Download to read offline
![Target IOP calculation
The Collaborative Initial Glaucoma Treatment Study equation:
Target IOP = 1 – ( [Reference IOP + VF score]/100 x reference IOP)
Alternative formula
Target IOP = Initial IOP([100 – Initial IOP]/100) – D
D - a constant based on the level of glaucomatous damage
D = –6 for no evidence of damage, 0 for mild damage, 3
for moderate damage, and 6 for severe damage
11
12/16/2023
Dr Moti](https://image.slidesharecdn.com/anti-glaucomamedications-231216192055-c9ff1a56/75/ANTI-GLAUCOMA-MEDICATIONS-pptx-Moti-pptx-11-2048.jpg)
![…
Initial IOP
(mmHg)
Level of damage & target IOP
None Mild Moderate Severe
15 18 12-13 9-10 6-7
20 22 16 13 10
25 24-25 18-19 15-16 12-13
30 27 21 18 15
40 30 24 21 18
12
TABLE . Target IOP (mmHg) Based on target IOP = initial IOP[(100 - initial IOP)/100] -D, where D = -6 for no
damage, 0 for mild damage, +3 for moderate damage, and +6 for severe damage, from Duane’s Clinical
Ophthalmology 2013 edition page 5613
12/16/2023
Dr Moti](https://image.slidesharecdn.com/anti-glaucomamedications-231216192055-c9ff1a56/75/ANTI-GLAUCOMA-MEDICATIONS-pptx-Moti-pptx-12-2048.jpg)
More Related Content
Similar to ANTI-GLAUCOMA MEDICATIONS.pptx Moti.pptx
More from fajrimohammed
ANTI-GLAUCOMA MEDICATIONS.pptx Moti.pptx
- 1.
- 2. OUTLINE Introduction Aqueoushumor dynamics Medical management of glaucoma Ocular hypotensive agents Summary References 2 12/16/2023 Dr Moti
- 3. INTRODUCTION IOP remainsthe only risk factor readily amenable to therapy. The goal of glaucoma treatment is to improve quality of life through the preservation of visual function. 3 12/16/2023 Dr Moti
- 4. Aqueous humor dynamics Aqueous humor is actively secreted by the ciliary epithelial bilayer. The net fluid secreted is an osmotic consequence of Na+- K+ ATP- ase driven Na+ movement and HCO3ˉ generation. HCO3ˉ is formed from CO2 & H2O by carbonic anhydrase enzyme. Amino acids and ascorbate are actively transported into the posterior chamber. 4 12/16/2023 Dr Moti
- 5. … The rateof aqueous humor formation averages 2.5 to 2.8 μL/min Fin = Ftrab + Fu F in- inflow of aqueous into the posterior chamber, F trab- conventional outflow, and Fu- uveoscleral outflow Ftrab = (IOP-Pv)/R Fin = (IOP-Pv)/R + Fu, R=1/C IOP = (Fin- Fu)/C + Pv 5 12/16/2023 Dr Moti
- 6. Medical Management ofGlaucoma Goal: Preserve visual function by lowering IOP to a level likely to prevent further optic nerve damage. Achieve this goal with the lowest risk, fewest adverse effects, the least amount of disruption to the patient’s life, & least cost. 6 12/16/2023 Dr Moti
- 7. Target IOP Therange of pressure deemed unlikely to cause further optic nerve damage in an individual with glaucoma An estimate & a means toward a goal of protecting the optic nerve. May vary among individuals and with the course of disease in an individual. Some patients may have a pressure-independent component of damage. 7 12/16/2023 Dr Moti
- 8. … Target IOP dependson: IOP level at which damage is thought to have occurred; Severity of the damage The previously observed rate of progression (if known) Life expectancy of the patient; and Presence of risk factors, e.g. history of disc hemorrhages, high myopia, thinner cornea, & family history of severe vision loss in the setting of glaucoma 8 12/16/2023 Dr Moti
- 9. Clinical trials andrisk factors The Early Manifest Glaucoma Trial (EMGT): After 6 years, The risk of progression was halved by treatment that reduced IOP by an average of 25% (approximately 5 mm Hg). The risk of progression increased by 10% for each mmHg of higher baseline IOP. Ocular Hypertension Treatment Study (OHTS) Average of 22.5% ↓in IOP ↓ development of POAG from 9.5% in controls to 4.4% in treated patients at 60 months' follow-up. 9 12/16/2023 Dr Moti
- 10. … The Collaborative NormalTension Glaucoma Study (CNTGS) Reducing IOP by >30% ↓ rate of VF progression from 35% to 12%. The Advanced Glaucoma Intervention Study (AGIS) Eyes with 100% of visits with IOP <18 mm Hg over 6 years had mean changes from baseline in VF defect score close to zero. Increasing age & greater IOP fluctuation were associated with increased progression of VF defect. 10 12/16/2023 Dr Moti
- 11. Target IOP calculation The Collaborative Initial Glaucoma Treatment Study equation: Target IOP = 1 – ( [Reference IOP + VF score]/100 x reference IOP) Alternative formula Target IOP = Initial IOP([100 – Initial IOP]/100) – D D - a constant based on the level of glaucomatous damage D = –6 for no evidence of damage, 0 for mild damage, 3 for moderate damage, and 6 for severe damage 11 12/16/2023 Dr Moti
- 12. … Initial IOP (mmHg) Level ofdamage & target IOP None Mild Moderate Severe 15 18 12-13 9-10 6-7 20 22 16 13 10 25 24-25 18-19 15-16 12-13 30 27 21 18 15 40 30 24 21 18 12 TABLE . Target IOP (mmHg) Based on target IOP = initial IOP[(100 - initial IOP)/100] -D, where D = -6 for no damage, 0 for mild damage, +3 for moderate damage, and +6 for severe damage, from Duane’s Clinical Ophthalmology 2013 edition page 5613 12/16/2023 Dr Moti
- 13. Compliance Patients usuallycomply with morning doses better than evening doses. In general, patients are less compliant than they claim. Factors associated with poor compliance include: - Frequent dosage, easily recognized side effects by patients - Multidrug regimens that require waiting a specified time between drops - Frequently missing appointments or poor understanding of the disease, elderly patients 13 12/16/2023 Dr Moti
- 14. To improve compliance: Limit dosing frequency if possible Advise use of medications that limit side effects Avoid confusing regimens. Use medication instruction sheet with dosing times clearly displayed. Consider combination therapy. Avoid drug interactions that can aggravate side effects. Educate patients about and engage them in their disease. 14 12/16/2023 Dr Moti
