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Interaksi Farmakodinamik

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F O Sistem Endokrin
Tukaran dgn WAKIDI
INTRODUCTION

Blok Control System

Sem II
Blok Control System
Sem II

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F O Sistem Endokrin

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F O Dermatomuskular
(AINS)

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F O Sistem Endokrin

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F O Dermatomuskular
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F O Sistem Endokrin

Blok DMS
(Dermatomuskuloskel
etal System) Sem V
Blok Control System
Sem II
Blok DMS
(Dermatomuskuloskel
etal System) Sem V
Blok Control System
Sem II

F O Dermatomuskular
(Farmakologi Nyeri dan AINS)

Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran
Universitas Sumatera Utara
Februari 2009, KBK-CCS2, FK USU, Medan

PAIN
An unpleasant sensory
and emotional experience
associated with actual
or potential tissue
damage, or described in
terms of such damage
IASP, Subcommittee on Taxonomy, 1979

Nociceptive pathways:
peripheral sensory nerves
Dorsal horn of
spinal cord

Spinothalamic
tract
Nociceptive

Dorsal Root
Ganglion
Peripheral
nerve

Sympathetic ganglion
Viscera

Blood vessels
Skeletal
muscle

Tendon
bundle
Muscle and skin Nociceptive
terminals
receptors

C and A
fibres

sensory fibres are

C-fibres and A
fibres
C-fibres
umyelinated
A myelinated
Slow conduction
velocity
Signal variety of
noxious stimuli polymodal

Ascending Pain Pathways

Cortex

Thalamus

Topographic representation
maintained
Sites for pain modulation are
spinal cord and thalamus

Mesencephalon
Pons
Trigeminal
ganglion
Medulla
oblongata
Spinal
cord

Trigeminal system has

special significance for
migraine

Pain, Hyperalgesia and Allodynia

100

pain sensation

hyperalgesia
75
injury
50

normal
pain

allodynia
25
pain
threshold

pain
threshold

innocuous

noxious

stimulus intensity
Cervero & Laird (1996)

Current Therapies for Pain

NSAIDs (Non-Steroidal Antiinflammatory
Drugs, COX-1 & COX-2)
Opiates (mu agonists)
Anticonvulsants (phenytoin), antidepressant
(amitriptyline), antiarrhythmics (mexylitine)
Sumatriptan, Zomig (5HT agonists) etc for
migraine
Gabapentin (off label)
Tramadol (mu opioid plus your guess as good as
mine)

Combinations (opioids plus)

Pain Rating Scales

paracetamol
NSAID
Strong opioid
Please do not
or

NSAIDs
NSAID
weak opioid useNSAID

first
as the
adjuvant
adjuvant
adjuvant
choice
10 Pain Intensity
Scale
analgesic
analgesic
analgesic
0

Mild

Moderate

Pain threshold
Pain tolerance

Severe

10

INVOLVEMENT OF
PROSTAGLANDIN IN
TRAUMATIC PAIN

TISSUE INJURY

Prostaglandins

Bradykinin
Leukotriens

PAIN
Histamine

NSAID

phospholipids
arachidonic acid
COX-2

COX

COX-1

cyclic
endoperoxides
PGI2

PGD2
inhibits platelet
aggregation,
vasodilator

5-HPETE
TXA2

inhibits platelet
aggregation
hyperalgesia,
vasodilator

stimulates platelet
aggregation,
vasoconstriction

PGE2
vasodilator,
hyperalgesia

LOX

PGF2alfa
bronchoconstriction
myometrial contr.
hyperalgesia

LTA4
LTB4
chemotaxis

LTC4
LTD4
LTE4

brochoconstriction
increase
vascular
permeability

NSAIDs: from pharmacological value

to clinical benefit
What is NSAID?
Pharmacological values of NSAIDs
Chemical structure
Mechanism of action
Pharmacokinetic

Clinical benefits of NSAIDs

Efficacy (indication)
Safety (side effect)

Drug interaction

Common issues of NSAIDs

Common mechanism of action
(cyclooxygenase inhibition)
Different selectivity to COX-1 and COX-2

Different chemical families

Different pharmacokinetics and potency
Common clinical indications
Analgesic (CNS and peripheral effect) may
involve non-PG related effects
Antipyretic (CNS effect)
Anti-inflammatory (mainly by PG inhibition)

