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Antiinflamatorii, antipiretice,

analgezice
Autacoizi lipidici
• Eicosanoizi – metaboliti ai acidului arahidonic
– Prostaglandine (PG)
– Prostaciclina (PGI2) prostanoizi
– Tromboxan A2 (TxA2)
– Leukotriene (LT)
– Lipoxine
– Hepoxiline
• Nu se stocheaza – produse ca raspuns la stimuli (fizici,
chimici, hormonali) – acil hidrolaze (PLA2 – Ca++,
indep, secr.) – elibereaza acid arahidonic din lipide
membranare
• Acid arahidonic – ciclooxigenaze, lipoxigenaze, CYP
Ciclooxigenaze
• Prima enzima pe calea de sinteza a
prostanoizilor
• PG endoperoxid G/H sintetaza = COX
• 2 izoforme
– COX-1 – constitutiv – principal housekeeping
• Ex. Citoprotectie epiteliu gastric
– COX – 2 – inducibila – citokine, stress forfecare,
factori de crestere
• Ex. Inflamatie, cancer
Antiinflamatoare non-steroidiene
• Istoric
• Aspirina
– Hipocrate – coaja/ frunze de salcie – antipiretic
– 1763 – scrisoare catre Royal Society (Edmund Stone)
– Spiraea ulmaria – “aspirin”
– Cristalizare salicina – 1829, acid salicilic – 1836
– Productie industriala 1874 – antipiretic, reumatism
– 1899 Hoffman (Bayer) – acid acetilsalicilic (primul
test pe animale)
Inflamatia
• Proces inflamator – raspuns la stimuli lezionali
• Proces esential supravietuirii
• Uneori – exagerat – fara beneficii biologice
• Simptome: calor, dolor, rubor, tumor
• Vasodilatatie locala – permeabilitate capilara –
infiltrare leucocite, fagocite – degenerare
tisulara – fibroza
• Histamina, bradikinina, 5-HT, LT, PAF
Inflamatia
• Biosinteza prostanoizi
– Inductie COX-2 – sursa majora; ore
– COX-1 – contribuie; acut
– PGE2, PGI2 – mediatori principali ai inflamatiei
•  debit sangvin, permeabilitate vasculara, infiltrare
leucocite (EP2, IP)
– PGD2 – mastocite – raspuns alergic
• DP1 – vasodilatatie, diferentiere Th2
• DP2 – eozinofile
Inflamatia
• Activarea endoteliala
– Targeting la sit inflamator
–  Molecule de adeziune – celule rezidente – L-, P-
selectine
– Adeziune leucocitara – E-selectina, ICAM-1
• Mediatori solubili
– C5a, PAF, LTB4 – chemotactici
– Citokine – TNF, IL-1 – din macrofage, monocite, adipocite
– + IL-6, IL-8, GM-CSF – expresie genica si sinteza proteica :
COX-2, molecule adeziune
• Rezolutie / antiinflamatori
– TGF-1, IL-10, IFN-
Durerea
• Activare nociceptori – caldura, acizi, presiune -
prag sensibilitate
• Bradikinina, H+, serotonina, ATP, LT, PG
• PGE2 si PGI2 – senzitizare periferica – scad
pragul – EP1, EP4 – fosforilare TRPV1 – cresc
excitabilitatea
• Senzitizare centrala – maduva – PGE2 –
dezinhibitie cai glicinergice
Febra
• Echilibru productie/ pierdere
• Hipotalamus – set point
• Pirogeni endogeni – IL-1, IL-6, TNF-, IFN –
eliberare ceramida n.preoptici hipotalamus
anterior – faza rapida, initiala
• Faza tardiva – inductie COX-2, mPGES-1 –
endoteliu vase arie preoptica – PGE2 – trece
H-E – EP3 – neuroni termosensibili – activare
generare caldura/ reducere pierdere
AINS
• Clasificare
– Structura chimica
– Selectivitate COX-2 – traditionali vs. COX-2
– T1/2
• Majoritatea AINS – inhibitori competitivi,
reversibili la sit activ al enzimei
– ASA – acetilare – ireversibil – turnover enzima
(plachete 8-12 zile)
– Acetaminofen – antipiretic, analgezic, nu
antiinflamator – peroxidare locala
• ASA si AINS – inhiba COX, nu LOX (LT)
• !Glucocorticoizi – inhiba inductia COX-2, PLA2
ADME
• Absorbtie orala rapida – peak 2-3 h
• Solubilitate apoasa redusa – AUC variabil cu
cresterea dozei
• Alimente, antiacide – intarzie absorbtia
• Legare albumina – stauratie dependenta de
concentratie
• Penetrabilitate sinoviala – ½ conc plasmatica
• Topic – minim (ex. diclofenac – sistemic)
• T1/2 = 1 – 50h
• Biotransformare hepatica si excretie renala
• Acetaminofen – NAPQI – supradoza (>10g) -
hepatotoxic
Utilitate terapeutica
• Inflamatie
– B. musculoscheletice – artrita reumatoida, osteoartrita –
nu sunt DMARDS (agenti modificatori de boala
reumatismala)
– Spondilita ankilopoietica, guta
– Artropatii moderate
• Durere
– Intensitate moderata – scazuta
– Eficienta < opioizi, dar EA reduse
– Pentru senzitizare centrala sau periferica ; nu durere
viscerala (exc. Durere menstruala – PG endometriale)
– Nu sunt eficienti in durerea neuropata
Utilitate terapeutica
• Febra
– Scade febra dar nu si variatia circadiana sau
raspunsul la exercitiu fizic
• Circulatia fetala
– Ductus arteriosus
• Cardioprotectie
– Antiagregant plachetar – creste timpul de
sangerare