- 15. Drug delivery Topicaltherapy does not eliminate systemic absorption The capacity of the human conjunctival cul-de-sac is about 10 μL. The shape a tip of the bottle to deliver 10 μL presents a significant hazard to the cornea. A “safe” tip design delivers 25 to 50 μl. Of the 20% to 40% of the medication initially present in the cul-de-sac, about 15% per minute exits the tear film. Medication absorbed by way of the nasal mucosa is not subjected to first-pass hepatic metabolism. 15 12/16/2023 Dr Moti
- 16. … To maximize ocularpenetration and minimize systemic absorption: Nasolacrimal occlusion or eyelid closure for several minutes after instillation. Time gap between drops. Increasing drop viscosity. Use of prodrugs that enhance ocular penetration. 16 12/16/2023 Dr Moti
- 17. OCULAR HYPOTENSIVE DRUGS Prostaglandin analogues Adrenergic drugs (β- antagonists and adrenergic agonists) Carbonic anhydrase inhibitors Parasympathomimetic (miotic) agents, (direct-acting and indirect-acting) Combination medications Hyperosmotic agents 17 12/16/2023 Dr Moti
- 18. 1.Prostaglandin Analogues Mechanism ofAction Prodrugs that penetrate the cornea and become biologically active after being hydrolyzed by corneal esterase. Increase outflow via uveoscleral pathway and, decrease outflow resistance to a variable extent. The precise mechanism has not been fully determined. 18 12/16/2023 Dr Moti
- 19. … Bind toPGF 2α , triggering a cascade of events >> activation of matrix metalloproteinases >> remodeling of CB, TM and possibly scleral extracellular matrix >> ↑ uveoscleral outflow Available Agents Latanoprost Travoprost Bimatoprost, and Tafluprost latanoprostene bunod 19 12/16/2023 Dr Moti
- 20. … Latanoprost andTravoprost reduce IOP by 25%–32%. Bimatoprost lowers IOP by 27%–33%. Latanoprostene bunod has been found to be slightly more effective than Latanoprost Used once daily, usually at night. Some patients may respond better to one agent in this class than to another. 20 12/16/2023 Dr Moti
- 21. … 21 AAO, BCSC Section10, Glaucoma, 2019-2020, page 201 12/16/2023 Dr Moti
- 22. … Adverse Effects Local Increasedpigmentation of iris & periorbital skin Conjunctival hyperemia, hypertrichosis , trichiasis, and distichiasis The development or exacerbation of preexisting cystoid macular edema (CME) Reactivation of herpetic keratitis can occur. Nongranulomatous anterior uveitis Prostaglandin-associated periorbitopathy 22 12/16/2023 Dr Moti
- 23. … Systemic Rare Upperrespiratory tract infection/cold/flu Chest pain/angina, muscle/joint/back pain, Rash/allergic skin reaction. 23 12/16/2023 Dr Moti
- 24. 2. Adrenergic Drugs A.β- antagonists Decrease aqueous humor formation by inhibiting cAMP production. Reduce aqueous formation by 20-50% with a corresponding IOP reduction of 20%–30%. Ineffective during sleep presumably because of reduced humoral or neural adrenergic tone IOP-lowering effect in the untreated contralateral eye. 24 12/16/2023 Dr Moti
- 25. … Drug Concentration Dosing Timololmaleate 0.25% & 0.5% 0.1% gel Solution: 1-2 times daily gel: once daily Timolol hemihydrate 0.5% As above Levobunolol 0.25%, 0.5% As above Metipranolol 0.3% Twice daily Carteolol hydrochloride 1% 1-2 times daily Betaxolol 0.25% Twice daily 25 AAO, BCSC Section 10, Glaucoma, 2019-2020, page 201 12/16/2023 Dr Moti
- 26. … Side effects Local blurring, irritation , punctate keratitis ,corneal anesthesia , allergy & possible aggravation of myasthenia gravis. Systemic Bradycardia, heart block, bronchospasm, lowered BP, CNS depression, mood swing, decreased libido & reduced exercise tolerance. Reduced glucose tolerance and masking of hypoglycemic signs and symptoms in DM patients. 26 12/16/2023 Dr Moti
- 27. Escape & driftin IOP on β- blocker therapy Escape Decreased effect after the first drop Quickly plateaus Might possibly relate to changes in the receptors Drift Slow but real upward drift in IOP in patients on long term therapy Due to slow decrease of trabecular meshwork function Not due to reduced effect of β- blockers. 27 12/16/2023 Dr Moti
- 28. B. Adrenergic Agonists Nonselective- epinephrine and dipivefrin (a prodrug of epinephrine) Reduce aqueous humor production, increase uveoscleral outflow, and improve conventional outflow facility. Rarely used α 2 –Selective- Apraclonidine, Brimonidine Reduce aqueous humor production by decreasing intracellular cAMP. Alternate mechanism: anterior segment vasoconstriction 28 12/16/2023 Dr Moti
- 29. … Apraclonidine hydrochloride (para– aminoclonidine ) Rarely used for long-term therapy because of the frequent occurrence of tachyphylaxis and hypersensitivity reaction Typically used perioperatively to diminish acute IOP spikes 29 12/16/2023 Dr Moti
- 30. … Brimonidine Similarly effectiveas apraclonidine when used perioperatively. Tachyphylaxis is less profound with brimonidine than with apraclonidine. Peak IOP reduction is 26% (2 hours post dose), and only 12-14% at trough (12hours post dose) Does not lower nocturnal IOP Should not be used in infants 30 12/16/2023 Dr Moti
- 31. … Adverse Effects Local Allergicreactions (e.g. follicular conjunctivitis and contact Blepharodermatitis α1 binding effect- conjunctival vasoconstriction, pupillary dilation, and eyelid retraction Systemic Xerostomia (dry mouth) and lethargy Decreased resting systolic BP and pulse rate. Hypothermia, hypotension, hypotonia (floppy baby), & apnea in children 31 12/16/2023 Dr Moti
