Pharmacotherapy of glaucoma

Pharmacotherapy of glaucoma

1. Presenter- Dr Sneha Dange JR1 Dept of pharmacology GMC Nagpur Pharmacotherapy of glaucoma 7/17/2021 Pharmacotherapy of glaucoma

2. Outline Introduction Anatomy Aqueous humor pathway Goals of therapy Pharmacotherapy Recent advances Conclusion 7/17/2021 Pharmacotherapy of glaucoma

3. Introduction Glaucoma is a group of disease characterised by- -increase in intraocular pressure leading to slow progressive degeneration of retinal ganglionic cells ,optic nerve axons and visual field defect, if untreated leads to irreversible blindness. 7/17/2021 Pharmacotherapy of glaucoma Normal IOP 10-21 mmHg

4. Glaucoma is 2 nd leading cause of blindness Prevalence increases with the age Predisposing or Risk factors – Increase intraocular pressure(IOP) Age Heredity Refractive errors Diabetics High blood pressure Thyrotoxicosis Cigarette smoking 7/17/2021 Pharmacotherapy of glaucoma Introduction contd..

5. Anatomy of anterior segment of eye 7/17/2021 Pharmacotherapy of glaucoma

6. Aqueous production and drainage 7/17/2021 Pharmacotherapy of glaucoma Secretion of aqueous humour ciliary body (posterior chamber) Route of drainage primary (90%) : trabecular meshwork uveo-scleral outflow(10%) Production Ultrafiltration Secretion Diffusion

7. Aqueous humour pathway 7/17/2021 Pharmacotherapy of glaucoma

8. Types of glaucoma Primary glaucomas Primary Open angle glaucoma (POAG) Primary angle closer glaucoma (PACG) Seconadary glaucomas caused by substances mechanically blocking anterior chamber angle(pigmentary or pseudoexfoliation ) or due to alteration in trabecular meshwork due to trauma, inflammation or ischaemia Congenital and developmental glaucomas Resulted due to developmental abnormalities of angle of anterior Chamber obstructing drainage 7/17/2021 Pharmacotherapy of glaucoma

9. 7/17/2021 Pharmacotherapy of glaucoma POAG/ wide angle/chronic simple glaucoma

10. 7/17/2021 Pharmacotherapy of glaucoma PACG/ narrow angle/acute congestive glaucoma

11. Chief therapeutic measure is to lower IOP to the target level either by 7/17/2021 Pharmacotherapy of glaucoma Reducing aqueous production in the ciliary body Promoting aqueous humour outflow through the trabecular meshwork Promoting aqueous humour outflow via the uveoscleral pathway Ciliary epithelium B2, a2 Ciliary vessels a1

12. Mode of action of anti-glaucoma drugs 7/17/2021 Pharmacotherapy of glaucoma Drugs reducing aqueous humour formation Drugs increasing outflow of aqueous humour β - Blockers Prostaglandins analogues α -Agonists Cholinergic agonists Carbonic anhydrase inhibitors

13. Topical drugs 7/17/2021 Pharmacotherapy of glaucoma Carbonic Anhydrase Inhibitors - e.g., dorzolamide,brinzolamide Classification of anti-glaucoma drugs Beta blockers – e.g., timolol,betaxolol,levobunolol,carteolo,metipranolol Adrenergic agonist – e.g., adrenaline,dipivefrin,apraclonidine,brimonidine Prostaglandin analogue – e.g., latanoprost,travoprost,bimatoprost Cholinergic agonist – e.g., pilocarpine,physostigmine,echothiophate,carbachol

14. 7/17/2021 Pharmacotherapy of glaucoma Systemic drugs Carbonic anhydrase inhibitor – e.g., acetazolamide Osmotic diuretics – e.g., mannitol,glycerol

15. β – Adrenergic blockers 7/17/2021 Pharmacotherapy of glaucoma Non selective β 1 and β 2 Selective β 1

16. 7/17/2021 Pharmacotherapy of glaucoma secondary effect due to reduction in ocular blood flow β - Blocker contd …. Mechanism of action

17. Side effects 7/17/2021 Pharmacotherapy of glaucoma Systemic Local Bronchospasm in asthmatics and COPD Bradycardia Accentuation of heart block CHF Diabetics Stinging Redness Dryness of eyes Corneal hypoesthesia Allergic Blepharo -conjunctivitis Blurred vision β - Blocker contd ….

