What are NSAIDs? their uses and side effects?

Antipyretic-analgesic and anti-inflammatory agents

Introduction
Have strong antipyretic
Analgesic 
Anti-inflammatory
Anti-rheumatic   effects
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

 Characteristics
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

Chlorpromazine
 - ¯ 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
Pain transmission

Functionary site---- mainly  periphery

 Characteristics
  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:
   ¯Vasodilation;
   ¯Vascular  permeability ;
   ¯Tissue edema 
-¯ Cellular adhesion molecule produce
Exception: Acetaminophen
Functionary site---- periphery
Characteristics
  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
• Anti-tumor
• 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 
Ibuprofen, Paracetamol
Aspirin, Indomethacin, Sulindac, Piroxicam, …….
-Selective COX-2 inhibitors
Celecoxib, Rofecoxib, Nimesulide

According to the chemical structures

• Salicylates:aspirin, sodium salicylate
• Anilines:phenacetin, acetaminophen
• Pyrazolons:phenylbutazone
• Others: Indomethacin, Ibuprofen       ……

Aspirin (Acetylsalicylic acid , ASA) 

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. 

Pharmacokinetics
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 )；
4、excretion--kidney,
   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)
    used for:

•  Prophylaxis of thromboembolism,  
•  Stroke,
•  Cardiac infarction.
•  Recommended dosage : 40mg/day  or 80mg every other day

3. Other effects and uses

• Gout
• Ascariasis of biliary tract 
• Alzheimer's disease
• Kawasaki disease 
• Patent ductus arteriosus
• Lower the incidence of Colon cancer

 Adverse   reactions
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

2、Coagulation disorders
↓TXA2→ ↓ platelet  aggregation→
   prolonged bleeding time 
↑dosage→↓prothrombin（Ⅱ）production →bleeding tendency 
Prevention and  cure ：vitamine K, 
     stop at 1 week before operation.
Contraindications:

•  severe hepatic diseases
•  hypothrombinemia 
•  vitamin K deficiency
•  hemophilia

3、Hypersensitivity 
 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 !
Contraindications:

1.  asthma
2.  nasal polyps
3.  chronic urticaria

4、Salicylism 
  overdosage（>5g/d）
  GI symptoms + CNS symptoms
Prevention and  cure ： 
 avoid overdosage; 
 withdrawal at once
 iv.gtt. NaHCO3 → excretion↑

5、Reye’s  syndrome

•  Infected with virus, especially in  children.
•  Fulminating hepatitis with cerebral edema.
•  Rare, but fatal

Prevention
 use other drugs 

6、Other syndromes

•  Edema,
•  Polyuria, 
•  Renal function impairment
•  Toxic doses→respiratory depression

Acetaminophen ( paracetamol)
Characteristics
   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 
         infections 
   4、Adverse  reaction:   mild
         overdosage ----- hepatic damage, 
         esp in persons who regularly consume 
         alcohol.

Phenylbutazone
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.

Indomethacin

•  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 
☆ 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