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  1. DRUGS IN GLAUCOMA Dr. Anshu Mallik 1st Year Resident Tilganga Institute of Ophthalmology
  2. Target IOP “A pressure rather a range IOP level within which progression of glaucoma and visual field loss will be delayed or halted” 30 40 30 20 0 5 10 15 20 25 30 35 40 Mild Damage Advance Damage NTG OHT 30 40 30 20 % reduction from baseline AAO Guidelines Target IOP
  3. Target IOP is based on overall glaucomatous damage Target IOP Optic Nerve Damage Risk Factors Visual Field IOP
  4. Calculated as: Target IOP = Maximum IOP - % of maximum IOP – Z Z: optic nerve damage severity factor 0 : normal disc and normal visual field 1: abnormal disc and normal visual field 2: visual field loss not threatening fixation 3: visual field loss threatening fixation Jample et al. Target pressure in glaucoma therapy. J Glaucoma. 1997;6:133-8.
  5. Therapeutic Goal The primary treatment in glaucoma is to prevent vision loss caused by damage to optic nerve. Though elevated IOP is just one of several risk factors that have a casual relationship to production of glaucomatous field loss, our therapeutic approach is primarily limited to reduction of IOP.
  6. Ideal Pharmacotherapy Control primary risk factors- IOP Prevent release of damaging stimuli Prevent apoptosis Neuroprotection and neuroregeneration
  7. Drugs are divided into several groups based on their chemical structure and pharmacologic action. The group of agents in common clinical use includes- 1. Prostaglandin analogues 2. β adrenergic antagonists (non selective and selective) 3. α adrenergic agonists 4. Carbonic anhydrase inhibitors (oral and topical) 5. Parasympathomimetic (miotic) agents, including cholinergic and anticholinesterase agents 6. Combination medications 7. Hyperosmotic agents
  8. Prostaglandin Analogues Most recent class of drugs for long term management of glaucoma Replaced β-blockers as 1st line of therapy Converted to active compound by corneal esterase 4 PG analogues are approved for clinical use • Latanoprost 0.005% • Travoprost 0.004% • Bimatoprost 0.01%, 0.03% • Tafluprost 0.0015%
  9. PG Analogues Mechanism Of Action By increasing uveoscleral outflow facility Binds and activate FP receptors in ciliary muscle Relaxation of ciliary body muscle and dilate spaces between ciliary muscle bundles Mediated through modulation of tissue matrix metalloproteinases
  10. Latanoprost (0.005%) • Prodrug • Single drop (about 1.5µg) for once daily use at night • Onset: 2 - 4 hours • Peak effect: 10 -12 hours after instillation • Washout: 4 - 6 weeks
  11. • Reduced IOP by 25-34% by increasing uveoscleral outflow • Additive reduction of IOP of 14-28% when combined with timolol • Maximum IOP lowering effect take up to 6 weeks • Requires refrigeration for long-term storage as well as protection from sunlight
  12. Travoprost (0.004%) • Synthetic prostaglandin (F2α analogue) • Prodrug • Effects similar to latanoprost • Reduced IOP by 25-34% by increasing uveoscleral outflow • Does not require refrigeration and protection from sunlight • In clinical trials, travoprost 0.004% once daily, used as monotherapy, produced greater IOP reduction than timolol 0.5% twice daily and equal or greater reduction than latanoprost 0.005% 1Li N et al. Travoprost compared with other prostaglandin analogues or timolol in patients with open-angle glaucoma or ocular hypertension: meta- analysis of randomized controlled trials. Clin Experiment Ophthalmol. 2006;34:755–64
  13. Bimatoprost (0.01%, 0.03%) • Prostamide analogue • Administered once daily in evening • Reduced IOP by 27-33% • Causes 50% increase in uveoscleral outflow and 35% increase in trabecular outflow • A six-month trial study revealed, IOP-lowering efficacies of Bimatoprost and timolol-dorzolamide combination were similar1 • Does not require refrigeration to maintain stability 1Ozturk F et al. Comparison of the ocular hypotensive effects of bimatoprost and timolol-dorzolamide combination in patients with elevated intraocular pressure: A 6-month study. Acta Ophthalmol Scand. 2007;85:80–3
