2 December 1951

Bukit Tinggi

MD, FK USU, 1978

PhD in Clinical Pharmacology

FUSA-Flinders Medical Centre
Australia, 1988

SpFK, Clinical Pharmacologist

PB-IDI & FK UI, 1995
Professor
Head of Department
Pharmacology & Therapeutic
School of Medicine, USU
Jln. Tridharma 22
Email: aznanlelo@yahoo.com Kampus USU, Medan
The Role of COX-2 Inhibitors
as anti-inflammatory,
analgesic and antipyretic
agents in ENT Diseases
Aznan Lelo
Dept. Pharmacology & Therapeutic,
School of Medicine
Universitas Sumatera Utara
23 August 2005, 11th ASEAN ORL-HSN, Bali
 pain
redness heat
swelling hoarseness
COX-1 COX-2
PROSTAGLANDIN

COX inhibitor
 COX-inhibitors = NSAIDs
the most widely used class of drugs
available as prescription & non-prescription (OTC)
Common mechanism of action (COX inhibition)
Different selectivity to COX-1 and COX-2
Common clinical indications
Analgesic (CNS and peripheral effect)
may involve non-PG related effects
useful when pain is accompanied by
inflammation
Antipyretic (CNS effect)
Anti-inflammatory (mainly by PG inhibition)
have various side effects
about 16,000 persons die every year due to NSAID used in
US
The role of COX in inflammatory pain
COOH

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

COX-2
Non-specific COX-inhibitor specific inhibitor

Gastric Inflammation
mucosal Pain
protection Fever

causes GI damage
anti-inflammatory
bleeding

Exposed issues in marketing of COX-2 inhibitor

 In Vitro Selectivity: COX-2/COX-1 Ratio
lumiracoxib
etoricoxib Selective COX-2 inhibitor
rofecoxib
valdecoxib > 50-fold COX-2 selective
etodolac
nimesulide
diclofenac Preferentially COX-2 inhibitor
celecoxib
meloxicam 5- 50-fold COX-2 selective

fenoprofen < 5-fold COX-2 selective

ibuprofen
tolmetin
naproxen
aspirin
indomethacin
ketoprofen
flurbiprofen
Warner et al. FASEB J. 18:790-804,2004 ketorolac
-3 -2 -1 0 1 2 3
Increasingly COX-2 Increasingly COX-1
Selective Selective

Range of COX Selectivity for COX-1 and COX-2

(log10 IC50 COX-2/COX-1)
 COX-2 inhibitors
COX inhibitor Administration Half-life
Specific
Celecoxib Oral 8-11 hr
Valdecoxib* Oral 8 hr
Parecoxib inj 8 hr
Rofecoxib* Oral 17 hr
Etoricoxib Oral 24 hr
Lumiracoxib Oral 3-6 hr
Preferential
Diclofenac Oral, inj., supp., topical 1.5 hr
Meloxicam Oral, inj., supp 20 hr
Nimesulide Oral 3 hr
this drug was voluntary withdrawn by pharmaceutical company, following official
request from FDA and EMEA, due to serious fatal adverse reactions
 Chemical structure of COX-2 inhibitors
Celecoxib (Celebrex) RofecoxibWiholm
(Vioxx)
BE. Identification of
Pfizer Merck sulfonamide-like adverse
1st generation 1st generationdrug reactions to celecoxib
in the WHO database.
Curr Med Res Opin
17(3):210-6,2001
Valdecoxib (Bextra) ParecoxibSchneider
(Dynastat)
F, et al. Fatal
Pfizer Pfizer allergic vasculitis
2nd generation 2nd generationassociated with celecoxib.
Lancet 359(9309):852-
Prodrug of Bextra
3,2002
IV injection
Kumar et al. Fatal
haemorrhagic pulmonary
Etoricoxib (Arcoxia) Lumiracoxib (Prexige)
oedema and associated
Merck Novartis angioedema after the
2nd generation 2 generation
nd
ingestion of rofecoxib.
NDA under review Phase III trials
Postgrad Med J. 78:439-
IV injection 40,2002
Distinct structure, similar mech.

