PHARMACOTHERAPY OF GLAUCOMA by Dr Fatima Rani
- 1. Pharmacotherapy Of Glaucoma Drug Interaction: Ace Inhibitors And Spironolactone Dr. Fatima Rani Junior resident-2 Dept. of Pharmacology and Therapeutics KGMU, Lucknow
- 2. CONTENTS • Introduction • Aqueous humor production and drainage • Risk factors • Pathophysiology • Symptoms • Drugs used in glaucoma • Management of Primary open angle glaucoma • Management of angle closure glaucoma • Drug interaction: Ace Inhibitors And Spironolactone
- 3. GLAUCOMA • Glaucoma is characterized by progressive damage to optic nerve associated with raised intraocular pressure • Normal IOP: 12-21 mmHg • Two principal clinical forms : ‘open angle’ and ‘angle closure’ glaucoma
- 4. AQUEOUS HUMOR PRODUCTION AND DRAINAGE
- 6. RISK FACTORS • Genetic • Old age • Family history • Myopia • Co-morbidities like Diabetes mellitus, Hypertension • Lifestyle factors (smoking, alcohol, stress)
- 7. PATHOPHYSIOLOGY OPEN ANGLE GLAUCOMA • Also known as wide angle/chronic simple glaucoma • Genetically predisposition affecting patency of the trabecular meshwork • Rise in intraocular tension is either due to excessive production or due to less drainage of aqueous humor • The IOP rises insidiously and progressively
- 8. ANGLE CLOSURE GLAUCOMA • Narrow angle/acute congestive glaucoma • Occurs in individuals with a narrow iridocorneal angle and shallow anterior chamber • IOP remains normal until an attack is precipitated, usually by mydriasis • IOP rises rapidly to very high values (40–60 mmHg) • It is an emergent condition with marked congestion of eyes and severe headache • Failure to lower IOP quickly may result in loss of sight
- 9. In narrow angle glaucoma, Iris blocks the entrance to the trabecular space at the canal of Schlemm ↑ IOP – severe pain, headache, nausea and loss of vision due to optic atrophy
- 12. DRUGS USED IN GLAUCOMA β-blockers- Cardioselective: Betaxolol, levo betaxolol Non selective: Timolol, levobunolol, carteolol Miotics: Pilocarpine, Physostigmine α-agonists: Apraclonidine, Brimonidine, Dipivefrine PG analogues: Latanoprost Bimatoprost Carbonic Anhydrase inhibitors: Acetazolamide, Brinzolamide, Dorzolamide Osmotic agents: Oral- glycerol,Isosorbide Intravenous- Mannitol
- 13. Tripathi, K. D. Essentials of medical pharmacology ,8th e. Jaypee Brothers Medical; 2018
- 14. β Adrenergic blockers • Earlier used as first line drugs • MOA: Lower IOP by reducing aqueous formation----from down regulation of adenylylcyclase due to β2 receptor blockade in the ciliary epithelium and Secondary effect due to reduction in ocular blood flow
- 15. • Adverse effects: Ocular:- Stinging, redness and dryness of eye, corneal anaesthesia, allergic blepharoconjunctivitis, blurred vision Systemic:- Bronchospasm(in asthamatics & COPD), bradycardia, accentuation of heart block and CHF (to avoid these-apply mild pressure over inner canthus of eye for 5min )
- 16. TIMOLOL • Prototype drug • Nonselective (β1 + β2) • The ocular hypotensive action (20–35% fall in IOP) becomes evident within 1 hour and lasts for ~12 hours • Dose- 0.25% and 0.5% eye drops; start with 0.25% drops BD, change to 0.5% drops in case of inadequate response
- 17. BETAXOLOL • Cardio selective ß1 blocker • Less effective in reducing IOP, because ocular β receptors are predominantly of the β2 subtype • Neuroprotective action • Adverse effects: less compared to Timolol • Dose: 0.5% solution –b.d
- 18. LEVOBUNOLOL • Non selective ß blocker, with longer duration of action • Once daily alternative to timolol, Better compliance • Ocular and systemic effects are very similar to timolol • Dose- 0.5% soln., OD
- 19. α Adrenergic agonists DIPIVEFRINE • Prodrug of epinephrine • Undergoes biotransformation by the esterases to epinephrine within the cornea. • ↑lipophilicity →penetration into cornea 17 times > epinephrine • MOA: Decreases aqueous humor formation by α adrenergic effect augmenting uveoscleral outflow, Increase in trabecular outflow by stimulating ß2 receptors in trabecular meshwork.
