Ocular Therapeutics Ocular Therapeutics

Dr Rajvin Samuel Ponraj

Pharmacodynamics

• Study of mechanisms of drug effects

• Receptor - special types based on transduction of signal • Regulation of receptors – Down regulation Up regulation • Therapeutic index

Pharmacokinetics Quantitative study of drug movement in,

through and out of the body

Transport across cell membrane

• Passive transport • Specialized transport

First Pass metabolism

Bioavailabilty

Distribution

• Barriers concerned with distribution Blood aqueous barrier Blood retinal barrierCorneal barrier

Tissue binding

Tissue perfusion

Biotransformation

• Phase 1 reactions• Phase 2 reactions

Excretion of drugs

• Elimination kinetics - First order kinetics Zero order kinetics

• Clearance

• Half life

ADVERSE DRUG EFFECTS

SIDE EFFECTS

TOXIC EFFECTS

INTOLERANCE

TERATOGENICITY

Routes of administration

• Local topical Periocular Intraocular

• Systemic oral injection

Topical drug methods

Eye drops

Eye ointment

Gels

Ocuserts

Soft contact lens

Drug penetration

• Topically : -Lipid and water solubility -Contact time , viscosity , - isotonicity

• Systemically : - Lipid solubility - eye inflammation - protein binding -molecular weight

Ocular anaesthetics

MOA :- Reduce nerve impulse conduction by reducing membrane to sodium ions.Common local anaestheitics :- Ester type = Tetracaine 0.5 % , propacaine 0.75 % Amide type = Lidocaine 2 % , Bupivacaine 0.75 %

Topical anaesthetic

Aim :- To block nerves of superficial cornea

Advantages :- No needle insertion No haemorrage Systemic anticoagulants can use Patient alert

Disadvantages :- No akinesia Not adequate anaesthesia

Adv effects :- Corneal stinging ,epithelial & endothelial toxicity Allergy & contact dermatitis

Contraindications :- Nystagmus , uncooperative patients

Retrobulbar block

Aim :- To block 3 rd cranial nerve in posterior intraconal space

Site of injection :- Above inferior orbital rim midway of lateral canthus & temporal limbus

Advantages :- Excellent akinesia quick onset of block

Disadvantages:- High complication rate

Complications :- Retrobulbar Haemorrhage Globe perforation Optic nerve contusion Oculocardiac reflex Respiratory depression

Peribulbar block

Aim :- To block extraconally the nerves

Site of injection :- midway b/w temporal limbus & lateral canthus -Inferomedial to superior orbital notch

Advantages :- All that of retrobulbar block Less complications

Disadvantages :- More than one injection needed Only good akinesia , anesthesia Longer time for anesthesia Chemosis

Sub tenon’s block

At 1 or 2 ‘0’ clock positions from corneal limbus [7-8 mm away] Using a 30 mm radius flexible cannula after perforating conjunctiva Passed beyond equator b/w tenon’s capsule & sclera Most frequent site is inferotemporal .

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Intraocular injections

• Intracameral or intravitreal• E.g.

– Intracameral acetylcholine (miochol) during cataract surgery

– Intravitreal antibiotics in cases of endophthalmitis

– Intravitreal steroid in macular edema

– Intravitreal Anti-VEGF for DR

INTRA-OCULAR INJECTIONS

Mydriatics & Cycloplegics Anticholinergic drugs :- Atropine 1 % - 1 week

Homatropine 2 % - 24 hrs Cyclopentolate 1 % - 24 hrs Tropicamide 0.5 % - 4 hrs

Indications :- corneal ulcer , uveitis , cycloplegic refractionSide effects :- blurry vision , photophobia ,precipitates angle closure glaucoma

Sympathomimetics :- Phenylephrine 5 %

Indications - Along with mydriatic in Preoperative cataract preparation , fundus examinationSide effects - Stinging , rise in Blood pressure

Anti glaucoma drugs

- B adrenergic blockers : MOA - Reduce aqueous production – down regulation of Adenylcyclase Advan : NO pupil change, induced myopia No headache, nor IOT fluctuation Side eff : Stinging,burning ,allergy,.. Bronchospasm,Heart block Timolol – Non selective 0.5 % Betaxolol - B 1 selective

