1. Antipyretic, analgesic and anti-inflammatory drugs
Liming Zhou (周黎明） Department of pharmacology
Huxi medical center
Sichuan university

2. Contents Overview History Common pharmacological effects Aspirin 阿斯匹林
Selective COS-2 inhibitor
Other Drugs

3. Overview
This kind of drug is a group of chemically dissimilar agents that have antipyretic, analgesic and anti-inflammatory effects.
The structure of this kind of drug differs from that of steroidal anti-inflammatory drugs.
Nonsteroidal anti-inflammatory drugs NSAIDs

4. History
In ancient Egypt & Greece, dried leaves of myrtle, the bark of willow & poplar tree
In England, active component from willow bark was identified as salicin (水杨苷）, which is metabolized to salicylate （水杨酸盐）in 1763.
In Germany, salicylic acid （水杨酸） was synthesized in 1860.
In 1875, acetylsalicylic acid （乙酰水杨酸） was synthesized.
Poplar n. 白杨, 白杨木
Myrtle n. [植]桃金娘科植物

5. History
In 1899， “Aspirin“ （acetylsalicylic acid） was named; the "a" --- acetyl grouping and the "spirin" --- botanical genus spiraea, from which salicylates could be extracted.
Now, more than 30 million people consume NSAIDs daily and of these 40% of the patients are more than 60 years of age.
The consumption of NSAIDs is No. 1 among all drugs.
Spiraea [植]绣线菊类的植物

6. History
In 1969 the first association between prostaglandin production and the actions of aspirin- like drugs
In 1992 new enzyme was cloned & was called cyclooxygenase 2 (COX- 2) or PGH 2 synthase 2

7. Common pharmacological effects
These drugs show the same pharmacological effects
-- antipyretic effect （解热）
-- analgesic effect （镇痛）
-- anti-inflammatory effect （抗炎）

8. 1. Antipyretic Effects "normal" temperature: slightly affected
"elevated" temperature: reduced
The higher temperature, the more potent
Mechanisms of Antipyretic Action
Blocks pyrogen-induced prostaglandin production in thermoregulatory center (CNS)

9. thermoregulatory center
Prostaglandins
pGE2
Pyrogen
NSAIDs
thermoregulatory center
Antipyretic Mechanism
Block prostaglandins production
Sites of action: Central Nervous System
set point ↑
heat production ↑
Heat dissipation ↓
Fever

10. Heat production and heat dissipation
Heat production and heat dissipation . In fever associated with an infection ,increased oxidative processes enhance heat production .
Aspirin causes cutaneous vasodilation, prompts perspiration, and enhance heat dissipation.

11. 2. Analgesic Effects Effective to mild to moderate pain
0.5g of aspirin is a weak or mild analgesic that is effective in short, intermittent types of pain as encountered in neuralgia, myalgia (肌肉痛), toothache.

12. Analgesic Effects Pain may arise from:
Musculature, dental work , vascular , postpartum conditions, arthritis , bursitis
Sites of action:
peripherally -- sites of inflammation
subcortical sites
Postpartum 产后的
Bursitis [解, 动]粘液囊炎

13. + factors NSAIDs Pain Prostaglandins pGE2 pGF2 Bradrkinin histamine
Nerve ending of pain
block prostaglandins production
Sites of action: peripheral tissue
Pain

14. 3. Anti-inflammatory Effects
NSAIDs only inhibit the symptoms of inflammation
But they neither arrest the progress of the disease nor do they induce remission

15. Anti-inflammatory Effects
Reduced synthesis:
--eicosanoid mediators
Interference:
--kallikrein system mediators
--inhibits granulocyte adherence
--stabilizes lysosomes
--inhibits leukocyte migration
Kallikrein [生化][药]激肽释放酶

16. How can NSAIDs inhibit the prostaglandin production?
The Mechanism of NSAIDs

17. Mechanism of action
The principal pharmacological effect of NSAIDs is due to their ability to inhibit prostaglandin synthesis by blocking the cyclooxygenase （COX） activity of both COX-1 and COX-2.
NSAIDs----- acetylation of COX
(reversible or irreversible)

18. Symptoms of inflammation
NSAIDs
Prostaglandins
pGE2 pGF2
Inflammatory factors +
Bradrkinin
Histamine
5-HT
Symptoms of inflammation
block prostaglandins production
Sites of action: peripheral tissue
Red, swelling,
Heating, Pain

21. PGE2 vasodilatation, pain sensitization, gastric cytoprotection [mucous/HCO3 secretion], fever
PGF2 bronchoconstriction, uterine contraction
PGI2 inhibition of platelet aggregation, gastric cytoprotection
TXA2 platelet aggregation