Common analgesic ceiling effect

The evolution of NSAID chemistry

for the control of pain
Coxib

Salicylic
Acid
Class

Propionic
Acid
Class

Aspirin

Ibuprofen
ketoprofen

1853

1970-

Oxicam
Class

Acetic
Acid
Class

Piroxicam
Meloxicam

Diclofenac
Etodolac

1980-

1990-

Class
Celecoxib
Rofecoxib
Valdecoxib
Etoricoxib
Parecoxib
Lumiracoxib

2000-

CHEMICAL STRUCTURE
and
CLINICAL BENEFITS

Chemical structure of NSAIDs

CO2H
O

H
N
O

CO2H

CO2H

HO

acetylsalicylic acid

acetaminophen

ibuprophen

ketoprophen

aspirin

Tylenol

Motrin, Nuprin

Orudis
Cl

CO2H
MeO

CO2

H
N
Cl

naproxen

diclofenac

Naprosyn, Alleve

Cataflam, Voltaren
O
Cl

N
CO2H

MeO
CO2H

ketorolac

indomethacin

Toradol

Indocin

Capone ML, et al. Int J Immunopathol Pharmacol. 16(2 Suppl):49-58,2003.

Clinical pharmacology of
selective COX-2 inhibitors
Acidic COX-2 inhibitors
have been hypothesized that this
peculiar chemical feature may lead to
an enhanced concentration in
inflammatory sites
that may translate into
an improved clinical efficacy

Chemical structure and clinical benefits

O
H2N

O
Me
N N

O
H2N

CF3

O
N

O
celecoxib
Celebrex

MK-966

valdecoxib

rofecoxib
Vioxx

su
lfo
n

am
i

O
N

de

Na

O
N

parecoxib sodium

neutral

Wiholm BE. Identification of

sulfonamide-like adverse
drug reactions to celecoxib
in the WHO database.
Curr Med Res Opin
17(3):210-6,2001
Schneider F, et al. Fatal
allergic vasculitis
associated with celecoxib.
Lancet 359(9309):8523,2002
Kumar et al. Fatal
haemorrhagic pulmonary
oedema and associated
angioedema after the
ingestion of rofecoxib.
Postgrad Med J. 78:43940,2002

Less GI side effects

More GI side effects
Acetosal
Diclofenac
Indomethacin Ibuprofen
Ketorolac
Meloxicam
Piroxicam Ketoprofen
Resveratrol
Nimesulide

COX-1
selective
inhibitor

preferentially

COX-1
selective
inhibitor

nonselective
COX
inhibitor

preferentially

COX-2
selective
inhibitor

anti-inflammatory
analgesic

Celecoxib
Rofecoxib
Valdecoxib

COXIB

COX-2
selective
inhibitor

Celecoxib vs Naproxen vs Placebo

Pain relief

single dose post-surgical dental pain study

Time (hours)
FDA Advisory Committee Meeting, December 1, 1998

Salo et al. (2003)

A randomized, clinical trial comparing oral
celecoxib 200 mg, celecoxib 400 mg, and
ibuprofen 600 mg for acute pain

VAS (mm) reduction

600 mg
Ibuprofen

200 mg
Celecoxib

400 mg
Celecoxib

the magnitude of pain relief for celecoxib,

coupled with the cost of the medication,
questions its use in the immediate ED setting

MECHANISM OF ACTION and

CLINICAL BENEFITS

Site of action
Bind to particular amino acid
of COX

ic
n
o
id
h
ac
r
A

The effect depend on:

Affinity of binding
(strong, weak)
type of binding
(competitive or not)
Reversibility of binding
(duration of action)

id
c
A

Arg 513
Hist 90

Kurumbail et.al (1996)

NSAIDs: COX-2 vs COX-1 selectivity

6-MNA

COX-2 IC50 (M)

100
Naproxen

Paracetamol

Ibuprofen

10

Meloxicam

Nimesulide

Rofecoxib
Indomethacin

Celecoxib

0.1

0.01
0.01

Diclofenac

0.1

10

COX-1 IC50 (M)

100

FitzGerald & Patrono. N Engl J Med 345:433,2001

COX inhibition and clinical benefits

COX-1 specific
inhibition
Aspirin
Ketorolac

COX-2 specific
inhibition
Celecoxib
Rofecoxib
Valdecoxib

Potent analgesics
Postoperative pain

Anti-platelet aggregation

Limited time use

Toxic for GI and renal
systems

Less GI side effects

Delayed fracture healing
Increase CV events

TISSUE INJURY
INFLAMMATION
MACROPHAGES

TNF-
IL-6

IL-8

IL-1

SYMPATHETIC
NERVE

COX-2

BK

PG
POLYMORPHS

FIBROBLASTS

NOCICEPTOR
Ferreira, 1993

PAIN

Actions of BK on Sensory Neurons

BK

B2R
G-protein

PLA2

PLC
DAG
Lipase

DAG
PKC
activation
Open ion
channels
Na influx &
depolarization

Phospho
lipid

Arachidonic
Acid

COX
PGs
Bevan, 2001

NSAIDs that can attenuate the

algesic action of BK

Acetylsalicylic acid,
Diclofenac,
Etodolac,
Indomethacin,
Ketoprofen,
Meloxicam,
Naproxen,
Phenylbutazone,
Piroxicam

