Pertanyaan sejawat

Prof, saya harus memberikan AINS

kepada pasien yang juga:
Sirosis hati dan
Perdarahan saluran cerna bagian atas

Prof, AINS kan menghambat

prostaglandin yang diperlukan mukosa
saluran cerna
Saya harus pilih AINS yang mana

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

redness, pain, swelling,

heat, dysfunction

Substance P
PAF

Histamine

Urokinase

Leukotrien

IL-1

BK

Slow
induction

Rapid
induction

PGs

Prostanoid profile in cultured human synovial cells

treated with bradykinin (BK) before and after
pre-incubation with IL-1 or control medium
Prostanoid (ng/ml)

25

none
bradykinin

20
15
10
5
0
Control

IL-1
PGE2

Bathon et al Inflammation 20:537-54,1996

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)

Heavy Kininogen is converted into BK by the

action of the enzyme Kallikrein

BK is inactivated by Kininases

BK binds to receptors on

 nerve endings, causing pain

 capillary wall, opening junctions between cells; allows
leukocytes and fluid into tissues
 capillary cells and stimulates production of PGE2 and
PGE2alpha, causing tissue swelling and pain
 mast cells in connective tissue, causing release of
histamine and then pain

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 induced pain

Administration of:
 Bradikinin
 Kallidin
 des-Arg9 bradykinin (DABK)
 des-Arg9-kallidin

will induce pain, inflammation and hyperalgesia

Directly and indirectly
(Dray & Perkins, 1993)

Depend on the dose administered
 Low dose (0.15 ug, IT) induce hyperlalgesia
 High dose (6.0 ug, IT) give analgesic effect

(Sot dkk, 2002)

Bradykinin receptors
There two main
types of receptors,
 B1 receptor
 B2 receptor
 (B3, B4 and B5)
B2 receptor is the
dominant type.

B2

B2 receptor on nerve endings

in normal tissue

B2

B1

Both belong to the B2 receptor and newly expressed

G-protein family of B1 receptor on nerve endings
receptors.
in inflamed tissue
(Regoli, et al.,1993; Belichard, et al., 2000; Mason, et al., 2002)

Actions of BK on Sensory Neurons

BK
B2R
G-protein

PLC

PLA2
DAG
Lipase

DAG
PKC
activation
Open ion
channels
Na influx &
depolarization

Phospho
lipid

Arachidonic
Acid

COX
PGs
Bevan, 2001

Mechanism of inflammatory pain

Fox A, et al. (2003)
 Activation of either B1 or B2 bradykinin receptors by
kinins released from damaged tissues contributes to
the development and maintenance of inflammatory
hyperalgesia.
 a functional role for B1 receptors expressed both in the
periphery and in the spinal cord, in mechanical
hyperalgesia during inflammation.

Gabra BH, Sirois P. (2003)

 Following acute i.p. administration of antagonists R715 or R-954 the STZ-induced hyperalgesic activity
was 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

HYPERALGESIA
Prostaglandin

BBB BBB BBB BBB BBB BBB BBB BBB BBB

INFLAMMATION
MACROPHAGES

TNF-
IL-6

IL-8

IL-1

SYMPATHETIC
NERVE

COX-2

PG

BK
POLYMORPHS

FIBROBLASTS

NOCICEPTOR
Ferreira, 1993

ALGESIA

synaptic transfer of pain signals

in the spinal cord
peripheral
afferent nerve

sensory
dorsal root

central
spinal cord
PAIN

COX-2
COX-2
inflammation
COX-1
EP1, EP3
EP4 & IP

DP & EP2

PGD(2), PGE(2), PGF(2alpha) and PGI(2)

BK bradykinin

PG receptor

BK receptor

Agents that can attenuate

the algesic action of BK
NSAID

Acetylsalicylic acid,

Diclofenac,

Etodolac,

Indomethacin,

Ketoprofen,

Meloxicam,

Naproxen,

Phenylbutazone,

Piroxicam
Non-NSAID

Eperison

Inoue K, et al. Effect of etodolac on prostaglandin

E2 biosynthesis, active oxygen generation and
bradykinin formation. Prostaglandins Leukot
Essent Fatty Acids. 51(6): 457-62,1994.

