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Antipyretic-analgesic and anti-inflammatory drugs. Objectives. The pharmacological action, mechanism of action , common adverse reactions of the antipyretic analgesic drugs. Antipyretic-analgesic and Anti-inflammatory Drugs.
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Objectives The pharmacological action, mechanism of action , common adverse reactions of the antipyretic analgesic drugs
Antipyretic-analgesic and Anti-inflammatory Drugs • a kind of antipyretic and analgesic, anti-inflammatory, and most antirheumatic effect of drugs
The structure of this kind of drug differs from that of steroidal anti-inflammatory drugs. • Nonsteroidal anti-inflammatory drugs NSAIDs
Nonsteroidal Anti-Inflammatory Drug relieves pain and fever by inhibiting the inflammatory response. 5
Common pharmacological effects These drugs show the same pharmacological effects • -- antipyretic effect • -- analgesic effect • -- anti-inflammatory effect
signs of inflammation • Redness - due to local vessel dilatation • Heat - due to local vessel dilatation • Swelling – due to influx of plasma proteins and phagocytic cells into the tissue spaces • Pain – due to local release of enzymes and increased tissue pressure
COX Mechanism of NSAIDs phospholipid PLA2 NSAIDs Arachidonic acid, AA Leukotrienes, LTs Prostaglandin, PG PGE2 PGF2 PGI2 TXA2
Basic pharmacological effects Common mechanism of action: Inhibition of cyclooxygenase (COX)， reduce biosynthesis of prostaglandin
Physiological Functions of Prostaglandins 1.Pain 2. Inflammation 3. Fever PGE2 sensitize nerve endings to bradykinin, histamine and substance P PGI2, PGD2 ,PGE2– vasodilators (edema, erythema) PGE2 5. Protection of the gastric mucosa 6. Uterus 4. Platelets PGI2 , PGD2 inhibit platelet aggregation TXA2 stimulates platelet aggregation PGD2 contracts uterus PGI2 9. Other 7. Maintenance of renal blood flow 8.Bronchial constrict PGE2 keeps ductus arteriosus open following birth PGF2 PGE2 15
Categories of NSAIDs NSAIDs non-selective COX inhibitors selective COX-2 inhibitors 16
Pain Treatment • Analgesics • Antipyretic-analgesic and anti-inflammatory drugs*
Pain An unpleasant experience associated with actual or potential tissue damage.
A. Analgesic properties • NSAIDs Prostaglandins pGE2 pGF2 Inflammatory factors + Bradykinin Histamine 5-HT Symptoms of inflammation • block prostaglandins production • Sites of action: peripheral tissue Red, swelling, Heating, Pain
A. Analgesic properties • Most frequently used for mild-to-moderate pain(opioids for moderate-to-severe pain) 21
To traumatic pain and visceral smooth muscle cramps is invalid. Analgesic action lies in peripheral site.
Prostaglandins by themselves do not cause pain but lower the threshold of the C fiber nociceptors.
B. Anti-pyretic properties Return the elevated set point during fever to normal. 26
The hypothalamus phospholipids NSAID virus bacteria antigen Antibodies are - Tissue damage IL-1β IL-6 IFN-α IFN-β TNF-α Unsaturated fatty acids Inhibition COX PGE2 The set-point ↑ fever（heat production >heat dissipation ） *Lower heating temperature ←Antipyretic effect
The concentration of cytokines such as IL-1B, IL-6, and TNF frequently are increased during inflammation which stimulate the synthesis of PGE2 near the hypothalamic area.
Heat loss set point (hypothalamus) Heat genera-tion Normal fever After aspirin 29
Points: (1).The normal temperature had no effect. Fever caused by direct injection of PG is invalid.
"elevated" temperature: reduced • The higher temperature, the more potent
Mechanisms of Antipyretic Action Blocks pyrogen-induced prostaglandin production in thermoregulatory center (CNS)
(3). The antipyretic mechanism is inhibition of prostaglandin synthetase of the hypothalamus
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
The history of antipyretic analgesics 1750： To use willow bark for treatment "fever" is a success, bitter -- called "salicin" 1875：Sodium salicylate successfully used in the treatment of rheumatic fever 1899：Aspirin (acetylsalicylic acid) on the market
Salicylates • Acetylsalicyclic acid Aspirin • Sadium Salicylate
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
Pharmacodynamics • Analgesic Effects (300-600mg) • Antipyretic Effects (300-600mg)
3.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
Anti-Thrombolytic Action of Aspirin COX-2 specific drugs are not anti-thrombolytic. Endothelial cell Pletelet COX-1 COX-1/COX-2 - - Aspirin LD HD TXA2 PGI2 +++ platelet aggregation +++platelet shape change +++platelet granule release +++vasoconstriction Inhibit platelet aggregation - platelet secretion +++vasodilation A single dose of aspirin approximately doubles the mean bleeding time of normal persons for a period of 4～7 days. 44
Platelets No nuclei No new COX1 produce TXA2 production ↓ Lifetime: 8-11 days Endothelial cell Has nuclei New COX1produce Low doses 40-100mg/day
Pharmacodynamics 5. Other effects • Immune inhibition
Anti-cancer property • A number of studies (animals and humans) have shown an up-regulation of COX-2 in colonic cancers. • A large body of epidemiological evidence points to an inverse association between aspirin use and colorectal cancer risk. 47
The mechanism, the dose and duration required for maximal efficacy still are not completely clear.
Prevention or relief of symptoms of Alzheimer’s Disease 49
Clinical Uses • Commonly used for management of mild to moderate pain (300-600mg) • Combination agents (cold)