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Antiglucoma medications

Medical management of Glaucoma

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Antiglucoma medications

  1. 1. Guide: Dr Shobha Pai Dr Madhurima Anti-Glaucoma Medications
  2. 2. Classification Decreasin g production • ADRENERGIC ANTAGONISTS • ADRENERGIC AGONISTS • CARBONIC ANHYDRASE INHIBITORS Increasing outflow • MIOTICS • PROSTAGLANDINS Others • HYPEROSMOTICS • NEWER DRUGS
  3. 3. PROSTAGLANDINS  Newer class of drugs  Introduced in the 1990s  Very potent in reducing IOP  Eicosanoids
  4. 4. Mechanism of action  Mixed pharmacological responses  4 types- EP, FP, IP and TP  Two mechanisms  Relaxation of ciliary muscle and increase in uveoscleral outflow  Remodelling of trabecular meshwork extracellular matrix
  5. 5. Latanoprost: o Potent prostaglandin F2α agonist o First to be approved for use o 0.005% dose OD-bed time o 25-30% reduction in IOP o Efficacy >Timolol BD >Timolol gel OD >Brimonidine
  6. 6. Latanoprost o No adverse systemic side effects o Effects continue for 24 hours unlike Timolol which does not act in the night o Increase in retinal microcirculation and pulsatile blood flow o Storage: refrigeration when not opened, once opened can be stored in room temperature for 6 weeks
  7. 7. Bimatoprost Travoprost  0.03% solution  Once daily  Chemical structure differs from other PGs  Approved in 2001  Efficacy is comparable to Latanoprost  More local side effects  0.004% solution  Twice daily dose is also effective  Available as BAK free  Duration of action can be more than 40 hours from once daily dose  Superior to Latanoprost and Timolol, in IOP control and visual field progression
  8. 8. Isopropyl Unoprostone  22-Carbon molecule  Trabecular flow  Prodrug derived from pulmonary metabolite  Efficacy comparable to Timolol given twice daily  0.12% solution BD  Reduces IOP by 11-23%
  9. 9. Drug combinations  All agents can be combined with Timolol with evening dosing  With topical Carbonic Anhydrase inhibitors  With Brimonidine  PG + Brimonidine> Timolol + Dorzolamide  With cholinergics
  10. 10. Side effects  Hyperpigmentation  Lashes-increase in length and number  Conjunctival hyperemia  Iris pigmentation  Dry eye, SPK  Reactivation of Herpes  Acute uveitis  Cystoid macular edema  Choridal effusion Contraindicated in inflammtory glaucoma
  11. 11. Adrenergic system  Adrenergic agonists have been used as ocular hypotensives since 1900, with sub conjunctival injection of epinephrine  In eye, stimulation of α1 receptors causes mydriasis, vasoconstriction, raise in IOP and eyelid retraction  Stimulation of α 2 receptors decreases aqueous formation and probably increases outflow  Associated with prostaglandin action
  12. 12. Epinephrine and Dipivefrin  Increases aqueous outflow by both conventional and uveoscleral outflow  Epinephrine has a low solubility and hence decreased efficacy  Dipivefrin is a prodrug with increased lipid solubility and increased corneal penetration.  As efficacious as betaxolol 0.5%
  13. 13. Side effects Hypertension, cardiac disease, thyrotoxicosis-C/I Tearing, hyperemia, blepharoconjunctivitis Adrenochrome deposits- cul de sac, upper tarsal conjunctiva, corneal epithelium, nasolacrimal system Macular edema- especially in aphakics
  14. 14. α2 ADRENERGIC AGONISTS  Clonidine, a potent α2 agonist was found to have IOP reducing activity  Clonidine has ability to penetrate blood brain barrier  Non selective adrenergic agonists are not approved for use  Mechanism of action: They reduce IOP by decreasing aqueous formation.
  15. 15. Apraclonidine  Derivative of clonidine without systemic side effects  Prodrug  Anterior segment vasoconstriction and thus reduces aqueous production  1% - acute rise in IOP  0.5% - long term control  Efficacy comparable to Timolol
  16. 16. Brimonidine  Potent ocular hypotensive  More selective to α 2 receptors  0.15% solution BD/TID  Neuroprotective properties  Can cause cardiovascular instability in children < 5 years  Sleepiness and lethargy- great caution in children less than 15 years  Not to be given with NSAIDs
  17. 17. Side effects Ocular Systemic  Follicular conjunctivitis  Apraclonidine has higher rates of tachyphylaxis and allergy  Hyperemia, itching and photophobia  Blurred vision  Dry mouth  Fatigue, drowsiness, headache  Hypotension  Bradycardia and hypothermia in neonates
  18. 18. Adrenergic antagonists  1967- Phillips and co workers reported IV propranolol decreased IOP  Until the advent of prostaglandins, adrenergic antagonists were among the most useful drugs  Act on β 2 receptors present on the ciliary epithelium and decrease aqueous production
