Non Steroidal Anti-Inflammatory Drugs (NSAIDs) is a name given to classify drugs which exhibit analgesic (pain relieving) and antipyretic (fever reducing) properties. NSAIDs are among the most frequently used medications worldwide, despite their capacity to cause gastrointestinal (GI) side effects, such as: ulcers, stomach pain and bleeding . Aspirin, paracetamol and ibuprofen are some of the most common NSAIDs which are manipulated; they are generally classified as GSL (General Sales List) medicines as often these drugs can be taken without prescription. These drugs often act as the active ingredient in many different medicines. NSAIDs are generally implemented to treat short term or prolonged chronic conditions caused by headache, backache, toothache, menstrual pains and so on. They do this by inhibiting the production of prostaglandins .
Prostaglandins are the name given to the group of chemicals which promote inflammation. Prostaglandins inhibit the secretion of gastric acid and promote mucus production. They are produced by the enzyme Cyclooxygenase (COX). There are two types of COX enzymes, COX-1 and COX-2. The COX-1 enzyme is present in almost all cells and produces prostaglandins, which support platelets for blood clotting and protects the lining of the stomach . On the other hand, the COX-2 enzyme is usually found in much smaller cells. Neighbouring cells at the sites of cell damage are programmed to manufacture the COX-2 enzyme. This leads to increased synthesis of prostaglandins causing inflammation and pain. This can be potentially harmful to the body in particular to the digestive system and the stomach . COX-2 inhibitors selectively inhibit the production of the inflammatory pain-producing prostaglandins (COX-2) at the affected areas. These can lead to cardiovascular side effects such as: heart attacks or strokes.
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Most NSAIDs have similar characteristics, primarily when they are taken in equivalent quantities. However differences occur in the route of administration for these drugs. This means that some of these drugs can be manipulated in different ways, such as: taken orally or by injection. Therefore analysing the chemical structure of these drugs allows distinguishing between them.
Signalling pathways and mechanisms of action
In humans one of the most important actions of NSAIDs is the inhibition of arachidonic acid, which metabolises the cyclooxygenase (COX) enzymes . These enzymes have two distinctive actions: the first being the production of prostaglandins or PGG2 (chemicals in the body that causes inflammation) and the second is a peroxidase action where PGG2 is converted to PGH2. Prostaglandins have a number of essential functions such as: promoting inflammation, fever, and pain. Prostaglandins also have a great influence on many organs such as: the gastrointestinal tract (GI), kidneys and the leukotriens. They have a consequential effect on the GI tract, they Inhibit gastric acid secretions in the tract, speed up the rate of healing of ulcers in humans, protect the mucosa of the stomach and intestine from becoming inflamed when this mucosa is in contact with harmful agents (cytoprotection) and stimulate smooth muscle contraction . They also increase blood flow in the kidneys and cause bronchi to constrict in the leukotriens, which can lead to Asthma or lung disease.
There are two types of COX enzymes, COX-1 and COX-2. Both enzymes produce prostaglandins. However, only the Cox-1 enzyme produces prostaglandins, which support platelets for blood clotting and protects the lining of the stomach from acidic disturbances. Both COX-1 and COX-2 inhibitors inhibit the production of prostaglandins . Also they both have a similar structure, both consisting of a long channel with a curved end and a largely hydrophobic opening where arachidonic acid can enter. The main difference between the two COX enzymes is that COX-1 has a bulky isoleucine and is immediate, while COX-2 has a valine- a smaller molecule that leaves a gap (binding site) for specific complementary COX-2 inhibitors and conversely COX-2 is not immediate like COX-1, it is dependent on time .
The effectiveness of NSAIDs varies constantly. Similarly the actions of the drugs, process of elimination of the drugs from the body, their inhibition strength and tendency to cause ulcers also varies . The better a NSAID is at blocking COX-1; the more likely it is to cause ulcers and bleeding. An NSAID called Celebrex, is an example of a selective COX-2 inhibitor, this is because it cannot block the COX-1 enzyme but can block the COX-2 enzyme. Selective COX-2 inhibitors like this cause fewer ulcers and promote less bleeding than other NSAIDs .
Common side effects
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There are many common side-effects associated with NSAIDs, these occur in different parts of the body, including: the gastrointestinal tract, the skin, liver and kidney. Gastrointestinal interferences are very common unwanted effects of NSAIDs; these mainly result from the inhibition of the COX-1 enzyme . As previously mentioned, the COX-1 enzyme produces prostaglandins, which inhibit acid secretion. Skin irritations are also very common effects. The skin conditions can vary from minor rashes to more serious and fatal diseases. Creams and ointments (topical) based NSAIDs can cause itching and irritation of the skin when they are applied. Renal side effects occur through the inhibition of prostaglandins . Research has shown that consuming a larger then required dosage of certain NSAIDs (e.g. Paracetamol) for a prolonged period of time can increase the risk of damaging the liver and ultimately can be life threatening. Other common side effects include headache, heartburn, vomiting, diarrhoea, bleeding, stomach ulcers and unusual buzzing sound in the ears (tinnitus).
