OCULAR PHARMACOLOGY

Moderator : Dr Preeti PandeyPresentor : Dr Shabnam Tanwar

Pharmacokinetics

Study of chemical alteration of drug in the body

1. Absorption 2. Distribution 3. Metabolism 4. Excretion

Absorption

Absorption is the movement of the drug from its site of administration to the target tissue (to produce the desired effect).

Not only the fraction of administered dose that gets absorbed but the rate of absorption is also important.

Factors influencing absorption of drug

Drug concentration and solubility: higher the concentration better will be the penetration.

Viscosity: increases the contact time with the cornea. Addition of methylcellulose and polyvinyl alcohol increases the viscosity of drug.

Lipid solubility: higher the lipid solubility more will be the penetration.

Surfactants: the preservatives used in ocular preparations alter cell membrane in the cornea and increase drug permeability eg- Benzylalkonium and Thiomersal

pH: the normal tear pH is 7.4 and if the drug pH

is different, it will cause reflex tearing.

when an alkaloid drug is put in relatively alkaline medium, the proportion of the uncharged form will increase, thus more penetration

Barrier for intraocular transport of drugs

Corneal epithelium and stroma: most impBlood ocular barriers: blood retinal barrier blood aqueous

barrierBlink rateAbsorption through conjunctival vessels and

mucosaNasolacrimal drainage of tears

Distribution Once the drug is absorbed, it has the

potential to penetrate most compartments of the body known as distribution.

Distribution largely depends on the route of administration.

Distribution: Topical

Transcorneal absorption

Accumulation in aqueous humor

Distribution to intraocular structures

Trabecular Meshwork Distribution in systemic

circulation

Factors affecting distribution

Physiochemical properties of drug:

Acidic/basic

Binding to plasma proteins

Binding to tissue proteins

Relative blood flow to different tissues

Metabolism Drugs are metabolized to facilitate clearance

& activate prodrugs for enhanced permeability

Enzymatic biotransformation Eg: Esterases, ketone reductase & phase 1 &2

oxidizing and conjugating enzymes

Eg. 1. Dipivefrine hydrochloride - Epinephrine 2. Latanoprost (isopropyl ester)- acid 3. Nepafenac 0.1% - Amfenac

Many of the drugs metabolized and excreted via kidneys or liver mostly

1. Timolol – Liver2. Mannitol – kidneys3. Acetazolamide – kidneys4. Latanoprost (PG)- liver5. Local anesthetics- liver/ plasma

Routes of administrationTopical Periocular Intraocular

Solutions Subconjunctival Intracameral

Gels Subtenon Intravitreal

Ointments Peribulbar

Contact lens Retrobulbar

Therapeutic applications

DRUGS FORMULATION INDICATION Onset of action& Duration of action

ATROPINE 0.5%, 1% & 2% solution. 1% ointment

•Cycloplegia•Mydriasis •Cycloplegic retinoscopy

OA: 30-40 minsMydriasis -15 daysCycloplegia -120 mins

HOMATROPINE 2% & 5% solution Cycloplegia Mydriasis

Same as above

SCOPALAMINE 0.25% solution Cycloplegia Mydriasis

Mydriasis-7 daysCycloplegia-30-60 mins

CYCLOPENTOLATE

0.5% & 1% solution

Cycloplegia Mydriasis

OA: 15-30 minsMydriasis -1dayCycloplegia-20-45 mins

PHENYLEPHRINE

2.5% solution Mydriatic only Mydriasis-4-6 hrs

TROPICANAMIDE

0.5% & 1% solution

Cycloplegia Mydriasis

OA: 15-30 minsMydriasis -4-5 hrsCycloplegia-15miins

Diagnostic purposes

Fluorescein dye

Corneal epithelial defects & corneal ulcers.Applanation tonometry -Goldmann

tonometer/Perkins hand-held tonometerSeidel's test: Concentrated fluorescein dye Jones dye test for assessment of lacrimal

passage functional potency.Fundus fluoroscein angiography: 10%-20% i/vFluorometry Tear film break up time(TBUT)

