Download Antipyretic, analgesic and anti

Antipyretic, analgesic and antiinflammatory
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 antiinflammatory 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)
Prostaglandins
pGE2
thermoregulatory
center
Pyrogen
NSAIDs
• Antipyretic Mechanism
set point ↑
heat production ↑
Heat dissipation ↓
Fever
Block prostaglandins
production
• Sites of action:
Central 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
factors
pGE2 pGF2
+
Bradrkinin
histamine
Nerve ending of
pain
Pain
• block prostaglandins
production
• Sites of action:
peripheral 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
Mechanism of action
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)
NSAIDs
Prostaglandins
Inflammatory
factors
pGE2 pGF2
+
Bradrkinin
Histamine
Symptoms of
inflammation
Red, swelling,
Heating, Pain
5-HT
• block prostaglandins
production
• Sites of action:
peripheral tissue
Phospholipids
Phospholipase
Arachidonic Acid
5-lipoxygenase
cyclooxygenase
5-HPTE
LTB4
PGG 2
peroxidase
LTC4
PGH2
TXA 2 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
Pharmacodynamics
1. 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
•Effects on Platelets (40-100mg)
血
管
壁
磷脂
血小板
磷脂
花生四烯酸
花生四烯酸
环氧化酶
抑
cAMP
制血小
PGH2
PGH2
板集聚
收缩
松弛血
管平滑肌
PGI2
血管平滑肌
TXA2
（－）
cAMP
阿斯匹林
血小板释
放ADP
促进血小板集聚
Low doses 40-100mg/day
• Platelets
• Endothelial cell
• No nuclei
• Has nuclei
• No new COX1
• New COX1 produce
produce
• TXA2
production ↓
• Lifetime:
8-11 days
Pharmacodynamics
5. 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 EFFECTS
1. 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 EFFECTS
3. 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
Acetaminophen
Anti
pyretic
analges Antiic
inflammatory
Side
action
++
++
+
Indomethacin
++++
++++
sulindac
++++
++
+
++
++
++
++
++
+++
+
+
tolmetin
+
diclofenac
Ibuprofen
+
meloxicam
----
Phenylbutazone
ketorolac
+++
+++
cox2
+++
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