Antiinflamatoarele Nonsteroidiene (Ains)
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Transcript of Antiinflamatoarele Nonsteroidiene (Ains)
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ANTIINFLAMATOARELE ANTIINFLAMATOARELE NONSTEROIDIENE NONSTEROIDIENE
(AINS)(AINS)
Prof. Dr Ruxandra IonescuProf. Dr Ruxandra Ionescu
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AINSAINS 1899 folosirea aspirinei in trat. PR1899 folosirea aspirinei in trat. PR 1949 marcheaza denumirea clasei 1949 marcheaza denumirea clasei sintetizata fenilbutazonasintetizata fenilbutazona
Dupa 1960 crestere impresionanta AINSDupa 1960 crestere impresionanta AINS286 substante inregistrate (DCI), 1850 denumiri 286 substante inregistrate (DCI), 1850 denumiri
comercialecomerciale 1. folosite frecvent1. folosite frecvent 30milioane consumatori zilnici30milioane consumatori zilnici 2.2. se urmareste cresterea tolerantei la se urmareste cresterea tolerantei la
AINSAINS
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FOSFOLIPIDE MEMBRANARE
ACID ARAHIDONIC
Leucotriene Prostaglandine
LOXLOX COXCOX
AINSAINS Fosfolipaza Fosfolipaza A2A2
MECANISMUL ACTIUNE AINS
J. R. Vane -1971
Ac.arahidonic
CICLOOXIGENAZA (COX)
Sinteza prostaglandinelor
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Evolutia Evolutia conceptului conceptului
COXCOX
COX-1COX-1
COX
COX-2
19711971
19921992
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CARACTERISTICILE CICLOOXIGENAZELORCARACTERISTICILE CICLOOXIGENAZELOR(COX1, COX2)(COX1, COX2)
Sunt produse de gene diferiteSunt produse de gene diferite
Au structuri asemanatoare dar Au structuri asemanatoare dar
neidenticeneidentice
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MECANISMUL INHIBITIEI COX-1 SI COX2 DE AINS
COX-1 COX-2
AINS
Acid Arachidoni
c
“buzunarlateral
AINS
AcidArachidon
icArg 120
Arg 120Diferente structuraleintre COX1 /COX2
canalul COX2 mai larg
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ISOENZIMELE COX IN INFLAMATIE SI DUREREISOENZIMELE COX IN INFLAMATIE SI DURERE
(model experimental(model experimental))
COX-2
COX-1
Niv
elu
l p
rost
agla
nd
ine
InflamatNormal
COX-1 COX-1
Durere si inflamatie
Lipsky PE, et al. J Rheumatol. 1998;25:2298–2303.Lipsky PE, et al. J Rheumatol. 1998;25:2298–2303.
IL-1, TNF-, LPS, oncogene
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Rolul PG via COX2 Rolul PG via COX2
VasodilatatieCresc permeabilitatea vasculara
INFLAMATIE
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Rolul PG produse via COX2Rolul PG produse via COX2
Durere Durere sensibilizarea periferica—sensibilizarea periferica—
sensibilizeaza nociceptoriisensibilizeaza nociceptorii sensibilizarea centrala –selectarea sensibilizarea centrala –selectarea
de noi fibre nociceptivede noi fibre nociceptive
FebraFebra
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Rolul COX2 in carcinogenezaRolul COX2 in carcinogeneza
PGE2 via COX2 induc :PGE2 via COX2 induc : angiogeneza in tumori cu rol in cresterea si viabilitatea tumorii angiogeneza in tumori cu rol in cresterea si viabilitatea tumorii
Rolul COX 2 in angiogeneza demonstrat pt. cancerul colonic, gastric, Rolul COX 2 in angiogeneza demonstrat pt. cancerul colonic, gastric, san, plamansan, plaman