CORNEAL EPITHELIAL DEFECT

DRY EYE

APPALANTION TONOMETER

SEIDELS TEST POSITIVE

Rose Bengal dyeRose bengal is actually a derivative of

fluoresceinStains the devitalized cells only Unlike fluoroscein, it’s a true histological

stain which binds strongly and selectively to cellular components

1% liquid rose bengal dye via dry impregnated paper strips

DRY EYESJOGREN’S SYN- KERATOCONJUNTIVITIS SICCA

DENDRITIC KERATITIS

Lissamine greenStains membrane-damaged or devitalized cells-

GREENThere is no stinging or discomfort such as that

associated with rose bengal.Stains the edges of the dendritic ulcer while

fluoroscence stains the central bedConcentration of 1% lissamine strips.

DRY EYE DENDRITIC ULCER

Indocyanine green(ICG)Absorbs light at about 805 nm and emits

835nm infrared radiationThese frequencies penetrate retinal layers

allowing ICG angiography to image deeper patterns of circulation then FFA

Tightly bound to plasma proteins, thus becomes confined to vascular system.

40mg in 2ml

VERTEPORFINVerteporfin,a benzoporphyrin derivativeUsed as a photosensitizer for photodynamic

therapy to eliminate the abnormal blood vessels in the eye associated with conditions such as the wet form of macular degeneration.

CENTRAL SEROUS CHORIORETINOPATHY

Ocular infections

Anti bacterials

Anti fungals Anti virals

AminoglycosidescephalosporinsFluoroquinoloneMacrolides Sulfonamides Others: Chloramphenicol

Polyenes-Azoles

Imidazole

Triazole

Acyclovir Valacyclovir Trifluridine GancicyclovirCidofovir Foscarnet Miconazole

ketoconazole

FluconazoleItraconazole voriconazole

Anti Parasitic:acanthamoeba

Polyhexamethyl biguanide 0.02%Chlorhexidine 0.02%Hydrogen peroxideBenzalkonium chloride(BKC)

NatamycinAmpho B

ANTIBACTERIALS

Anti BacterialsAnti Bacterials MOA Drugs available

Aminoglycosides Protein synthesis inhibitors

Gentamycin, Tobramycin & Amikacin

Flouoroquinolones DNA gyrase inhibitors Ciprofloxacin, gati, moxi, besifloxacin etc

