f. Antigout Drugs.pdf

Overview of Discussion
About gout
Classification of anti-gout drugs
Pharmacology of drugs for acute gout
Pharmacology of drug for chronic gout

1. Anti-gout drugs
Mr. Vishal Balakrushna Jadhav
Assistant Professor (Pharmacology)
School of Pharmaceutical Sciences, Sandip University, Nashik
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2. Overview of Discussion
About gout
Classification of anti-gout drugs
Pharmacology of drugs for acute gout
Pharmacology of drug for chronic gout
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3. About Gout
Ametabolicdisordercharacterizedbyhyperuricaemia(normalplasmaurate2–6
mg/dl).
Uricacid,aproductofpurinemetabolism,haslowwatersolubility,speciallyatlow
pH.Whenblooduricacidlevelsarehigh→itprecipitatesanddepositsinjoints,
kidneyandsubcutaneoustissue.
Secondaryhyperuricaemiaoccursin-
(a)Leukaemias,lymphomas,polycythaemia→especiallywhentreatedwith
chemotherapyorradiation:duetoenhancednucleicacidmetabolismanduricacid
production.
(b)Druginduced→thiazides,furosemide,pyrazinamide,ethambutol,levodopa
reduceuricacidexcretionbykidney.
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4. Classification of anti-gout drugs
Foracutegout
NSAIDs
Colchicine
Corticosteroids
Forchronicgout/hyperuricaemia
Uricosurics-Probenecid,Sulfinpyrazone
Synthesisinhibitors-Allopurinol,Febuxostat
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5. Pharmacology of drugs for acute gout
Acutegout
Manifestsassuddenonsetofsevereinflammationinasmall
joint(commonestismetatarso-phalangealjointofgreattoe)→
duetoprecipitationofuratecrystals(tophy)inthejointspace.
Thejointbecomesred,swollenandextremelypainful→
requiresimmediatetreatment.
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6. NSAIDs
Highandquicklyrepeateddosesofpotentantiinflammatorydrugs,e.g.naproxen,
piroxicam,diclofenac,indomethacinoretoricoxibarethedrugsofchoice.
Quiteeffectiveinterminatingtheattack,butmaytake12–24hours→sloweronset
ofactioncomparedtocolchicine,butaregenerallybettertolerated;preferredby
majorityofpatients.
Strongantiinflammatory(noturicosuric)actionisresponsibleforthebenefit.
Naproxenandpiroxicamspecificallyinhibitchemotacticmigrationofleucocytes
intotheinflamedjoint.Aftertheattackisover,theymaybecontinuedatlower
dosesfor3–4weekswhiledrugstocontrolhyperuricaemiatakeeffect.
Arenotrecommendedforlongtermmanagementduetoriskoftoxicity.
Substitutescolchicineforcoveringuptheperiodofinitiationoftherapy(6–8
weeks)withallopurinoloruricosuricsinchronicgout.
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7. Colchicine
AnalkaloidfromColchicumautumnalewhichwasusedingout
since1763.Thepurealkaloidwasisolatedin1820.
Neitheranalgesicnorantiinflammatory,butitspecifically
suppressesgoutyinflammation.
Doesnotinhibitthesynthesisorpromotetheexcretionofuric
acid→noeffectonblooduricacidlevels.
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8. 8
Precipitation of urate crystals
in the synovial fluid
An acute attack of gout
Engulfment of urate crystals
by the synovial cells
Release of inflammatory mediators
Production of chemotactic factors
Granulocyte migration into the joint
Urate crystals phagocytosis
Release of glycoprotein
aggravating inflammation
(i) Increasing lactic acid production from
inflammatory cells →local pH is reduced →
more urate crystals are precipitated in the
affected joint.
(ii) Releasing lysosomal enzymes
which cause joint destruction
HOW
???
Flowchart showing events occuring during the development of acute gout

