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Nsaids
- 1. NSAIDS (NON STEROIDALANTI- INFLAMMATORY DRUGS) BY SHOUVIK KUMAR NANDY
- 2. INFLAMMATION • Inflammation (Latin,inflamatio, to set on fire) is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. • It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue.
- 3. • Burns • Chemicalirritants • Frostbite • Toxins • Infection by pathogens • Physical injury • Immune reactions due to hypersensitivity • Radiation • Foreign bodies CAUSES OF INFLAMMATION
- 4. The classic signsand symptoms of acute inflammation • Redness • Swelling • Heat • Pain • Loss of function
- 5. Process of Inflammation •Inflammation can be classified as either acute or chronic. • The initial phase of cell injury is known as the acute phase and is mediated by several autacoids like : – Histamine – 5-HT – Bradykinin – Prostaglandins • When a tissue is injured, from any cause, prostaglandin synthesis in that tissue increases.
- 6. Synthesis of Prostaglandins Cyclo-oxygenase(COX) pathway Membrane Phospholipids Phospholipase A2 Arachidonic Acid Prostaglandins Thromboxanes Prostacyclin COX
- 7. • Among themost widely used all therapeutic agents world wide • They are frequently prescribed for ‘rheumatic’ musculo-skeletal complaints and are often taken without prescription for minor aches and pains • More than 50 different NSAIDs on the market and none of these is ideal in controlling or modifying the signs and symptoms of inflammation NSAIDs
- 8. • Analgesic • Antipyretic •Anti-inflammatory actions • Compared to Morphine: – Weaker analgesics – Do not depress CNS – Do not produce physical dependence – No abuse liability NSAIDs Continued..
- 9. • They arealso called: – Non norcotic – Non opioid – Aspirin like analgesics • They act primarily on peripheral pain mechanisms but also in CNS to raise pain threshold • These drugs are chemically diverse, but most are organic acids. NSAIDs Continued..
- 10. • All areanalgesic, antipyretic, anti-inflammatory (expect paracetamol). • Do not produce CNS depression. • Dose dependent uricosuric action. • Act by inhibition of PGs except Nimesulide, Nefopam. Common characteristics of all NSAIDs Continued..
- 11. Sl. No. ClassExample Structure 1. Salicylate derivative Aspirin 2. 3,5-Pyrazolinediones derivatives Phenylbutazone 3. Propionic acid derivative Naproxen 4. Anthranilic derivative Mephenamic acid 5. Aryl-acetic acid derivative Diclofenac 6. Oxicum derivative Piroxicam 7. Pyrrolo-Pyrrole derivative Ketorolac 8. Indole derivative Indomethacin Structure-based Classification Non selective COX inhibitors:
- 12. Preferential COX-2 inhibitors: Nimesulide SelectiveCOX-2 inhibitors Celecoxib Structure-based Classification Continued..
- 13. Analgesic –Antipyretics withpoor Anti inflammatory action Para amino phenol derivatives Paracetamol (Acetaminophen) Pyrazolone derivatives Metamizole Benzoxazocine derivative Nefopam Structure-based Classification Continued..
- 14. Mechanism of action •When a tissue is injured, from any cause, prostaglandin synthesis in that tissue increases. • PGs have TWO major actions: • They are mediators of inflammation • They also sensitize pain receptors at the nerve endings, lowering their threshold of response to stimuli and allowing the other mediators of inflammation
- 15. • Naturally, adrug that prevents the synthesis of PGs is likely to be effective in relieving pain due to inflammation of any kind • In 1971 Vane and coworkers made the landmark observation that aspirin and some NSAIDs blocked PG generation. • This is they do by inhibiting cyclo –oxygenase (COX) enzyme in the pathway for PGs synthesis Mechanism of action Continued..
- 16. Membrane Phospholipids Phospholipase A2 ArachidonicAcid Prostaglandins Thromboxanes Prostacyclin COX Synthesis of Prostaglandins Cyclo-oxygenase (COX) pathway NSAIDs
- 17. COX • Exists intwo isoforms: 1. COX-1 (constitutive) 2. COX-2 (inducible) – Oxidative stress – Injury – Ischemia – Neurodegenerative diseases
- 18. Advantageous actions dueto PG synthesis inhibition • Analgesia • Antipyresis • Antiinflammatory • Antithrombotic • Closure of ductus arteriosus
- 19. Some toxicities dueto PG synthesis inhibition • Gastric mucosal damage • Bleeding • Limitation of renal blood flow/Na+ & water retention • Delay/prolongation of labour • Asthma and anaphylactoid reactions in susceptible individuals
- 20. 1. Reducing theacidity of this group maintains the analgesic actions of salicylic acid derivatives but eliminates the anti-inflammatory properties. 2. Substitution on either the carboxyl or phenolic hydroxyl groups meta or para to the carboxyl group abolishes this activity. 3. Substitution of aromatic ring enhances potency and toxicity. 4. Substitution of aromatic ring at the 5-position of salicylic acid increases anti- inflammatory activity. 5. Substitution of halogen on aromatic ring increases the potency and decreases the toxicity. General Structure SAR of Salicylate derivatives DRUG R1 R2 Salicylic acid H H Methyl salicylate CH3 H sodium salicylate Na H Phenyl salicylate C6H5 H COOR1 OR2
- 21.