- 32. 3. Parasympathomimetics Classifiedinto: I. Direct acting a) Choline esters:- acetyl choline, carbachol b) Non-choline esters:- pilocarpine II. Indirect-acting(Anticholinesterases) a) Reversible- demecarium bromide (Humorsol), b) Irreversible- echothiophate iodide (Phospholine Iodide), and diisopropyl fluorophosphate(DFP or Floropryl) 32 12/16/2023 Dr Moti
- 33. … Bind toAch (muscarinic) receptors Increase conventional outflow facility • Iris sphincter contraction produces miosis, often pulling the peripheral iris away from the trabecular meshwork • ciliary muscle contraction pulling on the scleral spur • altering the cellular configuration of the trabecular meshwork and Schlemn's canal increased outflow facility 33 12/16/2023 Dr Moti
- 34. Pilocarpine The hydrochloridesalt penetrates the lipophilic cornea much better than the pure compound. Relatively short half-life partially improved by use of gel polymers and controlled ocular release systems. Low-dose pilocarpine is part of the recommended regimen for treating acute angle-closure glaucoma Induced myopia occasionally as high as 8 to 10 diopters in young patients. 34 12/16/2023 Dr Moti
- 35. … Indications Early pigmentaryglaucoma Plateau iris syndrome PACG Blunting postoperative IOP spikes Contraindications Secondary angle-closure glaucomas Active ocular inflammation Untreated retinal pathology predisposing to a retinal detachment 35 12/16/2023 Dr Moti
- 36. Currently available topicalCholinergic agents 36 Agent Dose Duration of action Peak IOP lowering(%) Remark Pilocarpine 1%,2%,4% 6-8 hrs 25 Dosing bid with nasolacrimal occlusion is possible Carbachol 0.75%, 1.5%, 3% 8-12 hr 30 Greater local side effects Poor penetration Phospholine iodide 0.03%, 0.06%, 0.125%, 0.25% 12-72 hr 35 Greater local side effects catarctogenic Pilopine HS Gel 4% 18-24 hr 25 Reduced miosis/myopia Corneal haze Ocusert 20 or 40 μg/hr 5-7 days 25 Zero-order delivery, foreign body Duane’s Clinical Ophthalmology 2012 Edition, page 5637 12/16/2023 Dr Moti
- 37. 4. Carbonic AnhydraseInhibitors The enzyme carbonic anhydrase (CA) catalyzes the reversible conversion of CO2 and hydroxide ion into bicarbonate. CA is found throughout the body Seven isoenzymes of CA have been described (CA I to CA VII) CA II appears to be the predominant ciliary epithelial subtype. Currently used systemic CAIs are CA I and CA II unselective, whereas some newer topical CAIs are more active against CA II. 37 12/16/2023 Dr Moti
- 38. … CAIs reduceaqueous humor formation by 20% to 40% A physiologic response to CAIs requires at least 99% inhibition of CA. Systemic CAIs: Acetazolamide, methazolamide, dichlorphenamide, and ethoxzolamide Topical: Dorzolamide, Brinzolamide 38 12/16/2023 Dr Moti
- 39. Acetazolamide Relatively nonselectivein its inhibition of CA I and CA II. 93% plasma protein bound and is excreted in the urine largely unmetabolized. Onset of action: 1hr, maximum effect: 2-4hr, duration of action: 6-8hrs. With IV administration IOP reduction was noted within 2 minutes, with a peak effect noted by 10 to 15 minutes. 39 12/16/2023 Dr Moti
- 40. … Adverse Reactions Symptomcomplex of malaise, fatigue, weight loss, depression, anorexia, and loss of libido, nausea and diarrhea. Paresthesias, urolithiasis, urinary frequency, blood dyscrasias Metabolic and respiratory acidosis, hypokalemia Hypersensitivity reactions Transient myopia Teratogenic, contraindicated in pregnancy Growth retardation in children 40 12/16/2023 Dr Moti
- 41. … Contraindications Severe hepaticor renal disease, and COPDs Known hypersensitivity to sulfonamide drugs. Pregnancy Relative contraindications include sickle cell anemia, DM, mild renal disease, urolithiasis, and thiazide diuretic, corticosteroid, or digoxin use. 41 12/16/2023 Dr Moti
- 42. Currently available CAIs DrugConcentra tion Dose IOP reduction(%) Remark Acetazolamide PO: 250mg 500mg (sustained release IV: 500mg, 5- 10mg/kg QID BID TID/QID 15-20 Systemic side effects: acidosis, depression, lethargy, renal stones, loss of libido… Methazolamide 25mg , 50mg BID, TID 15-20 Same as above Dorzolamide 2% BID, TID 15-20 Less likely to cause systemic side effects Brinzolamide 1% BID, TID 15-20 42 BCSC Section 10 Glaucoma , 2019-20page 201 12/16/2023 Dr Moti
- 43. 5. Hyperosmotic agents Cause a rapid increase in serum osmolality Fluid exit the eye, largely from the vitreous Transient decrease of IOP Posterior movement of the lens iris diaphragm is also common, resulting in deepening of the anterior chamber. IOP reduction depends on the osmotic gradient between the systemic circulation and the eye. 43 12/16/2023 Dr Moti
- 44. a) Intravenous agents Mannitol Intravenous hyperosmotic agent of choice; and the most effective ocular hypotensive medication available. Has the highest molecular weight of all hyperosmotic agents, penetrates the eye poorly, and is secreted unmetabolized in the urine. Indicated for situations requiring an urgent reduction in IOP for which an oral osmotic agent is contraindicated. Advantages : extracellular distribution, poor ocular penetration, and stable formulation. 44 12/16/2023 Dr Moti
- 45. … Adverse reactions Headache,back pain, and diuresis. Circulatory overload with angina, pulmonary edema, and CHF in patients with cardiac or renal disease. Hyponatremia, cellular dehydration and potassium depletion Subdural hematomas, anaphylactic reactions Relatively contraindicated in patients with renal disease Should be used cautiously in patients with a compromised cardiovascular status. 45 12/16/2023 Dr Moti
- 46. b) Oral Agents i)Glycerol Readily metabolized by the liver. Penetrates the eye poorly, distributes extracellularly, and is quite stable. Safer than Mannitol in patients with renal failure Adverse reactions Nausea, vomiting The increased caloric load and dehydration may cause DKA in diabetic patients. 46 12/16/2023 Dr Moti
