The mechanisms actions of non-steroidal anti-inflammatory drugs (NSAIDs) To summarise, non-steroidal anti-inflammatory drugs are drugs which have anti-inflammatory, analgesic and antipyretic properties due to their mechanism and enzymes involved COX-1 and COX-2. However as well as being beneficial NSAIDs have many unwanted side effects such as diarrhoea, nausea, vomiting, and constipation. In frequent high doses can be fatal and cause kidney and liver failure. Non-steroidal anti-inflammatory drugs (NSAIDs) are therapeutic agents.
They can be prescribed for ‘rheumatic’ musculoskeletal problems but are frequently taken without prescription for minor aches and pains. The expression ‘non-steroidal’ is used to tell the difference between corticosteroids (a class of steroid hormone) which also reduce inflammation but by a different method. NSAIDs have three main therapeutic effects: anti-inflammatory, analgesic and antipyretic.  NSAIDS generally work by inhibiting the fatty acid cyclooxygenase (COX) enzyme and therefore inhibit the production of prostaglandins and thromboxanes.
There are three isomers of the COX enzyme: COX-1, COX-2 and COX-3. COX-3 enzyme has not been proven to have a functional use in humans and is not discussed in this essay. COX-1 is a constitutive enzyme involved in tissue homeostasis and is responsible for the production of prostaglandins, while COX-2 is induced in inflammatory cells and is responsible for the production of the prostanoid mediators of inflammation. COX first oxidises arachidonic acid to prostaglandin G2 (PGG2) through a cyclooxygenase process and then peroxidises PGG2 to PGH2.
NSAIDs inhibit the cyclooxygenases thus reducing the change of arachidonic acid to prostaglandins.  Aspirin has three main therapeutic effects in the body: the antipyretic effect, the analgesic effect and the anti-inflammatory effect. This is due to the decreased production of prostaglandins and thromboxanes by the irreversible inactivation of the cyclooxygenase enzyme. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the COX enzyme. This makes Aspirin different to other NSAIDS whereby they are reversible inhibitors and aspirin is not.
The side effects are caused by the inhibition of COX-1 enzyme, which synthesises prostaglandin that serve essential physiological functions such as causing appropriate platelet aggregation, protection of the gastric mucosa, inhibition of thrombogenesis and maintenance of renal function. The therapeutic effects of NSAIDs are due to inhibition of COX-2, an enzyme induced by various factors released by bacteria, the vascular endothelium or other cells involved in the inflammatory response.  Anti-inflammatory effects reduce inflammation. Inflammation occurs due to the release of histamine.
Histamine causes vasodilation, increased vascular permeability and cell accumulation around damaged tissue. Non-steroidal anti-inflammatory drugs reduce the inflammatory results produced by COX-2. This includes pain signals sent to the brain as well as vasodilation and vascular permeability.  Antipyretic effects lower body temperature when this is raised in disease. Normal body temperature is regulated by hypothalamus in the brain which balances the heat lost and the production of heat made in the body. A raised body temperature occurs when there is a disturbance in the hypothalamus.
Antipyretic effect is exerted by the inhibition of the prostaglandin in the hypothalamus.  Analgesic effects reduce certain type of pain. Non-steroidal anti-inflammatory drugs inhibit the production of prostaglandins which stimulate receptors that cause pain. This means that NSAIDs are effective in pain of muscular and vascular origin, dysmenorrhoea (period pain), toothache and arthritis. They also relieve headaches due to stopping the dilation of cerebral vasculature caused by prostaglandins.  Aspirin (acetylsalisalic acid) is the oldest non-steroidal anti-inflammatory drug available.
  This diagram outlines the synthesis of aspirin. The synthesis of aspirin is split into four reactions starting with the reaction between two simple organic molecules sodium hydroxide and phenol, to reacting salicylic acid and acetic anhydride in the final step. This diagram outlines the synthesis of aspirin. The synthesis of aspirin is split into four reactions starting with the reaction between two simple organic molecules sodium hydroxide and phenol, to reacting salicylic acid and acetic anhydride in the final step.
