Pharmacology of drugs acting on the eye

Ø OutlinecommonroutesofadministrationofdrugstotheeyeØ DiscussthepharmacokineticsofdrugsappliedtopicallytotheeyeØ ClassifydrugsusedfortreatmentofdisordersoftheeyeØ Elaborateonautonomic,anti-inflammatorydrugs&drugsusedforglaucomaØ Hintonoculartoxicityofsomedrugs

extrainformationandfurtherexplanation

important

doctorsnotes

Drugsnames

Mnemonics

Objectives:

color index:

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MiosisMydriasis

Accommodationforlightintensity Anatomy

Accommodationfornear/farvision: Eyeaccommodation2:05min

Drugscanbedeliveredtooculartissueas

Locally(Topically)

Eyedrops Ointments Injections

Periocularinjection. Intraocularinjection.

Systemically

Orally IV

Locally:Advantages:• Convenient,Economic,Relativelysafe.Disadvantages:• Compliance,Corneal&conjunctivaltoxicity.

Overview

Eyedrops Ointments

Definition

• Eyedropsaresaline containingdrops“liquid”

• Mostcommonrouteofadministration.

• Onedrop=50μl /4hours(usually)

Ointmentisasmoothoilypreparation,Asaruleofthumb,anointmentbaseismoreocclusiveandwilldrivethemedicationintotheskinmorerapidlythanasolutionorcreambase.

AdvantagesConvenient,costsless,appliedfrequently.

Increasesthecontacttimeofocularmedicationtoocularsurfaceàprovidingbettereffect.

Disadvantages

Thecontacttimebetweenthedrugandtheeyeislow duetofastremovalbytears àThushastobeusedseveraltimes. Oneoftheproblemsofeyedropsis poorcompliantofthepatient.

Thedrughastobehighlylipidsolubletohavethemaximumeffectasointment.t’saGreasysubstancesothecontacttimebetweenthemedicationandthetissueislonger

Eyeinjections

Techniqu

es

intra-ocularin

jections

Fora

nteriorsegmen

tsurgery,

infections&re

tinitis

1- Intra-cameral:“insideanteriororposterior

chamberoftheeye”

E.g.•Intra-cameralacetylcholine or lidocaineduringcataractsurgery. ADRs

2- Intra-vitreal"insidetheeye"

E.g.• Intravitrealantibioticsincasesof

endophthalmitis (aninflammationoftheinternalcoatsoftheeye)

• Intravitrealsteroidinmacularedema(thebuild-upoffluidinthemacula,anareainthecenteroftheretina.)

-Retinaltoxicity.-Intraoculartoxicity.- Cornealtoxicity.

Peri-ocularinjections

1-SubconjunctivalSub=under

2- Retro-bulbar“behindtheeyeball”

Retro=behind

3- Peri-bulbar“aboveandbelowtheorbit”

Peri=around

4-subtenon

Advantages:• They reachbehindtheiris-lensdiaphragmbetterthantopicalapplications.• Drugspenetrationisgenerallyweakerforlowlipid-solubledrugs,howeverinjectionscan

bypasstheconjunctivalandcornealepitheliumwhichisgoodfordrugswithlowlipidsolubility(e.g.penicillins)

• Steroidandlocalanestheticscanbeappliedthisway.• Usedforinfectionofanteriorsegmentandinflammationofuvea.Disadvantages:• Localtoxicity,tissueinjury,globeperforation,opticnervedamage.

رابكلمة كامیتذكرنا للكامیراتالیكا وكانون شركة

(Leica=acetylcholine) (Canon=lidocaine)

TheAntibiotic andsteroidcansaveourvitality

vitalنربطھا بكلمة

Absorptio

nIsdeterm

inedby: Drugresidencetime→ thetimedrugremainsincul-de-sac,tear.Itcanbeprolongedbyplugging

tearductsorchanging the formulation.Metabolism →esterasesElimination → bynasolacrimaldrainageorbindingtotearprotein.Diffusion →acrosscornea&conjunctiva.

Distrib

ution Aftercornealabsorptionthedrugaccumulates

intheaqueoushumor,intraocularstructuresorsystemicallydistributed.*Melaninbindingprolongstheeffectofα-agonistsinpatientswithdarkpigmentediris.

Metab

olism

Significantbiotransformationtakesplaceintheeye.Esterases activatepro-drugs,e.g.:- Dipivefrin→(adrenaline)- Latanoprost →(PGF2α)

Pharmacokineticsoftopical(local)drugsOralorIV

- Factorsinfluencingsystemicdrugpenetrationintooculartissue:• lipidsolubilityofthedrug:Morepenetrationwithhighlipidsolubility• Proteinbinding: (bounddrug):Not Freetodistributealloverthebody,ItlocalizedinthebloodMoreeffectwithlowproteinbinding(inverseproportion)• Eyeinflammation:Morepenetrationwithocularinflammation.

