NSAIDS non steroidal anti inflammatory drugs

Pharmacology NSAIDS

1. NSAIDS Dr. Mrs. Aditi Nitin Patil

2. All drugs grouped in this class have analgesic, antipyretic and anti-inflammatory actions in different measures. In contrast to morphine they do not depress CNS , do not produce physical dependence , have no abuse liability and are weaker analgesics (except for inflammatory pain). A re also called nonnarcotic, non-opioid or aspirin like analgesics . They act primarily on peripheral pain mechanisms , but also in the CNS to raise pain threshold. They are more commonly employed and many are over-the-counter drugs . 07-Feb-25 2

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4. In 1971 Vane and coworkers made the landmark observation that aspirin and some NSAIDs blocked PG generation . To be the major mechanism of action of NSAIDs . COX-1 is an constitutive enzyme- serves physiological ‘house keeping’ functions , Inducible (COX-2) isoforms; normally present in minute quantities, is induced by cytokines and other signal molecules at the site of inflammation → generation of PGs COX-2 is constitutively present at some sites in brain, in juxtaglomerular cells and in the foetus ; 07-Feb-25 4

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11. SALICYLATES Aspirin Aspirin is acetylsalicylic acid . It is rapidly converted in the body to salicylic acid which is responsible for most of the actions. Other actions are the result of acetylation of certain macromolecules including COX. It is one of the oldest analgesic anti-inflammatory drugs and is still frequently used . 07-Feb-25 11

12. PHARMACOLOGICAL ACTIONS Analgesic , antipyretic, anti-inflammatory actions- Metabolic effects- Respiration- Acid-base and electrolyte balance- Renal - GIT- Urate excretion- Blood- 07-Feb-25 12

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19. PHARMACOKINETICS- Aspirin is absorbed from the stomach and small intestines . Its poor water solubility is the limiting factor in absorption: micro-fining the drug-particles and inclusion of an alkali (solubility is more at higher pH) enhances absorption. Higher pH also favours ionization, thus decreasing the diffusible form. Aspirin is rapidly de-acetylated in the gut wall , liver, plasma and other tissues to release salicylic acid which is the major circulating active form. 07-Feb-25 19

20. It is ~ 80% bound to plasma proteins and has a volume of distribution ~ 0.17 L/kg . Entry into brain is slow, but aspirin freely crosses placenta. Both aspirin and salicylic acid are conjugated in liver with glycine to form salicyluric acid (major pathway) . They are also conjugated with glucuronic acid. The metabolites are excreted by glomerular filtration and tubular secretion . The plasma t½ of aspirin as such is 15–20 min , but taken together with that of released salicylic acid, it is 3–5 hours. However, metabolic processes get saturated over the therapeutic range; t ½ of anti-inflammatory doses may be 8–12 hours while that during poisoning may be as high as 30 hours. Thus, elimination is dose dependent. 07-Feb-25 20

21. ADVERSE EFFECTS- Occurs at analgesic dose (0.3–1.5 g/day) are nausea, vomiting, epigastric distress, increased occult blood loss in stools. The most important adverse effect of aspirin is gastric mucosal damage and peptic ulceration. Hypersensitivity and idiosyncrasy P roduces the syndrome called salicylism —dizziness, tinnitus, vertigo, reversible impairment of hearing and vision, excitement and mental confusion, hyperventilation and electrolyte imbalance ‘Reye’s syndrome’, a rare form of hepatic encephalopathy seen in children having viral (varicella, influenza) infection . Acute salicylate poisoning- children- 07-Feb-25 21

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23. Precautions and contraindications- - who are sensitive to it and in peptic ulcer, bleeding tendencies , in children suffering from chicken pox or influenza . -Cautious use in chronic liver disease - Aspirin should be stopped 1 week before elective surgery . -Given chronically during pregnancy it may be responsible for low birth weight babies . - prolonged labor, greater postpartum blood loss and premature closure of ductus arteriosus -Avoid high doses in G-6PD deficient individuals— haemolysis can occur. 07-Feb-25 23

24. USES- As analgesic- As antipyretic- Acute rheumatic fever- Rheumatoid arthritis- Osteoarthritis- Post-myocardial infarction and post stroke patients- 07-Feb-25 24

