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Medical Management of Glaucoma (2) (1).pptx
- 1. Medical Management ofGlaucoma 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 ofneuroprotection 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.
- 4. CLASS OVERVIEW • Ocularpharmacology • Medications
- 5. Bioavailability of TopicalOcular 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 • Mostof 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.
- 9. CLASSIFICATION ANTI-GLAUCOMA MEDICATIONS Topical Systemic 1. α-adrenergicagonists 2. β-adrenergic antagonists 3. Miotics 4. Prostaglandins analogues 5. Topical carbonic anhydrase inhibitors 1. Oral carbonic anhydrase inhibitors 2. Hyperosmotic agents
- 10. RECEPTOR LOCATION ONCILIARY 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.
- 11. Mechanism of actionof Antiglaucoma medications
- 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
- 14. PROSTAGLANDIN ANALOGUES Hypotensivelipids 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.
- 17. LATANOPROST Available as0.005% 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 as0.03%, 0.01% When compared to latanoprost, bimatoprost seems to offer slightly improved pressure control Comparatively more local side effects BIMATOPROST
- 19. TRAVOPROST • Available as0.004% • It has greater duration of action 40hrs • Only PGA with different preservative than BAK
- 20. Tafluprost • Available as0.0015% • Currently ,preservative free PGA available in USA
- 21. Unoprostone • First prostanoidapproved for clinical use in world. • RESCULA (UF-201) • Pulmonary metabolite of PGF2α • Dose 0.15% BD
- 22. Indications Open angleglaucoma 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 lackof 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
- 24. SIDE EFFECTS OCULAR SYSTEMIC •Conjunctival Hyperemia Flu –like symptoms • Eye lash changes Joint /muscle pain • Iris changes Head ache • Periocular skin pigmentation • Anterior uveitis • HSV keratitis • Cystoid macular edema • PG- associated periorbitopathy
- 25. Conjunctival hyperemia Verymild 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 • Darkeningof 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
- 29. Cystoid macular edema •Risk factors PCR, vitreous loss Recent Intraocular surgery Recent iritis, retinal inflammation,vasculitis Prior h/o CME
- 30. Anterior uveitis • Dueto breakdown of blood aqueous barrier , especially in post cataract surgery and in eyes with predisposed inflammation OTHERS • Reactivation of HSV • Deepening of lid sulcus
- 31. Side effects ofProstaglandins
- 32. Beta blockers • Timololwas granted FDA approval for ocular use in 1978. • Timolol, levobunolol, metipranolol and carteolol are nonselective while Betaxolol has β1 –selective properties
- 33. • INDICATIONS • Openangle 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.
- 35. Contraindications • Severe COPD •Bronchial Asthma • Sinus bradycardia • Cardiogenic shock
- 36. Side effects • Ocular •Burning and stinging sensation • Conjunctival hyperemia • Corneal anaesthesia • Superficial punctate keratitis • Allergic blepharoconjunctivitis • Dry eye • Transient blurring of vision • Ptosis
- 37. • Systemic • CNS:Anxiety, depression, fatigue, Lethargy, confusion, sleep disturbance etc. • CVS: Bradycardia , arrhythmia, heart failure, syncope ,MI • PULMOLOGY: Bronchospasm ,airway obstruction • METABOLIC: Increased TG, decreased HDL • GASTROINTESTINAL: Nausea , Diarrhoea, Cramps etc.
- 38. Long term efficacy SHORTTERM 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 –selectivebeta 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 action30 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 betablocker • 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 betablocker • 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 beta1,2 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 beta1 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
- 45. PHARMACOKINETICS PEAK effect 2-3hrs WASHOUT period 1 month IOP reduction by 15-20% DOSING 2 t/day
- 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 prodrugof 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: Reducesaqueous 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 firstalpha 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: • Widesttherapeutic 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 IOPOIDINE0.5, 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-selectiveagonist, 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 ALPHAGAN0.2%,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-laserIOP 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 andcarbachol 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 directagonist (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
- 60.
- 61. • The deviceis 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%
- 62. Side effects: OCULAR Posterior synechiae,KP’s Angle closure potential Myopia, color vision changes Cataract progression, RD Dermatitis Brow ache Epiphora SYSTEMIC Increased salivation, gastric secretion Abdominal cramps
- 63. CAUTION CONTRAINDICATIONS Acute iritis Visually significantlens change h/o or predisposition to RD Proven sensitivity to drug Acute infections conjunctivitis/Keratitis Asthma / resp / cardiac failure / MI Parkinson’s , hyperthyroidism Peptic ulcer, GI spasm Poorly controlled BP INIDICATIONS OAG Acute PACG with pupillary block To break synechiae (Alternated with mydriatics)
- 64. CARBONIC ANHYDRASE INHIBITORS SYSTEMIC •Sulfonamide family of drugs • 2 drugs ACETALZOLAMIDE • Oral: 125, 250, 500 mg (sustained releases) • Parentral: 500 mg / 5-10 mg/kg METHAZOLAMIDE • 25, 50mg
- 65. • MOA: Reduction inthe accumulation of bicarbonate in the posterior chamber Decrease in sodium & associated fluid movement linked to bicarbonate ion Metabolic acidosis (relative)
- 66. CONTRAINDICATIONS Diabetic susceptible toketoacidosis 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
- 68. PHARMACOKINETICS PEAK effect 3-6 hrs. (sustained release) 2-4 hrs. (oral) DOSING 2-4 t/day (250mg) 2 t/day (500mg) IOP reduction by 20-30%
- 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
- 70. DORZOLAMIDE PHARMACOKINETICS AVAILABLE as 0.5,1, 2 % PEAK effect 2-3 hrs WASHOUT period 48 hrs DOSING 2-3 t/da EXCRETION Renal 60-75% IOP reduction by 15-20%
- 71. BRINZOLAMIDE PHARMACOKINETICS AVAILABLE as 1% PEAKeffect 2-3 hrs WASHOUT period 48 hrs DOSING 2-3 t/da EXCRETION Renal 32% IOP reduction by 15-20%
- 72. Side effects: OCULAR Induced myopia,blurred vision Stinging Conjunctivitis, Keratitis, SPK Dermatitis SYSTEMIC Numbness and tingling Bitter taste Hypokalemia Stevens Johnson syndrome Renal calculi • Ocular hyperemia, stinging – Dorzolamide >> • Blurred vision, FB Sensation – BRINZOLAMIDE >>
- 73. Contraindications Hypersensitivity MAO inhibitor therapy Tobe used with CAUTION Depression ,Coronary insufficiency Pregnant and lactating mothers Contact lens users
- 74. Other uses • Retinal–choroidal blood flow and Neuroprotection • Chronic macular edema
- 75.