rezistenta la apoptoza a celulelor tumorale si cresterea adeziunii la rezistenta la apoptoza a celulelor tumorale si cresterea adeziunii la matricematrice
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Rolul COX2 in procese patologice Rolul COX2 in procese patologice cerebralecerebrale
COX2 COX2 - constitutiva la nivel cerebral- constitutiva la nivel cerebral
- rol in raspunsul la stress- rol in raspunsul la stress
- rol in procese inflamatoare cerebrale- rol in procese inflamatoare cerebrale
Boala Alzheimer se coreleaza cu nivele crescute ARNm COX2Boala Alzheimer se coreleaza cu nivele crescute ARNm COX2
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CARACTERISTICILE CICLOOXIGENAZELOR
COX
COX-1constitutiva
COX-2inductibila
TROMBOCIT
MUCOASA GASTRICA
ENDOTELIU
RINICHI
LEUCOCITE SINOVIOCITE
CELULE
ENDOTELIALE
STIMULI INFLAMATORI
CONDITII FIZIOLOGICE
VasodilatatieEfectcitoprotector
PGI2, PGE2
Mentin perfuzia renala eliminarea de Na si K
Vasoconstr.Agregare plachetara
TxA2
PGI2, PGE2
•INFLAMATIE• NEOPLAZII•ALZHEIMER
COX 2 constitutiva (concentratii mici)
creier, rinichi,
PGI2, PGE2
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BLOCAREA COXBLOCAREA COX
COX-1 COX-2
EFECTE ADVERSE EFECTE ADVERSE AINSAINS
• digestive digestive • renale renale
• antiinflamatoareantiinflamatoare• antialgiceantialgice• antipireticeantipiretice• antineoplaziceantineoplazice• incetineste incetineste progresiaprogresia bolii bolii Alzheimer Alzheimer
EFECTEEFECTE
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MECANISMUL INHIBITIEI COX-1 SI COX2 DE AINS
COX-1 COX-2
AINS
Acid Arachidon
ic
“buzunarlateral
AINS
AcidArachidon
icArg 120
Arg 120
Diferente structuraleintre COX1 /COX2
canalul COX2 mai larg
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BAZELE MOLECULARE ALE INHIBITIEI COX2
COX-1
CELECOXIB
Acid Arachidonic
N N
COX-2
CELECOXIB
“buzunar lateral”
AcidArachidon
ic
NN
Arg 120
Arg 120
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Clasificarea AINS Clasificarea AINS
Derivati de ac. salicilic Acid acetil salicilic, Diflunisal,BenorilatAcid acetil salicilic, Diflunisal,Benorilat
Derivati de ac. acetic Diclofenac, Indometacin, Sulindac,Tolmetin,EtodolacDiclofenac, Indometacin, Sulindac,Tolmetin,Etodolac
Derivati de ac. propionic Ibuprofen, Ketoprofen, NaproxenIbuprofen, Ketoprofen, Naproxen
Derivati de ac. fenamic Ac. Flufenamic, Ac. niflumic, Ac. Flufenamic, Ac. niflumic,
Oxicami Piroxicam, Tenoxicam, MeloxicamPiroxicam, Tenoxicam, Meloxicam
Acizi carboxilici
Acizi enolici
Derivati de pirazolonã Fenilbutazona, OxifenbutazonaFenilbutazona, Oxifenbutazona
NimesulidNimesulidNon acide NabumetonaNabumetona
COXIBI Celecoxib, Rofecoxib, Etoricoxib
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CLASIFICAREA AINS IN FUNCTIE DE CLASIFICAREA AINS IN FUNCTIE DE CAPACITATEA INHIBARE COXCAPACITATEA INHIBARE COX
COX1 specifici : Aspirina 80mgCOX1 specifici : Aspirina 80mg COX nespecifici: AINS clasiceCOX nespecifici: AINS clasice COX 2 selective : Meloxicam, Nimesulide COX 2 selective : Meloxicam, Nimesulide COX2 specifice : Celecoxib, RofecoxibCOX2 specifice : Celecoxib, Rofecoxib
Grupul international de studiu al coxibilor
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FARMACOCINETICA AINSFARMACOCINETICA AINS
