ocular therapeutics2

-Ajay Kumar Singh-Shashi Sharma•Department of Ophthalmology•King George‘s Medical University, Lucknow (INDIA)

ANTIMICROBIALS

LOCAL ANAESTHETICS

ANTINEOPLASTIC DRUGS

ANTIOXIDANTS

ANTI VEGF

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.

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

On the basis of type of action

Primarily bacteriostatic Primarily bactericidal

Sulfonamides Penicillins

Tetracyclines Cephalosporins

Chloramphenicol Aminoglycosides

Fluoroquinolones

Vancomycin

Antibacterials

Used locally (topically and subconjunctivally) in prophylaxis (pre and postoperatively) and treatment of ocular bacterial infections.

Used systemically (orally and intravenously) for the treatment of preseptal/orbital cellulitis

e.g. amoxycillin with clavulanate, , cephalosporin, vancomycin

Can be injected intravitreally for the treatment of endophthalmitis

ANTIBACTERIAL AGENTSPENICILLINS:

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

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

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)

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DRUGS SPECTRUM DOSE

Penicillin derivatives

Penicillin Gram-positive organisms, Spirochetes SYSTEMIC- 4-30 million U in 24 divided doses 4-6 hourlyTOPICAL- 0.1 million U/mL (Fortified drops)

Cloxacillin Gram-positive organisms, also penicillinase producing

SYSTEMIC-50-100mg/kg/day oral/i.v. 6 hourly

Ampicillin Gram-positive organisms, H. influenzae, E. coli, Proteus, Salmonella, Shigella

SYSTEMIC-50-100mg/kg/day oral/i.v. 6 hourlyTOPICAL- 10 mg/mL (Fortified drops)INTRAVITREAL- 500 mg/mL

Amoxycillin Gram-positive organisms SYSTEMIC-25-50mg/kg/day oral 8 hourly

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

DRUGS SPECTRUM DOSE

Cephalosporins

1st Generation

Cephalexin Gram-positive organisms, penicillinase producing staphylococci, C.diphtheriae, Clostridia, Actinomyces, E. coli, Klebsiella, Shigella, Salmonella, Proteus, H. influenzae

25-50 mg/kg/day oral 6 hourly

Cephazolin Gram-positive organisms, E. coli, Proteus, H. influenzae

25-50 mg/kg/day i.m./i.v. 8 hourlyTOPICAL-50 mg/mL (Fortified drops)INTRAVITREAL- 2.25 mg in 0.1 mL

2nd Generation

Cefamandole Gram-positive organisms, E. coli, Proteus, H. influenzae

1 gram 4 hourly i.v.TOPICAL- 50 gram/mL (Fortified drops)

Cafaclor Gram-positive organisms, E. coli, Proteus, H. influenzae


Cefuroxime Gram-positive and negative organisms, penicillinase-producing N.gonorrhoeae, ampicillin-resistant H. influenzae

30-100 mg/kg/day i.m./i.v. 8-12 hourly

DRUGS SPECTRUM DOSE

3rd Generation

Cefotaxim Aerobic Gram-negative organisms 100-150 mg/kg/day i.m./i.v. 8-12 hourlyTOPICAL- 50 mg/mL (Fortified drops)

Ceftriaxone Aerobic Gram-negative organisms 80-150 mg/kg/day i.v. 8-12 hourly

Cefoperazone Gram-positive organisms, Pseudomonas, Salmonella, Bacteroides fragilis

50-200 mg/kg/day i.m. 8-12 hourly

Ceftazidime Aerobic Gram-negative organisms, Pseudomonas 50-100 mg/kg/day i.v. 8-12 hourlyINTRAVITREAL- 2.25 mg in 0.1 mL

AMINOGLYCOSIDES:

Bactericidal

Broad spectrum of activity against Gram-positive and Gram-negative organisms

Renal and vestibular toxicity

Interfere with neuromuscular conduction- may cause paralysis in Myasthenia gravis patients

Intravitreal injections may cause retinotoxicity

DRUGS SPECTRUM DOSE

Aminoglycosides

Gentamicin Aerobic Gram-negative organisms, Pseudomonas, Proteus, E.coli, Klebsiella

