Ocular therapeutics1

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  • Mucus membrane iris ciliiary body
  • However lipid solubility is more important than water.
  • 0.1%carbachol with 0.03% benzalkalium can elicit same response as 2% without it
  • Due to damage to blood aqeous barrier
  • Dry eye increases the population of goblet cells
  • The oculocardiac reflex, also known as Aschner phenomenon, 15mg/kg body wt of atropine iv blocks this effect.Physostigmine antidote for atropine toxicity 1-4 mg slow iv
  • Thus if absorbed systemically, even a single drop can cause systemic side effects.
  • Short term;The initial dose of timolol produces the maximum effect about 40% or more, followed by a partial decline over the following days or weeks. This may be due to alterations in the β adrenergic receptors in the ocular tissuesLong term drift: The IOP slowly increases over a period of time in patients who have well controlled IOP. This may be due to partial adaptation of the ciliary body to long term administration of timolol,due to decrease in cellular sensitivity. 
  • Carteolol it also lacks Timolol tendency to raise serum cholesterol and lower high density lipoprotein, a factor to consider in cardiovascular patients.
  • Alpha2 agonist blocks the release of norepinephrineNeuro protection is due to upregulation of neurotropin
  • Mao inhibitorsbcoz they accentuate the adrenergic effects
  • the ciliary muscle was relaxed so that there was enough space for the aqueous to go towards the uveoscleral space or the narrowing of the ciliary muscle fiber bundles or enzymatically mediated lysis of the intramuscular connective tissue, both of which could enhance the movement of fluid from the anterior chamber through the muscle into the suprachoroidal space.
  • Ocular therapeutics1

    1. 1. OCULAR THERAPEUTICS Shashi Sharma Ajay Kumar Singh• Department of Ophthalmology• King George‘s Medical University, Lucknow (INDIA)
    2. 2. GENERALPHARMACOLOGICALPRINCIPLES
    3. 3. PHARMACODYNAMICS it is the biological activity and clinical effect of the drug* if the drug is working at the receptor level, it can be agonist orantagonist if the drug is working at the enzyme level, it can be activator orinhibitor*American Academy of Ophthalmology Section 2;2010-11
    4. 4. PHARMACOKINETICS it is the absorption, distribution, metabolism, and excretion ofthe drug drug can be delivered to ocular tissue as: locally: eye drop ointment periocular injection intraocular injection systemically: oral intravenous
    5. 5. EYE AND TOPICAL MEDICATIONSTear Film under normal circumstances the volume of tear fluid is 5-7 µl withnormal rate of secretion about 1-2 µl /min drop added cause an increasing in blinking, squeezing which propelstears towards the sac. the drugs passes on lacrimal sac nasolacrimal systembypass the liveriris & ciliary body systemic circulation
    6. 6. Cornea it is a lipid - water - lipid layer the lipid content of the epithelium and the endothelium is 100 timesmore than that of stroma. and therefore allow lipophilic than to hydrophilic substance. because of the dual nature of the corneal barriers, drugs possessingboth lipid and water solubility penetrate the cornea more readily.