  14. Tafluprost (0.0015%) • Prostaglandin F2α analogue • Prodrug • MOA: Same as Latanoprost • Onset of action: 2-4 hours • Peak: 12 hours
  15. Side Effects Of PG Analogues Ocular • Conjunctival hyperemia • Iris hyperpigmentation • Blurred vision • Hyperpigmentation of periorbital skin (reversible)
  16. • Foreign body sensation • Exacerbation of herpes keratitis, cystoid macular edema and uveitis • Eyelash: lengthening, thickening, hyperpigmentation, hypertrichosis
  17. Systemic • Relatively uncommon • Includes: • Flu like symptoms • Cough • Occasional headache • Precipitation of migraine • Skin rash • Contraindicated in pregnancy (teratogenic)
  18. Advantage Of Prostaglandin Analogues • It is used only once daily • It has less cardiopulmonary side effects • Can be used as additive to other anti-glaucoma medications
  19. Contraindications Of Prostaglandin Analogues • Known allergy • Pregnant and nursing mother • Children • Uveitic glaucoma • Immediate post operative period • Healed or active herpes simplex keratitis
  20. β-adrenergic antagonists (β blockers) Nonselective (β1 and β2 blocker) • Timolol maleate 0.25%, 0.5% • Timolol hemihydrate 0.25%, 0.5% • Levobunolol 0.25%, 0.5% • Metipranolol 0.3% • Carteolol hydrochloride 1% Selective β1 blocker • Betaxolol 0.25%
  21. Mechanism Of Action Lowers IOP by suppressing formation of aqueous humour Binding of an agonist molecule to a beta receptor stimulates regulatory protein (G protein) to activate adenylate cyclase This enzyme catalyses conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), which act as a second messenger to trigger a cascade of biochemical events In ciliary epithelium cAMP is believed to regulate ion channels (Na+/K + pump) and the enzymes involved in secretion of aqueous humour
  22. β-blockers decrease cAMP levels and decrease IOP production by 20-50% (i.e 2.5 µl/min to 1.9 µl/min) and thus decrease IOP by 20–30% β2 antagonists have greater effect on aqueous secretion than β1 antagonists Systemic absorption occurs so IOP lowering effect seen in contralateral untreated eye Dose given in morning to blunt early morning rise in IOP
  23. Drugs Concentration Dosing IOP decrease Peak and washout Timolol 0.25%, 0.5% solution and gel (also 0.1%) 1-2 times daily 20-30% Peak: 2-3 hours Washout:1 month Levobunolol 0.25%, 0.5% solution 1-2 times daily 20-30% Peak: 2-6 hours Washout:1 month Metipranolol 0.3% 2 times daily 20-30% Peak: 2 hours Washout:1 month Carteolol hydrochloride 1.0% 1-2 times daily 20-30% Peak: 4 hours Washout:1 month Betaxolol 0.25% 2 times daily 15-20% Peak: 2-3 hours Washout:1 month
  24. Advantage of betaxolol It is cardioselective β blocker and can be used in bronchial asthma and other pulmonary problem as it cause less bronchoconstriction Advantage of levobunolol Action lasts longer Advantage of carteolol Less stinging In POAG best choice for patients having association with hyperlipidaemia or artherosclerotic damage since it has more selective action on eye than on cardiopulmonary system
  25. Side Effects Of β-blockers Ocular • Blurring of vision • Irritation, discomfort • Corneal anesthesia • Punctate keratitis • Allergy • Dry eyes
  26. Systemic • Bradycardia • Heart block • Myocardial infarction • Lowered blood pressure • Bronchospasm • Asthma • Decreased libido • CNS depression • Mood swings • Reduced exercise intolerance • Hyperthyroidism (abrupt withdrawal) • Alteration of serum lipid • Aggravation of myasthenia gravis
  27. Contraindications • Asthma • COPD • Bradycardia <55 bpm • 2nd or 3rd degree heart block • Congestive heart failure In patient with diabetes, masking of hypoglycemic sign and symptoms can occur
  28. α2 Adrenergic Agonists • Nonselective α2 agonists • Epinephrine 0.5%, 1%, 2% • Dipivefrin Hydrochloride 0.1% • Selective α2 agonists • Apraclonidine Hydrochloride 0.5%, 1% • Brimonidine Tartrate 0.1%, 0.15%, 0.2%