SYSTEMIC- 4-8 mg/kg.day i.m./i.v. 8 hourlyTOPICAL- 0.3% drops/ointmentINTRAVITREAL- 200-400 μg in 0.1 mL

Amikacin Aerobic Gram-negative organisms, gentamicin-resistant organisms

SYSTEMIC- 15-20 mg/kg.day i.m./i.v. 8 hourlyTOPICAL- 0.3% dropsINTRAVITREAL- 400 μg in 0.1 mL

Tobramycin Aerobic Gram-negative organisms, Proteus, Pseudomonas

SYSTEMIC- 6-7.5 mg/kg/day i.m./i.v. 8-12 hourlyTOPICAL- 0.3% drops/ointmentINTRAVITRAL- 150-200 μg/mL

Neomycin most Gram-negative bacilli and some Gram-positive cocci

SYSTEMIC- 4-12 gram/day 6 hourlyTOPICAL- 0.17% drops, 5 mg/gram ointment

Framycetin Activity similar to neomycin TOPICAL- 0.5% drops

TETRACYCLINES:

Broad spectrum antibiotics with bacteriostatic action against both Gram-positive and Gram-negative organisms as well as some fungi, rickettsiae and chlamydiae.

Get deposited in growing bones- not to be used in children and pregnant or lactating mothers

MACROLIDES:

Bacteriostatic agents with narrow spectrum against Gram-positive organisms, Chlamydia and Toxoplasma gondii.

DRUGS SPECTRUM DOSE

Tetracycline and its derivative

Tetracyclin Gram-positive and negative organisms SYSTEMIC-50 mg/kg/day oral 6 hourlyTOPICAL- 1% drops/ointment

Doxycyclin Gram-positive and negative organisms, spirochaetes, rickettsiae, chlamydiae, Mycoplasma, Actinomyces, Entamoeba histolytica

SYSTEMIC- 1.5-2 mg/kg/day oral 12-24 hourly

MacrolidesErythromycin Gram-positive cocci, H.influenzae,

E.coli, Mycoplasma, Salmonella, Chlamydia

SYSTEMIC- 1-4 gram/day oral/i.v. 6 hourlyTOPICAL- 0.5% ointmentINTRAVITREAL- 500 μg/mL

Azithromycin Gram-positive organisms, Chlamydia, Toxoplasma gondii

SYSTEMIC-20-30 mg/kg oral single doseTOPICAL- 1% drops

Vancomycin Gram-positive organisms, staphylococci, MRSA, enterococci, Streptococcus viridans, Clostridium

SYSTEMIC- 2 gram/day 6-12 hourlyTOPICAL- 50 mg/mL (Fortified drops)INTRAVITREAL- 1 mg in 0.1 mL

Combination drugs

Co-trimoxazole (400 mg sulphamethoxazole + 80 mg trimethoprim)

Gram-positive and negative organisms SYSTEMIC-6 mg of trimethoprim equivalent/kg/day oral 12 hourly

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

FLUOROQUINOLONES:

Derivatives of nalidixic acid

Broad spectrum agents

1st generation

• active mainly against Gram-negative organisms

• Eg. Norfloxacin, Ciprofloxacin, Ofloxacin, Pefloxacin

2nd generation

• also active against Gram-positive and anaerobe organisms

• Eg. Levofloxacin, Lomefloxacin, Gatifloxacin, Moxifloxacin

Get deposited in growing cartilage- not recommended in children

DRUGS SPECTRUM SYSTEMIC DOSE TOPICAL/ INTRAVITREAL DOSE

Fluoroquinolones

Ciprofloxacin Actinomyces, Nocardia spp., Toxoplasma spp.