    7. 7. FACTORS INFLUENCING LOCAL DRUG PENETRATION INTOOCULAR TISSUE Drug concentration and solubility: the higher the concentrationthe better the penetration e.g. pilocarpine 1-4% but limited by reflextearing Viscosity: addition of methylcellulose and polyvinyl alcoholincreases drug penetration by increasing the contact time with thecornea and aiding drug penetration Lipid solubility: the higher lipid solubility the more the penetration
    8. 8.  Surfactants: the preservatives used in ocular preparations alter cellmembrane in the cornea and increase drug permeability e.g.benzylkonium and thiomersal pH: the normal tear pH is 7.4 and if the drug pH is much different, thiswill cause reflex tearing Drug tonicity: when an alkaloid drug is put in relatively alkaloidmedium, the proportion of the uncharged form will increase, thus morepenetration
    9. 9. EYE DROPS one drop = 50 µl one ml contains approx 20 drops volume of conjunctival cul-de-sac after drug instillation is 7-10 µl,hence only 20% of the drug is retained topical medications are be used as• solutions/suspensions• ointments
    10. 10. OINTMENTS increase the contact time of ocular medication to ocularsurface thus better effect it has the disadvantage of vision blurring, hence night dosage the drug has to be high lipid soluble with some water solubilityto have the maximum effect as ointment
    11. 11. PERIOCULAR INJECTIONS bypass the conjunctival and corneal epithelial barrier subconjunctival, subtenon, retrobulbar injections allow medicationsbehind lens and diaphragm useful for drugs with low lipid solubility delivering medications closure to local site of action e.g. posteriorsubtenon retrobulbar and peribulbar anesthesia techniques
    12. 12. INTRAOCULAR Intracameral and Intravitreal Intracameral is used during surgery : antibiotics,mydriasis/miosis Intravitreal in diabetic macular edema, CRVO, retinal surgeries Intraocular implants : Gancicyclovir for CMV retinitis Retisert (Fluocinolone) for posterior uveitis
    13. 13. SYSTEMIC DRUGS Oral or Intravenous Factor influencing systemic drug penetration into oculartissue: lipid solubility of the drug: more penetration with high lipidsolubility protein binding: more effect with low protein binding better penetration in the inflamed eye
    14. 14.  New ocular drugs are designed aimed at improving penetration,minimizing side effects and improving efficacy Prodrugs Activated by enzymatic system in the eye Lanatoprost prostagladin F2α Sustained release devices and gels Collagen corneal shields New technology in drug delivery Liposomes* Iontophoresis*Mishra G, Mahuya B. Recent Applications of Liposomes in Ophthalmic Drug DeliveryJournal of DrugDelivery;Volume 2011,Article ID 863734Corneal esterases
    15. 15. ANTI INFLAMMATORYLUBRICANTSANTI GLAUCOMAMYDRIATICS & CYCLOPLEGICS
    16. 16. ANTI INFLAMMATORY THERAPYCORTICOSTEROID NSAIDs IMMUNOSUPPRESSIVEMAST CELL STABILIZERS
    17. 17. CORTICOSTEROIDS useful in control of inflammatory and immunological diseases of eye routes of administrationTopical Periocular Intravitreal Oral Intravenous their antiinflammatory and immunosuppressive action inhibition of lymphocytes proliferation, with a decrease of the cell-mediated immunity inhibition of the degranulation of neutrophil granulocytes,macrophages, mastcells and basophil granulocytes. decrease of vascular permeability decrease of prostaglandin production
    18. 18. Phospholipids from damaged cell membranesArachidonic acidLeucotrienes PG-G2,Thromboxane PG-D2, E2, F2Phospholipase A2 GlucocorticoidsLipo-oxygenaseCyclo-oxygenase I & IINSAIDS
    19. 19.  Indications post surgical inflammation allergic conjunctivitis and blepharitis vernal conjunctivitis, phylectunular keratoconjunctivitis disciform and interstitial keratitis corneal graft rejection scleritis and episcleritis, anterior and posterior uveitis traumatic inflammation of the eye papillitis and retrobulbar neuritis sympathetic ophthalmia herpes zoster ophthalmicus orbital pseudotumor VKH syndrome
    20. 20.  contraindicationsTOPICAL SYSTEMIC• acute viral infections•fungal diseases• ocular TB• acute conjunctivitis• caution in pregnancy and lactationS- psychosis, headaches, pseudotumourcerebri.T- thrombosis (venous)E- endocrinal- suppressed hypothalamicpituitaryadrenal axis, retarded growth,cushingoid state.R- retention of fluid & sodium but loss ofpotassium & systemic alkalosis.O- osteoporosis & myopathies.I- immunosuppression with secondaryinfections esp. TB & fungal,D- diabetes & hypertension, duodenal &gastric (peptic)ulcers.
