Farmakologi Nyeri

Tri Widyawati
Dept. Pharmacology & Therapeutic
School of Medicine
Universitas Sumatera Utara

April 2020, Blok 7 FKG 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 Spinothalamic
spinal cord tract ◆Nociceptive
Dorsal Root sensory fibres are
Ganglion C-fibres and Ad
fibres
Peripheral
nerve Sympathetic ganglion ◆C-fibres
Viscera umyelinated
◆Ad myelinated
◆Slow conduction
Blood vessels
velocity
Skeletal ◆Signal variety of
Tendon muscle
bundle
noxious stimuli -
C and Ad polymodal
Muscle and skin Nociceptive fibres
receptors terminals
 Ascending Pain Pathways
Cortex
Topographic representation
maintained
Thalamus Sites for pain modulation are
spinal cord and thalamus
Mesencephalon

Pons
Trigeminal system has
Trigeminal
ganglion special significance for
migraine
Medulla
oblongata

Spinal
cord
 Pain, Hyperalgesia and Allodynia
100
hyperalgesia
pain sensation

75

injury
50
normal
allodynia pain
25
pain pain
threshold threshold
0
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
or ± Please± do not
NSAID weak opioid useNSAID
NSAIDs
± ± as the± first
adjuvant adjuvant adjuvant
choice
10 Painanalgesic
Intensity Scaleanalgesic analgesic
0 1 2 3 4 5 6 7 8 9 10
Mild Moderate Severe
Pain threshold
Pain tolerance
INVOLVEMENT OF TISSUE INJURY
PROSTAGLANDIN IN
TRAUMATIC PAIN
Prostaglandins
Bradykinin

Leukotriens

PAIN
Histamine

NSAID
 phospholipids

arachidonic acid

COX LOX
COX-2 COX-1
cyclic
endoperoxides 5-HPETE

PGI2 TXA2
inhibits platelet LTA4
stimulates platelet
aggregation
aggregation,
hyperalgesia, LTB4
vasoconstriction
vasodilator chemotaxis

LTC4
PGD2 PGE2 PGF2alfa brochoconstriction
inhibits platelet bronchoconstriction LTD4 increase
vasodilator, vascular
aggregation, myometrial contr.
vasodilator hyperalgesia hyperalgesia permeability
LTE4
 Paracetamol
• Paracetamol has been in use for more
than a century
• It has both analgesic and antipyretic action
• However, the exact mechanism of its action is unclear

Absorption / Elimination from the body

• It is well tolerated when taken orally.
• On oral administration it is absorbed from the intestine (70%), stomach
and colon (30%)
• The rate of absorption is rapid and depends on the dose
 Absorption / Elimination

• The time taken to reach maximum plasma

concentration (Tmax) is 15 - 30 minutes
depends on the preparation
• It is available as tablets (adults), suspension
or syrup for children and suppositories
• Tmax is 2 - 3 hours with suppositories
• Bioavailability ranges from 60-90%

Elimination
 Indications and dosages

• It is used as an analgesic drug for mild to moderate pain

– E.g. Tooth ache / teething pain in children, backpain, joint and
muscle pain, headache, dysmenorrhoea
• Relief of fever in adults and children

Dosage
• Adults – Up to 1g oral / rectal, every 6 hours ( 4g should not be
exceeded / day
• Children – Oral / rectal 20 mg / kg – every 6 hours
 Side effects

• Paracetamol is well tolerated and has no

side effects at therapeutic doses

• It has good haematological tolerability and

does not alter haemostasis
 Caution

• Since it is metabolized in the liver it must

be used with caution / or omitted in the
presence of liver impairment

• In patients with renal impairment, the dose

of paracetamol should be reduced

• Do not exceed 4g/day in adults and 125

mg/ kg in children
 Adverse effects
Hepatotoxicity with an overdose of paracetamol
• This can occur when a patient does not get adequate relief with
paracetamol and decides to take more than the prescribed dose of a
maximum of 4g/day (8 - 10 g / day)

• Intentional overdose (Paracetamol overdose / poisoning is the leading

cause of acute liver failure in the US, UK and Australia)

