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Antipyretic-analgesic and anti-inflammatory drugs

Antipyretic-analgesic and anti-inflammatory drugs. Objectives. The pharmacological action, mechanism of action , common adverse reactions of the antipyretic analgesic drugs. Antipyretic-analgesic and Anti-inflammatory Drugs.

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Antipyretic-analgesic and anti-inflammatory drugs

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  1. Antipyretic-analgesic and anti-inflammatory drugs

  2. Objectives The pharmacological action, mechanism of action , common adverse reactions of the antipyretic analgesic drugs

  3. Antipyretic-analgesic and Anti-inflammatory Drugs • a kind of antipyretic and analgesic, anti-inflammatory, and most antirheumatic effect of drugs

  4. The structure of this kind of drug differs from that of steroidal anti-inflammatory drugs. • Nonsteroidal anti-inflammatory drugs NSAIDs

  5. Nonsteroidal Anti-Inflammatory Drug relieves pain and fever by inhibiting the inflammatory response. 5

  6. available over the counter and by prescription.

  7. Pharmacological Effects 7

  8. Common pharmacological effects These drugs show the same pharmacological effects • -- antipyretic effect • -- analgesic effect • -- anti-inflammatory effect

  9. Action

  10. signs of inflammation • Redness - due to local vessel dilatation • Heat - due to local vessel dilatation • Swelling – due to influx of plasma proteins and phagocytic cells into the tissue spaces • Pain – due to local release of enzymes and increased tissue pressure

  11. COX Mechanism of NSAIDs phospholipid PLA2 NSAIDs Arachidonic acid, AA Leukotrienes, LTs Prostaglandin, PG PGE2 PGF2 PGI2 TXA2

  12. Properties of Prostaglandins

  13. Basic pharmacological effects Common mechanism of action: Inhibition of cyclooxygenase (COX)， reduce biosynthesis of prostaglandin

  14. Distribution,function and inhibitors of COX 14

  15. Physiological Functions of Prostaglandins 1.Pain 2. Inflammation 3. Fever PGE2 sensitize nerve endings to bradykinin, histamine and substance P PGI2, PGD2 ,PGE2– vasodilators (edema, erythema) PGE2 5. Protection of the gastric mucosa 6. Uterus 4. Platelets PGI2 , PGD2 inhibit platelet aggregation TXA2 stimulates platelet aggregation PGD2 contracts uterus PGI2 9. Other 7. Maintenance of renal blood flow 8.Bronchial constrict PGE2 keeps ductus arteriosus open following birth PGF2 PGE2 15

  16. Categories of NSAIDs NSAIDs non-selective COX inhibitors selective COX-2 inhibitors 16

  17. Pain Treatment • Analgesics • Antipyretic-analgesic and anti-inflammatory drugs*

  18. Pain An unpleasant experience associated with actual or potential tissue damage.

  19. Pain Physiology

  20. A. Analgesic properties • NSAIDs Prostaglandins pGE2 pGF2 Inflammatory factors + Bradykinin Histamine 5-HT Symptoms of inflammation • block prostaglandins production • Sites of action: peripheral tissue Red, swelling, Heating, Pain

  21. A. Analgesic properties • Most frequently used for mild-to-moderate pain(opioids for moderate-to-severe pain) 21

  22. To traumatic pain and visceral smooth muscle cramps is invalid. Analgesic action lies in peripheral site.

  23. The antipyretic mechanism is inhibition of prostaglandin synthetase

  24. Prostaglandins by themselves do not cause pain but lower the threshold of the C fiber nociceptors.

  25. Little tolerance, addiction and euphoria.

  26. B. Anti-pyretic properties Return the elevated set point during fever to normal. 26

  27. The hypothalamus phospholipids NSAID virus bacteria antigen Antibodies are - Tissue damage IL-1β IL-6 IFN-α IFN-β TNF-α Unsaturated fatty acids Inhibition COX PGE2 The set-point ↑ fever（heat production >heat dissipation ） *Lower heating temperature ←Antipyretic effect

  28. The concentration of cytokines such as IL-1B, IL-6, and TNF frequently are increased during inflammation which stimulate the synthesis of PGE2 near the hypothalamic area.

  29. Heat loss set point (hypothalamus) Heat genera-tion Normal fever After aspirin 29

  30. Points: (1).The normal temperature had no effect. Fever caused by direct injection of PG is invalid.

  31. "elevated" temperature: reduced • The higher temperature, the more potent

  32. Mechanisms of Antipyretic Action Blocks pyrogen-induced prostaglandin production in thermoregulatory center (CNS)

  33. (2). Only enhances heat dissipation, does not affect heat production.

  34. (3). The antipyretic mechanism is inhibition of prostaglandin synthetase of the hypothalamus

  35. 3. Anti-inflammatory Effects • NSAIDs only inhibit the symptoms of inflammation

  36. But they neither arrest the progress of the disease nor do they induce remission

  37. The history of antipyretic analgesics 1750： To use willow bark for treatment "fever" is a success, bitter -- called "salicin" 1875：Sodium salicylate successfully used in the treatment of rheumatic fever 1899：Aspirin (acetylsalicylic acid) on the market

  38. Session 1 Non-selective COX inhibitors

  39. Salicylates • Acetylsalicyclic acid Aspirin • Sadium Salicylate

  40. Pharmacokinetics • Rapidly absorbed: stomach and upper small intestine • Distribution：through the body rapidly hydrolyzed --------- acetic acid + salicylate, catalyzed by tissue/blood esterases

  41. Elimination----- Pharmacokinetics • metabolite in liver dose ＜1g/day：one-order elimination t1/2: 3--5 hrs dose ＞1g/day：zero-order elimination ＞4g/day t1/2: • Excretion: kidney, influenced by pH of urine

  42. Pharmacodynamics • Analgesic Effects (300-600mg) • Antipyretic Effects (300-600mg)

  43. 3.Anti-inflammatory Effects (3-6g) do not influence the progress of disease • Effects on Platelets (40-100mg) Reduced platelet aggregation reduces thromboxane A2 (TXA2) formation

  44. Anti-Thrombolytic Action of Aspirin COX-2 specific drugs are not anti-thrombolytic. Endothelial cell Pletelet COX-1 COX-1/COX-2 - - Aspirin LD HD TXA2 PGI2 +++ platelet aggregation +++platelet shape change +++platelet granule release +++vasoconstriction Inhibit platelet aggregation - platelet secretion +++vasodilation A single dose of aspirin approximately doubles the mean bleeding time of normal persons for a period of 4～7 days. 44

  45. Platelets No nuclei No new COX1 produce TXA2 production ↓ Lifetime: 8-11 days Endothelial cell Has nuclei New COX1produce Low doses 40-100mg/day

  46. Pharmacodynamics 5. Other effects • Immune inhibition

  47. Anti-cancer property • A number of studies (animals and humans) have shown an up-regulation of COX-2 in colonic cancers. • A large body of epidemiological evidence points to an inverse association between aspirin use and colorectal cancer risk. 47

  48. The mechanism, the dose and duration required for maximal efficacy still are not completely clear.

  49. Prevention or relief of symptoms of Alzheimer’s Disease 49

  50. Clinical Uses • Commonly used for management of mild to moderate pain (300-600mg) • Combination agents (cold)

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