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Medical Management of Glaucoma (2) (1).pptx
1. Medical Management of Glaucoma
Sankara Eye Hospital
Bangalore
PRESENTER: DR. ANUSHA
MODERATORS: DR. MEENA G
DR. LALITHA
2. OLD DNB QUESTIONS
• Classify pharmacological agents available for glaucoma(2019,2000)
• Mechanism of action of topical agents(2019,2000)
• Adverse effects and contraindications of systemic agents(2019,2000)
• Pharmacokinetics of topical antiglaucoma drugs(2016)
• List the various prostaglandin analogues available in the management of
glaucoma. Mechanism of action, dose schedule and side
effects(2012,2008)
• Dynamics and pharmacomodulation of uveoscleral outflow(2007)
3. • Concept of neuroprotection in glaucoma(2005,2003)
• Role of newer drugs in the management of glaucoma and their benefit
over conventional drugs(2003)
• Discuss the role of beta blockers in glaucoma.
5. Bioavailability of Topical Ocular Medications
• The penetration of topically applied medication into the eye is
proportional to the concentration of the drug that comes in contact with
the cornea over time, which gets diluted by tears and gets washed out into
the lacrimal drainage system.
• The half-life of various drugs in the tears is said to be 2-20 mins.
6. TEAR FILM DYNAMICS
• The human cul-de-sac has a volume of 7microL,which can expand to 30microL.
• Most commercial drops have 30-75microL.
• Cul- de-sac to NLD within 15sec of instillation.
• A normal blink rate eliminates about 2microL of fluid from cul- de-sac.
• A 30sec interval between drops results in 45% washout of drug effect, 2min results
in 17% loss of effect, 5min no wash out effect.
7. Drug Elimination
• Most of the drug is lost in the Cul de sac, because of the over flow.
• 80% of applied eye drops leaves by lacrimal drainage ,not by entering the eye.
• In general , drugs are readily absorbed across the highly vascularized
nasopharyngeal mucosa into systemic circulation .
• Once in the anterior chamber the drug is eliminated with the bulk flow of the
aqueous humor via the trabecular mesh work or the uvea scleral out flow.
10. RECEPTOR LOCATION ON CILIARY PROCESS
α1 receptors constrict ciliary vessels
and reduce aqueous production
α2 receptors located on ciliary
epithelium reduce aqueous
secretion
β2 receptors located on ciliary
epithelium enhance aqueous
secretion via increased cAMP. Their
blockade decreases secretion
Carbonic anhydrase present in ciliary
epithelial cells, their blockage
decreases aqueous secretion.
12. GOAL
• A “target” pressure should be set as goal of long term therapy.
• The AAO defines target IOP as “ a range of IOP adequate to stop progressive
pressure – induced injury”
Formula: TP = IP(1-IP/100)-Z+Y±1mmHg
• TP=target pressure
• IP= initial pretreatment pressure
• Z=indicator of disease severity
• Y= burden of therapy
13.
14. PROSTAGLANDIN ANALOGUES
Hypotensive lipids Amide prodrug
The most effective AGM currently available
Higher concentration – increase IOP & inflammation
Lower concentration –decrease IOP
Ester prodrug
Least efficacious
15. MECHANISM OF ACTION
• Ciliary muscle relaxation which widens the connective tissue spaces. This
is responsible for the initial fall in IOP with topical Prostaglandins.
• Increasing dilated spaces between longitudinal muscle bundles
• PG stimulates collagenase and metalloproteinase to degrade ECM
between ciliary muscle bundles, which decreases resistance to uveoscleral
outflow.
16.
17. LATANOPROST
Available as 0.005%
It lowers IOP both night and day time (uniform)
Latanoprost is rapidly converted by the cornea into
acid which appears to be the active ingredient.
Therefore, latanoprost should be considered a prodrug.
In juvenile open angle glaucoma , better response
18. Available as 0.03%, 0.01%
When compared to latanoprost, bimatoprost seems to
offer slightly improved pressure control
Comparatively more local side effects
BIMATOPROST
19. TRAVOPROST
• Available as 0.004%
• It has greater duration of action 40hrs
• Only PGA with different preservative than BAK
21. Unoprostone
• First prostanoid approved for clinical use in world.