Macrolides Protein synthesis inhibitors

Azithromycin , erythromycin

Sulphonamides Anti folate antibiotics Chloramphenichol, sulphaacetamide

Cephalosporins Cell wall synthesis inhibitors

cefazoline

Aminoglycoside (cont)Drugs Dosage Indication Side effects

Gentamycin 0.3% every four hrs

Conjunctivitis, keratitis, corneal ulcers, dacrocystitis etc

Ocular burning & irritation, non specific conjuntivitis.Pregnancy & child

Tobramycin 0.3% every four hrs

Conjunctivitis, keratitis, corneal ulcers, dacrocystitis etc in children

Tearing, swelling of eye, stinging or blurred vision

fortified Amikacin

1.25%- 2.5% Severe bacterial infectionEg- mycobacterium chelonae keratitis

Ototoxicity NephrotoxicityPregnancy-D

Generic name formulations Toxicity Indications

Ciprofloxacin 0.3% solution 0.3% ointment

Hypersensitivities Drug related corneal deposits

Conjunctivitis KeratitisCorneal ulcer blephritisDacrocystitis

Ofloxacin 0.3% solution Hypersensitivity

Conjunctivitis Corneal ulcers

Fluroquinolones

Generic name

formulations Toxicity Indications

Gatifloxacin 0.3% solution Hypersensitivity

Conjunctivitis, post op & pre op prophylaxis, corneal pathologies etc

Moxifloxacin 0.5% solution Hypersensitivity

same as above

Besifloxacin 0.6% suspension

Redness, blurring of vision, pain, irritation etc

Same as above

Macrolides

Generic name

formulations Toxicity Indications

Azithromycin 1% ointment Hypersensitivity

Superficial infection involving cornea and conjunctiva

Erythromycin 0.5% ointment

Hypersensitivity

Superficial infection involving cornea and conjunctiva

MOA: Inhibits Protein synthesis by inhibiting the translocation on 50S ribosome

Sulphonamides

Generic name Formulations Dosage Indications

Chloramphenicol

0.5% solution 4-6 times daily Conjuntivitis Keratitis

Sulfacetamidesodium

10%, 15% and 30% w/v

Two hourly (for trachoma)

Conjuntivitis, trachoma and other superficial ocular infections

MOA: These are Anti folate antibiotics which inhibit folic acid synthesis

The use of fluoroquinolones as monotherapy for bacterial keratitis has proved as effective as combined fortified antibiotics

However, serious complications such as corneal perforation, evisceration, or enucleation of the affected eye were more common with fluoroquinolone therapy (16.7%) compared with the fortified therapy (2.4%, p= 0.02).

Caution should be exercised in using fluoroquinolones in large, deep ulcers in the elderly

Gangopadhyay N, Daniell M, Weih L,Taylor HR. Fluoroquinolone and fortified antibiotics for treating bacterial corneal ulcers; Br J Ophthalmol 2000;84:378–384

Antibiotic ResistanceMoxifloxacin resistance rates of coagulase

negative (70% of endophthalmitis in cataract surgey) are increasing. The mean resistance of moxi at a large university centre over past six years were almost 60%.

-JAMA Ophthalmology, November 2014

“ Recent studies suggest that repeated short courses of post injection topical antibiotic do not decrease the risk of endophthalmitis but also actually increase antibiotic resistance among conjunctival flora

-American Journal Of Ophthalmology, March 2014

“Use of only povidone iodine at the time of intravitreal injection without topical antibiotics appears to have the lowest risk of contributing to the wide spread problem of increasing endophthalmitis.”

-American Journal of Ophthalmology, March 2014

For topical agents, the MIC value is considered the Gold standard measurement of antibiotic efficacy

Antifungal agentsDrug Administratio

n Toxicity Indications

Natamycin 5% suspension2hourly

HypersensitivityIrritation

Yeast & fungal keratitis

Amphoteracin B 0.1-0.5% solution0.8-1mg subconjuctival 5 mcg intravitreal

Hypokalemia Infusion related toxicity

Yeast & fungal keratitis and endophthalmitis

Ketoconazole Topical 1-2%Oral 200-600mg/d

Allergic rashteratogenic

Yeast keratitis & endophthalmitis

Fluconazole Topical 1-2%Oral 200mg/d

Allergic rashteratogenic

Yeast keratitis & endophthalmitis

Itraconazole Topical 1-2%Oral 200-400 mg

Poor penetration so used in combination

Yeast & fungal keratitis & endophthalmitis

Voriconazole Extemporaneously prepared

No damage to the eye

Invasive Aspergillosis

POLYENS

A

Z

O

L

ES

Antiviral agentsGeneric name Route of

administration

Ocular toxicity

indications

Trifluridine Topical 1% solution

Punctate keratopathyhypersensitivity

Herpes simplex keratitis, keratoconjtivitis

Acyclovir Oral(200mg cap/ 800mg tab)

Herpes zooster ophthalmicus,HS iridocyclitis

Valacyclovir Oral (500-1000mg)

