aspek-fisikokimia-nsaid.pptx

8/12/2019 aspek-fisikokimia-nsaid.pptx

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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


1.1.2.2 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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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?

aspek-fisikokimia-nsaid.pptx

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