aspek-fisikokimia-nsaid.pptx
TRANSCRIPT
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Aspek Farmakokimia ObatAntiinflamasi NonSteroid
Kuliah Farmakokimia
FSTOA semester 6
Fak. Farmasi USB
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Struktur enzim COX Keduanya merupakan dimer yang terikat
pada membran mikrosomal
4 domain Domain Dimerization
Domain yang terikat Membran
Domain katalitikbeda pada struktur
Domain peptida Terminalbeda panjang
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Interaksi asam arakhidonat cox
binding site
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COX-1 enzyme COX-2 enzyme
Expression
Constitutional Inducible (by cytokines)
Unchanged by
glucocorticoidsBlocked by glucocorticoids
Expressed at baseline (in
stomach, kidneys, platelets,
intestines)
Expressed duringinflammation (in
macrophages,
synoviocytes)
Kinetics
Instantaneous inhibition Time-dependent inhibition
Inhibition via hydrogenbondin ?Covalent bonding
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Physiological stimulus
clotting, parturition,
gastrointestinal
and renal protection
COX-1
constitutive
TXA2platelet
aggregation
Prostacyclin
endothelium-anticlotting
stomach mucosa:
H+, HCO3-,
mucus
PGE2
Kidney:arteriolar
dilation;
Na+/H2O
excretion
A.
PGF2parturition
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
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Classification
1. Non-steroidal Anti-inflammatory Agents
1.1 Non-selective COX-1 Inhibitors
1.2 Selective COX-2 Inhibitors2. Antipyretic Analgesics
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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
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General Structure of NSAIDs
Acidic functional groupCOOH; 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
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NH3+
O-
O
N
H3C O
O
H3C
C H3
O
O-
5
6
8 9
11
12
14
15
CARBOXYL ORACIDIC GROUP
ARYL ORHETERORYL GROUP
ARACHIDONIC ACIDINDOMETHACIN
ARYL ORALKYL GROUP
CATIONIC SITE(ARG 120)
FLATAREA
LYPOPHILIC GROUP
Interaksi Indomethacin - COX
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Physicochemical and Pharmacokinetic
Properties of NSAIDs
Strong organic acid; pKa ~ 3-5physiological pH (~7.4)
plasma protein binding (~90-99%)karena ionic bond drug
interaction albumin-NSAIDsplasma protein binding
carboxylic group (-COOH) mengalami metabolize glucuronide
conjugation (phase II)
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Glucuronide Conjugation
OHO
HO
HOOC
OHH
O
R
O
UDP-GlucuronosylTransferase (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
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1.1.1 Salicylic acid
OH
O
OH
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Salicylate Salts
O-
O
OH
Na+ O-
O
OH
1/2Mg2+
O-
O
OH
(CH3)3NCH2CH2OH O-
O
SH
Na+
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Aspirin or Acetylsalicylic Acid
OH
O
O
C H3O
Tambahan acyl group
pada molekul salicylic
acid
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Mechanism of action of Aspirin
HO
OH
O
O
C H3O
O
OH
O
OH
H3C
O+
Serineresidue
acetylation
Irreverseble COX inhibition
COX-1 (Ser 530),
COX-2 (Ser 516) orCirculating protein
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NH
O
OH
COOH
O
O
OH
GL U
OH
O
OH
HO
OH
O
OH
OH
OH
O
OH
HO
OH
OH
O
O
GL U
OH
O
OH
GlycineConjugation
GlucuronideConjugation
GENTISIC ACID
SALICYLURIC ACID
Aromatic
hydroxylation
Plasmaesterase
OH
O
O
C H3O
Metabolism ofAspirin and Salicylates
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Salicylamide
NH2
O
OH
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Salsalate
OH
O
O
OH
O
Dimer Salicylic acid
Dihidrolisis menjadi 2 molekul salicylate
Efek samping GI bleeding
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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)
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1.1.2 Arylalkanoic Acids