HS KeratitisHZ ophthalmicus

Famicyclovir Intravenous intravitreal

HS KeratitisHZ ophthalmicus

Vidarabine 3% ointment Lacrimation, foreign body sensation, photo-phobia etc

HS KeratitisHZ ophthalmicusACUTE &RECURRENT

Gua-nosine nucleoside analogyes

Anti Parasitic : Protozoal keratitis

Acanthamoeba KeratitisSpecific treatment include

Topical agents DRUGS

Diamidines Propamidine isethionate 0.1%Hexamidine 0.1%

Biguanides Polyhexamethyl biguanide 0.02%Chlorhexidine 0.02%

Aminoglycosides Neomycinparomycin

Imidazoles ClotrimazoleMiconazole

Anti acanthamoeba for contact lens careAnti acanthamoeba agents (in contact lens solution)

Presevatives Type of contact lens

Polyaminopropyl biguanide,Sodium borate

0.11% disodium edentate

soft

Polyhexamethyl biguanide

Preservative free soft

Polyvinyl alcohol 0.004%

BKC, sodium edeate Gas permeable

Polyvinyl alcohol (25.0)

0.004% BKC Gas permeable & hard

Hydrogen peroxide 3%

soft

Drugs for CMV RETINITISCytomegalovirus infection can occur in

general population but CMV retinitis occur usually with advanced immunosuppression (CD4 + cells<100/mm3)

Treatment Anti viral agents Route Toxicity Ganciclovir & valganciclovir

Topically, IV, intravitreal

Headache, convulsion, behavioural change

Cidofovir intravitreal Vitritis, hypotony & vision loss

Foscarnet Intravitreal, IV Headache, tremors etc

Fomiversen Intravitreal Iritis, vitritis, cataract & rise in IOP

Ocular inflammationInflammation is a characteristic response of

the mammalian tissue to injury

Anti inflammatory agents:1. Steroidal Anti Inflammatory Drugs2. Non-Steroidal Anti Inflammatory Drugs

Action of steroidsINCREASE THE SYNTHESIS OF LIPOCORTIN

(-)PHOSPHOLIPASE A2

(-)ARACHIDONIC ACID

(-) PROSTAGLANDIN & LEUKOTRIENE PATHWAYS

(-) PROSTAGLANDINS: Inflammation, conjunctival hyperemia, change in IOP, break down of blood ocular barrier etc

PHOSPHOLIPIDS

ARACHIDONIC ACID

LIPOXYGENASES

CYCLOOXYGENASE, COX-1 & COX-2

LEUKOTRINES

LTB4, LTC4, LTD4 & LTE4

PROSTAGLANDINS

PGD2, PGE2, PGF2, PGI2 & TXA2

STEROIDS

NSAIDS

Steroids

Inhibits

1. Bradykinin2. Nitric oxide3. Antigen presenting cells & T-cell

macrophages4. Histamine production5. Eosinophil release

Corticosteroids CLASSIFICATION

CLASSIFICATION Steroid

Short acting Hydrocortisone, cortisone, prednisolone

Intermediate acting Triamcinolone , fluprednisolone

Long acting Dexamethasone & Betamethasone

Steroidal Anti Inflammatory agentsCorticosteroids

Strength (%) Indications

Steroid responsive inflammatory condition of conjunctiva, cornea & ant seg of eye like Uveitis, allergic conjunctivitis, SPK, episcleritis,Corneal abrasion, ocular inflammation, corneal injury from diff burns, optic neuritis etc

Dosage

Prednisolone acetate, prednisolone soduim phophate

0.125 & 1.0 In tapering doses

Dexamethasone sodium phosphate

0.1 In tapering doses

Fluromethalone acetate

0.1 In tapering doses

Loteprednol etabonate

0.5 & 0.2 In tapering doses

Methyl prednisolone

1mg/kg IV

Side effects of steroids

OCULAR SYSTEMIC

Glaucoma Peptic ulcerCataract

HypertensionActivation of infection increases

blood sugarDelayed wound healing Activation of

TB

Osteoporosis

Non-Steroidal Anti Inflammatory agentsNSAIDS OCULAR USESIndomethacin To prevent miosis & CME after

cataract sxDiclofenac Post operative inflammationKetorolac Seasonal conjunctivitis, CME after

cataract sxNepafenac It’s a prodrug, 6 times faster

permeationFlurbiprofen To counter unwanted intraoperative

miosis during cataract surgeryPiroxicam Activity is comparable & tolerance is

better than diclofenac sodium(0.1%)

