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Pharmacotherapy of
. Glaucoma
Dr Manjuprasad
Moderator: Dr Vijayalaxmi M.K
Overview
• Introduction
• Anatomy
• Aqueous humour dynamics
• pathophysiology
• Drugs used in the treatment
• Recent advan...
Introduction
• Glaucoma – ancient greek
meaning clouded or blue- green hue
• In Hippocratic aphorisms
Glaucoma – blindness...
• Glaucoma is not a single disease process but a group of
disorders characterized by a progressive optic neuropathy
result...
Anatomy of the eye
5
Aqueous humor
• Derived from the plasma
• 2.3µl/min
Production:
• Ultrafiltration
• Secretion
• Diffusion
6
Aqueous humor dynamics
7
Classification
• Congenital glaucoma
- Primary congenital glaucoma
- Developmental glaucoma
• Primary adult glaucoma
- Pri...
Pathogenesis
• All types of glaucoma – progressive optic neuropathy due to the
death of retinal ganglion cells(RGCs)
• RGC...
• Mechanical theory :
↑IOP – mechanical stretch of lamina cribrosa – axonal
deformation & altered capillary blood flow -- ...
Congenital glaucoma
• Seen in 1 in 10,000 births
• Pathology- mal development
of trabeculum
• True congenital glaucoma
• I...
Primary open angle glaucoma
• No obvious cause
• Polygenic inheritence
• ↑incidence in smokers
• Blacks > whites
• Patholo...
Primary angle closure glaucoma
• Increase in IOP – due to closure of angle of anterior chamber.
Acute & chronic
• Chronic ...
Risk factors:
• Hypermetropic eye
• Small eye
• 5th decade
• Female > male
• > in rainy season and dim light
14
Secondary glaucomas
• Lens induced glaucoma
• Pigmentary glaucoma
• Neovascular glaucoma
• Glaucoma associated with intrav...
16
Drugs used in the treatment
DRUGS THAT REDUCE AQUEOUS HUMOUR PRODUCTION
I. Beta-Blockers : levobunolol, timolol, carteolol...
DRUGS THAT INCREASE AQUEOUS OUTFLOW
I. Nonspecific Adrenergic Agonists :epinephrine,
dipivefrin
II. Parasympathomimetics :...
Cholinergic agonists
• Most commonly used – Pilocarpine
• Derived from shrub – pilocarpus jaborandi
MOA:-
• Acts on M3 rec...
• Onset of action – rapid
peak effect – 30min
lasts for 4 – 6hrs
• S/E:-
• LOCAL:- Superficial punctate keratitis , brow a...
• Pilocarpine gel (pilocarpine HCl 4%) HS
• Membrane controlled delivery system:-
-Insert placed in cul-de-sac that gradua...
ADRENERGIC AGONISTS
Includes:
• Non selective – epinephrine & dipivefrin
• Selective alpha2 agonists- Apraclonidine, Brimo...
• EPINEPHRINE:-
• Directly acting sympathomimetic
• MOA:
• Reduced aqueous production due to alpha action
• trabecular out...
• Onset of action-30min, peak effect – 1hr
• Used as an adjuvant therapy
• Available as 0.1% solution , dosage BD
A/E :
• ...
ALPHA2 AGONISTS
MOA:-
• Decrease aqueous humour production by alpha2
action on ciliary epithelium.
APRACLONIDINE:
• Also k...
BRIMONIDINE:-
• 30 times more selective α2 agonist than apraclonidine
• Additional neuroprotective effect
• Available as 0...
BETA BLOCKERS
• Introduced in 1979
• Considered to be 1st line therapy for all types of glaucoma
• Good efficacy
• Minimal...
TIMOLOL:
• Introduced 1978 as 1st approved beta blocker for
glaucoma
• Most widely used ocular hypotensive agent
• Due to ...