NSAIDs with ANTICYTOKINE activities

NSAIDs

TNF-

Ibuprofen
Indomethacin
Piroxicam
Diclofenac
Nimesulide
Celecoxib
Rofecoxib

IL-6 production

IL-8 production

Basal

Stimulated

Basal

Stimulated

Sanchez et al. J Rheumatol 29(4):772-82,2002

Henrotin YE, et al. Clin Exp Rheumatol. 17(2):151-60,1999

PHARMACOKINETICS
and
CLINICAL BENEFITS

pharmacokinetic and clinical benefits

absorption
rapid

Immediate onset of
action
Dispersible

Na K
Injection (iv, im)
slow

distribution
acidic
lipophilic

Delayed onset of
action
High concentration in
inflammatory tissue
Easily penetrate BBB into
CSF
Can modulate the pain
(abolish hyperalgesia)

T-max and Onset of action

of NSAIDs
onset
NSAID
T-max (hr)
Rapid Diclofenac
0.8
Nimesulide 1.2 2.7
Slow Celecoxib
24
Meloxicam
6

T-1/2 and Duration of action

of NSAIDs
duration
short
moderate
long

NSAID
Diclofenac
Nimesulide
Celecoxib
Naproxen
Meloxicam
Piroxicam

T-1/2 (hr)
1.1
1.8 4.7
11
14
20
57

= Enterohepatic circulation

Systemic effect
Liver
A

Kidney

Small
Intestine
Pancreas

PIROXICAM : long t1/2 (> 45 hr) enterohepatic cycle

Enterohepatic cycle and the

incidence of ADR of NSAIDs
NSAID

Half-life

EHC level

Incidence ADR

Diclofenac

1-2

Low

Small

Ibuprofen

1.5 3

Low

Small

Nimesulide

1.5

Small

Celecoxib

11

Small

Naproxen

13 15

Intermediate

Moderate

Nabumetone

22

Intermediate

Moderate

Indomethacin

11

High

High

Piroxicam

> 45

High

High

distribution into the synovial fluid

Route

NSAID

Reference

Systemic

diclofenac

Blagbrough et al,1992; Gallacchi & Marcolongo,1993

Davies & Anderson, 1997

ibuprofen

Blagbrough dkk,1992

Topical

ketoprofen

Barbanoj dkk, 2001; Audeval-Gerard dkk, 2000

meloxicam

Davies & Anderson, 1997

naproxen

Blagbrough dkk,1992

diclofenac

Davies & Anderson, 1997

ketoprofen

Audeval-Gerard dkk, 2000

meloxicam

Davies & Skjodt, 1999

distribution into CSF

Physicochemical

NSAID

Lipophilic
penetrate to CSF

oxyphenbutazone,
indomethacin,
ketoprofen

Reference
Bannwarth B, et al., 1989

diclofenac

Zecca L,et al., 1991

nimesulide

Ferrario P, Bianchi M., 2003

pharmacokinetic and clinical benefits

Useful for rescue

Half-life
short

Brief duration of action

slow
release
formulation

Long duration of action

long

Increase side effects

NSAID

Diclofenac

Naproxen

Piroxicam

Dose (mg/d)

100

750

20

Half-life (hr)

1.5

14

50

24 hr fecal blood
loss (mL)

0.53 +/- 0.21

2.76 +/- 2.22

1.16 +/- 0.62

Scharf, et al. Aust N Z J Med 28(4):436-9,1998

Incidence rates of major events possibly

prevented or caused by COX inhibitors,
as assessed in observational studies
among non-users
Event

Incidence rate
per 1,000 patient years

Heart failure

24

Myocardial infarction
Upper GI
bleeding/perforation

14
0.6 1.7

Colorectal cancer

0.4 0.7

Acute renal failure

0.002 0.08

Hidden issues of COX-2 inhibitor

COOH

COX-1
Prostaglandines
PGE2, PGI2, TXA2

Gastric
mucosal
protection

Arachidonic acid
bone
formation
TXA2
PGI2
stimulates
inhibits
platelet
platelet
aggregation,
aggregation
vasoconstriction vasodilation

causes GI damage

hidden
issues

thrombosis

ischemic

STROKE

MCI

COX-2
Prostaglandines
PGE2, PGI2, TXA2

COX-2
specific inhibitor

Inflammation
Pain
Fever

anti-inflammatory

OTHER SIDE EFFECTS

Bone fracture
healing
COX-2 specific
inhibitors
celecoxib and
rofecoxib
delay bone
fracture healing
Simon AM, Manigrasso MB, O'Connor JP.
Cyclo-oxygenase 2 function is essential
for bone fracture healing.
J Bone Miner Res. 17(6):963-76,2002.

