Inhibidores de la anhidrasa carbonica

INTRODUCCION A LOS INHIBIDORES INTRODUCCION A LOS INHIBIDORES DE LA ANHIDRASA CARBONICADE LA ANHIDRASA CARBONICADE LA ANHIDRASA CARBONICADE LA ANHIDRASA CARBONICA

Carlos Carlos AzañeroAzañero InopeInopeR id tR id t 22 ññResidente Residente 2 2 añoañoOftalmologíaOftalmología

Dr. Carlos Augusto Azañero Inope www.carlosvirtual.com

CarbonicCarbonic anhydraseanhydrase inhibitorsinhibitors

TheseThese drugsdrugs areare allall derivativesderivatives ofofsulfonamidessulfonamides andand werewere introducedintroducedintointo clinicalclinical practicepractice asas diureticsdiuretics..pp

EvenEven withwith chronicchronic use,use, theirtheir diureticdiureticactionaction isis onlyonly effectiveeffective forfor 11––22 weeksweeks..actionaction isis onlyonly effectiveeffective forfor 11 22 weeksweeks..



CAICAI dd i t li t lCAIsCAIs reducereduce intraocularintraocular pressurepressure(IOP(IOP)) byby decreasingdecreasing aqueousaqueous humorhumorformationformation..

AsAs suchsuch theythey areare usefuluseful inin essentiallyessentiallyallall formsforms ofof glaucoma,glaucoma, eveneven whenwhen thetheanterioranterior chamberchamber angleangle isis sealedsealed ororthethe outflowoutflow facilityfacility isis veryvery lowlow...



AcetazolamideAcetazolamide waswas introducedintroducedintointo clinicalclinical practicepractice asas ananintointo clinicalclinical practicepractice asas ananantiglaucomaantiglaucoma drugdrug inin 19541954 andandremainsremains thethe prototypeprototype forfor thisthisll ff ddclassclass ofof drugsdrugs..

OtherOther membersmembers ofof thisthis groupgroupincludeinclude thethe oraloral agents,agents,methazolamidemethazolamide,, ethoxzolamideethoxzolamide,,andand dichlorphenamidedichlorphenamide,, asas wellwell asasppthethe topicaltopical agents,agents, dorzolamidedorzolamideandand brinzolamidebrinzolamide..



The enzyme carbonic The enzyme carbonic anhydraseanhydrase (CA) catalyzes (CA) catalyzes the following the following reactionreaction::

COCO OHOH HCOHCOCACA

COCO22 + OH+ OH‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐HCOHCO‐‐33

ThisThis enzymeenzyme isis foundfound inin manymany tissuestissues inin thethe body,body, includingincluding thetherenalrenal cortexcortex gastricgastric mucosamucosa redred bloodblood cellscells (RBCs)(RBCs) lunglung pancreaspancreasrenalrenal cortex,cortex, gastricgastric mucosa,mucosa, redred bloodblood cellscells (RBCs),(RBCs), lung,lung, pancreas,pancreas,andand centralcentral nervousnervous systemsystem (CNS)(CNS)..



ItIt isis alsoalso foundfound inin manymany tissuestissuesinin thethe eye,eye, includingincluding thethe cornealcornealendotheliumendothelium nonnon pigmentedpigmentedendotheliumendothelium,, nonnon‐‐pigmentedpigmentedirisiris epitheliumepithelium,, pigmentedpigmented andandnonnon pigmentedpigmented epitheliumepithelium ofofhh iliili üllüllthethe ciliaryciliary processes,processes, MüllerMüllercells,cells, andand retinalretinal pigmentpigmentepitheliumepithelium.



CarbonicCarbonic anhydraseanhydrase existsexists ininCa bo cCa bo c a yd asea yd ase e stse stsmultiplemultiple formsforms.. AlthoughAlthough typetype II andandIIII CAsCAs areare bothboth presentpresent inin thethecornealcorneal endotheliumendothelium andand lenslenscornealcorneal endotheliumendothelium andand lenslens..

TThehe typetype IIII isoenzymeisoenzyme (type(type CC ininanotheranother classificationclassification system)system)anotheranother classificationclassification system)system)appearsappears toto bebe thethe onlyonly oneone ofof thethetwotwo formsforms presentpresent inin anyany quantityquantityhh ll h lh linin humanhuman ciliaryciliary epitheliumepithelium..