- 22.
- 23. Synthesis of Salol(Continued)
- 24.
- 25.
- 26. Synthesis of Sodiumsalicylate
- 27.
- 28. 1. 2,4-difluoro aniline, 2.Amyul nitrite, 3. Methyl Phenoate. Synthesis of Diflunisal
- 29.
- 30. 1. The acidicH at 4-position is related to their activity. 2. The dicarbonyl functions at the 3 and 5 positions enhance the acidity of hydrogen atom at the 4-position. 3. Decreasing or eliminating acidity by removing the acidic proton at the 4 position (e.g. 4,4-dialkyl derivatives) abolishes the activity. 4. If acidity is too much, anti-inflammatory and sodium-retaining activities decrease, while other properties such as uricosuric effect increase. 5. A single alkyl group (n-butyl group) at the 4-position enhances anti- inflammatory activity. SAR of 3,5-PYRAZOLINEDIONES Derivatives N N H O O R4 R DRUG R R4 Phenyl butazone H -C4H9 Oxyphenbutazon e OH -C4H9 Sulphinpyrazone H -(CH2)2SOC6H5General Structure
- 31. 6. Introduction ofpolar functions in these alkyl groups gives mixed results. 7. The gama-hydroxy-n-butyl derivative possesses pronounced uricosuric activity but gives fewer anti-inflammatory activity. 8. Substitution of phenylthiol group at the 4-position produces anti-gout drug. (Example: Sulfinpyrazone) 9. The presence of both phenyl groups is essential for both anti-inflammatory analgesic activity. 10. Various substituent's in the para position of one or both aromatic ring do not drastically affect activity. A p-hydroxy group present in oxyphenbutazone, the major metabolite of phenylbutazone, contributes therapeutically useful anti- inflammatory activity. Other derivatives such as methyl, chloro, or nitro groups also possess activity. SAR of 3,5-PYRAZOLINEDIONES Derivatives (Continued)
- 32. Synthesis of Phenylbutazone
- 33. 1. The presenceof a methyl group in the alkaline portion of the propionic acid derivative gives rise to the compound ibuprofen which is much more active or potent and much less toxicity (hepatototoxic) compared to the compound without the alpha-methyl group (ibufenac). Ibufenac 2. The (+) isomer of ibuprofen is much more active compared to (-) isomer. 3. The presence of the phenoxy group at 3rd position give rise to the compound fenoprofen. SAR of Propionic acid Derivatives
- 34. SAR of Propionicacid Derivatives (Continued) 4. The replacement of the oxygen ring with the keto group gives rise to the compound ketoprofen which is comparatively most active. 5. The presence of the methoxy group at 6 position of the naphthalene ring give rise to the compound naproxen which has much greater anti- inflammatory activity compared to ibuprofen. Naproxen 6. The (+) isomer of naproxen is much more active compared to (-) isomer.
- 35.
- 36. Synthesis of Ibufenac Willgerodtoxidation is is an organic reaction converting an aryl alkyl ketone to the corresponding amide and carboxylic acid as side reaction product by reaction with Sulphur, Con. NH4OH and pyridine.
- 37. Synthesis of Naproxen Willgerodtoxidation is is an organic reaction converting an aryl alkyl ketone to the corresponding amide and carboxylic acid as side reaction product by reaction with Sulphur, Con. NH4OH and pyridine.
- 38.
- 39.
