1. Welcome

2. Chapter 22 Antipyretic-analgesic and anti-inflammatory drugs

3. introduction

4. Antipyretic-analgesic and anti-
inflammatory drugs
non-steroidal anti-inflammatory
drugs(NSAIDs)
Aspirin-like drugs

5. Antipyretic-analgesic and anti-inflammatory drugs
Be grouped in different classes according to their chemical structures
Share similar pharmacological effects mechanism of action and adverse reactions
They all inhibit the biosynthesis of PGs

6. Membrane phospholipids
Arachidonic
acid
PGG2
PGH2
PGI PGF PGE TXA2
(vascular (bronchial (vascular dilation; (vascular
dilation; constriction) GI protection; constriction;
platelet pain,fever) thrombosis)
disaggregate;
pain)
PLA2
LTs
LTC4/
D4/E4
LTB4
chemotaxis
Bronchial
constriction ;
Alteration of
vascular
permeability
COX
lipoxygenase
glucocorticoid
NSAIDs

7. The Different biological Activities of the Products of AA
PGI2: vasodilation hyperalgesia
inhibit platelet aggregation
TXA2: platelet aggregation and
vasoconstriction.
PGE2: induce inflammation
fever and pain
vasodilation and hyperalgesia
PGF2α: bronchial constriction and

8. The Different biological Activities of the Products of AA
LTs : allergy, bronch-constriction
leukocytotaxis
increase vascular permeability
induce inflammation
The different anti-inflammatory mechanism
Glucocorticoids : inhibit PLA2
NSAIDs: inhibit COX and reduce the production of PGs

9. COX-1 COX-2 Production Constitutive Inducible
Function Physiological function Pathological function
gastric protection facilitate inflammation
platelet aggregation cause fever and pain
peripheral vessel regulation
renal blood distribution
NASIDs effects unwanted side effects therapeutic effects

10. 【Three major actions of NSAIDs】
Antipyretic effect
Analgesic effect
Anti-inflammatory effect

11. 1. Antipyretic effect : characteristics clinical applications
mechanism
characteristics
clinical applications

12. endogenous pyrogens (IL-1,IL-6,TNF)
Mechanism
pathogen and toxins
neutrophils
endogenous pyrogens (IL-1,IL-6,TNF)
cox NSAIDs
PGE2 (hypothalamus)
heat production
body
temperature
set point
heat dissipation

13. ① Central Characteristics ②“Elevated” temperature — reduced
“Normal ” temperature — no influence
③ To what extent the COX inhibited is consistent with the intensity of NSAIDs’s pharmacological effects.

14. Clinical applications
symptomatic treatment.
attention
As fever is a defense reaction of the body and heat pattern
is an important evidence in diagnosis, we should not hurry
to use antipyretic drugs for mild fever; but for high fever
and chronic fever, antipyretic drugs should be used in time
to reduce body temperature, avoid or alleviate the
complications.

15. Question 1
What is the difference between NSAIDs and chlorpromazine in body temperature regulation ?

16. Comparison between NSAIDs and Chlorpromazine
NSAIDs Chlorpromazine
Mechanism inhibit COX in inhibit thermoregulator
CNS → PGE2↓ make it out of function
Effect set point ↓ BT alters with the
BT ↓ environmental temperature
Clinical uses fever artificial hibernation
rheumatic fever

17. 2. Analgesic effect :
mechanism
characteristic
clinical application

18. Mechanism + PGs NSAIDs Other algesiogenic substance nociceptive
injury
PGs
pain
Other algesiogenic substance
(BK,histamine etc.)
nociceptive
nerve endings +
NSAIDs

19. Bradykinin: cause pain through stimulating the algesireceptors directly.
PG: (1) hyperalgesia
(2) PG(E1 E2 F2α) also have algesiogenic effect

20. Characteristics ① Peripheral ② mild to moderate pain.
③ No addiction or respiratory inhibition

21. Clinical applications
① have good effects on chronic dull pain—
headache , toothache, neuralgia, muscle
pain,arthralgia,dysmenorrhea.
② are not effective for traumatic pain, severe
visceral pain—myocardial infarction or renal
or biliary colic
③ Non-narcotic and no euphoria.
No respiratory inhibition.

