Prof. Aznan 0-Peran obat anti bradikinin dalam managemen nyeri.PDF

8/20/2019 Prof. Aznan 0-Peran obat anti bradikinin dalam managemen nyeri.PDF

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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

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t o m o x

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t e

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s o d

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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

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i r i n

f l u r b

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f e n

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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

Prof. Aznan 0-Peran obat anti bradikinin dalam managemen nyeri.PDF

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