Analgesics (commonly known as painkillers) are drugs primarily given to reduce pain and inflammation. Analgesic medications can be both POM (prescription only medicines) and GSL (General sales list medicines). Examples of analgesic drugs include aspirin, paracetamol, ibuprofen and naproxen. Aspirin, paracetamol and ibuprofen are commonly used for short term therapy, and naproxen is used for more long term chronic conditions. They can also be narcotic drugs such as: morphine. Analgesics may also be combined with other drugs in some types of medications (for example, analgesics can be combined with decongestants or antihistamine remedies) .
The analgesic action of NSAIDs can be understood when they inhibit the COX enzymes. NSAIDs can apply their analgesic effect through peripheral and central mechanisms. The COX-1 enzyme represents the normal cells and COX-2 is induced in inflammatory cells. The most likely analgesic mechanism of action is the inhibition of the COX-2 enzymes activity. NSAIDs have a central mechanism of action that enhances the peripheral mechanism, due to interference with the formation of prostaglandins. In addition, some NSAIDs (e.g. aspirin) can inhibit the lipoxygenase pathway, which may result in the production of algogenic metabolites .
Aspirin (acetylsalicylic acid) was one of the earliest drugs manufactured and so it has been established as one of the most well known NSAIDs with a high availability. As a result it is also one of the most commonly consumed or even misused drugs in the world. Aspirin is commonly administered orally . In general aspirin is utilised in low doses to prevent diseases such as heart attacks and atheroma formation. In addition aspirin can be bought over the counter without a doctor's prescription.
Aspirin inhibits the synthesis of prostaglandins from arachidonic acid. These inhibitors are important components of prostaglandin biosynthesis pathways. The cyclic pathway is the main pathway of arachidonate metabolism which is inhibited by aspirin . The initiation step in the pathway is catalyzed by the localized enzyme, prostaglandin hydrogen synthase (PGHâ‚‚). This enzyme consists of two important actions: a cyclooxygenase activity and a peroxidase activity. This PGHâ‚‚ enzyme is inhibited by aspirin. Aspirin can covalently modify the enzyme by acetylating (adding an acetyl radical) an important serine group next to the active site of the enzyme. The acetyl radical then blocks access to the enzyme active site, so the complementary substrate (i.e. arachidonic acid) is unable to accommodate this active site anymore . Although aspirin binds in the same site on the enzyme as salicylic acid, the acetyl group of aspirin has the capability to increase its effectiveness as a drug considerably . The substrate for this enzyme is arachidonic acid, which is a hydrophobic molecule produced by the hydrolysis of lipids in the plasma membrane. The substrate arachidonic acid can travel through a special hydrophobic channel in the protein to reach the enzyme active site. Ultimately aspirin prevents an enzyme-substrate complex from forming by blocking the channel and thus prevents prostaglandin synthesis, by inhibiting the cyclooxygenase activity of the PGHâ‚‚ enzyme .
Aspirin induces many effects through its inhibition of the COX enzymes, such as: acting as local hormones, causing pain, inflammation, muscle contraction, controlling blood pressure and the thermoregulation of the body. Besides inhibiting the COX enzymes aspirin also has many other effects. Aspirin can displace the plasma membrane thus causing a potentially hazardous increase in the effect of warfarin . Regular and controlled use of aspirin is said to reduce the risk of colon cancer and delay the action of Alzheimer's disease. Aspirin also affects radiation which provokes diarrhoea . Aspirin can irritate and damage the gastric mucosa mainly if the drug has been ingested in the form of a solid dose, the irritation can be reduced if the drug is taken in the form of a solution because it can be diluted instantaneously.
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Aspirin is a weak acid (low Ka value) which is fairly insoluble. This explains why it is commonly involved in facilitated absorption, most of which occurs in the liver. The main site of absorption is the ileum, where there are microvilli which provide a large surface area for diffusion. The half-life of aspirin for which it remains in the blood plasma depends on the dosage. However the duration of action of aspirin varies due to its irreversible character.
Aspirin can also be associated to salicylism. Salicylism is the ingestion of relatively large doses of salicylates which leads to poisonous effects such as: vomiting and dehydration. Salicylates can affect the oxidative phosphorylation stage of respiration in the muscles leading to increased oxygen consumption and thus increased production of carbon dioxide. Taking larger doses in particular can have a great impact on the rate of respiration, by producing unwanted respiratory components such as: pyruvic acid and lactate. Aspirin can also be associated with Reye's syndrome, a rare disorder in children accompanying an acute viral infection . The use of drugs tends to be monitored or completely avoided with most children so minimising the chances of being affected with this disorder.
