Aspek Farmakokimia Obat
Antiinflamasi NonSteroid
Kuliah Farmakokimia
FSTOA semester 6
Fak. Farmasi USB
Struktur enzim COX


Keduanya merupakan dimer yang terikat
pada membran mikrosomal
4 domain




Domain
Domain
Domain
Domain
Dimerization
yang terikat Membran
katalitik– beda pada struktur
peptida Terminal– beda panjang

Interaksi asam arakhidonat – cox
binding site
COX-1 enzyme
COX-2 enzyme
Expression
Constitutional
Inducible (by cytokines)
Unchanged by
glucocorticoids
Blocked by glucocorticoids
Expressed at baseline (in
stomach, kidneys, platelets,
intestines)
Expressed during
inflammation (in
macrophages,
synoviocytes)
Kinetics
Instantaneous inhibition
Time-dependent inhibition
Inhibition via hydrogen
bonding
?Covalent bonding
A.
Physiological stimulus
macrophages/other cells
COX-2
induced by cytokines (e.g., TNF)
COX-1
constitutive
platelet
aggregation
PGF2
parturition
Prostacyclin
PGE2
endotheliumanticlotting
Kidney:
arteriolar
dilation;
Na+/H2O
excretion
stomach mucosa:
 H+,  HCO3-,
 mucus
Inflammatory stimulus
(tissue injury, chronic arthritis)
clotting, parturition,
gastrointestinal
and renal protection
TXA2
B.
Proteases Prostaglandins Other inflammatory
especially PGE2
mediators
(histamine, etc)
Inflammation, redness,
swelling, pain
Figure 8. Actions of two known isoforms of cyclooxygenase (COX).
Classification
1. Non-steroidal Anti-inflammatory Agents
1.1 Non-selective COX-1 Inhibitors
1.2 Selective COX-2 Inhibitors
2. Antipyretic Analgesics
1. Anti-inflammatory Agents
1.1 Non-selective Cycloxygenase (COX) -1 Inhibitors
1.1.1 Salicylates
1.1.2 Arylalkanoic Acids
1.1.2.1 Aryl- and Heteroarylacetic Acids
1.1.2.2 Aryl- and Heteroarylpropionic Acids
1.1.3 N-Arylanthranilic Acids (Fenamic Acids)
1.1.4 Oxicams
1.1.5 Phenylpyrazolones
1.2 Selective COX-2 Inhibitors
General Structure of NSAIDs
• Acidic functional group –COOH;
– Membentuk ionic bond dengan arginine residue (120) dari COX
• Aromatic ring / heteroaromatic ring (Acidic functional group);
– hydrophobic interaction (van der waal force )dengan flat area enzim
COX
• lipophilic part / alkyl chain pada aromatic ring
– hydrophobic interaction melalui van der waal force
Interaksi Indomethacin - COX
O
CARBOXYL OR
ACIDIC GROUP
O NH
3
+
CATIONIC SITE
(ARG 120)
C H3
H 3C O
ARYL OR
HETERORYL GROUP
N
O
ARYL OR
ALKYL GROUP
FLAT
AREA
O
O-
5
11
6
8
12
9
14
LYPOPHILIC GROUP
H 3C
INDOMETHACIN
15
ARACHIDONIC ACID
Physicochemical and Pharmacokinetic
Properties of NSAIDs
• Strong organic acid; pKa ~ 3-5 physiological pH (~7.4)
• plasma protein binding (~90-99%) karena ionic bond  drug
interaction albumin-NSAIDs plasma protein binding
• carboxylic group (-COOH) mengalami metabolize glucuronide
conjugation (phase II)
Glucuronide Conjugation
O
-
O
Drugs (NSAIDs)
R
O
HO O C
O