The inhibitory action of etodolac on bradykinin formation
was the most potent among NSAIDs tested
(indomethacin, diclofenac Na, piroxicam, naproxen,
ketoprofen and aspirin)

Etodolac inhibited bradykinin-forming enzyme
activity in a concentration-dependent manner.

The inhibitory action of etodolac on PGE2 biosynthesis
in rabbit articular chondrocytes stimulated by interleukin1 (IL-1) beta was about 1/5 that of indomethacin

These results indicate that etodolac is an antiinflammatory drug which suppress IL-1 beta-stimulated
PGE2 biosynthesis and bradykinin formation.

The efficacy of etodolac and

other NSAIDs in patients with
Low Back Pain
Tested

Comparator Results Reference

etodolac

diclofenac

(2x200 or 300mg/d
or 3x200 mg/d)

(2x50 mg/d or
3x50 mg/d)

comparable

Pena,1990

It is important to inhibit the activity of

 BK and
 COX-2
in patients with LBP

diclofenac

tomoxiprol

celecoxib

suprofen
ketorolac

flurbiprofen

aspirin

ketoprofen

ampyrone

ibuprofen

tolmetin
naproxen

indomethacin

zomepirac

fenoprofen

sodium salicylate

niflumic acid

diflunisal

meclofenamate

piroxicam

sulindac sulphide

Warner et al. PNAS 1999; 96:7563-7568

nimesulide

meloxicam

etodolac

NS-398

rofecoxib

L-745,337

DFP

COX-1/COX
1/COX-2 IC80 (%)

COX-1/COX-2 ratios in whole

blood assay
100

80

60

40

20

Less GI side effects

FRIEND
FOE
More GI side effects
Acetosal
Indomethacin Ibuprofen
Ketorolac
Piroxicam Ketoprofen
Resveratrol

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

Mechanism of action of Etodolac

Has dual analgesic action

As anti-bradykinin,
 etodolac inhibits bradykinin-forming
enzyme activity in a concentrationdependent manner

As non-steroidal anti-inflammatory
drugs (NSAID),
 etodolac preferentially inhibits COX-2
activity

Brocks DR, et al. Stereoselective disposition

of etodolac enantiomers in synovial fluid
J Clin Pharmacol 31:741-6,1991

Concentrations of S-etodolac were greater in
SF than in plasma
(SF : plasma ratio = 1.98 +/- 0.8)

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 plasma
during the post-distributive phase, which may
be of possible clinical relevance.

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

Drug treatment

Efficacy

Williams et al, 1989

210 E vs placebo

E significantly better than

placebo

Brasseur et al, 1991

61

E vs diclofenac

No difference between drugs

Karbowski, 1991

64

E vs
Indomethacin

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 Ebetter

than naproxen

Paulsen et al, 1991

220 E vs Piroxicam

Drugs were comparable in

efficacy

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

No difference between drugs

Shnitzer et al, 1995

270 E vs Nabumetone Some evidence that E better

vs Placebo
than nabumetone

E vs Piroxicam

Pharmacokinetic and pharmacodynamic of

etodolac and other NSAIDs
parameter

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

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
aliran darah < & vasokonstriksi > kemungkinan trombosis >

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

the evidence showed that

Pain is not only induced by PG
but also induced by BK
ETODOLAC
 found before COXIB
marketed
 has dual action, ie
 more selectively inhibit
COX-2 and also
 inhibit the formation of BK
KEBANGGAAN INDONESIA
UNTUK DUNIA

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

Desprs JP et al.BMJ 322:716-20,2001

Low waist

Mork H, et al. Experimental muscle pain

and tenderness following infusion of

endogenous substances in humans.
Eur J Pain 7(2):145-53,2003
moderate muscle pain produced by:

PGE(2),

ATP, and

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