• Overdose causes acute liver failure, as the elimination pathways are

saturated resulting in elevated levels of toxic metabolites
 Adverse Effects

• N-acetylcysteine (NAC) is the antidote for

paracetamol poisoning and it is most
effective when administered within 8 - 10
hours after ingestion

• Renal toxicity – Overdose can cause severe

kidney necrosis

• Allergic reactions are rare

 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)
ØDifferent selectivity to COX-1 and COX-2
¥ Different chemical families
¥ Different pharmacokinetics and potency
¥ Common clinical indications
ØAnalgesic (CNS and peripheral effect) may
involve non-PG related effects
ØAntipyretic (CNS effect)
ØAnti-inflammatory (mainly by PG inhibition)
¥ Common analgesic ceiling effect
The evolution of NSAID chemistry
for the control of pain

Coxib
Class
Acetic
Oxicam Acid Celecoxib
Class Class Rofecoxib
Propionic
Acid Valdecoxib
Salicylic Diclofenac Etoricoxib
Class Piroxicam
Acid Meloxicam Etodolac Parecoxib
Class Lumiracoxib
Ibuprofen
Aspirin ketoprofen

1853 1970- 1980- 1990- 2000-

CHEMICAL STRUCTURE
and
CLINICAL BENEFITS
 Chemical structure of NSAIDs
CO2H H O
O N
CO2H CO2H
O O
HO
acetylsalicylic acid acetaminophen ibuprophen ketoprophen
aspirin Tylenol Motrin, Nuprin Orudis

CO2
Cl H
N
CO2H

MeO Cl
naproxen diclofenac
Naprosyn, Alleve Cataflam, Voltaren

O
O Cl
N
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
S
O O
S
O O
S
O Wiholm BE. Identification of
H2N Me H2N sulfonamide-like adverse
N N drug reactions to celecoxib
CF3 O O
N in the WHO database.
O
Curr Med Res Opin
celecoxib
®
MK-966 valdecoxib 17(3):210-6,2001
Celebrex rofecoxib
Vioxx® Schneider F, et al. Fatal
allergic vasculitis
su O O O associated with celecoxib.
lf on S
am N Lancet 359(9309):852-
ide Na 3,2002
O
N
Kumar et al. Fatal
haemorrhagic pulmonary
parecoxib sodium
oedema and associated
neutral angioedema after the
ingestion of rofecoxib.
Postgrad Med J. 78:439-
40,2002
 Less GI side effects

More GI side effects

Acetosal Diclofenac Celecoxib
Indomethacin Ibuprofen
Ketorolac
Resveratrol
Piroxicam Ketoprofen
Meloxicam
Nimesulide
COXIB
Rofecoxib
Valdecoxib

preferentially non- preferentially

COX-1 COX-1 COX-2 COX-2
selective
selective selective selective selective
COX
inhibitor inhibitor inhibitor inhibitor
inhibitor

anti-inflammatory
analgesic
 Celecoxib vs Naproxen vs Placebo
single dose post-surgical dental pain study
Placebo Celecoxib 100 mg

3 Celecoxib 200 mg Naproxen 550 mg

2.5
Pain relief

1.5

0.5

0
O 1 2 3 4 5 6 7 8
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

600 mg 200 mg 400 mg

Ibuprofen Celecoxib Celecoxib
0
VAS (mm) reduction

-5
-10
-15
-20
-25
-30
-35 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
The effect depend on:
• Affinity of binding
(strong, weak)
• type of binding
(competitive or not)
id
• Reversibility of binding
ic
Ac
(duration of action)
n
i do Arg 513
ach Hist 90
Ar

Kurumbail et.al (1996)

NSAIDs: COX-2 vs COX-1 selectivity

100 6-MNA
Naproxen Paracetamol
COX-2 IC50 (µM)

