Ocular therapeutics2


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Ocular therapeutics2

  1. 1. -Ajay Kumar Singh-Shashi Sharma•Department of Ophthalmology•King George‘s Medical University, Lucknow (INDIA)
  3. 3. ANTIMICROBIAL AGENTS Synthetic as well as naturally obtained drugs that attenuate microorganisms. CLASSIFICATION: On the basis of type of organism, they inhibit-Antibacterial- Penicillins, Aminoglycosides, Fluoroquinolones etc.Antifungal- Amphotericin B, Fluconazole etc.Antiviral- Acyclovir, Zidovudine etc.Antiprotozoal- MetronidazoleAntihelminthic- Albendazole, Niclosamide etc.
  4. 4.  On the basis of mechanism of action:Inhibit cell wall synthesis- Penicillins, CephalosporinsCause leakage from cell membrane- Amphotericin BInhibit protein synthesis- Tetracyclines, ChloramphenicolCause misresding of m-RNA code- AminoglycosidesInhibit DNA gyrase- FluoroquinolonesInterfere with DNA function- Metronidazole, RifampicinInterfere with DNA synthesis- Acyclovir, Zidovudin
  5. 5.  On the basis of type of actionPrimarily bacteriostatic Primarily bactericidalSulfonamides PenicillinsTetracyclines CephalosporinsChloramphenicol AminoglycosidesFluoroquinolonesVancomycin
  6. 6. Antibacterials Used locally (topically andsubconjunctivally) in prophylaxis (pre andpostoperatively) and treatment of ocularbacterial infections. Used systemically (orally andintravenously) for the treatment ofpreseptal/orbital cellulitise.g. amoxycillin with clavulanate, ,cephalosporin, vancomycin Can be injected intravitreally for thetreatment of endophthalmitis
  7. 7. ANTIBACTERIAL AGENTSPENICILLINS: Bactericidal Short half-life Excreted mainly via kidney; a small fraction via biliary tract Act by interfering with cell wall synthesis Most have narrow spectrum, mainly against Gram-positive organisms Have synergistic action with aminoglycosides
  8. 8.  3 major groups: Penicillins effective against cocci and Gram-positive bacilli Eg. Benzyl penicillin (non acid stable) and penicillin V (acid stable) Penicillinase resistant penicillins Eg. Cloxacillin and flucloxacillin Extended spectrum penicillins Aminopenicillins: Ampicillin, Amoxycillin Carboxypenicillins: Ticarcillin, Carbenicillin Ureidopenicillins: Piperacillin, Mezlocillin
  9. 9.  β- LACTAMASE INHIBITORS:Clavulanic acid: Obtained from Streptomyces clavuligerus Tissue distribution and elimination matches Amoxicillin Combination- COAMOXYCLAV (Amoxycillin 250/500 mg + clavulanic acid 125 mg)Sulbactum: Less potent than clavulanic acid Oral absorption inconsistent: given parenterallyTazobactum: Pharmacokinetics matches Piperacillin (combination- TAZOMAC : Piperacillin 4g + tazobactum 0.5g)
  10. 10. Here comes your footer DRUGS SPECTRUM DOSEPenicillinderivativesPenicillin Gram-positive organisms, Spirochetes SYSTEMIC- 4-30 million U in 24 divided doses 4-6hourlyTOPICAL- 0.1 million U/mL (Fortified drops)Cloxacillin Gram-positive organisms, also penicillinaseproducingSYSTEMIC-50-100mg/kg/day oral/i.v. 6 hourlyAmpicillin Gram-positive organisms, H. influenzae, E. coli,Proteus, Salmonella, ShigellaSYSTEMIC-50-100mg/kg/day oral/i.v. 6 hourlyTOPICAL- 10 mg/mL (Fortified drops)INTRAVITREAL- 500 mg/mLAmoxycillin Gram-positive organisms SYSTEMIC-25-50mg/kg/day oral 8 hourly