- 47. ii) Isosorbide Notmetabolized, less side effect than glycerol. Distributes in total body water and penetrates the eye. Less likely to cause nausea and vomiting but more likely to cause diarrhea than glycerol. Safe in DM patients. 47 12/16/2023 Dr Moti
- 48. … Glycerol andisosorbide are indicated when an urgent transient reduction in IOP is necessary. Particularly useful in the management of AACG. Also useful in malignant glaucoma and other situations with a shallow or flat anterior chamber. 48 12/16/2023 Dr Moti
- 49. Frequently used osmoticagents Agent Molecular weight Dose (g/kg) Onset of Action (min) Peak(min) Remark Mannitol 182 0.5-1.5 g/kg 20% solution given 3-5 ml/min 10-30 30-60 IOP reduction >30mmHg in30min Duration of action: 6hrs Glycerol 92 1-1.5 g/kg 50% or 75% solution given 2-3ml/kg 10-30 45-120 100-g glycerol solution occupies 80 mL volume Isosorbide 146 1-1.5 g/kg 45% solution given 2.2- 3.3ml/kg 10-30 45-120 Duration of action: 4-5hrs, similar with glycerol 49 Duane’s Clinical Ophthalmology 2012 Edition, page 5657 12/16/2023 Dr Moti
- 50. Combined medications Advantages:improve compliance, decrease toxicity Timolol + PGAs e.g. Xalacom, DuoTrav, Ganfort + CAIs e.g.. Xolamol, Zolicheck, Cosopt, Optodrop-CO , Xolatim, Ocudor-T + 2 agonist e.g.. Combigan Brimonidine + Brinzolamide (Simbrinza) 50 12/16/2023 Dr Moti
- 51. Neuroprotection: new avenuesfor glaucoma treatment Calcium Channel Blockade Glutamate Blockade Heat-Shock Proteins Nitric Oxide Synthase Inhibition Antioxidants Optic nerve regeneration 51 12/16/2023 Dr Moti
- 52. Considerations in pregnant& nursing mothers Pregnancy Brimonidine – category B - concentrated in breast milk CNS depression, apnea, hypotension in infants, should be discontinued before labor. Others – category C CAls are teratogenic in rodents- avoid in women of child bearing age. Beta blockers- cross placenta, secreted in breast milk bradycardia & arrhythmias in fetus or infants. 52 12/16/2023 Dr Moti
- 53. … Consider : Minimizingsystemic absorption Laser trabeculoplasty or Observation off medical treatment. https://eyewiki.org/Glaucoma_Management_in_Pregnancy_and_Post-Partum by Ahmad A. Aref, MD, MBA , June 11, 2019. 53 12/16/2023 Dr Moti
- 54. Considerations in children Beta blockers- potentially high plasma levels of the medication from topical instillation, use the lowest concentration available 2 agonist – strictly contraindicated below 2 years, avoid or use with caution in those < 6yrs or < 20kgs. Miotics- not effective in small children 54 12/16/2023 Dr Moti
- 55. SUMMARY Drug Example Mechanismof Action Efficacy Side Effects β-Blockers Non selective Selective Timolol Levobunolol Carteolol Metipranolol Betaxolol Decreased aqueous production (?Daytime only) Same +++ ++ Bronchoconstriction, bradycardia/heart block Exacerbation of CCF, Depression Impotence, Death impotence Adrenergic agents Epinephrine Dipivefrin Outflow enhancement + (+) External eye - toxic reaction α2-Adrenergic agonists Apraclonidine Decreased aqueous production + + (+) External eye - toxic reaction Brimonidine additionally increase uveoscleral outflow Lethargy, Dry mouth Miotics Carbachol Pilocarpine Echothiophate Increased tonographic outflow +++ Brow ache, headache, dim vision 55 Yanoff & Duker Ophthalmology 3rd Edition, Section 4, Chapter 10.24 12/16/2023 Dr Moti
- 56. … Drug Example Mechanismof Action Efficacy Side Effects Oral CAIs Acetazolamide Methazolamide Decreased aqueous production + + + + Malaise, depression, weight loss, kidney stones Topical CAIs Dorzolamide Brinzolamide same as above + + Risk of rare aplastic anemia, metallic taste, eye irritation Prostaglandin analogues Latanoprost Travoprost Bimatoprost Unoprostone Enhanced outflow + + + + ++ Iris color change, Hyperemia Periocular skin pigmentation Eyelash growth Hyperosmotic Agents Mannitol Isosorbide Glycerol Decrease vitreous volume ++++ Headache, back pain, diarrhea Circulatory overload Hyperglycemia, hyponatremia 56 Modified from Yanoff & Duker Ophthalmology 3rd Edition, Section 4, Chapter 10.24 12/16/2023 Dr Moti
- 57. … Important points: -Determine target IOP and revise if necessary - Advice on appropriate drug application - Identify and manage poor compliance 57 12/16/2023 Dr Moti
- 58. REFERENCES AAO, BCSCSection 10, Glaucoma, 2020-2021 Duane’s Clinical Ophthalmology 2013 Edition Yanoff & Duker ophthalmology Third Edition Chandler and Grant’s Glaucoma 6th Edition The Glaucoma Book, 2010 Kanski clinical ophthalmology 9th Edition 58 12/16/2023 Dr Moti
- 59.
Editor's Notes
- #4 Major risk factors for the development of glaucomatous optic nerve damage include the level of IOP, increasing age, black race, positive finding for the condition in the family history, and thin central corneal thickness. IOP remains the only risk factor readily amenable to therapy; therefore, almost all currently used strategies for the treatment of glaucoma are aimed at lowering or preventing a rise in IOP Although the long-term efficacy of treatment is judged by stability of the visual field, optic nerve, and other structural parameters, it is also regularly assessed by ensuring adequate IOP reduction
- #6 Medical strategies to lower IOP manipulate three components of Eq. 3: aqueous inflow, conventional outflow, and uveoscleral outflow. These three variables ([F in – F u ]/C) together can be termed outflow pressure. This is easily estimated, as outflow pressure = IOP – P v . The fourth variable, episcleral venous pressure, cannot be altered pharmacologically and presents a theoretic limit for the amount of pressure lowering attainable through medical means.
