Ocular pharmacologyOcular pharmacology

Section 1Section 1Pharmacologic principles Pharmacologic principles Pharmacologic principles Pharmacologic principles Especial forms and administrations Especial forms and administrations routes of eye drugs routes of eye drugs Section 2 Section 2 Ocular pharmacotherapeuticsOcular pharmacotherapeuticsCurrent and common drug groupsCurrent and common drug groups

Pharmacokinetics Pharmacokinetics

To achieve a therapeutic effect , a drug must To achieve a therapeutic effect , a drug must reach it's site of action in sufficient reach it's site of action in sufficient concentration : concentration :

•• Amount administered Amount administered •• Extent & rate of absorption at the Extent & rate of absorption at the •• Extent & rate of absorption at the Extent & rate of absorption at the administration site administration site

•• Distribution & binding in tissues Distribution & binding in tissues •• Movement by bulk flow in circulating Movement by bulk flow in circulating fluids fluids

•• Transport between compartments Transport between compartments •• Biotransformation Biotransformation •• ExcretionExcretion

Eye dropsEye drops

••Most ocular medications Most ocular medications

•• Adequate concentration in anterior Adequate concentration in anterior segmentsegment

••••Without incurring unwanted effects in Without incurring unwanted effects in other systemsother systems

Eye dropsEye drops

Some features limit its effectiveness :Some features limit its effectiveness :* Very little of an administered drop * Very little of an administered drop When a 50 When a 50 µµl eye drop is delivered , the l eye drop is delivered , the volume of lachrymal fluid rises about 10 volume of lachrymal fluid rises about 10 µµl l volume of lachrymal fluid rises about 10 volume of lachrymal fluid rises about 10 µµl l in the blinking eye of an upright patient. in the blinking eye of an upright patient. (20% of administered drug is retained )(20% of administered drug is retained )

* Rapid turnover of fluid , 16% per minute , * Rapid turnover of fluid , 16% per minute , and much more if the drop elicits reflex and much more if the drop elicits reflex tearing tearing

Eye dropEye dropSome measures improve ocular absorption:Some measures improve ocular absorption:

•• More than one eye drop More than one eye drop →→ wait 5minutes wait 5minutes

between drops between drops

•• Compress the nasolachrymal duct to prevent Compress the nasolachrymal duct to prevent •• Compress the nasolachrymal duct to prevent Compress the nasolachrymal duct to prevent egress of tears and to reduce systemic egress of tears and to reduce systemic absorption through the nasal mucosa absorption through the nasal mucosa

Eye dropEye drop

•• Contact time of eye drop medication is short , Contact time of eye drop medication is short ,

•• The rate of transfer from the tear fluid into the The rate of transfer from the tear fluid into the cornea is critical .cornea is critical .

•• Corneal epitheliuum and endothelium have tight Corneal epitheliuum and endothelium have tight •• Corneal epitheliuum and endothelium have tight Corneal epitheliuum and endothelium have tight intercellular junctions intercellular junctions

•• Drug concentration Drug concentration

•• Solubility Solubility

•• Viscosity Viscosity

•• Reflex tearing Reflex tearing

SolubilitySolubility

To traverse the cornea , a drug must pass in To traverse the cornea , a drug must pass in turn through : turn through :

•• Lipid rich environment of the epithelial cell Lipid rich environment of the epithelial cell •• Lipid rich environment of the epithelial cell Lipid rich environment of the epithelial cell membrane membrane

•• Water rich environment of the stroma Water rich environment of the stroma

•• Lipid barrier at the endothelium Lipid barrier at the endothelium

Reflex tearingReflex tearing

•• Reduces the contact time of the drug with Reduces the contact time of the drug with the cornea the cornea

•• Any physical contact that elicit blinking Any physical contact that elicit blinking •• Any physical contact that elicit blinking Any physical contact that elicit blinking reflex reflex

•• PH value very different from 7.4 PH value very different from 7.4

Ointments Ointments

•• Increasing the contact time of ocular Increasing the contact time of ocular medications medications

•• Consist of petrolatum and mineral oil Consist of petrolatum and mineral oil •• Consist of petrolatum and mineral oil Consist of petrolatum and mineral oil

