Antipyretic-analgesic and anti-inflammatory agents
Have strong antipyretic
Non-steroidal anti-inflammatory drugs (NSAIDs)
Mechanism of NSAIDs
The basis of antipyretic, analgesic and anti-inflammatory effects of NSAIDs is due primarily to the inhibition of cyclooxygenase (COX) that catalyze the first step in prostanoid biosynthesis.
This leads to decreased prostaglandins(PGs) synthesis.
Ways to inhibit COX
Most NSAIDS : compete the active site of COX with AA, reversible
Aspirin: irreversibly acetylates (and thus inactivates) COX
Common pharmacological effects of NSAIDs
1- Antipyretic action
Process of pyrexia
1) ¯ elevated T > normal
( patients with fever );
2) independent of environment T;
3) mainly influence heat dissipation.
Compare chlorpromazine with NSAIDs on regulation of T
- ¯ both elevated and normal T
- dependent of environment T
( T ↑ or ¯ )
- Influence both production and dissipation of heat
Meaning of pyrexia
Advantages：Defense ，diagnose ；
Disadvantages: High fever or durative fever> consume physical force，CNS function disorders .
T > 39ºc (especially wean !)
2- Analgesic action
Functionary site---- mainly periphery
1) Moderate analgesia:
Inflammatory pain well,
but severe or colic pain useless;
2) No addiction ，
No respiratory depression .
Compare Opioids with NSAIDs on analgesic action
3-Anti-inflammatory and antirheumatic action
In the inflammatory reaction
-¯ PGs produce:
¯Vascular permeability ;
-¯ Cellular adhesion molecule produce
Functionary site---- periphery
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.
Compare SAIDs with NSAIDs on anti-inflammation action
Other effects of NSAIDs
- To inhibit platelet aggregation and thrombosis
- To prevent and delay the onset of Alzheimer's disease
- To slow down the aging of cornea
Development of NSAIDs
- 1860 Rev.Edmond Stone found the bark and leaves of the willow tree could effectively relieve pain
- 1863 salicylic acid was synthesized
- 1899 aspirin came into the market
- 1960 a great deal of NSAIDs were gradually developed
- 1971 John Vane lodged the theory of the mechanism of
- NSAIDs : to inhibit the activity of PG synthase (COX)
- 1991-1995 discovery of COX-1and COX-2, formation of the notion of COX
- Recent years application of COX-2 inhibitors in clinic promote the development of the notion
- 2002 discovery of COX-3
Effects of NSAIDs on COX-1 and COX-2（IC50：mol/L）
Drugs COX-1 COX-2 COX-2/COX-1
Piroxicam 0.0015 0.906 600
Aspirin 1.6 277.0 173
Indomethacin 0.028 1.680 68
Ibuprofen 4.8 72.8 15.16
Meloxicam 0.214 0.171 0.08
Naproxen 9.5 5.0 0.58
Nabumetone 7.0 1.0 0.143
Nimesulide ＞10 0.07 ＜0.007
Celecoxib 15 0.04 0.0027
Rofecoxib 0.018 0.0015 ＜0.0833
Classification of NSAIDs
According to IC50 of COX-2 / IC50 of COX-1
-Non-selectivity COX inhibitors
Naproxen, Flurbiprofen, Diclofenac
Aspirin, Indomethacin, Sulindac, Piroxicam, …….
-Selective COX-2 inhibitors
Celecoxib, Rofecoxib, Nimesulide
According to the chemical structures
- Salicylates:aspirin, sodium salicylate
- Anilines:phenacetin, acetaminophen
- Others: Indomethacin, Ibuprofen ……
History: Centuries ago Greek physician Hippocrates prescribed the bark and leaves of the willow tree to relieve pain and fever.
The active ingredient, salicin was first isolated in 1829 and was demonstrated to have antipyretic effect.
A German chemist experimented with salicin and created salicylic acid in 1832. Felix Hoffmann, a chemist at Bayer in Germany, chemically synthesized a stable form of acetylsalicylic acid powder that relieves his father’s rheumatism.