18. Nonselective Causes decrease in IOT 20-35 % action evident within 1 hr and last for 12 hrs Chronic dosing, action persist for 1-2 weeks so high level of safety 7/17/2021 Pharmacotherapy of glaucoma Concentration- 0.25-0.5% eye drops BD Gelforming eyedrops OD Timolol β - Blocker contd …. “Timolol is considered as the gold Standard drug for glaucoma therapy against which all new medications must be compared prior to approval”

19. Selective β₁ selective blocker Less effective as β ₂ recetors are mainly involved in aqueous production Onset in 30 mins and max observed in 2 hrs Can be used in asthmatic patients but latanoprost is DOC in asthamtics Has additional neuroprotective role 7/17/2021 Pharmacotherapy of glaucoma Concentration- 0.25- 0.5% BD Betaxolol β - Blocker contd ….

20. 7/17/2021 Pharmacotherapy of glaucoma Levobunolol Non-selective Available as 0.5 – 1% solution apllied OD Longer acting, action seen in 1hr and max effect 2-6hrs Carteolol – Available in 1% BD Reduce IOP 22-25% Is as effective as timolol and better tolerated Metipranolol – available in 0.3% β - Blocker contd ….

21. α - Adrenergic agonist 7/17/2021 Pharmacotherapy of glaucoma Nonselective agonist Selective α 2 agonist

22. 7/17/2021 Pharmacotherapy of glaucoma α - Agonist contd.. Facilitate the trabecular outflow via uveoscleral veins ↓ formation of aqueous humour by stimulating α receptors present on ciliary epithelium. Nonselective Selective alpha 2 agonists α - agonists Ciliary epithelium B2, a2 Ciliary vessels a1

23. Dipivefrin Prodrug converted to adrenaline by corneal esteras Penetrates cornea 17 times more than epinephrine so lesser doses required Onset within 30mints effect seen after 1 hr reduce IOP 20-24% S/E – burning ,stinging ,follicular conjunctivitis ,blurred vision, allergy, headache,cystoid macular edema in aphakic eye Epinephrine Directly acting sympathomimetic Due to its CVS side effects , allergic reaction – no longer used 7/17/2021 Pharmacotherapy of glaucoma α - Agonist contd.. Conc.- 0.1%

24. Apraclonidine Also known as para amino clonidine Selective α₂ agonist It is highly polar doesn’t cross BBB Lowers IOT by 25% Not used as long term therapy due S/E itching,lid retraction, follicular conjunctivitis, dryness of mouth Short term control of IOP after glaucoma surgery and adjunctive in POAG 7/17/2021 Pharmacotherapy of glaucoma Concentration- 0.5%- 1% topically BD α - Agonist contd..

25. Brimonidine - Clonidine congener 30times more α2 selective Lipophilic and easily penetrates cornea , doesnt cross BBB Lowers IOT by 20-27% Neuroprotective effect First line therapy for pts contraindicated for β-blocker Control post surgery IOP and as adjuvant with other drugs S/E – anterior uveitis 7/17/2021 Pharmacotherapy of glaucoma Concentration- 0.15%- 0.2% topically BD α - Agonist contd..

26. Prostaglandin analogues 7/17/2021 Pharmacotherapy of glaucoma MOA – Lower IOP by ↑ uveoscleral outflow Low concentration PGF2a-  IOP without ocular inflammation Good efficacy, once daily application, absence of systemic complications- 1 st choice drug POAG Disadvantage- high cost

27. 7/17/2021 Pharmacotherapy of glaucoma Latanoprost Prodrug Reduce IOP upto 50% Efficacy similar to timolol and effect is well sustained for long time, effective during evening and day time too Greater ocular tolerability, no systemic side effects S/E – Blurring of vision,increased iris pigmentation,thickening darkening of eyelashes Macular edema in aphakic patients Prostaglandin analogues contd.. Concentration-0.005% OD