22. ? Question 2 What is the difference between NSAIDs
and analgesics in analgesic effect ?

23. Drug Analgesics NSAIDs location mechanism characteristics
representative
Analgesics
NSAIDs
powerful ；
sharp pain ；
cause euphoria and
addiction ;
respiratory inhibition
morphine
dolantin
aspirin
(+)opium
receptor
(-)PG
synthesis
CNS
periphery
CNS(？)
moderate ；
chronic dull pain ；
not addictive
no respiratory
inhibition

24. 3.Anti-inflammatory effect :
mechanism
characteristic

25. 3. Anti-inflammatory effect
Mechanism of inflammation:
phospolipids
injury
factor PLA2
neutrophilic arachidonic acid
granulocyte
cytokines induce COX-2
( IL-1,6,8 TNF)
PGs BK cell adhesion
molecules
inflammation
( redness, swelling, heat and pain )

26. The role of PGs in inflammation
1.cause vasodilation and tissue edema
2.coordinate with bradykinin to cause inflammation
Mechanism of anti-inflammatory effect
(1)Reducing biosynthesis of
prostaglandins by inhibiting COX.
(2)inhibition of the expression of some cell adhesion molecules

27. Characteristics ① Peripheral ② They have certain effect on the control
of rheumatoid arthritis.
③ can’t effect a radical cure. They can
neither alter the course nor prevent
complications.

28. 【 NSAIDs classifications 】
According to selectivity for COX:
①Non-selective COX inhibitors
②Selective COX-2 inhibitors
According to chemical structures:
① Salicylates
② Anilines
③ Pyrazolones
④ Other organic acids

29. Section 1 Nonselective COX inhibitors

30. Salicylates
Anilines
Pyrazolones
Other organic acids

31. Aspirin (Acetylsalicylic acid)

32. 【Pharmacokinetics】 Absorption: stomach，upper small intestine
aspirin acetic acid＋salicylate
Distribution: in the form of salicylate
articular cavity, CSF and placenta
PPBR= 80~90%
CSF :cerebrospinal fluid

33. Metabolism: ＜1g,first-order kinetics,t1/2=2~3h;
≥1g,zero-order kinetics,t1/2=15~30h;
Still larger dosage→intoxication
Excretion: renal
the PH of urine: alkaline→85%;
acidic→5%
In salicylate acute intoxication, we can increase the
excretion of free salicylates by alkalizing the urine!

34. and clinical uses】 【pharmacological actions
(1)Antipyretic-analgesic effect
(2)Anti-inflammatory and antirheumatic effects
(3)Platelet effect

35. (1)Antipyretic-analgesiceffects:
most effective for fever and mild to moderate pain
fever—profuse sweating,enough water supplement

36. (2)Anti-inflammatory and antirheumatic effects:
①used in therapy and differential diagnosis
of acute rheumatic fever
②the preferred drug for rheumatoid arthritis
③adult: 3~5g/d
④In rheumatism treatment, we should
monitor the blood drug level

37. blood vessel endothelium
(3)Platelet effect: AA
TXA2
PGI2
(-)platelet aggregation；
vascular dilation
(+)platelet aggregation；
vascular constriction
platelet
blood vessel endothelium

38. Aspirin irreversibly acetylates and blocks platelet COX
→TXA2 biosynthesis(-)→platelet aggregation(-)→
thrombosis (-). (8-10d)
TXA2↓
Low dose thrombosis is inhibited
PGI2 not affected
High dose unbeneficial for thrombosis inhibition
PGI2↓

39. ①low aspirin dose (50~100mg) is recommended;
Clinical uses:
①low aspirin dose (50~100mg) is recommended;
②prevent thrombosis:
cardiac or brain ischemic diseases.
angioplasty,coronary artery bypass grafting.