MIOTICS : Pilocarpine –cholinomimetic drug MOA : increases tone of ciliary muscles -pull trabecular meshwork - outflow of aqueous

Advant : Rapid but short acting Disadv : IOT fluctuation ,dim visual loss Side eff : Spasm of accomadation ,brow ache, git disturbances

0.5 % - drops , ocuserts, gel

Adrenergic agonists

EpinephrineMOA - On alpha , beta receptors – reduce aqueous formation increases aqueous outflow Side effects : Burning , stinging , Conjunctival blanching , CME , Endothelial toxicity follicular conjunctivitis [0.5 -2 %] tachycardia , hypertension Contradicted in aphakic & Closed angle glaucoma

ApraclonidineMOA- On alpha 1,2 receptors –reduce aqueous formation Side eff : Itching ,dryness in mouth, follicular conjunctivitis, mydriasis Use : to reduce IOT after laser trabeculoplasty [0.25 – 1 %] Brimonidine – alpha 2 selective Side eff :- dryness in mouth ,fall in Bp,

Carbonic anhydrase inhibitors

ACETAZOLAMIDE MOA - inhibits bicarbonate ion production , osmotic gradient reduce aqueous formation Side effects – Paraesthesia, anorexia, malaise ,Gi irritation Oral 0.25 gms BD DORZOLAMIDE – 2 % DROPS

PROSTOGLANDINS LATANOPROST MOA – On prostanoid FB receptors Increase uveoscleral flow & permeability of CBM Side effects – eye irritation , pain, blurry vision 0.005 % drops

Hypertonic agents

MOA - Raises the osmotic pressure to reduce intra ocular pressure Glycerol [10 % infusion / 1 gm /kg oral ] Side effects : nauseating sweet

taste ,diarrhoea,headache

Mannitol [ 20 % infusion ] Side effects : Hypervolemia , pulmunory edema

Drugs during glaucoma surgery

ANTIFIBROBLASTIC AGENTS – 5 FU & MITOMYCIN C

MOA -Inhibit collagen and protein synthesis by interfering with DNA transcription and replication Side effects : 5 FU – keratopathy Mitomycin - scleral ulcer & iritis

Administration : 5 FU - 50 mg/ml Sponge / sub conjunctival mitomycin – 0.5 mg/ml topically

Antibacterials

PENICILLINS MOA :- Bactericidal Destroys cell wall [gram + , gram – cocci,spirochetes] - penicillin G [1 lakh U/ml topical] [0.5 M U/ ml sub conj inj ] [5 M U / 4 hrs IV] - Cloxacillin [penicillinase resistant] [50-100 mg/kg] 6 hrly oral [staphylococci] - Amoxycillin [25-50 mg/kg] 6 hrly oral [ gram +,- bacteria]

Adverse eff :- Hypersensitivity reactions , rash ,..

QUINOLONES

MOA :- [Bacterial] Anti DNA gyrase – inhibits division & supercoiling [gram -- bacteria , gram + bacteria ,chlamydia,

mycoplasma]

- Ciprofloxacin :- 0.3 % topical , 500 mg BD oral , 5-10 mg/kg IV 200 mg /ml intravitreal Uses :- Keratoconjunctivitis, ulcers,blepharitis, dacryocystitis , infectious

endoophthalmitis S/E :- Arthropathy in children ,GIT irritation, Photosensitivity ,rash, liver damage - Gatifloxacin :-

CEPHALOSPORINS MOA :- Bactericidal – destroys cell wall

1 st generation :- gram + cocci & gram – bacilli Cephazolin – 0.5 – 1 g/ml 8 hrly IM /IV 2000 ug Intravitreal , 100 mg S/C Cefadroxil – 0.5 -1 g BD oral S/E :- GIT disturbances ,hypoprothrombinemia 2 nd generation :- gram – bacteria ,some anaerobes Cefuroxime axetil – 250-500 mg BD oral Cefoxitin – 1-2 gm 8 hrly IM/IV S/E :- GIT disturbances , migraines, headache 3 rd generation :- gram – bacteria Cefixim – 200-400 mg bd oral ceftazidim -1-2 gm 8 hrly IM/IV S/E: diarrhoea , neutropenia, thrombocytopenia

• 4 th generation :- against many bacteria ,highly resistant to B –lactamases Cefepime & cefpirome :- 1-2 gm 8 hrly

IM/IV S/E : allergic reactions , breathing difficulty, swelling of face ,..