- 20. • Dose: 0.25 to 2 % eye drops bd • Adverse effects: Ocular: Ocular irritation , conjuctival hyperemia, allergic lid reaction Systemic: hypertension, headache, palpitation
- 21. APRACLONIDINE • α2 agonist –a para amino derivative of clonidine which does not cross bloodbrain barrier • It lowers IOP by ~25%. • MOA: It decreases aqueous production by primary α2 and subsidiary α1 action in the ciliary body. • Adverse effects: Itching, lid dermatitis, follicular conjunctivitis, mydriasis, eyelid retraction, dryness of mouth and nose are common • Dose: 1 % and 0.5 % soln
- 22. BRIMONIDINE • Clonidine congener- more α2 selective and more lipophilic than apraclonidine • It lowers IOP by 20–27% • MOA: by reducing aqueous production and by increasing uveoscleral flow • Adverse effects: Allergic conjunctivitis and other ocular side effects are similar to but less frequent than with apraclonidine • Dose: 0.1%, 0.15%, 0.2% soln, TDS
- 23. PROSTAGLANDIN ANALOGUES Latanoprost • Highly lipophilic, PGF2α analogue • Undergoes enzymatic hydrolysis in cornea and gets activated to the acid latanoprost • MOA: increase the permeability of extracellular matrix--↑ uveoscleral outflow mainly (minor action on trabecular outflow) • Dose- 0.005 % eye drops, at bed time
- 24. • Adverse effects of Latanoprost mild conjunctival hyperemia, cystoid macular oedema, Punctate corneal erosions, Brownish pigmentation of iris, lengthening and thickening of eye lashes • Other PG analogues Unoprostone- 0.12% eye drops twice daily Bimatoprost-0.03% eye drops once daily Travoprost- 0.004% eye drops once daily
- 25. CARBONIC ANHYDRASE INHIBITORS • Oral – acetazolamide ,methazolamide • Topical – dorzolamide,brinzolamide • MOA- Carbonic anhydrase inhibitors block enzyme carbonic anhydrase in the ciliary body and ↓ aqueous humor production Inhibition of Carbonic anhydrase in ciliary epithelium Slows down bicarbonate production Reduction in sodium and fluid transport Reduction in aqueous humor production Decrease in IOP
- 26. Acetazolamide • Action lasts for 8-12hrs • Oral dose: 125 – 250 mg 4 times daily • Adverse effects: gastrointestinal upset, paraesthesia, peripheral neuropathy, anorexia, hypokalemia, metabolic acidosis, hypersensitivity reactions
- 27. Dorzolamide • Topical carbonic anhydrase inhibitor • It lowers IOP by ~20% • Dorzolamide is used only as add on drug to topical β blockers/PG analogues, or when these drugs are contraindicated • 2% eye drops BD-TDS • Adverse effects: Burning, stinging of eye, blurred vision, corneal edema
- 28. MIOTICS Directly acting cholinomimetics:- Pilocarpine Reversible Anticholinesterases:- Physostigmine Irreversible Anticholinesterases:- Ecothiophate
- 29. Pilocarpine • MOA: M3 receptors present on iris and ciliary muscle causes miosis and contraction of ciliary muscle--- opening of trabecular meshwork--- increased trabecular outflow • 0.5% to 4% eye drops, tid • Adverse effects: Ocular effects: Change in pupil size (Induced myopia), diminution of vision, Persistent spasm of iris and ciliary muscles (Headache) Systemic effects: excessive sweating, salivation, bronchospasm, bradycardia, vasodilatation
- 30. OSMOTIC AGENTS • MOA: ↑ osmotic pressure of plasma with respect to ocular structures→ fluid moves out from eye to hyper osmotic plasma of ocular blood vessels→ reduced vitreous volume • Useful for short term emergencies like acute angle closure glaucoma, preoperative control of ↑ IOP
- 31. Drugs used as osmotic agents: • Oral- glycerol,Isosorbide (dose 1-2 g /kg body wt of 10% solution) • Intravenous- Mannitol (1-2g / kg body wt of 20% solution),Urea (1-2 g / kg body wt of 30% solution) Adverse effects: • Headache, nausea, vertigo, mental confusion • Rarely, cardiovascular overload, intracranial haemorrhage, pulmonary oedema, acidemia
