Aspek Farmakokimia Obat Antiinflamasi NonSteroid
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
ONH 3
+
CH3
H3CO N
ARYL OR HETERORYL GROUP
O
ARYL OR ALKYL GROUP
O
CATIONIC SITE (ARG 120)
FLAT AREA
O-
5 11
6 8
12
9
14
LYPOPHILIC GROUP H3C
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
HOOC O
HO HO
OH O
H O P
NH
O O
O-
P
O
H
O-
H OH
UDP-Glucuronosyl Transferase (UGT) HOOC HO HO
O
N
O
H OH
R
O OH
H
O O H
Acyl-glucuronide metabolite
+ UDP
1.1.1 Salicylic acid O OH OH
Salicylate Salts O
O O- Na+
OH
O
O- 1/2 Mg2+ OH
O O- Na+
O- (CH3)3NCH2CH2OH 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
CH3
HO
acetylation O
COX-1 (Ser 530), COX-2 (Ser 516) or Circulating protein
OH OH
+
H3 C
Irreverseble COX inhibition
O O
Metabolism of Aspirin and Salicylates
O OH O
O
O
O
OH
HO
OH OH
O
OH
Aromatic hydroxylation O
OH
SALICYLURIC ACID
Glycine Conjugation
OH
COOH
OH
Plasma esterase O
OH
O
N H
C H3
HO
OH
O OH O
Glucuronide Conjugation
OH
OH O
GENTISIC ACID
OH
GL U
GL U
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
5
F
4
6 3
COOH 1 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 ALKYL GROUP
ACIDITY , ACTIVITY
O 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 CH3
H3C O N
Indole ring
O
P-Chlorobenzoyl Cl
Metabolism of Indomethacin O
O H3CO
H3CO
OH
O
OH CH3
CH3
N H
N
OH CH3
O
O O
HO
HO
N H
OH C H3
Cl
H3CO
N
OGL U
O
CH3 N O
NH2
Cl
HO Cl
N H
Serotonin (5HT)
Sulindac O
INDENE
OH CH3
F
LIPOPHILIC
BENZYLIDENE SULFINYL GROUP
SOLUBILITY
H3C
S O
Metabolism of Sulindac O
O
OH CH3
F
H3C S
O
OH
reduction
C H3
F
H3C S ACTIVE SULFIDE METABOLITE
Tolmetin (Sodium) O O-Na+ N
CH3
O
H3C
PYROLE RING
Metabolism of Tolmetin O O-Na+
O N
OGL U N
CH3
O
CH3
OH N
O
CH3
O
O H3C HOOC
H3C
Glucuronide conjugation
Diclofenac (Sodium) O-Na+
NH Cl
O Cl
Nabumetone NAPHTHALENE
CH3
O
O OH
H3CO
CH3
naproxen H3CO
oxidation
Nabumetone (pro-drug) O OH
H3CO
6-MNA (38%) (active metabolite)
1.1.2.2 Aryl- and Heteroarylpropionic Acids • • • • • • •
Ibuprofen Fenoprofen (Calcium) Ketoprofen Naproxen Flurbiprofen Ketorolac (Tromethamine) Oxaprozin
Isomerization O
O
OH
S
C H3 R
H
CoA
O
CH3 H
R
S
C oA
C H3 R
R-ENANTIOMER
O
OH
-
O
CH3 R S-ENANTIOMER
H
S CH3
R
CoA
•
IBUPROFEN
FLURBIPROFEN CH3
CH3
F
O
O
OH
H3C
CH3
OH
ISOBUTYL GROUP
•
CARPROFEN
NAPROXEN
CH3
C H3
O
O
OH Cl
OH
H3CO
NH
CARBAZOLE
NAPHTHALENE
•
•
FENOPROFEN
KETOPROFEN
C H3
CH3
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
C H3
Mefenamic Acid
Cl
Cl
N-aryl ring C H3
Meclofenamate (Sodium)
SAR OXICAM R : aryl atau heteroaryl sybstituent
Enolic group; pKa ~ 4-6
OH 6 5 7
4
S O
N H
3
1 2
8
O
N
O
R1
R
R1–CH3 untuk optimum activity
4-hydroxy-1,2-benxothiazine carboxamides
2-pyridyl group OH
O
OH N H
S O
2-(5-methtyl)thiazolyl group
N O
Piroxicam
C H3
O
N
Primary carboxamide
S N H
S O
N O
Meloxicam
C H3
C H3 N
Primary carboxamide
Stabilization of Enolate Anion OH
HN
N
O
H
-
N
N
O S O
N O
O
CH3
N O
S O
O
O
-
+
N
S
N
N
O CH3
O
HN
O
H
N O-
CH3
S O
N O
CH3
H+
Piroxicam OH
O N H
S O
N O
C H3
N
Meloxicam OH
O
S N H
S O
N
C H3 N
C H3
O
selective cox-2 inhibitor (by FDA approving)
Selective COX-2 Inhibitors O H2N
O
O
S
H3C N
S
O
N CF3
O O
H3 C
Celecoxib
Rofecoxib
O H2N
O
O
S
O
CH3
N H
O S
CH3
O
O
N
N
Valdecoxib O
O N
Parecoxib (IM) (pro-drug of Valdecoxib)
O S
CH3
Na+ O N
Parecoxib Sodium (IV)
COX-1 and COX-2
Flurbiprofen; Non-Selective COX inhibitors CH3 F
O OH
Interaksi dengan COX-1 & COX-2 : Non-selective COX inhibitor
Celecoxib;Selective COX-2 inhibitors O H2N
O S
N
H3 C
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
OCH2CH3
Phenacetin
Acetanilide
Metabolism and Toxicity O HN
O
O
C H3
MAJOR
HN
C H3
HN
C H3
MINOR
MAJOR OH
NH2
O
O
MINOR METHEMOGLOBINEMIA
NH2
METHEMOGLOBINEMIA HEMOLYTIC ANEMIA
HEMOLYTIC ANEMIA
Metabolism and Toxicity O HN
O
O HO
C H3
N
C H3
-H2O
N
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
SG
O
Excreted form
S OH
OH NHCOCH3
OH
NU OH
Metabolic Intoxicification O
COOH N H
HS HN
O
COOH NH2
HN
C H3
O
O
GLUTATHIONE S
O HS
OH OH
HN O
N-ACETYLCYSTEINE
DETOXIFIES URINARY METABOLITE
OH NHCOCH3
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?