(Dipivefrin=adrenaline)(dipivefrin=Adrenaline) أو ممكن نقول أبي أدرنالین

Eye ParasympatheticN.S. SympatheticN.S.

Iris

radialmuscle Noeffect Contraction(Mydriasis)(α1)

circularmuscle Contraction(miosis)(M3) Noeffect

Ciliarymuscle Contraction(M3)(accommodationfornearvision)

Relaxation(β2)

Lens Thick,moreconvex Thin,moreflat

Conjunctivalbloodvessels ConjunctivalVasodilatationandcongestionofbloodvessels

ConjunctivalVasoconstriction(α1)anddecongestionofbloodvessels

Accommodation nearvision farvision

Suspensoryligaments relaxation contraction

*Ciliarymuscleistheoppositeofthesuspensoryligament

اح ھذا بیتك الثاني ارت

Drugsa

ctingon

parasympatheticsystem

Cholinergicagonists

Directagonists

Indirectagonists(anticholinesterases)

Reversible

Irreversible

Cholinergic(muscarinic)antagonists

NaturalAlkaloids

Syntheticatropinesubstituses

sympatheticsystem

Adrenergicagonists

Non-selectiveagonists

Selectiveα1agonists

Selectiveα2agonists

Betablocker

Selectiveβ1Non-selective

Non-selective

Oculardrugs

Autonomicdrugs

Miotics

Mydriatics

Cycloplegics

AntiglaucomaDrugs

Anti-inflammatory

drugs

Steroids

NSAIDs

Chemotherapeutics

Antibacterial

Antifungal

Antiviral

Localanesthetics

Ocularlubricants

Cholinergicagonists

Drug

Directagonists Indirectagonists(anticholinesterases)

AcetycholineMreceptorMethacholineM+NreceptorCarbachol

PilocarpineMreceptor

ReversibleBindforshorttimewithAchesterasethenleaveit

Irreversible

PhysostigmineDemecarium

EchothiophateIsoflurophate

Indicatio

ns

Specificuses:

1-Inductionofmiosis insurgery2- Openangleglaucoma*Acetylcholinehasveryshortdurationofactionsonomedicalapplicationforit.

OpenangleglaucomaWhynotforclosedaswell?Closedangleglaucomaisanemergencycasewhichrequiredsurgery

Specificuses:1- Glaucoma2- Accommodative esotropia

Generaluses:1- Glaucoma(open&closedangle).2- Counteractactionofmydriatics.afterfunduscopicexamination3- Tobreakiris-lensadhesions.Sequencesofmydriatics drugsfollowedbymiotics drugs(Contractionfollowedbyrelaxation)4- Inaccommodativeesotropia (ecothiophate).الحول5- inliceinfestationoflashes(physostigmine)

0Mech.Ofa

ction 2contractions:

1- ConstrictionofthepupillaryCircularmuscle(sphinctermuscle)(miosis)drugscausesconstrictionarePreferredintreatmentofglaucoma2-Contractionoftheciliarymuscle(accommodationfornearvision)Decrease inintraocularpressure↓IOP.increases aqueousoutflowthroughthetrabecularmeshworkintocanalofSchlemm**IncreasedlacrimationConjunctivalVasodilatationmayLeadtocongestionineye

ADRs - Diminishedvision(myopia).

- Headache

صار (Carb)من كثرة الكرب(achol)شخص اكول

tropiaEso=thiophateEco

**Theaqueoushumorissecretedbytheepitheliumofciliarybody.Producedbyacombinationofactivetransportofionsandultrafiltrationofinterstitialfluid.Thefluidflowsoverthesurfaceofthelens,outthroughthepupilintotheanteriorchamber.FlowsthroughthetrabecularmeshworkintoSchlemm’s canalbyciliarymusclecontraction.andiscollectedinthescleralveins.Asaresultofmiosis oftheirismusclewhichpulledawayfromthecanalofSchliemannsotheangleoffiltrationwillincrease

Cholinergic(muscarinic)antagonists

Drug Naturalalkaloids Syntheticatropinesubstitutes

1- AtropineNotusedbecauseithasverylongdurationofaction2- Scopolamine(Hyoscine)

1- Homatropine2- Tropicamide3- Cyclopentolate

Duratio

n Longdurationofaction1- Atropine:7-10days2- Scopolamine(Hyoscine):3-7days

Shortdurationofaction1- Homatropine:1-3days2- Tropicamide:6hoursWidelyused

3- Cyclopentolate:24hours

Mech.of

actio

n

2 Relaxations:1- Passive*mydriasis→duetorelaxationofcircularmuscles.2- Cycloplegia (lossofnearaccommodation)→duetorelaxationofciliarymuscle.(ThiseffectisduetoblockingofparaS only!)- Increased IOP→glaucoma.(especiallyangleclosureglaucoma)- Decreased lacrimalsecretion→sandyeye.- Lossoflightreflex.

