1 / 72

Aspek Farmakokimia Obat Anti inflamasi Non Steroid

Aspek Farmakokimia Obat Anti inflamasi Non Steroid . Kuliah Farmakokimia FSTOA semester 6 Fak. Farmasi USB. Stru ktur enzim COX. Keduanya merupakan dimer yang terikat pada membran mikrosomal 4 domain Domain Dimerization Domain yang terikat Membran

abra
Télécharger la présentation

Aspek Farmakokimia Obat Anti inflamasi Non Steroid

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

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

  2. 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

  3. Interaksi asam arakhidonat – cox binding site

  4. A. Physiological stimulus B. Inflammatory stimulus (tissue injury, chronic arthritis) macrophages/other cells clotting, parturition, gastrointestinal and renal protection COX-2 induced by cytokines (e.g., TNF) COX-1 constitutive Proteases Prostaglandins especially PGE2 Other inflammatory mediators (histamine, etc) Prostacyclin endothelium-anticlotting stomach mucosa:  H+,  HCO3-,  mucus PGE2 Kidney: arteriolar dilation; Na+/H2O excretion TXA2 platelet aggregation PGF2 parturition Inflammation, redness, swelling, pain Figure 8. Actions of two known isoforms of cyclooxygenase (COX).

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

  6. 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

  7. General Structure of NSAIDs • Acidic functional group –COOH; • Membentuk ionic bond dengan arginine residue (120) dari COX • Aromatic ring / heteroaromatic ring (Acidicfunctional group); • hydrophobic interaction (vander waal force )dengan flat area enzim COX • lipophilic part/ alkyl chain pada aromatic ring • hydrophobic interaction melalui vander waal force

  8. NH3+ Interaksi Indomethacin - COX CARBOXYL OR ACIDIC GROUP CATIONIC SITE (ARG 120) ARYL OR HETERORYL GROUP FLAT AREA ARYL OR ALKYL GROUP LYPOPHILIC GROUP INDOMETHACIN ARACHIDONIC ACID

  9. 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)

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

  11. 1.1.1 Salicylic acid

  12. Salicylate Salts

  13. Aspirin or Acetylsalicylic Acid Tambahan acyl group pada molekul salicylic acid

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

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

  16. Salicylamide

  17. Salsalate • Dimer Salicylic acid • Dihidrolisis menjadi 2 molekul salicylate • Efek samping GI bleeding

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

  19. 1.1.2 Arylalkanoic Acids 1.1.2.1 Aryl- and Heteroarylacetic Acids 1.1.2.2 Aryl and Heteroarylpropionic Acids (“-profen”)

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

  21. 1.1.2.1 Aryl- and Heteroarylacetic Acids • Indomethacin • Sulindac • Tolmetin (Sodium) • Diclofenac(Sodium) • Etodolac • Nabumetone

  22. Indomethacin Indole ring P-Chlorobenzoyl

  23. Metabolism of Indomethacin Serotonin (5HT)

  24. Sulindac INDENE LIPOPHILIC BENZYLIDENE SULFINYL GROUP  SOLUBILITY

  25. Metabolism of Sulindac reduction ACTIVE SULFIDE METABOLITE

  26. Tolmetin (Sodium) PYROLE RING

  27. Metabolism of Tolmetin Glucuronide conjugation

  28. Diclofenac (Sodium)

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

  30. 1.1.2.2 Aryl- and Heteroarylpropionic Acids • Ibuprofen • Fenoprofen (Calcium) • Ketoprofen • Naproxen • Flurbiprofen • Ketorolac (Tromethamine) • Oxaprozin

  31. Isomerization R-ENANTIOMER S-ENANTIOMER

  32. IBUPROFEN • FLURBIPROFEN ISOBUTYL GROUP • NAPROXEN • CARPROFEN CARBAZOLE NAPHTHALENE

  33. FENOPROFEN • KETOPROFEN KETONE PHENOLIC GROUP • OXAPROZIN

  34. 1.1.3 N-Arylanthranilic Acids (Fenamic Acids) Salicylic acid Anthranilic acid Bioisosteric group ของ -OH • Turunan Anthranilic acid merupakan modifikasi salicylic acid dengan bioisosteric replacement

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

  36. SAR OXICAM Enolic group; pKa ~ 4-6 R : aryl atau heteroaryl sybstituent R1–CH3 untuk optimum activity 4-hydroxy-1,2-benxothiazine carboxamides

  37. 2-pyridyl group 2-(5-methtyl)thiazolyl group Primary carboxamide Primary carboxamide Meloxicam Piroxicam

  38. Stabilization of Enolate Anion + H+

  39. Piroxicam

  40. Meloxicam selective cox-2 inhibitor (by FDA approving)

  41. Selective COX-2 Inhibitors Celecoxib Rofecoxib

  42. Valdecoxib Parecoxib (IM) (pro-drug of Valdecoxib) Parecoxib Sodium (IV)

More Related