28. Bimatoprost Synthetic prostamide analogue More effective and similar side effects like latanoprost Doesn’t require refrigeration 7/17/2021 Pharmacotherapy of glaucoma c Prostaglandin analogues contd.. Concentration- 0.03% OD in evening Travoprost Synthetic PGF2α analogue Increase uveoscleral outflow Lower IOP by 7-8mmHg Effect start in 2hrs, peak- 12hrs, lasts- 24hrs Doesn’t require refrigeration Concentration- 0.004% OD in evening

29. 7/17/2021 Pharmacotherapy of glaucoma Concentration– 0.12% BD Unoprostone – Lower IOP by increasing outflow facility Lower IOP equivalent to betaxolol when used as monotherapy Neuroprotective- It increases blood flow to retinal head Less side effects compared to other PG analogues

30. Cholinergic A gonists Directly acting cholinomimetics – acts directly on parasympathetic receptors in eye E.g., Pilocarpine Indirect acting, inhibit acetylcholinesterase enzyme reversible anti AchE - Physostigmine, Demecarium irreversible anti AchE - Ecothiophate , Isoflurophate 7/17/2021 Pharmacotherapy of glaucoma

31. Most commonly used – Pilocarpine Derived from shrub – pilocarpus jaborandi 7/17/2021 Pharmacotherapy of glaucoma Onset of action – rapid effect 30mints lasts for 4- 6hrs Side effects – Superficial punctate keratitis brow ache, induced myopia, accomodation increased risk of retinal detachment & iritis Concentration – 0.5-10% eye drops QID Cholinergic agonists contd..

32. Delivery system for pilocarpine Pilocarpine gel (pilocarpine HCl 4%) used at night produces effect for 24 hrs 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 7/17/2021 Pharmacotherapy of glaucoma Cholinergic agonist contd..

33. 7/17/2021 Pharmacotherapy of glaucoma MOA - Acts on M3 receptor contraction of sphincter pupillae which opens angle Causes contraction of longitudinal ciliary muscle increase trabecular outflow Cholinergic agonist contd..

34. 7/17/2021 Pharmacotherapy of glaucoma In open angle glaucoma Cholinergic stimulators - mechanism of action Cholinergic agonist contd..

35. 7/17/2021 Pharmacotherapy of glaucoma In angle closure glaucoma Cholinergic stimulators - mechanism of action Cholinergic agonist contd..

36. 7/17/2021 Pharmacotherapy of glaucoma Advantages of β- blockers over cholinergic drugs No change- pupil size No diminution of vision in dim light & in cataract patients No induced Myopia- troublesome young patients No headache/brow pain- persistant spasm: iris, ciliary muscle No fluctuation of IOP Convenience – once/ twice daily application sufficient

37. Carbonic Anhydrase (CA) Inhibitors 7/17/2021 Pharmacotherapy of glaucoma MOA – Inhibit carbonic anhydrase enzyme present in ciliary epithelium reduce formation of bicarbonate ion that reduce formation of aqueous by reducing fluid transport

38. Systemic CA inhibitors DOSAGE:- Acetazolamide 125mg, 250mg p.o TID or QID Methazolamide 25mg, 50mg p.o BD or TID Used as short term indications like angle closer glaucoma before and after surgery SIDE EFFECTS - Paresthesias of finger tips and toes,fatigue,acidosis , hypokalaemia , depression Kidney stones, aplastic anaemia 7/17/2021 Pharmacotherapy of glaucoma CA inhibitors contd..

39. Topical CA inhibitor Dorzolamide lowers IOT by 20% Less efficacious than timolol Systemic S/E are less than with oral drugs, local S/E includes corneal edema, allergic reaction, burning & stinging sensation Used as add on drug with b-blockers/PG analogues Brinzolamide Better tolerated than dorzolamide 7/17/2021 Pharmacotherapy of glaucoma Concentration-2% BD-TDS Concentration- 1%

40. Hyper osmotic agents 7/17/2021 Pharmacotherapy of glaucoma IV Preparation Mannitol 2 % s o lution 1 - 2 g m/kg over 20 min Onset:15-30min Peak:30-60min Last : 6hrs MOA – Reduce IOP by inducing intraocular dehydration by osmotic action Mainly used to terminate acute attack of PACG

41. 7/17/2021 Pharmacotherapy of glaucoma Oral Preparation Glycerol 50% solution ,1gm/kg or 1.5-3 ml/kg Onset: 20min Peak:45mins -2 hrs Duration:4-5hrs Isosorbide 45% solution 1.5-4 ml/kg Hyperosmotic agents contd..