    21. 21.  Side effectsTOPICAL SYSTEMIC• glaucoma• cataract (PSC)• dry eye• reduced resistance to bacterial, fungaland viral infections and secondaryinfections• scleral melting• delayed wound healing• eyelid skin atrophy• ocular•suppresion of hypothalamic pitutiaryadrenal axis• hyperglycemia• peptic ulcer• osteoporosis• psychiatric disturbances• cushing’s habitus• fetal abnormalities• susceptibility to infections
    22. 22. TOPICAL CORTICOSTEROIDS available as solution, suspension and ointment Hydrocortisone 0.5-1.5% Prednisolone 0.12, 0.25, 1 % Dexamethasone 0.1% Betamethasone 0.1 % Triamcinolone 0.1% Fluromethalone 0.1% Loteprednol 0.2%,0.5% Difluprednate 0.005% anti-inflammatory action * prednisoloneacetate > fluorometholone acetate > dexamethasone acetate >betamethasone*Samudre S, Lattanzio F, Williams P, Sheppard J. Comparison of topical steroids .J OculPharmacolThe. 2011;20:533-47.
    23. 23.  rise in IOP- maximum rise due to dexamethasone (0.1%) andfluorometholone 0.1% is least Loteprednol 0.2%- ―soft‖ steroid- minimal effect on IOP & systemic side effects, approved for allergic conjunctivitis and combined with tobramycin 0.3%for superficial bacterial infection with inflammation Triamcinolone acetonide (40mg/ml) (Kenacort) was approved by FDAin 2007 for intraocular use in visualization during vitrectomy, chronicnon infectious uveitis, diabetic macular edema Retisert( flucinolone actetonide) used as intraocular implantation forchronic uveitis
    24. 24. RECENT ADVANCES…. DIFLUPREDNATE 0.05%( Diflucor, Diflupred) prednisolone derivative, in emulsion form exhibits enhanced , strongefficacy and low side effects indicated in post operative inflammation and uveitis only qid dosing is required OZURDEX® (Allergan)(dexamethasone intravitreal implant 0.7mg),indicated in macular edema following retinal vein occlusion noninfectious posterior uveitis
    25. 25. ORAL CORTICOSTEROIDSShort actingHydrocortisone 20mg/day  rapid actingmineralocorticoidactivityCortisone 20-100mg/dayIntermediatePrednisolone 1-2mg/kg/day 4 times more potentthan hydrocortisoneMethyprednisolone 4-32mg/day Selective thanprednisoloneTriamcinolone 4-32mg/day Only glucocorticoidactionLong actingDexamethasone 0.5- 5mg/dayHighly selectiveglucocorticoidMarked pitutiary axissuppressionBetamethasone 0.5- 5 mg/day
    26. 26.  Oral prednisolone in a dose of 1-2 mg/kg/day (or alternate days) isused to treat orbital inflammations, panuveitis, postoperativeinflammation and systemic diseases causing ocular problemsalternate day therapy reduces the suppression of adrenal functions High dose of methylprednisolone i/v are given in pulses to treat opticneuropathies DEFLAZACORT(Defcort) Recent glucocorticoid, derivative of prednisolone with lesscomplications 6mg of deflazacort is equivalent to 5 mg of prednisolone
    27. 27. NON STEROIDAL ANTIINFLAMMATORY DRUGS Has 3 types of effects Anti-inflammatory Analgesic Antipyretic (COX-2) Inhibits the cyclooxygenase pathway
    28. 28. ORAL NSAIDSNon selectiveCOX inhibitorPropionic acidderivativeIbuprofen 400mg/day potent analgesicAryl aceticderivativeDiclofenacAceclofenac50mg tds analgesic,antipyretic,antiinflammatoryCOX 2 inhibitor Nimesulide 100mg bd analgesic,antipyreticPoor antiinflammatoryParaaminophenol Paracetamol 300-600mg antipyretic
    29. 29. OCULAR INDICATIONS FOR USE OF NSAIDs prevention of intraoperative miosis reduction of postoperative inflammation prevention and treatment of cystoid macular edema non infectious uveitis scleritis and episcleritis allergic and giant papillary conjunctivitis after refractive surgery