INDOLE DERIVATIV

ARYL ACETIC ACID DERIVATIVE

ARYL PROPIONOC ACID DERIVATIVE

ENOLIC ACID DERIVATIVE

ANTI-INFLAMMATORY, ANALGESIC, ANTI-PYRETIC, FREE RADICAL SCAVENGING ACTIVITY etc

Ocular anti Allergic drugs

Classification Drugs Allergy

Seasonal allergic conjuntivitis(SAC)Perennial allergic conjuntivitis(PAC)Vernal keratoconjunctivitis (VKC)Atopic kerato conjunctivitis( AKC)Giant Papillary conjunctivitis(GPC)

Anti histamines Pheniramine, antazoline, emedastine etc

Mast cell stabilizers

Cromolyn sodium, nedocromil, pemirolast, ketotifen

Dual action anti allergic drugs

Olapatidine,, azelatine & epinastine

NSAIDS Ketorolac Corticosteroids Loteprednol,

fluromethalone, dexamethasone, prednisolone etc

ANTI GLAUCOMA DRUGSAIM OF TREATMENT

DECREASE THE FORMATION OF IOP

-Beta blockers-Alpha agonist-Carbonic anhydrase inhibitors

INCREASE AQUEOUS DRAINAGE

-Prostaglandins-Topical miotics

Cholinergics MOA : stimulates the muscarinic receptors

producing increased aqueous outflow.

Indiacation : pupillary block glaucoma

Dosage : Pilocarpine 0.25%, 0.5% one drop two to three times a day

Anti cholinergicsMOA : block the response of response of

acetylcholine at the receptor

Agents :1. Atropine2. Cyclopentolate3. Tropicanamide Not used routinely in glaucoma treatment Use: Inflammatory & Malignant glaucoma

Alpha adrenergics agonistMOA: stimulate alpha 2 receptors in the

ciliary epithelium and thereby decrease the rate of aqueous production.

Agents :1. Dipivefrin 0.1%, one drop 2-3 times a day 2. Brimonidine 0.15% one drop 2-3 times a day

Beta blockersMechanism of action: lower IOP by reducing

aqueous formationAlso reduces ocular outflow

Non selective betablocker

Selective beta 1 blockers

Timolol maleate betaxolol

Levobunolol

Metipranolol

Carteolol

TIMOLOL

BETAXOLOL

20-35% fall in IOP within 1hr and last for 12 hours.

30% patients- additional medications

Less efficacious than Timolol

Protective effect on retinal neurons by blocking calcium channels

Adverse effects

Ocular Stinging, redness &

dryness of eyesCorneal hypothesiaAllergic

blephroconjuntivitisBlurred vision

Systemic Bronchospasm in

asthamatics & COPD patients

Bradycadia and accentuation of heart block

Prostaglandins First line medical therapy for open angle

glaucoma

PGF2 alpha analogs Good efficacy, once daily, No systemic

sideeffects

MOA: facilitate aqueous outflow through uveoscleral outflow pathway

Agents : 1. Latanoprost : 0.005% HS2. Bimatoprost: 0.03% HS3. Travoprost

Adverse effects: Ocular irritation & pain Blurring of vision Increased iris pigmentation Macular edema

Carbonic anhydrase inhibitorsAdd on drugs to topical beta blockers or PG

analogues

MOA: inhibits carbonic anhydrase enzyme on ciliary body epithelium

reduces formation of bicarbonate ions

reduces fluid transport

reduces aqueous formation

decrease in IOP

Topical CAI: 1. Dorzolamide 2. Brinzolamide

Systemic CAI: Acetazolamide 125-250 mg, two to four times a day

Indication : open & closed angle glaucoma

Immunosuppressive & Anti Mitotic agents Agents commonly used1. 5- fluorouracil2. Mitomycin C

Indications : Intermediate uveitis Peripheral ulcerative keratitis Ocular surface squamous neoplasia(OSSN) Trabeculectomy GVHD

Immunomodulators

TOPICAL CYCLOSCPORINE

-Approved for the treatment of Chronic dry eye associated with inflammation.