  11. 11.  CEPHALOSPORINS:Structure and mode of action similar to penicillins (bactericidal)Relatively resistant to staphylococcal penicillinasePatients allergic to penicillin may develop allergyIntraocular penetration not very good
  12. 12. DRUGS SPECTRUM DOSECephalosporins1stGenerationCephalexin Gram-positive organisms, penicillinase producingstaphylococci, C.diphtheriae, Clostridia, Actinomyces,E. coli, Klebsiella, Shigella, Salmonella, Proteus, H.influenzae25-50 mg/kg/day oral 6 hourlyCephazolin Gram-positive organisms, E. coli, Proteus, H.influenzae25-50 mg/kg/day i.m./i.v. 8 hourlyTOPICAL-50 mg/mL (Fortified drops)INTRAVITREAL- 2.25 mg in 0.1 mL2ndGenerationCefamandole Gram-positive organisms, E. coli, Proteus, H.influenzae1 gram 4 hourly i.v.TOPICAL- 50 gram/mL (Fortified drops)Cafaclor Gram-positive organisms, E. coli, Proteus, H.influenzae25-50 mg/kg/day oral 8 hourlyCefuroxime Gram-positive and negative organisms, penicillinase-producing N.gonorrhoeae, ampicillin-resistant H.influenzae30-100 mg/kg/day i.m./i.v. 8-12 hourly
  13. 13. DRUGS SPECTRUM DOSE3rdGenerationCefotaxim Aerobic Gram-negative organisms 100-150 mg/kg/day i.m./i.v. 8-12hourlyTOPICAL- 50 mg/mL (Fortified drops)Ceftriaxone Aerobic Gram-negative organisms 80-150 mg/kg/day i.v. 8-12 hourlyCefoperazone Gram-positive organisms, Pseudomonas, Salmonella,Bacteroides fragilis50-200 mg/kg/day i.m. 8-12 hourlyCeftazidime Aerobic Gram-negative organisms, Pseudomonas 50-100 mg/kg/day i.v. 8-12 hourlyINTRAVITREAL- 2.25 mg in 0.1 mL
  14. 14.  AMINOGLYCOSIDES:BactericidalBroad spectrum of activity against Gram-positive and Gram-negativeorganismsRenal and vestibular toxicityInterfere with neuromuscular conduction- may cause paralysis inMyasthenia gravis patientsIntravitreal injections may cause retinotoxicity
  15. 15. DRUGS SPECTRUM DOSEAminoglycosidesGentamicin Aerobic Gram-negative organisms,Pseudomonas, Proteus, E.coli, KlebsiellaSYSTEMIC- 4-8 mg/kg.day i.m./i.v. 8 hourlyTOPICAL- 0.3% drops/ointmentINTRAVITREAL- 200-400 μg in 0.1 mLAmikacin Aerobic Gram-negative organisms,gentamicin-resistant organismsSYSTEMIC- 15-20 mg/kg.day i.m./i.v. 8 hourlyTOPICAL- 0.3% dropsINTRAVITREAL- 400 μg in 0.1 mLTobramycin Aerobic Gram-negative organisms,Proteus, PseudomonasSYSTEMIC- 6-7.5 mg/kg/day i.m./i.v. 8-12 hourlyTOPICAL- 0.3% drops/ointmentINTRAVITRAL- 150-200 μg/mLNeomycin most Gram-negative bacilli and someGram-positive cocciSYSTEMIC- 4-12 gram/day 6 hourlyTOPICAL- 0.17% drops, 5 mg/gram ointmentFramycetin Activity similar to neomycin TOPICAL- 0.5% drops
  16. 16.  TETRACYCLINES:Broad spectrum antibiotics with bacteriostatic action against both Gram-positive and Gram-negative organisms as well as some fungi, rickettsiae andchlamydiae.Get deposited in growing bones- not to be used in children and pregnant orlactating mothers MACROLIDES:Bacteriostatic agents with narrow spectrum against Gram-positiveorganisms, Chlamydia and Toxoplasma gondii.