Ibuprofen
10
Meloxicam Nimesulide
1 Rofecoxib
Indomethacin Celecoxib

0.1
Diclofenac

0.01
0.01 0.1 1 10 100
COX-1 IC50 (µM)
FitzGerald & Patrono. N Engl J Med 345:433,2001
 COX inhibition and clinical benefits
¥ COX-1 specific • Potent analgesics
inhibition – Postoperative pain
– Aspirin
– Ketorolac
• Anti-platelet aggregation
• Limited time use
• Toxic for GI and renal
systems

¥ COX-2 specific • Less GI side effects

inhibition
• Delayed fracture healing
– Celecoxib
• Increase CV events
– Rofecoxib
– Valdecoxib
 TISSUE INJURY
INFLAMMATION
MACROPHAGES

TNF-a
IL-6 IL-8
IL-1 SYMPATHETIC
NERVE
The picture can't be displayed.

COX-2 PG BK
POLYMORPHS
FIBROBLASTS

NOCICEPTOR

Ferreira, 1993
PAIN
Actions of BK on Sensory Neurons
BK
B2R
Phospho
G-protein lipid

PLC PLA2
DAG
Lipase Arachidonic
­ DAG Acid ­­

PKC Å
activation COX

Open ion
channels
­ PGs

­ Na influx &
Bevan, 2001
depolarization
NSAIDs that can attenuate the
algesic action of BK
¥ Acetylsalicylic acid,
¥ Diclofenac,
¥ Etodolac,
¥ Indomethacin,
¥ Ketoprofen,
¥ Meloxicam,
¥ Naproxen,
¥ Phenylbutazone,
¥ Piroxicam
NSAIDs with ANTICYTOKINE activities
IL-6 production IL-8 production
NSAIDs TNF-a
Basal Stimulated Basal Stimulated

Ibuprofen - - ¯ - ­
Indomethacin ­ ¯ ¯ - -
Piroxicam - - - - -
Diclofenac ¯ ¯ ¯ - -
Nimesulide ¯ ¯ ¯ - -
Celecoxib - - ¯ - ­
Rofecoxib - - - - -
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 • Immediate onset of
– rapid
action
Dispersible
Na ® K
Injection (iv, im) • Delayed onset of
– slow action
¥ distribution • High concentration in
– acidic inflammatory tissue
– lipophilic • 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 2–4
Meloxicam 6
T-1/2 and Duration of action
of NSAIDs
duration NSAID T-1/2 (hr)
short Diclofenac 1.1
Nimesulide 1.8 – 4.7
moderate Celecoxib 11
Naproxen 14
long Meloxicam 20
Piroxicam 57
 A = Enterohepatic circulation

Systemic effect

Liver

A
Kidney

Small
Intestine
Pancreas

A
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

ketoprofen Barbanoj dkk, 2001; Audeval-Gerard dkk, 2000

meloxicam Davies & Anderson, 1997

naproxen Blagbrough dkk,1992

Topical diclofenac Davies & Anderson, 1997

ketoprofen Audeval-Gerard dkk, 2000

meloxicam Davies & Skjodt, 1999

distribution into CSF

Physicochemical NSAID Reference
Lipophilic oxyphenbutazone, Bannwarth B, et al., 1989
penetrate to CSF indomethacin,
ketoprofen
diclofenac Zecca L,et al., 1991
nimesulide Ferrario P, Bianchi M., 2003
 pharmacokinetic and clinical benefits
¥ Half-life • Useful for “rescue”
– short
slow • Brief duration of action
release
formulation
– long • Long duration of action
• Increase side effects

NSAID Diclofenac Naproxen Piroxicam

Dose (mg/d) 100 750 20
Half-life (hr) 1.5 14 50
24 hr fecal blood 0.53 +/- 0.21 2.76 +/- 2.22 1.16 +/- 0.62
loss (mL)

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
Incidence rate
Event
per 1,000 patient years
Heart failure 2–4
Myocardial infarction 1–4
Upper GI
bleeding/perforation 0.6 – 1.7
Colorectal cancer 0.4 – 0.7
Acute renal failure 0.002 – 0.08
 Hidden issues of NSAIDs
COOH

COX-1 COX-2
Arachidonic acid
Prostaglandines Prostaglandines
PGE2, PGI2, TXA2 PGE2, PGI2, TXA2