- #8 The term target pressure refers to an IOP below which the clinician estimates the rate of disease progression to be sufficiently slow as to minimize the patient’s risk of experiencing further symptomatic vision loss in his or her lifetime. The value of establishing a target pressure after an initial evaluation period of a patient with glaucoma or ocular hypertension is that it encourages thoughtful appraisal of various clinical factors that influence the future risk of progression and allows for an efficient assessment of the patient’s IOP level at each subsequent visit. Even if the target pressure is achieved, the clinician must continue to evaluate the stability of structural and functional measures important in glaucoma
- #9 three methods for setting a target IOP for a new glaucoma patient: 1) a percentage reduction from the baseline pressure, 2) a fixed number or range based on the disease stage, or 3) a formula that includes individual factors such as age, visual field loss, and baseline pressure. His preferred method is the percentage reduction from baseline. Downward revision if further progression does occur Sometimes it may be necessary to accept an IOP level above the established target pressure because the adverse effects or risks of intensified therapy may be unacceptable. Evidence suggests that the severity of optic nerve injury may increase the likelihood of continued disease progression. Therefore, the more advanced the disease is on initial presentation, the lower the target pressure required to minimize the risk of further symptomatic vision loss will be. Furthermore, if severe vision loss is already present, further damage (loss of retinal ganglion cells) is likely to have a disproportionately greater impact on visual function and quality of life. Establishing a target IOP is part of the art of glaucoma management, because many different approaches can be used.
- #10 In the Early Manifest Glaucoma Trial (EMGT), patients with newly detected open-angle glaucoma with early glaucomatous visual field defects were randomized to treatment with laser trabeculoplasty plus topical betaxolol hydrochloride or no treatment. For patients with ocular hypertension without glaucomatous optic neuropathy or visual field defects, the Ocular Hypertension Treatment Study (OHTS) showed that an average of 22.5% decrease in IOP with topical ocular hypotensive medication was effective in reducing the development of primary open-angle glaucoma (POAG) from 9.5% in controls to 4.4% in treated patients at 60 months' follow-up. The EMGT demonstrated that the following factors were predictors of glaucoma progression: elevated IOP, older age, bilaterality, exfoliation, disc hemorrhages, and relatively thin central cornea. In addition, lower systolic perfusion pressure, lower systolic blood pressure, and cardiovascular disease history emerged as new predictors, suggesting a vascular role in glaucoma progression
- #11 the Advanced Glaucoma Intervention Study (AGIS), which compared the clinical outcomes of two treatment outcome sequences for patients with open-angle glaucoma uncontrolled by medical therapy. increasing age (each 5-year increment in age) and greater IOP fluctuation (each 1-mm Hg increase in IOP fluctuation) were associated with increasing the odds of visual field progression by 30%. However, some patients continue to suffer disease progression despite the reduction in IOP. Clearly, other risk factors exist, both major (age, race, family history, thin central cornea ) and minor (diabetes, hypertension, myopia). Major clinical trials in the last two decades have identified other risk factors of disease progression, including reduced central corneal thickness, pseudoexfoliation, frequent disc hemorrhage, and migraine headache.
- #12 In the first equation where the reference pressure represents the baseline pretreatment IOP and the visual field score is based on the Advanced Glaucoma Intervention Study technique for scoring visual field damage. These visual field scores range from 0 (no damage) to 20 (all sites deeply depressed). One problem with this technique is its requirement for reliable perimetry to provide the visual field score. In addition, the scoring process itself is somewhat complex and time-consuming.
- #14 Several studies have suggested that poor compliance with glaucoma medication is a common problem. A study of patient compliance with systemic carbonic anhydrase inhibitors (CAIs) that involved monitoring serum bicarbonate levels suggested that 35% of patients were not taking the drug at all and another 22% were using the medication infrequently. 55 . Alward PD, Wilensky JT: Determination of acetazolamide compliance in patients with glaucoma. Arch Ophthalmol 99:1973, 1981 Compliance is difficult to evaluate. It is a good idea to consider noncompliance in any case of progression despite seemingly good pressure control in the office. At times, it may be helpful to contact a family member to inquire about the use of medications Generally, topical agents such as prostaglandin analogs and long-acting β-blockers that allow effective IOP reduction with once-daily dosing will produce better compliance. In fact, the increased effectiveness of contemporary medical regimens has achieved better IOP reduction and a reduction in number of glaucoma operations performed.58,59,60
- #15 Advise use of medications that limit side effects. Nasolacrimal occlusion, prodrugs, and high-viscosity preparations limit systemic absorption. • Avoid confusing regimens. Carbachol three times daily, acetazolamide four times daily, and a β-blocker twice daily is a confusing regimen. Echothiophate iodide, sustained-release acetazolamide, and a β-blocker, all twice daily, is much easier to remember. Educate patients about and engage them in their disease. Tell them their IOP and target pressure, show them their visual field printouts, and discuss the optic disc findings.
- #16 Of the 20% to 40% of the medication initially present in the cul-de-sac, about 15% per minute exits the tear film by new tear formation, blinking, and lacrimal drainage Although the total dose of medications reaching the nasal mucosa may seem trivial compared with typical oral doses, medication absorbed by way of the nasal mucosa is not subjected to first-pass hepatic metabolism. Clinically significant blood levels can be achieved at target tissues, producing undesired adverse reaction
- #17 Efforts to maximize ocular penetration and minimize systemic absorption by way of the nasal mucosa generally limit lacrimal drainage. These efforts include increasing drop viscosity and using nasolacrimal occlusion or eyelid closure for several minutes after instillation. Another powerful strategy to reduce systemic absorption is the use of prodrugs that enhance ocular penetration and reduce the total dose requirement. To maximize ocular absorption, a second topical agent should not be given for at least 10 minutes after the first.
