1. Antipyretic-analgesic and anti-inflammatory drugs

2. Objectives
The pharmacological action, mechanism of action and 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 5

6. Nonsteroidal Anti-Inflammatory Drug
available over the counter and by prescription.

7. Pharmacological Effects7

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. Mechanism of NSAIDs phospholipid Arachidonic acid, AA
PLA2
NSAIDs
COX
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. COX Distribution,function and inhibitors of COX COX-1 COX-2 COX-3
Expression
Function
Inhibitors
COX-1
Constitutively throughout the body
organ pain, platelet function, stomach pro-tection
NSAIDs including aspirin
COX-2
Inducible and constitutively in brain, kidney
Inducible:  inflammation, pain, fever,consti-tutive:  synaptic plasticity
NSAIDs, COX 2 inhibitors including celecoxib (Celobrex )
COX-3
Constitutively, high in brain, heart
pain pathways, not inflammation pathways
Acetamino-phen some NSAIDs 14 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
4. Platelets
5. Protection of the
gastric mucosa
6. Uterus
PGI2 , PGD2 inhibit
platelet aggregation
TXA2 stimulates
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. non-selective COX inhibitors selective COX-2 inhibitors
Categories of NSAIDs
NSAIDs
non-selective COX inhibitors
selective COX-2 inhibitors 16

17. Classification of NSAIDs
Aspirin （sodium salicylate）Acetaminophen
Indomethacin
Ibuprofen
Phenylbutazone
Nonselective COX inhibitors
Selective COX-2 inhibitors
Rofecoxib
Celecoxib
Nimesulide

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

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

20. Pain Physiology

21. Symptoms of inflammation
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

22. A. Analgesic properties
Most frequently used for mild-to-moderate pain(opioids for moderate-to-severe pain) 22

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

24. The antipyretic mechanism is inhibition of prostaglandin synthetase

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

26. Little tolerance, addiction and euphoria.

27. B. Anti-pyretic properties
Return the elevated set point during fever to normal. 27

28. NSAID COX PGE2 *Lower heating temperature ←Antipyretic effect
The hypothalamus
phospholipids
NSAID
virus
bacteria
antigen
Antibodies
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

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

30. 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.

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

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

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

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

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

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

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

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

39. Session 1 Non-selective COX inhibitors

40. Salicylates
Acetylsalicyclic acid
Aspirin
Sodium Salicylate

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

42. 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

43. Pharmacodynamics Analgesic Effects (300-600mg)
Antipyretic Effects ( mg)

44. 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

45. 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. 45

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

47. Pharmacodynamics
5. Other effects
Immune inhibition

48. Anti-cancer property 5. Other effects
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. 48

49. 5. Other effects
The mechanism, the dose and duration required for maximal efficacy still are not completely clear.

50. Prevention or relief of symptoms of Alzheimer’s Disease
5. Other effects
Prevention or relief of symptoms
of Alzheimer’s Disease 50

51. Clinical Uses

52. 1. Analgesic Effects:
Aspirin is most effective in reducing pain of mild to moderate intensity (headache, toothache,arthralgia,etc).

53. 1. Analgesic Effects:
It is not effective for severe visceral pain, e.g. myocardial infarction or renal or biliary colic.
☆ It acts peripherally through its effects on inflammation but probably also inhibits pain stimuli at a subcortical site.

54. Aspirin
2. Antipyretic Effects:
☆ Aspirin reduces elevated temperature, whereas normal body temperature is not affected.
☆Aspirin’s antipyretic effect is mediated by cyclooxygenase-2 (COX-2) inhibition

55. 2. Antipyretic Effects:
The fall in temperature is related to increased dissipation of heat caused by vasodilation of superficial blood vessels and may be accompanied by profuse sweating.

56. Aspirin
3. Anti-inflammatory Effects:
in high dosge (3-6 g/d) is responsible for treatment various kinds of inflammation including acute rheumatic fever, rheumatoid and other types of arthritis.

57. 3. Anti-inflammatory Effects:
It has been advocated as a diagnostic test when acute rheumatic fever is suspected.

58. Aspirin
4. Effect on platelets
☆Low doses of aspirin can inhibit platelet aggregation and produce a slightly prolonged bleeding time by inhibition of platelet COX.

59. 4. Effect on platelets
Low doses of aspirin can irreversibly inhibit the production of TXA2 in platelets without markedly interfering with PGI2 production in endothelial cells.

60. 4. Effect on platelets
In general, Aspirin should be stopped 1 week prior to surgery to avoid bleeding complication.