•• Melt at body temperature Melt at body temperature

Periocualr injectionsPeriocualr injections

•• Sub conjunctiva Sub conjunctiva

•• Sub tenon Sub tenon

••Retrobulbar Retrobulbar ••Retrobulbar Retrobulbar

•• PeribulbarPeribulbar

Intraocualr injectionsIntraocualr injections

••Intracameral Intracameral

••IntravitrealIntravitreal

Systemic therapySystemic therapy

•• Blood ocular barriers limit access through Blood ocular barriers limit access through vascular channels vascular channels

•• More readily penetrated by drugs with More readily penetrated by drugs with •• More readily penetrated by drugs with More readily penetrated by drugs with higher lipid solubilities higher lipid solubilities

•• The unbound to plasma proteins drugs The unbound to plasma proteins drugs can cross the blood ocular barriers can cross the blood ocular barriers

Cholinergic agentsCholinergic agents

•• Affect the activity acetylcholine Affect the activity acetylcholine receptors in synaps of the peripheral receptors in synaps of the peripheral nervous system nervous system

•• parasympatetic effectors sites are in parasympatetic effectors sites are in •• parasympatetic effectors sites are in parasympatetic effectors sites are in the iris sphincter and ciliary bodythe iris sphincter and ciliary body

Cholinergic agentsCholinergic agents

•• Direct acting agonists act on the receptor Direct acting agonists act on the receptor to elicit an excitatory postsynaptic to elicit an excitatory postsynaptic potential potential

•••• Indirect acting agonists inhibit the Indirect acting agonists inhibit the acetylcholine esterase of the synaptic cleft acetylcholine esterase of the synaptic cleft , preventing deactivation of endogenous , preventing deactivation of endogenous acetylcholine acetylcholine

•• Antagonists block the action of Antagonists block the action of acetylcholine on the receptors acetylcholine on the receptors

Cholinergic agentsCholinergic agents

•• Parasympathomimetic agents :Parasympathomimetic agents :

•• Contraction of the iris sphincter (miosis) Contraction of the iris sphincter (miosis) and changes the anatomical relationship and changes the anatomical relationship and changes the anatomical relationship and changes the anatomical relationship of the iris to the lens and chamber angleof the iris to the lens and chamber angle

•• Contraction of the circular fibers of the Contraction of the circular fibers of the cilliary muscle ( accommodation) cilliary muscle ( accommodation)

•• Contraction of the longitudinal fibers of Contraction of the longitudinal fibers of the cilliary muscle ( outflow facility the cilliary muscle ( outflow facility ↑↑) )

Parasympathomimetic Parasympathomimetic agentsagents

•• Miosis Miosis →→ narrow angle glaucoma narrow angle glaucoma

•• Accommodation Accommodation →→ accommodative accommodative

esotropia esotropia esotropia esotropia

•• increasing outflow facility increasing outflow facility →→ open angle open angle

glaucoma glaucoma

accommodative esotropia accommodative esotropia

•• The near response is a synkinetic of The near response is a synkinetic of accommodation , miosis and convergence accommodation , miosis and convergence

•• Parasympathomimetic agents reduce the Parasympathomimetic agents reduce the •• Parasympathomimetic agents reduce the Parasympathomimetic agents reduce the need to accommodate , the patient not need to accommodate , the patient not only experience lees accommodation but only experience lees accommodation but also less convergence also less convergence

Parasympathomimetic Parasympathomimetic agents agents

•• Acetylcholine ( miochol ) Acetylcholine ( miochol ) →→ intracameral intracameral

•• Carbacol ( more effective and longer Carbacol ( more effective and longer lasting ) lasting ) →→ intracameral intracameral lasting ) lasting ) →→ intracameral intracameral

•• Pilocarpine 0.12% confirm Adie tonic pupil Pilocarpine 0.12% confirm Adie tonic pupil

″″ 11-- 6% in the treatment 6% in the treatment of glaucoma of glaucoma

Parasympathomimetic agentsParasympathomimetic agents

Side effects :Side effects :

