Beruflich Dokumente
Kultur Dokumente
The role of
antibradykinin in
pain management
Aznan Lelo
Dept. Pharmacology & Therapeutic,
School of Medicine
Universitas Sumatera Utara
1 Juli 2005, KONAS IRA, Jogjakarta
trauma
irritation
infection
chemical
thermal
allergy
etc.
PROSTAGLANDIN
Substance P
PAF
Histamine
Urokinase
Leukotrien
IL-1
BK
Slow
induction
Rapid
induction
PGs
25
none
bradykinin
20
15
10
5
0
Control
IL-1
PGE2
Control
IL-1
6-keto-PGF1alfa
is the metabolite
of prostacyclin
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)
Disposition of bradykinin
Half-life BK 15 sec.
LMW
Kallikrein
HMW
Kininogen
Kallidin
BK
des-Arg9desArg9bradykinin
Angiotensinogen
AI
inactive
metabolite
vasodilatation
A II
vasoconstriction
Bradykinin receptors
There two main
types of receptors,
B1 receptor
B2 receptor
(B3, B4 and B5)
B2 receptor is the
dominant type.
B2
B2
B1
PLC
PLA2
DAG
Lipase
DAG
PKC
activation
Open ion
channels
Na influx &
depolarization
Phospho
lipid
Arachidonic
Acid
COX
PGs
Bevan, 2001
HYPERALGESIA
Prostaglandin
TNF-
IL-6
IL-8
IL-1
SYMPATHETIC
NERVE
COX-2
PG
BK
POLYMORPHS
FIBROBLASTS
NOCICEPTOR
Ferreira, 1993
ALGESIA
sensory
dorsal root
central
spinal cord
PAIN
COX-2
COX-2
inflammation
COX-1
EP1, EP3
EP4 & IP
DP & EP2
BK bradykinin
PG receptor
BK receptor
etodolac
diclofenac
(2x200 or 300mg/d
or 3x200 mg/d)
(2x50 mg/d or
3x50 mg/d)
comparable
Pena,1990
diclofenac
tomoxiprol
celecoxib
suprofen
ketorolac
flurbiprofen
aspirin
ketoprofen
ampyrone
ibuprofen
tolmetin
naproxen
indomethacin
zomepirac
fenoprofen
sodium salicylate
niflumic acid
diflunisal
meclofenamate
piroxicam
sulindac sulphide
meloxicam
etodolac
NS-398
rofecoxib
L-745,337
DFP
COX-1/COX
1/COX-2 IC80 (%)
80
60
40
20
COX-1
selective
inhibitor
preferentially
COX-1
selective
inhibitor
Diclofenac
Etodolac
Meloxicam
preferentially
nonselective COX-2
selective
COX
inhibitor inhibitor
anti-inflammatory
analgesic
Celecoxib
Rofecoxib
Valdecoxib
COXIB
COX-2
selective
inhibitor
Etodolac
pyranocarboxylic acid
() 1,8 diethyl-1,3,4,9tetrahydropyrano-[3,4b]indole-1-acetic acid
a racemic mixture of
R- and S- etodolac
C17H21NO3
the S-form is
biologically active and
the R form is not
there is no R-to-S
conversion in vivo
S-etodolac
was metabolized
more rapidly than
R-etodolac
in human
As non-steroidal anti-inflammatory
drugs (NSAID),
etodolac preferentially inhibits COX-2
activity
http://www.jr2.ox.ac.uk/bandolier/booth/painpag/Chronrev/OARA/oanstab.html
Drug treatment
Efficacy
210 E vs placebo
61
E vs diclofenac
Karbowski, 1991
64
E vs
Indomethacin
62
E vs Naproxen
56
E vs Naproxen
220 E vs Piroxicam
116
E vs Piroxicam
172 E vs Diclofenac
57
E vs Piroxicam
Ibuprofen
Ketoprofen
Etodolac
Celecoxib Rofecoxib
COX-2 inh
++
++
+++
Anti-BK
++
pKa
4.65
11.1
12.5
t-max
12
0.5 2
1.7
2.8
t-
1.8 2.5
2-4
7.5
11.2
17
Duration
4-6
Up to 6
4 6 (12)
12
Daily dose
400
25 50
200
100 - 200
12.5 - 25
Dosing
interval
Q 4 6 hr
Q 6 8 hr
Q 6 8 hr
Q 12 hr
Q 24 hr
Max. daily
dose
3200 mg
300 mg
1200 mg
400 mg
25 mg
AINS
COXIB aggregasi trombosist >> kemungkinan trombosis >
Non-COXIB aggregasi trombosit < kemungkinan trombosis <
Yang lebih aman dari kemungkinan CV event adalah nonCOXIB, misalnya etodolac
Yang terbaik TIDAK memberikan AINS COXIB atau nonCOXIB bila hanya nyeri yang menjadi problema, gunakan
analgetika lain
Pain with
Cardiometabolic Syndrome
Deteriorated
Lipid profile
Improved
Impaired
Insulin sensitivity
Improved
Impaired
Insulinemia
Improved
Impaired
Glycemia
Improved
Impaired
Susceptibility
to thrombosis
Improved
Impaired
Inflammation
markers
Improved
Impaired
Endothelial
function
Improved
CHD Risk
Low
Abdominally
obese
High waist
High
Reduced
obese
Low waist