Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Nonsteroidal anti-inflammatory drugs, usually abbreviated as NSAIDs with analgesic and antipyretic (fever-reducing) effects and which have, in higher doses, anti-inflammatory effects. The term "nonsteroidal" is used to distinguish these drugs from steroids, which, among a broad range of other effects, have a similar eicosanoid-depressing, anti-inflammatory action. As analgesics, NSAIDs are unusual in that they are non-narcotic.
CLASSIFICATION OF NSAIDs 1) COX-1 SELECTIVE INHIBITORS - acetylsalicylic acid at low dosage 2) NONSELECTIVE COX INHIBITORS - acetylsalicylic acid at high dosage - diclofenac - ibuprofen - ketoprofen - flurbiprofen - indomethacin - piroxicam - naproxen 3) MORE COX-2 SELECTIVE INHIBITORS - nimesulid - etodolak - meloxicam - nabumeton 4) COX-2 SELECTIVE INHIBITORS - celecoxib - etorcoxib - valdecoxib

General Mechanism of action

Most NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase (COX), inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A2). Prostaglandins act (among other things) as messenger molecules in the process of inflammation. This mechanism of action was elucidated by John Vane (19272004), who later received a Nobel Prize for his work (see Mechanism of action of aspirin
Pharmacokinetics

They are absorbed well from the stomach and intestinal mucosa. They are highly protein-bound in plasma
ANTI-INFLAMMATORY EFFECTS OF NSAIDs This effect of NSAIDs is due to the inhibition of the enzyme COX, which converts arachidonic acid to prostaglandins, TXA2 and prostacyclin. Acetylsalicylic acid irreversibly inactivates COX-1 and COX-2 by acetylation of a specific serine resideu. Other NSAIDs reversibly inhibit COX-1 and COX-2 Additional anti-inflammatory mechanism may include: - interference with the potentiative action of other mediators of inflammation bradykinin, histamine, serotonin - modulation of T-cell function - stabilization of lysosomal membranes - inhibition of chemotaxis

ANALGESIC EFFECT OF NSAIDs This effect of NSAIDs is thought to be related to the peripheral inhibition of prostaglandin production, but it may also be due to the inhibition of pain stimuli at a subcortical site. NDAIDs prevent the potentiating action of prostaglandins on endogenous mediators of peripheral nerve stimulation ( e.g. bradykinin )

ANTIPYRETIC EFFECT OF NSAIDs

NSAIDS have antipyretic activity and can be used to treat fever. Fever is caused by elevated levels of prostaglandin E2, which alters the firing rate of neurons within the hypothalamus that control thermoregulation. Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of prostanoid biosynthesis (PGE2) within the hypothalamus.PGE2 signals to the hypothalamus to increase the body's thermal set point. Ibuprofen has been shown to be more effective as an antipyretic than acetaminophen. Arachidonic acid is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D & E.
CLINICAL USES OF NSAIDs 1) analgesia 2) inflammation 3) antipyresis 4) antiplateled effect 5) cancer preventive agents ADVERSE EFFECTS OF NSAIDs 1) gastrointestinal effects: abdominal pain, gastric and duodenal ulcer, diarrhea, pancreatis gastrointestinal hemorrhage, hepatotoxicity 2) renal effects - disturbances of renal function with water and sodium retention 3) inhibition of platelet aggregation 4) central symptoms: headache, decreased hearing, tinnitus, dizziness, confusion, dpression 5) allergic reactions: asthma, rashes, photosensitivity

PHARMACODYNAMIC INTERACTION NSAIDs WITH OTHER DRUGS NSAIDs + hypotensive drugs ( -blockers, ACE-inhhibitors, diuretics ) = hypotensive effect NSAIDs + ehanol = risk of bleeding from gastrointestinal tract NSAIDs + ticlopidine or clopidogrel = risk of bleeding NSAIDs + lithium = lithium toxicity

NSAIDs + cylosporine or ACE-inhibitors or takrolimus= nephrotoxicity of drugs NSAIDs + fluoroquinolons = toxic action of fluoroquinolons on CNS NSAIDs +oral antidiabetic drugs = risk of hypoglycemia NSAIDs + cumarines = risk of bleeding from gastrointestinal tract

PHARMACOKINETIC INTERACTION NSAIDs WITH OTHER DRUGS NSAIDs + oral antidiabetic drugs = risk of hypoglycemia NSAIDs + cumarines =risk of bleeding NSAIDs + corticosteroids = risk gastropathy and bleeding from gastrointestinal tract NSAIDs + aminogycosides = ototoxicity and nephrotoxicity of aminogycosides NSAIDs + fenytoine or valproinic acid = action of fenytoine or valproinic acid NSAIDs + metotrexat or digoxin = action and toxicity metotrexat or digoxin NSAIDs + tricycles antidepressive drugs neuroleptics or antiarrhytmic drugs or selective serotonin reuptake inhibitors ( SSRI ) = action of drugs