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