•• Miosis Miosis •• Miosis Miosis

•• Induced myopia and accommodation Induced myopia and accommodation

•• CataractogenesisCataractogenesis

•• Retinal tear or even rhegmatogenous Retinal tear or even rhegmatogenous detachment detachment

Parasympathomimetic Parasympathomimetic agentsagents

Indirect agonist such as echothiophate Indirect agonist such as echothiophate ( phospholine iodide ) ( phospholine iodide )

•• Longer duration of action Longer duration of action •• Longer duration of action Longer duration of action

•• Frequently more potent Frequently more potent

•• Twice daily treatment is sufficient Twice daily treatment is sufficient

Parasympathomimetic Parasympathomimetic antagonist antagonist

•• Paralysis of the iris sphincter Paralysis of the iris sphincter →→ mydriasis mydriasis →→ facilitating fundus examination , facilitating fundus examination ,

preventing posterior synechia preventing posterior synechia

•••• Paralyze the ciliary muscle Paralyze the ciliary muscle →→ inhibit inhibit

accommodation , relieve pain associated accommodation , relieve pain associated with iridocyclitis , accurate refraction with iridocyclitis , accurate refraction

Parasympathomimetic Parasympathomimetic antagonistantagonist

•• Atropine 7Atropine 7-- 14 days lasting 14 days lasting

•• Homatropine 3 days Homatropine 3 days •• Homatropine 3 days Homatropine 3 days

•• Cyclopentolate 1Cyclopentolate 1-- 2 days 2 days

•• Tropicamide 4Tropicamide 4-- 6hours 6hours

Parasympathomimetic Parasympathomimetic antagonistantagonist

Side effects :Side effects :

•• OcularOcular→→ due to midriasis due to midriasis

•• Systemic Systemic →→ dose related toxicity dose related toxicity •• Systemic Systemic →→ dose related toxicity dose related toxicity

Flashing , fever , tachycardia , Flashing , fever , tachycardia , …………

Adrenergic receptorsAdrenergic receptors

•• αα1 1 mediate smooth muscle contraction mediate smooth muscle contraction

•• αα2 2 mediate feedback inhibition of mediate feedback inhibition of presynaptic sympathetic presynaptic sympathetic presynaptic sympathetic presynaptic sympathetic

•• ββ1 1 predominantly in the heart predominantly in the heart

•• ββ22 mediate relaxation of smooth mediate relaxation of smooth muscle in most blood vessels and in the muscle in most blood vessels and in the bronchi bronchi

αα1 1 adrenergic agonist adrenergic agonist

•• Stimulation of the iris dilator muscle Stimulation of the iris dilator muscle

⇒⇒⇒⇒⇒⇒⇒⇒ mydriasismydriasis

•• Systemic absorption may elevate Systemic absorption may elevate systemic blood pressuresystemic blood pressure

•• Systemic absorption may elevate Systemic absorption may elevate systemic blood pressuresystemic blood pressure

•• Such as phenylephrine Such as phenylephrine

αα2 2 adrenergic agonistadrenergic agonist

•• prevents release of norepinephrine at prevents release of norepinephrine at nerve terminals nerve terminals

•• Decrease aqueous production as well as Decrease aqueous production as well as •• Decrease aqueous production as well as Decrease aqueous production as well as episcleral venous pressure & improves episcleral venous pressure & improves trabecular outflow trabecular outflow

•• Such as apraclonidine hydrochloride Such as apraclonidine hydrochloride

αα1 1 adrenergic antagonist adrenergic antagonist

•• Inhibit adrenergic tone to the dilator Inhibit adrenergic tone to the dilator muscle muscle ⇒⇒ miosis miosis

•• Differentiating angle closure glaucoma Differentiating angle closure glaucoma •• Differentiating angle closure glaucoma Differentiating angle closure glaucoma from POAG from POAG

•• Such as thymoxamine Such as thymoxamine

ββ2 2 adrenergic agonist adrenergic agonist

•• Lower IOP by increasing uveoscleral Lower IOP by increasing uveoscleral outflow and perhaps through the outflow and perhaps through the trabecular meshwork trabecular meshwork