9. Colchicinedoesnotaffectphagocytosisofuratecrystals,butinhibitsrelease
ofchemotacticfactorsandglycoprotein,thussuppressingthesubsequent
events.
Bybindingtofibrillarproteintubulin,itinhibitsgranulocytemigrationintothe
inflamedjointandthusinterruptstheviciouscycle.
Otheractionsofcolchicineare:
(a)Antimitotic:causesmetaphasearrestbybindingtomicrotubulesofmitotic
spindle.
Itwastriedforcancerchemotherapybutabandonedduetotoxicity.
Itisusedtoproducepolyploidyinplants.
(b)Increasesgutmotilitythroughneuralmechanisms.
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10. Pharmacokinetics
Rapidoralabsorption,
Partialhepaticmetabolism
Biliaryexcretion→ undergoes
enterohepaticcirculation;ultimate
disposaloccursinurineandfaeces
overmanydays.
Largevolumeofdistributionand
slowelimination→duetobindingof
colchicinetointracellulartubulin.
CYP3A4inhibitorsretardcolchicine
metabolismandenhanceitstoxicity.
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Toxicity
Highanddoserelated.
Doselimitingadverseeffects→Nausea,
vomiting,wateryorbloodydiarrhoeaand
abdominalcrampsoccuras.
Accumulationofthedruginintestineand
inhibitionofmitosisinitsrapidturnover
mucosaisresponsibleforthetoxicity.
Overdose→kidneydamage,CNSdepression,
intestinalbleeding;deathisduetomuscular
paralysisandrespiratoryfailure.
Chronictherapy→notrecommended→
causesaplasticanaemia,agranulocytosis,
myopathyandlossofhair.

11. Uses
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(a)Treatmentofacutegout
Fastestactingdrug→controlanacuteattackof
gout→0.5mg1–3hourlywithatotalof3doses
inaday;maximum6.0mginacoursespread
over3–4days.
Controlofattackisusuallyachievedin4–12
hours.
Asecondcourseshouldnotbestartedbefore3–
7days.
Theresponseisdramatic&diagnostic.
UsedonlywhenNSAIDsareineffectiveor
cannotbeused→becauseofhighertoxicity.
Maintenancedoses(0.5–1mg/day)maybegiven
for4–8weeksinwhichtimecontrolof
hyperuricaemiaisachievedwithotherdrugs.
(b)Prophylaxis
Colchicine0.5–1mg/daycanprevent
furtherattacksofacutegout,but
NSAIDsaregenerallypreferred.
Takenatthefirstsymptomofanattack,
smalldoses(0.5–1.5mg)ofcolchicine
abortit.

12. Corticosteroids
Intraarticularinjectionofasolublesteroidsuppressessymptomsofacute
gout.
Crystallinepreparationsshouldnotbeused.
Itisindicatedinrefractorycasesandthosenottolerating
NSAIDs/colchicine.
Systemicsteroidsarerarelyneeded.
Theyarehighlyeffectiveandproducenearlyasrapidaresponseas
colchicine,butarereservedforpatientswithrenalfailure/historyofpeptic
ulcerbleedinwhomNSAIDsarecontraindicatedorforcasesnotresponding
toornottoleratingNSAIDs.
Prednisolone40–60mgmaybegiveninoneday,followedbytapering
dosesoverfewweeks.
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13. Pharmacology of drugs for chronic gout
Chronicgout
Gouthasbecomechronic→whenpainandstiffnesspersistina
jointbetweenattacks.
Othercardinalfeatures→hyperuricaemia,tophi(chalk-likestones
undertheskininpinna,eyelids,nose,aroundjointsandother
places)anduratestonesinthekidney.
Inmajorityofpatients,hyperuricaemiaisduetoundersecretionof
uricacid,whileinfewitisduetooverproduction.
Chronicgoutyarthritismaycauseprogressivedisabilityand
permanentdeformities.
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14. A.URICOSURICDRUGS
1.Probenecid
Ahighlylipid-solubleorganicaciddevelopedin1951toinhibitrenaltubularsecretion
ofpenicillinsothatitsdurationofactioncouldbeprolonged.
Competitivelyblocksactivetransportoforganicacidsbyorganicaniontransporting
polypeptides(OATP)atallsites→mostprominentinrenaltubules.
Thistransportisbidirectional→neteffectdependsonwhethersecretionor
reabsorptionoftheparticularorganicacidisquantitativelymoreimportant,e.g.:
(a)Penicillinispredominantlysecretedbytheproximaltubules,itsreabsorptionis
minimal.Neteffectofprobenecidisinhibitionofpenicillinexcretion;more
sustainedbloodlevelsareachieved.
(b)Uricacidislargelyreabsorbedbyactivetransport,whilelessofitissecreted;only
1/10
th
ofthefilteredloadisexcretedinurine.Themajortransporterinvolvedis
URAT-1,amemberoftheOATPfamily.Probenecid,therefore,promotesuricacid
excretionandlowersitsbloodlevel.
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15. Probeneciddoesnothaveanyothersignificantpharmacologicalaction;itisneitheranalgesic
norantiinflammatory.
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Interactions
Inadditiontopenicillins,probenecidinhibits
theurinaryexcretionofcephalosporins,
sulfonamides,methotrexateandindomethacin.
Itinhibitsbiliaryexcretionofrifampicin.
Pyrazinamideandethambutolmayinterfere
withuricosuricactionofprobenecid.
Probenecidinhibitstubularsecretionof
nitrofurantoinwhichmaynotattainantibacterial
concentrationinurine.
Salicylatesblockuricosuricactionof
probenecid.
Pharmacokinetics
Completeoralabsorption
90%plasmaproteinbound
Partlyconjugatedinliver
Excretedbythekidney
Plasmat½is6–8hours.
Adverseeffects
Probenecidisgenerallywelltolerated.
Commonsideeffect→Dyspepsia(upto25%
incidencewithhighdoses).
Caution→pepticulcerpatients.
Rarely→rashesandotherhypersensitivity
phenomena.
Toxicdoses→convulsionsandrespiratory
failure.