  17. 17. DRUGS SPECTRUM DOSETetracycline and itsderivativeTetracyclin Gram-positive and negative organisms SYSTEMIC-50 mg/kg/day oral 6 hourlyTOPICAL- 1% drops/ointmentDoxycyclin Gram-positive and negative organisms,spirochaetes, rickettsiae, chlamydiae,Mycoplasma, Actinomyces, EntamoebahistolyticaSYSTEMIC- 1.5-2 mg/kg/day oral 12-24 hourlyMacrolidesErythromycin Gram-positive cocci, H.influenzae,E.coli, Mycoplasma, Salmonella,ChlamydiaSYSTEMIC- 1-4 gram/day oral/i.v. 6 hourlyTOPICAL- 0.5% ointmentINTRAVITREAL- 500 μg/mLAzithromycin Gram-positive organisms, Chlamydia,Toxoplasma gondiiSYSTEMIC-20-30 mg/kg oral single doseTOPICAL- 1% dropsVancomycin Gram-positive organisms,staphylococci, MRSA, enterococci,Streptococcus viridans, ClostridiumSYSTEMIC- 2 gram/day 6-12 hourlyTOPICAL- 50 mg/mL (Fortified drops)INTRAVITREAL- 1 mg in 0.1 mLCombination drugsCo-trimoxazole (400 mgsulphamethoxazole + 80 mgtrimethoprim)Gram-positive and negative organisms SYSTEMIC-6 mg of trimethoprimequivalent/kg/day oral 12 hourly
  18. 18.  GLYCOPEPTIDES:Very effective against nearly all Gram-positive as well as against methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis.toxic if used topically or subconjunctivallyVANCOMYCIN: High systemic toxicity Nephro and ototoxic Used intravitreally/parenterally for treatment of endophthalmitis
  19. 19.  FLUOROQUINOLONES:Derivatives of nalidixic acidBroad spectrum agents 1stgeneration• active mainly against Gram-negative organisms• Eg. Norfloxacin, Ciprofloxacin, Ofloxacin, Pefloxacin 2ndgeneration• also active against Gram-positive and anaerobe organisms• Eg. Levofloxacin, Lomefloxacin, Gatifloxacin, MoxifloxacinGet deposited in growing cartilage- not recommended in children
  20. 20. DRUGS SPECTRUM SYSTEMIC DOSE TOPICAL/ INTRAVITREALDOSEFluoroquinolonesCiprofloxacin Actinomyces, Nocardiaspp., Toxoplasma spp.Aerobic Gram-negativeorganisms15-20 mg/kg/day oral 12hourly7-10 mg/kg/day i.v. 12 hourlyTOPICAL- 0.3% drops/ointmentINTRAVITREAL- 100 μg in 0.1 mLNorfloxacin Aerobic Gram-negativeorganisms10 mg/kg/day oral12 hourly TOPICAL- 0.3% drops/ointmentINTRAVITREAL- 100 μg in 0.1 mLOfloxacin Gram-positive andnegative organisms200-400 mg oral 12 hourly TOPICAL- 0.3% drops/ointmentINTRAVITREAL- 100 μg in 0.1 mLLevofloxacin Gram-positive andnegative organisms250-750 mg oral/i.v. 24 hourly TOPICAL- 0.5% dropsINTRAVITREAL- 150 μg in 0.1 mLGatifloxacin Gram-positive andnegative organisms200-400 mg oral 24 hourly TOPICAL- 0.3%, 0.5% drops,0.3% ointmentMoxifloxacin Gram-positive andnegative organisms200-400 mg oral/i.v. 24 hourly TOPICAL- 0.5% drops/ointment
  21. 21.  CHLORAMPHENICOL:Bacteriostatic agentActive against bacteria, spirochaetes, rickettsiae, chlamydiae andmycoplasmasWidest spectrum for superficial ocular infectionsToxic to the corneal epitheliumMay lead to blood dyscrasias
  22. 22.  SULPHONAMIDES:Bactriostatic agentsUsed against Gram-positive bacteria and Chlamydia.Eg. Topical 10-30% sulphacetamide- Trachoma
  23. 23. ANTI FUNGALSClassified on the basis of molecular structurePolyenes Imidazole TriazolesAmphotericin B Natamycin KetoconazoleFluconazole Itraconazole Voriconazole
  24. 24. Polyenes First effective antifungal used Bind preferentially to ergosterol in fungal plasma membrane, thereby altering membrane permeabilityand disruption of fungal cells Has poor corneal penetration Used effectively against variety of filamentous fungi Aspergillus, Candida, Histoplasma Local hypersensitivity and corneal epithelial toxicity may occur Prolong use may cause renal, bone marrow or CNS toxicity
  25. 25. AMPHOTERICIN B NATAMYCINProduced from Streptomycetes nodosus Streptomyces natalensesDosage •TOPICAL: 0.075-0.3% drops/hourly•SUBCONUJNCTIVAL: 0.8-1 mg•INTRAVITREAL: 500 μg in 0.1 mL•SYSTEMIC: 1mg/kg in 5% dextrose 4 hourly i.v.*Pretreat with 25mg hydrocortisoneTOPICAL: 5% ophthalmic suspension/hourlyinterval followed by gradual taperingTopical suspension should be shaken wellbefore useIndications Aspergillus, Candida, Cryptococcus andmucormycosisCandida, Histoplasma and ActinomycetesConsidered superior but has to be reconstitutedand has low shelf lifeDOCEasily available in solution formTrade names Amphocin, Fungizone Natamet, Nataone, NataAid