•••• LL-- epinephrine (epinephrine (αα,, ββ agonist)agonist)

•• Side effects : black deposits in the Side effects : black deposits in the conjunctiva conjunctiva

Reversible cystoid maculopathy ( 25% of Reversible cystoid maculopathy ( 25% of aphakic eyes ) aphakic eyes )

ββ adrenergic antagonist adrenergic antagonist ββ blocker blocker

•• Lower IOP by reducing aqueous humor Lower IOP by reducing aqueous humor production as much as 50% production as much as 50%

•• Timolol maleate ( timoptic ) and Timolol maleate ( timoptic ) and •• Timolol maleate ( timoptic ) and Timolol maleate ( timoptic ) and levobunolol ( betagan ) are mixed levobunolol ( betagan ) are mixed ββ1 1 ,,ββ2 2

antagonistsantagonists

ββ1 1 adrenergic antagonist adrenergic antagonist

•• Significantly safer when pulmonary , Significantly safer when pulmonary , cardiac , CNS or other systemic conditions cardiac , CNS or other systemic conditions are considered are considered

•••• Such as Betaxolol ( a selective drug ) Such as Betaxolol ( a selective drug )

Carbonic anhydrase inhibitor Carbonic anhydrase inhibitor

•• Mechanisms of aqueous secretion are not Mechanisms of aqueous secretion are not fully understood fully understood

•• Decrease of aqueous secretion depend Decrease of aqueous secretion depend active transport Na by Naactive transport Na by Na++ ,K,K++ , ATP ase on , ATP ase on active transport Na by Naactive transport Na by Na++ ,K,K++ , ATP ase on , ATP ase on the surface of nonpigmented epithelial the surface of nonpigmented epithelial cells cells

•• NaNa+ + transport partially linked to Hco3transport partially linked to Hco3_ _

formation formation

•• Hco3Hco3_ _ formation reduced by inhibition of formation reduced by inhibition of

the enzyme carbonic anhydrase the enzyme carbonic anhydrase

CAIs drugs CAIs drugs

••Systemic : Acetazolamide Systemic : Acetazolamide ( diamox ) 250( diamox ) 250-- 500mg 4 500mg 4 -- 6h 6h duration of actionduration of actionduration of actionduration of actionMethazolamide Methazolamide

•• Topical : Dorzolamide ( trusopt )Topical : Dorzolamide ( trusopt )

Brinzolamide ( azopt)Brinzolamide ( azopt)

Treatment of all glaucomas Treatment of all glaucomas

CAIs drugs side effects CAIs drugs side effects

•• Metabolic acidosis Metabolic acidosis

•• Urinary tract stone formationUrinary tract stone formation

•• Numbness and tingling of the hands , Numbness and tingling of the hands , •• Numbness and tingling of the hands , Numbness and tingling of the hands , feet and lips feet and lips

•• Malaise Malaise

•• Anorexia and weight loss , nausea Anorexia and weight loss , nausea

•• Depression Depression

Prostaglandin analogs Prostaglandin analogs

•• New class of ocular hypertensive agents New class of ocular hypertensive agents

•• Latanoprost ( Xalatan) Latanoprost ( Xalatan)

Lower IOP by enhancing uveoscleral outflow Lower IOP by enhancing uveoscleral outflow –– reduce the pressure ( 25reduce the pressure ( 25-- 35% ) 35% )

Lower IOP by enhancing uveoscleral outflow Lower IOP by enhancing uveoscleral outflow –– reduce the pressure ( 25reduce the pressure ( 25-- 35% ) 35% )

Once daily dosing Once daily dosing

Lack of cardiopulmonary effects Lack of cardiopulmonary effects

Ocular side effects : darkening of the iris Ocular side effects : darkening of the iris and periocular skin , cystoid macular and periocular skin , cystoid macular edema , uveitis edema , uveitis

Osmotic agents Osmotic agents

•• Reduce IOP and vitreous volume by Reduce IOP and vitreous volume by drawing fluid out of the eye across drawing fluid out of the eye across vascular barriers vascular barriers

•••• Used in the short management of acute Used in the short management of acute glaucoma and prior to cataract surgery glaucoma and prior to cataract surgery