– Inhibare TxA2 plachetar
Efecte adverse
• GI
– Anorexie, greata, dispepsie, durere abdominala, diaree
– Ulceratii – 15-30% pacienti cronic
– COX-1 epiteliu gastric – PGI2, PGE2 – inhiba secretie acida,
cresc debit sangvin mucoasa, secretie mucus – misoprostol
(PGI1)
– Iritatie locala – minor (aspirina tamponata)
• C-V
– COX-2 selectivi – celecoxib, valdecoxib, refecoxib
– Cresc incidenta IM, AVC, tromboza
– Inhibitie COX-2 vascular si renal
– Retentie hidrosalina
– Nefropatia analgezica – IR, scaderea cap concentrare,
piurie sterila
Efecte adverse
• Sarcina si lactatia
– PGE2, PGF2 - contractie miometru travaliu
– Stenoza ductus arteriosus, oligohidramnios
– Hemoragie post-partum
– CI – in special tardiv >32 sapt
• Hipersensibilitate
– Aspirina – incrucisat AINS – soc anafilactic (non-imun)
– inhibitie COX, activare LOX
• Sdr. Reye - aspirina
– Encefalopatie, disfunctie hepatica, infiltrare grasa ficat
– <20 ani, febra – inf. Virala
– acetaminofen
Interactiuni
• IECA – kinine – PG vasodilatatoare, natriuretice
– Hiperkaliemie
• Corticosteroizi – GI
• Warfarina - sangerare
Aspirina/ alti salicilati
• Cel mai consumat analgezic, antipiretic, antiinflamator
– standard
• Esteri acid salicilic (iritant)
• Absorbtie – rapida – stomac/ intestin superior
– Difuzie pasiva dependenta de pH –
• Distributie – generala
– Legare albumina 80-90%
• Metabolism – hepatic – acid saliciluric, phenolic
salicilat, acil glucuronid
• Doze antiinflamatorii – 4-5 g – 120-350g/mL (EA
>300)
• DMR – 4g/zi adulti, copii >12 ani
• Mesalamina – boala inflamatorie colon
• Local – salicilat - keratolitic
Efecte adverse
• Repirator
–  consum O2 si productia CO2 (decuplarea fosforilarii oxidative)
– Stimuleaza centrii respiratori – cresc ventilatia – scade PCO2 –
alcaloza respiratorie
• Echilibru acido-bazic si renal
– Excretie renala HCO3- si Na+, K+
– Acidoza renala compensatorie
– Retentie hidrosalina
• CV
– >3g/zi – creste volum plasmatic - ! Fct cardiaca
• Hepatic
– Leziuni hepatice progresive – luni
• Sangvin
– Inhibitie plachetara ireversibila
Acetaminofen
• Analgezic – antipiretic
• Antiinflamator slab
• Biodisponibilitate excelenta – t1/2 ~ 2h
• Metabolizare hepatica – conjugare
– CYP – NAPQI – GSH
• Doza zilnica totala – 4g
• Intoxicatie >7,5 g
– Necroza hepatica – fatal
– Inductie CYP – alcool
– Depletie GSH – malnutritie
– NAC
Derivati de acid acetic
• Indometacin
– Inhibitor neselectiv COX > aspirina
– Vasoconstrictor COX-independent
– Intoleranta – EA
– IV – inchidere DA
• Sulindac
– Prodrog – metabolit >500X, ½ indometacin
– Aceleasi precautii AINS – contact mucoasa, PG renale
– contrazise
– Utilizare – artrita reumatoida, osteoartrita, spondilita,
tendinita, bursita, sdr. Umar dureros, guta
Derivati de acid acetic
• Ketorolac
– Analgezic bun, slab antiinflamator
– <5 zile – durere acuta, im, iv, oral
– Postoperator
• Diclofenac
– Cel mai utilizat EU
– Analgezic, antipiretic, antiinflamator
– Selectivitate relativa COX-2 (~celecoxib)
– Scade disponibilitatea acidului arahidonic
– t1/2 scazut (1-2h), pasaj hepatic – dozare crescuta
– Acumulare lichid sinovial
Derivati de acid propionic
• Ibuprofen, naproxen, flurbiprofen, ketoprofen
• Inhibitori COX neselectivi
• Eficienta variabila COX – fara consecinte
terapeutice
• Toleranta GI – relativ
• Ketoprofen
– Mai potent
– Stabilizator membrana lizozomala
– Antagonist brdikinina
• Fenamati
– Acid mefenamic, meclofenamat
– Similare AINS traditionale
• Acizi enolici (oxicami)
– Nespecifici – meloxicam – COX-2 modest
– Piroxicam – inhiba activarea neutrofilelor
– Eficacitate similara cu aspirina, indometacin,
naproxen
– T1/2 lung – dozaj unic
• Derivati pirazolona
– Fenilbutazona, oxifenbutazona, dipirona
– Agranulocitoza - abandonati
AINS COX-2 selectivi – diaril heterociclici
• Coxibi
Coxibi
• Identificare prin screening de biblioteci
combinatorice
• Buzunar hidrofob – COX-2 (absent COX-1)
• Lant lateral (aromatic)
• Avertizare EMA – cea mai mica doza pentru cel
mai scurt timp
• Celecoxib (Celebrex ®)– singurul US – FDA
aprobat
– OA, AR, ARJ, SA, durere acuta
– Risc IM, AVC
• Parecoxib
– Administrare injectabila – im
– Analgezic – perioperator
• Etoricoxib (Arcoxia ®)
– T1/2 lung – 20-26 h
• Rofecoxib (Vioxx®)
– Introdus 1999
– Retras 2004
Alti AINS
• Apazona
– Inhiba migrarea neutrofilelor, degranularea si
productia de ROS
• Nimesulid
– Selectivitate COX-2 ~ celecoxib
Table 34–3 Disease-Modifying Anti-Rheumatic Drugs