42. Treatment of open angle glaucoma 7/17/2021 Pharmacotherapy of glaucoma

43. Acute congestive glaucoma 7/17/2021 Pharmacotherapy of glaucoma Narrow angle, Shallow chamber Attack precipitate- mydriasis IOP rises rapidly (to 40-60 mmHg) Marked congestion, severe headache May result- loss of sight

44. 7/17/2021 Pharmacotherapy of glaucoma Treatment for closed angle glaucoma

45. Surgical procedures Trabeculoplasty Iridotomy Iridectomy Canaloplasty Goniotomy Goniocurettage Ciliarotomy 7/17/2021 Pharmacotherapy of glaucoma

46. 7/17/2021 Pharmacotherapy of glaucoma Antioxidants – Free radical scavengers like catalase and vitamins C and E useful for mopping up of by-products generated during secondary degeneration. Alpha lipoic acid reduces nerve cell damage from oxidative stress Vitamin C increases aqueous humour drainage, through reducing the viscosity of hyaluronic acid in the trabecular meshwork. Other treatment modalities

47. 7/17/2021 Pharmacotherapy of glaucoma Other treatment modalities contd.. Forskolin – derivative of plant Coleus forskohlii , acts on adenylate cyclase and ↑ cAMP. Ginkgo Biloba extract – Increased ocular blood flow Antioxidant activity Nitric oxide inhibition Neuroprotective activity Inhibition of apoptosis

48. 7/17/2021 Pharmacotherapy of glaucoma Chinese medicine – Pueraria flavonoids Areca seed extract eye drops works better than pilocarpine Salvia miltiorrhiza - Inj I.V. helps to improve microcirculation of RGCs. Other treatment modalities contd..

49. Mechanism of action of retinal ganglionic cell death 7/17/2021 Pharmacotherapy of glaucoma

50. Future glaucoma therapy NMDA receptor antagonist – Provides neuroprotection by blocking increase in glutamate which causes cell death by increasing entry into cell Eliprodil – Non-competitive NMDA antagonist Riluzole - Is a presynaptic glutamate release inhibitor Neuroprotective nature   7/17/2021 Pharmacotherapy of glaucoma

51. Neuroprotective vaccines- It provides T-cell induced neuroprotection to retinal ganglionic cells (RGC) eg. , R16 STAT-3 activation – Plays important role in cell growth and differentiation Ciliary neurotropic factor (CNTF) reduce apoptosis IL-10 7/17/2021 Pharmacotherapy of glaucoma Future glaucoma therapy contd..

52. Caspase inhibitors - Inhibits apoptosis of RGCs Promising approach in terms of treatment of glaucoma Nitric oxide synthase (NOS2) inhibitors - Increased level of NO – neuronal damage via apoptosis 7/17/2021 Pharmacotherapy of glaucoma Future glaucoma therapy contd..

53. 7/17/2021 Pharmacotherapy of glaucoma Endothelin receptor antagonist – Bosentan blocks the blood pressure protein endothelin 2 and protects mice from developing visible damage to retina due to glaucoma. Future glaucoma therapy contd..

54. Conclusion 7/17/2021 Pharmacotherapy of glaucoma Current treatment of glaucoma is to decrease major risk factor (IOP) by drugs acting on aqueous humour production or by increasing aqueous outflow. With recognition that Glaucoma is a neurodegerative disease, existing treatment options for glaucoma that are targeting IOP are complemented by the neuroprotective agents thereby preventing blindness.

55. References 7/17/2021 Pharmacotherapy of glaucoma The pharmacological basis of therapeutics – Goodman and Gilman – 13th edition Basic and clinical Pharmacology (Bertram G. Katzung & Anthony J. Trevor) 14 th edition Principles of Pharmacology (HL Sharma & KK Sharma) 3 nd edition A Complete Textbook of Medical Pharmacology (S K Shrivastav ) volume II Comprehensive Ophthalmology by A.K. Khurana