prof. aznan 0-peran obat anti bradikinin dalam managemen nyeri.pdf
TRANSCRIPT
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Pertanyaan sejawat
• Prof, saya harus memberikan AINS
kepada pasien yang juga: – Sirosis hati dan
– • Prof, AINS kan menghambat
prostaglandin yang diperlukan mukosa
saluran cerna• Saya harus pilih AINS yang mana
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The role ofThe role of
antibradykinin inantibradykinin inpain managementpain management
Aznan LeloAznan Lelo
Dept. Pharmacology & Therapeutic,Dept. Pharmacology & Therapeutic,School of MedicineSchool of MedicineUniversitas Sumatera UtaraUniversitas Sumatera Utara
1 Juli 2005, KONAS IRA, Jogjakarta
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infectionirritation
chemical thermal
trauma
redness, pain, swelling,heat, dysfunction
PROSTAGLANDIN
.
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HistaminePAF
Urokinase Leukotrien
Substance P
BKIL-1
PGsSlowinductionRapid
induction
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Prostanoid profile in cultured human synovial cells
treated with bradykinin (BK) before and afterpre-incubation with IL-1 or control medium
15
20
25
d ( n g / m l ) none
bradykinin
0
5
10
Control IL-1 Control IL-1
PGE2 6-keto-PGF1alfa
P r o s t a n o
i
is the metaboliteof prostacyclinBathon et al Inflammation 20:537-54,1996
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Bradykinin (BK) a protein belonging to the family called kininogens Kininogen is an a-globulin in plasma.
High MW (110 000)
Low MW (70 000) Heavy Kininogen is converted into BK by the
action of the enzyme Kallikrein
BK binds to receptors onnerve endings, causing paincapillary wall, opening junctions between cells; allows
leukocytes and fluid into tissuescapillary cells and stimulates production of PGE2 and
PGE2alpha, causing tissue swelling and painmast cells in connective tissue, causing release of
histamine and then pain
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LMW
KallikreinAngiotensinogenAngiotensinogen
HMW
Kininogen
Half-life BK 15 sec.
Disposition of bradykinin
BK
desdes--Arg9Arg9--bradykininbradykinin
vasoconstriction
A I
A IIinactiveinactive
metabolitemetabolite
vasodilatation
Kallidin
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Bradykinin induced painAdministration of:
BradikininKallidindes-Arg9 bradykinin (DABK)des-Arg9-kallidin
will induce pain, inflammation and hyperalgesiaDirectly and indirectly
(Dray & Perkins, 1993)
Depend on the dose administeredLow dose (0.15 ug, IT) induce hyperlalgesiaHigh dose (6.0 ug, IT) give analgesic effect
(Sot dkk, 2002)
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Bradykinin receptors
B2
B2 receptor on nerve endings
There two main
types of receptors, B1 receptor B2 receptor
B2 B1
B2 receptor and newly expressedB1 receptor on nerve endings
in inflamed tissue
, an
B2 receptor is thedominant type.
Both belong to theG-protein family ofreceptors.
(Regoli, et al.,1993; Belichard, et al., 2000; Mason, et al., 2002)
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DAG
Actions of BK on Sensory Neurons
PhosphoPhospho
lipidlipid
B2R
BK
PLA2
G-protein
PLC
Lipase
⊕
Bevan, 2001
ArachidonicArachidonicAcidAcid ↑↑↑↑↑↑↑↑↑↑↑↑↑↑↑↑
COX
↑↑↑↑ PGs
↑↑ DAGDAG
PKCPKCactivationactivation
Open ionchannels
↑↑↑↑ Na influx &depolarization
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Mechanism of inflammatory pain Fox A, et al. (2003)
Activation of either B1 or B2 bradykinin receptors bykinins released from damaged tissues contributes tothe development and maintenance of inflammatoryhyperalgesia.
a functional role for B1 receptors expressed both in the
per p ery an n e sp na cor , n mec an cahyperalgesia during inflammation.