DRUG CLASS OR ACTION

Small molecules
Methotrexate Anti-folate
Leflunomide Pyrimidine synthase inhibitor

Hydroxychloroquine Anti-malarial
Minocycline 5-lipoxygenase inhibitor, tetracycline antibiotic

Sulfasalazine Salicylate
Azathioprine Purine synthase inhibitor
Cyclosporine Calcineurin inhibitor
Cyclophosphamide Alkylating agent
Biologicals
Adalimumab Ab, TNF- antagonist
Golimumab Ab, TNF- antagonist
Infliximab IgG-TNF receptor fusion protein (anti-TNF)

Certolizumab Fab fragment toward TNF-


Abatacept T-cell co-stimulation inhibitor (binds B7 protein on antigen-
presenting cell)

Rituximab Ab toward CD20 (cytotoxic toward B cells)

Anakinra IL-1-receptor antagonist


Farmacoterapia gutei
• Precipitare cristale urati in tesuturi – inflamatie
• Acut – monoartrita extrem de dureroasa
– Distrugere articulara, depozite subcutanate – tofi
– 0.5- 1% populatie occidentala
• Hiperuricemia – nu duce inevitabil la guta
– URAT-1 – transportor renal urat
– Eliminare scazuta, nu supraproductie
– Cristale urati – activare monocit/macrofag via TLR –
raspus imun innascut – IL-1beta, TNF-alfa, activare
endoteliala
Guta
• Scopuri tratament
– Scaderea simptomelor atacului acut
– Scaderea riscului de recurenta atac
– Scaderea urat seric
• Medicamente
– Antiinflamatoare analgezice (AINS, colchicina, GC)
– Previn raspuns inflamator la cristale (colchicina,
AINS)
– Inhibitia formarii de urat, cresterea eliminarii
Colchicina
• Extract plante – secol VI
• MA
– Antimitotic (arest G1) ~ alcaloizi vinca
• Efect pe celule cu turnover rapid
– Scade activarea neutrofilelor ca raspuns la cristale
– Inhiba activarea endoteliala – expresia molecule adeziune
– Inhiba degranularea mastocitara
• Atac acut
– Eficient in 2/3 pacienti – in primele 24h
– Preventie atac guta – off-label
• EA
– Greata, varsaturi, diaree – toxicitate cumulata
Allopurinol
• Inhiba xantin oxidaza – scade formarea de urat din
hipoxantina si xantina
• Metabolit activ – oxipurinol
• Inhibitie competitiva – doze mici; non-competitiv –
doze mari
• Scade concentratia de acid uric sub limita solubilitatii
• Excretie urinara xantina/ hipoxantina
• Febuxostat
– Nou inhibitor XO
• Rasburicaza
– Urat oxidaza recombinanta - alantoina
Uricozurice
• Cresc rata de excretie urinara a acidului uric
• Urat – filtrat, secretat, reabsorbit (fractie
excretie 10%)
• Reabsorbtia – URAT-1
• Probenecid
– Inhibitor URAT-1
– Inhibat de salicilati