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

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

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?