• LEVOBUNOLOL
• Available as 0.5 – 1% solution, applied BD /OD
• Metabolized to di- hydrolevobunolol
• BETAXOLOL
• Introdu...
CARBONIC ANHYDRASE INHIBITORS
2 types:-
• Systemic CA inhibitors:-
• Acetazolamide, Methazolamide
• Topical CA inhibitors:...
SYSTEMIC CARBONIC ANHYDRASE INHIBITORS
DOSAGE:-
• Acetazolamide 125mg, 250mg p.o TID or QID
• Methazolamide 25mg, 50mg p.o...
TOPICAL CARBONIC ANHYDRASE INHIBITOR
• DORZOLAMIDE:-
• 1st topical CA inhibitor launched in market
• Advantage – not absor...
PROSTAGLANDIN ANALOGUES
• Includes latanoprost, unoprostone, bimatoprost,
travoprost.
• MOA:-
• Decreases IOP by increasin...
LATANOPROST:-
• Introduced in 1996
• An ester prodrug analogue of PGF2α
• Available as 0.0005% solution, OD (evening)
• Re...
UNOPROSTONE:-
• Available as 0.15% solution, BD
• Additional neuroprotective effect – increasing
microcirculation in optic...
TRAVAPROST
• Synthetic PGF2α analogue
• Available as 0.004% solution, OD at evening
• Does not require refrigeration/ prot...
Surgical procedures
37
• Trabeculoplasty
• Iridotomy
• Iridectomy
• Filtering procedures
• Canaloplasty
• Goniotomy
• Goni...
Other treatment modalities
ALPHA LIPOIC ACID:-
• Powerful antioxidant
• Useful in glaucoma by decrease in nerve cell damag...
CANNABINOIDS
• Believed to improve uveoscleral outflow
• Not yet available for this purpose
39
Herbal products
• Boerhavia Diffusa
• Emblica Officinalis
• Terminalia Chebulia
• Commiphora Mukul
• Curcuma Longa
40
FUTURE GLAUCOMA THERAPY
• NMDA receptor antagonist:-
• Provides neuroprotection by blocking glutamate
mediated death of RG...
Erythropoetin:-
• Neuroprotective by inhibiting RGCs apoptosis
• In animal studies – intravitreal injection enhances
RGC s...
DRUG ELUTING MICRO STENTS
• Microstents were coated with a polymer-drug compound
and is implanted in the angle of iris and...
Acute angle closure glaucoma
• IOP – 40-70 mmHg
• Systemic hyperosmotic agent- IV mannitol 1mg/kg
• Actazolamide 500mg IV ...
BIBLIOGRAPHY
• Pharmacological aspects of therapeutics – Goodman and Gilman – 12th edition
• Principles of pharmacology Sh...
46
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Pharmacotherapy of glaucoma

Pharmacotherapy of glaucoma

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Pharmacotherapy of glaucoma

  1. 1. Pharmacotherapy of . Glaucoma Dr Manjuprasad Moderator: Dr Vijayalaxmi M.K
  2. 2. Overview • Introduction • Anatomy • Aqueous humour dynamics • pathophysiology • Drugs used in the treatment • Recent advances • Conclusion 2
  3. 3. Introduction • Glaucoma – ancient greek meaning clouded or blue- green hue • In Hippocratic aphorisms Glaucoma – blindness coming from advancing years • Second leading cause of blindness 3
  4. 4. • Glaucoma is not a single disease process but a group of disorders characterized by a progressive optic neuropathy resulting in a characteristic appearance of optic disc & specific pattern of irreversible visual field defects that are associated frequently but not invariably with ↑IOP 4
  5. 5. Anatomy of the eye 5
  6. 6. Aqueous humor • Derived from the plasma • 2.3µl/min Production: • Ultrafiltration • Secretion • Diffusion 6
  7. 7. Aqueous humor dynamics 7
  8. 8. Classification • Congenital glaucoma - Primary congenital glaucoma - Developmental glaucoma • Primary adult glaucoma - Primary open angle glaucoma - Primary angle closure glaucoma - Primary mixed mechanism glaucoma • Secondary glaucoma 8