- #19 Bimatoprost is an active drug, not a pro-drug requiring activation by corneal enzymes Prostaglandins and thromboxanes belong to a family of compounds called prostanoids, which are defined as cyclo-oxygenase products derived from C-20 unsaturated fatty acids (namely, arachidonic acid) PGAs increase aqueous drainage, primarily by enhancing uveoscleral outflow up to 60%.7,10-12 Additionally, bimatoprost, latanoprost, and travoprost all have some effect on trabecular outflow.13 PGAs are chemical derivatives of prostaglandin F2 and agonists of the prostanoid FPA and FPB receptors It is thought that the ocular hypotensive prostaglandin analogues bind to various prostaglandin receptors, most importantly prostaglandin F2 (PGF2), triggering a cascade of events that lead to activation of matrix metalloproteinases. This in turn leads to remodeling of the ciliary body, trabecular meshwork, and possibly scleral extracellular matrix, so that the flow rate of aqueous humor through these tissues is increased. Topical prostaglandin analogue therapy results in increased space between the muscle fascicles within the ciliary body, which is thought to be the primary location of uveoscleral outflow. Currently, 5 prostaglandin analogues are in widespread clinical use: (1) latanoprost, (2) travoprost, (3) bimatoprost, (4) tafluprost, and (5) latanoprostene bunod. These agents reduce IOP by 25%–33%. Tafluprost appears to be slightly less efficacious than latanoprost (see Table 12-2; see also the section General Approach to Medical Treatment, later in this chapter, for discussion of preservatives). Latanoprostene bunod lowers mean diurnal IOP by 32% and is unique in that it is a nitric oxide–donating PGF2 analogue. Nitric oxide is thought to increase trabecular outflow facility with a resultant 1 mm Hg IOP-lowering advantage over latanoprost in 1 clinical trial
- #20 Topical therapy results in increased space between the muscle fascicles within the ciliary body, thought to be the main site of uveoscleral outflow.
- #21 Latanoprostene bunod—a new, chemically modified prostaglandin analogue with a nitric oxide–donating moiety—has been found to be slightly more effective than Latanoprost, presumably because nitric oxide acts on the meshwork and Schlemm canal to improve trabecular outflow facility.
- #22 BCSC Sec10 , page 201
- #23 Increased iris pigmentation is permanent, and the frequency of this effect depends on the baseline iris color. Most published data relate to latanoprost and suggest a risk of up to 33% after 5 years of use. In particular, up to 79% of persons with green-brown irides and up to 85% of persons with hazel (yellow-brown) irides may be affected, compared with 8% of persons with blue irides. There is no evidence to suggest that increased iris or periocular skin pigmentation is associated with any risk to the patient such as an increased risk of melanoma. conjunctival hyperemia (a result of vasodilation, more common with bimatoprost and travoprost), hypertrichosis (Figs 12-1, 12-2), trichiasis, and distichiasis. These effects are reversible upon drug discontinuation. Use of prostaglandin analogue eyedrops has also been associated with the development of prostaglandin-associated periorbitopathy (see Fig 12-2), a complex of abnormalities that includes deepening of the upper eyelid sulcus, upper eyelid ptosis, enophthalmos, inferior scleral show, and possibly a tight orbit. These abnormalities appear to be the result of periorbital fat atrophy. It is not clear whether this periorbitopathy is reversible
- #24 No systemic side effects were demonstrated in the initial three large multicenter studies of latanoprost. This is likely because of the extremely low concentration of drug required to reduce IOP and the short plasma half-life. Preoperative use of PG agents may increase the likelihood of cystoid macular oedema following cataract surgery. This is more likely to occur if PG agents are used in the postoperative period, particularly if there has been vitreous loss at the time of the surgery.
- #25 because beta-blockers can also bind to Ca+2 channel receptors and Ca+2 blockers have been shown to decrease IOP, this mechanism may also play a role. In particular, this pathway may play a role in betaxolol’s effect. The effect on aqueous production occurs within 1 hour of instillation and can last for up to 4 weeks after discontinuation of the medication. Because systemic absorption occurs, an IOP-lowering effect may also be observed in the untreated contralateral eye. -Blockers have much less effect on aqueous production during sleep, as aqueous production is already reduced during the nocturnal period; thus, they are ineffective in lowering IOP during sleep
- #26 Betimol is timolol hemihydrate, Timoptic is timolol maleate, and Istalol is a potassium salt, but the 3 salts appear to have approximately equal efficacy. Betaxolol is a selective beta-1 blocker and does not produce the same magnitude of IOP lowering as timolol. However, it has a greater systemic safety profile. More than 90% of the beta receptors in the ciliary epithelium are of the beta-2 class. 45 Thus, it is surprising that beta-1 selective blockers, such as betaxo- lol, work well to decrease aqueous humor production. Therefore, its cross-reactivity with beta-2 receptors and its calcium channel–blocking effects produce its clinical effect. Levobunolol (Betagan) 51 is a nonselective beta-blocker that is probably equivalent to timolol in both efficacy and potential for side effects. Carteolol (Ocupress) is a nonselective beta-blocker with some intrinsic sympathomimetic activity and has fewer adverse systemic effects on lipoprotein profiles than other beta-blockers. In approximately 10%–20% of patients treated with topical -blockers, IOP is not significantly lowered. Patients already taking a moderate or high dose of a systemic -blocker may experience little additional IOP lowering from the addition of a topical ophthalmic -blocker. Extended use of -blockers may result in tachyphylaxis due to receptor upregulation. Physiologic changes in the trabecular meshwork may occur in response to decreased IOP and aqueous humor flow rate, resulting in decreased outflow facility. The underlying disease process responsible for decreased outflow facility and IOP elevationmay also worsen during the course of therapy.
- #27 Plasma drug levels from topical medications can approach those achieved with systemic administration because of their absorption in the nasolacrimal drainage system and lack of first-pass hepatic metabolism. However, administering topical medications in a gel vehicle results in reduced systemic absorption and decreased plasma concentrations of -blockers compared with the equivalent solution. Punctal occlusion also reduces systemic absorption. Systemic adverse effects of -adrenergic antagonists include bronchospasm, bradycardia, increased heart block, systemic hypotension, reduced exercise tolerance, and central nervous system (CNS) depression. Patients with diabetes mellitus may experience reduced glucose tolerance and masking of hypoglycemic signs and symptoms. In addition, abrupt withdrawal of ophthalmic -blockers can exacerbate symptoms of hyperthyroidism. Before a -blocker is prescribed, the clinician should ask whether the patient has a history of asthma, because -blockers may induce severe, life-threatening bronchospasm in susceptible patients. 2-Receptors are present in bronchial smooth muscle cells, and their inhibition results in bronchospasm in susceptible individuals. Because betaxolol is a 1-selective antagonist, it is safer than the nonselective -blockers for use in patients with asthma. In addition, betaxolol may be less likely to cause depression. However, -blocker– related adverse effects can still occur with its use. Prior to initiation of therapy with a topical -blocker, the patient’s pulse should be measured; the -blocker should be withheld if the pulse rate is slow or if more than firstdegree heart block is present. Administration of topical -blockers has been associated with the development of signs and symptoms of myasthenia gravis in patients without a preexisting diagnosis and can exacerbate the condition in patients already known to have the disease. The mechanism by which this occurs is unclear. Other adverse effects of -blockers include lethargy, mood changes, depression, altered mentation, light-headedness, syncope, visual disturbance, corneal anesthesia, punctate keratitis, allergy, impotence, reduced libido, and alteration of serum lipids (reduction in high-density lipoprotein). In children, -blockers should be used with caution, because of the relatively high systemic levels achieved.