- 32. MANAGEMENT OF PRIMARY OPEN ANGLE GLAUCOMA
- 33. • Current medical therapy for POAG is limited toward lowering intraocular pressure • Medications- mainstay of treatment • Laser trabeculoplasty- Indicated in cases of noncompliance with medications or If the patient is on maximum tolerated medical therapy and needs further intraocular pressure reduction • Surgery- Trabeculectomy/Minimal invasive glaucoma surgery Indicated when medical therapy fails to lower IOP
- 34. Sihota, Ramanjit & Angmo, Dewang & Ramaswamy, Deepa & Dada, Tanuj. (2018). Simplifying “target” intraocular pressure for different stages of primary open-angle glaucoma and primary angle-closure glaucoma. Indian Journal of Ophthalmology. 66. 495. 10.4103/ijo.IJO_1130_17.
- 35. MANAGEMENT OF ACUTE ANGLE GLAUCOMA
- 36. • Hypertonic mannitol (20%) 1.5–2 g/kg or glycerol (10%): infused i.v. decongest the eye by osmotic action A retention enema of 50% glycerine is also some times used • Acetazolamide: 0.5 g i.v. followed by oral twice daily is started concurrently
- 37. • Miotics: Once the IOP starts falling due to the above i.v. therapy, pilocarpine 1–4% is instilled every 10 min initially and then at longer intervals MOA: Contraction of sphincter pupillae changes the direction of forces in the iris to lessen its contact with the lens and spreads the iris mass centrally → pupillary block is removed and iridocorneal angle is freed
- 38. • Topical β blocker: Timolol 0.5% is instilled 12 hourly • Apraclonidine (1%)/latanoprost 0.005% instillation may be added • Drugs are used only to terminate the attack of angle closure glaucoma • Definitive treatment is surgical or laser iridotomy
- 39. DRUG INTERACTION: ACE INHIBITORS AND SPIRONOLACTONE
- 40. Mechanism of Interaction 1. ACE Inhibitors: These drugs inhibit the enzyme angiotensin-converting enzyme, which results in decreased production of angiotensin II. This leads to vasodilation, reduced blood pressure, and decreased aldosterone secretion. Reduced aldosterone levels can result in increased potassium retention 2. Spironolactone: This is a potassium-sparing diuretic that works as an aldosterone antagonist. It prevents aldosterone from binding to its receptors in the kidneys, leading to increased sodium excretion and potassium retention
- 42. Potential Risks • Hyperkalemia: Since both ACE inhibitors and spironolactone promote potassium retention, their combined use can significantly increase the risk of hyperkalemia. High potassium levels can cause muscle weakness, fatigue, arrhythmias, and potentially life-threatening cardiac issues • Renal Dysfunction: Both medications can affect kidney function. In combination, they may increase the risk of renal impairment, especially in patients with pre- existing kidney conditions
- 43. Monitoring and Management • Potassium Levels: Regular monitoring of serum potassium levels is crucial • Renal Function: KFT should be monitored regularly • Dosage Adjustments: Lower starting doses and gradual dose adjustments can help mitigate the risk of adverse effects • Patient Education: Patients should be educated about the signs and symptoms of hyperkalemia (such as muscle weakness, palpitations, and fatigue) and advised to seek medical attention if they experience these symptoms
- 44. REFERENCES: • Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J. eds. Harrison's Principles of Internal Medicine, 21e. McGraw-Hill Education; 2022. • Tripathi, K. D. Essentials of medical pharmacology ,8th e. Jaypee Brothers Medical; 2018. • Brunton LL, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 14th Edition. McGraw-Hill Education; 2023.
- 45. Thank You