  26. 26. Clotrimazole Chlorinated imidazole derivative Broad antifungal activity more active in treatment of aspergillus infections DOSAGE: 1% topical ophthalmic drops and ointment Topical drops are instilled hourly followed by gradual tapering Ointment is applied 4 times a day Adverse reactions include ocular irritation and punctate keratopathy
  27. 27. Fluconazole Most effective against yeast species Candida and Cryptococcus DOSAGE: 0.3% solution Every 4 hour interval with gradual tapering Has faster and deeper penetration Highly effective in fungal keratitis with deep abscess Adverse reactions are minimal irritation and transient burning of the eyes
  28. 28. Itraconazole Shares a similar pharmacokinetic profile with fluconazole Used in Aspergillius infections, has moderate effects against Candida DOSAGE: 1% ophthalmic solution 8 times a day is the recommended dosage
  29. 29. Voriconazole Indicated for use in the treatment of fungal keratitis caused byAspergillus spp., Fusarium spp.,Candida spp. and Scedosporiumapiospermum PREPARATION:Lyophilized form enhances drug stability and solubility30 mg powder reconstituted with 3 mL to get 10 mg/mL(1% solution) ADVERSE EFFECTS:it may cause serious hepatic reactions
  30. 30. ANTI VIRAL DRUGS Anti viral drugs are activated to triphosphate by viral and cellular thymidinekinases (TK) This active metabolite then inhibits DNA/RNA replication by competitiveinhibition and direct incorporation into viral DNA resulting in chain termination Oral Acyclovir- 800 mg, 5 times/day ADVERSE EFFECTS:Blurring of vision, dizziness, drowsiness, tremors, severe allergic reactions, hematuria Acyclovir and Ganciclyovir ointment are available for topical use
  31. 31. ACYCLOVIR (3%) GANCICYCLOVIR (0.15%)Indications • Primary HSV keratitis, dendritic ulcers• Herpes zoster and varicella infections• Acute retinal necrosis syndromeAdverse effects • Vision blurred,irritation,Punctate keratitis• Conjunctival hyperemia• Erythema of eyelid, SPK• Dry eye, Foreign body sensationDosage 5 times a day, followed by taperingAcyclovir vs Gancicyclovir Ganciclovir ophthalmic gel 0.15% is a new dosage form recently approved bythe FDA for the treatment of acute herpetic keratitis (dendritic ulcers).Better penetration than acyclovir with lesser side effectsTrade name ACIVIR OINTMENT® VIRSON GEL®
  32. 32. LOCAL ANAESTHETICS Topical: (drops/jelly)E.g. Proparacaine 0.5%, Lignocaine 2%Uses: applanation tonometry, goniscopy,removal of corneal foreign bodies,removal of sutures, examination of patients, cataract surgeryAdverse effects: toxic to corneal epithelium, rarely allergic reactions
  33. 33.  Orbital infiltration: Peribulbar Retrobulbarcause anesthesia and akinesia for intraocular surgerye.g. Lidocaine 2%, Bupivacaine 0.25%-0.5%
  34. 34. ANTINEOPLASTIC AGENTS These are used in chemotherapy of ocular tumours some are used to decrease the fibroblastic response in ocular surgeries CLASSIFICATION:Alkylating agents: eg. CarboplatinAntimetabolites: eg. Methotrexate, Azathioprine, 5- FluorouracilNatural products: Plant products: eg. Vincristine, Etoposide Microorganism product: eg. Mitomycin C
  35. 35. DRUG GROUP MECHANISM USED IN DOSESCarboplatin Alkylating agent-Platinum co-ordination complexAlkylation of nucleicacid resulting in crosslinking/ abnormal basepairing of DNA strandsOcular tumours 560 mg/m2 BSA (bodysurface area) i.v.Vincristine Vinca alkaloids Arrest the cell cycle inmitotic phase bydisrupting mitoticspindleOcular tumours 1.5 mg/m2 BSA i.v.Etoposide Epipodophyllotoxins Arrests cells in G2phase and inhibits DNAtopoisomerase IIOcular tumours 150 mg/m2 BSA i.v.5-Fluorouracil Antimetabolite-PyrimidineantagonistIinhibition ofpyrimidine synthesisTo prevent excessivescarring in postoperativeperiod (eg. pterygiumsurgery, trabeculectomy)25 mg/mL topicalMitomycin C Antibiotic alkylatingagentcross linking of DNA aswell as an inhibition ofRNA and proteinsynthesisAfter pterygium andglaucoma surgery(trabeculectomy) to reducescarring and recurrenceOcular surface neoplasias0.2-0.5 mg/mL (0.02%-0.05%) solution topical
