ocular pharmacology
TRANSCRIPT
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
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