  19. 19. Timolol Maleate  Non selective β antagonist  Reduces IOP without change in refractive status, pupil size  0.25%, 0.5% twice daily formulation  Action begins in 20-30 minutes and lasts till 24-48 hours  Long term drift is seen  Additive properties with pilocarpine, carbonic anhydrase inhibitors and adrenergic agonists  Timolol Hemihydrate
  20. 20. Betaxolol  Selective β1 antagonist  It is thought to decrease IOP by either acting on β receptors or through a non adrenergic pathway  0.5% used twice daily  Neuroprotective effect  Safe is asthmatics  40% patients experience burning  Microsuspension forms
  21. 21. Levobunolol: Non selective β antagonist, available in 0.5% given once daily Carteolol: Preferred for cardiac patients. 1% and 2% solution, twice daily dosage Metipranolol : Non selective β antagonist, 0.3% solution for twice daily dosage
  22. 22. Side effects Ocular Systemic  Stinging, itching, burning  Keratoconjunctivitis Sicca  Corneal anaesthesia  Systemic side effects can be caused even with low concentration  CNS symptoms, CVS symptoms  Bronchoconstriction, Increase in serum tryglycerides  Altered response to hypoglycemia  Fetal arrhythmias— contraindicated in pregnancy
  23. 23. CARBONIC ANHYDRASE INHIBITORS  Sulfonamides  Only systemic group of drugs still approved for long term use  Acetazolamide was first introduced in 1954 as an antiglaucoma drug  Methazolamide, ethoxzolamide, dichlorphenamide  Dorzolamide, brinzolamide- Topical
  24. 24. Mechanism of action  This enzyme is present in many tissues in the body-renal cortex, gastric mucosa, RBC, lung, pancreas, CNS  Type II isoenzyme is present in the ciliary epithelium, in the basolateral surface  Decreases production of bicarbonate and decreased formation of aqueous  Also, intracellular pH that is needed for ion transport is disturbed by CAIs.
  25. 25. Topical CAIs • Acts on CAI II isoenzyme in ciliary epithelium and also RBCs • 2% solution, BD • Response peaks 3 hours after dosing Dorzolamide • 1% solution for TID application • As efficacious as Dorzolamide 2% BD • Lesser ocular side effects • Effects are additive to Timolol Brinzolamide
  26. 26. Acetazolamide  Reduce the formation of aqueous by 40%  Many other mechanisms proposed: buffer system, vasoconstriction of anterior uveal tract  Penetrates cornea poorly  250mg every 6 hours given orally  125mg, 250mg and 500 mg, sustained release preparation  “Emergency ampuoles”
  27. 27. Methazolamide  It is a systemic CAI  Lesser protein bound than acetazolamide  25-50mg given twice daily  Can cause urolithiasis  Advantages over Acetazolamide:  Not actively secreted by kidney, can be given in patients with renal problems  Diffuses more easily into eye  Dosing is convenient
  28. 28. Side effects  Ocular side effects:  Irritation, myopic shift, SPK  Systemic side effects:  Paraesthesia around mouth and finger tips,  Increased frequency urination, gastric irritation  Electrolyte imbalance  Metabolic acidosis  Caution: liver disease, adrenal insufficiency, sickle cell disorder, pregnancy  Blood dyscrasias and Steven Johnson Syndrome Contraindicated in Fuchs endothelial dystrophy
  29. 29. CHOLINERGIC DRUGS  Oldest effective anti glaucoma medications  Mechanism of action  In angle closure: They constrict the pupil and pull the peripheral iris away from the trabeculum.  In open angle: They contract the ciliary body thus opening the scleral spur and opening the trabecular meshwork
  30. 30. Directly acting agents  Acetyl choline:  Prototype of this group  Not used topically  Pilocarpine:  Most widely prescribed miotic  Available in 0.25-10%, QID application  1%- light irides  2%- dark irides  Various methods are devised to decrease the number of applications
  31. 31. Soft contact lens Ocusert Pilocarpine gel Pilocarpine polymer
  32. 32. METHACHOLINE: •Used in the past •Diagnosis of Adie’s pupil •Synthetic derivative acetyl choline CARBACHOL: •More powerful miotic than pilocarpine •More side effects •Intracameral injection in post opperative patients ACECLIDINE: •Used in Europe •Less effective than piolcarpine •Less ciliary spasm and accomodation
  33. 33. Indirectly acting agents  They inhibit the enzyme acetylcholinesterase and potentiate the effect of endogenous acetylcholine  More side effects than directly acting agents 1. Echothiophate: cataract and iris epithelial cyst 2. Demecarium Bromide: Long acting 3. Isoflurophate: Not in clinical use 4. Physostigmine and Neostigmine: Short acting agents
  34. 34. Side effects Ocular:  Conjunctival injection  Periocular pain  Miosis and dim illumination  Fluctuating myopic shift  Anterior subcapsular opacity and iris epithelial cysts  Allergic blepharoconjunctivitis  Retinal hole and detachment  Vitreous abnormalities to be ruled out before starting on miotics