Uses :- along with aminoglycosides In endoophthalmitis and bacterial corneal ulcers,..

Chloramphenicol

MOA :- Bacteriostatic , Inhibits Protein synthesis by binding to 50 S ribosomal subunit [gram +,- aerobes , chlamydia,ricketssia,mycoplasma] 0.5 % ointment, 50 mg /kg 4 times oral 2 mg/ml intravitreal

Uses :- Intraocular infections Conjunctivitis

Side eff :- Bone marrow depression Aplastic anemia , agranulocytosis

Tetracycline

MOA :- Bacteriostatic - inhibits protein synthesis by binding to 30 S Ribosome - 250-500 mg 4 hrly oral - 1 % topical

Uses :- Chlamydial diseases phlyctenular conjunctivitis Toxoplasmosis ocular rosacea

Side eff :- GIT disturbances discolouration of teeth photosensitivity , rashes nephrotoxicity

AMINOGLYCOSIDES

MOA :- Bacteriocidal - inhibits protein synthesis ,binding 30 S ribosome sub unit [gram negative bacteria & staph aureus ADR : Ototoxicity , nephrotoxicity ,corneal , retinotoxicity,..

Gentamycin :- 0.3 % drops, 20 mg sub conjunctival inj 200 ug/ml intravitreal inj Uses :- Endoophthalmitis , ocular injuries ,retained FB conjunctival necrosis

Amikacin :- 0.3 % drops , 15 mg / kg 8 hrly IV , 0.4 mg intravitreal Uses :- along vancomycin in post op endophthalmitis

Tobramycin :- including proteus,pseudomonas 0.3 % drops , 3 - 5 mg /kg /day IV , 150-200 ug /ml

SULPHONAMIDES

MOA :- Bacteriostatic - Inhibits folate synthesis [PABA folic acid ] [gram - ,+ bacteria] - Sulfacetamide , Sulfamethoxazole , sulfadiazine

- Topically 10% ,20 % ,30 % drops- Oral 2-4 gm/day TDS

COTRIMOXAZOLE MOA :- Inhibits Dihydro folate reductase in conversion of DHF THF Sulfamethoxazole [400 mg ] + trimethoprim [80 mg]

USES :- In trachoma along with pyrimethamine in toxoplasmosis S/E :- GIT disturbances , Hypersensitivity reactions , urticaria , renal toxicity-crystalluria.

Antifungals

Polyene antibiotics :-MOA - Selective action on ergosterol of fungal cell membrane forming micropores – increase permeability

Amphotericin B – Against yeast ,filamental fungi [0.25 % topical ] [ 0.25 mg/kg oral] Nystatin - against candida [ 1 lakh u/gm oint]Natamycin – against candida , aspergillus ,fusarium [ 5 % suspension]

Uses in keratomycosis and endophthalmitis[5-10 ug intravitreal]

Common side effects : allergic hypersensitivity reactions

Imidazoles :-MOA - Block fungal cytochrome P-450 enzyme in ergosterol [increase permeability tru membrane]Clotrimazole :- [1 % topical]Miconazole :- [ 1 % drops,2 % oint, 5-10 mg sub conj ]Ketoconazole :- [200-800 mg oral daily , 0.5 mg intravitreal] Uses :- candida,fungal , endoophthalmitis Side effect:- liver toxicity

Triazoles :- Fluconazole - [100-200 mg oral]

[0.2% topical] [0.1 mg intravitreal] Uses :- Candida,cryptococcus

Anti virals PYRIMIDINE DERIVATIVES Idoxuridine :- 0.1 % drops hrly / 0.5 % ointment TRIFLUOROTHYMIDINE :- 1 % drops

MOA : By incorporation - inhibition of viral DNA synthesis Uses :- Dendritic ulcer , herpes simplex keratoconjunctivitis

Side effects :- with corticosteroids – SPK, follicular conjunctivitis,..

