Non-Steroidal Anti-Inflammatory drugs (NSAIDs)

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Non-Steroidal Anti-Inflammatory drugs (NSAIDs)

Eicosanoids are local hormones derived from arachidonic acid.

synthesis of eicosanoids

 

Prostanoids

  • The term “prostanoids” encompasses the prostaglandins and thromboxanes.
  • Cyclo-oxygenase (COX) acts on arachidonate to produce prostanoids.
  • There are three forms of Cox :
  1. COX-1 : constitutive enzyme, involved in tissue homeostasis.
  2. COX-2: induced in inflammatory cell by inflammatory stimulus.
  3. COX-3: has only recently been discovered; may be implicated in fever.

Prostacyclin (PGI2) – predominantly from vascular endothelium. Main effects of prostacyclins are :

  1. Vasodilatation.
  2. Inhibition of platelet aggregation.
  3. Sensizitation of nerve pain terminals
  4. Renin relase and natriurises

Thromboxane A2 (TXA2) – predominantly from platelets.The main effects of thromboxane are:

  1. Platelet aggregation
  2. Vasoconstriction

Prostoglandins E1 (PGE1) and E2 (PGE2)

  1. Prominent in inflammatory responses and mediators of fever
  2. Inhibition of gastric acid secretion
  3. Contraction of pregnant uterus and GI smooth muscle

 

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS(NSAIDs)

Non Selective Cox Inhibitors

  • Salicylates  = Acetylsalicylic acid (Aspirine)
  • Derivatives of acetic acid = Diclofenac, Aceclofenac, Indomethacin
  • Oxicams = Proxicam, Tenoxicam
  • Derivatives of propionic acid = Iboprofen, Ketoprofen, Dexketoprofen, Naproxen

COX-2 Selective Inhibitors

  • Moderately selective = Nimesulide, Meloxicam
  • Highly selective (Coxibs) = Celocoxib, Etoricoxib

 

Pharmacokinetic proporties of NSAIDs

  • Most of the NSAIDs are weak acids
  • Well absorbed orally
  • Most are highly bound to plasma proteins. (Albumins)
  • Most are highly metabolized
  • Renal excretion but biliary elimination and reabsorption (enterohepatic circulation) is typical for most of the NSAIDs.

 

Pharmacodynamics proporties of NSAIDs

 The Action of NSAIDs are the result of COX-2 inhibition:

  • Anti-inflammatory effect, mainly acute reactions, due to inhibiting PG-dependant symptoms:
  1. Vasodilitation
  2. Edema
  • Antipyretic effect : NSAIDs reduce hight temparature due to action at hypothalamus.
  • Analgesic effect : NSAIDs reduce pain in inflammation owing to decreased sensitization of nociceptive nerve terminals to substances such as bradykinin or serotonin.

 

Common adverse effects of NSAIDs

  • Due to inhibition of the constitutive COX-1 :
  1. Dyspepsia, nausea and vomiting; gastric damage in chronic users, with risk of hemorrhage, resulting from the diminished protective effect of PGE on gastric mucosa (least with ibuprofen)
  2. Reversible renal insufficiency through lack of compensatory PG-mediated vasodilation.
  3. Analgesic-associated nephropathy following prolonged use of NSAIDs
  4. Hypertension with long-term use
  5. Bronchospasm in “aspirin-sensitive” asthmatics.
  6. Increased risk of cardiovascular events –with chronic use(except naproxen).
  • Due to other mechanisms:
  1. Liver disorders (the highest risk –nimesulide)
  2. Bone marrow suppression

 

Clinical uses of NSAIDs

  • For analgesia in painful conditions (e.g. headache, dysmenorrhoea, backache, bony metastases in cancers, postoperative pain)
  • For anti-inflammatory effects in rheumatic conditions (acute gout, osteoarthritis, rheumatoid arthritis, soft tissue inflammation)
  • To lower temperatura-ASA,Ibuprofen
  • ASA should be avoided in children with viral infection (syndrome of Reye).
  • ASA at a low dose (75-325 mg) – to reduce platelet aggregation: for the prevention and therapy of arterial thrombosis (e.g. MI)

 

Selective COX-2 inhibitors (coxibs)

  • Relatively recently introduced with the belief that they will provide better tolerability.
  • The coxibs are equally effective anti-inflammatory drugs as the non-selective COX-inhibitors.
  • The GI side profile is improved, but the renal unwanted effects are not spared.
  • The coxibs do not inhibit platelets, but they do suppress PGI2synthesis.
  • Increased incidence of MI and stroke
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About The Author
Kadir Timuçin Güneren
Kadir Timuçin Güneren
F*** the medicine!
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