• RESCULA (UF-201)
• Pulmonary metabolite of PGF2α
• Dose 0.15% BD
22. Indications
Open angle glaucoma
Ocular hypertension
Normotension glaucoma
Pigment dispersion glaucoma
Exfoliative glaucoma
Chronic angle closure glaucoma
To be used with CAUTION
Allergy /sensitivity to these drugs
Pregnancy
Iritis
Herpes simplex keratitis
Complicated aphakic
/pseudophakic eyes
23. ADVANTAGES
• Apparent lack of systemic side effects
• Most potent and effective with OD dosing
• As effective at night as during day
• Potentially can reduce IOP below EVP
ROLE IN NTG
25. Conjunctival hyperemia
Very mild for most of the patients
Due to NO/ substance P induced vasodilatation
Discontinuation of drops not required
26. Eye lashes changes
• Increase in number, length, thickness, pigmentation(hypertrichosis)
• It is by stimulation of growth phase of hair cycle
27. Iris changes
• Darkening of iris within 8mon of exposure.
• By increased melanogenesis , increase
in iris stromal melanocyte number
• Permanent change
• IRIS CYSTS, related to flow pressures caused
by Uveo-scleral drainage
28. Periocular skin pigmentation
• Darkening, mostly noted in skin of eyelids
• Disappears with drug withdrawl (7weeks)
• PG induced melanogenesis
30. Anterior uveitis
• Due to breakdown of blood aqueous barrier , especially in post cataract
surgery and in eyes with predisposed inflammation
OTHERS
• Reactivation of HSV
• Deepening of lid sulcus
32. Beta blockers
• Timolol was granted FDA approval for ocular use in 1978.
• Timolol, levobunolol, metipranolol and carteolol are nonselective while
Betaxolol has β1 –selective properties
33. • INDICATIONS
• Open angle glaucoma
• OHT
• Glaucoma in children
Betaxolol (>sideffects , lower concentration with punctal occlusion)
34. Mechanism of action
• Adrenergic blocking agents decrease aqueous humor formation by
antagonizing a resting adrenergic tone in the ciliary processes.
• Such a tone would have to be supplied by either the sympathetic nervous
system or circulating catecholamines.
• Reiss and co-workers noted that aqueous humor production is reduced
greatly during sleep and that little additional reduction occurs with the
administration of timolol either just before or during sleeping hours.
38. Long term efficacy
SHORT TERM ESCAPE
(By Boger & Co-workers)
First few days, reduction in IOP
Rises next few days
Plateau thereafter
Due to increase in betanergic
receptors in first few days
Best to await for 1month to
determine the efficacy
LONG TERM DRIFT
(By Steinert & Co-workers)
Decline in IOP 3months to one year
later
Some regain responsiveness after
washout period of drug
PULSATILE THEARAPY of TIMOLOL 0.5%
for 6months and Dipivefrin for 2mon >>
minimises the drift
39. TIMOLOL
• Non –selective beta adrenergic antagonist
• Lack side effects -> corneal anaesthesia, subconjuctival fibrosis
• Has contralateral IOP lowering effect like other OBB’s.
0.25% - light iris
0.5% - dark iris
AVAILABLE FORMS CONCENTRATION
T. MALEATE 0.25, 0.5%
T. HEMIHYDRATE 0.5%
T. MAKEATE (gel) 0.25, 0.5. 0.1%
40. PHARMACOKINETICS
ONSET of action 30 min
PEAK effect After 2 hrs
PERSISTS till 12 hrs
MEASURABLE IOP REDUCTION till 24 hrs
WASHOUT PERIOD 1 month
DOSING Solution 1-2 t/day
Gel OD
IOP reduction by 20-30%
41. CARTEOLOL
• Nonselective beta blocker
• Available as 1,2% in hydrochloride form (OCUPRESS)
Theoretical advantage of causing less frequent or
less severe adverse effects
PHARMACOKINETICS
ONSET of action 1 hr
PEAK effect After 4 hrs
PERSISTS till 12 hrs
WASHOUT period 1 month
DOSING 1-2t/day
42. LEVOBUNOLOL
• Nonselective beta blocker
• Available as 0.25, 0.5%
PHARMACOKINETICS
ONSET of action 1 hr
PEAK effect 2-6 hrs
PERSISTS till 24 hrs
IOP reduction by 20-30%
DOSING Solution 1-2 t/day
Gel OD
43. METIPRANOLOL
• Nonselective beta 1,2 blocker
• Available as 0.3%
PHARMACOKINETICS
ONSET of action 30 min
PEAK effect 2 hrs
PERSISTS till 24 hrs
IOP reduction by 20-30%
DOSING 2 t/day
44. BETAXOLOL
• Selective beta 1 blocker
• Available as 0.5% (suspension & microsuspension)
• 0.5% (solution)
• Highly lipid soluble & binds well to plasma protein lesser
CNS side effects
• Neuroprotective (seems to reduce VF defects over timolol).