Aerobic Gram-negative organisms


7-10 mg/kg/day i.v. 12 hourly

TOPICAL- 0.3% drops/ointmentINTRAVITREAL- 100 μg in 0.1 mL

Norfloxacin Aerobic Gram-negative organisms

10 mg/kg/day oral12 hourly TOPICAL- 0.3% drops/ointmentINTRAVITREAL- 100 μg in 0.1 mL

Ofloxacin Gram-positive and negative organisms

200-400 mg oral 12 hourly TOPICAL- 0.3% drops/ointmentINTRAVITREAL- 100 μg in 0.1 mL

Levofloxacin Gram-positive and negative organisms

250-750 mg oral/i.v. 24 hourly TOPICAL- 0.5% dropsINTRAVITREAL- 150 μg in 0.1 mL

Gatifloxacin Gram-positive and negative organisms

200-400 mg oral 24 hourly TOPICAL- 0.3%, 0.5% drops,0.3% ointment

Moxifloxacin Gram-positive and negative organisms

200-400 mg oral/i.v. 24 hourly TOPICAL- 0.5% drops/ointment

CHLORAMPHENICOL:

Bacteriostatic agent

Active against bacteria, spirochaetes, rickettsiae, chlamydiae and mycoplasmas

Widest spectrum for superficial ocular infections

Toxic to the corneal epithelium

May lead to blood dyscrasias

SULPHONAMIDES:

Bactriostatic agents

Used against Gram-positive bacteria and Chlamydia.

Eg. Topical 10-30% sulphacetamide- Trachoma

ANTI FUNGALS Classified on the basis of molecular structure

Polyenes Imidazole Triazoles

Amphotericin B Natamycin Ketoconazole

Fluconazole Itraconazole Voriconazole

Polyenes

First effective antifungal used

Bind preferentially to ergosterol in fungal plasma membrane, thereby altering membrane permeability and 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

AMPHOTERICIN B NATAMYCIN

Produced from Streptomycetes nodosus Streptomyces natalenses

Dosage •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 hydrocortisone

TOPICAL: 5% ophthalmic suspension/hourly interval followed by gradual taperingTopical suspension should be shaken well before use

Indications Aspergillus, Candida, Cryptococcus and mucormycosis

Candida, Histoplasma and Actinomycetes

Considered superior but has to be reconstituted and has low shelf lifeDOC

Easily available in solution form

Trade names Amphocin, Fungizone Natamet, Nataone, NataAid

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

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

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

Voriconazole

Indicated for use in the treatment of fungal keratitis caused by Aspergillus spp., Fusarium spp.,Candida spp. and Scedosporium apiospermum

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

ANTI VIRAL DRUGS

Anti viral drugs are activated to triphosphate by viral and cellular thymidine kinases (TK)

This active metabolite then inhibits DNA/RNA replication by competitive inhibition 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

ACYCLOVIR (3%) GANCICYCLOVIR (0.15%)

Indications • Primary HSV keratitis, dendritic ulcers• Herpes zoster and varicella infections• Acute retinal necrosis syndrome

Adverse effects • Vision blurred,irritation,Punctate keratitis• Conjunctival hyperemia• Erythema of eyelid, SPK• Dry eye, Foreign body sensation

Dosage 5 times a day, followed by tapering

Acyclovir vs Gancicyclovir Ganciclovir ophthalmic gel 0.15% is a new dosage form recently approved by the FDA for the treatment of acute herpetic keratitis (dendritic ulcers). Better penetration than acyclovir with lesser side effects

Trade name ACIVIR OINTMENT® VIRSON GEL®

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

Orbital infiltration:

Peribulbar

Retrobulbar

cause anesthesia and akinesia for intraocular surgery

e.g. Lidocaine 2%, Bupivacaine 0.25%-0.5%

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

DRUG GROUP MECHANISM USED IN DOSES

Carboplatin Alkylating agent-Platinum co-ordination complex

Alkylation of nucleic acid resulting in cross linking/ abnormal base pairing of DNA strands

Ocular tumours 560 mg/m2 BSA (body surface area) i.v.

Vincristine Vinca alkaloids Arrest the cell cycle in mitotic phase by disrupting mitotic spindle

Ocular tumours 1.5 mg/m2 BSA i.v.

Etoposide Epipodophyllotoxins Arrests cells in G2 phase and inhibits DNA topoisomerase II

Ocular tumours 150 mg/m2 BSA i.v.