22. Salicylates 水杨酸类 Acetylsalicyclic acid 乙酰水杨酸 Aspirin 阿斯匹林
Sadium Salicylate 水杨酸钠

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

24. 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

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

26. Effects on Platelets (40-100mg)
磷脂 血小板 磷脂
花生四烯酸
PGH PGH2
PGI2
血管壁
花生四烯酸
（－）
阿斯匹林
环氧化酶
cAMP 抑
制血小
板集聚
松弛血
管平滑肌
cAMP 血小板释
放ADP
促进血小板集聚 收缩
血管平滑肌
TXA2

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

28. Pharmacodynamics 5. Other effects Immune inhibition
Effect on metabolism of connective tissue
Effects on metabolism of glucose, fat, protein catabolism ↑
ACTH release ↑

29. Clinical Uses
Commonly used for management of mild to moderate pain ( mg)
Combination agents (cold)
Used for reducing fever ( mg)
Useful in treatment of:
(high doses 3-6g) T1/2 > 12 hours
0 rheumatic fever
0 rheumatoid arthritis
0 other inflammatory joint diseases

30. Clinical Uses Antiplatelet: (low doses) 40-100mg
reduce incidence of transient ischemic attacks (prophylaxis)
reduce incidence of unstable angina (prophylaxis)
may reduce incidents of coronary artery thrombosis

31. Clinical Uses Hypertension in pregnancy : (low doses) 60-100mg TXA2↓
Local indication
GI inflammation : 5-amido-salicylic acid

33. SIDE EFFECTS CNS: excitation----inhibition
salicylic acid reaction: Headaches; confusion; hallucinations; tremors; vertigo; behavior disturbance
GI effects: direct stimulation
PGE2 & PGI2 ↓
Esophagitis; gastric ulcerations; GI hemorrhage

34. 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

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

36. Acetaminophen 乙酰氨基酚（醋氨酚，扑热息痛） Phenacetin 非拉西丁
Rapidly absorbed from GI
Phenacetin is largely converted to Acetaminophen
Similar antipyretic, analgesia to aspirin
Weak anti-inflammatory properties
used to reduce fever and pains (a major ingredient in numerous cold and flu medications) (choice for child)
used appropriately, side effects are rare

37. Indomethacin 吲哚美辛（消炎痛）
More potent than aspirin
As an anti-inflammatory agent
More adverse reaction
Ibuprofen 布洛芬
More analgesia
Fewer adverse reaction
Brufen；Benzeneacetic acid； Fenbid； Emodin；Motrin 异丁苯丙酸；异丁洛芬；拔怒风；芬必得；炎痛停；

38. Phenylbutazone 保泰松 羟基保泰松
Powerful anti-inflammatory effects
Weak analgesic & antipyretic activities
Promote excretion of uric acid
Used for acute gout, rheumatic & rheumatoid arthritis
More adverse reaction
Can induce activities of drug metabolize-E
Can displace other drugs from plasma proteins

39. Selective COX-2 inhibitors
Less adverse reactions
Do not impact platelet aggregation
Meloxicam 美洛昔康
Celecoxib 塞来昔布
Nimesulide 尼美舒力
Rofecoxib
Valdecoxib

40. 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

41. Selective COS-2 inhibitor
Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that is used to treat arthritis .As a consequence, inflammation and its accompanying pain, fever, swelling and tenderness are reduced.
Celecoxib is approved as an adjunctive (secondary) treatment among patients with FAP.
PRESCRIBED FOR: Celecoxib is used for the relief of pain, fever, swelling, and tenderness caused by osteoarthritis and rheumatoid arthritis .

42. NSAIDs have been found to prevent the formation and reduce the size of polyps in patients with the genetic disease, familial adenomatous polyposis (FAP)
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.

43. Celecoxib does not prevent the progression of either type of arthritis
Celecoxib does not prevent the progression of either type of arthritis. It reduces the symptoms and signs of arthritis. Celecoxib also has been approved for patients with FAP who have not had their colons removed.
Celebrex is also approved for the relief of acute pain and the pain of menstrual cramps (dysmenorrhea) (痛经).

44. 常用感冒药组成 解热镇痛药：对乙酰氨基酚、布洛芬 H1受体阻断药：氯苯那敏、苯海拉明 止咳药：右美沙芬等 缩血管药：伪麻黄碱
抗病毒药：金刚烷胺
中枢兴奋药：咖啡因
其他：中草药、人工牛黄