The Mechanism Of Actions Of Nsaids Biology Essay

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NSAIDs work by reducing inflammation. They block a vital enzyme of inflammation called cyclooxygenase, which converts arachidonic acid to prostaglandins and leukotrienes, which causes local inflammation. HHHHHence by inhibiting COX, NSAIDs reduce inflammation. On the other hand there are many side effects to NSAIDs ranging from gastrointestinal problems to rare ones such as aseptic meningitis. NSAIDs are indicated for the treatment of mild to moderately severe and chronic pain, inflammation pyrexia. NSAIDs are contraindicated in some cases, if they have hypersensitivity, if they are pregnant and may cause renal failure. They differ widely in therapeutic efficacy and there potency. Differences in there efficiency can be explained by the enzyme COX and cytokine inhibition, non-COX mechanisms and individual variation in response, within and between species. All NSAIDs are considered to have comparable efficiency, as a result the considerations for selecting one agent over another is based on the incidence of gastric side effects, cost and frequency of administration.


Non-steroidal anti-inflammatory drugs (NSAIDs) are drugs with analgesic and antipyretic effects and which have in higher doses, anti-inflammatory effects. NSAIDs are the most commonly prescribed categories of drugs in the treatment of pain and inflammation in many conditions worldwide. Anti-inflammatory refers to the property of a substance that reduces inflammation. They make up about half of the analgesics, remedying pain by reducing inflammation. There are many NSAIDs which are used today for example aspirin which is most commonly used and ibuprofen.

The mechanism of NSAIDs is that it inhibits the enzyme cyclooxygenase (COX), which inhibits both the cyclooxygenase-1 (COX) and cyclooxygenagse-2 (COX-2) isoenzymes. COX enzymes are bio-functional and have two distinct activities, the main action gives prostaglandin G2 (PGG2) and peroxidase action which converts PGG2 to PGH2. COX-1 is a constitutive enzyme expressed in most tissues and blood platelets, and it's involved in cell signalling and in tissue homeostasis. COX-2 is induced in inflammatory cytokines interleukin-1 and tumour necrosis therefore is responsible for the production of the prostanoid mediators of inflammation. COX catalyses the formation of prostaglandins and thromboxanes which promotes platelet aggregation and is a vasoconstrictor from arachidonic acid. Prostaglandins act as messenger molecules in the process of inflammation. Both COX-1 and COX-2 are dissociated in the membrane and consists of long channels; COX-2 channels are wider. The openings of the channels are hydrophobic. Arachidonic acid enters the channels and inserts two oxygen's and a free radical extracted which forms a 5-carbon ring, the characteristics of prostanglandins. This mechanism of action was discovered by John Vane (1927-2004). During inflammation reaction, bacterial endotoxins cause the release from macrophages of a pyrogen which stimulates the generation, in the hypothalamus of E-type prostaglandins (PGEs) which causes the elevation of the set-point temperature. (1)

NSAIDs have anti-inflammatory properties as stated above as well as having analgesic effects which reduces pain and antipyretic effects which lowers the body temperature when fever occurs. High levels of prostaglandin E2 cause fever, which alters the firing rate of neurons within the hypothalamus that controls thermoregulation. This mechanism is due to the inhibition of the enzyme COX, which causes inhibition of prostanoid biosynthesis (PGE2) in the hypothalamus. This signals the hypothalamus to increase the body's thermal set point. NSAIDs are effective against pain associated with inflammation or tissue damage because this decreases the production of prostaglandin that sensitise nociceptors to inflammatory mediators e.g. Bradykinin which is effective in arthritis and in pain of muscular and vascular origin. With the combination of opioids, NSAIDs decrease prostoperative pain and can reduce the need for opioids by as much as one third. NSAIDs are also effective in some neuropathic pain syndromes when used with other analgesics. They are generally used in the treatment of rheumatoid arthritis, headaches, sports injuries, pain from kidney stones and dental pain. NSAIDs do not cure diseases or injuries but are still included in cold and allergy preparations. (2)

When NSAIDs are used extensively they can cause gastric erosions which can become stomach ulcers and can cause severe haemorrhage in extreme cases resulting in death. This is because NSAIDs block the COX enzymes and reduce prostaglandins throughout the body. Therefore as a result, ongoing inflammation, pain, and fever are reduced. The prostaglandins guard the stomach and support the platelets and reduce blood clotting because of this NSAIDs cause ulcers in the stomach and encourage bleeding. The side effects that occur because of gastrointestinal tract are dyspepsia, gastric bleeding, diarrhoea, nausea and vomiting. "Larkai et al studied 245 rheumatic patients taking NSAIDs and reported that 16% had daily dyspepsia, 29% had symptoms in the prior week, and 37% had symptoms in the preceding 2 months." Journal of Cardiovascular Pharmacology (2006). Other found side effects are cardiovascular hematopoietic, hepatic and central nervous system toxicities. Adverse effects are edema; hypertension which is caused by salt and fluid retention associated with altered renal functions, these effects are more commonly found. These substances can also cause renal impairment particularly with other nephrotoxic agents. This occurs through the inhibition of biosynthesis of the prostanoids (PGE2 and prostaglandin I2). NSAIDs can also cause damage to your kidneys as they reduce the blood flow to the kidneys making them work slowly which causes built up fluid. This can lead to kidney failure and require dialysis, because there is more fluid in the bloodstream the blood pressure increases. Reduced blood flow can permanently damage your kidneys if NSAIDs is taken in higher doses. NSAIDs can in addition cause extreme allergic reactions. People with asthma are at a higher risk of encountering serious allergic reactions to NSAIDs. (3)

(4) Fig showing the Pharmacology of NSAIDs and selective COX-2 Inhibitors on Prostaglandin Synthesis.