•• Used with care in cardiovascular disorders: Used with care in cardiovascular disorders: CHF , hypertension , recent MI CHF , hypertension , recent MI

Anti inflammatory agents Anti inflammatory agents

•• glucocorticoids glucocorticoids

•• Non Steroidal AntiNon Steroidal Anti--Inflammatory Agents Inflammatory Agents

( NSAIDs )( NSAIDs )( NSAIDs )( NSAIDs )

•• Antihistamine Antihistamine

•• Histamine release blocker Histamine release blocker

•• Anti fibrotics Anti fibrotics

GlucocorticoidsGlucocorticoids

•• Prevent or suppress corneal graft Prevent or suppress corneal graft rejectionrejection

Anterior chamber reactionAnterior chamber reactionAnterior chamber reactionAnterior chamber reaction

Immune or traumatic Immune or traumatic uveitis Severe ocular uveitis Severe ocular inflammation: inflammation:

Subconj, retrobulbar , systemicSubconj, retrobulbar , systemic

Glucocorticoids Glucocorticoids

Adverse effects of Adverse effects of glucocorticoidsglucocorticoids••Glaucoma Glaucoma •• Post subcapsualr cataract Post subcapsualr cataract •• Exacerbation of bacterial and Exacerbation of bacterial and viral infection viral infection viral infection viral infection

•• Ptosis , mydriasis , scleral Ptosis , mydriasis , scleral melting melting

•• Suppression of the pituitary Suppression of the pituitary adrenal axis adrenal axis

••Gluconeogenesis Gluconeogenesis •• Peptic ulcerPeptic ulcer

NSAIDsNSAIDs

•• Salicylates : aspirin , mefenamic acidSalicylates : aspirin , mefenamic acid

•• Indoles : indomethacin Indoles : indomethacin

•• Phenyl alkanoic acid : diclofenac , Phenyl alkanoic acid : diclofenac , •• Phenyl alkanoic acid : diclofenac , Phenyl alkanoic acid : diclofenac , ibuperofen , naproxen ibuperofen , naproxen

•• Pyrazolones : phenylbutazonePyrazolones : phenylbutazone

Mast cell stabilizer & Mast cell stabilizer & antihistamineantihistamine

•• Allergic conjunctivitis : an immediate Allergic conjunctivitis : an immediate hypersensivity reaction ( IgE) hypersensivity reaction ( IgE)

•• Released histamine : capillary Released histamine : capillary •• Released histamine : capillary Released histamine : capillary dilation & increased permeability dilation & increased permeability →→

injection & swelling injection & swelling

•• Topical antihistamine : antazoline Topical antihistamine : antazoline →→

mild allergic symptoms mild allergic symptoms

Cromolyn sodium Cromolyn sodium

••Blocker of histamine release Blocker of histamine release

•• The therapy of choice for severe The therapy of choice for severe •• The therapy of choice for severe The therapy of choice for severe vernal & atopic conjunctivitis vernal & atopic conjunctivitis

Anti proliferative agents Anti proliferative agents

•• In the treatment of severe ocular In the treatment of severe ocular inflammatory diseases : inflammatory diseases :

Behjet syndromeBehjet syndromeBehjet syndromeBehjet syndrome

sympathetic ophthalmiasympathetic ophthalmia

•• Fluorouracil Fluorouracil –– mitomycine C mitomycine C

Antibiotic therapy Antibiotic therapy

•• Drug penetration in cornea Drug penetration in cornea

•• Blood ocular barriers Blood ocular barriers

•• Select effective antibiotics Select effective antibiotics •• Select effective antibiotics Select effective antibiotics

•• Gram stain , culture and antibiogramGram stain , culture and antibiogram

•• Immediate intravitreal injection of Immediate intravitreal injection of broad spectrum antibiotics in severe broad spectrum antibiotics in severe endophthalmitis endophthalmitis

