Post on 27-May-2018
Aspek Farmakokimia Obat Antiinflamasi NonSteroid
Struktur enzim COX
Keduanya merupakan dimer yang terikat pada membran mikrosomal
4 domain
Domain Dimerization
Domain yang terikat Membran
Domain katalitik– beda pada struktur
Domain 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
Physiological stimulus
clotting, parturition,
gastrointestinal
and renal protection
COX-1
constitutive
TXA2
platelet
aggregation
Prostacyclin
endothelium-
anticlotting
stomach mucosa:
H+, HCO3-,
mucus
PGE2
Kidney:
arteriolar
dilation;
Na+/H2O
excretion
A.
PGF2
parturition
Figure 8. Actions of two known isoforms of cyclooxygenase (COX).
Inflammatory stimulus
(tissue injury, chronic arthritis)
macrophages/other cells
Proteases
Inflammation, redness,
swelling, pain
B.
COX-2
induced by cytokines (e.g., TNF)
Other inflammatory
mediators
(histamine, etc)
Prostaglandins
especially PGE2
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
NH3+
O-
O
N
H3CO
O
H3C
CH3
O
O-
5
6
8 9
11
12
14
15
CARBOXYL OR ACIDIC GROUP
ARYL OR HETERORYL GROUP
ARACHIDONIC ACID INDOMETHACIN
ARYL OR ALKYL GROUP
CATIONIC SITE (ARG 120)
FLAT
AREA
LYPOPHILIC GROUP
Interaksi Indomethacin - COX
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
OHO
HO
HOOC
OHH
O
R
O
UDP-Glucuronosyl Transferase (UGT)
Acyl-glucuronide metabolite
O
HOOC
HO
HO
OH
H
O P
O
O-
O P
O
O
O- O
H
H
OH
H
OH
N
H
NH
O
O
-O R
O
Drugs (NSAIDs)
+ UDP
1.1.1 Salicylic acid
OH
O
OH
Salicylate Salts
O-
O
OH
Na+ O-
O
OH
1/2 Mg2+
O-
O
OH
(CH3)3NCH2CH2OH O-
O
SH
Na+
Aspirin or Acetylsalicylic Acid
OH
O
O
CH3O
Tambahan acyl group pada molekul salicylic acid
Mechanism of action of Aspirin
HO
OH
O
O
CH3O
O
OH
O
OH
H3C
O+
Serine residue
acetylation
Irreverseble COX inhibition
COX-1 (Ser 530),
COX-2 (Ser 516) or Circulating protein
NH
O
OH
COOH
O
O
OH
GLU
OH
O
OH
HO
OH
O
OH
OH
OH
O
OH
HO
OH
OH
O
O
GLU
OH
O
OH
Glycine Conjugation
Glucuronide Conjugation
GENTISIC ACID
SALICYLURIC ACID
Aromatic
hydroxylation
Plasma esterase
OH
O
O
CH3O
Metabolism of Aspirin and Salicylates
Salicylamide
NH2
O
OH
Salsalate
OH
O
O
OHO
• Dimer Salicylic acid • Dihidrolisis menjadi 2 molekul salicylate • Efek samping GI bleeding
Diflunisal
COOH
OH
F
F
1
23
4
56
• phenyl group (or aromatic ring) pada molekul salicylic acid
• 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
OH
O
R CARBOXYL GROUP ALKYL GROUP
ARYL OR HETERO ARYL GROUP
ARYL OR ALKYL GROUP
ACIDITY , ACTIVITY 1-C ATOM
1.1.2.1 Aryl- and Heteroarylacetic Acids
• Indomethacin • Sulindac • Tolmetin (Sodium) • Diclofenac (Sodium) • Etodolac • Nabumetone
Indomethacin
OH
O
N
H3CO
O
Cl
CH3
Indole ring
P-Chlorobenzoyl
Metabolism of Indomethacin
N
H3CO
O
OH
CH3
O
Cl
N
HO
O
OH
CH3
O
Cl
NH
H3CO
O
OH
CH3
NH
HO
O
OH
CH3
N
H3CO
O
OGLU
CH3
O
Cl
NH
NH2
HO
Serotonin (5HT)
Sulindac
OH
O
F
S
CH3
H3C
O
INDENE
BENZYLIDENE
SULFINYL GROUP
SOLUBILITY
LIPOPHILIC
Metabolism of Sulindac
OH
O
F
S
CH3
H3CO
OH
O
F
S
CH3
H3C
ACTIVE SULFIDE METABOLITE
reduction
Tolmetin (Sodium)
O-Na+
O
N
H3C
CH3
O
PYROLE RING
Metabolism of Tolmetin
O-Na+
O
N
H3C
CH3
O
OGLU
O
N
H3C
CH3
O
OH
O
N
HOOC
CH3
O
Glucuronide conjugation
Diclofenac (Sodium)
NH
ClCl
O-Na+
O
Nabumetone
CH3
O
H3CO
H3CO
O
OH
NAPHTHALENE
6-MNA (38%) (active metabolite)
Nabumetone (pro-drug)