NEPHROTOXICITY
AA
NSAIDs

LTs
vasoconstriction

PGs
vasodilatation
fluid &
electrolyte

OCULAR TOXICITY
AA

NSAID

LTs

PGs

vasoconstriction

vasodilatation

temporary
reversible
color-blindness

OTOTOXICITY
AA
LTs

NSAID

PGs

nimesulide
and NS-398 do not
increase LT synthesis

RESPIRATORY TOXICITY
AA

LTs
bronchoconstriction

NSAID

PGs
bronchodilatation

NSAID-induced asthma

TOXICITY IN PREGNANCY
AA

LTs

NSAID

PGs
uterocontraction

NSAIDs
deplete folic acid levels and then
increase the risks of birth defects
increase risk of miscarriage

prolong
gestation
and labor

NSAID FOR ELDERLY

blindness

dementia

anorexia

hearing loss

heart disease
liver impairement
cancer
arthralgia

dyspnoe
Concomitance
diseases
CVS, etc

renal impairment
constipation
weakness

Pharmacological problems in the elderly

Where are my
medicines ?

I have got them, but

I forgot how to
consume the drugs

Have I taken them

before?

3x11x3
Therapeutic effect Adverse effect

Avoid the dangerous drug . .

. . . . . . . choose the safest drug
. . with a simple drug administration

Kinetic profile of NSAID in

young and elderly subjects

time (hour)

t-1/2 associated to drug accumulation

give once daily of short half-life NSAID

The use of NSAIDs in the elderly

Self medication

Prescription

Fatal toxic
reactions
Concomitance
diseases
Concomitance
drugs

elderly
NSAID +
NSAIDs

women

Safe
chronic
use
Long t-

short t-
single
NSAID

topical

COX-2 inh.

DRUG INTERACTION

Double-blind, placebo-controlled analgesic

study of ibuprofen or rofecoxib in combination
with paracetamol for tonsillectomy in children

Pickering AE, et al (2002)

the need of early analgesia

VAS

Analgesic effect of paracetamol and

its combination with codeine or
diclofenac

Breivik K, et al. (1999)

Time (hours)

Analgesic combination and clinical benefits

CARBAMAZEPINE
Steven Johnson sd

MORPHINE

adjuvant
analgesic

opioid
analgesic

NSAID

AMITRYPTILIN
hypotension

GABAPENTIN
DEXTROMETHORPHAN
CYP2D6 substrate

CODEINE

CELECOXIB

CYP2D6 inhibitor

CYP2D6
MORPHINE

Ismail R, et al. J Clin Pharm Ther. 25(5):379-83,2000.

Slow CYP2D6 phenotypes among Malay are greater than China

COST

COMPARATIVE COSTS for 28 DAYS THERAPY

(in , spent by the General Medical Services on NSAID in 1999)
DICLO 50 mg TDS +
Lansoprazol 15 mg OD
DICLO/MISO 75 mg BD
NIMESULIDE 200 mg BD
NIMESULIDE 100 mg BD
MELOXICAM 15 mg OD
MELOXICAM 7.5 mg OD
ROFECOXIB 25 mg OD
ROFECOXIB 12.5 mg OD
CELECOXIB 400 mg OD
CELECOXIB 200 mg OD
DICLOFENAC 50 mg TDS
IBUPROFEN 800 mg TDS

The rational approach of NSAID usage

based on pharmacological values
NSAID

Acid

Sulfa

COX-2

A-Cyt

BK

T 1/2

Distr

+ Prct

Formula

Cost

Celecoxib

++

PO

>>

Diclofenac

+++

++

PO,INJ,
SUP,TOP

<

Etodolac

++

PO

>>

Ibuprofen

PO

<

Indomethacin

++

++

PO

<

Ketoprofen

++

PO,SUP

<

Meloxicam

PO,INJ,
SUP

>>

Naproxen

PO

>>

Nimesulide

+++

PO

>>

Piroxicam

PO,TOP

<

Rofecoxib

++

PO

>>

Are they different?

Another consideration
Halal or haram
Gelatin is derived mostly from
collagen (which is found in the skin
and bones of animals) and
used in capsules
Most of the soft gel capsules
on the market are made from
an animal source, bovine or porcine
There are two types of gelatins:
type A, which is derived from pork
skin by hydrolysis with an acid; and
type B, which is derived from bones
and animal skin by hydrolysis with
an alkaline solution

KEBANGGAAN INDONESIA
UNTUK DUNIA

Ya ALLAH limpahkan kemuliaan dihadapan MU dan makhlukMU

baik di dunia maupun di akhirat kepada guru kami
yang telah menyampaikan ilmu yang bermanfaat