Nsaids Acu Lec 2025 PDF

Analgesics: Non-Steroidal Anti-inflammatory Drugs (NSAIDs) & Opioids. Dr. Rawda Mahmoud Lecturer of Pharmaceutical Chemistry Faculty of Pharmacy, Cairo University Pain ❑ An unpleasant warning of tissue or organ due to injury or damage. Pain Acute Chronic...

Analgesics: Non-Steroidal Anti-inflammatory Drugs (NSAIDs) & Opioids. Dr. Rawda Mahmoud Lecturer of Pharmaceutical Chemistry Faculty of Pharmacy, Cairo University Pain ❑ An unpleasant warning of tissue or organ due to injury or damage. Pain Acute Chronic Pain Mild Moderate Severe 2 Types of Pain Nociceptive Due to injury Inflammatory Due to infection or inflammation Neuropathic Due to nerve injury 3 Types of Analgesics (Pain Killers) 01 NSAIDs & acetaminophen (Non-narcotics). Mild to moderate pain. Reduce fever. 02 Act mainly peripherally. No addiction. Opioid Analgesics (Narcotics). Acute pain. Moderate to severe chronic pain. Act centrally. Addiction. 4 Inflammation ❑ Inflammation is a part of the body's natural defense system. ❑ It is a process by which the body’s & natural chemicals protect us from physical damage & infections. ❑ This protective response involves immune cells, blood vessels, & molecular mediators to : Eliminate the cause of cell injury. Destroy harmful agents. Remove damaged tissue. Generate new tissue. 5 Inflammation Signs 6  Inflammatory “ Mediators Eicosanoids Others Prostaglandins Cytokines (ILs, TNF, (Prostanoids), Prostacyclin, interferons & chemokines), Thromboxane, Bradykinin, Histamine, Leukotrienes. ……..etc 7 Eicosanoids Inflammatory (Prostaglandins) stimuli Unsaturated fatty acids: 20 Carbons with cyclic ring Physiological Role Inflammatory Role 8 Eicosanoids Roles Physiological Role 1) PGE2 & PGI2 stimulate biosynthesis & release of HCO3- & alkaline mucus gel by increasing mucosal blood flow (Mucus-HCO3- barrier) restoring the integrity of the stomach lining (Cytoprotective effect). 9 Eicosanoids Roles Physiological Role 2) PGE2 & PGI2 maintain normal renal blood flow → maintain good renal functions. 3) Maintaining normal blood flow & vascular homoeostasis. I. Prostaglandins (PGE2, PGD2 and PGF2α): maintain normal blood flow in most tissues. II. Prostacyclin (PGI2): is produced mainly in blood vessels endothelial cells causing vasodilatation & inhibit platelet aggregation. III. ThromboxaneA2 (TXA2) : is produced mainly in platelets causing vasoconstriction & induce platelet aggregation. 10 Eicosanoids Roles Inflammatory Role 1) Mediate inflammation & increase the blood flow to the inflamed site (Heat, redness & swelling). 2) Induce fever. 3) Induce pain. 4) Wound healing. 11 Sites of Action of Anti-inflammatory Drugs 12 Sites of Action of Anti-inflammatory Drugs Corticosteroids LOX- Inhibitors NSAIDs 13  ❑ An Oxidoreductase enzyme. ❑ 5-LOX is a non-heme, iron-containing LOX enzyme. ❑ It transforms essential fatty acids substrates into leukotrienes as well as a (Lipoxygenase) wide range of other biologically active products. 14 Zileuton * ❑ An orally active specific inhibitor of 5-LOX → Inhibition of leukotrienes formation. ❑ R & S enantiomers equally inhibit 5-LOX, (marketed as the racemic mixture). Glucuronidation ❑ Used for the prophylaxis & chronic treatment N-dehydroxylation of asthma. →(NH) 15  Constitutive (Present in all tissues). COX Physiological role (Housekeeping functions). Inducible (except in kidneys & CVS). Cyclooxygenase Inflammatory role. (PG Synthase) Cerebral cortex & Heart. 