• Additional CCB effect
Suspension
same efficacy as
solution but
lesser ocular
iritation
46. ADRENERGIC AGENTS
• Epinephrine – the least selective (activating alpha-1, alpha-2 and beta
receptors.
• Among the alpha-2 – selective agonists, Brimonidine – the most alpha-2-
selective .
47. EPINEPHRINE
• Mixed alpha – and beta-adrenergic agonist
• First topical adrenergic agent used to lower IOP in patients with OAG
• ADDITIVE to long-term treatment with pilocarpine and oral acetazolamide
PHARMACOKENETICS
Available as Hydrochloride 0.5, 1,2%
Borate 0.5, 1%
Bitartrate
ONSET Within 1 hr
MAXIMUM IOP REDUCTION 2-6 hrs
PERSISTS till 12-24 hrs
DOSING 1-2 t/day
48. Side effects:
OCULAR SYSTEMIC
Tearing, stinging Tachycardia, palpitations
Allergic blepharoconjunctivitis Extra-systoles
CME Hypertension
Black adrenochrome deposits on palpebral
Conj, CL, cornea
Anxiety
49. DIPEVEFRINE
• Derivative prodrug of epinephrine
• Made less hydrophilic by the d-iesterification of epinephrine and pivalic
acid
• Less potent that most beta blockers, except perhaps for betaxolol 0.25%
• Rest of the features same as the epinephrine
PHARMACOKENETICS
AVAILABLE as PROPINE 0.1%
DOSING 2 t/day
50. • MOA:
Reduces aqueous humor production by vasoconstriction in uveal tract
Transient reduction in EVP
Central and peripheral alpha 2 agonist
BRIMONIDINE: additional – increases uveo-scleral outflow
ALPHA 2 SELECTIVE AGONISTS
51. CLONIDINE
• The first alpha agonist used systematically and topically glaucoma
• Narrow therapeutic index
• Side effects of systemic hypotension and sedation have limited its
widespread use in ophthalmology
• Of the 3, is the most lipophilic (good corneal, BBB penetrance)
PHARMACOKENETICS
AVAILABLE as CATAPRESS 0.125%
DOSING 3 t/day
52. APRACLONIDINE
• Available as: hydrochloride
• Hydrophilic derivative of clonidine – NO centrally mediated side effects of
systemic hypotension and drowsiness.
• Reduced systemic absorption & BBB penetration
• Poor corneal penetration
• MOA:
Reduced aqueous production
Improved trabecular outflow and
Reduced episcleral venous pressure
53. Side effects:
• Widest therapeutic index for CVS & CNS effects of the available alpha-2
agonists, with no or minimal effect on pulse, blood pressure, or alertness
at approved dosages.
OCULAR
Pruritis, irritation
Transient eyelid retraction
Subtle conjunctival blanch
Follicular conjunctivitis
Periorbital dermatitis
Ocular ache, Photopsia
TACHYPHYLAXIS may limit long-term
use
SYSTEMIC
Dry nose / mouth
Hypotension
Vasovagal attack
Fatigue
54. PHARMACOKENETICS
AVAILABLE as IOPOIDINE 0.5, 1%
PEAK effect <1-2 hrs
WASHOUT period 7-14 days
DOSING 2-3 t/day
IOP reduction by 20-30%
INDICATION
Prophylaxis for acute IOP spike post NdYAG laser
capsulotomy/PI/trabeculoplasty
55. BRIMONIDINE
• Highly alpha-2-selective agonist, tartarate
• Newer formulation with purite as the preservative agents
and 0.15% brimonidine has been shown to the well
tolerated and as effective in IOP lowering.
• While sedation and systemic hypotension were more common with 0.5%,
newer formulations have been better tolerated.
56. PHARMACOKINETICS
AVAILABLE as ALPHAGAN 0.2%,0.15%,0.1%
PEAK effect 2 hrs
WASHOUT period 7-14 days
DOSING 2-3 t/day
IOP reduction by 20-30%
• MOA:
Reduces aqueous flow (20%),
Increasing uveo-scleral outflow
Central mechanism
57. INDICATIONS
Prophylaxis for post-laser IOP spike
OAG & OHT
Neuroprotection
OCULAR
Blurring
FB Sensation
Lid edema
Dryness
• Less ocular sensitivity / allergy than Apraclonidine
SYSTEMIC
Dry nose / mouth
Hypotension, Insomnia, Anxiety
Depression, Synocape
Headache, Fatigue
58. CHOLINERGIC DRUGS
Pilocarpine and carbachol
MECHANISM OF ACTION
Contraction of iris sphincter, pupil constriction (miosis)
Contraction of longitudinal fibres of ciliary musle ,causing tension on
scleral spur: opening TM and facilitating aqueous outflow
Contraction of circular muscles , relaxing the zonular tension on lens
equator (accommodation)
59. PILOCARPINE
• Partial direct agonist (cholinergic agonist)
• Available as hydrochloride
• Usual Vehicles for pilocarpine are HPMC and PVA
• Also formulated in a high-viscosity gel.
