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Aspirin, Paracetamol and Ibuprofen are examples of commonly used NSAIDS (non-steroidal anti-inflammatory drugs). They are the most widely used therapeutic drugs used by the general public today mainly for muscle complaints and relief of pain. NSAIDS vary in there action, strength, potency and the way in which they react in the body and are eliminated. An NSAID such as Aspirin, largely an analgesic has many pharmacological effects in the body which are anti-inflammatory, analgesic, and antipyretic and is an inhibitor of platelet aggression. Aspirin has many actions in the body however it suppresses the production of prostaglandins. Like many other NSAIDS such as Ibuprofen and Paracetamol, Aspirin works by inhibiting the action of the COX enzymes (arachidontate cyclo-oxygenase) and therefore stopping the production of prostaglandins and thromboxanes. Prostaglandin and Thromboxanes are essential messengers related to inflammation. They are involved in producing a response when inflammation occurs. Inflammation is a response of a tissue to an injury. 
However Aspirin is the only NSAID that prevents the cyclo-oxygenase by means of an irreversible action of acetylating. Aspirin is the only NSAID known to behave in this manner in which the COX enzyme is altered in a way where synthesis of Prostaglandins and thromboxanes can no longer have any effect within the body. The specific target sites for NSAIDS are the COX1 and COX 2.Many other NSAIDS are different and are reversible inhibitors of the COX enzyme.  This shows that the mechanisms in which these drugs react are different to one another. This is one of the reasons that when manufacturing drugs it is essential to have an understanding of the mechanism of drug action to ensure that side effects do not occur. In this essay I am going look into depth about the mechanisms in which NSAIDS work within in the body; particularly Aspirin, Paracetamol, Ibuprofen and Naproxen.
All these drugs vary in structure therefore chemical activity however all are related to the principal action of the inhibition of the COX enzyme. COX1 is an enzyme that is expressed in most tissues including blood platelets. The enzyme is involved in tissue homeostasis, cell signalling and is responsible for the production of Prostaglandins. These are involved in physiological processes such as protection on the stomach mucosa, platelet aggression and kidney function. It is due to the inhibition of this particular COX that the adverse effects such as stomach ulcers occur. COX 2 is induced and activated at site of inflammatory cells. The enzyme that is responsible for the production of prostanoids mediators of inflammation is COX1. The inhibition of COX 1 is undesirable. The COX 2 enzyme is found in the central nervous system. Most NSAIDS either inhibit both of the enzymes or one of the enzymes. The inhibition of these enzymes causes different effects such as causing bleeding and ulcers. The anti-inflammatory action of NSAIDS is related to the inhibition of COX 2 whereas unwanted effects are largely due to the inhibition of COX 1.The more likely an NSAID blocks the COX 1 there is a greater tendency to causes ulcers and increase promotion of bleeding.
There are three major pharmacological actions in which NSAIDS suppress the synthesis of prostaglandins and inhibit the cyclo-oxygenase enzymes.
- Anti-inflammatory effect:
The effect of many NSAIDS is a result of a response to a specific stimulus; this occurs generally during times of inflammation where stress or pain is caused at a particular point in the body. A decrease in the production of Prostaglandin in COX 2 which therefore reduces vasodilatation. NSAIDS suppress feeling of pain, swelling and increased blood flow associated with inflammation. Complex interactions cause vasodilatation and increased permeability and cell accumulation. Small amounts of nitric oxide stimulate COX activity. 
- Antipyretic effect:
Body temperature is regulated in the thermoregulatory centre in the hypothalamus within the brain. It is here where heat loss is detected and altered to maintain a constant internal body temperature which is essential. Fluctuations in heat are detected and any disturbances are counteracted to maintain this constant; the hypothalamus therefore acts as a thermostat. Fever occurs due to an imbalance with the thermostat as temperature is being increased in the body. NSAIDS inhibit the prostaglandin production in the hypothalamus of the brain. Bacterial endotoxins cause the release from macrophages to enable this process to occur. The inhibition of the Prostaglandins enables temperature reducing mechanisms such as vasodilatation and increased sweating to balance the temperature. This decreased production of the hormones enables the hypothalamus to signal to other parts of the body to reduce body temperature. It is via the inhibition of the COX enzyme that this can occur. 
- Analgesic effect:
Most common use of NSAIDS is the reduction of pain. These drugs are very effective against moderate pain that may arise from inflammation or tissue damage. They respond by reducing the production of prostaglandin. The decreased production is initiated by the stimulus being detected by the sensitive peripheral receptors. The ability to relieve headache is related to the abrogation of vasodilator effect of prostaglandins on the cerebral vasculature.  It is the sensitive receptors that are able to produce a response and allow vasodilatation to occur; more blood is allowed to pass within the blood vessels reducing friction.