Based on chemical structure, COXIB is not an ideal one

Which one has the role as
analgesic:

inhibition of COX-1 activity

or
inhibition of COX-2 activity
 Jain NK, Kulkarni SK, Singh A. Differential Antinociceptive
Effect of Cyclooxygenase Inhibitors in Acetic Acid-Induced
Chemonociception in Mice. Analgesia 5(3-4):211-6,2001
Purpose: to compare the profile of antinociceptive action of various
cyclooxygenase inhibitors (i.e., selective COX-2 inhibitors,
preferential COX-2 inhibitors, and nonselective COX inhibitors).
Method: 1% acetic acid-induced chemonociception was used as an
animal model of acute nociception in mice.
Results:
nonselective cyclooxygenase naproxen (ED50 26.52 mg/kg) and
preferential COX-2 inhibitor nimesulide (ED50 6.31 mg/kg) and
meloxicam (ED50 1.26 mg/kg) were found potent antinociceptive
agents in comparison to
selective COX-2 inhibitors NS-398, celecoxib, and rofecoxib were not
antinociceptive agents (ED50 value not achieved over the whole dose
range of 540 mg/kg).
Conclusion:
cyclooxygenase-1 inhibition is essential to exert maximum
antinociceptive effect.
Selective COX-2 inhibitors may be good anti-inflammatory agents but
they are relatively less potent antinociceptive agents.
 Torres-Lopez JE, et al. Comparison of the
antinociceptive effect of celecoxib, diclofenac and
resveratrol in the formalin test.
Life Sci. 70(14):1669-76,2002
Purpose: to compare the antinociceptive action of:
selective COX-2 inhibitor (celecoxib),
preferential COX-2 inhibitor (diclofenac), and
selective COX-1 inhibitor (resveratrol)
Method: formalin-induced inflammatory pain in rat.
Results:
Peripheral administration of celecoxib did not produce
antinociception
diclofenac and resveratrol produced a dose-dependent
antinociceptive effect
Conclusion:
selective COX-2 inhibitor celecoxib does not produce peripheral
antinociception in formalin-induced inflammatory pain.
NSAIDs inhibiting COX-1 activity, i.e. selective COX-1
(resveratrol) and preferential COX2 inhibitor (diclofenac) are
effective drugs in this model of pain.
 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
VAS (mm) reduction

Acidic NSAID is a friend

 Clinical evidence of the efficacy of
COX inhibitor in ENT disease
COX-inhibitor Control Efficacy Reference
Preferential
Nimesulide Ketoprofen Yes Coscarelli
et al., 1993
Nimesulide Ibuprofen Yes Aho
et al., 2003
Specific
Celecoxib Paracetamol No Issioui
et al., 2002
Rofecoxib Ibuprofen Less Pickering
et al., 2002
Addition paracetamol to maximize
analgesic effect of COX inhibitor
COX Paracetamol Analgesic Reference
inhibitor effect
Ibuprofen 20 mg/kg Pickering et
5 mg/kg (1000 mg/50 kg) Enhance al. 2002
(250 mg/50 kg)
Diclofenac 1000 mg Enhance Breivik et al.
150 mg 1999
Celecoxib 2000 mg None Issioui et al.
200 mg 2002
Rofecoxib 20 mg/kg Pickering et
0.625 mg/kg (1000 mg/50 kg) None al. 2002
(31.25 mg/50kg)
 Hyperalgesia and ENT disease
synaptic transfer of pain signals in the spinal cord
peripheral sensory central
afferent nerve dorsal root spinal cord

PAIN
cytokine
COX-2
COX-2
inflammation
COX-1
EP1, EP3 DP & EP2
EP4 & IP

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

PG receptor BK receptor
 The role of NSAID pharmacokinetic
profiles in modulating pain
Inflammation is often accompanied with hyperalgesia
Pain after tonsillectomy is significant and persists relatively
unchanged for the first 5-7 days (Aho M, et al., 2003).
This hyperalgesia is mediated partly by prostaglandin
produced in the CNS through the COX-2 dependent
pathway (Ibuki T, et al. 2003)