AbsorbtiaAbsorbtia Transport 95% legate proteine Transport 95% legate proteine
plasmaticeplasmatice Distributia tropism zonele lezateDistributia tropism zonele lezate Metabolizare hepatica, ciclul enterohepaticMetabolizare hepatica, ciclul enterohepatic Eliminare hepatica, renalaEliminare hepatica, renala T1/2 < 6 h aspirina, diclofenacT1/2 < 6 h aspirina, diclofenac
> 6h fenilbutazona, meloxicam, > 6h fenilbutazona, meloxicam, piroxicam piroxicam
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EFECTE ADVERSEEFECTE ADVERSE GastrotoxicitateaGastrotoxicitatea ( ()) reprezintă 50-60% din reprezintă 50-60% din
toxicitatea totalătoxicitatea totală ( ()) toxicitatea renala, hepatica, hematologicatoxicitatea renala, hepatica, hematologica
Fries J., Curr. Opin. Rheum. 1996, 8 (Suppl.): S3-S7
6
5
4
3
2
1
0a b c d e f g h i j k l
a. aspirină b. salsalatc. naproxend. sulindace. piroxicamf. tolmeting. fenoprofenh. diclofenaci. ketoprofenj. ibuprofenk. indometacinal. meclofenamat
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TOXICITATE TOXICITATE GASTROINTESTINALAGASTROINTESTINALA
EFECTE EFECTE PROSTAGLANDINEPROSTAGLANDINE
1.1. Cresterea barierei Cresterea barierei mucusmucus
2.2. Cresterea secretiei Cresterea secretiei bicarbonatbicarbonat
3.3. Scaderea secretiei Scaderea secretiei acideacide
EFECTE AINSEFECTE AINS
1.1. Scad secretia Scad secretia mucusmucus
2.2. Scad secretia Scad secretia bicarbonatbicarbonat
3.3. Cresc secretia Cresc secretia acidaacida
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SPECTRUL LEZIUNILOR SPECTRUL LEZIUNILOR GASTROINTESTINALE INDUSE DE GASTROINTESTINALE INDUSE DE
AINSAINS
EROZIUNI ULCER GASTRIC HEMORAGII PERFORATIE
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LEZIUNI GASTRICELEZIUNI GASTRICE
Prezente la> 20% din pacientii care iau AINSDetermina complicatii severe la unii pacienti
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MORTALITATEA DATORATA MORTALITATEA DATORATA COMPLICATIILOR GI AINSCOMPLICATIILOR GI AINS
LeucemieSIDA
Toxicitate AINS
Mielom multiplu
Astm Neoplasm cervicalB. Hodgkin
Clinic of chronic pain Oxford - Tramer and colab.
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Factori risc efecte adverse Factori risc efecte adverse digestivedigestive
varsta >60anivarsta >60aniantecedente ulcerantecedente ulcerdoze mari AINSdoze mari AINSasocieri AINSasocieri AINS -alte AINS-alte AINS -cortizonice-cortizonice -anticoagulante-anticoagulanteinfectie infectie Helicobacter pyloriHelicobacter pylorifumatul,fumatul, consumul alcool, consumul alcool, cafeacafeaadm inhibitori receptori H2adm inhibitori receptori H2
Contracarare efecte adverseMISOPROSTOL
IPPCOXIBI
AINS SELECTIVE
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Risc crescut
1. Antecedente de ulcer complicat, mai ales dacă este recent
2. Factori de risc multipli (>2)
Risc moderat (1-2 factori de risc)
1. Vârsta >65 ani
2. Doză crescută de AINS
3. Antecedente de ulcer necomplicat
4. Administrare concomitentă de acid acetilsalicilic (inclusiv în doză mică), corticosteroizi sau anticoagulante
Risc scăzut
1. Fără factori de risc
H. Pylori este un factor de risc independent şi aditiv şi trebuie să fie abordat separat (a se vedea textul şi recomandările).
