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 Expression Constitutional

COX-2 enzyme

Inducible (by cytokines)

Unchanged by glucocorticoids
Expressed at baseline (in stomach, kidneys, platelets, intestines) Kinetics Instantaneous inhibition Inhibition via hydrogen bonding

Blocked by glucocorticoids
Expressed during inflammation (in macrophages, synoviocytes) Time-dependent inhibition

?Covalent bonding

A.

Physiological stimulus

B.

Inflammatory stimulus
(tissue injury, chronic arthritis) macrophages/other cells COX-2 induced by cytokines (e.g., TNF)

clotting, parturition, gastrointestinal and renal protection COX-1 constitutive

TXA2
platelet aggregation

Prostacyclin
endotheliumanticlotting stomach mucosa: H+, HCO3-, mucus

PGE2
Kidney: arteriolar dilation; Na+/H2O excretion

Proteases Prostaglandins Other inflammatory especially PGE2 mediators (histamine, etc)

PGF2
parturition

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

CARBOXYL OR ACIDIC GROUP
O
ONH 3

CATIONIC SITE (ARG 120)

O O-

H3CO

CH3 N O

5 6 8 9 11 12

ARYL OR HETERORYL GROUP

FLAT AREA

ARYL OR ALKYL GROUP

H3C

LYPOPHILIC GROUP

14 15

INDOMETHACIN

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
-

Drugs (NSAIDs)
O

HOOC HO HO O OH O H O P OO O P OO H

NH N O

UDP-Glucuronosyl Transferase (UGT)

HOOC HO HO O OH H O O R

H OH

H OH

+ UDP

Acyl-glucuronide metabolite

1.1.1 Salicylic acid

O OH OH

Salicylate Salts
O O- Na+ OH OH O O- 1/2 Mg2+

O O- (CH3)3NCH2CH2OH OH

O O- Na+ 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 O O CH3 HO

Serine residue

acetylation
O OH OH
+

COX-1 (Ser 530), COX-2 (Ser 516) or Circulating protein

O O

H3C

Irreverseble COX inhibition

Metabolism of Aspirin and Salicylates

O OH O
O

O OH OH OH
OH OH OH

C H3

N H OH
SALICYLURIC ACID

COOH

Plasma esterase
O

O HO

Glycine Conjugation
OH

O O OH O GL U

Aromatic hydroxylation
O

OH

HO

Glucuronide Conjugation
OH
O

OH

GENTISIC ACID

OH

GL U

Salicylamide
O NH2 OH

Salsalate
OH O O O OH

Dimer Salicylic acid Dihidrolisis menjadi 2 molekul salicylate Efek samping GI bleeding

Diflunisal
phenyl group (or aromatic ring) pada molekul salicylic acid
F COOH
1 2

6 3

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

R

O OH

ACIDITY , ACTIVITY

CARBOXYL GROUP

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 H3C O CH3 N O

Indole ring

P-Chlorobenzoyl
Cl

Metabolism of Indomethacin
O H3CO N O
O H3CO N O

O H3CO N H
HO

OH CH3

OH CH3
O OH CH3 N O

O HO OH CH3 N H

Cl

OGL U CH3

Cl

NH2 HO

Cl

N H

Serotonin (5HT)

Sulindac
O

INDENE
F

OH CH3

LIPOPHILIC

BENZYLIDENE SULFINYL GROUP SOLUBILITY

H3C S O

Metabolism of Sulindac
O OH F CH3
O OH

reduction

C H3

H3C S

H3C S
ACTIVE SULFIDE METABOLITE

Tolmetin (Sodium)
O O-Na+ N C H3

PYROLE RING

H3C

Metabolism of Tolmetin
O O-Na+ N CH3
N O OH CH3

O OGL U N CH3

O
H3C
HOOC

H3C

Glucuronide conjugation

Diclofenac (Sodium)
O-Na+ O Cl NH Cl

Nabumetone
NAPHTHALENE
CH3

O CH3
H3CO OH

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 OH C H3 R H R H O S CH3
R

CoA

S CH3

CoA

R-ENANTIOMER
O OH CH3 R H
-

S CH3

CoA

S-ENANTIOMER

IBUPROFEN
CH3 O OH

FLURBIPROFEN
CH3 F OH O

H3C

CH3

ISOBUTYL GROUP

CARPROFEN
CH3 O OH Cl NH

NAPROXEN
C H3 O OH

H3CO

CARBAZOLE

NAPHTHALENE

FENOPROFEN
C H3 O OH O

KETOPROFEN
CH3 O OH

KETONE

PHENOLIC GROUP

OXAPROZIN
O OH

1.1.3 N-Arylanthranilic Acids (Fenamic Acids)

Salicylic acid
COOH

Anthranilic acid
COOH

OH

NHR

Bioisosteric group -OH

Turunan Anthranilic acid merupakan modifikasi salicylic acid dengan bioisosteric replacement