  29. Nonselective α2 agonists • Increase conventional trabecular and uveoscleral outflow • Dipivefrin is prodrug of epinephrine, with better corneal penetration (lipophilic) • IOP reduction with both drugs are comparable (15-25%) • Both drugs are replaced by other classes of drugs and are no longer in use
  30. Selective α2 agonists Apraclonidine hydrochloride (0.5%, 1%) • α2 agonist and clonidine derivative that prevents norepinephrine release at nerve terminal • Decreases aqueous production and episcleral venous pressure • Improves trabecular outflow • True ocular hypotensive mechanism not known
  31. • Used to diminish acute rise in IOP after • Laser iridectomy • Argon laser trabeculoplasty • Nd:YAG laser capsulotomy • Cataract extraction • IOP decreases by 20 to 30%, with peak at 1 to 2 hours, and wash out up to 7-14 days • Effective for short term lowering of IOP but there is risk of development of topical sensitivity • Tachyphylaxis limits long term use
  32. Brimonidine Tartrate (0.1%, 0.15%, 0.2%) • Reduce aqueous production as well as increase uveoscleral outflow • Dose: 2-3 times daily • Peak IOP reduction 20-30% (2 hours postdose) • At peak, comparable to non selective β blocker and superior to selective β blocker
  33. • At trough 14-15% reduction of IOP (12 hours postdose) • Washout 7-14 days • Brimonidine 0.1%, preserved with purite has been shown to be as efficacious as brimonidine 0.2% preserved with benzylalkonium chloride and have lower incidence of side effects (fatigue, depression, allergy) • It contains a lower concentration of brimonidine tartrate at a neutral pH
  34. • Brimonidine is more selective for the α2 receptor than apraclonidine • Tachyphylaxis occur less with brimonidine • Brimonidine should not be used in young children or infant because of risk of respiratory arrest, apnea, hypotension, seizures, and serious derangement of neurotransmitter in CNS due to increased CNS penetration
  35. Side Effects Of α2 Adrenergic Agonists Ocular • Allergy/Contact dermatitis • Blurred vision • Burning/stinging • Follicular conjunctivitis • Hyperemia • Itching • Photophobia • Foreign body sensation • Eyelid edema • Dryness
  36. Systemic • Dry mouth, nose • Fatigue • Sedation • Drowsiness • Headache • Hypotension • Bradycardia and hypothermia in neonates
  37. Carbonic Anhydrase Inhibitors (CAIs) • Belong to sulfonamide class of drugs • Oral • Acetazolamide (250mg, 500mg) • Methazolamide (50mg) • Dichlorphenamide (50mg) • Topical • Dorzolamide 2% • Brinzolamide 1%
  38. Oral Carbonic Anhydrase Inhibitor • Basically used for short term treatment, particularly in patients with acute glaucoma. Because of their systemic side effects, long term use is reserved for patients at high risk of visual loss. • Sulphonamide allergy is relative contraindication as they are derived from sulpha drugs. • Concentration: Acetazolamide - 250 mg, 500 mg Methazolamide - 25, 50, 100 mg • Dosing: Acetazolamide 250 mg is given 2-4 times daily, while 500 mg 2 times daily Methazolamide is 2-3 times daily
  39. • MOA- Decrease aqueous production by direct antagonist activity on ciliary epithelial carbonic anhydrase. >90% of enzyme activity must be abolished to decrease aqueous production and lower IOP. • IOP decreases by 15 to 20% • Oral drugs • Onset of action: 1 hour • Peak effect: 2 hours, 8 hours (SR) • Duration of action: 6 hours, 12 hours (SR)
  40. • Methazolamide has longer duration of action and is less protein bound than Acetazolamide so needs small dose. However, it is less effective than Acetazolamide. • Methazolamide is metabolized by liver thereby decreasing some systemic side effects whereas Acetazolamide is not metabolized and is excreted by urine.
  41. Intravenous Carbonic Anhydrase Inhibitor • Intravenous • Dose: Powder 500mg vials • Onset of action: 2 minutes • Peak effect: 15 minutes • Lasts up to 4 hours
  42. Topical Carbonic Anhydrase Inhibitor • Concentration: Dorzolamide 2% Brinzolamide 1% • Dosing: 2-3 times daily • MOA- Decrease aqueous production by direct inhibition of carbonic anhydrase in ciliary body. • IOP decreases by 15 to 20% with peak at 2-3 hours and washout at 48 hours.