    30. 30. FLURBIPROFEN KETOROLAC DICLOFENACSalient features 0.03% solution 0.5% solutionanalgesic and anti-inflammatory0.1% solutionpotent NSAID withanalgesiaIndicationinhibition ofintraoperative miosisocular itching due toseasonal allergicconjunctivitisForeign body sensationand photophobiaiatrogenicinflammation, postcataract surgery painDosage1 drop every 30minutes, 2 hrspreoperatively (total offour drops)TDS QIDSide effects• transient burning andstinging• may cause increasedbleeding tendency ofocular tissues duringsurgery• transient burning and stinging• decrease in corneal sensitivity
    31. 31. NEWER DRUGS Nepafenac 0.1% and Bromfenac 0.09%are topical, nonsteroidalanti-inflammatory, recently introduced Nepafenac is a prodrug, converted by ocular tissue hydrolases toamfenac, which inhibits the action of prostaglandin Hsynthase(cyclooxygenase) patients treated with these drugs were less likely to have ocular painand measurable signs of inflammation (cells and flare) in the earlypostoperative period as compared to ketorolac* indicated for the treatment of post operative pain and inflammation,cystoid macular edema*Ke TL, et al. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocularinflammation.. Inflammation. 2000;24(4):371-84
    32. 32. MAST CELL STABILIZERS AND ANTIHISTAMINES Human eye has about 50 million mast cells, which containspreformed chemical mediatorsAllergic conjunctivitisIgE mediated hypersensitivity reactionMast cells and basophilsHistamine Leucotrines Chemotactic factorscapillary dilatation stimulates nerve endingsincreased permeabilitypain and itchingconjunctival injection and swelling
    33. 33. Class GenericnameMechanism Dosage Side effectsMast cellinhibitorCromolynsodiuminhibit neutrophil,eosinophil,monocyte0.01% BD does not provideimmediate reliefH1 antagonist+ mast cellinhibitorAzelastine HCLprovidesimmediate reliefand preventfurtherdegranulationrapid onset0.05% BD ocular burning,stinging, dry eyeEpinastine HCLKetotifenfumarateNedocromilsodiumOlopatadine 0.05%, 0.01%BD/ODH1 antagonist+decongestantNaphazolineHCL/phenaramine maleateshort term relieffor mild allergy 0.05%/0.01% BD
    34. 34. IMMUNOSUPPRESSIVE not used as primary therapy cases non responding to steroids or steroids responders or startedhaving steroid complications avoided in children and pregnant women effect may take 1-4 weeks to develop, hence initial therapy withcorticosteroids is needed Azathioprine, Cyclosporin, Methotrexate are commonly being used
    35. 35. Drug Formulation Dosage AdverseeffectsSpecialpointsMethotrexate 2.5, 5, 7.5 mg Weekly GI symptoms,hepatotoxic( LFT)Less cost,Well toleratedAzathioprine 25, 50 mg 1mg/kg MyelosuppressionOnset take 4-5weeksCyclosporine 25, 50 mg0.05%,0.1%emulsion5mg/kg/day Nephrotoxic(urea, creatinine)Fast onset ofactionMore efficaciousDry eyeMycophenolatemofetil250, 500 mg 1gm BD MyelosuppressionHigh costLeflunomide 10, 20 mg 100mg/day GI upset,hepatotoxicStill under trial
    36. 36. MYDRIATICS AND CYCLOPLEGICS Mydriatics are the drugs which dilate the pupil andcycloplegics are agents which causes paralysis of ciliarymusclesMydriaticsAdrenergic agonist Cholinergic antagonistsAdrenaline Phenylephrine Tropicamide
    37. 37. PHENYLEPHRINE (2.5%) most common sympathomimetic agent used acts on alpha 1 receptors of the dilator pupillae indication pupil dilation refraction before intraocular surgeries contraindication hypersensitive narrow angle glaucoma cardiac patients elderly patients
    38. 38.  Side effects initial stinging and burning systemic side effects include palpitation, tachycardia, headache,arrythmias reflex bradycardia, pulmonary embolism, myocardial infaction
    39. 39. ADRENALINE acts on dilator fibres and directly produces dilation afterinstillation of four drops of 1:1000 solution may be combined with procaine and atropine to achievemydriasis in severe iritis