16. Uses
1.Chronicgoutandhyperuricaemia:
Probenecidisasecondline/adjuvantdrugtoallopurinol.Startedat0.25gBDand
increasedto0.5gBD,itgraduallylowersblooduratelevel;arthritis,tophiandother
lesionsmaytakemonthstoresolve.Colchicine/NSAIDcoverisadvisedduringthe
initial1–2monthstoavoidprecipitationofacutegout.
Probenecidandotheruricosuricsareineffectiveinthepresenceofrenalinsufficiency
(serumcreatinine>2mg/dl).
Plentyoffluidsshouldbegivenwithprobenecidtoavoiduratecrystallizationin
urinarytract.
2.Probenecidisalsousedtoprolongpenicillinorampicillinactionbyenhancingand
sustainingtheirbloodlevels,e.g.ingonorrhoea,subacutebacterialendocarditis
(SABE).
3.Probenecidisgivenalongwithcidofovir,adrugforCMVretinitisinAIDSpatients,
topreventitsnephrotoxicity.
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17. 2.Sulfinpyrazone
Apyrazolonederivative,relatedtophenylbutazone,havinguricosuricaction,butis
neitheranalgesicnoranti-inflammatory.
Inhibitstubularreabsorptionofuricacid,butsmallerdosescandecreaseurate
excretionasdosmalldosesofprobenecid.
Thoughequallyefficaciousasprobenecid,sulfinpyrazonehasgoneintodisuse
becauseofmoregastricirritationandothersideeffects.
IthasbeenwithdrawninUSA.
Sulfinpyrazoneinhibitsplateletaggregationaswell.
3.Benzbromarone
Anotheruricosuricdrugwithrestricteduseduetohepatotoxicity.
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18. B.URICACIDSYNTHESISINHIBITORS
1.Allopurinol
Hypoxanthineanaloguesynthesizedasapurineantimetaboliteforcancer
chemotherapy→hadnoantineoplasticactivitybutwasasubstrateaswellasinhibitor
ofxanthineoxidase,theenzymeresponsibleforuricacidsynthesis(asshownbelow).
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19. Allopurinolitselfisashort-acting(t½2hrs)competitiveinhibitorofxanthine
oxidase,butitsmajormetabolitealloxanthine(oxypurine)isalong-acting(t½24hrs)
noncompetitiveinhibitor→primarilyresponsibleforin-vivouricacidsynthesis
inhibition.
Athighconcentrations,allopurinolalsobecomesnoncompetitiveinhibitor.
Administrationofallopurinol→reducesplasmaconcentrationofuricacidand
increasesthatofhypoxanthineandxanthine.
All3oxypurineareexcretedinurineinpresenceofuricacidalone.
xanthineandhypoxanthinearemoresoluble,haveahigherrenalclearancethanthat
ofuricacidandeachhasitsindividualsolubility→precipitationandcrystallizationin
tissuesandurinedoesnotoccur.
Raisedlevelsofxanthineandhypoxanthinecausesfeedbackinhibitionofdenovo
purinesynthesisandreutilizationofmetabolicallyderivedpurine.
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Pharmacokinetics
About80%ofadministeredallopurinolisorally
absorbed.
Notboundtoplasmaproteins.
Metabolizedlargelytoalloxanthine.
Duringchronicmedication→inhibitsitsown
metabolism
About1/3
rd
isexcretedunchanged,therestas
alloxanthine.
Interactions
(a)Allopurinolinhibitsthedegradationof6-
mercaptopurineandazathioprine→their
dosesshouldbereducedto1/3rd,butnotthat
ofthioguanine,becauseitfollowsadifferent
metabolicpath(S-methylation).
(b)Probenecidgivenwithallopurinolhas
complexinteraction→probenecidshortens
t½ofalloxanthine,allopurinolprolongst½of
probenecid.
(c)Allopurinolcanpotentiatewarfarinand
theophyllinebyinhibitingtheirmetabolism.
(d)Ahigherincidenceofskinrasheshasbeen
reportedwhenampicillinisgiventopatients
onallopurinol.
Adverseeffects→Uncommon.
Hypersensitivityreaction→rashes,fever,malaise
andmusclepain→settledonstoppingthedrug.
Renalimpairmentincreasestheincidenceofrashes
andotherreactionstoallopurinol.
Rare,seriousrisk→Stevens-Johnsonsyndrome.
Infrequent→gastricirritation,headache,nausea
anddizziness-donotneedwithdrawal.
Rare→liverdamage.

