Nsaids

Full detail of NSAIDS

1. NSAIDS (NON STEROIDAL ANTI-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 Chemical irritants Frostbite Toxins Infection by pathogens Physical injury Immune reactions due to hypersensitivity Radiation Foreign bodies CAUSES OF INFLAMMATION

4. The classic signs and 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 A 2 Arachidonic Acid Prostaglandins Thromboxanes Prostacyclin COX

7. Among the most 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 are also 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 are analgesic, 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. Class Example 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 Selective COX-2 inhibitors Celecoxib Structure-based Classification Continued..

13. Analgesic –Antipyretics with poor 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, a drug 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 A 2 Arachidonic Acid Prostaglandins Thromboxanes Prostacyclin COX Synthesis of Prostaglandins Cyclo-oxygenase (COX) pathway NSAIDs

17. COX Exists in two isoforms: COX-1 (constitutive) COX-2 (inducible) Oxidative stress Injury Ischemia Neurodegenerative diseases

18. Advantageous actions due to PG synthesis inhibition Analgesia Antipyresis Antiinflammatory Antithrombotic Closure of ductus arteriosus

19. Some toxicities due to 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 the acidity 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 R 1 R 2 Salicylic acid H H Methyl salicylate CH 3 H sodium salicylate Na H Phenyl salicylate C 6 H 5 H

21. Synthesis of Aspirin

22. Synthesis of Salol

23. Synthesis of Salol (Continued)

24. Synthesis of Salsalate

25. Synthesis of Salicylamide

26. Synthesis of Sodium salicylate

27. Synthesis of Benorilate

28. 2,4-difluoro aniline, Amyul nitrite, Methyl Phenoate . Synthesis of Diflunisal

29. Synthesis of Sulphasalazine

30. The acidic H at 4-position is related to their activity. The dicarbonyl functions at the 3 and 5 positions enhance the acidity of hydrogen atom at the 4-position. Decreasing or eliminating acidity by removing the acidic proton at the 4 position (e.g. 4,4-dialkyl derivatives) abolishes the activity. If acidity is too much, anti-inflammatory and sodium-retaining activities decrease, while other properties such as uricosuric effect increase. A single alkyl group (n-butyl group) at the 4-position enhances anti-inflammatory activity. SAR of 3,5-PYRAZOLINEDIONES Derivatives DRUG R R 4 Phenyl butazone H -C 4 H 9 Oxyphenbutazone OH -C 4 H 9 Sulphinpyrazone H -(CH 2 ) 2 SOC 6 H 5 General Structure

31. 6. Introduction of polar 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 Phenyl butazone

33. The presence of 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 The (+) isomer of ibuprofen is much more active compared to (-) isomer. The presence of the phenoxy group at 3 rd position give rise to the compound fenoprofen . SAR of Propionic acid Derivatives

34. SAR of Propionic acid 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. Synthesis of Ibuprofen

36. Synthesis of Ibufenac Willgerodt oxidation 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. NH 4 OH and pyridine.

37. Synthesis of Naproxen Willgerodt oxidation 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. NH 4 OH and pyridine.

38. Synthesis of Flurbiprofen

39. Synthesis of Caprofen

40. Substitution on the anthranilic acid ring generally reduces the activity. The NH moiety of anthranilic acid appears to be essential for activity since replacement of NH function with O, S, CH 2 functionalities significantly reduced the activity. In the UV erythema assay for anti-inflammatory activity, the order of activity is generally 3’>2’>4’ for mono substitution with the CF 3 derivative ( Flufenamic acid) particularly potent. General Structure SAR of Anthranilic acid Derivatives DRUG R 1 R 2 R 3 Mefinamic acid CH 3 CH 3 H Flufinamic acid H CF 3 H Meclofinamic acid Cl CH 3 Cl

41. In rat paw edema assay, with 2’-Cl derivative is more potent than 3’-Cl analogue. In di-sustituted derivatives, where the nature of the two substituents is the same, 2’3’ distribution appears to be more effective. 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. Meclofenamic acid has greater anti-inflammatory activity over flufenamic acid and 25 times more than mefenamic acid. 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 Flufenamic acid Synthesis of Mefanamic acid Ullman condensation is type of Aromatic amination reaction between aryl halogen acids and aryl amines.

43. The p- toluoyl and acetic acid function must be coplanar in tolmetin . 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 Aryl Alkanoic 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 –CH 3 group on the carbon atom separating the aromatic ring tends to increase the anti-inflammatory activity.

45. 4. The function of 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. Synthesis of Tolmetin

47. Synthesis of Zomepirac

48. Synthesis of Diclofenac Wolf- kishner reduction 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. The replacement of the carboxyl group with any other acidic functionalities lead decreases the activity. Acylation of the indole nitrogen with aliphatic carboxylic acid or aryl alkyl carboxylic acids result in the decrease of activity. Amide analogues are inactive. The N- benzoyl derivatives substituted in the p-position with F, Cl , CF 3 groups are the most active. The 5-position of the indole when F, OCH 3 groups was more active than the unsubstituted indole analogue. 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. Synthesis of Indomethacin

52. Synthesis of Sulindac Reformatski is an organic reaction, which condenses aldehydes or ketones with α-halo esters using a metallic zinc to form β- hydroxy -esters.

53. Optimum activity is observed when methyl substituent present at 2-position. The carboxamide sustituent R is generally an aryl or hetero aryl substituent because alkyl substituents are less active. N-heterocyclic carboxamides ( piroxicam ) are generally more acidic than the corresponding N-aryl carboxamides . Tenoxicam Interchanging of benzene ring with thiophene ( tenoxicam ) gives biologically active compounds. For optimum activity 4-hydroxy-1,2-benzothiazine carboxamide ring is required. SAR of Oxicam Derivatives

54. Synthesis of Piroxicam

55. Synthesis of Meloxicam

56. SAR of Pyrollo pyrollo 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. Esterification of the phenolic function with methyl or propyl produces derivatives with greater toxic side effects than ethyl groups. The substituent on the nitrogen atom which reduces basicity also reduces activity except for acetyl which is metabolically labile. Amides derived from aromatic acid. E.g., N-phenyl benzamides -are less active or inactive. SAR of Para aminophenol Derivatives Paracetamol

58. Synthesis of Paracetamol

59. Synthesis of Phenacetin

60. Synthesis of Phenacetin (Continued)

61. Synthesis of Acetanilide

62. M echanism 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 from other 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. Synthesis of Nimesulide

66. Synthesis of Nimesulide (Another Method)

67. Selectively block COX-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 : The most 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, the use 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-2 Inhibitors - 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 – SO 2 NH 2 grp Parecoxib – SO 2 NHCOCH 3 grp ( Prodrug for Valdecoxib ) Rofecoxib and Etoricoxib – SO 2 CH 3 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. Synthesis of Celecoxib

72. Gout & Anti-gout Drugs 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: By inhibiting uric acid synthesis: Allopurinol By increasing uric acid excretion: Probenecid , Sulfinpyrazone Miscellaneous: Colchicine (alkaloid obtained from Colchicum autumnale )

73. Mechanism of Action of 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. Synthesis of Allopurinol

75. Synthesis of Probenecid

76. Gold Compounds In general, 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. Synthesis of Auranofin

78. Synthesis of Aurothioglucose Synthesis of Sodium aurothiomalate

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