• Ocusert: Diffusion-controlled, reservoir-type device (release at very low
constant rate over 7-days), release rate-20-40µg/hr
61. • The device is sterile and contains no preservative
• Penetrates the cornea well
• Produces a low incidence of allergic reactions
PHARMACOKINETICS
AVAILABLE as 0.5, 1,2,3,4, 6%
PEAK effect 1.5-2 hrs (75 min.)
IOP reduction PERSISTS for 4-14hrs
WASHOUT period 48 hrs
DOSING 2-4 t/day
IOP reduction by 15-25%
65. • MOA:
Reduction in the accumulation of
bicarbonate in the posterior chamber
Decrease in sodium & associated fluid
movement linked to bicarbonate ion
Metabolic acidosis (relative)
66. CONTRAINDICATIONS
Diabetic susceptible to ketoacidosis
Hepatic insufficiency
COPD
INIDICATIONS
Immediate / urgent reduction of
IOP
Very young patients awaiting
surgery
Elderly with arthritis/ cognitive
difficulties
67. Side effects:
SYSTEMIC
Numbness, Paraesthesias
Malaise, anorexia, nausea, flatulence,
diarrhea poor tolerance of carbonated
beverages
Depression, decreased libido, hirsutism
Thrombocytopenia, idiosyncratic aplastic
anemia (rarely)
Urolithiasis, hypokalemia, acidosis
• May cause allergic reaction
in patients with sulpha
allergy
• It is reasonable and
relatively inexpensive to
obtain a pre-treatment
“complete blood count”
and one or two follow-up
studies during first 6
months of treatment
69. CARBONIC ANHYDRASE INHIBITORS
(Topical)
• Specially inhibit carbonic anhydrase II – found in ocular tissue such as
ciliary processes (PIGMENTED & NONPIGMENTED), corneal endothelium,
and Muller Cells in the retina.
• Used mainly as adjunctive theraphy, in very young / elderly
77. MOA:
• By increasing the osmotic gradient
between the blood and the ocular
fluids.
• Following the administration of
osmotic drugs, the blood osmolality is
increased by up to 20 to 30mOsm/L,
which results in loss of water from the
eye to the hyperosmotic plasma.
• Likely due to reduction of Vitreous
volume.
Factors affecting osmotic gradient
Ocular penetration
Distribution of body fluids
Molecular weight & concentration
Dosage
Rate & route of administration
Rate if systemic clearance
Type of diuresis
OSMOTIC AGENTS
78. GLYCEROL MANNITOL
Onset 20min, peak 45min-2hr Onset 15 -30min, Peak 30-60 min.
Dose – 2-3ml/kg Dose- 1-2 g/kg
Prepared as a 50% vol/vol (0.628
g/mL) solution
Available- 20%(w/v)
80. CONTRAINDICATIONS
Well established anuria
Severe dehydration
Frank / impending pulmonary edema
Severe cardiac decompensation
Hypersensitivity to drug
SHORT TERM USE IN
ACG
Malignant glaucoma
Certain secondary glaucoma
Long term use avoided because of:
• Risk of dehydration
• Electrolyte imbalance
• Other adverse effects
81. • When osmotic drugs are administrated prior to surgery, the patient’s
bladder should be empty
CAUTION TO BE TAKEN IN:
Congestive heart disease
Hypervolemia
Electrolyte abnormalities
Confused mental states
Dehydration
Diabetics(oral GLYCEROL)
82. Novel targets
• Rock inhibitors
• Adenosine receptor antagonists
• NO donors
• Oligonucleoside based components
• Gene therapy
• Stem cell therapy
• Neuroprotection
83. WHY NEED FOR NEW DRUGS??
• Neural damage irreversible – need for neuroprotective agents
• Patients with asthma, bradycardia, allergy to sulfa drugs or topical
brimonidine – not much options left other than Surgery
• Need for preservative free drugs
• Benzalkonium – punctate /ulcerative keratopathy
• Thiomersal – hypersensitivity
• Drugs for newer drug delivery systems
84. ROCK INHIBITORS
• Rho are small GTP-binding proteins
• Include RhoA, RhoB, RhoC
• Cycle between a GTP-bound active, GDP-bound inactive conformation
• This cycling b/w bound GDP and GTP is regulated by
Guanine nucleotide exchange factors (GEFs)
GTPase activating proteins (GAPs)
Guanine nucleotide dissociation inhibitors (GDIs)
85. • ROCKs are intracellular serine/threonine kinases (ROCK1/ROCK2)
• Structurally: ROCKs consist of three domains
1. N-terminal kinase domain
2. C-terminal pleckstrin homology domain
3. Coiled-coil domain.
These domains interact with Rho–GTP to regulate ROCK activity.