HO
H
O
HO
OH
O
P
NH
O
O
O-
P
O
H
OH
UDP-Glucuronosyl
Transferase (UGT)
HO O C
HO
OH
N
O
H
OH
R
O
O
HO
OH
O
H
O
H
Acyl-glucuronide metabolite
+ UDP
1.1.1 Salicylic acid
O
OH
OH
Salicylate Salts
O
O
+
O- Na
OH
O
2+
O - 1 /2 M g
OH
O
+
O- Na
O - (C H 3 ) 3 N C H 2 C H 2 O H
OH
SH
Aspirin or Acetylsalicylic Acid
O
OH
O
O
C H3
Tambahan acyl group
pada molekul salicylic
acid
Mechanism of action of Aspirin
O
OH
Serine
residue
O
O
C H3
HO
acetylation
O
COX-1 (Ser 530),
COX-2 (Ser 516) or
Circulating protein
OH
OH
+
H 3C
Irreverseble COX inhibition
O
O
Metabolism of
Aspirin and Salicylates
O
OH
O
O
O
O
OH
N
H
C H3
OH
OH
OH
O
OH
Aromatic
hydroxylation
O
OH
SALICYLURIC ACID
Glycine
Conjugation
O
HO
OH
Plasma
esterase
O
OH
C OOH
HO
OH
O
OH
O
Glucuronide
Conjugation
OH
OH
O
GENTISIC ACID
OH
GLU
GLU
Salicylamide
O
NH2
OH
Salsalate
OH
O
O
O
• Dimer Salicylic acid
• Dihidrolisis menjadi 2 molekul salicylate
• Efek samping GI bleeding
OH
Diflunisal
• phenyl group (or
aromatic ring) pada
molekul salicylic acid
F
C OOH
6
5
F
4
1
3
2
OH
• Efek samping : GI disturbance, dermatologic reaction , CNS side effect (dizziness
and headache)
1.1.2 Arylalkanoic Acids
1.1.2.1 Aryl- and Heteroarylacetic Acids
1.1.2.2 Aryl and Heteroarylpropionic Acids (“-profen”)
SAR
1-C ATOM
ACIDITY , ACTIVITY 
O
ALKYL GROUP
R
CARBOXYL GROUP
OH
ARYL OR
HETERO ARYL GROUP
ARYL OR
ALKYL GROUP
1.1.2.1 Aryl- and Heteroarylacetic Acids
•
•
•
•
•
•
Indomethacin
Sulindac
Tolmetin (Sodium)
Diclofenac (Sodium)
Etodolac
Nabumetone
Indomethacin
O
OH
C H3
H 3C O
N
Indole ring
O
P-Chlorobenzoyl
Cl
Metabolism of Indomethacin
O
O
H 3C O
H 3C O
OH
O
OH
C H3
C H3
N
H
N
OH
C H3
O
O
O
HO
HO
N
H
OH
C H3
H 3C O
N
OGL U
Cl
O
C H3
N
O
NH2
Cl
HO
Cl
N
H
Serotonin (5HT)
Sulindac
O
INDENE
OH
C H3
F
LIPOPHILIC
BENZYLIDENE
SULFINYL GROUP
 SOLUBILITY
H 3C
S
O
Metabolism of Sulindac
O
O
OH
C H3
F
H 3C
S
O
OH
reduction
C H3
F
H 3C
S
ACTIVE SULFIDE METABOLITE
Tolmetin (Sodium)
O
O -Na +
N
C H3
O
H 3C
PYROLE RING
Metabolism of Tolmetin
O
O -Na +
O
N
OGL U
N
C H3
O
C H3
OH
N
O
C H3
O
O
H 3C
HO O C
H 3C
Glucuronide conjugation
Diclofenac (Sodium)
O -Na +
NH
Cl
O
Cl
Nabumetone
NAPHTHALENE
C H3
O
O
OH
H 3C O
C H3
naproxen
H 3C O
oxidation
Nabumetone
(pro-drug)
O
OH
H 3C O
6-MNA (38%)
(active metabolite)
1.1.2.2 Aryl- and Heteroarylpropionic Acids
•
•
•
•
•
•
•
Ibuprofen
Fenoprofen (Calcium)
Ketoprofen
Naproxen
Flurbiprofen
Ketorolac (Tromethamine)
Oxaprozin
Isomerization
O
OH
O
S
C H3
R
H
C oA
O
C H3
H
R
S
C oA
C H3
R
R-ENANTIOMER
O
OH
-
O
C H3
R
S-ENANTIOMER
H
S
C H3
R
C oA
•
IBUPROFEN
 FLURBIPROFEN
C H3
C H3
F
O
O
OH
H 3C
C H3
OH
ISOBUTYL GROUP
•
 CARPROFEN
NAPROXEN
C H3
C H3
O
O
OH
Cl
OH
H 3C O
NH
CARBAZOLE
NAPHTHALENE
•
•
FENOPROFEN
KETOPROFEN
C H3
C H3
O
O
OH
OH
O
O
KETONE
PHENOLIC GROUP
•
OXAPROZIN