TXA2 PGI2
stimulates inhibits COX-2
specific inhibitor
platelet platelet
aggregation, aggregation
Gastric
mucosal
protection
hidden
vasoconstriction vasodilation Inflammation
Pain
Fever

causes GI damage
issues
thrombosis
STROKE
ischemic
MCI
anti-inflammatory

Myth:
NSAID causes dangerous GI tract events only !?
OTHER SIDE EFFECTS
 Bone fracture
healing
COX-2 specific
inhibitors
ü celecoxib and
ü 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 PGs
vaso- vaso-
constriction dilatation
fluid &
electrolyte
OCULAR TOXICITY

AA
NSAID

LTs PGs
vaso- vaso-
constriction dilatation

temporary
reversible
color-blindness
 OTOTOXICITY

AA
NSAID

LTs PGs

nimesulide
and NS-398 do not
increase LT synthesis
 RESPIRATORY TOXICITY
AA
NSAID

LTs PGs

bronchoconstriction bronchodilatation

NSAID-induced asthma
TOXICITY IN PREGNANCY
AA
NSAID

LTs PGs
utero-
contraction
NSAIDs
deplete folic acid levels and then prolong
increase the risks of birth defects gestation
increase risk of miscarriage and labor
NSAID FOR ELDERLY
 blindness dementia

anorexia hearing loss

heart disease dyspnoe

liver impairement renal impairment

Concomitance
diseases
cancer CVS, etc constipation

arthralgia weakness

Pharmacological problems in the elderly

 I have got them, but Where are my
I forgot how to medicines ?
consume the drugs

Have I taken them

before?

3x1≠1x3
Therapeutic effect ≠ Adverse effect
Avoid the dangerous drug . . N
. . . . . . . choose the safest drug
. . with a simple drug administration
 Kinetic profile of NSAID in
young and elderly subjects
800
young
700
elderly
600
500
400
300
200
100
0
0 2 4 6 8 10 12 14 16 18 20 22 24

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 Safe

elderly short t-½

Concomitance chronic
diseases use
NSAID + single
NSAIDs NSAID
topical
Concomitance
drugs
Long t-½
COX-2 inh.
women
DRUG INTERACTION
 Double-blind, placebo-controlled analgesic
study of ibuprofen or rofecoxib in combination
with paracetamol for tonsillectomy in children

Ibuprofen

Ibuprofen + Paracetamol

Rofecoxib

Rofecoxib + Paracetamol

0 20 40 60 80

Pickering AE, et al (2002) the need of early analgesia

 Analgesic effect of paracetamol and
its combination with codeine or
diclofenac
70
P 1 gr
60 P 1 gr + C 60 mg
P 1 gr + D 100 mg
50 P 1 gr + C 60 mg + D 100 mg
VAS

40

30

20

10

0
0 1 2 3 4 5 6 7 8
Breivik K, et al. (1999) Time (hours)
Analgesic combination and clinical benefits

CARBAMAZEPINE
Steven Johnson sd MORPHINE

adjuvant opioid
analgesic NSAID analgesic

AMITRYPTILIN
CODEINE
hypotension

GABAPENTIN CELECOXIB
CYP2D6 inhibitor
CYP2D6

DEXTROMETHORPHAN
CYP2D6 substrate 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

0 10 20 30 40 50
 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 - + ++ + ? M ? ? PO >>
Diclofenac + - + +++ + S ++ + PO,INJ, <
SUP,TOP

Etodolac + - ++ ? + M ? ? PO >>
Ibuprofen + - - + ? S + + PO <
Indomethacin + - - ++ + S ++ + PO <
Ketoprofen + - - ? + S ++ ? PO,SUP <
Meloxicam + - + ? + L + ? PO,INJ, >>
SUP

Naproxen + - - ? + M + ? PO >>
Nimesulide - + + +++ ? S + ? PO >>
Piroxicam + - - - + L ? ? PO,TOP <
Rofecoxib - + ++ - ? L ? - PO >>

Are they different?