16  ❑ An Oxidoreductase enzyme. COX ❑ COX-1 & COX-2 are heme-containing, membrane-bound proteins that share a Cyclooxygenase high degree of sequence identity with a (PG Synthase) very similar active site topography. 17  COX-1 & COX-2 Active Sites ❑ The binding site of COX-2 is approximately 20 % larger than the COX-1 due to the replacement of Ile-523 in COX-1 with a smaller Val- 523 in COX-2. ❑ The COX-2 isozyme has an additional hydrophilic side pocket accessible for drug binding as a result of further substitutions of Ile- 434 & His-513 in COX-1 with a smaller Val-434 & a more Side pocket basic Arg-513. 18 Mechanism of Action of NSAIDs: NSAIDs occupy the arachidonic acid site → sterically prevent its interaction with COX-1 & COX-2 enzymes → prevent the ecosanoids synthesis. 19 Side Effects of Non-selective NSAIDs: 1) GIT problems (e.g., abdominal pain, heartburn & back diffusion of hydrogen ions leading to wall perforation, gastric erosion, peptic ulcer formation, gastritis & bleeding) treated with misoprostol (Cytotec®) PG prodrug analogue. Misoprostol 20 Side Effects of Non-selective NSAIDs: 2) Renal disorders (e.g., renal ischemia, acute renal failure, tubular necrosis & analgesic nephropathy) leading to Na+ & water retention & hypertension. So, it is contraindicated in patients with: ❑ Renal insufficiency. ❑ Congestive heart failure. 21 Side Effects of Non-selective NSAIDs: 3) Tinnitus & headache (affect inner ear functions “Aspirin ototoxicity”). 4) Platelet dysfunction (TXA2 & PGI2 inhibition). 5) Bronchospasm (shift toward leukotriene synthesis pathway leading to overproduction of leukotrienes to causes severe asthma) (“Aspirin-induced asthma”). 22 Side Effects of Non-selective NSAIDs: Side effects Therapeutic effects Inhibition of COX-2 isoenzyme at Inhibition of COX-1 isoenzyme. inflammation site. GIT problems. Anti-inflammatory. Renal problems. Antipyretic. CVS problems. Analgesic. ❑ The NSAID benefit / risk profile depends on its COX selectivity. ❑ NSAIDs showing selective COX-2 inhibitory activity should be free from these side effects. 23 Non-selective COX Inhibitors 24 Non-selective NSAIDs possess the following common structural features: General SAR 14-Δ Non-coplanar 11-Δ Alkyl chain or extra aromatic 5-Δ 8-Δ ring Aromatic or heteroaromatic ring Arachidonic acid Acidic center (Native ligand) 25 Classification of Non-selective NSAIDs: ❑ Salicylic acid derivatives (e.g., aspirin & diflunisal). ❑ Aryl & heteroaryl acetic acid derivatives (e.g., indomethacin & diclofenac). ❑ Arylpropionic acid derivatives (Profens, e.g., ibuprofen & ketoprofen). ❑ N-aryl anthranilic acid derivatives (Fenamates, e.g., mefenamic acid & meclofenamic acid). ❑ 4-Hydroxy-1,2-benzothiazine carboxamides (Oxicams, e.g., meloxicam & piroxicam). 26 1) Salicylic acid derivatives Salicylic acid Salicin from Willow Bark Analgesic Antipyretic Anti-inflammatory ↑uric acid excretion (antigout) 27 1) Salicylic acid derivatives Aspirin Diflunisal The most potent derivative. Long duration of action. 28 Structure-Activity Relationship (SAR) of Salicylic acid Derivatives 1ry insult COOH is EFA & causes side effects (1ry insult). Its conversion to amide maintains the analgesic activity but Aspirin Salicylate eliminates the anti- inflammatory activity. Substitution on the phenyl ring with halogen →  potency & toxicity. Substitution on the phenyl ring at position 5 with difluorophenyl →  the OH in ortho- position, if meta- or para- potency & duration (Diflunisal). abolish the activity. Substitution on COOH or OH may affect Its removal gives weak activity (benzoic potency & toxicity. acid). 