Stratificarea riscului GI al AINS
Pacienţii cu risc crescut de toxicitate GI a AINS
Adaptat dupa Guidelines for Prevention of NSAID-related Ulcer Complications, Frank L. Lanza et al, Am J Gastroenterol 2009, 104:728-738
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Acid arahidonic
COX-1 COX-2
PG fiziologice PG fiziologicePG rol in :
• inflamaţie• durere• febră• neoplazii• Alzheimer
COXIBIICOXIBII
AINSAINS
• Efect citoprotector• Mentin perfuzia renala• Transportul ionic• Agregare plachetara
Lipsky PE et al. J Rheumatol 1998;25:2298-2303 and Smith WL, Dewitt DL. Adv Immunol 1996;62:167-215
constitutiva inductibila constitutiva RINICHI
creierrinichi
Mentinerea perfuziei renaleHomeostazia hidro electrolitica
EXPLICATIA EFECTELOR ADVERSE CARDIO-RENALE
AINS vs COXIBI
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SistemulRenina-angiotensina
S.N. adrenergic
Vasoconstrictierenala P G
Vasodilatatierenala
aldosteron
PG E2 , PG I2
PG E2, PG I2
MENTINEREA FILTRARII GLOMERULARE
ROLUL PROSTAGLANDINELOR RENALE
HIPOVOLEMIE
EFECT NATRIURETIC, KALIURETIC
CATECOLAMINE
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EFECTELE CARDIORENALE ALE PG vs EFECTELE CARDIORENALE ALE PG vs AINS/coxibiAINS/coxibi
Rolul PG renaleRolul PG renale
VASODILATATIEVASODILATATIE Mentin FPR, FGMentin FPR, FG
NATRIURETIC NATRIURETIC KALIURETICKALIURETIC
EFECTE AINS/COXIBIEFECTE AINS/COXIBI
VASOCONSTRICTIEVASOCONSTRICTIEScade perfuzia renala, scade FGScade perfuzia renala, scade FG
RETENTIE Na/apaRETENTIE Na/apa HIPERKALIEMIEHIPERKALIEMIE
CONSECINTE:CONSECINTE:
EDEME, HTA, KEDEME, HTA, K
INSUFICIENTA CARDIACA INSUFICIENTA CARDIACA
IRA, N. INTERSTITIALEIRA, N. INTERSTITIALE
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Rolul prostaglandinelor in mentinerea Rolul prostaglandinelor in mentinerea homeostaziei cardiovascularehomeostaziei cardiovasculare
COX 1(plachete)
COX 2(endoteliu)
TxA2 PGI2prostaciclina
•agregare plachetară, •vasoconstricţie, •proliferare celule musc.netede
•inhibă agregarea plachetară•inhiba adeziunea leucocitara •vasodilatatie
1
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AINS
CLASICE
COX-1constitutiva
COX-2inductibila
TROMBOCIT
CELULE
ENDOTELIALE
TxA2 PGI2
COXIBII
Inhibita selectiva COX2 vs nonselectiva
TeoreticAINS clasice scad risc trombotic
Coxibii cresc riscul trombotic !! Vioxx retras !