  43. Side Effects Of Oral Carbonic Anhydrase Inhibitor Gastrointestinal: Diarrhea, weight loss, anorexia, abdominal cramp, poor tolerance to carbonated beverages CNS: Malaise, fatigue, depression, drowsiness, decrease libido Genitourinary: Nocturia, urolithiasis, impotence Blood dyscrasias: Thrombocytopenia, agranulocytosis, aplastic anemia, neutropenia, leg cramps
  44. Electrolyte imbalance: Metabolic acidosis, hyperkalemia, uric acid retention Paresthesia of fingers, toes Dermatologic: Rash, exfoliative dermatitis, pruritis, hirsutism
  45. Side Effects Of Topical Carbonic Anhydrase Inhibitor Ocular • Blurred vision • Burning and stinging (Dorzolamide has more stinging and transient burning because of its lower pH) • Blepharoconjunctivitis • Itching • Dry eyes • Superficial punctate keratopathy
  46. Systemic • Less likely to cause systemic effect but may cause bitter taste • Headache • Dizziness • Gastrointestinal distress • Neutropenia
  47. Contraindications Of Carbonic Anhydrase Inhibitor • Hypersensitivity to sulphonamide • Chronic respiratory acidosis • Clinically significant liver disease • Secondary glaucoma • Renal disease including kidney stone • Pregnancy • Addison’s disease, adrenal insufficiency
  48. Parasympathoimetics (Miotics) Classification 1. Cholinergic Agonist (Direct Acting) a) Pilocarpine Hydrochloride and gel 2. Anti Cholinesterase Agent (Indirect Acting) a) Echothiophate iodide (phospholine iodide) 3. Dual action parasympathomimetic a) Carbachol
  49. Mechanism Of Action • In primary open angle glaucoma • Contraction of the longitudinal ciliary muscle Pulls scleral spur, alters configuration of Trabecular Meshwork and Schlemm's canal Increase aqueous outflow
  50. • In primary angle closure glaucoma • Contraction of sphincter pupillae and the resultant miosis, pulls the peripheral iris away from the trabecular meshwork thus opening the angle
  51. • Dose: Pilocarpine Hydrochloride drops (1.0%, 2.0%, 4.0%) and gel- 4.0% Applied 2-4 times daily for drops, twice daily for combination therapy and once daily at night time for gels Echothiophate (0.125%) applied 1-2 times daily • Peak effect: 2-3 hours • Washout: 48 hours • Lower IOP by 15-25% • Additive to β blockers, adrenergic agent and carbonic anhydrase inhibitors
  52. • Delivery systems for pilocarpine • Pilocarpine Hydrochloride gel 4%: • Applied once daily at bedtime • Reported to produce significant reduction in IOP for 24 hours • Membrane-controlled delivery system (Ocusert): • Insert placed in cul-de-sac, where it gradually releases pilocarpine at the rate of 20µg/hour, roughly equivalent to 2% eye drops • Effective for seven days
  53. Carbachol • It has dual action i.e it is agonist as well as weak cholinesterase inhibitor. • Indication: Good alternative to pilocarpine in resistant or intolerant cases. • Available: 0.75% and 3% eyedrop • Dose : Action starts in 40 minutes and lasts 12 hours, so used 2-3 times daily
  54. Side Effects Of Parasympathomimetic Agents (Miotics) Ocular • Induced myopia due to ciliary muscle contraction • Brow ache accompany ciliary spasm • Posterior synechiae • Keratitis • Miosis
  55. • Cataract growth (more in indirect-acting agents) • Retinal tear, detachment • Change in retinal sensitivity • Color vision changes • In child and adult it may cause epiphora by both punctal stenosis and lacrimal stimulation
  56. • In children induced formation of iris pigment epithelial cyst • Paradoxical angle closure- contraction of ciliary muscle causes forward movement of lens-iris-diaphragm leading to pupillary block in eye with large lens • Miotics break the blood aqueous barrier so it must be avoided in uveitic glaucoma.