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27. PROPIONIC ACID DERIVATIVES 07-Feb-25 27

28. All propionic acid derivatives enter brain, synovial fluid and cross placenta. They are largely metabolized in liver by hydroxylation and glucuronide conjugation and excreted in urine as well as bile . Uses- Dysmenorrhoea rheumatoid arthritis, osteoarthritis and other musculoskeletal disorders, especially where pain is more prominent than inflammation soft tissue injuries, fractures , vasectomy, tooth extraction, postpartum and postoperatively: suppress swelling and inflammation 07-Feb-25 28

29. ENOLIC ACID DERIVATIVES (Oxicams) Piroxicam -It is a long-acting potent NSAID with anti-inflammatory potency got good analgesic-antipyretic action. It is a nonselective, reversible inhibitor of COX; lowers PG concentration in synovial fluid and platelet aggregation—prolonging bleeding. In addition, it decreases the production of IgM , rheumatoid factor and leucocyte chemotaxis . Uses - use as long-term anti-inflammatory drug in rheumatoid and osteo-arthritis, ankylosing spondylitis, acute gout, musculoskeletal injuries and in dentistry. 07-Feb-25 29

30. FENAMATE- Mephenamic acid An analgesic, antipyretic and weaker anti-inflammatory drug, which inhibits synthesis of PGs as well as antagonises some of their actions . Mephenamic acid exerts peripheral as well as central analgesic action Uses- Mephenamic acid is indicated primarily as analgesic in muscle, joint and soft tissue pain where strong antiinflammatory action is not needed . It is quite effective in dysmenorrhoea. 07-Feb-25 30

31. ACETIC ACID DERIVATIVES Ketorolac- This arylacetic acid NSAID has potent analgesic but modest antiinflammatory activity . In postoperative pain it has equalled the efficacy of morphine, but does not interact with opioid receptors and is free of opioid side effects. it inhibits PG synthesis and relieves pain primarily by a peripheral mechanism. In short-lasting pain, it has compared favourably with aspirin. 07-Feb-25 31

32. Indomethacin- This indole acetic acid derivative is a potent antiinflammatory drug with prompt antipyretic action. Indomethacin relieves only inflammatory or tissue injury related pain. It is a highly potent inhibitor of PG synthesis and suppresses neutrophil motility. In toxic doses it uncouples oxidative phosphorylation It is 90% bound to plasma proteins, partly metabolized in liver to inactive products and excreted by kidney. Plasma t½ is 2–5 hours. indomethacin is used as a reserve drug in conditions requiring potent antiinflammatory action like ankylosing spondylitis, acute exacerbations of destructive arthropathies , psoriatic arthritis and acute gout or rheumatoid arthritis that are not responding to better tolerated NSAIDs. Malignancy associated fever refractory to other antipyretics may respond to indomethacin. It has been the most common drug used for medical closure of patent ductus arteriosus: 07-Feb-25 32

33. PREFERENTIAL COX-2 INHIBITORS Nimesulide- It is a relatively weak inhibitor of PG synthesis and moderately COX-2 selective. Anti-inflammatory action may be exerted by other mechanisms as well, e.g. reduced generation of superoxide by neutrophils, inhibition of PAF synthesis and TNF α release, free radical scavenging, inhibition of metalloproteinase activity in cartilage . The analgesic, antipyretic and anti-inflammatory activity of nimesulide has been rated comparable to other NSAIDs. U sed primarily for short-lasting painful inflammatory conditions like sports injuries, sinusitis and other ear-nose-throat disorders, dental surgery, bursitis , low backache, dysmenorrhoea, postoperative pain, osteoarthritis and for fever. 07-Feb-25 33

34. Diclofenac sodium Aceclofenac Meloxicam Etodolac 07-Feb-25 34

35. SELECTIVE COX-2 INHIBITORS (Coxibs) Because of the theoretical advantage of inhibiting COX-2 without affecting COX-1 function, some highly selective COX-2 inhibitors -They cause less gastric mucosal damage; occurrence of peptic ulcer and ulcer bleeds is clearly lower than with traditional NSAIDs. They do not depress TXA2 production by platelets (COX-1 dependent); do not inhibit platelet aggregation or prolong bleeding time , but reduce PGI2 production by vascular endothelium. Celecoxib , Etoricoxib , Parecoxib 07-Feb-25 35