The inhibition of the COX enzymes occurs due to the NSAID inhibiting the binding site of the enzymes consequently not allowing the enzyme to carry on with synthesis. Both COX 1 and 2 contain haem groups and are found in the intracellular membranes of cells. Structurally both the enzymes are similar as they both contain a long hydrophobic channel into which oxygenation reaction can occur. Most NSAIDS are 'competitive reversible inhibitors'. They enter via the hydrophobic channel forming hydrogen bonds with an arginine positioned. This prevents substrate fatty acids from entering the active site where catalysis occurs. The formation of the hydrogen bonds is how NSAIDS causes inhibition. Aspirin however is a unique NSAID in the way in which it interacts inside the body. As most NSAIDS only inhibit one of the COX enzymes; Aspirin however inhibits both COX enzymes by an irreversible reaction. It is able to inhibit blood clotting for a prolonged period of up to 7 days. 
Aspirin undergoes an irreversible reaction with the COX enzyme where it selectively acetylates the hydroxyl group on one of the serine residues (serine 530) located 70 amino acids from the carbon terminus of the enzyme. Acetylation leads to an irreversible COX inhibition therefore a new enzyme must be synthesised before more prostanoids are produced. When the enzyme is acetylated, only the COX, not the hydro peroxidise, activity is inhibited. The stoichiometry of this reaction is 1:1 with one acetyl group transferred per enzyme.  The Acetylation that occurs is due to a permanent bond that is formed between the aspirin and the COX enzyme. The inhibition of COX 2 inhibits the transcription of prostaglandins reducing the inflammatory response. COX-1 is permanently deactivated and, as anucleate cells, platelets cannot replace the defective enzyme. This effectively halts platelet TXA2 production for the entire 10-day life span of the platelets.
The simple diagram  below shows the action of Aspirin and the way in which bonding occurs for inhibition. This is in very simple context as due to this reaction occurring the production of eukotrienes, prostaglandins, thromboxane A2 (TXA2) and prostacyclin, or prostaglandin I2 (PGI2) is stopped.
Despite the diverse chemical structure of aspirin like drugs, the effect of NSAIDS is mainly due to their common property of inhibiting cyclo-oxygenase involved in formation of prostanoids. The conversion of arachiodonic
As stated above Aspirin like many NSAIDS inhibits the function of the desirable COX 2 enzyme which therefore results in the inactivity and production of Prostaglandins. This mechanism occurs due to a number of steps. Prostanoids are synthesised by many cells however are synthesised and released by Arachidonic acid. This acid is stimulated (PLA2 ) during times of trauma and pain. Conversion of Arachidonic acid to prostanoids is carried out by cyclo-oxygenase (COX); also referred to as prostaglandin H synthase (PGHS). Arachidonic acid is primarily cyclised and oxidized to PGG2 at the cyclo-oxygenase site of the COX and the product is then reduced to a second PGH2; classified at a particular peroxide site. The further formation of prostaglandin products initiated from PGH2 depends on the presence of synthases that produce the particular prostanoids TXA2 PGD2, PGE2, and PGI2 PGF2. These particular prostaglandins are transported out of the cell by transporters that signal to different parts of the cell; particular receptor sites. During intake of NSAIDS the COX is inhibited therefore the arachiodonic acid is unable to produce prostaglandin which causes the peripheral sensory receptors to become less responsive to the site of inflammation, pain and fever is relieved. 
Due to this simple mechanism that occurs it can be said that Aspirin is a useful drug for preventing the blood clots that cause heart attacks etc. The effect of this particular NSAID Is used for relieving headache or pain, reducing fever, arthritis and swelling. At low dosages (70mg) aspirin inhibits COX therefore preventing the production of thromboxanes by blood cells which are called platelets. This particular chemical causes platelets to clump together and initiate the clotting process. By stopping the production minimises the chances of a clot forming. Taking high dosages of aspirin such as 300mg blocks the COX therefore preventing the production of prostaglandins.  This particular chemical is produced in response to pain. Some cases have suggested that Aspirin can now be taken in small doses as an effective use for chronic heart disease, and specific types of cancer. 
Alongside many advantages there are also many disadvantages that arise by taking the NSAID Aspirin. Due to prostaglandins being involved in gastric cytoprotection, platelet aggression and renal vascular auto regulation some effects of NSAIDS can be shown. Gastrointestinal is one of the most common unwanted side effects. 'Upper GI symptoms, such as dyspepsia, occur in 15% to 60% of NSAID users, twice as often as in individuals not taking NSAIDS'.This is due to the inhibition of the gastric COX 1 which inhibits the production of prostaglandins. As the gastric COX 1 is inhibited the production of acid secretion and production of mucosa is stopped. One other common effect that is suggested is that NSAIDS such as Aspirin affects the hydrophobic barrier of the GI tract therefore decreasing the barrier properties to the tissue. As the membrane permeability is effected therefore increased susceptibility for the membranes to rupture and form pores or aqueous channels for protons. NSAIDS have a large effect on the membrane causing changes in the pathways for back diffusion. The common gastrointestinal side effects are dyspepsia, diarrhoea, nausea and vomiting. The inhibition of the COX 2 enzymes is to synthesise regulator of the cardiovascular function. 
