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Aspek Farmakokimia Obat Antiinflamasi NonSteroid Kuliah Farmakokimia FSTOA semester 6 Fak. Farmasi USB.

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Presentasi berjudul: "Aspek Farmakokimia Obat Antiinflamasi NonSteroid Kuliah Farmakokimia FSTOA semester 6 Fak. Farmasi USB."— Transcript presentasi:

1 Aspek Farmakokimia Obat Antiinflamasi NonSteroid Kuliah Farmakokimia FSTOA semester 6 Fak. Farmasi USB

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3 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

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5 Interaksi asam arakhidonat – cox binding site

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10 COX-1 enzymeCOX-2 enzyme Expression ConstitutionalInducible (by cytokines) Unchanged by glucocorticoids Blocked by glucocorticoids Expressed at baseline (in stomach, kidneys, platelets, intestines) Expressed during inflammation (in macrophages, synoviocytes) Kinetics Instantaneous inhibitionTime-dependent inhibition Inhibition via hydrogen bonding ?Covalent bonding

11 Physiological stimulus clotting, parturition, gastrointestinal and renal protection COX-1 constitutive TXA 2 platelet aggregation Prostacyclin endothelium- anticlotting stomach mucosa:  H +,  HCO 3 -,  mucus PGE 2 Kidney: arteriolar dilation; Na + /H 2 O excretion A. PGF 2  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 PGE 2

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13 Classification 1. Non-steroidal Anti-inflammatory Agents 1.1 Non-selective COX-1 Inhibitors 1.2 Selective COX-2 Inhibitors 2. Antipyretic Analgesics

14 1. Anti-inflammatory Agents 1.1 Non-selective Cycloxygenase (COX) -1 Inhibitors Salicylates Arylalkanoic Acids Aryl- and Heteroarylacetic Acids Aryl- and Heteroarylpropionic Acids N-Arylanthranilic Acids (Fenamic Acids) Oxicams Phenylpyrazolones 1.2 Selective COX-2 Inhibitors

15 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

16 NH 3 + 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

17 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)

18 Glucuronide Conjugation UDP-Glucuronosyl Transferase (UGT) Acyl-glucuronide metabolite Drugs (NSAIDs) + UDP

19 1.1.1 Salicylic acid

20 Salicylate Salts

21 Aspirin or Acetylsalicylic Acid Tambahan acyl group pada molekul salicylic acid

22 Mechanism of action of Aspirin Serine residue acetylation Irreverseble COX inhibition COX-1 (Ser 530), COX-2 (Ser 516) or Circulating protein

23 Glycine Conjugation Glucuronide Conjugation GENTISIC ACID SALICYLURIC ACID Aromatic hydroxylation Plasma esterase Metabolism of Aspirin and Salicylates

24 Salicylamide

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

26 Diflunisal phenyl group (or aromatic ring) pada molekul salicylic acid Efek samping : GI disturbance, dermatologic reaction, CNS side effect (dizziness and headache)

27 1.1.2 Arylalkanoic Acids Aryl- and Heteroarylacetic Acids Aryl and Heteroarylpropionic Acids (“-profen”)

28 SAR CARBOXYL GROUP ALKYL GROUP ARYL OR HETERO ARYL GROUP ARYL OR ALKYL GROUP ACIDITY , ACTIVITY  1-C ATOM

29 Aryl- and Heteroarylacetic Acids Indomethacin Sulindac Tolmetin (Sodium) Diclofenac (Sodium) Etodolac Nabumetone

30 Indomethacin Indole ring P-Chlorobenzoyl

31 Metabolism of Indomethacin Serotonin (5HT)

32 Sulindac INDENE BENZYLIDENE SULFINYL GROUP  SOLUBILITY LIPOPHILIC

33 Metabolism of Sulindac ACTIVE SULFIDE METABOLITE reduction

34 Tolmetin (Sodium) PYROLE RING

35 Metabolism of Tolmetin Glucuronide conjugation

36 Diclofenac (Sodium)

37 Nabumetone NAPHTHALENE 6-MNA (38%) (active metabolite) Nabumetone (pro-drug) oxidation naproxen

38 Aryl- and Heteroarylpropionic Acids Ibuprofen Fenoprofen (Calcium) Ketoprofen Naproxen Flurbiprofen Ketorolac (Tromethamine) Oxaprozin

39 Isomerization R-ENANTIOMER S-ENANTIOMER

40 IBUPROFEN ISOBUTYL GROUP FLURBIPROFEN CARBAZOLE CARPROFEN NAPHTHALENE NAPROXEN

41 FENOPROFEN PHENOLIC GROUP KETONE KETOPROFEN OXAPROZIN

42 Bioisosteric group ของ -OH Turunan Anthranilic acid merupakan modifikasi salicylic acid dengan bioisosteric replacement Salicylic acidAnthranilic acid N-Arylanthranilic Acids (Fenamic Acids)

43 Mefenamic Acid Meclofenamate (Sodium) Anthranilic Acid (Fenamic Acid) N-aryl ring Anthranilic acid ring

44 SAR OXICAM R 1 –CH3 untuk optimum activity R : aryl atau heteroaryl sybstituent Enolic group; pKa ~ hydroxy-1,2-benxothiazine carboxamides

45 Piroxicam Meloxicam Primary carboxamide Primary carboxamide 2-pyridyl group 2-(5-methtyl)thiazolyl group

46 + H + Stabilization of Enolate Anion

47 Piroxicam

48 Meloxicam selective cox-2 inhibitor (by FDA approving)

49 CelecoxibRofecoxib Selective COX-2 Inhibitors

50 Valdecoxib Parecoxib (IM) (pro-drug of Valdecoxib) Parecoxib Sodium (IV)

51 COX-1 and COX-2

52 Flurbiprofen; Non-Selective COX inhibitors

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

54 Celecoxib;Selective COX-2 inhibitors

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

56 antipyretic analgesics AcetaminophenolPhenacetinAcetanilide

57 Metabolism and Toxicity METHEMOGLOBINEMIA HEMOLYTIC ANEMIA METHEMOGLOBINEMIA HEMOLYTIC ANEMIA MAJOR MINOR

58 Metabolism and Toxicity N-ACETYLIMIDOQUINONE TOXIC METABOLITE GSH -H 2 O HEPATIC OR RENAL PROTEIN MAJOR MINOR SULFATE OR GLUCURONIDE CONJUGATION HEPATIC NECROSIS AND RENAL FAILURE Excreted form

59 Metabolic Intoxicification GLUTATHIONE N-ACETYLCYSTEINE DETOXIFIES URINARY METABOLITE

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62 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.

63 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.

64 Structure of rofecoxib (in magenta) and ketoprofen (in yellow) docked into the binding site of COX-2, whose inner surface is shown in blue.

65 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

66 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

67 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.

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69 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

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71 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

72 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?


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