Aspirin interferes with nerve impulses which detect pain in the thalamus part of the brain. Aspirin also inhibits chemical mediators of inflammation, which produce pain and further inflammatory reactions . These chemical mediators are released in response to cell damage. Antipyretics (such as aspirin and paracetamol) cause the hypothalamus to adjust to increase the temperature of the body, thus affecting thermoregulation in the central nervous system (CNS) and brain, this can often lead to sweating and vasodilation. The aspirin then attempts to lower the temperature of the body to reduce fever.
Moreover aspirin is a unique NSAID, not only because of its many uses, but because it is the only NSAID that inhibits the clotting of blood (atheroma) for a prolonged period of time by inhibiting the formation of thromoboxanes. Thromoboxanes are involved in the aggregation of platelets and thus blood clotting . Consequently, even a low dose of 100mg of aspirin per day can reduce platelet aggregation. This ideally makes aspirin a principle drug to reduce the risk of heart attacks and other heart diseases, by reducing the danger of getting an atheroma, which would block the coronary arteries which supply oxygen to the heart.
Another commonly used NSAID is paracetamol. Paracetamol consists of both analgesic and antipyretic properties. It has relatively weak anti-inflammatory activity in comparison to other NSAIDs. Hypothetically it is known to selectively inhibit the infrequent COX-3 enzyme. Paracetamol is usually administered orally and is easily absorbed in the body, and tends to metabolise in the liver . With therapeutic doses, side effects are minimal and uncommon but rare allergic skin reactions can sometimes occur. Exploiting paracetamol inappropriately (i.e. by taking an overdose), can cause potentially fatal liver and kidney damage. Preliminary symptoms of paracetamol poisoning are nausea, vomiting, abdominal pain, tiredness, loss of appetite and diarrhoea. This is shortly followed by the delayed liver damage occurring a few days later. However, selective agents for COX-2, such as: celecoxib are now readily available for medical use . These agents are quite effective and there analgesic properties can be acknowledged during dental pain. Also paracetamol can be less dangerous if it is taken at correct intervals. It works by hindering the way in which pain impulses are processed in the brain. Paracetamol also affects the hypothalamus in the brain similar to aspirin, by lowering the body's temperature to reduce fever. However unlike aspirin, paracetamol has not been known to cause any gastric side effects or bleeding and has not yet been linked with Reye's syndrome in children either .
Another commonly used NSAID is ibuprofen. Ibuprofen is classed as a propionic acid. This is especially useful in athletic medicines and this also affects prostaglandin synthesis . Ibuprofen is generally used for the relief of flu, back pain, arthritis pain, period (menstrual) pain, dental pain and common fever. Ibuprofen has the lowest incidence of unwanted side effects, so it is sometimes referred to as the safest of all NSAIDs . Although they still incur a few side effects such as: gastrointestinal side effects. However if ibuprofen is taken with food, this minimises the irritation in the stomach. Someone who has a medical history of peptic ulcers should not consume ibuprofen. Increased bleeding may occur if ibuprofen is used to cure minor injuries . The route of which ibuprofen is administered is usually orally i.e. in the form of a tablet. It is readily absorbed into the stomach and intestines. Once absorbed into the blood the drug is transferred to the liver before being excreted out of the body . It is advised that Ibuprofen should not be taken during pregnancy, during breast feeding or with other coagulants. Also ibuprofen consumption is prohibited for anyone with an NSAID allergy.
After analysing the mechanisms of the actions of NSAIDs, I have come to the conclusion that NSAIDs are very useful. As a result they are widely used for many different ailments. NSAIDs can alone alleviate there analgesic properties immediately, following insignificant to intermediate surgery. NSAIDs should be used appropriately to minimise the potential side effects which they entail. If these drugs are misused, they are subjected to more serious diseases, for example: taking an overdose of paracetamol can lead to fatal liver damage. NSAIDs all function in principally the same way. However, the routes of administration for these drugs may differ. The primary function they impose is to reduce inflammation and pain through the inhibition of the COX enzymes which produce prostaglandins.
However, many other actions apart from the COX inhibition may also contribute to the inflammatory reducing effects of some NSAIDs, such as: the reactive oxygen free radicals produced by neutrophils (a type of white blood cell), which ultimately decrease damage done to the tissues. Overall, I believe that the advantages of NSAIDs override the potential risks and complications associated with them. Consequently NSAIDs such as aspirin have many unique properties. This includes aspirin being the only NSAID able to inhibit the formation of a blood clot (atheroma) thus reducing the risk of a heart attack. Therefore NSAIDs have proved to be effective anti-inflammatory and analgesic agents.