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									Non-steroidal Anti-Inflammatory Drugs
• Inflammation (Latin, inflammare, to set on fire) is part
  of the complex biological response of vascular tissues
  to harmful stimuli, such as pathogens, damaged cells,
  or irritants. Inflammation is a protective attempt by the
  organism to remove the injurious stimuli and to initiate
  the healing process.
• The inflammatory response is a normal (desirable)
  defense mechanism.
• The side effects are undesirable.
• Normal inflammatory response has an on/off switch.
• In chronic inflammation something has gone wrong
  with the OFF switch
• Therefore we need drugs to control the inflammatory
                 Injury; Invading Pathogens;
Trigger          Foreign Material


            Injured cells   Mast cells    Macrophages

               kinins; peptides; interleukins;
               heparin; enzymes;arachidonic acid
               metabolites; chemokines......

                      Nerve                Epithelial
Cell and Organ        cells                  cells
Responses      Renal    effects of inhibition

                            Pain            Secretion

             Blood          Brain          Liver
             Redness;       Fever;       Acute Phase
             Swelling       Malaise       Response
               4 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
 Nonsteroidal Anti-Inflammatory Drug

• A therapeutic agent which relieves pain and
  fever by inhibiting the inflammatory

• These drugs are available over the counter
  and by prescription.

• Some common examples include aspirin,
  ibuprofen, Celecoxib, and less commonly
         Biosynthesis of Prostaglandins

• The goal is to inhibit the biosynthesis of
  prostaglandins in order to relieve the
  symptoms caused by the inflammatory

• Prostaglandins     are    synthesized   from
  arachidonic acid in a pathway mediated by the
  Cyclooxygenase enzymes.

• There are several forms of cyclooxygenase,
  COX1 (the predominant form), COX2 and
COX          Expression               Function               Inhibitors
                            organ pain, platelet
        constitutively      function, stomach           NSAIDs including
        throughout the body                             aspirin
                                 Inducible: inflammation,
        Inducible and            pain, fever              NSAIDs, COX 2
COX-2   constitutively in brain, Constitutive: synaptic inhibitors including
        kidney                                            celecoxib

        Constitutively, high in pain pathways, not    acetaminophen
        brain, heart            inflammation pathways some NSAIDs
NSAID's have three major actions
all of which are due mainly to the inhibition of Cyclo-oxygenase
isozymes (Cox I and Cox 2) and the resultant decrease in
prostanoid synthesis.
 An anti-inflammatory action: the decrease in vasodilator
prostaglandins (PGE2, PGI2) means less vasodilation and,
indirectly, less edema. Accumulation of inflammatory cells is not
 An analgesic effect: decreased prostaglandin generation
means less sensitization of nociceptic nerve endings to the
inflammatory mediators bradykinin and 5-Hydroxyt ryptamine.
Relief of headache is probably due to decreased prostaglandin
mediated vasodilatation.
 An antipyretic effect: this is partly due to a decrease in the
mediator prostaglandin (which is generated in response to the
inflammatory pyrogen interleukin-1) that is responsible for elevating
the hypothalmic set-point for temperature control in fever.
                     Categories of NSAIDs

• There are two major categories for non-
  steroidal anti-inflammatory drugs

• The first is non-selective anti-inflammatory

• The second is selective anti-inflammatory
  drugs, COX-2 inhibitors.
Non- Selective COX Inhibitors
                               Selective COX-2 Inhibitors

http://en.wikipedia.org/wiki   http://en.wikipedia.org/wiki   http://en.wikipedia.org/wiki
/Image:Valdecoxib.png          /Image:Rofecoxib.png           /Image:Celecoxib.png
   Mechanism of Action of COX Inhibitors

Figure 16.2 Schematic diagram comparing the action of traditional non-steroidal anti-inflammatory drugs
(NSAIDs) and NSAIDs that are selective for cyclooxygenase (COX) 1 or 2. A Arachidonic acid enters the
COX enzyme channel and is converted first to prostaglandin G2 then to prostaglandin H2 (these steps
not shown) then into a prostaglandin, the example shown here being prostaglandin E2.
    Mechanism of Action of COX Inhibitors

Figure 16.2 Schematic diagram comparing the action of traditional non-steroidal anti-inflammatory drugs
(NSAIDs) and NSAIDs that are selective for cyclooxygenase (COX) 1 or 2. A Arachidonic acid enters the
COX enzyme channel and is converted first to prostaglandin G2 then to prostaglandin H2 (these steps
not shown) then into a prostaglandin, the example shown here being prostaglandin E2.
                                        Cox-2 Hypothesis
The current Cox-2 Hypothesis generally accepted by the pharmaceutical
community is that Cox-2 specific inhibitors will reduce pain, fever, and
inflammation without causing gastrointestinal or renal injury. There are two
central tenets to this hypothesis:
1) The prostaglandins that mediate inflammation, fever and pain are
produced only via Cox-2
2) The prostaglandins that are important in gastrointestinal and renal function
are produced solely via Cox-1.