COX-2 inhibitor Efficacy Reference

administration
Intra-thecal Yes Ibuki et al, 2003
Sub-cutan None Medhurst et al, 2002
NSAIDs which can penetrate
the blood-brain barrier
NSAID Reference
oxyphenbutazone, Bannwarth B, et al.,
indomethacin, 1989
ketoprofen
diclofenac Zecca L, et al., 1991
nimesulide, Ferrario P, Bianchi
hydroxynimesulide M., 2003
non-acidic COX-2-selective should only weakly affect COX-2 related
functions of the CNS, due to slow blood-brain barrier penetration
(Brune & Neubert, 2001)
 Dembo G, Park SB, Kharasch ED.
Central nervous system concentrations of
cyclooxygenase-2 inhibitors in humans.
Anesthesiology. 102(2):409-15,2005
Celecoxib Rofecoxib Valdecoxib
Dose (mg) 200 50 40
CSF (ng/ml) 22 57 25 10 4
CSF/Dose 1 : 100 1:1 1:4

There is no indication for COX-2 inhibitors in ENT disease

(Devillier. 2001)
Schwartz JI, et al. Cyclooxygenase-2 inhibition by
rofecoxib reverses naturally occurring fever in
humans. Clin Pharmacol Ther. 65(6):653-60,1999.
The role of COX-2 in the genesis of fever in monkeys and humans.
Monkeys
made febrile by 6 microg/kg intravenous lipopolysaccharide.
Induced pyrexia was followed by oral :
rofecoxib (1 or 3 mg/kg), diclofenac (3 mg/kg), or vehicle.
Rofecoxib and diclofenac rapidly reversed the elevated temperature (P < .05 versus
vehicle for 3 mg/kg rofecoxib and diclofenac at 70 to 90 minutes after dosing).
Humans
A single-dose, parallel-group, double-blind randomized trial
94 patients with fever caused by a viral-type illness.
oral doses of 12.5 mg rofecoxib, 25 mg rofecoxib, 400 mg ibuprofen, or placebo
Specific inhibition of COX-2 by rofecoxib results in antipyretic activity in
monkeys and humans comparable to dual COX-1/COX-2 inhibitors such as
diclofenac or ibuprofen

oral 12.5 mg 25 mg 400 mg placebo

temperature rofecoxib rofecoxib ibuprofen
mean SE -0.97 0.11 -1.19 0.09 -1.20 0.11 0.01 0.17
Which one has the role in
the safety of NSAIDs:

inhibition of COX-1 activity

or
inhibition of COX-2 activity
 Weighing the Benefits and the Risks:
COX inhibitors
platelet
aggregation
COX-1
inhibitor
fewer heart attack Bleeding

platelet
bleeding
aggregation

Bleeding
more heart attack
COX-2
platelet inhibitor
aggregation

Lelo A, 2000
 tonsillectomy and the risk of
postoperative bleeding
NSAIDs may prolong the bleeding time by inhibiting
biosynthesis of thromboxane A2 and can therefore
increase blood loss during and after surgery.
Preoperative treatment with ketoprofen or diclofenac
was compared in controlling postoperative dental pain.
Following surgery, the incidence of dental bleeding was
similar for the two groups (Tai & Baker, 1992).
Another study demonstrated that one patient (3%) in the
nimesulide group and five patients (12%) [p = 0.22] in the
ibuprofen group needed electrocautery to stop
postoperative bleeding (Aho M, et al., 2003).
There were no differences between ibuprofen and
rofecoxib in operative blood loss (Pickering et al., 2002).
 Both COX-1 and COX-2 are important in
gastric mucosal defense
Gastric damage score (%)

Celecoxib dose (mg/kg)

Celecoxib dose-dependently increases the severity of gastric damage

induced by a low dose of aspirin
Fiorucci S, et al. Gastroenterology, 2002

Beermann B. The truth behind the study in JAMA. 2004

 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
Renal function
Bone anti-
formation
inflammatory
Reproduction
 Data are from the FDA hearings of
February 16 to 18, 2005 (
www.fda.gov/ohrms/dockets/ac/05/minutes/2005-4090M1_Final.htm)

Do the available data support a conclusion that

coxib significantly increases the risk of
cardiovascular events?

