Chapter 20 AnalgChapter 20 Analgeesic-Antipsic-Antipyyrreetic and Antiitic and Antiinflnflaammatory Drugsmmatory Drugs

(Non-st(Non-steeroidal Anti-inflroidal Anti-inflaammatory Drugs,NSAIDmmatory Drugs,NSAIDs)s)

MMeechanism of NSAIDschanism of NSAIDs

•The basis of these action of NSAIDs is due primarily to the inhibinhibiition of prostagltion of prostaglaandin(PGs) sndin(PGs) syynthnthesis.esis.

PLA2

血管舒张剂

血管通透性增加

支气管收缩

趋化性增强

steroidals-

Leukotriene

5-LipoxygenaseCOX-1 CO

X-2

TXA2

血栓形成血管收缩

PGE2 PGD2

PGF2

体温、炎症疼痛传递、胃粘膜保护

PGI2

血管舒张 血小板解聚

Arachidonic acid(AA) PAF

Cell membrane phospholipids

NSAIDs

—

参与过敏反应诱发炎症 支气管收缩 白细胞趋化

PGG2 PGH2

• Analgestic action mild or moderate pain following injury,disease,or minor surgery,as well as chronic pain states including arthritis and cancer.

• Antipyretic action NSAIDs reset the set-point to the normal level and lower the elevated body temperature in patients with fever by inhibiting the endogenous synthesis of PGs in hypothalamus.

• Anti-inflammatory action NSAIDs may provide symptomatic relief from fever,pain,and other signs of rheumatic or rheumatoid arthritis,but do not arrest the progression of pathological injury to tissue.

• Some nonselective NSAIDS also have anti-thrombotic actions.

PhPhaarmacolrmacoloogical effects of NSAIDsgical effects of NSAIDs

ClassificClassificaation of NSAIDstion of NSAIDs

Nonselective COX inhibitors

Selective COX-2 inhibitors

aspirin （ sodium salicylate ）阿司匹林

Acetaminophen 醋氨酚（扑热息痛）

Indomethacin 吲哚美辛（消炎痛）

Ibuprofen 布洛芬（芬必得）

Phenylbutazone 保泰松

Rofecoxib 罗非昔布

Celecoxib 塞来昔布

Etodolac 依托度酸

Nimesulide 尼美舒利

Salicylates---Aspirin

• 1. Analgesic Effects: ☆ Aspirin is most effective in reducing pain of mild reducing pain of mild

to moderate intto moderate inteensity (headache, toothache,dysmnsity (headache, toothache,dysmenenoorrhearrhea<< 痛经痛经 >> ，， arthrarthraalgia,etc)lgia,etc).

☆ 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.

[Pharmacological Effects and clcliinical nical UsesUses]

• 2. Antipyretic Effects:

☆ Aspirin reduces reduces eelevated temperaturelevated temperature, whereas normal body temperature is not affected.

☆Aspirin’s antipyretic effect is mediated by cyclooxygenase-2 (COX-2) inhibition in the central nervous system.

☆ 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.

Aspirin

• 3. Anti-inflammatory Effects:

☆ The anti-inflammatory property of aspirin in high dosage (3-6 g/d) is responsible for treatment various kinds of inflammation including acute rheumatic fever, rheumatoid and other types of arthritis.

☆ It has been advocated as a diagnostic test when acute rheumatic fever( 风湿热 ) is suspected.

Aspirin

• 4. Effect on platelets ☆Low doses of aspirin can inhibit platelet aggregation and

produce a slightly prolonged bleeding time by irrevirreveersiblrsible inhibition of ple inhibition of plaatelet COX.telet COX.

☆Low doses of aspirin can irrevirreveersibly inhibit the productirsibly inhibit the production of TXAon of TXA2 in platelets without markedly interf in platelets without markedly interfeering witring with PGIh PGI22 production in endoth production in endotheelial cells.lial cells.

☆ In general, Aspirin should be stopped 1 week prior to surgery to avoid bleeding complication.

☆ Aspirin has been shown to decrease the decrease the iincidence of trncidence of traansnsient isochient isocheemic attmic attaacks cks (( 短暂局部缺血性休克）短暂局部缺血性休克） , unstable , unstable angangiina,corna,coroonary nary aartery thrombrtery thromboosissis （血栓形成）（血栓形成） with mwith myocyocaardial infarction,and thrombosis after corrdial infarction,and thrombosis after coroonary artery nary artery bypass grbypass graafting.fting.

Aspirin

Adverse Effects

• 1. Gastrointestinal tract

• This effect can be decreased with suitable buffering(taking Aspirin with meals ). 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.

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

Aspirin

• 2.Blood Aspirin increases bleeding time,decreases platelet adhesiveness,,and ,at large doses,may cause hypoprothrombinaemia.

• 3.hepatotoxicity

• 4.Hypersensitivity aspirin asthma aspirin asthma

• 5.Salicylate intoxication

• 6. Reye’s syndrome

AspirinAdverse Effects

Acetaminophen and Phenacetin▽ Acetaminophen is the active metabolite of phenac

etin responsible for its analgesics effect.

▽ It is a weak prostaglandin inhibitor in peripheral tissues and possesses no significant anti-inflammatno significant anti-inflammatory effects.ory effects.

▽ Acetaminophen is one of the most important drugs used for the treatment of mild to moderate pain when an anti-inflammatory effect is not necessary.

▽ Phenacetin is more toxic and has no rational indications

Antipyretic-analgesic and antiinflammatory drugs-- 苯胺类

Indomethacin （吲哚美辛）

▽ Indomethacin is an indole derivative.▽ It enjoys the usual indications for use in rhe

umatic conditions and is particularly popular for gout and ankylosing spondylitis （强直性脊柱炎） . In addition,it has been used to treat patient ductus arteriosus （动脉导管闭锁不全） .

▽ It is one of the most potent COX inhibitors, and has more adverse effects.

Antipyretic-analgesic and antiinflammatory drugs

Ibuprofen ( 布洛芬）其缓释胶囊称“芬必得” .

☆ Ibuprofen is a simple derivative of Arylpropionic acid （芳基丙酸） .

☆ In doses of about 2400 mg daily,ibuprofen is equivalent to 4 g of aspirin in anti-inflammatory effect.Oral ibuprofen is often prescribed in lower doses(<2400mg/d),at which it has analagesic but not anti-inflammatory efficacy.

☆ It is used for treatment oftreatment of rhrheueumatoidmatoid(( 类风湿的类风湿的 )) arthr arthriittis and other inflammatory joint conditionsis and other inflammatory joint conditions

☆ It is available over the counter in lower dosage under several trade names.

Antipyretic-analgesic and antiinflammatory drugs-- 其他有机酸类

Phenylbutazone ( 保泰松） • Phenylbutazone,a pyrazolone derivative ra

pidly gained favor after its introduction in 1949 for the treatment of rheumatic syndromes, but its toxicities,particularly the hematologic effects (including aplastic anemia),have resulted in its withdrawal from many markets.It is rarely used today.

Antipyretic-analgesic and antiinflammatory drugs-- 吡唑酮类

Celecoxib( 塞来昔布 )

• Celecoxib is a selective COX-2 inhibitor, having slight action on COX-1 in therapeutic dosage.

• The incidence of gastric toxicity is much lower with it than with non-selective COX inhibitors.

• It is used for treatment oftreatment of osteoarthritis and osteoarthritis and rhrheueumatoidmatoid(( 类风湿的类风湿的 )) arthr arthriitis.tis.

Antipyretic-analgesic and antiinflammatory drugs—selective COX-2 inhibitors