40. Others (1)Alzheimer,s disease(AD):
AD is related to the over-expression of COX-2 in brain.
Aspirin 100 mg p.o. daily has repression effect on AD
(2) Pregnancy-induced hypertension syndrome and preeclampsia:
is related to the increase of the ratio of TXA2 to PGI2 in blood
Aspirin mg p.o. daily can reduce the
incidence of PIH and the danger of preeclamapsia

41. 【Adverse effects】 Gastrointestinal side effects
Disturbance of blood coagulation
Salicylism reaction
Hypersensitivity reactions
Reye’s syndrome
Nephrotoxicity

42. 1、Gastrointestinal side effects
gastric upset，gastric ulcer，gastric hemorrhage
Due to：
① direct irritation of the gastric mucosa
② high concentration→irritate CTZ: nausea and vomiting
③ inhibition of production of protective PGs
Countermeasures:
① take after meals, chew up the tablet,antacids
② enteric-coated aspirin
Contraindications: patients with peptic ulcer

43. 2. Disturbance of blood coagulation
general dose—prolong bleeding time;
high dose or long-term use—inhibit prothrombin biosynthesis (VitK can prevent)
contraindications: hemophilia, pregnancy, sever hepatic insufficiency, hypoprothrombinemia, VitK deficiency
be stopped 1 week prior to surgery

44. 3. Salicylism reaction Large dosage(>5g/d)
headache, vertigo, nausea, vomiting, tinnitus,
decreased vision and hearing；hyperpnea, acid-base disturbance, insanity.
Therapy: ①aspirin be stopped at once,
②sodium bicarbonate infusions.
(fluid replacement)

45. 4. Hypersensitivity reactions
urticaria，angioneuro edema，allergic shock
“aspirin asthma”: related to PG biosynthesis inhibition

46. When COX pathway is inhibited,LOX pathway is strengthened,whose metabolites increase accordinglyAA
PGs
LTs
NSAIDs
aspirin asthma

47. 4. Hypersensitivity reactions
aspirin asthma
①mechanism: AA: → PG↓
→LTs↑→bronchospasm→asthma
②therapy: adrenalin ( )
antihistaminic, glucocorticoid ( )

48. 4. Hypersensitivity reactions
contraindications: asthma
chronic urticaria
nasal polyps

49. 5. Reye’s syndrome Severe hepatic dysfunction with
complication of encephalopathy
Substitute aspirin with acetaminophen

50. 6. Nephrotoxicity
Also has been observed.

51. Anilines
Acetaminophen (paracetamol):

52. Similar antipyretic and analgesic effects to aspirin,no significant anti-inflammatory effect
It inhibits synthesis of PG in CNS more effectively than in periphery
Less frequent gastrointestinal irritation

53. Ibuprofen： Less frequent gastrointestinal irritation
It can be slowly released into synovial fluid and remains there with a high concentration
Widely used in rheumatoid arthritis(RA), and osteoarthritis

54. Section 2 Selective COX-2 inhibitors

55. COX-2 inhibitors (Celecoxib,Rofecoxib) have been developed.
In 1998 and 1999,highly selective
COX-2 inhibitors (Celecoxib,Rofecoxib)
have been developed.

56. Celecoxib a highly selective COX-2 inhibitor，COX-2:COX-1 =375:1
gastrointestinal adverse effects are less frequent
not affect TXA2 biosynthesis, but PGI2 synthesis can be inhibited
Contraindications: patients with thrombosis tendency

57. Rofecoxib a highly selective COX-2 inhibitor
does not inhibit platelet aggregation
is approved mainly for osteoarthritis

58. Drugs used in gout

59. purine uric acid excretion hyperuricemia joints kidney connective
xanthine oxidase
purine
uric acid
excretion
hyperuricemia
joints
kidney
connective
tissue
arthritis
Kidney
damage
Connective tissue
damages

60. Treatment aim Drug Mechanism Acute gout chronic gout
①relieve the acute
gouty arthritis
attack
②control the
hyperuricemia
colchicine
(-) inflammation
NSAIDs
Indomethacin
chronic gout
reduce the serum level of uric acid
allopurinol
↓uric acid
synthesis
probenecid
↑uric acid
excretion

61. allopurinol probenecid NSAIDs colchicine
xanthine oxidase
purine
uric acid
excretion
hyperuricemia
joints
kidney
Other
tissues
NSAIDs
Indomethacin
colchicine
arthritis
Kidney
damage
Other tissue
damages

62. Thank you for your attention