antipyretic, analgesic and anti- inflammatory drugs liming zhou ( 周黎明） department of...

Antipyretic, analgesic and anti-inflammatory

drugs

Liming Zhou ( 周黎明）

Department of pharmacology

Huxi medical center

Sichuan university

Contents

• Overview

• History

• Common pharmacological effects

• Aspirin 阿斯匹林• Selective COS-2 inhibitor

• Other Drugs

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

•

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.

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.

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

Common pharmacological effects

These drugs show the same pharmacological

effects

• -- antipyretic effect （解热）• -- analgesic effect （镇痛）• -- anti-inflammatory effect （抗炎）

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)

NSAIDs

PyrogenProstaglandins

pGE2

thermoregulatory center

heat production ↑Heat dissipation ↓

set point ↑

Fever

• Antipyretic MechanismAntipyretic MechanismBlock prostaglandins Block prostaglandins productionproduction • Sites of actionSites of action:: Central Nervous SystemCentral Nervous System

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.

Analgesic Effects

• Pain may arise from:

Musculature, dental work , vascular , postpartum conditions, arthritis , bursitis

• Sites of action:

peripherally -- sites of inflammation

subcortical sites

NSAIDs

Prostaglandins

pGE2 pGF2

Nerve ending of pain

Pain

Bradrkinin

histamine

factors

+

• block prostaglandins block prostaglandins productionproduction

• Sites of actionSites of action: : peripheral tissueperipheral tissue

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

Anti-inflammatory Effects

• Reduced synthesis:

--eicosanoid mediators

• Interference:

--kallikrein system mediators

--inhibits granulocyte adherence

--stabilizes lysosomes

--inhibits leukocyte migration

How can NSAIDs inhibit the prostaglandin production?

The Mechanism of NSAIDs

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)

Mechanism of action

NSAIDs

Prostaglandins

pGE2 pGF2

Symptoms of inflammation

Red, swelling, Heating, Pain

Bradrkinin

Histamine

5-HT

Inflammatory factors

+

• block prostaglandins block prostaglandins productionproduction

• Sites of action: Sites of action: peripheral tissueperipheral tissue

Phospholipids Phospholipase

Arachidonic Acid 5-lipoxygenase cyclooxygenase

5-HPTE PGG2 peroxidase

LTB4 LTC4 PGH2

TXA2 PGI2 PGE2 PGF2 PGD2

• PGE2 vasodilatation, pain

sensitization, gastric cytoprotection [mucous/HCO3 secretion], fever

• PGF2 bronchoconstriction, uterine

contraction

• PGI2 inhibition of platelet aggregation,

gastric cytoprotection

• TXA2 platelet aggregation

Salicylates 水杨酸类

• Acetylsalicyclic acid 乙酰水杨酸

Aspirin 阿斯匹林• Sadium Salicylate 水杨酸钠

Pharmacokinetics• Rapidly absorbed: stomach and upper small

intestine

• Distribution ： through the body

rapidly hydrolyzed --------- acetic acid + salicylate, catalyzed by tissue/blood esterases

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

Pharmacodynamics1. Analgesic Effects (300-600mg)

2. Antipyretic Effects (300-600mg)

3. Anti-inflammatory Effects (3-6g)

do not influence the progress of disease

4. Effects on Platelets (40-100mg)

Reduced platelet aggregation

reduces thromboxane A2 (TXA2) formation

血管壁

磷脂 血小板

磷脂

花生四烯酸

PGH2 PGH2

PGI2

TXA2

花生四烯酸环氧化酶 （－） 阿斯匹林

cAMP 血小板释

放 ADP

促进血小板集聚

收缩

血管平滑肌

cAMP 抑

制血小

板集聚

松弛血

管平滑肌

•Effects on Platelets (40-100mg)

Low doses 40-100mg/day• Platelets

• No nuclei

• No new COX1 produce

• TXA2 production ↓

• Lifetime:

8-11 days

• Endothelial cell

• Has nuclei

• New COX1 produce

Pharmacodynamics5. Other effects

• Immune inhibition

• Effect on metabolism of connective tissue

• Effects on metabolism of glucose, fat, protein ---- catabolism ↑

• ACTH release ↑

Clinical Uses

1. Commonly used for management of mild to moderate pain (300-600mg)

2. Combination agents (cold)

3. Used for reducing fever (300-600mg)

4. Useful in treatment of:

(high doses 3-6g) T1/2 > 12 hours

0 rheumatic fever

0 rheumatoid arthritis

0 other inflammatory joint diseases

Clinical Uses

5. 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

Clinical Uses

6. Hypertension in pregnancy : (low doses) 60-100mg

TXA2↓

7. Local indication

GI inflammation : 5-amido-salicylic acid

SIDE EFFECTS1. CNS: excitation----inhibition

salicylic acid reaction: Headaches; confusion; hallucinations; tremors; vertigo; behavior disturbance

2. GI effects: direct stimulation

PGE2 & PGI2 ↓

Esophagitis; gastric ulcerations; GI hemorrhage

SIDE EFFECTS3. 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

SIDE EFFECTS

4. Other reaction

Hematologic: decreased platelet aggregation; prolonged bleeding time.

Exacerbations of asthma

Hypersensitivity: rashes

Acid-base Imbalance

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

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；

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

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

Anti

pyretic

analgesic

Anti-inflam-matory

Side action

Acetaminophen ++ ++ +

Indomethacin ++++ ++++

sulindac ++++ ++

tolmetin + + ++ ++

diclofenac ++ ++ ++

Ibuprofen + +++ + +

meloxicam ---- cox2Phenylbutazone +++ +++

ketorolac +++ i.m

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