  9. 9. Pathogenesis • All types of glaucoma – progressive optic neuropathy due to the death of retinal ganglion cells(RGCs) • RGCs death is initiated – block in transport of neurotrophins from brain to RGCs damaging cascade activation Apoptosis of RGCs • RGCs death – loss of retinal fibers – optic neuropathy & visual field defects 9
  10. 10. • Mechanical theory : ↑IOP – mechanical stretch of lamina cribrosa – axonal deformation & altered capillary blood flow -- ↓neurotrophins to reach RGC`s • Pressure independent factors - Failure of autoregulation - Vasospasm - Systemic hypotension - Blood / fluid loss • Excitotoxicity theory: glutamate , oxygen free radicals, nitric oxide 10
  11. 11. Congenital glaucoma • Seen in 1 in 10,000 births • Pathology- mal development of trabeculum • True congenital glaucoma • Infantile glaucoma • Juvenile glaucoma • Diagnosis – corneal diameter measurement - ophthalmoscopic evaluation of disc - gonioscopic examination 11
  12. 12. Primary open angle glaucoma • No obvious cause • Polygenic inheritence • ↑incidence in smokers • Blacks > whites • Pathology: - Age related thickening & sclerosis of trabeculae - Absence of giant vacuoles in cell lining canal of schlemm 12
  13. 13. Primary angle closure glaucoma • Increase in IOP – due to closure of angle of anterior chamber. Acute & chronic • Chronic PACG:- progress slowly with / without symptoms • Acute PACG:- -Is an emergency -Severe eye pain -Nausea, vomiting, prostration -Redness, photophobia, lacrimation -Rapid, progressive impairment of vision 13
  14. 14. Risk factors: • Hypermetropic eye • Small eye • 5th decade • Female > male • > in rainy season and dim light 14
  15. 15. Secondary glaucomas • Lens induced glaucoma • Pigmentary glaucoma • Neovascular glaucoma • Glaucoma associated with intravascular tumor • Traumatic glaucoma • Steroid induced glaucoma 15
  16. 16. 16
  17. 17. Drugs used in the treatment DRUGS THAT REDUCE AQUEOUS HUMOUR PRODUCTION I. Beta-Blockers : levobunolol, timolol, carteolol, betaxolol II. Alpha-2 Adrenergic Agonists : apraclonidine, brimonidine III. Carbonic Anhydrase Inhibitors :acetazolamide, dorzolamide 17
  18. 18. DRUGS THAT INCREASE AQUEOUS OUTFLOW I. Nonspecific Adrenergic Agonists :epinephrine, dipivefrin II. Parasympathomimetics : pilocarpine, carbachol, echothiophate III. Prostaglandin Analogues : latanoprost 18
  19. 19. Cholinergic agonists • Most commonly used – Pilocarpine • Derived from shrub – pilocarpus jaborandi MOA:- • Acts on M3 receptors – contraction of sphincter pupillae • Causes contraction of longitudinal ciliary muscle → trabecular outflow 19
  20. 20. • Onset of action – rapid peak effect – 30min lasts for 4 – 6hrs • S/E:- • LOCAL:- Superficial punctate keratitis , brow ache, induced myopia, increased risk of retinal detachment & iritis • SYSTEMIC – rare • Available as 0.5 to 10 % eye drops 20
  21. 21. • Pilocarpine gel (pilocarpine HCl 4%) HS • Membrane controlled delivery system:- -Insert placed in cul-de-sac that gradually release drug at rate of 20mcg/hr -Effective for 7 days • Pilocarpine soaked contact lens • Liposomal pilocarpine 21
  22. 22. ADRENERGIC AGONISTS Includes: • Non selective – epinephrine & dipivefrin • Selective alpha2 agonists- Apraclonidine, Brimonidine 22