    40. 40. CYCLOPLEGIC MYDRIATICS parasympatholytic agents are commonly used blocks the action of cholinergic stimulation causing paralysis ofaccomodation and pupillary dilation indication refraction inflamation of uvea malignant glaucoma adverse reaction transient stinging and burning, increase in IOP, allergic lid reaction,hyperemia flushing and dryness of skin, blurred vision, dryness of mouth andnose, anhidrosis, fever, bladder distention and CNS disturbances
    41. 41.  precautions permanent mydriasis may occur in patients of keratoconus longer acting agents may cause posterior synechiae formation whentreating anterior segment inflammation avoid driving or any other task requiring alertness overdosage Administer parenteral physostigmine commonly used agents are atropine sulfate, homatropine,cyclopentolate, tropicamide
    42. 42. ATROPINE(1%)HOMATROPINE (2%)TROPICAMIDE(0.5,1%)CYCLOPENTOLATE (0.5,1)Instillation regime rice grain size thricea day for 3 days6-8 drops 10min apart2 drops 5 minapart2 drops 5 minapartOnset 18 hr after lastinstillation40 min after 2nddrop20 min after 2nddrop30 min after 2nddropRecovery 10-14 days 3 days 4 hours 2 daysIndications refraction children<7 yrs, strongestcycloplegicacts morequickly andshorter action,early recoverydiagnosticproceduresrefraction, fundusexaminationshort actingOther Uses drug of choice inanterior segmentinflammation,penalisation inamblyopialow gradeUveitispre and postoperatively,provocative testfor glaucomamost commonlyused post cataractsurgerySide effects dose related sideeffectsSimilar as discussed before
    43. 43.  Atropine is the most effective cycloplegic followed by Cyclopentolate(1%) & then Homatropine (2%) & Tropicamide(0.5-1%). Cyclopentolate should not be prescribed in uveitis as it haschemotactic effect on leucocytes. mydriasis is quickest with Tropicamide among allparasympathomimetics (in 20 minutes) and is also shortest lasting 2.5% Phenylephrine (selective Alpha-1 agonist) along withanticholinergics like tropicamide 0.8 % inducesmaximum mydriasis
    44. 44. TOPICAL HYPEROSMOTIC AGENTS these agents are helpful in treating corneal edema of diverseetiology epithelial edema is more responsive as compared to stromal edema osmotic gradient is created between epithelium and tear film bythese agents water is then drawn towards the more osmotic compartment and isthus eliminated from the epithelium and stroma
    45. 45.  commercially available are Topical NaCl solution (2% & 5%) Topical NaCl ointment (6% gel) dosage is 5 to 6 times a day for drops and 2-3 times a day for gelstill the desired response is achieved gel form is more superior in terms of efficacy and tolerability
    46. 46. OCULAR LUBRICANTS available as drops, gels and ointments indication protection and lubrication exposure keratitis, decreased corneal sensitivity, recurrent cornealerosionsHydrogels are the viscosityenhancing active ingredientsof artificial tearsReduce the risk of bacterialcontamination inmultidose containers,and to prolong shelf life. E.g.benzalkoniumChloride, oxychloro complex
    47. 47.  adverse effects of tear substitute redness stinging and temporary blurring of vision hypersensitivity reactions various tear substitutes available can be categorized asCellulose derivatives Polyvinyl polymersCarboxymethyl cellulose (CMC)Hydroxyethyl cellulose (HEC)Hydroxypropyl cellulose (HPC)Hydroxypropylmethyl cellulose (HPMC)Polyvinyl alcoholPolyvinyl pyrrolidonePolyethylene glycol
    48. 48. CELLULOSE DERIVATIVES POLYVINYL ALCOHOL BASEDpolysaccharides synthetic polymermix well with other ophthalmicproductsdoes not mix well with otherophthalmic productsonly benefit in aqueous defeciency beneficial in lipid, aqueous and mucinlayer defeciencieshypromellose can cause crusting oflids mimicking blepharitisshort retention time on ocular surfaceavailable as 0.5%, 1% soultion 1%, 1.4% solutionblurring of vision is common water soluble, does not blur vision