O
OH
O
N
1.1.3 N-Arylanthranilic Acids (Fenamic Acids)
Salicylic acid
Anthranilic acid
C OOH
C OOH
OH
NHR
Bioisosteric group ของ -OH
• Turunan Anthranilic acid merupakan modifikasi salicylic acid dengan
bioisosteric replacement
Anthranilic Acid (Fenamic Acid)
O
O
OH
OH
Anthranilic acid ring
NH
NH
C H3
Cl
Cl
N-aryl ring
C H3
Mefenamic Acid
C H3
Meclofenamate (Sodium)
SAR OXICAM
R : aryl atau heteroaryl
sybstituent
Enolic group; pKa ~ 4-6
OH
6 5
7
4
8
1
S
O
O
N
H
3
2
N
O
R1
R
R1–CH3 untuk
optimum activity
4-hydroxy-1,2-benxothiazine carboxamides
2-pyridyl group
OH
2-(5-methtyl)thiazolyl group
O
OH
N
H
N
O
C H3
O
Piroxicam
N
Primary
carboxamide
S
N
H
N
S
O
S
O
C H3
O
Meloxicam
C H3
N
Primary
carboxamide
Stabilization of Enolate Anion
OH
HN
N
O
H
-
N
N
O
N
S
O
CH3
O
N
N
O
S
N
O
-
+
N
S
O
O
O
O
CH3
O
HN
O
N
H
O-
CH3
S
O
N
O
CH3
H+
Piroxicam
OH
O
N
H
N
S
O
C H3
O
N
Meloxicam
OH
O
S
N
H
C H3
N
N
S
O
C H3
O
selective cox-2 inhibitor (by FDA approving)
Selective COX-2 Inhibitors
O
H 2N
O
O
S
H 3C
N
S
O
N
CF3
O
O
H 3C
Celecoxib
Rofecoxib
O
O
H 2N
O
S
O
O
CH3
N
H
S
CH3
O
O
N
N
Valdecoxib
O
O
O
N
Parecoxib (IM)
(pro-drug of Valdecoxib)
S
CH3
N a+
O
N
Parecoxib Sodium (IV)
COX-1 and COX-2
Flurbiprofen; Non-Selective COX inhibitors
C H3
F
O
OH
Interaksi dengan COX-1 & COX-2 : Non-selective COX inhibitor
Celecoxib;Selective COX-2 inhibitors
O
H 2N
O
S
N
H 3C
N
CF3
Interaksi dengan COX-1 & COX-2 : Selective COX-2 inhibitor
antipyretic analgesics
O
HN
O
CH3
OH
Acetaminophenol
HN
O
CH3
HN
CH3
O C H 2C H 3
Phenacetin
Acetanilide
Metabolism and Toxicity
O
HN
O
O
C H3
MAJOR
HN
C H3
HN
C H3
MINOR
MAJOR
OH
NH 2
O
O
MINOR
METHEMOGLOBINEMIA
NH 2
METHEMOGLOBINEMIA
HEMOLYTIC ANEMIA
HEMOLYTIC ANEMIA
Metabolism and Toxicity
O
HN
O
O
HO
C H3
N
C H3
N
-H2O
C H3
N-ACETYLIMIDOQUINONE
MINOR
TOXIC METABOLITE
OH
O
OH
GSH
HEPATIC OR
RENAL PROTEIN
MAJOR
O
O
SULFATE OR
GLUCURONIDE
CONJUGATION
HN
C H3
HN
C H3
HEPATIC NECROSIS
AND RENAL FAILURE
O
HN
C H3
Excreted
form
S
OH
NU
SG
O
OH
NH C O C H 3
OH
OH
Metabolic Intoxicification
O
COOH
N
H
HS
HN
O
COOH
NH2
HN
C H3
O
O
GLUTATHIONE
S
O
OH
HS
OH
HN
DETOXIFIES URINARY
METABOLITE
O
N-ACETYLCYSTEINE
OH
NH C O C H 3
Boundary
surface
defining the
cyclooxygenas
e binding
pocket
computed on
the COX-1
isozyme with
GRID.
Different
regions of the
pocket as well
as the side
chains of key
residues are
explicitly
shown.
Superposition of the optimized structures of ketoprofen bound according to model 2 to
each of the two isozymes. Docking onto COX-1 is shown in yellow, and onto COX-2 in
magenta. The inner surface of the binding pocket is shown in blue.
•
Structure
of rofecoxib
(in
magenta)
and
ketoprofen
(in yellow)
docked into
the binding
site of
COX-2,
whose
inner
surface is
shown in
blue.
Inhibitor Selektif COX -2


