ocular hypotensive
• prevent an acute rise in IOP after
laser trabeculoplasty.
• History of allergy to brimonidine
• Eyelid swelling, tenderness, itching,
follicular reaction
• Patients prone to hypotension
• Patients with complaints of somnolence
Advantages ADRs
CURRENT THERAPIES
13. Prostaglandins
analogues
13
CURRENT THERAPIES
• a first line treatment for open angle
glaucoma or ocular hypertension
• Eye Lash Changes
• Pigmentation
• Iris
• Periocular skin
• Pro-Inflammatory
• Hyperemia of Conjunctiva
• Uveitis
• Reactiviation of HSV keratitis
Advantages ADRs
14. Carbonic
anhydrase
inhibitors
CURRENT THERAPIES
14
• Bitter taste
• Stinging
• Conjunctival hyperemia
• Concerns with history of sulfa allergies
• Hyponatremia, hyperkalemia
• Hepatic, renal dysfunction
ADRsAdvantages
• As adjuvant with B-blocker and
miotics
• Donot affect pupil size
15. • Ciliary musle contraction, pupillary constriction pulling of iris
opening of TM increase draining of AH decrease IOP
• Directly action M3 agonist/reversible or irreversible Anti-AchE
drugs
Miotics:
cholinomimetics
15
• Pupil constriction
• Permanent after long term use
• Induced myopia
• Headache
• Accommodative spasm
• Blurred vision
• Accommodative spasm
• Retinal detachment
• Acute angle closure Glaucoma
• Prophylaxis of ACG
Advantages ADRs
CURRENT THERAPIES
17. Pilocarpine was the first drug introduced
in 1877 for treatment of glaucoma.
Twenty years have passed since the
development of the last drug class in
glaucoma: Latanoprost
1990–2010
new drugs of same class,
fixed dose combinations,
formulation improvements,
there were no new classes drugs approved
HISTORY OF GLAUCOMA
PHARMACOTHERAPY
17
18. ▪ Neural damage irreversible – need for
neuroprotective agents
▪ Patients with asthma, bradycardia,
allergy to sulfa drugs or topical
brimonidine
▪ complex multiple drug regimen, side
effects on long-term use and poor
tolerability profile
▪ Drugs for newer drug delivery systems
decreasing side effect profile and
improving adherence and overall
quality of life.
WHY NEW DRUGS?
18
21. RHO-kinase associated protein inhibitors
(ROCK inhibitors)
a change of cell shape and actin
cytoskeleton structure
cell bodies become rounded and
there is disruption of actin
production
greater outflow of AH through the
trabecular meshwork
decrease of IOP
Moshirfar M, Parker L, Birdsong OC, et al. Use of Rho kinase Inhibitors in Ophthalmology: A Review of the
Literature. Med Hypothesis Discov Innov Ophthalmol. 2018;7(3):101–111.
21
22. RHO-kinase associated protein inhibitors
(ROCK inhibitors)
Moshirfar M, Parker L, Birdsong OC, et al. Use of Rho kinase Inhibitors in Ophthalmology: A Review of the
Literature. Med Hypothesis Discov Innov Ophthalmol. 2018;7(3):101–111.
Approved
in USA
December
18, 2017
Approved
in Japan
22
23. ADENOSINE RECEPTORS IN EYE
A1
• Reduce
outflow
resistance of
IOP*
• Reduce
vascular
resistance
and increase
optic nerve
head blood
flow
A2a
• Reduce
vascular
resistance
and increase
optic nerve
head blood
flow
A3
• Anatagonist
reduce Cl
channel
activation of
Ciliary Epi,
reduce IOP
formation
23
24. ADENOSINE RECEPTORS IN EYE
Failed to achieve its primary
endpoint of superiority in the
reduction of intraocular pressure
(IOP) compared with placebo
24
25. NO donating Prostaglandin F-2 α analogue
latanoprostene bunod
latanoprost acid (active metabolite) butanediol mononitrate
1,4-butanediol NO (active metabolite)
matrix metalloproteinase (MMP)-1, MMP-3 and MMP-9
remodelling of its extracellular matrix increased aqueous humour outflow through the
uveoscleral pathway
decreasing cell contractility
aqueous humour outflow through
the trabecular meshwork pathway
prostanoid FP receptor
Hoy SM. Latanoprostene Bunod Ophthalmic Solution 0.024%: A Review in Open-Angle
Glaucoma and Ocular Hypertension [published correction appears in Drugs. 2018
Jun;78(8):857]. Drugs. 2018;78(7):773–780. doi:10.1007/s40265-018-0914-6
25
27. 27
Prostaglandin action on EP2
DE-117 (Santen Pharmaceutical, Japan)
Taprenepag isopropyl
ONO-9054 (Ono Pharmaceuticals, Japan)
UNDER
TRIAL
Omidenepag isopropyl
It is hypothesized that EP2 agonists may
increase aqueous humor outflow via
relaxing TM tissues
remodeling of extracellular matrix which
is particularly relevant in TM tissues
Prasanna G, et al; Effect of PF-04217329 a prodrug of a selective prostaglandin EP(2) agonist on intraocular pressure in preclinical models of glaucoma.