    49. 49. OINTMENTS major advantage is that ointment is retained longer than solution available as petrolatum, lanolin, mineral oil topical ointment dosage bed time is preferred Solution should be instilled prior to application of ointment recent advances Carbopal 980(polyacrylic acid) containing gel is developed minimisesblurring and less dose is required
    50. 50. ANTI GLAUCOMA DRUGS
    51. 51. Beta blockers AlphaAgonists(sympathomimetics)Prostaglandin analoguesCarbonicanhydraseinhibitorsCholinergic(parasympathomimetic)NonselectiveSelectiveTimolol Betoxolol Brimonidine0.2%Latanoprost0.005%Dorzolamide2% PilocarpineLevobunolol Apraclonidine0.5-1%Bimatoprost -0.03%Brinzolamide1%CarbacholMetipranolol Dipivefrin0.1%Travoprost –0.004%Carteolol Epinephrine1-2%Unoprostone0.15%
    52. 52. CHOLINERGIC AGENTS Cholinergic drugs either act directly by stimulating cholinergicreceptors or indirectly by inhibiting the enzyme cholinesterase Topically applied cholinergic agents causes contraction1] iris sphincter miosis2] circular muscles of ciliary body relaxing zonular tension & forward lensmovement accommodation3] longitudinal muscle of ciliary body Tension on scleral spurOpening of trabecular meshworkaqueous outflow
    53. 53. SIDE EFFECTS OF CHOLINERGIC AGENTS Lids orbicularis muscle spasm and lid twitching, Conjunctiva irritation,conjunctival hyperemia, allergic conjunctivitis Cornea epithelial staining and vascularisation, atypical band keratopathy. Iris hyperemia, pigment epithelial cyst formation, post operative iritis andsynechiae formation.
    54. 54.  Lens cataract, increase lens thickness – myopia Systemic sweating, salivation and lacrimation, nausea, vomiting andabdominal cramps, night mare, bronchial spasm, asthma andpulmonary edema.
    55. 55. PILOCARPINE oldest and most widely used cholinergic agent,derived from the plant pilocarpus microphylus. Topical solution is available in two salts: Pilocarpine hydrochloride in the strengths of 0.25, 0.50, 1, 2, 3, 4%. Pilocarpine nitrate in the strengths of 1, 2 & 4%. produces a reduction in IOP that starts after one hour and lasts for 4 -8 hours. IOP decrease is 15-20%
    56. 56. In open angle glaucomaIn angle closure glaucoma
    57. 57. INDICATIONS FOR PILOCARPINE First line for acute and chronic angle closure glaucoma, primaryopen angle glaucoma Less certain indications in neovascular glaucoma,uveitisrelated glaucoma Also used in laser trabeculoplasty, accommodative esotropia Diagnostically in Adie tonic pupil
    58. 58. CARBACHOL It is a synthetic derivative of choline. longer acting than pilocarpine. indications intracameral use 0.1% during anterior segment surgery can be used in patients who are allergic to pilocarpine
    59. 59. Β– BLOCKERS usually first line agent for treating most types of glaucoma excellent IOP lowering efficacy long duration of action few ocular side effects first commercially available β blocker for systemic use , was propanolol for topical use was timolol reduce IOP 20-30% with little or no effect on pupil size oraccomodation blurred vision associated with miotics is not seen here
    60. 60. MECHANISM OF ACTION decrease aqueous humour production by inhibition of catecholaminestimulated synthesis of c-AMP effective in glaucomatous and normotensive eyes, indicated in primary and secondary open angle glaucoma secondary angle closure glaucoma after penetrating keratoplasty aphakic and pseudophakic glaucoma acute and chronic primary angle closure glaucoma developmental glaucoma
    61. 61. SYSTEMIC SIDE EFFECTS AND CONTRAINDICATIONS OF BBLOCKERSSide effects burning sensation hyperemia. superficial punctate Keratitis. corneal anesthesia. allergic blepharoconjunctivitis dry eye bronchospasm masking of hypoglycemia indiabetes heart failure in pulmonary edema A-V dissociation and cardiac arrestin patients with pre-existing partialheart blockContraindications bronchial asthma COPD sinus bradycardia 2nd or 3rd degree A-V block sexual dysfunction