Due to the inhibition of the prostaglandins PGE2 and PGI2 involved in the conservation of renal blood flow it is possible that adverse renal effects are a symptom from NSAIDS. It is because of the decreased production of the prostaglandins that the damages the kidneys. Kidney diseases and a decreased affect in the way in which blood circulating volume occurs. Like some NSAIDS such as aspirin severe symptoms that can arise, although they understandably prolonged use of the drugs can cause the most harmful effects. 
Other side effect that may arise due to the use of NSAIDS is skin rashes. Inflammation occur which causes skin irritation and rashes can build up. Other effects of aspirin are ulcers, stomach disorders and stomach bleeding. The inhibition of the COX 2 prevents platelet aggression and therefore prolongs bleeding. 
Aspirin is made by the chemical synthesis of salicylic acid. A series of reactions take place by Acetylation. The synthesis takes place with a series of 4 reactions. The diagram below shows how aspirin is made. 
Aspirin being a weak acid itself can be protonated in the acid environment of the stomach. More absorption occurs in the ileum due the increased surface area that transpires because of the microvilli. In the body aspirin readily hydrolyses by esterase's the plasma producing salicylate. The salicylate itself has anti-inflammatory forms as it can inhibit the COX enzyme.
Ibuprofen is another NSAID that is extremely popular on the market today. The drug itself is sold under the generic name Nurofen®.It is sold in a number of forms such as most commonly tablets, capsules and gel This NSAID has similar interactions and mechanisms to that of aspirin. It is believed to work by the inhibition of cyclo-oxygenase, thus inhibiting prostaglandin synthesis. Ibuprofen inhibits both forms of the enzymes COX-1 and COX-2. The inhibition of the COX 1 is responsible for unwanted side effects on platelet aggression of the mucosa and gastrointestinal tract. To achieve beneficial effects without causing bleeding and ulcers to be formed it is essential that selective COX 2 inhibitors are formed that don not affect the isoform COX 1. Antipyretic effects are due to action on the hypothalamus, resulting in an increased peripheral blood flow which causes vasodilatation. 
Paracetamol is another widely used drug that is used most for headaches, pains and relief of fever. Unlike other common analgesics such as Ibuprofen and aspirin Paracetamol does not affect platelet aggression, nor has any relationship with irritation of the stomach lining and blood clotting. It is though that this drug is related with the central nervous system, increasing the pain threshold by inhibiting COX 1 and COX 2. Unlike NSAIDs, Paracetamol does not inhibit cyclo-oxygenase in peripheral tissues and, thus, has no peripheral anti-inflammatory affects. Studies have found that Paracetamol indirectly blocks COX, and that this block is ineffective in the presence of peroxides. This might explain why Paracetamol is effective in the central nervous system and in endothelial cells but not in platelets and immune cells which have high levels of peroxides.
Naproxen is a member of the 2-arylpropionic acid (profen) family of NSAIDs. The mechanism of action of naproxen, like that of other NSAIDs, is believed to be associated with the inhibition of cyclo-oxygenase activity. The constitutive cyclo-oxygenase, COX-1, synthesizes prostaglandins necessary for normal gastrointestinal and renal function. The COX-2 generates prostaglandins involved in inflammation. Inhibition of COX-1 is thought to be associated with gastrointestinal and renal toxicity while inhibition of COX-2 provides anti-inflammatory activity. The most common side effects from naproxen are rash, ringing in the ears, headaches, dizziness, drowsiness, abdominal pain, nausea, diarrhoea, constipation, heartburn, fluid retention and shortness of breath. Naproxen also may cause stomach and intestinal bleeding and ulcers. Sometimes, stomach ulceration and intestinal bleeding can occur without any abdominal pain. 
Due to the side effects that many NSAIDS have within the body and the side effects that are expressed in numerous cases it must be noted that NSAIDS should not be taken in these circumstances. These circumstances are during Pregnancy and in times of breast feeding and when allergies are known. It is also essential that on thinning agents called anticoagulants and when suffering from a defect of the clotting system that NSAIDS should not be taken. Sometimes severe skin reactions and allergies can worsen when NSAIDS are taken. At times of severe heart failure adverse side effects can occur as. People with inflammatory bowel disease are to take caution as NSAIDS increase the risk of ulcerative colitis or Crohn's disease. People with hepatic impairment have an increased risk of gastrointestinal bleeding and fluid retention. Many people that encounter hypertension and heart failure; NSAIDS may impair renal function therefore they should not be taken. As mentioned above in any of these circumstances it is recommended that NSAIDS should not be taken.
All NSAIDS (non-steroidal anti-inflammatory drugs) have a relationship of activity related towards the inhibition of the cyclo oxygenase (COX).The way in which they work relates to the mechanism of the drug and the COX enzymes. It is due to the selectiveness of the NSAIDS and the way in which they interact with the COX enzymes that theses side effects can occur. The mechanisms of Aspirin demonstrate that there are beneficial and side effects however the benefits weigh larger therefore these NSAID drugs should be used. All of these NSAIDS mentioned above are beneficial in small doses however can cause side effects if stronger doses are used and over prolonged period use.