COXIB Yes No Abstain

CELECOXIB 32 0 0
ROFECOXIB 32 0 0
VALDECOXIB 32 0 0
 The Role of COX-2 Inhibitors as anti-
inflammatory, analgesic and antipyretic
agents in ENT Diseases
Analgesic efficacy is absolutely different among NSAIDs
COX-1 inhibition is essential to exert maximum
antinociceptive effect
Since hyperalgesia is mediated through the COX-2
dependent pathway in the CNS, a good NSAID should
be able to penetrate BBB
For acute pain, it is preferable to use oral NSAID
absorbed rapidly to achieve rapid relief.
Incidence of bleeding is similar for selective and non-
selective COX-2 inhibitors.
There is no indication for specific COX-2 inhibitors in
ENT disease
The ideal NSAID is preferential COX-2 inhibitor with
short half-life
Dirgahayu negeriku
Dirgahayu FK USU
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-

traditional, classic, non-COXIB NSAID COXIB

 Pain tolerance threshold (% reduction) EFFICACY of COXIBs
Nimesulide
30 Diclofenac
* Celecoxib
* * * Rofecoxib
20 *
* * * * * * * * *

10
*

0
0 15 30 60 120 180
Time (min)
Bianchi M & Broggini M. (2001)

Based on analgesic potency, COXIB is not an ideal one

 Schwartz JI, et al. Cyclooxygenase-2 inhibition by
rofecoxib reverses naturally occurring fever in
humans. Clin Pharmacol Ther. 65(6):653-60,1999
antipyretic activity (temp. change OC)
 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

Based on therapeutic cost, COXIB is not an ideal one

 PAIN
ALZHEIMER
CANCER DISEASE

NSAID
Rp

fluid increase
PUB CV event
retention BP

Anti-
Rp
diuretic Rp
hypertension Rp
PPI Rp
???

Iatrogenic COSTCascade
Prescribing of COXIB
August 20, 2005
 Sandler RS,et al. Risk Reduction and the GI Tract: From Theory to Reality.
http://www.medscape.com/viewprogram/2416 Release Date: June 5, 2003
Valdes C. Evolution in arthritis management: focus on COX-2 inhibitors April 14, 2002
 The 10 leading causes of death
as a percentage of all deaths
in the United States, 1990 and 1996
1990 1996

Source: CDC, National Center for Health Statistics

 WHO Statistical Information System (WHOSIS)
Numbers and rates (per-100.000) of registered deaths
United States of America - 2000
No Cause N Rate
1 CVS 941.524 668.5
2 Malignancy 553.091 393.4
3 Respiratory disease 186.346 132.5
4 Gastrointestinal disease 84.015 58.8
5 Accidents 73.785 55.1
6 Diabetes Mellitus 69.301 49.2
7 Infectious & Parasitic disease 69.007 42.0
8 Skin & Subcutaneous tissue disease 3.753 2.6
9 Drug, medicaments causing adverse 2.059 2.1
effects in therapeutic use

+ Ulcer of stomach and duodenum 4.504 3.2

CLASS results in JAMA and with the FDA

JAMA
reports

FDA
data
 Which one is ideal?
Risk of CV events

Solomon SD, et al.; Nussmeier NA, et al.; Bresalier RS, et al. N Engl J Med 352,2005
 Meta-analysis of relative risk of total mortality and
serious adverse events (SAEs) (including death,
admission to hospital, and any life- threatening event
or event leading to serious disability) with COX-2
selective and non selective NSAIDs
COXIBs must not be used in patients with established CV problems
Medical
journals are
an extension of
the marketing
arm of drug
companies

Richard Smith
Chief executive,
United Health
Europe
Formerly editor BMJ
An ideal one
is due to
wrong
information,
so sad !
 Very few studies have been
published at the time of approval!