    62. 62. β blockersNONSELECTIVEβ1 β2TIMOLOL LEVOBUNOLOL CARTEOLOLSELECTIVEβ1BETAXOLOL
    63. 63. TIMOLOL first β-blocker to be commercially used inophthalmics in 1978 it is non selective. inhibits both β1 and β2 receptors peak level of drug within 1-2 hours clinical effect may last upto 2 weeks after last use available in 0.25% and 0.5% administered in B.D. dose
    64. 64.  also available in gel solution : hence can be administered once daily Short term escape due to receptor alteration Long term drift due to tachyphylaxis contraindicated in asthmatic, heart failure patients
    65. 65. BETAXOLOL CARTEOLOL LEVOBUNOLOL• Cardioselective B1blocker•Non Selective (Beta 1 andBeta 2) blocker• Non selective β1, β2blocker• safely used in asthmaticand cardiac patients•It has fewer side effects,better for cardiovascularpatientsThe long term drift is lessthan timolol.• 0.25%, 0.5% in BD dosage •1, 2% BD • 0.25% and 0.5%•IOP lowering effect 26%•response may require fewweeks to stabilise•IOP lowering effect is 32%. •IOP lowering effect is 30%•used in OD dosing aslonger half – life• OPTIPRESS (0.5%) • OCUPRESS (1%) • BETAGAN (0.5 %)
    66. 66. ALPHA ADRENERGIC AGONIST Directly acting sympathomimetics Epinephrine Dipivefrin Alpha2 adrenergic agonists Apraclonidine Brimonidine Indicated in open angle glaucoma to control IOP spikes after laser procedures ocular hypertension
    67. 67. BRIMONIDINE recently introduced 2nd generation α-adrenergic receptor agonist,with high degree selective to α2 receptors. dual action. it decreases aqueous humor production like β-blockers and alsoincreases the uveo scleral out flow like prostagladins. has binding sites in the iris epithelium, ciliary epithelium, ciliarymuscle, retina and retinal epithelium and choroid IOP reduction is 26% (2 hrs post dose) and has an additiveneuroprotective action
    68. 68.  available in 0.2% (0.15%, 0.1% )solution (5, 10, 15ml Packs). Instilone drop 2-3 times daily. side effects include ocular allergy, follicular conjunctivitis, lid edema,dry mouth, headache contraindicated in patients receiving MAO inhibitor therapy, tricyclicantidepressant, produces cardiovascular instability in infants and istherefore contraindicated in the first 5 years of life. Brimonidine’s effectiveness may be reduced by concomitantadministration of NSAIDs **Sponsel WE, et al: Latanoprost and brimonidine therapeutic and physiologic assessment before andafter oral nonsteroidal anti-inflammatory therapy,Am J Ophthalmol 133:11, 2002
    69. 69. CARBONIC ANHYDRASE INHIBITORS inhibits enzyme carbonic anhydrase present in pigmented and nonpigmented epithelium of ciliary body prevents the bicarbonate and sodium influx and decreases aqueousformation useful in short term treatment of acute glaucoma onset of action within 1 hour and maximum effect in 4 hours
    70. 70. DORZOLAMIDE BRINZOLAMIDE• local inhibition of CA in ciliary body minimizing side effects• adverse effects include burning, stinging, blurred vision ,lsystemic side effect israre• caution must be exercised in patients with compromised epithelium2% solution, TDS 1% solution, TDShas better penetration safe and well toleratedDORZOX, TRUSOPT AZOPTTOPICAL CARBONIC ANHYDRASE INHIBITORS
    71. 71. PROSTAGLADINS The PGs derivates primarily lower IOP by enhancing the uveo-scleral outflow of the eye. two possible mechanism exists that have been studied are relaxationof the ciliary muscle and remodeling the extra cellular matrix of theciliary muscle. first line for open angle glaucoma, ocular hypertension, exfoliationand pigmentary glaucoma less certain indications in angle closure,neovascular glaucoma contraindicated in allergic patient, pregnancy, uveitic glaucoma