Studii modele experimentale:
-deficienta receptori PGI2- creste risc trombotic
-deficienta r. PGI2,TXA2 scade riscul trombotic
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Rofecoxib 25
Placebo
ROFECOXIBROFECOXIB - APPROVE – - APPROVE –EVENIMENTE EVENIMENTE ATEROTROMBOTICE ATEROTROMBOTICE
Bresalier RS et al.-NEJM 2005;352:1092-1101
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Adaptat dupa Guidelines for Prevention of NSAID-related Ulcer Complications, Frank L. Lanza et al, Am J Gastroenterol 2009, 104:728-738
GHID DE PRACTICĂ ACG
Rezumatul recomandărilor pentru prevenţia complicaţiilor ulcerului indus de AINS
Riscul gastrointestinala
Scăzut Moderat Crescut
Risc CV scăzut
Doar AINS (AINS cel mai puţin ulcerogen în cea mai mică doză eficientă)
NSAID+IPP/misoprostol
Terapie alternativă dacă este posibil sau inhibitor COX-2 inhibitor+IPP/misoprostol
Risc CV crescutb (doză mică de acid acetilsalicilic necesară)
Naproxen + IPP/misoprostol
Naproxen + IPP/misoprostol
De evitat AINS sau inhibitori COX-2. De administrat terapie alternativă
aRiscul gastrointestinal este stratificat în scăzut (fără factori de risc), moderat (prezenţa a unul sau doi factori de risc) şi crescut (factori de risc multipli sau complicaţii ale unui ulcer în antecedente sau administrarea concomitentă de corticosteroizi sau anticoagulante). bRiscul CV crescut este definit arbitrar drept necesarul de acid acetilsalicilic pentru prevenţia evenimentelor CV severe. Toţi pacienţii cu antecedente de ulcer care necesită AINS trebuie testaţi pentru prezenţa H. pylori, iar dacă este prezentă infecţia, trebuie administrată terapia de eradicare.
Stratificarea riscului GI al AINSACG PRACTICE GUIDELINES
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Efecte adverseEfecte adverse
HEPATICEHEPATICE
Crestere enzime Crestere enzime serice (TGP/TGO)serice (TGP/TGO)
ColestazaColestaza
Sindrom hepatorenalSindrom hepatorenal
(ciroza hepatica)(ciroza hepatica)
ALERGICEALERGICE RespiratoriiRespiratorii
rinitarinita
polipozapolipoza
astm bronsicastm bronsic CutanateCutanate
eritem multiform eritem multiform
urticarieurticarie
dermatite exfoliativedermatite exfoliative
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Alte efecte adverseAlte efecte adverse
NeurologiceNeurologice
cefalee, cefalee,
ameteliameteli
meningita asepticameningita aseptica
Infectioase – mascheaza boli Infectioase – mascheaza boli infectioase!infectioase!
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Administrare AINS conditionata Administrare AINS conditionata dede
Interactiuni medicamentoaseInteractiuni medicamentoasePotenteaza: Potenteaza: antidiabetice oraleantidiabetice orale anticoagulanteanticoagulante digoxin, litiudigoxin, litiu metotrexatmetotrexat
Scade efectul: Scade efectul: diuretice, betablocante, diuretice, betablocante,
inhibitori enzima conversieinhibitori enzima conversie Efecte adverseEfecte adversePatologia conexa bolnavPatologia conexa bolnav
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ASPIRINAASPIRINA MEC. ACTIUNE- acetileaza ireversibil COXMEC. ACTIUNE- acetileaza ireversibil COX FARMACOCINETICAFARMACOCINETICAAbsorbtie rapidaAbsorbtie rapidaT1/2 dependent doza T1/2 dependent doza Doza mici 2-4hDoza mici 2-4h Doze mari >15hDoze mari >15hEliminare renalaEliminare renala INDICATIIINDICATII: antiagregant plachetar 75-100mg: antiagregant plachetar 75-100mg antiinflamator 3-8g/ziantiinflamator 3-8g/zi antialgic, antipiretic 2-3g/ziantialgic, antipiretic 2-3g/zi uricozuric 4g/ziuricozuric 4g/zi EFECTE ADVERSE digestive, hepatice, renale, alergiceEFECTE ADVERSE digestive, hepatice, renale, alergice INTERACTIUNI MEDICAMENTOASE INTERACTIUNI MEDICAMENTOASE alcalinele scad conc serica aspirina, alcalinele scad conc serica aspirina, vit C creste conc serica aspirinavit C creste conc serica aspirina