- #28 The first drop of a beta-blocker such as timolol has hirhest effect than the subsequent drops over the next couple of days. Some have called this phenomenon beta-blocker escape. 27,28 This effect quickly plateaus in a steady state of sustained, clinically meaningful IOP reduction for more than 90% of glaucoma patients. Timolol (and likely other beta-blockers) does not diminish in ability to decrease the rate of AHF in glaucoma eyes once the patient is beyond the short-term escape phenomenon. Rather, the disease process in the trabecular meshwork in such early glaucoma patients continues to worsen (in both control and timolol-treated patients), which results in the apparent drift upward of IOP. Chandler page 137
- #29 The major side effects non-selective alpha agonists are ocular irritation, injection, and palpebral conjunctival follicle formation that necessitates discontinuation of the agent. Mechanism of action 2-Selective agonists lower IOP primarily by reducing aqueous humor production. The 2-adrenoceptor found on the ciliary epithelium is coupled to an inhibitory G protein. It is thought that when this adrenoceptor is bound by catecholamines or pharmacologically active 2-agonists, an intracellular cascade results in reduction in the activity of adenylate cyclase and the intracellular concentration of cAMP, with a resultant reduction in the rate of aqueous humor production. An alternate or possibly complementary mechanism by which aqueous humor production is reduced may be anterior segment vasoconstriction and reduced blood flow to the ciliary body. After a longer period of therapy, increased uveoscleral outflow was observed with the selective 2-adrenergic agonist brimonidine, but not with apraclonidine. How uveoscleral outflow may be increased with brimonidine is unclear, but evidence points to relaxation of ciliary smooth muscle cells. As with -blockers, systemic absorption of 2-selective agonists may lead to a crossover effect, although it appears to be small
- #30 Increased uveoscleral outflow with long term Brimonidine How uveoscleral outflow may be increased with brimonidine is unclear, but evidence points to relaxation of ciliary smooth muscle cells. Apraclonidine is typically used perioperatively to diminish acute IOP spikes that may occur after laser iridotomy, laser trabeculoplasty, Nd:YAG laser capsulotomy, and cataract extraction. Tachyphylaxis is less profound with brimonidine than with apraclonidine. Brimonidine’s peak IOP reduction is approximately 26% (2 hours post dose), which is comparable to the reduction achieved by a nonselective -blocker and superior to that of the selective -blocker betaxolol. At trough (12 hours post dose), the IOP reduction is only 14%–15%, or less than the reduction achieved with nonselective -blockers. Studies have shown that brimonidine does not lower nocturnal IOP. Though approved for therapy 3 times daily in the United States, brimonidine is commonly used twice daily, particularly when used in combination with at least 1 other agent.
- #31 Brimonidine should not be used in infants and young children because of the risk of CNS depression, apnea, bradycardia, and hypotension, presumably due to increased CNS penetration of the drug.
- #32 Increased susceptibility to these central actions occurs particularly in very young and older individuals and is a relative contraindication for use in the pediatric population.
- #33 Carbachol is both a direct-acting agonist in addition to having indirect agonist activities. Although the indirect-acting agents are used less frequently in glaucoma management, they are generally much more potent and longer-acting than the direct-acting agents. The direct-acting agent pilocarpine continues to be used in certain circumstances, although it is not commonly prescribed for long-term use. In patients with pigmentary glaucoma, pilocarpine is effective in blunting the IOP spike that can occur with jarring physical activities such as running. This drug is also useful in the management of elevated IOP in aphakic eyes and in patients whose drainage angles are persistently occludable despite laser iridotomy (plateau iris syndrome). It has been associated with poor patient adherence to the treatment regimen because of its adverse effect profile and because of its 3- or 4-times-daily dosing schedule; therefore, it is infrequently used. Lower concentrations and dosing frequencies may be acceptable for management of angles with persistent iridotrabecular contact with a patent peripheral iridotomy
- #34 Cholinergic agonists bind to ACh receptors and appear to act through G-protein–coupled second-messenger pathways. Glaucoma-related responses involve the muscarinic receptors. Although these receptors are found in the ciliary epithelium, cholinergic agents have little effect on aqueous production. They also can increase relative pupil block due to accommodative effect. Indirect-acting agents fell out of favor because of their ocular and systemic adverse effects. They can, however, be very effective and well tolerated in aphakic eyes with glaucoma, but they are rarely used.
- #35 Low-dose pilocarpine is part of the recommended regimen for treating acute angle-closure glaucoma, where its benefit involves a reduction in iris bombé, pulling the peripheral iris away from the trabecular meshwork.
- #36 Pilocarpine has been demonstrated to reduce iris concavity and has been shown to block the exercise-induced elevation of IOP found in some patients.[18][27][50] However, pilocarpine treatment can induce additional myopia and accommodative spasms. Peripheral retina should be carefully examined before the initiation of miotics since lattice degeneration is present in up to 20% of these eyes, and the incidence of retinal detachment in patients with PDS and PG is higher than in general population.[12]Therefore, treatment with pilocarpine has largely been replaced by newer medical agents including topical prostaglandins, beta-blockers, carbonic anhydrase inhibitors, and alpha-adrenergic agonists. Prostaglandin analogues may be preferred over aqueous suppressants as treatment with aqueous suppressants slows down the clearance of pigment from the trabecular meshwork.
- #37 Controlled-release pilocarpine aqueous gel polymer (Pilopine HS Gel; Alcon Laboratories) contains 4% pilocarpine in a slow-release gel Controlled-release pilocarpine polymers (Ocusert) release pilocarpine at either 20 or 40 μg/hr with essentially zero-order kinetics. The Ocusert Pilo-20 is roughly equivalent to pilocarpine 1% or 2%, whereas the Ocusert Pilo-40 approaches pilocarpine 3% to 4% in efficacy with a duration of 5- 7 days.