    72. 72. LATANOPROST TRAVOPROST BIMATOPROST•Increases uveoscleral outflow Decreases resistance tooutflow•Duration of action 12-24 hrs•Wash out period 3-4 weeks•burning stinging, conjunctival hyperemia, iris pigmentation, anterior uveitis,hypertrichosis of eyelashes0.005% OD 0.004% OD 0.03%, ODSafest and most efficacious Best in maintenance ondiurnal variation of IOPControls diurnal variationbetter than latanoprostcontraindicated withpilocarpinestable, safe and welltolerablehighest incidence red eyerateXALANTAN, 9PM TRAVATAN LUMIGAN, CAREPROST
    73. 73. FIXED COMBINATIONS Advantages- Convenience Compliance Effectiveness Cost effectiveness Safety and tolerability Disadvantage Not always as additive as expected Best scientific combination one drug from group that reduce aqueous formation one that increases aqueous outflow
    74. 74. Few combinations available are Timolol 0.5% and Dorzolamide 2% Brimonidine 0.2% and Timolol 0.5% Latanoprost 0.005% and Timolol 0.5% Travaprost 0.004% and Timolol 0.5% Bimatoprost 0.03% and Timolol 0.5.
    75. 75. SYSTEMIC ANTI GLAUCOMA Oral Acetazolamide Glycerine Intravenous Mannitol Neuroprotective agents Calcium channel blockers Nitric oxide synthase inhibitors Vasodialators Antioxidants
    76. 76. ACETAZOLAMIDE oral carbonic anhydrase inhibitora) Tablet 125mg/250mg, TDS/BD onset of action within 1 hr Peak at 4 hrs Duration of action 8-12 hrsb) Slow release capsule Given OD/BD Duration of action upto 24 hrsc) Intravenous 500mg vials Immediate onset , peak action at 30 minutes useful in acute glaucoma, cystoid macular edema, altitude sickness,epilepsy, respiratory stimulant
    77. 77. ADVERSE EFFECTS OF ORAL CAIS intolerance due to their adverse effects common in elderly people neurological/psychiatric Paresthesia, fatigue, malaise, Depression, headache, decreased libido gastrointestinal— metallic taste and discomfort, Nausea, abdominal cramps diarrhea
    78. 78.  renal/metabolic Increased micturation frequency Renal stones,hypokalemia(metabolic acidosis) May cause exacerbation of gout hematological Bone marrow depression,aplastic anemia teratogenic effect rarely: contraindicated in first trimester
    79. 79. HYPEROSMOTIC AGENTSIncrease the osmolarity of plasmaLeads to absorption of water from ocular tissues( mainly vitreous) indication acute glaucoma secondary glaucoma, preparation of patients before OT malignant glaucoma adverse effects headache, nausea, vomitting systemic hypertension congestive heart failure and pulmonary edema urinary retention and hyperglycemia
    80. 80.  Oral Glycerol 50% solution in dose of 1.5 to 3 ml/kg body weight poorly penetrates into the eye diabetics may have problem due to caloric value, osmotic diuresisand dehydration Mannitol 20% concentration 1-2gm/kg body weight or 5-10ml/kg body weight peak action-within 30 mins duration of action-upto 6hours choice for intravenous therapy
    81. 81. NEUROPROTECTIVE AGENTS To protect the optic nerve damage by- Block the endogenous substances which may have damaging effect onganglion cells Prevent neuronal degeneration and promoting regeneration Endogenous substances released during glaucoma are Excitotoxins-glutamate and aspartate Elevated intracellular Ca++ Nitric oxide Free radicals Agents that promote regeneration Calcium channel blockers Nitric oxide synthase inhibitors Antioxidants Vasodilators
    82. 82.  Prostagladins analogs, beta blockers, alpha2 agonist are resonablechoices for first line therapy However, prostagladins with once daily dose are most effectiveagents for IOP lowering and provide good 24 hr IOP control
    83. 83. THANK YOU

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