Anthranilic Acid (Fenamic Acid)

O OH

O OH

Anthranilic acid ring

NH C H3

NH Cl Cl

C H3

N-aryl ring
C H3

Mefenamic Acid

Meclofenamate (Sodium)

SAR OXICAM
Enolic group; pKa ~ 4-6

R : aryl atau heteroaryl sybstituent

N H R

OH
6 5 7 8 4 3

S O

1 2

R1

R1CH3 untuk optimum activity

4-hydroxy-1,2-benxothiazine carboxamides

2-pyridyl group
OH O N H S O N O CH3 N

2-(5-methtyl)thiazolyl group
OH O N H S O N O C H3 S N C H3

Piroxicam

Primary carboxamide

Meloxicam

Primary carboxamide

Stabilization of Enolate Anion

OH HN O S O N O CH3
S O N O

N O

+
CH3

H+

N O
-

N H

HN O-

S O

N O

CH3

S O

N O

CH3

Piroxicam
OH O N H S O N O C H3 N

Meloxicam
OH O N H S O N O C H3 S N C H3

selective cox-2 inhibitor (by FDA approving)

Selective COX-2 Inhibitors

O H2N S N CF3 O

O H3C
N

O O

H3C

Celecoxib

Rofecoxib

O H2 N

O S CH3 O N

O N H

O S CH3 O N

Valdecoxib
O O N Na+ O N O S

Parecoxib (IM) (pro-drug of Valdecoxib)

CH3

Parecoxib Sodium (IV)

COX-1 and COX-2

Flurbiprofen; Non-Selective COX inhibitors

CH3 F OH O

Interaksi dengan COX-1 & COX-2 : Non-selective COX inhibitor

Celecoxib;Selective COX-2 inhibitors

O H2N S N CF3 O

H3C

Interaksi dengan COX-1 & COX-2 : Selective COX-2 inhibitor

antipyretic analgesics
O HN CH3
HN O CH3

O HN CH3

OH

OCH2CH3

Acetaminophenol

Phenacetin

Acetanilide

Metabolism and Toxicity

O HN C H3
HN O C H3

O HN CH3
NH2

MAJOR MINOR
NH2

MAJOR
OH

MINOR
O
O

METHEMOGLOBINEMIA METHEMOGLOBINEMIA HEMOLYTIC ANEMIA HEMOLYTIC ANEMIA

Metabolism and Toxicity

O HN C H3

O HO N CH3

O N CH3

-H2O

MINOR
O

N-ACETYLIMIDOQUINONE TOXIC METABOLITE

OH

OH

GSH
MAJOR
SULFATE OR GLUCURONIDE CONJUGATION
O HN CH3 O S OH OH NHCOCH3

HEPATIC OR RENAL PROTEIN

O HN C H3

O HN C H3

HEPATIC NECROSIS AND RENAL FAILURE

SG OH
NU OH

Excreted form

Metabolic Intoxicification
O HS HN O N H COOH COOH NH2

O HN CH3 O S OH OH NHCOCH3

GLUTATHIONE
O HS HN O OH

DETOXIFIES URINARY METABOLITE

N-ACETYLCYSTEINE

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

Preferential COX 2 inhibitors

Competitive

Aspirin

Nimesulide Meloxicam Nabumetone

Phenylbutazone Ibuprofen Naproxen Diclofenac Piroxicam Ketorolac

Selective COX -2 inhibitors

Analgesic with Antipyretic without anti inflammatory action

Paracetamol Metamizol Nefopam

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 COX1 / COX2 Aktivitas COX-1 : kemampuan untuk menghambat produksi TXB 2 dari platelets Aktivitas COX2 : 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?