Non-Steroidal Anti-Inflammatory drugs (NSAIDs)
Eicosanoids are local hormones derived from arachidonic acid.
- The term “prostanoids” encompasses the prostaglandins and thromboxanes.
- Cyclo-oxygenase (COX) acts on arachidonate to produce prostanoids.
- There are three forms of Cox :
- COX-1 : constitutive enzyme, involved in tissue homeostasis.
- COX-2: induced in inflammatory cell by inflammatory stimulus.
- COX-3: has only recently been discovered; may be implicated in fever.
Prostacyclin (PGI2) – predominantly from vascular endothelium. Main effects of prostacyclins are :
- Inhibition of platelet aggregation.
- Sensizitation of nerve pain terminals
- Renin relase and natriurises
Thromboxane A2 (TXA2) – predominantly from platelets.The main effects of thromboxane are:
- Platelet aggregation
Prostoglandins E1 (PGE1) and E2 (PGE2)
- Prominent in inflammatory responses and mediators of fever
- Inhibition of gastric acid secretion
- 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:
- 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 :
- 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)
- Reversible renal insufficiency through lack of compensatory PG-mediated vasodilation.
- Analgesic-associated nephropathy following prolonged use of NSAIDs
- Hypertension with long-term use
- Bronchospasm in “aspirin-sensitive” asthmatics.
- Increased risk of cardiovascular events –with chronic use(except naproxen).
- Due to other mechanisms:
- Liver disorders (the highest risk –nimesulide)
- 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