PURINE DERIVATIVES

ADENINE ARABINOSIDE MOA :- Blocking DNA synthesis of virus Acyclovir - 3 % ointment , 400-800 mg 5 times/day a week Uses :- EB virus, CMV ,Herpes zoster virus,.. S/E :- Allergic reactions,.. Valacyclovir - 1000 mg TDS Famciclovir - 500 mg TDS S/E :- GIT disturbances Ganciclovir - 5-6 mg intravitreal inj , 5 mg IV S/E :- bone marrow depression , rashes

Ocular antiallergicsMOA – Competitive antagonist of H1 receptors

Uses - vernal keratoconjunctivitis , Giant papillary conjunctivitis Allergic conjunctivitis

CPM – 4 times /day topicalAzelastine - 2 times/dayLoratadine/ cetrizine – at bed time

Mast cell stabilizers

MOA – Stabilizes mast cells and prevent release of histmaine

Cromolyn sodium [2-4 % ] 6 hrlyOlapatadine [0.1 % ] 12 hrly

Corticosteroids

MOA :

In general : Anti inflammatory action - fibroblast formation reduce capillary permeableTopical steroids : 1 % prednisolone 0.1 % FML 0.1 % dexamethasone in conjunction to antibioticUses : Allergic conjunctivitis , iritis, keratitis ,episcleritis

Injection steroids : 40 mg Triamcinolone acetate - periocular 1 mg dexamethasone - intravitrealUses : Endoophthalmitis, Cysotid macular edema ,…

Oral steroids : 1 - 2 mg /kg /wt - orbital inflammation post operative inflammation panuveitisAdverse drug reaction :

Prolonged use - posterior sub capsular cataract glaucoma

NSAID• E.g. ketorolac 0.5 % , flurbiprofen 0.03 %,..

• Mechanism: inactivation of cyclo-oxygenase

• Uses: postoperatively mild allergic conjunctivitis episcleritis, mild uveitis, cystoid macular edema

• Side effects: stinging , burning

Anti VEGF

• MOA : Inhibits vascular EGF in retinal ischaemia

Uses : Diabetic retinopathy , macular edema , ROP ARMD - Intravitreal inj - Pegaptanib [macugen ] Ranibizumab [ lucentis ]

Drugs for dry eye

Characteristics of ideal tear drops : - Soothing effect - proper wetting agent , viscious - No epithelial toxicity - Alkaline p H

MOA : mucomimetic - bind to corneal epithelium form

hydrophilic layer to stabilize tear film . Hydroxy propyl methyl cellulose – 0.5 - 1 % Polyvinyl alcohol -- 1.4 %Carboxy methyl cellulose -- 0.5 %

ViscoelasticsProperties - optical - cohesive [ space maintaining tissue manipulation in surgery] - dispersive [ Coating ocular surface protecting corneal endothelium lower surface tension] - Elasticity

Sodium hyaluronate 1 %Sodium hyaluronate 3 % & chondroitin sulphate 4 % Hydroxy propyl methyl cellulose 3 %

Uses :- - In gonioscopy - in intra ocular surgeries

IRRIGATING SOLUTIONS

Characteristics of an ideal solution : -- Maintain moisture of & cleanse ocular tissues -- Isotonicity electrolyte and p H same as aqueous -- Maintain pressure of globe -- Protect delicate ocular structures -- Endothelial nourishment

Available preparations :- Balanced salt solution[BSS] BSS plus Dextran containing soln Glucose fortified BSS plusUSES :- Intraocular – in cataract surgery Extraocular – FB removal,tonometry,gonioscopy

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Ocular diagnostic drugs

• Fluorescein dye– Available as drops or strips – Uses: stain corneal abrasions,

applanation tonometry, detecting wound leak, NLD obstruction, fluorescein angiography

– Caution:• stains soft contact lens• Fluorescein drops can be

contaminated by Pseudomonas sp.

Ocular Diagnositic Drugs

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• Rose bengal stain– Stains devitalized epithelium– Uses: severe dry eye, herpetic keratitis

Ocular toxicology :

Amiodarone :- Vortex keratopathy Digitalis :- Chromatopsia [seeing yellow colour ] Chloroquine :- Bull’s eye maculopathy Ethambutol :- Optic neuropathy , colour vision disturbedCorticosteroids :- Posterior sub capsular cataractsThioridazine :- Pigmentary retinopathyCopper, Gold :- Lenticular opacitiesRifabutin :- Anterior uveitis

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