- 40. 1. Substitution onthe anthranilic acid ring generally reduces the activity. 2. The NH moiety of anthranilic acid appears to be essential for activity since replacement of NH function with O, S, CH2 functionalities significantly reduced the activity. 3. In the UV erythema assay for anti-inflammatory activity, the order of activity is generally 3’>2’>4’ for mono substitution with the CF3 derivative (Flufenamic acid) particularly potent. General Structure SAR of Anthranilic acid Derivatives COOH NH R1 R2 R3 DRUG R1 R2 R3 Mefinamic acid CH3 CH3 H Flufinamic acid H CF3 H Meclofinamic acid Cl CH3 Cl
- 41. 4. In ratpaw edema assay, with 2’-Cl derivative is more potent than 3’-Cl analogue. 5. In di-sustituted derivatives, where the nature of the two substituents is the same, 2’3’ distribution appears to be more effective. 6. The substituents on the N-aryl ring which force the ring to be non coplanar with anthranilic acid ring should enhance the binding at the site thereby increase the activity. 7. Meclofenamic acid has greater anti-inflammatory activity over flufenamic acid and 25 times more than mefenamic acid. 8. Finally, the position of the acidic function is critical for activity. Anthranilic acid (O) derivatives are active, whereas the m- and p- aminobenzooic acid analogues are not. Replacement of carboxylic acid funcvtions with the isosteric tetrazole has little effect on activity. SAR of Anthranilic acid Derivatives (Continued)
- 42. Synthesis of Flufenamicacid Synthesis of Mefanamic acid Ullman condensation is type of Aromatic amination reaction between aryl halogen acids and aryl amines.
- 43. 1. The p-toluoyland acetic acid function must be coplanar in tolmetin. 2. Introduction of methyl group at 4-position of pyrrole ring produces Zomipirac. is more potent than tolmetin. 3. Propionic acid analogue slightly less potent than tolmetin. SAR of Arylacetic acid Derivatives
- 44. SAR of ArylAlkanoic Acid Derivatives a) All the agents posses a centre of acidity, which can be represented by –COOH, an enol, hydroxamic acid, sulphonamide or tetrazole. b) The centre of acidity is generally located one carbon atom adjacent to a flat surface represented by an aromatic / heteroaromatic ring. c) The distance between these centres is critical because increasing this distance to 2 or 3 carbons generally decreases the activity. d) Susbt. of –CH3 group on the carbon atom separating the aromatic ring tends to increase the anti-inflammatory activity.
- 45. 4. The functionof 2-ortho chloro group is to force anilino-phenyl ring out of the plane of the phenyl acetic portion. Diclofenac Sodium SAR of Arylacetic acid Derivatives (Continued)
- 46.
- 47.
- 48. Synthesis of Diclofenac Wolf-kishnerreduction is a chemical reaction that fully reduces a ketone or aldehyde to an alkane. It involved heating the hydrazine with Na-ethoxide in a sealed vessel at about 180 °C. Diethylene glycol (DEG) is usually used as solvent.
- 49. 1. The replacementof the carboxyl group with any other acidic functionalities lead decreases the activity. 2. Acylation of the indole nitrogen with aliphatic carboxylic acid or aryl alkyl carboxylic acids result in the decrease of activity. 3. Amide analogues are inactive. 4. The N-benzoyl derivatives substituted in the p-position with F, Cl, CF3 groups are the most active. 5. The 5-position of the indole when F, OCH3 groups was more active than the unsubstituted indole analogue. 6. The presence of indole ring nitrogen is not essential for activity because the corresponding 1-benzylidenylindene analogue (Sulindac) was active. SAR of Indole Derivatives
- 50. 7. Alkyl groups,especially methyl group, at 2-position are much more active than aryl-substituted analogues. 8. Substitution of a methyl group at the alpha-position of the acidic acid side chain leads to equiactive analogues. 9. Anti-inflammation activity is displayed only by the (S) (+) enantiomer. SAR of Indole Derivatives (Continued)
- 51.
- 52. Synthesis of Sulindac Reformatskiis an organic reaction, which condenses aldehydes or ketones with α-halo esters using a metallic zinc to form β-hydroxy-esters.
- 53. 1. Optimum activityis observed when methyl substituent present at 2-position. 2. The carboxamide sustituent R is generally an aryl or hetero aryl substituent because alkyl substituents are less active. 3. N-heterocyclic carboxamides (piroxicam) are generally more acidic than the corresponding N-aryl carboxamides. 4. Tenoxicam 4. Interchanging of benzene ring with thiophene (tenoxicam) gives biologically active compounds. 5. For optimum activity 4-hydroxy-1,2-benzothiazine carboxamide ring is required. SAR of Oxicam Derivatives
- 54.
- 55.
- 56. SAR of Pyrollopyrollo Derivatives 1. Ketorolac which lacks this benzylic methyl group is not susceptible to the type of oxidation observed for tolmetin and as a result its half-life is longer (4- 6 hours). 2. This drug is unique in that it is formulate for orally and IM administration. 3. Good oral activity with primarily analgesic activity, but also has antiiflammatory activity and antipyretic actions. Tolmetin
- 57. 1. Esterification ofthe phenolic function with methyl or propyl produces derivatives with greater toxic side effects than ethyl groups. 2. The substituent on the nitrogen atom which reduces basicity also reduces activity except for acetyl which is metabolically labile. 3. Amides derived from aromatic acid. E.g., N-phenyl benzamides-are less active or inactive. SAR of Para aminophenol Derivatives Paracetamol
- 58.