  23. 23. • EPINEPHRINE:- • Directly acting sympathomimetic • MOA: • Reduced aqueous production due to alpha action • trabecular outflow via Beta receptor stimulation • Due to its CVS s/e , allergic reaction – no longer used • DIPIVEFRIN:- • Is a prodrug • Formed by di-esterification of epinephrine – lipophilicity– increased penetration to anterior chamber . 23
  24. 24. • Onset of action-30min, peak effect – 1hr • Used as an adjuvant therapy • Available as 0.1% solution , dosage BD A/E : • Less compared to epinephrine • Follicular conjunctivitis, blurring of vision, stinging 24
  25. 25. ALPHA2 AGONISTS MOA:- • Decrease aqueous humour production by alpha2 action on ciliary epithelium. APRACLONIDINE: • Also known as para amino clonidine • Available as 0.5 – 1 % , dosage BD • Short term use – Post op rise in IOP & adjuvant in POAG 25
  26. 26. BRIMONIDINE:- • 30 times more selective α2 agonist than apraclonidine • Additional neuroprotective effect • Available as 0.2 - 0.5% , applied BD • Uses:- in patients with contraindications to beta blockers, -short term use in post op raise in IOP 26
  27. 27. BETA BLOCKERS • Introduced in 1979 • Considered to be 1st line therapy for all types of glaucoma • Good efficacy • Minimal S/E MOA: • Decreases aqueous humour production by blocking beta2 receptors on ciliary epithelium. 27
  28. 28. TIMOLOL: • Introduced 1978 as 1st approved beta blocker for glaucoma • Most widely used ocular hypotensive agent • Due to its non selective beta action – cautious in COPD, asthma & heart failure • Available as 0.5 % solution & gel • S/E:- • Systemic • Local:- superficial punctate keratitis, corneal anesthesia CARTEOLOL: • Available as 1% solution 28
  29. 29. • LEVOBUNOLOL • Available as 0.5 – 1% solution, applied BD /OD • Metabolized to di- hydrolevobunolol • BETAXOLOL • Introduced in 1980s as 1st topical β1 blocker used in glaucoma • Clinical trials – lesser efficacy in reducing IOP compared to timolol • Additional neuroprotective effect. 29
  30. 30. CARBONIC ANHYDRASE INHIBITORS 2 types:- • Systemic CA inhibitors:- • Acetazolamide, Methazolamide • Topical CA inhibitors:- • Dorzolamide, Brinzolamide MOA:- • Blocks CA enzyme reversibly in ciliary body – reduces aqueous humour production 30
  31. 31. SYSTEMIC CARBONIC ANHYDRASE INHIBITORS DOSAGE:- • Acetazolamide 125mg, 250mg p.o TID or QID • Methazolamide 25mg, 50mg p.o BD or TID SIDE EFFECTS:- • High risk of systemic S/Es. • Paraesthesias, Kidney stones, aplastic anaemia, depression 31
  32. 32. TOPICAL CARBONIC ANHYDRASE INHIBITOR • DORZOLAMIDE:- • 1st topical CA inhibitor launched in market • Advantage – not absorbed systemically • Available as 2 % solution- applied TID • S/E:- systemic is minimal - local S/E includes corneal edema, allergic reaction, burning & stinging sensation • BRINZOLAMIDE • Available as 1% solution • Better tolerated than dorzolamide – its pH is 7.4 32
  33. 33. PROSTAGLANDIN ANALOGUES • Includes latanoprost, unoprostone, bimatoprost, travoprost. • MOA:- • Decreases IOP by increasing uveoscleral outflow 33
  34. 34. LATANOPROST:- • Introduced in 1996 • An ester prodrug analogue of PGF2α • Available as 0.0005% solution, OD (evening) • Requires refrigeration & protection from sunlight • S/E – conjunctival hyperemia ( initially), Iris pigmentation, cystoid macular odema 34