Aspirin is prepared by chemical synthesis from salicylic acid, by acetylation with acetic anhydride (final step). Aspirin is prepared by chemical synthesis from salicylic acid, by acetylation with acetic anhydride (final step). The effect of aspirin are reducing fever, relieving headaches and other pain, arthritis, menstrual cramps and also reduces swelling. As well as having an anti-inflammatory benefit, it also helps in cardiovascular disorders through the antiplatelet action. Salicylates produce both local and systemic toxic effects.
Aspirin share many unwanted effect like NSAIDs which include dyspepsia, nausea and vomiting, skin reactions, reversible renal insufficiency, “analgesic-associated nephropathy”, liver disorders and bone marrow depression, and finally bronchospasm. In addition there are certain specific unwanted effects such as Reyes syndrome, salicylism and salicylate poisoning. Reyes syndrome is a rare disorder of children that is characterised by hepatic encephalopathy following an acute viral illness. Salicylism is characterised by tinnitus, vertigo, decreased hearing, and sometimes also nausea and vomiting, occurs with over dosage of any salicylate.
Gastric damage may occur in chronic users, with risk of haemorrhage, which caused by the suppression of gastroprotective prostaglandins in the gastric mucosa. Reversible renal insufficiency is seen mainly in individuals with compromised renal functions when the compensatory prostaglandin E? -mediated vasodilation is inhibited.  Paracetamol is classed as a non-steroidal anti-inflammatory drug even though it has very little inflammatory effects. This is because it is thought that paracetamol inhibits COX-3 enzymes which are found in the spinal chord and brain. This would explain why paracetamol is a good analgesic and antipyretic drug.
Paracetamol is given orally and metabolised in the liver (half-life 2-4 hours). Side effects are few and common in Paracetamol although allergic skin reactions sometimes occur, or using the drug for a long period of time may cause kidney damage.  Ibuprofen is used for relief of symptoms of arthritis, primary dysmenorrhea, fever, and as an analgesic, especially where there is an inflammatory component. Ibuprofen is known to have an antiplatelet effect, though it is relatively mild and short-lived when compared with that of aspirin or other better-known antiplatelet drugs.
Ibuprofen also generally acts as a vasodilator, having been shown to dilate coronary arteries and some other blood vessels.  Common side effects include nausea, dyspepsia, gastrointestinal ulceration/bleeding, raised liver enzymes, headache, dizziness, salt and fluid retention, and hypertension. Diclofenac is used for musculoskeletal complaints, especially arthritis (rheumatoid arthritis, osteoarthritis, spondylarthritis, ankylosing spondylitis), gout attacks, and pain management in case of kidney stones and gallstones.
An additional indication is the treatment of acute migraines. Diclofenac is used commonly to treat mild to moderate post-operative or post-traumatic pain, particular when inflammation is also present, and is effective against menstrual pain.  Contraindications for Aspirin are:  * Children under 16 years old (Reyes Syndrome) * Use in the elderly * Previous or active peptic ulceration * Haemophilia * Not for treatment of gout * Hypersensitivity for aspirin or any other NSAIDs * Pregnancy Contraindications for Paracetamol are: 
* Pregnancy * Severe heart failure * Use in elderly * hypersensitivity Contraindications for Diclofenac are:  * Pregnancy * Use in elderly * Hypersensitivity * Avoid injections containing benzyl alcohol in neonates REFRENCES: 1. Rang, H. P. , Dale, M. M. , Ritter, J. M. , Flower, R. J. , 2007, Churchill Livingstone, Pharmacology, 6th Edition, pg 226-230 2.
http://rheumatology. oxfordjournals. org/content/35/suppl_1/1. full. pdf 3. http://en. wikipedia. org/wiki/Mechanism_of_action_of_aspirin/ 4. Frans, Nijkamp, N. , and Parnham, M. J., Principles of Immunopharmacy, 2nd revised and extended edition 5. Novartis Consumer Healthcare.
Effective pain and inflammation relief. London: Communications International Group. P5-7 6. http://www. aspirin-foundation. com/what/reactions. html 7. Rang, H. P. , Dale, M. M. , Ritter, J. M. , Flower, R. J. , 2007, Churchill Livingstone, Pharmacology, 6th Edition, pg 234-236 8. http://en. wikipedia. org/wiki/Ibuprofen 9. http://www. medic8. com/medicines/Diclofenac. html 10. BNF – March 2010, edition 59 http://en. wikipedia. org/wiki/Ibuprofen.