1.1.2.1 Aryl- and Heteroarylacetic Acids
1.1.2.2 Aryl and Heteroarylpropionic Acids (-profen)
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SAR
OH
O
R CARBOXYL GROUPALKYL GROUP
ARYL ORHETERO ARYL GROUP
ARYL ORALKYL GROUP
ACIDITY , ACTIVITY1-C ATOM
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1.1.2.1 Aryl- and Heteroarylacetic Acids
Indomethacin
Sulindac
Tolmetin (Sodium)
Diclofenac(Sodium)
Etodolac
Nabumetone
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Indomethacin
OH
O
N
H3C O
O
C l
C H3
Indole ring
P-Chlorobenzoyl
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Metabolism of Indomethacin
N
H3C O
O
OH
C H3
O
C l
N
HO
O
OH
C H3
O
C l
NH
H3CO
O
OH
C H3
NH
HO
O
OH
C H3
N
H3C O
O
OGLU
C H3
O
C l
NH
NH2
HO
Serotonin (5HT)
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Sulindac
OH
O
F
S
C H3
H3C
O
INDENE
BENZYLIDENE
SULFINYL GROUP
SOLUBILITY
LIPOPHILIC
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Metabolism of Sulindac
OH
O
F
S
C H3
H3CO
OH
O
F
S
C H3
H3C
ACTIVE SULFIDE METABOLITE
reduction
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Tolmetin (Sodium)
O-Na
+
O
N
H3C
C H3
O
PYROLE RING
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Metabolism of Tolmetin
O-Na
+
O
N
H3C
C H3
O
OGLU
O
N
H3C
C H3
O
OH
O
N
HOOC
C H3
O
Glucuronide conjugation
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Diclofenac (Sodium)
NH
C lC l
O-Na
+
O
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Nabumetone
C H3
O
H3C O
H3C O
O
OH
NAPHTHALENE
6-MNA (38%)(active metabolite)
Nabumetone(pro-drug)
oxidation
H3CO
OH
O
CH3
naproxen
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1.1.2.2 Aryl- and Heteroarylpropionic Acids
Ibuprofen
Fenoprofen (Calcium)
Ketoprofen
Naproxen
Flurbiprofen
Ketorolac (Tromethamine)
Oxaprozin
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Isomerization
R
C H3
H
OHO
R
C H3
S-O C oA
R
C H3
SO C oA
R
C H3
H
OHO
R
C H3
H
SO C oA
R-ENANTIOMER
S-ENANTIOMER
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IBUPROFEN
C H3
OH
O
H3C C H3 ISOBUTYL GROUP
C H3
O
OH
F
FLURBIPROFEN
OH
O
C H3
NHC l H3C O
OH
O
C H3
CARBAZOLE
CARPROFEN
NAPHTHALENE
NAPROXEN
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FENOPROFEN
C H3
O
OH
O
PHENOLIC GROUP
C H3
O
OH
O
KETONE
KETOPROFEN
OXAPROZIN
O
N
OH
O
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COOH
OH
COOH
NHR
Bioisosteric group -OH
Turunan Anthranilic acid merupakan modifikasi salicylic acid denganbioisosteric replacement
Salicylic acid Anthranilic acid
1.1.3 N-Arylanthranilic Acids (Fenamic Acids)
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OH
NH
O
C H3
C H3
OH
NH
O
C l
C H3
C l
Mefenamic Acid Meclofenamate (Sodium)
Anthranilic Acid (Fenamic Acid)
N-aryl ring
Anthranilic acid ring
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SAR OXICAM
S
N
OH
NH
R
O
R1O O
1
4
2
356
78
R1CH3 untuk
optimum activity
R : aryl atau heteroaryl
sybstituent
Enolic group; pKa ~ 4-6
4-hydroxy-1,2-benxothiazine carboxamides
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S
N
OH
O O
N
H
O
N
C H3 S
N
OH
O O
N
H
O
N
S
C H3
CH3
Piroxicam Meloxicam
Primary
carboxamide
Primary
carboxamide
2-pyridyl group 2-(5-methtyl)thiazolyl group
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S
N
OH
O
HN
CH3O O
N
SN
O
O-
HN
CH3
O O
N
S
N
O-
O
N
CH3O O
NH
SN
O
O-
N
CH3O O
N
H
+ H+
Stabilization of Enolate Anion
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Piroxicam
S
N
OH
O O
NH
O
N
C H3
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Meloxicam
S
N
OH
O O
NH
O
N
SC H3
C H3
selective cox-2 inhibitor (by FDA approving)
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NN
CF3
H3C
SH2N
O O
Celecoxib
O
O
SH3C
O O
Rofecoxib
Selective COX-2 Inhibitors
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N
O
CH3
S
H2N
O O
Valdecoxib Parecoxib (IM)(pro-drug of Valdecoxib)
N
O
CH3
S
NH
O OO
N
O
CH3
S
N
O OO
Na+
Parecoxib Sodium (IV)
COX 1 d COX 2