RecentRecent animalanimal studiesstudies havehaveplacedplaced bothboth typestypes IIIIII andand IVIV CACAinin thethe nonnon‐‐pigmentedpigmented ciliaryciliaryepitheliumepithelium ofof bothboth rabbitsrabbits andandhumanshumans andand havehave implicatedimplicated ititasas havinghaving aa rolerole inin aqueousaqueousproductionproduction..



TheThe bulkbulk ofof evidenceevidence stronglystrongly suggestssuggests thatthat CAIsCAIs reducereduce aqueousaqueoushumorhumor formationformation byby aa directdirect effecteffect onon ciliaryciliary epithelialepithelial CACA::

11.. CarbonicCarbonic anhydraseanhydrase isis foundfound ininthethe nonnon‐‐pigmentedpigmented epitheliumepithelium ofofthethe ciliaryciliary processesprocesses.. ThisThismetabolicallymetabolically activeactive tissuetissue isisyythoughtthought toto bebe responsibleresponsible forfor thethesecretionsecretion ofof aqueousaqueous humorhumor..



TheThe bulkbulk ofof evidenceevidence stronglystrongly suggestssuggests thatthat CAIsCAIs reducereduce aqueousaqueoushumorhumor formationformation byby aa directdirect effecteffect onon ciliaryciliary epithelialepithelial CACA::

22.. TopicalTopical applicationapplication ofof CAIsCAIslowerslowers IOPIOP withoutwithout inducinginducingchangeschanges inin systemicsystemic acidacid––basebase ororelectrolyteelectrolyte balancebalance..yy

FurthermoreFurthermore,, topicaltopical CAICAIadministrationadministration toto oneone eyeeye withwithadministrationadministration toto oneone eyeeye withwithgoodgood reductionreduction inin IOPIOP failsfails totosignificantlysignificantly lowerlower IOPIOP inin thethefellowfellow eyeeyefellowfellow eyeeye..



AA fewfew investigatorsinvestigators havehave proposedproposedee est gato sest gato s a ea e p oposedp oposedthatthat CACA playsplays anan indirectindirect rolerole ininaqueousaqueous humorhumor formationformation..

ItIt hashas beenbeen suggestedsuggested thatthat ininvariousvarious speciesspecies thethe nonnon‐‐pigmentedpigmentedciliaryciliary epitheliumepithelium secretessecretes eithereither ananciliaryciliary epitheliumepithelium secretessecretes eithereither ananacidicacidic oror aa basicbasic aqueousaqueous humorhumorandand thenthen requiresrequires CACA toto generategenerateh dh d b bb b ffhydrogenhydrogen oror bicarbonatebicarbonate ionsions forfor ananintracellularintracellular bufferingbuffering systemsystem..



SuchSuch aa systemsystem wouldwould helphelp maintainmaintainintracellularintracellular pHpH forfor thethe enzymesenzymesinvolvedinvolved inin ionion transporttransport..

CarbonicCarbonic anhydraseanhydrase inhibitorsinhibitorsCarbonicCarbonic anhydraseanhydrase inhibitorsinhibitorswouldwould interfereinterfere withwith thisthis bufferingbufferingsystemsystem andand indirectlyindirectly reducereduceaqueousaqueous humorhumor formationformationaqueousaqueous humorhumor formationformation..

AlthoughAlthough thisthis proposedproposed mechanismmechanismhashas generatedgenerated considerableconsiderablehashas generatedgenerated considerableconsiderablediscussiondiscussion,, therethere isis nono directdirect proofprooftoto supportsupport thethe hypothesishypothesis..



SomeSome authoritiesauthorities proposepropose thatthat CAIsCAIsinfluenceinfluence aqueousaqueous humorhumor formationformationbyby alteringaltering systemicsystemic acidacid––basebase ororbyby alteringaltering systemicsystemic acidacid basebase ororelectrolyteelectrolyte balancebalance..

SystemicSystemic administrationadministration ofof CAIsCAIsSystemicSystemic administrationadministration ofof CAIsCAIsproducesproduces diuresisdiuresis andand metabolicmetabolicacidosisacidosis..



However,However, thethe diuresisdiuresis andand thethe,,concomitantconcomitant lossloss ofof sodium,sodium,potassiumpotassium,, andand bicarbonatebicarbonate inin thetheurineurine areare transienttransient inin naturenature andandurineurine areare transienttransient inin naturenature andandcannotcannot explainexplain thethe longlong‐‐termtermloweringlowering ofof IOPIOP thatthat isis producedproduced bybyCAIsCAIsCAIsCAIs..