29 Binding Interactions of Aspirin Irreversible acetylation of Ser-530 at COX-1 totally blocks the accessibility of substrate AA from entering the active site. Aspirin M.O.A. It’s a preferential block COX-1 > Cox-2 (10-100-fold) → it can selectively & irreversibly inhibit platelet TXA2 production for 8 to 10 days (until new platelets are formed) at low dose (75-100mg). 30 Aspirin Synthesis Acetylation with acetic anhydride Salicylic acid Aspirin Aspirin Side effects The risk of Reye's syndrome (severe illness characterized by acute encephalopathy & fatty liver) when children & teenagers are given aspirin. 31 Break 32 2) Aryl & heteroaryl acetic acid derivatives Indomethacin Sulindac Diclofenac Fast metabolism & short half life (1 hr) Tolmetin Nabumetone (Prodrug) 33  Indomethacin Sulindac Active Inactive Reduction Oxidation SCH3 SO2CH3 ❑ Bio-isostere of indomethacin. ❑ One of the most potent NSAIDs. ❑ Prodrug with sulfoxide moiety that ❑ High affinity to COX-1 (10-60 fold). undergoes in vivo reduction by the hepatic ❑ High GIT side effects. enzymes into methyl sulfide that exhibits ❑ Highly potent anti-inflammatory + analgesic + potent & non-selective COX inhibition. antipyretic more than aspirin or ❑ It doesn't inhibit COX enzyme in gastric acetaminophen. mucosa, thus producing minimum 2ry insult. 34 SAR of Indomethacin Substitution at α position of acetic COOH is EFA. Amide is inactive. N: not EFA. acid gives active analogues (propionic acid derivatives=Profens). N-p-chlorobenzoyl should be: Cis to the methoxyphenyl of Substitution at the 5- the indol ring. (Trans causes position with OCH3, F clashes with the binding site). (sulindac), N(CH3)2, CH3 Noncoplanar with the indol & acetyl groups are ring due to the steric more active than hinderance produced by CH3 unsubstituted indol ring. at position 2 & H at position 7. N-Benzoyl group : substituted in the para-position with F, Cl, CF3 or SCH3 are the most active groups. 35 Indomethacin Metabolism Glucuronic acid conjugation Inactive metabolites 36  Relative to Relative to Diclofenac Activity Indomethacin Aspirin Anti- 2-folds 450-folds inflammatory Analgesic 6-folds 40-folds Antipyretic 2-folds 350-folds ❑ K+ salt is fast acting → treatment of acute pain & primary dysmenorrhea, while Na+ salt is available as delayed release tablet used for short- & long- term treatment of rheumatoid arthritis & osteoarthritis. ❑ Most potent NSAID, Anti-inflammatory, Analgesic & Antipyretic. 37 Diclofenac Mechanism of Action It has 3 possible M.O.A. ❑ Inhibit COX enzymes. ❑ Inhibit 5-LOX pathway. ❑ Inhibit Phospholipase A2 (inhibit arachidonic acid release & inhibit its reuptake). 38 Diclofenac Synthesis 39 Nabumetone Metabolism Prodrug 6-MNA Inactive Active 6-methoxy-2-naphthylacetic acid As non-acidic prodrug: ❑ It doesn’t produce significant 1ry insult to the GI mucosa (No free COOH). ❑ It doesn’t inhibit COX in gastric mucosa, thus producing minimum 2ry insult. 40 3) Aryl propionic acid derivatives (Profens) Ibuprofen Ketoprofen Flurbiprofen S-Naproxen 41 SAR of Aryl propionic Acid Derivatives α- CH3 of acetic acid → * * more potent derivatives than acetic acid analogues Ibuprofen (due to  binding with COX Ketoprofen enzymes). COOH is EFA. * * S- is the active enantiomer. Flurbiprofen S- Naproxen ❑ Marketed as racemic mixture (except naproxen), R- (inactive enantiomer) is epimerized in vivo via 2-arylpropionyl Co enzyme A epimerase to its active S- enantiomer. 