  35. 35.  Pupil to be dilated twice a year to  visualize the disc  visualize peripheral retina  prevent formation of posterior synichiae  2.5% phenylephrine can be used without decreasing outflow capacity  Contraindicated in intraocular inflammation and hypersensitivity  Peptic ulcer, retinal abnormalities, chronic obstructive pulmonary disease and high myopia- relative contraindications
  36. 36. Systemic side effects  Nausea, vomiting, abdominal cramping  Salivation, sweating  Bradycardia, hypotension and bronchospasm  Multiple applications should be avoided, punctal occlusion  “Choline apnoea” Cholinergic toxicitiy:  2mg Atropine s.c or i.v  Inj. Pralidoxime 25mg/kg infused over 2 hours
  37. 37. HYPEROSMOTIC AGENTS  Useful in short term management of glaucoma  Osmoreceptors present in hypothalamus send efferent to the optic nerve Increase the osmolality of plasma Draw water from eye to intravascular compartment through blood vessels of uvea and retina
  38. 38. Oral agents  Slow onset of action and less efficacious  Isosorbide: 45% solution, 1.5-4ml/kg  It is not metabolized; no effect on blood sugar levels  Absolute alcohol: 1-1.8ml/kg, 40-50% solution Glycerol: most common. 50% solution, 1- 3ml/kg Penetrates eye poorly Nausea and vomiting Ketoacidosis
  39. 39. Intravenous agents  Faster action with more efficacy  Urea:  20% solution, 2-7ml/kg  Penetrates eye better, less efficacious  Old solutions not to be used Mannitol: agent of choice as intravenous agent 2.5-7ml/kg of 20% solution Action starts in 20-30 minutes, lasting for 6 hours Cellular dehydration in CNS- dementia and disorientation Congestive heart failure
  40. 40. Side effects  Nausea, vomiting, headache and diuresis  Intense diuresis- acute retention  Pulmonary edema and congestive cardiac failure  Subdural hematoma due to shrinkage of vessels  Cellular dehydration  Extravasation of urea can lead to skin necrosis
  41. 41. Class of drug Mechanism of action Concentration % IOP reduction Important side effect Prostaglandin s •Latanoprost •Bimatoprost •Travoprost Increase uveoscleral pathway 0.005% 0.03% HS 0.004% 25-32% Hypertrichosis Increased pigmentation Hyperemia β antagonists •Timolol •Levobunolol •Betaxolol Decrease aqueous production 0.5% BD 20-30% 15-20% Bradycardia, heart block, bronchospas m Stinging Adrenergic agonists •Apraclonidine •Brimonidne Decrease aqueous production Increase outflow 0.5-1% BD, TID 20-30% Hypotension, tachyphylaxis, follicular conjunctivitis
  42. 42. Class of drug Mechanism of action Concentratio n % IOP reduction Important side effect CAIs •Acetazolamide •Dorzolamide •Brinzolamide Decrease aqueous production 250mg QID 2% BD,TID 1% BD, TID 15-20% SJS, blood dyscrasias Miotics •Pilocarpine Increase outflow 1% QID 15-25% Myopic shift, Retinal detachment Hyperosmotics •Glycerol •Mannitol Draw water from eye to intravascular compartmen t 50% solution 1.5-3ml/kg 20% solution 2,5-7ml/kg Nausea, ketoacidosis Urine retention, CCF
  43. 43. Prostaglandins β blockers αAgonists Carbonic anhydrase inhibitors Miotics Nonselective adrenergic agonists Selective β blockers
  44. 44. Drug combinations Combination Trade name Concentration % IOP reduction Timolol/Dorzolamide Cosopt 0.5%/2% BD 25-30% Timolol/ Latanoprost Xalcom 0.5%/0.005% HS Greater than monotherap y Timolol/Travoprost Duotrav 0.5%/0.004% HS Greater than monotherap y Timolol/ Bimatoprost Ganfort 0.5%/0.003% HS Greater than monotherap y Timolol/ Brimonidine Combigan 0.5%/0.2% BD Greater than
  45. 45. Newer investigational drugs Neuroprotective agents:  Anecoratve: Not in clinical use  Cannabinoids: Schedule I drug, many systemic side effects  Cellular skeletal modulators:  Ethacrynic acid- corneal edema  Latrunculin B – no corneal edema
  46. 46.  Memantine:  NMDA antagonist  Used for parkinconism  Prevents calcium influx  Completed stage III clinical trial with promising results  Other cellular signaling pathways  Olmesartan  Lomerizine  Nilvadipine
  47. 47.  Nitrous oxide:  Aminoguanidine-inhibitor of iNOS  Rat model study  NO generated by glial cells  Prostanoid agents:  Tafluprost  Not efficacious, withdrawn  Rho kinase inhibitors  Increase aqeuous outflow  In clinical trials
  48. 48. References  Becker –Shaffer’s diagnosis and therapy of the glaucomas, 8th edition  Shields Textbook of Glaucoma, 6th edition  AAO- Glaucoma, 2011-12  Kanski and Bowling- Clinical Ophthalmology

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Medical management of Glaucoma

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