  57. Systemic • Increased salivation • Increased secretion, sweating, lacrimation • Weakness, muscle spasm • Bronchospasm, asthma • Diarrhea • Nausea, vomiting, abdominal pain, abdominal cramps
  58. Fixed Combinations • Medications that are combined in a single bottle • Improved convenience • Compliance • Reduced cost • Fixed combinations usually consist of timolol and another agent
  59. S.N Combination Concentration Dosing MOA IOP Decreases 1. Timolol/ Brinzolamide 0.5%/1% 2 Times Daily Reduces Aqueous Secretion 25-30% 2. Timolol/ Dorzolamide 0.5%/2% 2 Times Daily Decreases Aqueous Production 25-30% 3. Timolol/ Latanoprost 0.5%/0.005% 1 Time Daily (Night) Same As Non Selective β Blocker And Latanoprost Greater Than Monotherapy With Each Drug Individually
  60. S.N Combination Concentration Dosing MOA 4. Timolol/ Travoprost 0.5%/0.004% 1 Time Daily (Night) Same As Non Selective β Blocker And Travoprost 5. Timolol/ Bimatoprost 0.5%/0.03% 1 Time Daily (Night) Same As Non Selective β Blocker And Bimatoprost 6. Timolol/ Brimonidine Tartrate 0.5%/0.2% 2 Times Daily Same As Non Selective β Blocker And Brimonidine
  61. Hyperosmotic Agents Control acute episodes of elevated IOP Agents • Mannitol 20% (I/V) • Glycerol 50% solution (Oral) • Isosorbide 50% solution Clinical uses • Acute angle closure glaucoma • Prior to intraocular surgery when IOP is very high
  62. Mechanism Of Action Increase blood osmolality Osmotic gradient between blood and vitreous Water drained out of vitreous Decreases IOP
  63. Mannitol • Concentration: 20% • Route: Parenteral (I/V) • Dosing: 0.5 - 2 gm/kg body weight over 30-60 minutes • Peak action occurs within 30 minutes • Duration of action: 6 hours • MOA- Creates osmotic gradient; dehydrates vitreous
  64. Side Effects Of Mannitol Ocular • IOP rebounds • Increased aqueous flare
  65. Systemic • Urinary retention • Congestive heart failure • Expansion of blood volume • Diabetic complications • Nausea • Vomiting • Diarrhea • Electrolyte disturbance • Renal failure • Headache • Mental confusion • Backache • Myocardial infarction
  66. Glycerol • Concentration: 50% • Route: Oral • Dosing: 1-1.5 gm/kg body weight • Peak action occurs within 1 hour • MOA- Creates osmotic gradient; dehydrates vitreous
  67. Side Effects Of Glycerol Ocular • IOP rebounds • Increased aqueous flare Systemic • Similar to mannitol • Can cause problem in diabetic patients as glycerol is metabolized to glucose and ketone bodies, it may cause hyperglycemia and ketoacidosis.
  68. Pregnant And Lactating Mothers Majority of glaucoma medications are within pregnancy category C Brimonidine has pregnancy category B rating β-blockers are concentrated 5-fold in breast milk Brimonidine to be avoided in nursing mothers Prostaglandins increase uterine contractility and may induce premature labour
  69. Neuroprotection • Neuroprotection is a therapeutic paradigm that slows or prevent neuronal death • Maintains physiological functioning • Blocks primary cell destructive events and enhance cell survival mechanisms • The rationale for neuroprotection in neuro ophthalmology includes blocking of retinal ganglion cells apoptosis through interruption of excitotoxic factors like Glutamate, N-methyl-D-aspartate (NMDA) receptors, Nitric oxide and delivery of neurotrophins to enhance cell survival.
  70. Glutamate • It is a excitatory neurotransmitter found in brain and retina • In glaucomatous eye, increase fold of glutamate has been found in posterior vitreous. • It is most reactive to NMDA receptors • When glutamate binds to NMDA receptors it opens channel which allow influx of calcium. This calcium initiate apoptotic mechanism.
  71. Nitric Oxide • It is formed from L- arginine by NO synthetase (NOS). • There are 3 forms of NOS NOS-1: It is neuronal, a constitutive enzyme that has been detected in diminished nerve fiber bundle at prelaminar region and lamina cribrosa of glaucomatous eye NOS-2: It is an inducible enzyme produced in response to high IOP, it also has genetic associations in patient with POAG NOS-3: It is endothelial, constitutive enzyme found in pre laminar region of optic nerve which functions as vasodilators
  72. Evidence On Currently Available Topical Drugs α2 adrenergic agonist: • These receptor are located in ganglion cell layers of retina • Activation of these receptors inhibit neuronal cell death as it inhibit pro apoptotic pathway, glutamate release • They activate the phosphatidyl inositol kinase and protein kinase which are major pathway for cell survival Neuroprotection of brimonidine • It confers neuroprotection by upregulation of brain derived neurotropic receptors
  73. β blockers: • It inhibit calcium and sodium ion influx into neuron which occurs in hypoxia, ischaemia, excitotoxicity. • It reduced NMDA and glutamate affinity thereby reducing calcium ion influx in retinal ganglion cells Prostaglandins: • They exert neuroprotection effect by impending glutamate and hypoxia induced apoptosis and is postulated to act by negative cyclooxygenase 2 pathway
  74. References • Becker-Shaffer's Diagnosis and Therapy of the Glaucomas • Glaucoma: The American Academy of Ophthalmology, 2018-2019 • Fundamentals and principles of ophthalmology, 2018-2019 • Intraocular inflammation and uveitis The American Academy of Ophthalmology, 2018-2019

Editor's Notes

  1. Used in day not night. In early morning to prevent early morning pressure rise and minimizing risk of systemic hypotension during sleep, a time when b -blocker act minimal...Activity of b1 is cardiac and b2 is pulm as betaxolol is only b1 antagonist it is safe in BA and CNS disease.