Gabra BH, Sirois P. (2003) Following acute i.p. administration of antagonists R-
715 or R-954 the STZ-induced hyperalgesic activitywas blocked in a dose-dependent manner the acute administration of DABK significantly
potentiated diabetes-induced hyperalgesia, an effect
that was totally reversed by R-715 and R-954
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TNF-α
IL-6 IL-8
MACROPHAGES
INFLAMMATION
BBB BBB BBB BBB BBB BBB BBB BBB BBBProstaglandin ↑↑↑↑↑↑↑↑
HYPERALGESIA
PG
ALGESIA
POLYMORPHS
IL-1 SYMPATHETICNERVE
FIBROBLASTS
COX-2
PGBK
NOCICEPTOR
PG
Ferreira, 1993
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synaptic transfer of pain signals
in the spinal cordperipheral
afferent nervecentral
spinal cordsensory
dorsal root
PAIN
PG receptor
DP & EP2EP1, EP3EP4 & IP
PGD(2), PGE(2), PGF(2alpha) and PGI(2)
COX-2
COX-1
inflammation
COX-2
BK bradykinin
BK receptor
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Agents that can attenuatethe algesic action of BK
NSAID
Acetylsalicylic acid, Diclofenac, Etodolac,
n ome ac n, Ketoprofen, Meloxicam, Naproxen,
Phenylbutazone, PiroxicamNon-NSAID
Eperison
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Inoue K, et al. Effect of etodolac on prostaglandin
E2 biosynthesis, active oxygen generation andbradykinin formation. Prostaglandins Leukot
Essent Fatty Acids. 51(6): 457-62,1994.
The inhibitory action of etodolac on bradykinin formationwas the most potent among NSAIDs tested(indomethacin, diclofenac Na, piroxicam, naproxen,
Etodolac inhibited bradykinin-forming enzymeactivity in a concentration-dependent manner.
The inhibitory action of etodolac on PGE2 biosynthesis
in rabbit articular chondrocytes stimulated by interleukin-1 (IL-1) beta was about 1/5 that of indomethacin These results indicate that etodolac is an anti-
inflammatory drug which suppress IL-1 beta-stimulated
PGE2 biosynthesis and bradykinin formation.
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The efficacy of etodolac andother NSAIDs in patients with
Low Back Pain
Tested Comparator Results Reference
etodolac diclofenac E
Pena,1990
(2x200 or 300mg/dor 3x200 mg/d)
(2x50 mg/d or3x50 mg/d)
comparableD
It is important to inhibit the activity of BK and COX-2
in patients with LBP
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6060
8080
100100
- 2 I C 8 0 ( %
)
COX-1/COX-2 ratios in wholeblood assay
D F P
L - 7
4 5
, 3 3 7
r o f e c o x i b
N S - 3
9 8
e t o d o l a c
m e
l o x
i c a m
n i m e s u
l i d e
c e l e c o x i b
t o m o x
i p r o
l
d i c l o f e n a c
s u l i n
d a c s u
l p h i d e
p i r o x
i c a m
m e c
l o f e n a m a
t e
d i f l u n
i s a
l
n i f l u m
i c a c
i d
s o d
i u m
s a
l i c y
l a t e
f e n o p r o
f e n
z o m e p
i r a c
i n d o m e
t h a c
i n
t o l m e
t i n
n a p r o x e n
i b u p r o
f e n
a m p y r o n e
k e
t o p r o
f e n
a s p
i r i n
f l u r b
i p r o
f e n
s u p r o
f e n
k e
t o r o
l a c
00
2020
4040
C O X - 1 / C O
Warner et al. PNAS 1999; 96:7563-7568
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Ibuprofen
Ketoprofen
Diclofenac
EtodolacMeloxicam
CelecoxibRofecoxibValdecoxib
AcetosalKetorolac
Resveratrol
Indomethacin
Piroxicam COXIB
Less GI side effectsLess GI side effectsFRIENDFRIEND
FOEFOEMore GI side effectsMore GI side effects
non-selective
COX
inhibitor
preferentially
COX-2selective
inhibitor
COX-2selectiveinhibitor
COX-1selectiveinhibitor
preferentially
COX-1selective
inhibitor
analgesic
anti-inflammatory
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Etodolac pyranocarboxylic acid
(±
) 1,8 diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid
R- and S- etodolac C17H21NO3 the S-form is
biologically active andthe R form is not
there is no R-to-S
conversion in vivo
S-etodolac
was metabolizedmore rapidly thanR-etodolac
in human
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Mechanism of action of Etodolac Has dual analgesic action
As anti-bradykinin, etodolac inhibits bradykinin-forming
-
dependent manner
As non-steroidal anti-inflammatory
drugs (NSAID), etodolac preferentially inhibits COX-2activity
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Brocks DR, et al. Stereoselective dispositionof etodolac enantiomers in synovial fluid
J Clin Pharmacol 31:741-6,1991
Concentrations of S-etodolac were greater inSF than in plasma
= . + - . No such difference was seen for R-etodolac
(SF : plasma = 0.91 +/- 0.3). Therapeutically active S-etodolac has greater
concentrations in synovial fluid than plasmaduring the post-distributive phase, which maybe of possible clinical relevance.