Since 1899 aspirin has been an important drug for an anti-inflammatory indication.
Aspirin—“a” from acetyl, “spir” from the spirea plant (which yields salicin) and “in,” a common suffix for medications.
1、absorb rapidly，distribution wide ;
2、metabolism--liver; individual variation ;
3、dosage < 1g, linear kinetics , t1/2 2~3h;
dosage non-linear kinetics, t1/2
( >1g, t1/2 15~30h )；
influenced by urine pH
Effects and Uses
1. Antipyretic 、analgesic and anti-inflammatory effects
usually used for:
- Moderate pain;
- Various inflammatory pain;
- Rheumatic arthritis first choice ;
- Rheumatoid arthritis first choice; 3-5g / d, qid.
- Rheumatic fever
2. Antiplatelet effects (small dose)
- Prophylaxis of thromboembolism,
- Cardiac infarction.
- Recommended dosage : 40mg/day or 80mg every other day
3. Other effects and uses
- Ascariasis of biliary tract
- Alzheimer's disease
- Kawasaki disease
- Patent ductus arteriosus
- Lower the incidence of Colon cancer
1、Gastrointestinal symptoms the most common reaction, induce or aggravate ulcer
Caused by: Direct stimulation, (-) parietal cell COX-1→ PGE2↓, (+) CTZ.
Prevention and cure ：
Medicated after a meal
Use buffered and enteric-coated preparations
Used with misoprostol, omeprazol,antacids, cimetidine
Contraindications: Peptic ulcer
↓TXA2→ ↓ platelet aggregation→
prolonged bleeding time
↑dosage→↓prothrombin（Ⅱ）production →bleeding tendency
Prevention and cure ：vitamine K,
stop at 1 week before operation.
- severe hepatic diseases
- vitamin K deficiency
rash, rhinitis, angioneurotic edema, and anaphylactic shock
some asthmatic patients---aspirin asthma (Constrict the bronchial smooth muscle)
Note: Be avoided in patients receiving anticoagulants such as coumarin and heparin
Prevention and cure ：
GCS or H1-R (-)
Adrenaline --- inefficient !
- nasal polyps
- chronic urticaria
GI symptoms + CNS symptoms
Prevention and cure ：
withdrawal at once
iv.gtt. NaHCO3 → excretion↑
- Infected with virus, especially in children.
- Fulminating hepatitis with cerebral edema.
- Rare, but fatal
use other drugs
Acetaminophen ( paracetamol)
1、Inhibits synthesis of PGs in CNS but not in periphery.
2、No anti-inflammatory or anti-platelet
effects, but is good for mild pain and fever
antipyretic 、analgesic ≈ aspirin
3、Mostly used for：
headache、fever can’t take aspirin;
first choice for children with virus
4、Adverse reaction: mild
overdosage ----- hepatic damage,
esp in persons who regularly consume
Phenylbutazone,a pyrazolone derivative rapidly 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.
NOTE: It is rarely used today.
- It is an indole derivative.
- It is one of the most potent COX inhibitors.
- Anti-inflammatory 、antipyretic and analgesic effects are remarkable.
- Used to treat acute gouty arthritis, ankylosing spondylitis, and osteoarthritis of the hip. In addition,it has been used to treat patent ductus arteriosus.
- Adverse reactions: severe; cross-sensitization with aspirin.
☆ Ibuprofen is a simple derivative of Arylpropionic acid.
☆ 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 analgesic but not anti-inflammatory efficacy.
☆ It is used for treatment of rheumatoid arthritis and other inflammatory joint conditions
☆ It is available over the counter in lower dosage under several trade names.
Selective COX-II Inhibitors
- Anti-inflammatory with less adverse effects, especially GI events.
- Potential toxicities: kidney and platelets - ? increased risk of thrombotic events
- Role in Cancer prevention
- Role in Alzheimer’s disease
Data suggested an increased risk for cardiovascular events in patients receiving rofecoxib.
On the morning of 30 Sep.2004, the U.S. FDA issued a Public Health Advisory about the withdrawal of rofecoxib