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COX-1 and COX-2
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Flurbiprofen; Non-Selective COX inhibitors
C H3
O
OH
F
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Interaksi dengan COX-1 & COX-2 : Non-selective COX inhibitor
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Celecoxib;Selective COX-2 inhibitors
NN
CF3
H3C
SH2N
O O
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Interaksi dengan COX-1 & COX-2 : Selective COX-2 inhibitor
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antipyretic analgesics
HN CH3
O
OCH2CH3
HN CH3
O
OH
Acetaminophenol Phenacetin
HN CH3
O
Acetanilide
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Metabolism and Toxicity
HN C H3
O
HN C H3
O
OH
HN C H3
O
O
NH2
O
NH2
METHEMOGLOBINEMIA
HEMOLYTIC ANEMIA
METHEMOGLOBINEMIA
HEMOLYTIC ANEMIA
MAJOR MAJORMINOR
MINOR
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Metabolism and Toxicity
HN C H3
O
OH
N C H3
O
HO
OH
N C H3
O
O
HN C H3
O
OH
S G
HN C H3
O
OH
NU
N-ACETYLIMIDOQUINONE
TOXIC METABOLITE
GSH
-H2O
HEPATIC ORRENAL PROTEINMAJOR
MINOR
SULFATE OR
GLUCURONIDECONJUGATION
HEPATIC NECROSISAND RENAL FAILURE
HN C H3
O
OH
S
NHCOCH3
O
OH
Excreted
form
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Metabolic Intoxicification
HS NH
COOHO
HNNH2
COOH
O
HS
HN
O
OH
O
GLUTATHIONE
N-ACETYLCYSTEINE
HN C H3
O
OH
S
NHCOCH3
O
OH
DETOXIFIES URINARYMETABOLITE
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Boundary
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Boundarysurface
defining the
cyclooxygenase binding
pocket
computed on
the COX-1
isozyme withGRID.
Different
regions of the
pocket as wellas the side
chains of key
residues are
explicitly
shown.
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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
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Structure
of rofecoxib
(in
magenta)and
ketoprofen
(in yellow)
docked into
the bindingsite of
COX-2,
whose
innersurface is
shown in
blue.
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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, tapamengganggu fungsi homeostatic prostaglandin
di organ yg tidak radang. Secara teroritis, inhibitor selektifCOX-2 masih
akan memberikan efek anti-inflamasi
COX inhibitors
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COX inhibitors Non Selective COX
inhibitors Non competitive
Aspirin
Competitive Phenylbutazone Ibuprofen Naproxen Diclofenac Piroxicam Ketorolac
Analgesic with Antipyreticwithout anti inflammatoryaction
Paracetamol Metamizol Nefopam
Preferential COX 2
inhibitors Nimesulide Meloxicam Nabumetone
Selective COX -2inhibitors
Celcoxib Rofecoxib Valdecoxib Etoricoxib Parecoxib Lumoracoxib
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Golongan inhibitor selektif COX-2
1. turunan karbosiklis dan Heterosiklis yangterikat 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.
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Selektivitas
Ratio aktivitas penghambatan COX1 /COX2
Aktivitas COX-1 : kemampuan untukmenghambat produksi TXB 2dariplatelets
Aktivitas COX
2 : kemampuanpenghambatan produksi PGI2darimonosit sebagai respon stimuli
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Inhibitor selektif COX-2
Pada penanganan pasien-pasien osteo- danrheumatoidarthritis, inhibitor selektif COX-2
menunjukkan kerja antiradang yang setaradengan obat antiradang bukan steroid klasiktetapi dengan toksisitas lebih ringan padasaluran gastrointestinal.
Namun demikian, dilaporkan pula adanyakecendrungan peningkatan tekanan darahsebagai efek samping inhibitor selektif COX-2
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Inhibitor selektif COX-2
Muncul pertanyaan, apakah inhibitor selektifCOX-2 benar-benar toksisitasnya lebih
ringan sehingga lebih aman digunakan ataubahkan memiliki efek merugikan lain yangberbeda dari efek merugikan yang
disebabkan oleh obat anti radang bukansteroid klasik?