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http://www.jr2.ox.ac.uk/bandolier/booth/painpag/Chronrev/OARA/oanstab.html
NSAID Cochrane Table data for OA (1/7/99) by Henry McQuay
Reference N Drug treatment Efficacy
Williams et al, 1989 210 E vs placebo E significantly better thanplacebo
Brasseur et al, 1991 61 E vs diclofenac No difference between drugs
Karbowski, 1991 64 E vsIndomethacin
E better than indomethacin
Pena & Lizarazo, 1991 62 E vs Naproxen No difference between drugs
Palfreman et al, 1991 56 E vs Naproxen Minor evidence that Ebetterthan naproxen
Paulsen et al, 1991 220 E vs Piroxicam Drugs were comparable inefficacy
Dick et al, 1992 116 E vs Piroxicam No difference between drugs
Grisanti et al, 1992 172 E vs Diclofenac No difference between drugs
Waterworth & Dove,
1992
57 E vs Piroxicam No difference between drugs
Shnitzer et al, 1995 270 E vs Nabumetone
vs Placebo
Some evidence that E better
than nabumetone
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Pharmacokinetic and pharmacodynamic of
etodolac and other NSAIDs
parameter Ibuprofen Ketoprofen Etodolac Celecoxib Rofecoxib
COX-2 inh + + ++ ++ +++
Anti-BK ? + ++ ? ?
pKa 3 3 4.65 11.1 12.5
t-max 1 – 2 0.5 – 2 1.7 2.8 3t-½ 1.8 – 2.5 2 - 4 7.5 11.2 17
Duration 4 - 6 Up to 6 4 – 6 (12) 8 12
Daily dose 400 25 – 50 200 100 - 200 12.5 - 25
Dosinginterval
Q 4 – 6 hr Q 6 – 8 hr Q 6 – 8 hr Q 12 hr Q 24 hr
Max. dailydose
3200 mg 300 mg 1200 mg 400 mg 25 mg
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Jawaban pertanyaan sejawat• Pertimbangan farmakologi dalam pemilihan AINS kepada
pasien yang juga: – Sirosis hati dan – Perdarahan saluran cerna bagian atas
• Obat yang bakal diberikan AINS + PPI + beta-bloker• Beta-blocker
– → a ran ara < vaso ons r s > → emung nan rom os s >
• AINS – COXIB → aggregasi trombosist >> → kemungkinan trombosis > – Non-COXIB → aggregasi trombosit < → kemungkinan trombosis <
• Yang lebih aman dari kemungkinan CV event adalah non-
COXIB, misalnya etodolac• Yang terbaik TIDAK memberikan AINS COXIB atau non-
COXIB bila hanya nyeri yang menjadi problema, gunakananalgetika lain
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the evidence showed thatPain is not only induced by PG
but also induced by BKETODOLAC
KEBANGGAAN INDONESIAUNTUK DUNIA
marketed has dual action, ie more selectively inhibit
COX-2 and also inhibit the formation of BK
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Pain with
Cardiometabolic Syndrome
Deteriorated Lipid profile ImprovedImproved
Impaired Insulin sensitivity ImprovedImprovedImpaired Insulinemia ImprovedImproved
Impaired Glycemia ImprovedImproved
Impaired Susceptibilityto thrombosis ImprovedImproved
Impaired Inflammationmarkers
ImprovedImproved
Impaired Endothelialfunction
ImprovedImproved
CHD RiskCHD Risk LowLowHighHigh
AbdominallyobeseHigh waist
AbdominallyobeseHigh waist
Reducedobese
Low waist
Reducedobese
Low waist
Després JP et al.BMJ 322:716-20,2001
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Mork H, et al. Experimental muscle pain
and tenderness following infusion ofendogenous substances in humans.
Eur J Pain 7(2):145-53,2003
moderate muscle pain produced by: PGE(2),
a combination of BK, 5-HT, His, and PGE(2).Infusion of the combination of BK (92nmol),5-HT (156nmol), His (140nmol) &
PGE(2) (1.95nmol) produced a : moderate pain intensity (P=0.04) and mild tenderness (P=0.04)
without inducing unacceptable side effects