36. PARA-AMINO PHENOL DERIVATIVES Paracetamol (acetaminophen )- The central analgesic action of Paracetamol is like aspirin, i.e. it raises pain threshold, but has weak peripheral anti-inflammatory component . Analgesic action of aspirin and paracetamol is additive. Paracetamol is a good and promptly acting antipyretic. 07-Feb-25 36

37. Pharmacokinetics – Paracetamol is well absorbed orally , only about 1/4th is protein bound in plasma and it is uniformly distributed in the body. Metabolism occurs mainly by conjugation with glucuronic acid and sulfate: conjugates are excreted rapidly in urine. Plasma t½ is 2–3 hours. Effects after an oral dose last for 3–5 hours. 07-Feb-25 37

38. Uses- Paracetamol is one of the most commonly used ‘ over-the-counter’ analgesic for headache, mild migraine, musculoskeletal pain, dysmenorrhoea. One of the best drugs to be used as antipyretic, especially in children (no risk of Reye’s syndrome ). 07-Feb-25 38

39. Acute Paracetamol poisoning- Occurs especially in small children who have low hepatic glucuronide conjugating ability. If a large dose (> 150 mg/kg or > 10 g in an adult) is taken, serious toxicity can occur. Fatality is common with > 250 mg/kg . Early manifestations are just nausea, vomiting, abdominal pain and liver tenderness with no impairment of consciousness. After 12–18 hours centrilobular hepatic necrosis occurs which may be accompanied by renal tubular necrosis and hypoglycaemia that may progress to coma. Jaundice starts after 2 days. 07-Feb-25 39

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41. Treatment If the patient is brought early, vomiting should be induced or gastric lavage done. Activated charcoal is given orally or through thetube to prevent further absorption. Other supportive measures , as needed, should be taken N- acetylcysteine (MUCOMIX, ANTIFEN 200 mg/ml inj in 2, 5 ml amps) 150 mg/kg should be infused- It replenishes the glutathione stores of liver and prevents binding of the toxic metabolite to other cellular constituents 07-Feb-25 41

42. Topical NSAIDs Preparations Diclofenac 1% gel : VOLINI GEL, RELAXYL GEL, DICLONAC GEL Ibuprofen 10% gel : RIBUFEN GEL Naproxen 10% gel : NAPROSYN GEL Ketoprofen 2.5% gel : RHOFENID GEL Flurbiprofen 5% gel : FROBEN GEL Nimesulide 1% gel : NIMULID TRANS GEL, ZOLANDIN GEL, NIMEGESIC-T-GEL Piroxicam 0.5% gel : DOLONEX GEL, MOVON GEL, PIROX GEL, MINICAM GEL 07-Feb-25 42

43. Some guidelines 1. Mild-to-moderate pain with little inflammation— paracetamol or low-dose ibuprofen . 2. Postextraction or similar acute but shortlasting pain—ketorolac , a propionic acid derivative , diclofenac or nimesulide . 3. Gastric intolerance to conventional NSAIDs or predisposed patients— etoricoxib or paracetamol . 4. Patients with history of asthma or anaphylactoid reaction to aspirin/other NSAIDs— nimesulide , COX-2 inhibitor. 5. Paediatric patients—only paracetamol , aspirin , ibuprofen and naproxen have been adequately evaluated in children— should be preferred in them. Due to risk of Reye’s syndrome , aspirin should be avoided unless viral infection can be ruled out. 6. Pregnancy— paracetamol is the safest; lowdose aspirin is probably the second best. 7. Hypertensive, diabetic, ischaemic heart disease , epileptic and other patients receiving long-term regular medication—possibility of drug interaction with NSAIDs should be considered and the physician consulted. 8. Patients with risk factors for cardiovascular diseases , stroke—avoid etoricoxib / celecoxib ; ibuprofen or low-dose aspirin may be used. 07-Feb-25 43

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