  36. 36. ANTIOXIDANTS Oxidative damage plays a major role in development of many ophthalmicconditions; viz.Senile cataract, age related macular degenerations (ARMD), diabetic retinopathy etc. Mechanism of oxidative damage:Free radicals and reactive oxygen species are main culpritsAttack proteins (enzymes), neurotransmitters, nucleic acids, phospholipids, retinalpigment epithelium, lens tissue Antioxidants react rapidly with free radicals and reactive oxygen species Act as scavengers for free radicals
  37. 37.  INDICATIONS:Senile cataractAge related macular degenerationDiabetic retinopathyRetinopathy of prematurityIschemic ophthalmopathyCorneal inflammatory disordersOpen angle glaucoma
  38. 38.  PREPARATIONS:Various standardised antioxidant combinations, available in form ofcapsules; eg. i) Zn 30mg, Cu 1.5mg, Se 60 μg, Mn 5mg, vit.A 6000 IU, vit.B2 20 mg, vit.C200 mg, vit.E 60 IU ii) mixed carotenoids, i.e. α-carotene, β-carotene, cryptoxanthin, leutin,zeaxanthin
  39. 39.  Major role of various antioxidant elements: Zinc: integral part of two endogenous antioxidant enzymes viz. catalase andsuperoxide dismutase Copper: cofactor for superoxide dismutase Selenium: cofactor for glutathione peroxidase Vitamin C: directly reacts with and scavenges free radicals; major function isprotection of lens from oxidative damage Vitamin E: intercalates into cell membrane and protects cellular constituentsagainst free radicals
  40. 40.  Carotenoids: major action is to suppress lipid peroxidation (responsible forgeneration of free radicals) Lutein and zeaxanthin: only carotenoids found in the retina and lens of the eye.They help reduce risk of developing age-related cataracts and maculardegeneration Astaxanthin: The most powerful of the carotenoids, by far. Astaxanthin canpenetrate into every part of the cell
  41. 41.  Newer Drug: PENTOXIFYLLIN: (TRENTAL®) Xanthine derivative Major action: improves blood flow in microcirculation Mechanism:competitive phosphodiesterase inhibitor raises intracellular cAMP inhibits TNF-alpha and leukotriene synthesis reduces inflammation USES:Hemorrhagic and ischemic retinal damage,arteriosclerotic chorioretinal dystrophy,ischemic optic nerve damage in glaucoma
  42. 42. ANTI VEGF Anti Vascular Endothelial Growth factors VEGF stimulates both angiogenesis and increased vascular permeability Major angiogenic factor implicated in the pathogenesis of neovascular andexudative eye diseases Anti VEGFs inhibit VEGF and thus evolution of the disease
  43. 43. Wet ARMD Diabetic retinopathy BRVOROLE OF ANTI VEGF:
  44. 44. Retinopathy of PrematurityEales’ DiseaseRefractory post surgical CMECentral serous chorioretinopathyTrabeculectomy (to modulate wound healing)Coat’s disease
  45. 45.  INDICATIONS IN ANTERIOR SEGMENT:Neovascular glaucomaIris neovascularizationBefore keratoplasty to reduce corneal vascularization
  46. 46. PEGAPTANIB RANIBIZUMAB BEVACIZUMABTRADE NAME Macugen® Lucentis ® Avastin®COMPOUND Aptamer Antibody fragmentRhuFabFull humanized mouseMonoclonal antibodyVEGF BINDINGPROPERTYVEGF-A 165SelectiveVEGF-A all forms VEGF-A all formsDOSE 0.3 mg in 90 μl 0.5mg in 0.05 mL 1.25 mg in 0.05 mLDURATION OFACTION1/6 weeks 1/month 1/3 monthsCOST Rs 47,000/syringe Rs 56,000/vial Rs 37,000/vialADVANTAGES Low immunogenicitySelective actionLonger acting thanpegaptanibcost effectiveLong actingDISADVANTAGES cost CVS risks HTN, CVS risksRebound macular edema
  47. 47. FUTURE DRUGS…
  48. 48. TOPICAL IMMUNE THERAPY Relatively new concept To treat iatrogenic inflammation following any type of intraocular surgery To make up the decreased levels of ocular immunoglobulins vital for oculardefence system against external infections
  49. 49.  WHY REQUIRED:In immediate postoperative period (≈7 days) there is significant decrease inglobulin levels of tearsThere is increase in tear secretion following surgeries, resulting in dilution ofimmunoglobulinsThere is physical breach in the continuity of ocular tissue, predisposing toinfections
  50. 50.  DOSAGE:Available as: Topical solution (ASPAC) 0.1% each of IgG and IgA and 0.05% of IgM1-2 drops 3-4 times/day for 7-14 days ADVERSE EFFECTS:Only occassionaly- transient burning sensation, stinging, conjunctivalinjection, hypersensitivity reactions (rarely)