Indicatio

ns

1- Topreventadhesioninuveitis&iritis.(becausetheyaredoingmydriasis)2- Funduscopicexaminationoftheeye.3- Measurementofrefractiveerror.(problemwithfocusingoflightontheretinaduetotheshapeoftheeye)

Contra-

indicatio

ns Glaucoma(angleclosureglaucoma) →Becausethereisnomiosis →whichmakesthefiltrationC.Ieasier>IOPmayrisedangerously→ acuteattackofeyepain.

ngcomiaredropEye

totreattheglaucomatolateIt

أي مرض بالعین یسبب كربة وھم للشخص

*Active vs. passive mydriasis:• Atropine (anticholinergic): Blocking muscarinic receptorsà relaxing circular muscles à Passive Mydriasis• Sympathetic stimulation: activation of a receptors in radial muscles à contraction àActive mydriasis** in the sympathetic system, activation of a receptors leads to smooth muscle contraction, and activation of b2 receptors leads to smooth muscle relaxation

• Contractionofdilator(radial) Pupillae (Active mydriasis)→ α1• meantheirisgototheback.• Relaxation ofciliarymuscles(accommodationforfarvision)β2** =reducefiltrationangle.

• Increase inintraocularpressureIOP• Lacrimationα1• Vasoconstriction ofconjunctivalbloodvesselsα1 .(usedasdecongestiondrug)• α&βreceptorsinthebloodvesselsoftheciliaryprocesseshelpinregulationofaqueoushumour formation

Adrenergicagonists

Drug

Non-selectiveagonists(α1,α2,β1,β2)

Selectiveα1agonists Selectiveα2agonists

1- Epinephrine2- Dipivefrin(pro-drugofepinephrine)

Phenylephrine Apraclonidine(eyedrop)

Mecha

nism

of

actio

n

- Increaseuveoscleraloutflowofaqueoushumor.

- ActiveMydriasis(withoutcycloplegia).becausetheireffectisontheradialmuscle,nottheciliarymusclewhichisinnervatedbyparasympathetic*nolossofaccommodation

- Decrease productionofaqueoushumor.

- Increaseuveoscleraloutflowofaqueoushumor.

- Inhibitssympatheticworking.

Routeof

administration Usedlocallyaseye

drops.Eyedrops

Indicatio

ns Openangleglaucoma. 1- Funduscopicexaminationof

theeye.2- Topreventadhesioninuveitis&iritis.3- Decongestantinminorallergichyperemiaofeye.

1- Openangleglaucomatreatment2- ProphylaxisagainstIOPspikingafterglaucomalaserprocedures.

ADRs

1- Headache.2- Arrhythmia.3- Increasedbloodpressure.

1- Maycausesignificantincreaseinbloodpressure.2- Reboundcongestion.3- Precipitationofacuteangle-closureglaucomainpatientswithnarrowangles.

1- Headache.2- Bradycardia.3- Hypotension.

Contra-

indicatio

ns

Inpatientswithnarrowangles(lowdrainage)astheymayprecipitateclosedangleglaucoma.(α1effect)→becauseitisdoingmydriasis.

بمعجزة عیستذكرنا Epinephrine=Dipivefrin) إبراء األكمة(ى

Drug Non-selective Selectiveβ1Non-selective(cardio-selective)

1- Timolol2- Carteolol

Betaxolol

Mech.

Of

actio

n

• Actonciliarybodytodecrease productionofaqueoushumor.• Blockingofβ2 >blockingtherelaxationeffectontheciliarymuscle.

Rout

ofad

min.

Giventopicallyaseyedrops

Indicatio

ns - Canbeusedinpatientswithhypertension&ischemicheartdisease.

- Used intreatmentofopenangleglaucoma.- β-adrenergicblockertimolol,areeffectiveintreatingchronicglaucomabutare

notusedforemergencyloweringofintraocularIndicationspressure.

ADRs Ocularirritation.