- 59.
- 60. Synthesis of Phenacetin(Continued)
- 61.
- 62. Mechanism of Action(MOA) of Paracetamol Paracetamol inhibits prostaglandin synthesis in the CNS but not in there periphery. Therefore, by its CNS effects: 1. It reduces pain sensation, 2. It produces anti-pyrexia by exerting its action on the hypothalamic heat regulating centre and analgesia but has virtually, 3. It is having no affect on inflammation, 4. It produces no hemorrhage.
- 63. Nefopam: • Different fromother NSAIDs since it has atropin like actions • Effective in traumatic and post operative pain, and in musculoskeletal pain not responding to other NSAIDs • Atropine like adverse effects • Contraindicated in epilepsy Benzoxazocine Derivatives
- 64. These are: Nimesulide, Meloxicam,Nabumatone Nimesulide: • Relative weak PGs inhibitor with COX-2 selective action • Other mechanisms implicated are reduced superoxide generation by neutrophils, inhibition of PAF synthesis and free radical scavenging action • Gastric and other adverse effects are similar to other NSAIDs Has been reported to cause nephrotoxicity and hepatotoxicity Not licensed in some developed countries And it has been withdrawn from others Use should be avoided especially in children and old persons Pref COX-2 inhibitors
- 65.
- 66. Synthesis of Nimesulide(Another Method)
- 67. • Selectively blockCOX-2 activity more than COX-1 activity • Less action on stomach, blood vessels and kidneys This group includes: Celecoxib, Rofecoxib and Valdecoxib • Given orally, absorption is complete • Established analgesic- antiinflammatory NSAIDs • They have to be shown effective in treatment of osteoarthritis and rheumatoid arthritis • Their major advantage is that they cause fewer gastric ulcers and do not inhibit platelet aggregation • Stomach friendly Selective COX-2 Inhibitors
- 68. Adverse effects: • Themost common adverse effects are nausea, vomiting, dyspepsia, abdominal pain, diarrhoea and edema of the lower extremities • Share some of the renal adverse effects of non selective COX inhibitors and renal toxicity • Hence their use should be restricted to patients who do not tolerate other NSAIDs Selective COX-2 Inhibitors (Continued)
- 69. Recently, theuse of rofecoxib and valdecoxib has been reported to be associated with increased incidence of MI and stroke Hence, they have been withdrawn by the original manufacturers Currently all the selective COX -2 inhibitors are under suspicion regarding their long term toxicity They have been described as drugs with “marginal efficacy, heighted risk and excessive cost compared with traditional NSAIDs” Selective COX-2 Inhibitors (Continued)
- 70. SAR of COX-2Inhibitors - Diaryl heterocycle with Cis-Stilbene moiety and changes in the Para position of one of the aryl rings play an important role in the COX-2 selectivity. (e.g) Celecoxib – SO2NH2 grp Parecoxib – SO2NHCOCH3 grp (Prodrug for Valdecoxib) Rofecoxib and Etoricoxib – SO2CH3 grp - The oxidation state on the sulphur is important for selectivity. - Sulfones and Sulfonamides are selective for COX-2 but Sulfoxides and Sulfides are not.
- 71.
- 72. Gout & Anti-goutDrugs • Gout is usually characterized by excruiating, sudden, unexpected, burning pain, as well as swelling, redness, warmth, and stiffness in the affected joint. This occurs most commonly in men’s toes but can appear in other parts of the body and affect women as well. Drugs used to treat gout may act in the following ways: • Classification of anti-gout drugs: 1. By inhibiting uric acid synthesis: Allopurinol 2. By increasing uric acid excretion: Probenecid, Sulfinpyrazone 3. Miscellaneous: Colchicine (alkaloid obtained from Colchicum autumnale)
- 73. Mechanism of Actionof Allopurinol In human beings, uric acid is formed primarily by the metabolism of adenine. Adenine is converted to hypoxanthine which in turn to xanthine and uric acid by the enzyme xanthine oxidase. At low concentrations, allopurinol is a competitive inhibitor of xanthine oxidase enzyme; at high concentration, it is a non-competitive inhibitor.
- 74.
- 75.
- 76. Gold Compounds • Ingeneral, gold compounds either suppress or prevent, but do not cure arthritis and synovitis. • The use of organic gold derivatives for the treatment of rheumatoid arthritis was first reported in 1927. • However, the monovalent gold compounds bring symptomatic relief to rheumatoid arthritis in patients. • A few classical examples of this class of compounds are discussed below. • Examples: auranfin; aurothioglucose; aurothioglycanide; sodium aurothiomalate.
- 77.
- 78. Synthesis of Aurothioglucose Synthesisof Sodium aurothiomalate
- 79.