- 76. Hyperosmotic agents • ORAL–Glycerol ,Isosorbide,Ethanol • Intravenous-Mannitol, Urea
- 77. MOA: • By increasingthe 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)
- 79. Side effects: OCULAR IOP rebound Increasedaqueous flare SYSTEMIC Urinary retention Headache CHF, MI Nausea, Vomiting, diarrhea, electrolyte imbalance, confusion Diabetic complications
- 80. CONTRAINDICATIONS Well established anuria Severedehydration 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 osmoticdrugs 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 • Rockinhibitors • Adenosine receptor antagonists • NO donors • Oligonucleoside based components • Gene therapy • Stem cell therapy • Neuroprotection
- 83. WHY NEED FORNEW 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 • Rhoare 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 areintracellular 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.
- 86.
- 87. Additional benefits • ProtectTM cells from oxidative damage • Improve blood flow to optic nerve • Facilitate corneal endothelial wound healing • Increase ganglion cell survival • Reduce bleb scarring in glaucoma surgery
- 88. Draw backs • Noteffective in ACG • Potent vasodilators Conjunctival hyperemia Increased systemic absorption – ocular and systemic sideeffects Can worsen uveitis
- 89. Ripasudil • Approved inJapan in sep 2014 • For OAG and OHT • 0.4%, b.i.d dosing • 15% IOP reduction • Conjunctival hyperemia 55-74%
- 90. Netarsudil • Rock +Norepinephrinetransporter(NET) inhibitor • 0.02% ,Once daily dosing • 22% IOP reduction • MOA Increasing AH outflow through the TM NET inhibition reduces aqueous inflow Decreases Episcleral venous pressure
- 91. SIDE EFFECTS • Conjunctivalhyperemia-53% • Cornea verticillata • Conjunctival haemorrhage • Instillation site- pain/erythema • Corneal staining , blurred vision, increased lacrimation
- 92. • Netarsudil-associated reticular epithelialedema in decompensated corneal ulcer
- 93.
- 94. Rocklatan • Netarsudil 0.02%+Latanoprost 0.005% • Superiority in terms of ocular hypotensive efficacy • Uveoscleral and trabecular outflow • Ocular hyperemia – higher
- 95. Fixed drug combinationNetarsudil 0.02%/ latanoprost 0.005% phase 3 clinical trails
- 96. Trabodenoson • Highly selectiveα1 agonist • 4 different doses 50 to 500µg • B.i.d dosing • Significant IOP reduction in 25%
- 98.
- 99. NITRIC OXIDE DONORSOR PROSTANOID RECEPTOR AGONISTS
- 100. LATANOPROSTENE BUNOD • Doserange 0.006 to 0.040% • Once daily • It has two metabolites • Latanoprost acid Butanediol mononitrate 1,4 butane diol NO
- 101.
- 102. STUDY DURATION DESCRIPTIONCONCLUSION 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 approvedOMLONTI® (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 Theseare designed to target specific genes or RNAs with the aim of altering gene expression or even exert a direct interaction by binding to molecules
- 107.
- 109.
- 111. • EXCITOTOXICITY • Glutamatein 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
- 112.
- 113.
- 114. Mechanism of RGCloss Potential neuroprotective class Examples Neurotrophin deprivation Exogenous Neurotrophins, Neurotrophin receptor agonists BDNF,NGF, TrKA receptor agonist, TrKB receptor agonist Ischemia Vasodilators, Calcium channel blockers Ginkgo biloba, vitamin E ,Nifedipine, Verapamil etc,. Mitochondrial dysfunction Antioxidants, Vasodilators Coenzyme Q10, Vit E, melatonin , Ginkgo biloba Excitotoxicity NMDA antagonists, Calcium channel blockers Memantine , Riluzole, Dextromethorphan, Flunarizine Oxidative stress Antioxidants, Nitric oxide synthase inhibitors Coenzyme Q10, vit E, ginkgo biloba, Aminoguanide Glial cell modification, apoptotic pathways Growth factors, caspase inhibitors , TNF – α inhibitors TGF,CNGF GLC756
- 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 mesenchymalstem 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.
- 117.
- 119.
- 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
- 121. ANTERIOR CHAMBER IMPLANTS BimatoprostSR (FDA Approved)
- 122. • Durysta isa 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 iscontraindicated 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
- 124. Different drug deliverysystems