Contra-

indicatio

ns 1- Inasthmapatients.(becausetheeffectofβ2> bronchospasm)2- PatientswithCVSdisorders.(becausetheeffectofβ1 ontheheart)

Notes

Β blockersarethemostpopular&effectivetreatmentofopenangleglaucomaAFTERprostaglandins.

!(blockers)طلع مقفل (beta)باب البیت(lol) لووول

العینجاء وقت قطرة

للعینالجزر مفید

عینبیتك من جمالھ كسر العدو

Timolol =longtime

Adrenergicagonists:Betablockers

OcularactionsParasympatheticN.S.

SympatheticN.S.

Cholinergicagonists Cholinergic(muscarinic)antagonists

*These 2areoppositetoeachother • Contraction ofdilator(radial)Pupillae (Active mydriasis)→ α1

• Relaxation ofciliarymuscles(accommodationforfarvision)→β2

2contractions:1- ConstrictionofthepupillaryCircularmuscle(sphinctermuscle)(miosis)drugscausesconstrictionarePreferredintreatmentofglaucoma2-Contractionoftheciliarymuscle(accommodationfornearvision).

2 relaxations:1- Passive *mydriasis →duetorelaxationofcircularmuscles.2- Cycloplegia (lossofnearaccommodation)→duetorelaxationofciliarymuscle.

Decrease inintraocularpressure↓IOP.

Increased IOP→ glaucoma.(especiallyangleclosureglaucoma)

Increase inintraocularpressureIOP

increasesaqueousoutflow α&βreceptorsinthebloodvesselsoftheciliaryprocesseshelpinregulationofaqueoushumour formation

Increasedlacrimation Decreased lacrimalsecretion→sandyeye.

Lacrimationα1

ConjunctivalVasodilatationmayLeadtocongestionineye

Lossoflightreflex. Vasoconstriction ofconjunctivalbloodvesselsα1 (used asdecongestiondrug)

Decreasing productionofaqueoushumor:

Betablockers.

Alpha-2agonists.

Carbonicanhydraseinhibitors.

Increasing outflowofaqueoushumor:

Prostaglandins.

Adrenergicagonists,nonspecific.

Parasympathomimetics.

ThemaingoalistodecreaseIOP by:

Prostaglandins andBetablockersarethemostpopular

Howglaucomaoccurs?1- open:angleoffiltrationisopen(canalofSchlemm )buttheproblemisincreasingintheproductionofaqueoushumor.2- closedangleglaucoma:heretheangleoffiltrationisnarrowbymydriatic drugsneedsurgerytotreatit.

Watchitfrom4:30

)برا )Prost(aglandinsإن فیھ دجاج بروست )nergic)Adreأدري sympathomimetics)Para عشان كذا تبي تصرفني بسرعةincrease(

ouflow) اني سیارةdraseinhibitors)anhybonicCar( ؟ قدام بیتكBeta(blockers) 1+1=2((فیھ ألف وحدة ووحدة(Alpha(

Carbonicanhydraseinhibitors&prostaglandinanaloguesDrug

CarbonicanhydraseinhibitorsE.g.acetazolamide(oral)

dorzolamide (topical)preferred

ProstaglandinanaloguesE.g.latanoprost,

travoprost

Mech.ofa

ction Decrease productionofaqueoushumorbyblocking

carbonicanhydraseenzymerequiredforproductionofbicarbonateions →(transportedtoposteriorchamber,carryingosmoticwaterflow).

Increaseuveoscleral aqueousoutflow.Latanoprost ispreferredduetolesseradverseeffects.TheyhavereplacedbetablockersTheyareusedtopicallyaseyedrops&onceaday.

Indi-

catio

n

openangleglaucoma

ADRs

• Myopia (Nearsightedness), malaise, anorexia, • GI upset, headache.• Metabolic acidosis, renal stone.

• Pigmentationoftheiris(heterochromiairidis)

• Intraocularinflammation.• Macularedema.

Contra-

indicatio

n • Sulfaallergy becausetheyaresulfaderivatives.• Pregnancy• Digitalisusers.

مرة (Prost)جربت دجاج البروست (dayaonce)وحدة بحیاتي

IriseupwithBigbroast=(iris)(Pigmentation)(Prostaglanin)

Ops!IcannotseeanyCars=(carbonicanhydrase)becauseIhaveMyopia

Developmentofangleclosureglaucomaanditsreversalbymiotics:

Mydriasisoccursinaneyewithnarrowiridocorneal angle,andtheirismakescontactwiththelensblockingpassageoftheaqueousfromtheposteriortotheanteriorchamber.

Possiblybuildsupbehindtheiriswhichbulgesforwardandclosestheiridocornealanglethusblockingaqueousoutflow.