  35. 35. UNOPROSTONE:- • Available as 0.15% solution, BD • Additional neuroprotective effect – increasing microcirculation in optic nerve head. BIMATOPROST: • A synthetic prostamide analogue • Available as 0.03% solution , OD • Does not require refrigeration 35
  36. 36. TRAVAPROST • Synthetic PGF2α analogue • Available as 0.004% solution, OD at evening • Does not require refrigeration/ protection from sunlight 36
  37. 37. Surgical procedures 37 • Trabeculoplasty • Iridotomy • Iridectomy • Filtering procedures • Canaloplasty • Goniotomy • Goniocurettage • Cyclodialysis • Ciliarotomy
  38. 38. Other treatment modalities ALPHA LIPOIC ACID:- • Powerful antioxidant • Useful in glaucoma by decrease in nerve cell damage due to oxidative stress VITAMIN C :- • Said to increase aqueous outflow by reducing viscosity of hyaluronic acid in trabecular meshwork SALVIA MILTIORRHIZA:- • Chinese herb, given i.v said to improve microcirculation of RGCs 38
  39. 39. CANNABINOIDS • Believed to improve uveoscleral outflow • Not yet available for this purpose 39
  40. 40. Herbal products • Boerhavia Diffusa • Emblica Officinalis • Terminalia Chebulia • Commiphora Mukul • Curcuma Longa 40
  41. 41. FUTURE GLAUCOMA THERAPY • NMDA receptor antagonist:- • Provides neuroprotection by blocking glutamate mediated death of RGCs • Includes memantine & eliprodil • Riluzole:- • Is a presynaptic glutamate release inhibitor • Neuroprotective nature • Neuroprotective vaccines:- R16 41
  42. 42. Erythropoetin:- • Neuroprotective by inhibiting RGCs apoptosis • In animal studies – intravitreal injection enhances RGC survival Caspase inhibitors:- • Inhibits apoptosis of RGCs • Promising approach in terms of Rx of glaucoma iNOS inhibitors:- • Increased level of NO – neuronal damage via apoptosis 42
  43. 43. DRUG ELUTING MICRO STENTS • Microstents were coated with a polymer-drug compound and is implanted in the angle of iris and cornea • Diffusion controlled release of paclitaxel or mitomycin is used to avoid blocking of stent 43
  44. 44. Acute angle closure glaucoma • IOP – 40-70 mmHg • Systemic hyperosmotic agent- IV mannitol 1mg/kg • Actazolamide 500mg IV followed by 250mg TID • Analgesics and Antiemetics • Corticosteroids e/d like dexamethasone 3-4/day to reduce inflammation • Sx- periferal iridotomy filteration surgery 44
  45. 45. BIBLIOGRAPHY • Pharmacological aspects of therapeutics – Goodman and Gilman – 12th edition • Principles of pharmacology Sharma and sharma 2nd edition • Textbook of medical pharmacology – Dr.PadmajaUdaykumar – third edition • Essentials of medical pharmacology – K.D.Tripathi • A. K. Khurana - comprehensive ophthalmology • Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90:262–7 • Killer HE, Miller NR, Flammer J, Meyer P, Weinreb RN, Remonda L, Jaggi GP. Cerebrospinal fluid exchange in the optic nerve in normal-tension glaucoma. Br J Ophthalmol. 2012;96:544–8. • Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol. 1998;126:498–505 • . Bergeå B, Bodin L, Svedbergh B. Impact of intraocular pressure regulation on visual fields in open-angle glaucoma. Ophthalmology. 1999;106:997–1004 • Rao HL, Addepalli UK, Jonnadula GB, Kumbar T, Senthil S, Garudadri CS. Relationship between intraocular pressure and rate of visual field progression in treated glaucoma. J Glaucoma. 2012 In press. 45
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