When present, Rho–GTP binds the coiled-coil domain and enhances ROCK activity.
When absent, N-terminal kinase activity diminishes through an autoinhibitory
intramolecular fold of the pleckstrin homology domain.
100. LATANOPROSTENE BUNOD
• Dose range 0.006 to 0.040%
• Once daily
• It has two metabolites
•
Latanoprost acid Butanediol mononitrate
1,4 butane diol NO
102. STUDY DURATION DESCRIPTION CONCLUSION
VOYAGER study 28days LBN
0.006%,0.012%,0.00.04
0% vs latanoprost
0.005%
LBN 0.024% cause significant mean
diurnal IOP reduction
APOLLO study 3 mon LBN 0.024% vs Timolol
0.5% bd
IOP reduction significantly higher in LBN
group
LUNAR study 3 mon LBN 0.024% vs Timolol
0.5% bd
LBN was non–inferior to Timolol
JUPITER study 1 year Long term safety and
efficacy of LBN 0.024%
LBN 0.024% was safe & well- tolerated ,
significant IOP reduction when used upto
1year
103. OMLONTI
FDA has approved OMLONTI® (omidenepag isopropyl
ophthalmic solution) 0.002% eye drops for the reduction of
elevated intraocular pressure (IOP) in patients with primary
open-angle glaucoma or ocular hypertension. The approval date
was September 22.
104. Mechanism of action
Omidenepag isopropyl, the active pharmaceutical ingredient is a relatively
selective prostaglandin EP2 receptor agonist,which increases aqueous humor
drainage through the conventional (or trabecular) and uveoscleral outflow
pathways.
U.S. Phase 3 study confirmed OMLONTI®to be non-inferior to timolol, the
standard of care.
Two different Phase 3 studies conducted in Japan and Asia showed
OMLONTI®to be non-inferior to latanoprost, another standard of care.
105. OLIGONUCLEOTIDE –BASED COMPOUNDS
These are designed to target specific genes or RNAs with the aim
of altering gene expression or even exert a direct interaction by
binding to molecules
111. • EXCITOTOXICITY
• Glutamate in excessive amounts or excessive period of time can excite
cells to death
• Site -NMDA
• Modulation of NMDA receptor has been constituted a major area of
research in glaucoma neuroprotection.
• NMDA ANTAGONISTS
• MEMANTINE – the only phase 3 cleared neuroprotective agent for OAG
• CALCIUM CHANNEL BLOCKERS
115. STEM CELL THERAPY
• In recent years, stem cells have been the subject of great
attention as a potential source of cell replacement in diseases
that lead to blindness, such as glaucoma.
• Several studies have shown that retinal precursor cells
extracted from embryonic retina of animal models have been
successfully transplanted into the sub retinal space of mice.
116. • Autologous mesenchymal stem cells (MSCs) derived from human bone marrow
could represent a further source of stem cells for regenerative purposes given
their greater ease of extraction and their ability to migrate to retina and optic
nerve head (ONH) after intravitreal injection in murine models.
120. PUNCTAL OR CANALICULAR
PLUGS
Shining of cobalt blue filtered
light on device can confirm its
retention because it contains
fluorescein
IOP reduction
• 24% at day 10
• 15.6% at day 30
• 42% with 30 day plug retention
122. • Durysta is a PG analog indicated for the IOP reduction in patients with
OAG or OHT.
• It is a ophthalmic drug delivery system for single intracameral
administration of biodegradable implant containing 10μg Bimatoprost.
• The ARTEMIS trails demonstrated ,DURYSTA lowered IOP 30% through
12week primary efficacy period.
123. • It is contraindicated in patients with active or suspected
ocular or periocular infection, corneal dystrophy , absent or
ruptured posterior capsule ,hypersensitivity to drug,
Pseudophakic or aphakic patients.
• It is associated with increased risk of endothelial loss
• Caution in patients with narrow iridocorneal angles that may
prohibit settling in inferior angle