Miotic makestheiristhinandpushesitawayfromthelensremovingthepupillaryblockandrestoringaqueousdrainage.

- Acute,painfulincreasesofintraocularpressureduetoocclusionoftheoutflowdrainagepathway.- TheonlywaytotreatitisSurgery,butbeforesurgerywegivehimtreatmenttodecreaseIOP.- Emergencysituationthatrequiretreatmentbeforesurgery(Iridectomy).

Treatmentofnarrowclosedangleglaucoma(acute):

Theuseofdrugsislimitedto:

Oral Acetazolamide

Topicalcholinomimetics e.g.:pilocarpine

Osmoticagents hypertonicsolutionsof(Mannitol,Glycerol).

Analgesics pethidineormorphine(forpain)

Mech.

ofaction 1. Canrapidly↓IOPby↓vitreousvolume.

2. Glycerol50%syrup,orally(causenausea,hyperglycemia).3. Mannitol20%IV(causefluidoverloadandnotusedinheartfailure).4. DehydratevitreousbodywhichreduceIOPpriortoanteriorsurgical

procedures5. IV infusion ofhypertonicsolution(mannitolol,Glycerol)

Indi-

catio

ns UsedonlyinacutesituationstotemporarilyreducehighIOPuntilmoredefinitive

treatmentscanberendered.(priortoanteriorsurgicalprocedure)

ADRs

- Diuresis,circulatoryoverload,pulmonaryedema- Heartfailure- Centralnervoussystemeffectssuchasseizure,andcerebralhemorrhage.

Drug

Corticosteroids NSAIDsTopical Systemic 1- Ketorolac

2- Diclofenac3- Flurbiprofen

1- Prednisolone2- Dexamethasone3- Hydrocortisone

1- Prednisolone2- Cortisone

Mech.

of

actio

n - InhibitionofarachidonicacidreleasefromMOAphospholipidsbyinhibitingphosphlipase A2

- COX(cyclo-oxygenase)inhibitors

Indicatio

ns

1- Anterioruveitis.2- Severeallergicconjunctivitis.3- Scleritis.4- Preventionandsuppressionofcornealgraftrejection.5-postoperatively

2- Posterioruveitis.1- Opticneuritis.

1- Ketorolac:Cystoidmacularedemaoccurringaftercataractsurgery.2- Diclofenac:Postoperativeinflammation,mildallergicconjunctivitis,milduveitis.3- Flurbiprofen:Preoperativelytopreventmiosis duringcataractsurgery.*Becausetheyinhibitprostaglandinswhichproducemiosiswithoutactionofcholinergic.

ADRs

- Glaucoma,cataract,mydriasis(especiallyifitis usedforalongtime)- Skinatrophy.- Secondaryinfection.- Delayedwoundhealing.(healingisslowbecauseitisanimmunesuppression)

- Stinging(irritation)- Sterilecornealmelt&perforation.

AmiodaroneChloroquine

1- Pigmenteddepositsofcornea.2- Opticneuropathy(milddecreasedvision+visualfielddefects)3- Retinopathy.

Digitalis 1- Oculardisturbances2- Chromatopsia (objectsappearyellow,overdosingcancauseoculardisturbances)(FACT:Van gogh usedtotakedigitalis)

Phenothizines 3- Brown pigmentarydepositsinthecornea,conjunctiva&eyelid.

Steroids 1- Cataractformation2- IncreaseIOP3- Glaucoma(longtermuse)

Ethambutol(TB Medication)

1- OpticneuropathyCharacterizedbygradualProgressivecentralscotomasandvisionloss.

Sildenafil 1- Causesabluish haze2- LightsensitivityItInhibitsPDE5inthecorpuscavernosum toachievepenileerectionItalsomildlyinhibitsPDE6whichcontrolsthelevelofcyclicGMPintheretina→seeingabluishhaze&causinglightsensitivity

ومصابة تاجتلبس أمي الملكةبالعمى

)بنيبعید عن موزیتي ) ذا زیتي لونھ كأنو( نقرأ اسم الدرق

لھا العمىإثم بتول سبب

ة الدكاتر بسالیدزتذكرنا أزرق دایم لونھا

:قادة فريق علم األدوية

عبدالرحمن ذكري &لي التميمي :الشكر موصول ألعضاء الفريق املتميزين

الشثريري

باراسيرنا جواهر اخليال

شذا الغيهب روان سعد القحطاني

الشيبيمال آ

References:1- 436doctorsslides2- Team4353-Pharmacology(Lippincotts IllustratedReviewsSeries),5thedition.

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