Decreases inflammatory markers in lacrimal gland & increases tear production

Angle closure glaucoma Hypertonic Mannitol 20% IV infusion- 1.5-2

g/kg

Acetazolamide 0.5g iv followed by oral twice daily started cncurrently

Miotic : Pilocarpine 1-4%

Timolol 0.5%

Latanoprost

DEFINITIVE TREATMENT: Surgical or Laser Iridotomy

Anti Angiogenic drugs

VEGF Inhibitors ANGIOSTATIC STEROIDS

•BEVACIZUMAB•RANIZUMAB•PEGATINIB•siRNA•VEGF TRAP

•ANECORTAVE ACETATE•SQUALINE

VEGF InhibitorsMOA: These are anti VEGF anti bodies that bind the

VEGF receptors thereby blocks both increased vascular permeability and angiogenesis

VEGF Inhibitors Administration Indications

Bevacizumab Intravitreal injection 1.25 mg/0.05ml

WET ARMD

Ranizumab Intravitreal injection every four wks

Choroidal neovascularization due to ARMD

Pegatanib Intravitreal injection every six wks

WET ARMDDiabetic macular edema

siRNA VEGF Trap

Under clinical trail for WET ARMD

Ocular LubricantsPolymer composition of Artificial tears

Hydroxymethyl cellulose/ carboxy methyl celluloseCarbomers (polyacrylic acid)Hypomellose (hydroxypropylmethyl cellulose)Liquid paraffin

Polyvinyl alcohol

Polyvinyl pyrrolidone

polycarbophil

Indications: Ocular irritation Dry Eyes

Preservatives

Ophthalmic solutions and ointments must be sterile so wide variety of preservatives are used for anti-microbial activity

PRESERVATIVESBenzalkonium chlorideChlorbutol Phenyl mercuric nitrateStabilized oxychloro compoundThiomersal ChlorhexidineSorbic acid

Adverse effects of preservativesToxic to precorneal tear film and epithelium,

thus impedes epithelial healing and disrupting the tear film

Direct cellular damageReduces oxygen utilization of cornea Hypersensitivity reaction1. Papillary conjunctivitis2. Punctate keratitis3. Corneal edema

Ophthalmic Anesthesia

Requirements for ophthalmic surgeries

Akinesia Profound analgesiaMinimal bleedingAvoidance of oculocardiac reflexControl of IOP

Anaesthesia Techniques

General

Local : 1. Topical 2. Regional

Local Anaesthesia

According to chemical nature

ESTER groupProcaineCocaineTetracaineBenzocaine

AMIDE groupLidocaineBupivacaine RopivacaineMepivacaine

LA ONSET OF ACTION

DURATION OF ACTION

CONCENTRATION

Lignocaine 5-10 mins10-35 secs

30-60 mins15-20 mins

Infiltration(1/2/3%)Topical 4%

Proparacaine 15-30 secs 15-20 mins Topical (0.5%)

Bupivacaine Moderate 75-90 mins Infiltration (0.25-0.75%)

Ropivacaine Moderate 1.5-6hrs Infiltration 1%

In patients with uncomplicated cataract at high risk for thromboembolic events, phacoemulsification cataract surgery under topical anaesthesia was safely performed without discontinuing systemic anticoagulant and antiplatelet treatment.

40 pts of mean age 72yrs on anticoagulants had phaco surgery done and none had any hemmorhagic complications or a thromboembolic event during surgery or at 1 week followup

Barequet IS etal,Risk assesment of simple phacoemulsification in patients on combined anticoagulant and antiplatelet therapy: J Cataract Refractive surgery, 2011

Thank you