oxidation
H3COOH
O
CH3
naproxen
1.1.2.2 Aryl- and Heteroarylpropionic Acids • Ibuprofen • Fenoprofen (Calcium) • Ketoprofen • Naproxen • Flurbiprofen • Ketorolac (Tromethamine) • Oxaprozin
Isomerization
R
CH3
H
OHO
R
CH3
S-O CoA
R
CH3
SO CoA
R
CH3
H
OHO
R
CH3
H
SO CoA
R-ENANTIOMER
S-ENANTIOMER
• IBUPROFEN
CH3
OH
O
H3C CH3 ISOBUTYL GROUP
CH3
O
OH
F
FLURBIPROFEN
OH
O
CH3
NHCl H3COOH
O
CH3
CARBAZOLE
CARPROFEN
NAPHTHALENE
• NAPROXEN
• FENOPROFEN
CH3
O
OH
O
PHENOLIC GROUP
CH3
O
OH
O
KETONE
• KETOPROFEN
• OXAPROZIN
ON
OH
O
COOH
OH
COOH
NHR
Bioisosteric group ของ -OH
• Turunan Anthranilic acid merupakan modifikasi salicylic acid dengan bioisosteric replacement
Salicylic acid Anthranilic acid
1.1.3 N-Arylanthranilic Acids (Fenamic Acids)
OH
NH
O
CH3
CH3
OH
NH
O
Cl
CH3
Cl
Mefenamic Acid Meclofenamate (Sodium)
Anthranilic Acid (Fenamic Acid)
N-aryl ring
Anthranilic acid ring
SAR OXICAM
SN
OH
NH
R
O
R1O O
1
4
2
356
78
R1–CH3 untuk optimum activity
R : aryl atau heteroaryl sybstituent
Enolic group; pKa ~ 4-6
4-hydroxy-1,2-benxothiazine carboxamides
SN
OH
O O
NH
O
N
CH3 SN
OH
O O
NH
O
N
SCH3
CH3
Piroxicam Meloxicam
Primary carboxamide
Primary carboxamide
2-pyridyl group 2-(5-methtyl)thiazolyl group
SN
OH
O
HN
CH3O O
N
SN
O
O-
HN
CH3O O
N
SN
O-
O
N
CH3O O
NH
SN
O
O-
N
CH3O O
N
H
+ H+
Stabilization of Enolate Anion
Piroxicam
SN
OH
O O
NH
O
N
CH3
Meloxicam
SN
OH
O O
NH
O
N
SCH3
CH3
selective cox-2 inhibitor (by FDA approving)
NN
CF3
H3C
SH2N
O O
Celecoxib
O
O
SH3C
O O
Rofecoxib
Selective COX-2 Inhibitors
N
O
CH3
SH2N
O O
Valdecoxib Parecoxib (IM) (pro-drug of Valdecoxib)
N
O
CH3
SNH
O OO
N
O
CH3
SN
O OO
Na+
Parecoxib Sodium (IV)
COX-1 and COX-2
Flurbiprofen; Non-Selective COX inhibitors
CH3
O
OH
F
Interaksi dengan COX-1 & COX-2 : Non-selective COX inhibitor
Celecoxib;Selective COX-2 inhibitors
NN
CF3
H3C
SH2N
O O
Interaksi dengan COX-1 & COX-2 : Selective COX-2 inhibitor
antipyretic analgesics
HN CH3
O
OCH2CH3
HN CH3
O
OH
Acetaminophenol Phenacetin
HN CH3
O
Acetanilide
Metabolism and Toxicity
HN CH3
O
HN CH3
O
OH
HN CH3
O
O
NH2
O
NH2
METHEMOGLOBINEMIA
HEMOLYTIC ANEMIA
METHEMOGLOBINEMIA
HEMOLYTIC ANEMIA
MAJOR MAJOR MINOR
MINOR
Metabolism and Toxicity
HN CH3
O
OH
N CH3
O
HO
OH
N CH3
O
O
HN CH3
O
OH
SG
HN CH3
O
OH
NU
N-ACETYLIMIDOQUINONE
TOXIC METABOLITE
GSH
-H2O
HEPATIC OR RENAL PROTEIN MAJOR
MINOR
SULFATE OR
GLUCURONIDE CONJUGATION
HEPATIC NECROSIS AND RENAL FAILURE
HN CH3
O
OH
S
NHCOCH3
O
OH
Excreted form
Metabolic Intoxicification
HS NH
COOHO
HNNH2
COOH
O
HS
HN
O
OH
O
GLUTATHIONE
N-ACETYLCYSTEINE
HN CH3
O
OH
S
NHCOCH3
O
OH
DETOXIFIES URINARY METABOLITE
Boundary
surface
defining the
cyclooxygenas
e binding
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
Analgesic with Antipyretic without anti inflammatory action
Paracetamol Metamizol Nefopam
Preferential COX – 2 inhibitors
Nimesulide Meloxicam Nabumetone
Selective COX -2 inhibitors
Celcoxib Rofecoxib Valdecoxib Etoricoxib Parecoxib Lumoracoxib
Golongan inhibitor selektif COX-2
1. turunan karbosiklis dan Heterosiklis yang terikat visinal dengan moieties aril (Ex. Celexocib, rofexocib),
2. turunan diaril- atau aril/heteroaril-eter dan –tioeter,
3. turunan cis-stilben,
4. 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?