42 Ibuprofen Metabolism ꞷ Major ꞷ-1 Minor ꞷ-2 Minor 43 4) N-aryl anthranilic acid derivatives (Fenamates) ❑ Application of classical medicinal chemistry bio-isosteric drug design concept (Nitrogen bio-isostere of salicylic acid). Salicylic acid Anthranilic acid Fenamic acid 44 4) N-aryl anthranilic acid derivatives (Fenamates) Mefenamic acid Meclofenamic acid Flufenamic acid 45 SAR of N-aryl anthranilic acid derivatives COOH is EFA. Meta- and para- amino benzoic acids are inactive. Mefenamic acid Flufenamic acid Meclofenamic acid 46 Meclofenamic acid The most potent N- aryl anthranilic acid derivatives (25 times greater anti-inflammatory activity than mefenamic acid)?? ❑ It has the most hydrophobic N-aryl ring. ❑ The two Cl ortho-substituents forcing the N-aryl out of the plane of the anthranilic acid (non-coplanar) enhancing the binding at the binding site. ❑ Active metabolite. Metabolism Active metabolite 47 5) 4-Hydroxy-1,2-benzothiazine carboxamides (Oxicams) Meloxicam Piroxicam Lower GIT High GIT Side effects Side effects 10-fold more selective to COX-2 due to 600-fold more selective to COX-1. steric restrictions in COX-1. 48 Tautomerism Non- carboxylic acid in nature. Keto-enol tautomerism which stabilize the enolate anion→ acidic in nature (pKa 4-6). 49 Oxicams Metabolism Piroxicam 5’-Hydroxypiroxicam Meloxicam 5’-Hydroxymethylmeloxicam 5’-Carboxymeloxicam ❑ Piroxicam has a plasma half-life of 50 hrs, thus requiring a dose of 20 to 30 mg once daily. ❑ Meloxicam has a plasma half-life of 20 hrs , thus requiring a dose of 15 mg once daily. 50 Selective COX-2 Inhibitors 51 Side Effects of Non-selective NSAIDs: 1) GIT problems (peptic ulcer formation & bleeding). 2) Renal disorders (acute renal failure & hypertension). 3) Tinnitus & headache. 4) Platelet dysfunction. 5) Bronchospasm. ❑ The NSAID benefit / risk profile depends on its COX selectivity. ❑ NSAIDs showing selective COX-2 inhibitory activity should be free from Side pocket these side effects. 52 Selective COX-2 inhibitors possess the 14-Δ following common structural features: 11- Δ 8-Δ 5-Δ Alkyl chain or extra aromatic ring Arachidonic acid (Native ligand) Aromatic or heteroaromatic Side pocket ring 53 Selective COX-2 Inhibitors (Coxibs): Celecoxib Etoricoxib Rofecoxib Lumiracoxib 54 M.O.A. of Selective COX-2 Inhibitors: 55 Problems of Selective COX-2 Inhibitors Thrombosis Platelets Endothelial cells Antithrombosis Imbalance Increased risk of CVS side effects as stroke & myocardial infarction. Consequently; Rofecoxib Valdecoxib 56 Future Therapeutic Applications for COX-2 Inhibitors COX-2 expression is upregulated in colon carcinoma cells (selective COX-2 inhibitors reduce the risk of colon cancer). Cancer They also are used for prevention & treatment of prostate & breast cancer. Patients on selective COX-2 inhibitors show lower incidence & decreased Alzheimer rate of AD progression. disease (AD) COX-2 is upregulated in the brain following seizure’s induction which cause increase in seizure’s severity & upregulation of P-glycoprotein at the BBB causing reduced delivery of AEDs to the brain target site. Epilepsy Such studies proposed that inhibition of COX-2 enzyme → reduce seizure’s severity & pharmacoresistance to AEDs. 57  Thanks! You can find me at: [email protected] 58