Antibacterial agents Antibacterial agents

•• Penicillin'sPenicillin's

•• Cephalosporine Cephalosporine

•• Sulfonamids Sulfonamids •• Sulfonamids Sulfonamids

•• Tetracyclin Tetracyclin

•• Chloramphenicol Chloramphenicol

••Aminoglycosids Aminoglycosids

•• Fluoroquinolonbs Fluoroquinolonbs

Antifungal Antifungal

•• Polyenes : natamycine 5% suspension for Polyenes : natamycine 5% suspension for topical ophthalmic use topical ophthalmic use

•• Amphotericine B at .25% Amphotericine B at .25% -- 0.5% in sterile 0.5% in sterile water water water water

•• These agents penetrate the cornea poorly These agents penetrate the cornea poorly

•• Active topically against a variety of Active topically against a variety of filamentous fungi : aspergillus , filamentous fungi : aspergillus , cephalosporium, fusarium , penicillium , cephalosporium, fusarium , penicillium , yeast candida albicans yeast candida albicans

AntifungalAntifungal

•• Imidazols : miconazole 1% solution Imidazols : miconazole 1% solution subconjunctivally or topically subconjunctivally or topically

•• Miconazole penetrate the cornea Miconazole penetrate the cornea poorly poorly poorly poorly

•• Ketoconazole 200 mg tablet Ketoconazole 200 mg tablet ( every 6( every 6-- 8h)8h)

•• Penetrates the blood Penetrates the blood –– ocular barrier ocular barrier poorly but therapeutic levels can be poorly but therapeutic levels can be achieved in inflamed eyes achieved in inflamed eyes

•• Aspergillus , coccidioides , Aspergillus , coccidioides , cryptococus & candida cryptococus & candida

AntifungalAntifungal

•• Flucytosine: orally at 50 Flucytosine: orally at 50 --150 mg/kg daily 150 mg/kg daily divided into four doses divided into four doses

•• Penetrates the blood ocular barrier well Penetrates the blood ocular barrier well •• Penetrates the blood ocular barrier well Penetrates the blood ocular barrier well

•• Use primarily as an adjunct to systemic Use primarily as an adjunct to systemic amphotericin B therapy amphotericin B therapy

Antiviral agents Antiviral agents

••Topical : Topical :

idoxuridine idoxuridine

trifluridine ( TFT)trifluridine ( TFT)trifluridine ( TFT)trifluridine ( TFT)

vidarabine vidarabine

Antiviral agentsAntiviral agents

•• Systemic : Systemic :

Acyclovir Acyclovir →→ herpes zoster, herpes zoster,

prevent of HSV kratitisprevent of HSV kratitisprevent of HSV kratitisprevent of HSV kratitis

Can be used topically , orally or Can be used topically , orally or intravenously intravenously

Medication for Medication for acanthamoeba infection acanthamoeba infection

•• A corneal pathogen A corneal pathogen →→ contact lens contact lens

users users

•• No single drug is effective in treating No single drug is effective in treating •• No single drug is effective in treating No single drug is effective in treating all acanthamoeba keratitis all acanthamoeba keratitis

•• Polyhexamethylene biguanid Polyhexamethylene biguanid ( 0.02% solution ) first line agent ( 0.02% solution ) first line agent

•• Chlorhexidine , neomycine Chlorhexidine , neomycine ,polymyxin, B gramicidine ,polymyxin, B gramicidine mixtures , natamycine 5% mixtures , natamycine 5%

Anesthetics agents Anesthetics agents

•• Topical : for tonometery , gonioscopy Topical : for tonometery , gonioscopy , removal of superficial Fb , , removal of superficial Fb , corneal scraping , laser procedurescorneal scraping , laser procedurescorneal scraping , laser procedurescorneal scraping , laser procedures

•• Local : retrobubar and eyelid blocks Local : retrobubar and eyelid blocks →→ excellent anesthesia for surgery excellent anesthesia for surgery

Anesthetics agentsAnesthetics agents

••Esters : proparacaine , tetracaine Esters : proparacaine , tetracaine

••Amides : lidocaine 40 Amides : lidocaine 40 –– 60 min 60 min bupivacain ( marcaine ) long bupivacain ( marcaine ) long bupivacain ( marcaine ) long bupivacain ( marcaine ) long acting several hours acting several hours