Aspirin is a salicylate drug; its chemical term is acetylsalicylic acid (ASA). It is used as an analgesic to relieve pain, antipyretic to reduce fever and as an anti-inflammatory and cardio-protector. Aspirin causes irreversible inactivation of cyclo-oxygenases of both isoforms, COX-1 and COX-2 and therefore is able to suppress the production of prostaglandins and thromboxanes it is also non-selective. COX is needed for prostaglandin and thromboxane synthesis. An acetyl group is covalently bonded to a serine residue in the active side of a COX enzyme; therefore aspirin acts as an acetylating agent. This makes aspirin different from other NSAIDs which are reversible inhibitors. COX normally produces prostaglandins which are pro-inflammatory and thromboxanes which promote blood clotting. Aspirin modified COX-2 enzymes produces lipoxins which are anti-inflammatory. COX-2 selective inhibitors have been developed that only inhibit COX-2 in the hope of reducing gastrointestinal side effects. Therapeutic doses show gastric bleeding and increased doses show dizziness, deafness, tinnitus. Toxic doses show respiratory acidosis and metabolic acidosis. Newer NSAIDs have fewer gastrointestinal adverse effects than aspirin and have more suitable dosage schedules, but they are more expensive. (5) Regular and sustained use of aspirin reduces the risk of cancer of the colon and rectal cancer, as evidence shows. "They followed up four study groups over a period of 20 years to identify the impact of regular small doses of the drug - the tablets given for medical reasons are often a quarter of a strength of those used to treat headaches. They found it reduced the risk of the incidence of bowel cancer by 24% and of dying from the disease by 35%. One in 20 people in the UK develops bowel cancer over their lifetime, making it the third most common cancer. About 16,000 people die each year as a result of it." Health, BBC news. (6) "There could be a link between the use of aspirin and the development of Reye's syndrome. Reye's syndrome is a rare but possibly fatal disease seen most often in children and teenagers. It usually affects those recovering from chicken pox or a viral illness such as the flu." By Nathan Wei a rheumatologist. (7) There is no definite proof showing if Reye's syndrome occurs in children with arthritis whether they are or are not taking aspirin. Children who frequently take large doses of aspirin with arthritis do not have a high risk of developing Reye's syndrome as results show from a survey of doctors who specialise in childhood arthritis. Conversely there have been some reports of a few children with arthritis developing Reye's syndrome. (8)

Paracetamol has both analgesic and antipyretic actions but only has weak anti-inflammatory effects. The mechanism of action is believed to be the inhibition of COX and evidence shows that it is highly selective for COX-2 which does not inhibit the production of pro-clotting thromboxanes. However, their action in blocking COX-1 is responsible for also causing the unwanted gastrointestinal side effects associated with these drugs. Toxic doses symptoms are nausea and vomiting, increased risk of upper gastro complications. (9) Recent research has shown that COX-3, a new previously unknown enzyme has been found in the brain and spinal cord, which is selectively inhibited by Paracetamol, and is different from COX-1 and COX-2. It is now suspected that the enzyme COX-3 is selectively inhibited in the brain and spinal cord which explains the effectiveness of Paracetamol in relieving pain and reducing fever without giving gastrointestinal side effects. (10)

Ibuprofen is used to treat pain or inflammation and to reduce fevers which are caused by many conditions such as headache, toothache, arthritis, back pain, menstrual cramps, or minor injury. It works by inhibiting COX which converts arachidonic acid to prostaglandin H2 (PGH2) which is converted by other enzymes to several other prostaglandins and to thromboxanes. Ibuprofen is considered a non-selective COX inhibitor which inhibits two isoforms COX-1 and COX-2. Selective COX-2 inhibitors were developed to inhibit the COX-2 isoform without inhibition of COX-1, to achieve the beneficial effects of ibuprofen and other NSAIDs without gastrointestinal ulceration and bleeding. Adverse effects are dizziness, nausea, dyspepsia, constipation, inflammation bowel disease, gastrointestinal bleeding and myocardial infarction. (11)

(12) Fig showing the formation of aspirin.

NSAIDs are contraindicated in the following cases: People who have a history of hypersensitivity or allergic reactions to an NSAID, severe skin reactions, if you have asthma and severe heart failure. NSAIDs should be used with caution in: The elderly may have increase risk of serious adverse effects, people who have a history of peptic ulceration or those who are at a high risk of gastrointestinal adverse effects. People with inflammatory bowel disease as NSAIDs may increase the risk of developing or cause Crohn's disease. People with hepatic impairment they have an increased risk of gastrointestinal bleeding and fluid retention. People with heart failure and hypertension as NSAIDs may impair renal function. They should not be given to children under 16 years old, during pregnancy and during breast feeding. You should avoid using NSAIDs in people with: Estimated glomerular filtration rate less than 30-15 mL, Renal failure, NSAIDs can provoke acute renal failure if given to someone who is dehydrated, especially if they have diabetes. (13)