OtherOther diureticdiuretic agentsagents thatthat areare moremore potentpotent andand moremore persistentpersistent inin theirtheir effectseffects dodonotnot lowerlower IOPIOP..



SystemicSystemic acidosisacidosis fromfrom eithereitherdiseasedisease (e(e..gg..,, diabeticdiabetic coma)coma) oror thetheadministrationadministration ofof pharmacologicpharmacologicadministrationadministration ofof pharmacologicpharmacologicagentsagents (e(e..gg..,, ascorbicascorbic acidacid ororcalciumcalcium chloride)chloride) isis associatedassociated withwithdecreaseddecreased IOPIOPdecreaseddecreased IOPIOP



CarbonicCarbonic anhydraseanhydrase inhibitorsinhibitorsLütjenLütjen‐‐DrecollDrecoll andand coco‐‐workersworkers notednotedthatthat CAIsCAIs blockblock thethe developmentdevelopment ofofcapillarycapillary fenestrationsfenestrations inin aa varietyvariety ofof

hh l dl d hh hhtissuestissues.. TheyThey postulatedpostulated thatthat thisthisphenomenonphenomenon mightmight bebe involvedinvolved inin thethetherapeutictherapeutic effecteffect ofof thesethese drugsdrugs..

MacriMacri reportedreported decreaseddecreased episcleralepiscleralvenousvenous pressurepressure afterafter CAICAIadministrationadministrationadministrationadministration..

ThomasThomas andand RileyRiley postulatedpostulated thatthat CAIsCAIsactact throughthrough anan adrenergicadrenergic mechanismmechanismactact throughthrough anan adrenergicadrenergic mechanismmechanismbecausebecause thethe effectseffects ofof thethe drugsdrugs ininanimalsanimals areare alteredaltered byby adrenalectomyadrenalectomyandand adrenergicadrenergic blockingblocking agentsagents..andand adrenergicadrenergic blockingblocking agentsagents..



wewe lacklack aa completecomplete understandingunderstanding ofofthethe mechanismmechanism ofof actionaction ofof CAIsCAIs..

TheThe bestbest evidenceevidence suggestssuggests thatthat theytheygggg yylowerlower IOPIOP byby reducingreducing bicarbonatebicarbonate(and(and possiblypossibly chloridechloride ion)ion)movementmovement andand aqueousaqueous humorhumormovementmovement andand aqueousaqueous humorhumorformationformation viavia aa directdirect effecteffect ononciliaryciliary epithelialepithelial CACA..



SeveralSeveral sulfonamidesulfonamide‐‐derivedderivedtopicaltopical agentsagents werewere examinedexamined..topicaltopical agentsagents werewere examinedexamined..

TheThe originaloriginal agentagent((ethoxzolamideethoxzolamide gel)gel) showedshowed((ethoxzolamideethoxzolamide gel)gel) showedshowedpromisepromise,, butbut bothboth thethe drugdrug andanditsits vehiclevehicle werewere notednoted toto causecauseb lbb lb i it tii it ti ii hi hhi hbulbarbulbar irritationirritation inin aa veryvery highhighpercentagepercentage ofof patientspatients..



FinallyFinally,, dorzolamidedorzolamide (formerly(formerly knownknownasas LL‐‐671671,, 152152,, thenthen MKMK 507507)) waswasasas LL 671671,, 152152,, thenthen MKMK 507507)) waswasfoundfound toto havehave thethe rightright balancebalance ofofeffectivenesseffectiveness andand minimalminimal locallocal sidesideeffectseffectseffectseffects..



SeveralSeveral yearsyears afterafter thetheSeveralSeveral yearsyears afterafter thetheintroductionintroduction ofof dorzolamidedorzolamide,,brinzolamidebrinzolamide,, anotheranother topicaltopicalCAICAI f df d tt hh i ili ilCAICAI,, waswas foundfound toto havehave similarsimilarclinicalclinical efficacyefficacy..

TheseThese agentsagents seemseem toto havehave ananequivalentequivalent effecteffect onon aqueousaqueoushumorhumor inhibitioninhibition andand differdiffer onlyonlyinin smallsmall waysways asas farfar asas sidesideeffectseffects areare concernedconcerned..


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Inhibidores de la anhidrasa carbonica