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DERIVATI ACID ACETICDERIVATI ACID ACETIC
INDOMETACININDOMETACIN
Foarte bun AIFoarte bun AI
T1/2 variabilT1/2 variabil
Indicatii :SS,PR, guta, Indicatii :SS,PR, guta,
Doze 75-150mg/ziDoze 75-150mg/zi
Efecte adverse Efecte adverse
specifice: cefalee, specifice: cefalee, ameteli, stari ameteli, stari confuzionaleconfuzionale
SULINDACSULINDAC: Nu are : Nu are efecte adverse renaleefecte adverse renale
DICLOFENACDICLOFENACReduce producerea Reduce producerea
leucotrieneleucotrieneT1/2 scurtT1/2 scurtDoze 100-150mg/ziDoze 100-150mg/ziEfecte adverse-toxicitate Efecte adverse-toxicitate
hepaticahepatica Atentie!Atentie! - determinare periodica - determinare periodica
TGP,TGOTGP,TGO
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Derivatii acid propionicDerivatii acid propionic
IbuprofenulIbuprofenul
F.Bun analgezicF.Bun analgezic
T1/2 scurtT1/2 scurt
Doze:Doze: 600-1200mg/zi efect analgezic600-1200mg/zi efect analgezic
>1200mg/zi efect AI>1200mg/zi efect AI
Efecte adverse –nervoaseEfecte adverse –nervoase
meningita aseptica limfocitarameningita aseptica limfocitara
NaproxenNaproxen
F.bun antiinflamatorF.bun antiinflamator
T1/2 >12 hT1/2 >12 h
Doza 1g/ziDoza 1g/zi KetoprofenKetoprofen
F bun analgezicF bun analgezic
T1/2 scurtT1/2 scurt
Doza 300mg/zi atacDoza 300mg/zi atac
150mg/zi 150mg/zi intretinereintretinere
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Derivatii enoliciDerivatii enolici
FenilbutazonaFenilbutazonaCel mai bun AICel mai bun AICel mai toxicCel mai toxicT1/2 > 60hT1/2 > 60h Efecte adverse:Efecte adverse:Retentie hidrosalinaRetentie hidrosalinaAgranulocitozaAgranulocitozaAnemie aplasticaAnemie aplasticaDermatite exfoliativeDermatite exfoliativeHepatite granulomatoaseHepatite granulomatoase
Piroxicam Piroxicam T1/2 50hT1/2 50h Doza 20-40mg/ziDoza 20-40mg/ziEfect maxim 7 zileEfect maxim 7 zile
MeloxicamMeloxicamT1/2 lungT1/2 lungDoza 15mg/ziDoza 15mg/ziToleranta dig. bunaToleranta dig. buna
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Derivati neaciziDerivati neacizi
NimesulideNimesulide
T1/2 - 5hT1/2 - 5h
Doza 200mg/ziDoza 200mg/zi
CelecoxibCelecoxib
Specific COX2Specific COX2
Toleranta dig bunaToleranta dig bunaDoza 200- 400mg/ziDoza 200- 400mg/zi
Contraindicat la pacientii cu Contraindicat la pacientii cu AVC, BCI, factori risc AVC, BCI, factori risc aterotromboticaterotrombotic
Etoricoxib (Arcoxia)Etoricoxib (Arcoxia) 60,90,120mg60,90,120mg
indicatii artroza, PR, SA, atac indicatii artroza, PR, SA, atac acut gutaacut guta
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Concluzii AINSConcluzii AINS
Utile in tratamentul simptomatic al Utile in tratamentul simptomatic al inflamatiei si dureriiinflamatiei si durerii
Raspuns bun 7-10 zileRaspuns bun 7-10 zileNu se recomanda combinatii AINSNu se recomanda combinatii AINSAINS specifice COX2 toleranta dig bunaAINS specifice COX2 toleranta dig bunaCoxibii contraindicati la pacientii cu Coxibii contraindicati la pacientii cu
factori risc aterotrombotic si la cei cu factori risc aterotrombotic si la cei cu BCI, AVC BCI, AVC