Antiinflamatorii,

antipiretice, analgezice

Autacoizi lipidici
Eicosanoizi metaboliti ai acidului arahidonic
Prostaglandine (PG)
Prostaciclina (PGI2)
Tromboxan A2 (TxA2)
Leukotriene (LT)
Lipoxine
Hepoxiline

prostanoizi

Nu se stocheaza produse ca raspuns la stimuli

(fizici, chimici, hormonali) acil hidrolaze (PLA2 i,
c, s) 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 nonsteroidiene
Istoric
Aspirina
Hipocrate coaja/ frunze de salcie
antipiretic
1763 scrisoare catre Royal Society
Spiraea ulmaria aspirin
Cristalizare salicina 1829, acid salicilic
1836
Productie industriala 1874 antipiretic,
reumatism

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-, Pselectine
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 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 (nonimun) 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 120-350g/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, 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
conbinatorice
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 343 Disease-Modifying Anti-Rheumatic

Drugs

DRUG
Small molecules
Methotrexate
Leflunomide
Hydroxychloroquine
Minocycline
Sulfasalazine
Azathioprine
Cyclosporine
Cyclophosphamide
Biologicals
Adalimumab
Golimumab
Infliximab
Certolizumab
Abatacept
Rituximab
Anakinra

CLASS OR ACTION

Anti-folate
Pyrimidine synthase inhibitor
Anti-malarial
5-lipoxygenase inhibitor, tetracycline antibiotic
Salicylate
Purine synthase inhibitor
Calcineurin inhibitor
Alkylating agent

Ab, TNF- antagonist

Ab, TNF- antagonist
IgG-TNF receptor fusion protein (anti-TNF)
Fab fragment toward TNFT-cell co-stimulation inhibitor (binds B7 protein on
antigen-presenting cell)
Ab toward CD20 (cytotoxic toward B cells)
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