The toxicity of non-steroidal anti-inflammatory drugs (NSAIDS) in the GI and
renal systems would therefore be due to a lack of selectivity of those drugs
with respect to inhibition of Cox-1 and Cox-2.

Thus, if Cox-2 selective inhibitors can be made that will spare Cox-1, then it
should be possible to design a drug without the adverse side-effects. To do
this, it is important to understand the biochemical and structural differences
between Cox-1 and Cox-2.
        Current Pros and Cons of Cox-2 Selective
        (Cox-1 sparing) Drugs

Pros of Cox-2 Selective Drugs

1. They are effective anti-inflammatory drugs
2. They have a lower incidence of gastrointestinal side effects.
3. They typically have less frequent, or once a day dosing compared to
traditional NSAIDs.

Cons of Cox-2 Selective Drugs

1. Expensive
2. NSAIDS and proton-pump inhibitors, e.g. Diclofenac and omeprazole can
be just as efficacious as Cox-2 selective without the GI side-effects.
3. Higher incidence of cardiovascular problems!
4. COX-2 inhibitors were initially thought to have fewer negative renal
effects than NSAIDs. Recent literature concludes that COX-2 inhibitors and
NSAIDs pose similar risks for renal adverse effects.
Inhibition of COX by Aspirin
                         Aspirin, Platelets and Cox 1
In platelets, only the Cox-1 isozyme is detectable. Aspirin inactivates
Cox-1 leading to a loss of Arachidonic acid induced platelet
aggregation by decreased production of Thromboxane A2 (TXA2).

Since platelets do not form new enzyme, TXA2 synthesis is therefore
irreversibly inhibited for the entire platelet lifetime (8 to 10 days) in
circulation. In humans, aspirin blocks Cox-1 activity in platelets
within 1 hour of oral administration and hence inhibits platelet
function for several days after a single dose. This is the basis and
therapeutic aim of the "half an aspirin a day" prophylaxis against
thromboembolic disease. Thus, in addition to its anti-inflammatory
actions, aspirin inhibits platelet aggregation and is important in
myocardial infarction.
                       Aspirin (Actions & Uses)

• Analgesic
  Peripheral & central effects;  synth. of PGs & other
• Use: Mild to moderate pain, like headache, musculoskeletal
  pain & arthritic pains
• Anti-inflammatory
   Synthesis and release of inflammatory mediators; 
  Leukocyte migration &  release of lysosomal enzymes
• Use: Rheumatic fever, rhematoid arthritis, osteoarthritis
• Antipyretic
   Pyrogen induced PGE2 synthesis,  interleukin-I,  Temp
  Use: Fever
                     The Salicylates - Aspirin
• Duration of action ~ 4 hr.

• Orally taken.

• Weak acid (pKa ~ 3.5); so, non-ionized in
  stomach  easily absorbed.

• Hydrolyzed by esterases in tissues and blood to
  salicylate (active) and acetic acid.

• Most salicylate is converted in liver to H2O-sol
  conjugates that are rapidly excreted by kids.
                        Aspirin: Adverse effect
Gastrointestinal: The most common GI effects of the
salicylates are epigastric distress, nausea, and vomiting.
Microscopic GI bleeding is almost universal in patients treated
with salicylates.
Blood: The irreversible acetylation of platelet cyclooxygenase
reduces the level of platelet TXA2, resulting in inhibition of
platelet aggregation and a prolonged bleeding time. For this
reason, aspirin should not be taken for at least 1 week prior to
surgery. When salicylates are administered, anticoagulants may
have to be given in reduced dosage, and careful monitoring
and counseling of patients are necessary.
Respiration: In toxic doses, salicylates cause respiratory
depression and a combination of uncompensated respiratory
and metabolic acidosis.
                         Aspirin: Adverse effect

Metabolic processes: Large doses of salicylates uncouple
oxidative phosphorylation.The energy normally used for the
production of adenosine triphosphate is dissipated as heat,
which explains the hyperthermia caused by salicylates when
taken in toxic quantities.
Hypersensitivity: Approximately 15 percent of patients taking
aspirin experience hypersensitivity reactions. Symptoms of true
allergy include urticaria, bronchoconstriction, or angioedema.
Fatal anaphylactic shock is rare.
Reye's syndrome: Aspirin and other salicylates given during
viral infections has been associated with an increased incidence
of Reye's syndrome, which is an often fatal, fulminating hepatitis
with cerebral edema. This is especially encountered in children,

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