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 Dimerization Domain yang terikat Membran Domain katalitik– beda pada struktur Domain peptida Terminal– beda panjang

Interaksi asam arakhidonat – cox binding site

Inducible (by cytokines) Unchanged by glucocorticoids 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

Inflammatory stimulus 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 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 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 CATIONIC SITE (ARG 120) NH3+ ARYL OR HETERORYL GROUP FLAT AREA ARYL OR ALKYL GROUP LYPOPHILIC GROUP 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 Drugs (NSAIDs) UDP-Glucuronosyl Transferase (UGT) + UDP Acyl-glucuronide metabolite

1.1.1 Salicylic acid

Salicylate Salts

Aspirin or Acetylsalicylic Acid Tambahan acyl group pada molekul salicylic acid

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

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

Salicylamide

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

Diflunisal 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 1-C ATOM ACIDITY , ACTIVITY  ALKYL GROUP 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 Indole ring P-Chlorobenzoyl

Metabolism of Indomethacin Serotonin (5HT)

Sulindac INDENE LIPOPHILIC BENZYLIDENE SULFINYL GROUP  SOLUBILITY

Metabolism of Sulindac reduction ACTIVE SULFIDE METABOLITE

Tolmetin (Sodium) PYROLE RING

Metabolism of Tolmetin Glucuronide conjugation

Diclofenac (Sodium)

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

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

Isomerization R-ENANTIOMER S-ENANTIOMER

IBUPROFEN FLURBIPROFEN NAPROXEN CARPROFEN CARBAZOLE NAPHTHALENE ISOBUTYL GROUP NAPROXEN CARPROFEN CARBAZOLE NAPHTHALENE

FENOPROFEN KETOPROFEN KETONE PHENOLIC GROUP OXAPROZIN

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

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

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

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

Stabilization of Enolate Anion + H+

Piroxicam

Meloxicam selective cox-2 inhibitor (by FDA approving)

Selective COX-2 Inhibitors Celecoxib Rofecoxib

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

COX-1 and COX-2

Flurbiprofen; Non-Selective COX inhibitors

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

Celecoxib;Selective COX-2 inhibitors

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

antipyretic analgesics Acetaminophenol Phenacetin Acetanilide

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

Metabolism and Toxicity -H2O MINOR N-ACETYLIMIDOQUINONE TOXIC METABOLITE GSH HEPATIC OR RENAL PROTEIN MAJOR SULFATE OR GLUCURONIDE CONJUGATION HEPATIC NECROSIS AND RENAL FAILURE Excreted form

Metabolic Intoxicification GLUTATHIONE DETOXIFIES URINARY METABOLITE N-ACETYLCYSTEINE

Boundary surface defining the cyclooxygenase 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 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 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?