61. 4. Effect on platelets
Decrease the incidence of transient ischemic attacks,
unstable angina,
coronary artery thrombosis with myocardial infarction,
thrombosis after coronary artery bypass grafting.

62. SIDE EFFECTS
CNS:
salicylic acid reaction: Headaches; confusion; tremors; vertigo; behavior disturbance
GI effects :
direct stimulation or ↓ PGE2 & PGI2
Esophagitis; gastric ulcerations; GI hemorrhage

63. SIDE EFFECTS GI effects
The gastritis that occurs with Aspirin may be due to irritation of gastric mucosa by the undissolved tablet, or to inhibition of production of protective prostaglandins.

64. SIDE EFFECTS GI effects
Aspirin
SIDE EFFECTS
GI effects
This effect can be decreased with suitable buffering(taking Aspirin with meals ).

65. Therefore, aspirin should be avoided by individuals with peptic ulcer disease.

66. SIDE EFFECTS 3. Liver & renal toxicity Dose dependence toxicity
Reye's syndrome
a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver.
The disease causes hepatitis with jaundice and encephalopathy

67. SIDE EFFECTS Other reaction
Hematologic: decreased platelet aggregation; prolonged bleeding time.
Exacerbations of asthma
Hypersensitivity: rashes
Acid-base Imbalance

68. Acetaminophen Phenacetin
Rapidly absorbed from GI
Phenacetin is largely converted to Acetaminophen
Similar antipyretic, analgesia to aspirin

69. Weak anti-inflammatory properties

70. used to reduce fever and pains (a major ingredient in numerous cold and flu medications) (choice for child)

71. used appropriately, side effects are rare

72. Indomethacin
More potent than aspirin
As an anti-inflammatory agent
More adverse reaction

73. Ibuprofen
More analgesia
Fewer adverse reaction
Brufen； Benzeneacetic acid； Fenbid；

74. Phenylbutazone Powerful anti-inflammatory effects
Weak analgesic & antipyretic activities
Promote excretion of uric acid
Used for acute gout, rheumatic & rheumatoid arthritis

75. More adverse reaction
Can induce activities of drug
Can displace other drugs from plasma proteins

76. Selective COX-2 inhibitors
Less adverse reactions
Do not impact platelet aggregation
Meloxicam
Celecoxib
Nimesulide

77. SELECTIVE COX-2 INHIBITION77 77

79. Celecoxib is used for the relief of pain, fever, swelling, and tenderness caused by osteoarthritis and rheumatoid arthritis .

80. Celecoxib is approved as an adjunctive (secondary) treatment among patients with FAP(familial adenomatous polyposis ).

81. In FAP, patients develop large numbers of polyps in their colons, and the polyps invariably become malignant.
The only cure of FAP requires removal of the entire colon.

82. Celecoxib also has been approved for patients with FAP who have not had their colons removed.

83. Celebrex is also approved for the relief of acute pain and the pain of menstrual cramps (dysmenorrhea).

84. It is a powerful analgesic anti-inflammatory drugs
It gives 10 times analgesic effect than that of aspirin, antipyretic effect is stronger than aspirin and acetaminophen . 

85. cox2 i.m Acetaminophen ++ + Indomethacin ++++ sulindac tolmetin
Anti
pyretic
analgesic
Anti-inflam-matory
Side action
Acetaminophen ++ +
Indomethacin
++++
sulindac
tolmetin
diclofenac
Ibuprofen
+++
meloxicam
----
cox2
Phenylbutazone
ketorolac
i.m

86. Antigout drugs

88. Antirheumatic Drugs (drugs used to treat rheumatoid arthritis)

90. Colchicine The general pain and other arthritis is invalid.
Acute gouty arthritis, anti-inflammatory (inhibition of granulocyte infiltrates) relieve symptoms

91. Allopurinol Inhibit Uric acid production
The main treatment of chronic gout

92. The characteristics of antipyretic effect of NSAIDs is
A. can reduce the temperature of normal body
B.can only reduce fever temperature of
the of the patient
C. both can reduce the normal temperature and the fever temperature of the patient
D. antipyretic effect is affected by environmental temperature obviously
E. all above

93. The analgesic mechanism of acetylsalicylic acid
A. excited central opioid receptors
B. control pain center
C. inhibit the synthesis of peripheral PG D. block of central opioid receptor
E. directly paralysis of peripheral endings nerve

94. Questions 1. What pharmacological actions and adverse effects can aspirin produce by inhibition PG synthesis? 2. The difference in analgesic action between NSAIDS and morphine ？