Exp Eye Res. 2011 Sep;93(3):256-64
28. CANNABINOIDS
ciliary epithelium, the trabecular meshwork, Schlemm’s canal,
ciliary muscle, ciliary body vessels, and retina
CB 1
receptor
decreased the secretion of ciliary processes
dilatation of the ocular blood vessels
through a possible β adrenergic action
reduce the noradrenaline release in the
ciliary body, leading to a decrease in the
production of aqueous humour
prostaglandin E2 mediated mechanism
better trabecular and uveoscleral aqueous humour outflow, prevent neural nerve damage
Tomida I, Pertwee RG, Azuara-Blanco A. Cannabinoids and glaucoma. Br J Ophthalmol. 2004;88(5):708–713. doi:10.1136/bjo.2003.032250
28
Antioxidant properties
inhibit glutamic acid release
29. 29
CANNABINOIDS
• short duration of action, lasting usually between 3-4
hour
• Drug tolerance and tachyphylaxis
• Abuse potential
• Existing stigmas, beliefs, political, and legislative
issues
• monthly cost would be estimated at $690, significantly
more than the cost of current medications.
• lowering of blood pressure
• conjunctival hyperemia, decreased lacrimation exist
• long-term effects - higher occurrence of psychosis,
impaired immune system response, motor
coordination
Danial OH, et al; Eyewiki.aao.org. (2020). Cannabinoids for Glaucoma - EyeWiki. [online] Available at:
https://eyewiki.aao.org/Cannabinoids_for_Glaucoma [Accessed 13 Mar. 2020].
30. 30
Local application of verapamil was associated with ocular outflow
enhancement in animal models and humans
but their use is limited by systemic effects including severe
bradycardia and
blood hypotension.
Local administration of calcium channel blockers
31. 31
Small interfering RNAs (siRNAs) : artificially synthesized 19–
23 nucleotide long double-stranded RNA molecules transient silencing of
gene of interest
beta-2 adrenergic receptor blockade
decreasing aqueous production by the ciliary body
BAMOSIRAN
currently being evaluated
against comparator in
a Phase 2b clinical trial
(SYLTAG study)
Martínez T, González V, Roehl I, Wright N, Pañeda C, Jiménez AI. In vitro and in vivo efficacy of SYL040012, a novel siRNA compound for
treatment of glaucoma. Mol Ther, 2014, 22(1):81-91.
33. 33
progression and RGC loss can occur despite IOP lowering
mechanisms and drugs that retard neuronal
apoptosis and degeneration
oxidative stress Mitochondrial
dysfunction
NEUROPROTECTIVE AGENTS
Antioxidant/antiapoptotic agents
35. 35
NEUROTROPHIC GROWTH FACTORS
• CNTF: ciliary neurotrophic factor
• BDNF : brain derived neurotrophic factor
• neuronal growth factor (NGF)
• and the glial cell line-derived neurotrophic factor (GDNF)
Intrinsic growth factors can be given exogenously
Intrinsic GF are NOT sufficient in maintaining the viability of RGC in
conditions of chronic disease
36. 36
GENE THERAPY
viral and nonviral vectors
delete, replace/inactivate an aberrant gene, or introduce a new gene to target tissue of interest such as
trabecular meshwork, ciliary epithelium, ciliary body, and RGC
helps in targeted therapeutic protein expression
intracameral injection of
adenovius carrying the
recombinant MMP1
reversal of corticosteroid-
induced OHT
intracameral delivery of
lentivirus vectors
expressing COX-2 and FP
IOP reduction in POAG
Adeno-associated viral
vectors (AAV) deliver Brain
derived neurotrophic factor
RGC survival for a month
in rodent models
37. 37
STEM CELL
retinal precursor cells extracted from embryonic retina of animal
models
transplanted into the subretinal space of
mice.
retina and optic nerve head degeneration counteracted
38. 38
NEW DRUG DELIVERY SYSTEM
Nanoparticle-based topical formulations Contact lens-based drug delivery
Better corneal penetration of the drug
In vivo studies of carbonic anhydrase
inhibitors, brimonidine, pilocarpine
• Silicone hydrogel soft contact lenses
loaded with nanoparticles containing
timolol
• topical bimatoprost ocular insert
• Travoprost punctal plug encapsulating
the active drug in the vertical portion of
the superior or inferior canaliculus.
39. 39
CONCLUSION
• Newer strategies will get better results with fewer side effects and
invasiveness.
• Great efforts have been made regarding animal and cellular
research, and the results appear encouraging.
Let me explain you AH dynamics
AH flows from pc to ac, drains out from Ac by two pathways
Outflow pathway
Congestion in TM in open angle
Iris blocking outflow in closed angle
To summarized differet types of glaucoma, there is ocular hypertension with only iop increased
Now the current pharmacotherapy which are available
To explain further regarding basis of using these therapies, firstly I will explain you about BB
But these drugs also have typical ADRs as seen with BB drugs
Alfa agonists are also used in Glaucoma because of their effect on alfa 1 and 2 r
aSelective or non selective
Non-selective: DIPIVEFRINE ( prodrud of adr)
Selective: apraclonidine, brimonidine
Latanoprost
Travoprost
Bimatoprost
Dorzolamide
Brinzolamide
WE Can see timeline of introduction of Glaucoma drugs in market
Most recently approved new class
To further elaborate how A1 receptors are reducting resistance to outflow is by secreation of
Even though these effects are seen in animal and phase 2 studies,