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Precautionsandcontraindications
Liberalfluidintakeisadvocatedduringallopurinoltherapy.
Itiscontraindicatedinhypersensitivepatients,duringpregnancyandlactation.
Itshouldbecautiouslyusedintheelderly,childrenandinpatientswithkidneyorliverdisease.
Uses
Firstchoicedruginchronicgout→usedinbothoverproducersandunderexcretorsofuricacid,
particularlyinmoreseverecaseswithtophiornephropathy.
UricosuricsareinfrequentlyusedinIndia;theyarelesseffectivewheng.f.r.islowandare
inappropriateinstoneformers.Thetwoclassesofdrugscanalsobeusedtogetherwhenthe
bodyloadofurateislarge.
Tophigraduallydisappearandnephropathyisarrestedevenreversedwithlong-termallopurinol
therapy.
Controlssecondaryhyperuricaemiaduetocancerchemotherapy/radiation/thiazidesorother
drugs,canevenbeusedprophylacticallyinthesesituations.
Topotentiate6-mercaptopurineorazathioprineincancerchemotherapyand
immunosuppressanttherapy.
DoseStartwith100mgOD,graduallyincreaseasneededto300mg/day;maximum600mg/day.

22. Caution
Allopurinolaswellasuricosuricsshouldnotbestartedduringacuteattackofgout.
Duringtheinitial1–2monthsoftreatmentwiththesedrugs,attacksofacutegout
aremorecommon-probablyduetofluctuatingplasmauratelevelsfavouring
intermittentsolubilizationandrecrystallizationinjoints→coverwithNSAIDs/
colchicine.
Kala-azar
AllopurinolinhibitsLeishmaniabyalteringitspurinemetabolism.
Itwastriedasadjuvanttosodiumstibogluconate,butabandonedduetopoor
efficacy.
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23. 2.Febuxostat
Recentlyintroducednonpurinexanthineoxidaseinhibitor,equallyormoreeffective
thanallopurinolinloweringblooduricacidlevelinpatientswithhyperuricaemiaand
gout.
Pharmacokinetics
Rapidoralabsorption
highplasmaproteinbinding,
Hepaticoxidationandglucuronideconjugation
Renalexcretion
Plasmat½is~6hours.
AdverseeffectsImportant-liverdamage→liverfunctionneedstobemonitored
duringfebuxostattherapy.Usual→Diarrhoea,nauseaandheadache.
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24. Interaction
Byinhibitingxanthineoxidase,ithasthepotentialtointeractwithmercaptopurine,
azathioprineandtheophylline→shouldnotbegiventopatientsreceivingthese
drugs.
UsesFebuxostatisanalternativedrugfortreatingsymptomaticgoutonlyin
patientsintoleranttoallopurinol,orinthosewithsomecontraindications.
Itisnotindicatedinmalignancyassociatedhyperuricaemia.
Likeotherdrugsusedtotreathyperuricaemia,NSAID/colchicinecovershouldbe
providedfor1–2monthswhileinitiatingfebuxostattherapy.
Dose40–80mgOD.
3.Rasburicase,anewrecombinantxanthineoxidaseenzymethatoxidizesuricacid
tosolubleandeasilyexcretedallantoinform.Itisindicatedonlyforpreventing
chemotherapyassociatedhyperuricaemiawhenmassivelysisofleukaemicorsolid
tumormassisinducedbycytotoxicdrugsinchildren.
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