5-Fluorouracil Antimetabolite-Pyrimidine antagonist

Iinhibition of pyrimidine synthesis

To prevent excessive scarring in postoperative period (eg. pterygium surgery, trabeculectomy)

25 mg/mL topical

Mitomycin C Antibiotic alkylating agent

cross linking of DNA as well as an inhibition of RNA and protein synthesis

After pterygium and glaucoma surgery (trabeculectomy) to reduce scarring and recurrence

Ocular surface neoplasias

0.2-0.5 mg/mL (0.02%-0.05%) solution topical

ANTIOXIDANTS

Oxidative damage plays a major role in development of many ophthalmic conditions; 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, retinal pigment epithelium, lens tissue

Antioxidants react rapidly with free radicals and reactive oxygen species

Act as scavengers for free radicals

INDICATIONS:

Senile cataract

Age related macular degeneration

Diabetic retinopathy

Retinopathy of prematurity

Ischemic ophthalmopathy

Corneal inflammatory disorders

Open angle glaucoma

PREPARATIONS:

Various standardised antioxidant combinations, available in form of capsules; eg.

i) Zn 30mg, Cu 1.5mg, Se 60 μg, Mn 5mg, vit.A 6000 IU, vit.B2 20 mg, vit.C 200 mg, vit.E 60 IU

ii) mixed carotenoids, i.e. α-carotene, β-carotene, cryptoxanthin, leutin, zeaxanthin

Major role of various antioxidant elements:

Zinc: integral part of two endogenous antioxidant enzymes viz. catalase and superoxide dismutase

Copper: cofactor for superoxide dismutase

Selenium: cofactor for glutathione peroxidase

Vitamin C: directly reacts with and scavenges free radicals; major function is protection of lens from oxidative damage

Vitamin E: intercalates into cell membrane and protects cellular constituents against free radicals

Carotenoids: major action is to suppress lipid peroxidation (responsible for generation 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 macular degeneration

Astaxanthin: The most powerful of the carotenoids, by far. Astaxanthin can penetrate into every part of the cell

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

ANTI VEGF

Anti Vascular Endothelial Growth factors

VEGF stimulates both angiogenesis and increased vascular permeability

Major angiogenic factor implicated in the pathogenesis of neovascular and exudative eye diseases

Anti VEGFs inhibit VEGF and thus evolution of the disease

Wet ARMD Diabetic retinopathy BRVO

ROLE OF ANTI VEGF:

Retinopathy of Prematurity

Eales’ Disease

Refractory post surgical CME

Central serous chorioretinopathy

Trabeculectomy (to modulate wound healing)

Coat’s disease

INDICATIONS IN ANTERIOR SEGMENT:

Neovascular glaucoma

Iris neovascularization

Before keratoplasty to reduce corneal vascularization

PEGAPTANIB RANIBIZUMAB BEVACIZUMAB

TRADE NAME Macugen® Lucentis ® Avastin®

COMPOUND Aptamer Antibody fragmentRhuFab

Full humanized mouseMonoclonal antibody

VEGF BINDING PROPERTY

VEGF-A 165

Selective VEGF-A all forms VEGF-A all forms

DOSE 0.3 mg in 90 μl 0.5mg in 0.05 mL 1.25 mg in 0.05 mL

DURATION OF ACTION

1/6 weeks 1/month 1/3 months

COST Rs 47,000/syringe Rs 56,000/vial Rs 37,000/vial

ADVANTAGES Low immunogenicitySelective action

Longer acting than pegaptanib

cost effectiveLong acting

DISADVANTAGES cost CVS risks HTN, CVS risksRebound macular edema

FUTURE DRUGS…

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 ocular defence system against external infections

WHY REQUIRED:

In immediate postoperative period (≈7 days) there is significant decrease in globulin levels of tears

There is increase in tear secretion following surgeries, resulting in dilution of immunoglobulins

There is physical breach in the continuity of ocular tissue, predisposing to infections

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, conjunctival injection, hypersensitivity reactions (rarely)

ocular therapeutics2

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