- #38 Seven isoenzymes of CA have been described (CA I to CA VII). CA I and CA II are located within the cell cytoplasm. CA II appears to be the predominant ciliary epithelial subtype. The autosomal recessively inherited CA II deficiency abolishes acetazolamide-induced IOP reduction. There is evidence that CA IV present in the nonpigmented epithelial cell membrane may also be an important enzyme in aqueous secretion Carbonic anhydrase inhibitors (CAIs) decrease aqueous humor production by inhibiting the activity of ciliary epithelial carbonic anhydrase. Systemic CAI therapy may further decrease aqueous humor formation because of the resultant renal metabolic acidosis, which may reduce the activity of the Na+,K+-ATPase in the ciliary epithelium. The enzyme carbonic anhydrase is present in many tissues, including corneal endothelium, iris, retinal pigment epithelium, red blood cells, epithelial cells lining the choroid plexus of the brain, and kidney. More than 90% of the ciliary epithelial enzyme activity must be inhibited todecrease aqueous production and lower IOP
- #39 Acetazolamide appears to reduce flow both day and night
- #40 Total outflow pressure reduction with β-blocker + CAI is 50% to 60%
- #41 The most serious adverse reactions of CAIs are rare blood dyscrasias, including aplastic anemia. One third of these reactions are fatal. 485 Most hematologic events are noted within 6 months of starting therapy, and reactions within 14 days have been reported. Acetazolamide in therapeutic doses often causes a metabolic and respiratory acidosis that can be particularly problematic in patients with diabetes, in patients with COPD, 489 and in patients with sickle cell anemia and hepatic or adrenal insufficiency. Transient myopia has been described and is possibly related to ciliary body edema and lens swelling. Ciliochoroidal detachments have been described in patients with a history of previous glaucoma-filtering surgery who were given acetazolamide. Paresthesias of the extremities are very common, as is a reduction in the taste of carbonated beverages. Incidence of urolithiasis increases tenfold in patients receiving chronic acetazolamide,481 probably from metabolic acidosis with decreased urinary citrate and decreased solubilization of urinary calcium.482,483,484 Patients often note transient urinary frequency from the diuretic effect. Electrolyte abnormalities, particularly hypokalemia, are more common with acetazolamide initiation and may be compounded by coadministration with thiazide diuretics and systemic corticosteroids. Hypokalemia can be especially dangerous in patients using digoxin. Increased uric acid levels have been reported.491 Varying effects of acetazolamide on bone resorption have been reported. The initial diuretic effect can be accompanied by a reduction in systemic blood pressure.492 CNS effects include an increase in cerebral blood flow and a reduction in cerebrospinal fluid (CSF) production, although a transient increase in CSF pressure has been reported in humans.493 Hypersensitivity reactions to acetazolamide, including rash and hepatic or renal effects, can occur in idiosyncratic fashions. Growth retardation has been reported in children receiving long-term therapy, believed secondary to chronic acidosis. Another potential drug interaction is aspirin toxicity resulting in severe acidosis.497,498 Protein binding by nonsteroidal antiinflammatory drugs may elevate acetazolamide plasma levels.49
- #43 BCSC Glaucoma page 201 Dorzolamide is relatively contraindicated in patients with known skin allergies to sulfa drugs, and it is more strongly contraindicated in patients with known hematologic, hepatic, and renal reactions to the sulfonamides.
- #44 A reduction in vitreous weight of 3% to 4% has been measured after hyperosmotic use in animals. 740 This translates to a 120- to 160-μL reduction in a typical 4-mL human eye. A second mechanism of hyperosmotic agent-induced ocular hypotension has been postulated to occur by way of central effects acting on the hypothalamus.
- #45 Intravenous agents provide more rapid and greater IOP lowering than oral agents. They are more likely to rapidly overload the cardiovascular system. Intravenous agents are the agents of choice in patients with severe nausea or vomiting, coma, or the need for intraoperative administration. It is commonly indicated for severe acute angle-closure glaucoma in which nausea and vomiting preclude use of oral agents, and before eye surgery. Vitreous dehydration and a reduction in IOP may be desired before or during cataract surgery, retinal detachment repair, corneal transplantation, and repair of ocular trauma.
- #47 In general, these agents are slower in onset and cause a less profound hypotensive effect than that seen with mannitol.
- #49 This elevated pressure can render the iris sphincter ischemic and relatively insensitive to pilocarpine. Hyperosmotic agents can often rapidly lower IOP, allowing miotics to open the angle and facilitate outflow, thereby medically breaking the acute attack. Hyperosmotic agents are also useful for severe acute intraocular spikes, such as those seen after severe alkaline burns, cyclocryotherapy, anterior segment laser procedures, cataract surgery, and occasionally cycloplegia.
- #50 Duane’s Clinical Ophthalmology 2012 Edition, page 5657
- #52 ccb;-lomerizin , Flumarizin
- #53 Ideally, a discussion of the treatment plan of a woman’s glaucoma should be initiated before pregnancy begins. Brimonidine, a Category B drug, may be the safest option for the first trimester. Other anti glaucoma medications such as beta-blocker, prostaglandins and carbonic anhydrase inhibitors should be avoided when possible in first trimester to reduce potential teratogenic effects or premature abortion For glaucoma surgery, anesthetics, sedative agents, and antimetabolites are all possible teratogenic agents. Therefore, avoiding surgery in first trimester may decrease the risk of teratogenicity and spontaneous abortion. in second trimester, brimonidine continues to be considered the first-line agent. Beta-blockers can be used with regular fetal heart rate and fetal growth monitoring. If prostaglandin analogues are used, premature labor symptoms and signs should be described to the patient, and the medication should be stopped if such symptoms are noted. When topical or oral carbonic anhydrase inhibitors are used, fetal growth retardation monitoring may be considered. Brimonidine, beta-blocker, or topical carbonic anhydrase inhibitors, can be used with caution. Avoidance of prostaglandins may decrease the risk of premature labor, which is particularly important early in the third trimester. Late in the third trimester, brimonidine should be discontinued because it can induce central nervous system depression in newborns. Beta-blockers should be used with careful fetal growth and heart rate monitors. Topical carbonic anhydrase inhibitors should be used with careful monitoring of acidosis status. Glaucoma surgery can be performed with caution in second and third trimester if the patients have a strong indication for the procedure. However, anesthetics, sedative agents, and antimetabolites still have potential risk for the fetus.
- #56 Yanoff & Duker Ophthalmology 3rd Edition, Section 4, Chapter 10.24