Penghambatan COX-2 : efek anti-inflamasi
Penghambatan COX-1 : toksisitas NSAID,





a) peptic ulcer dan resiko perdarahan,
b) memperlama bleeding time;
c) renal insufficiency .
Ditargetkan pada jaringan yg radang, tapa
mengganggu fungsi homeostatic prostaglandin
di organ yg tidak radang.
Secara teroritis, inhibitor selektifCOX-2 masih
akan memberikan efek anti-inflamasi
COX inhibitors

Non Selective COX
inhibitors

Non competitive




Aspirin

Competitive






Phenylbutazone
Ibuprofen
Naproxen
Diclofenac
Piroxicam
Ketorolac
Preferential COX – 2
inhibitors


Selective COX -2
inhibitors



Analgesic with Antipyretic
without anti inflammatory
action



Paracetamol
Metamizol
Nefopam
Nimesulide
Meloxicam
Nabumetone




Celcoxib
Rofecoxib
Valdecoxib
Etoricoxib
Parecoxib
Lumoracoxib
Golongan inhibitor selektif COX-2
1.
2.
3.
4.
turunan karbosiklis dan Heterosiklis yang
terikat visinal dengan moieties aril (Ex.
Celexocib, rofexocib),
turunan diaril- atau aril/heteroaril-eter dan
–tioeter,
turunan cis-stilben,
keton diaril dan aril/heteroaril.
Selektivitas



Ratio aktivitas penghambatan COX–1 /
COX–2
Aktivitas COX-1 : kemampuan untuk
menghambat produksi TXB 2 dari
platelets
Aktivitas COX–2 : kemampuan
penghambatan produksi PGI 2 dari
monosit sebagai respon stimuli
Inhibitor selektif COX-2


Pada penanganan pasien-pasien osteo- dan
rheumatoidarthritis, inhibitor selektif COX-2
menunjukkan kerja antiradang yang setara
dengan obat antiradang bukan steroid klasik
tetapi dengan toksisitas lebih ringan pada
saluran gastrointestinal.
Namun demikian, dilaporkan pula adanya
kecendrungan peningkatan tekanan darah
sebagai efek samping inhibitor selektif COX-2
Inhibitor selektif COX-2

Muncul pertanyaan, apakah inhibitor selektif
COX-2 benar-benar toksisitasnya lebih
ringan sehingga lebih aman digunakan atau
bahkan memiliki efek merugikan lain yang
berbeda dari efek merugikan yang
disebabkan oleh obat anti radang bukan
steroid klasik?