上海交通大学：《药理学 Pharmacology》课程教学资源（讲义课件）Antipyretic-analgesic and anti-inflammatory drugs（nonsteroidal anti-inflammatory drugs,NSAIDs）

® 上游充通大 SHANGHAI JIAO TONG UNIVERSITY 1896 1920 1987 2006 漏 Antipyretic-analgesic and anti-inflammatory drugs (nonsteroidal anti-inflammatory drugs,NSAIDs) UALAO TONG UNIVEDSK MAAA

Antipyretic-analgesic and anti-inflammatory drugs (nonsteroidal anti-inflammatory drugs,NSAIDs)

上浒充通大 SHANGHAI JIAO TONG UNIVERSITY 1896 1920 1987 2006 Non-steroidal anti-inflammatory drugs (NSAIDs) NSAIDs have three major actions,all of which are due mainly to the inhibition of arachidonic acid cyclo-oxygenase in inflammatory cells (the COX-2 isoenzyme), and the resultant decrease in prostanoid synthesis. AJIAO TONG U

Non-steroidal anti-inflammatory drugs (NSAIDs) NSAIDs have three major actions, all of which are due mainly to the inhibition of arachidonic acid cyclo-oxygenase in inflammatory cells (the COX-2 isoenzyme), and the resultant decrease in prostanoid synthesis

上降充通大警 SHANGHAI JIAO TONG UNIVERSITY 1896 1920 1987 2006 Common Pharmacological Effects to be covered below Analgesic (CNS and peripheral effect)may involve non-PG related effects Antipyretic (CNS effect) Anti-inflammatory (except acetaminophen)due mainly to PG inhibition. Some shown to inhibit activation,aggregation,adhesion of neutrophils release of lysosomal enzymes Some are Uricosuric

Common Pharmacological Effects to be covered below • Analgesic (CNS and peripheral effect) may involve non-PG related effects • Antipyretic (CNS effect) • Anti-inflammatory (except acetaminophen) due mainly to PG inhibition. Some shown to inhibit activation, aggregation, adhesion of neutrophils & release of lysosomal enzymes • Some are Uricosuric

上浒充通大 SHANGHAI JIAO TONG UNIVERSITY 1896 1920 1987 2006 COX: COX-1:constitutive enzyme:is involved in tissue homeostasis. COX-2:inducible enzyme:is responsible for the production of the prostanoid mediators of inflammation. VG JIAO TONG UNIVERSI 1三三5

• COX: • COX-1: constitutive enzyme: is involved in tissue homeostasis. • COX-2: inducible enzyme: is responsible for the production of the prostanoid mediators of inflammation

上浒充通大学 SHANGHAI JIAO TONG UNIVERSITY 1896 1920 1987 2006 COX1 and COX2 Figure 3:The Current COX concept Arachidonic Acid Cytokines IL-1,TNF Growth factors C0X-1 C0X-2 Glucocorticoids Constitutive Induced Cytokines IL-4 1三 Inhibition Inhibition undesirable desirable Homeostatic functions Inflammation Gastrointestinal tract IAO Renal tract Platelet Function Macrophage differentiation

• COX1 and COX2

上浒充通大学 SHANGHAI JIAO TONG UNIVERSITY Phospholipase 1896 1920 1987 2006 Steroids Arachidonic acid Cyclooxygenase Lipoxygenases NSAIDs Lipoxygenase inhititors Prostaglandins PMNs PGF2a PGE2 PGL, ON Lymphokines algesic pyrexia vasodilation The events of the inflammtory response and mechanisms of anti-flammatory

Phospholipase Arachidonic acid Cyclooxygenase Lipoxygenases ----- Steroids NSAIDs ----- Prostaglandins PGF2α PGE2 PGI2 algesic pyrexia vasodilation PMNs Lymphokines ----- Lipoxygenase inhititors The events of the inflammtory response and mechanisms of anti-flammatory

上降充通大警 SHANGHAI JIAO TONG UNIVERSITY 1896 1920 1987 2006 Pharmacological Effects Diverse group of chemicals,but all inhibit cyclooxygenase. Resultant inhibition of PG synthesis is largely responsible for their therapeutic effects. But,inhibition of PG synthase in gastric mucosa>GIT damage(dyspepsia, gastritis)

Pharmacological Effects • Diverse group of chemicals, but all inhibit cyclooxygenase. • Resultant inhibition of PG synthesis is largely responsible for their therapeutic effects. • But, inhibition of PG synthase in gastric mucosa  GIT damage (dyspepsia, gastritis)

上降充通大警 SHANGHAI JIAO TONG UNIVERSITY 1896 1920 1987 2006 Common Adverse Effects Platelet Dysfunction Gastritis and peptic ulceration with bleeding (inhibition of PG+other effects) Acute Renal Failure in susceptible o Sodium+water retention and edema Increase in risk of cardiovascular events Hypersensitivity(not immunologic but due to PG inhibition) ·Headache,dizziness

Common Adverse Effects • Platelet Dysfunction • Gastritis and peptic ulceration with bleeding (inhibition of PG + other effects) • Acute Renal Failure in susceptible • Sodium+ water retention and edema • Increase in risk of cardiovascular events • Hypersensitivity (not immunologic but due to PG inhibition) • Headache ,dizziness

上降充通大警 SHANGHAI JIAO TONG UNIVERSITY 1896 1920 1987 2006 Non-steroidal anti-inflammatory drugs (NSAIDs) An anti-inflammatory action: (1)The decrease in vasodilator prostaglandinds (PGE2,PGI,)means less vasodilatation and, indirectly,less edema (2)The inhibition of activity of adhesion molecule. (3)Accumulation of inflammatory cells is also reduced

Non-steroidal anti-inflammatory drugs (NSAIDs) • An anti-inflammatory action: (1) The decrease in vasodilator prostaglandinds (PGE2 , PGI2 ) means less vasodilatation and, indirectly, less edema. (2) The inhibition of activity of adhesion molecule. (3) Accumulation of inflammatory cells is also reduced

上降充通大警 SHANGHAI JIAO TONG UNIVERSITY 1896 1920 1987 2006 Non-steroidal anti-inflammatory drugs (NSAIDs) .An analgesic effect:decreased prostaglandin generation means less sensitisation of nociceptive nerve endings to inflammatory mediators such as bradykinin and 5-hydroxytryptamine Relief of headache is probably due to decreased prostaglandin-mediated vasodilatation

Non-steroidal anti-inflammatory drugs (NSAIDs) • An analgesic effect: decreased prostaglandin generation means less sensitisation of nociceptive nerve endings to inflammatory mediators such as bradykinin and 5-hydroxytryptamine. • Relief of headache is probably due to decreased prostaglandin-mediated vasodilatation