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This essay will describe and explain how NSAIDs, particularly aspirin, produce both their desired and undesired effects in the human body. This will include information about how they interact with receptors in the body and their mechanisms for action.
Non-steroidal anti-inflammatory drugs are a popular category of drugs available as both general sales list medicines and prescription only medicines. They have analgesics, antipyretics and anti-inflammatory properties, each which take different lengths of time to occur, analgesic effects being the quickest (as soon as before the first dose) and anti-inflammatory effects taking the longest amount of time (up to 3 weeks). [i] They are used to treat a huge variety of conditions, including rheumatoid arthritis, muscular pain and dental pain.
Aspirin, acetylsalicylic acid, was developed as an alternative to salicylic acid. Salicylic acid has been used for millennia for its pain relief properties, mainly taken as it is found in nature, in willow bark. However, because of its major gastrointestinal side effects, an alternative was greatly needed. To reduce these effects, an acetyl group and an oxygen where added to the aromatic ring to produce aspirin. The aspirin converts to salicylic acid in a hydrolysis reaction in the body [ii] , which is then metabolised, but reduces the unwanted side effects on the gastrointestinal tract.
Aspirin, like other NSAIDs, work by inhibiting a class of enzymes called cyclooxygenase inhibitors. It does this by covalently acylating the serine residue in the enzymes' active site. Aspirin is unique as it is the only NSAID that inhibits the enzymes permanently. [iii] The COX enzymes synthesise a group of substances called prostaglandins in the body. Prostaglandins are responsible for pain and inflammation, as they are secreted by damaged cells. When the cell membrane is damaged, the phospholipids in the membrane are broken down by an enzyme called phospholipidase. When phospholipidase is broken down in the body, arachidonic acid is produce, which is then metabolised into different materials: leukotrienes, prostaglandins, thromboxanes and prostacyclins. The latter three are produced by the COX enzymes, and by inhibiting the COX enzymes, these prostaglandins are unable to be synthesised. [iv] Aspirin inhibits two types of COX, COX-1 and COX-2. When COX-1 is inhibited, arachidonic acid can no longer enter the active site, so it cannot be metabolised. COX-2, however, can still break down arachidonic acid after reacting with aspirin, but it no longer converts it to a prostaglandin. Instead, it converts it to a fatty acid. [v]
The prostaglandin particularly involved in the inflammatory process is PGE2. [vi] When the cell is damaged, a "cytokine cascade" is initiated locally. This raises the COX-2 levels, which then initiates the production of the prostaglandin. When there is a high concentration of PGE2, along with other chemicals such as cysteinyl leukotrines and PGI2 (another prostaglandin), inflammatory cells accumulate locally. This is because blood flow is increased, due to the vasodilation caused by the prostaglandin, and also because of increased vascular permeability. The increase in vascular permeability causes fluid to leak in and out of the cell, and allows leukocytes to infiltrate the cell, resulting in swelling [vii] .
Pain is the body's response to outside stimuli that could be damaging to itself: pain lets a person know if something is so hot that it will cause damage to skin, for example, so that the person would move himself from the source of damage. Pain is caused mainly by sensors interacting with chemicals released by damaged cells. The chemicals include bradykinin in particular, but also some amino acids, cytokines and neuropeptides. When the sensors, called nociceptors, interact with these substances, they send electric pulses to the brain and spinal cord, which causes the pain sensation. [viii]
Prostaglandins' role in pain production is believed to be the sensitisation of nociceptors, both at the site of injury and in the spinal cord. [ix] The sensitisation means that the sensors need a lower degree of stimulation before the sensory neurons shoot signals to the brain. The prostaglandins affect the different ion channels, including potassium and sodium channels, in the body. This causes the neurons to be more excitable, causing hyperalgesia. Because aspirin stops COX enzymes synthesising prostaglandins, there is no sensitisation of the nociceptors. This causes the pain to lessen, but probably not completely go away, as the receptors can still sense the bradykinin and other molecules released by the damaged areas.
An increase in prostaglandins can also lead to fever. This is mainly caused by an infection or an autoimmune disorder; fever can be caused by other means but aspirin only reduces fever produced by an increase in prostaglandins. The bacteria from an infection release toxins into the body, which stimulates the production of E prostaglandins in the hypothalamus. These raise the set point temperature of the body, so the hypothalamus initiates mechanisms to raise the temperature, such as vasoconstriction. This causes the temperature of the body to rise. When aspirin is introduced to the blood stream, the prostaglandins are no longer produced, so the set point temperature returns to normal, and the hypothalamus instigates mechanisms to reduce temperature, for example sweating and vasodilation.
Aspirin is also well known for its use in preventing myocardial infarctions and strokes. [x] These conditions occur when platelets aggregate in the blood stream, causing a clot. These clots can move to stop blood flow to the heart, causing a MI (heart attack), or stop blood flow to the brain, causing a stroke. Aspirin's inhibition of COX-1 prevents the synthesis of Thromboxane A2 (TXA2), which is responsible for promoting aggregation of platelets. This reduces the likelihood of a clot forming, which is why people with a history of heart attacks or heart disease are recommended to take a low dose of aspirin frequently to reduce their risk of another event occurring. The dose has to be low, not only because of unwanted gastrointestinal side effects after prolonged use, but because the inhibition of COX-1 stops the production of the prostaglandin PGI2. [xi] This prostaglandin actually inhibits aggregation of platelets, so it is not preferable to prevent the production of PGI2. It requires a much higher dose of aspirin to inhibit the production of the prostaglandin, so as long as the dose remains low, platelet aggregation should be limited. Because of its prevention of aggregation, aspirin should not be taken with blood thinning drugs such as warfarin, as this could cause controllable bleeding.
The use of aspirin, like most drugs, can produce unwanted side effects. The most common complaints connected with aspirin are issues with the gastrointestinal tract. This is because when COX-1 is inhibited, the production of the prostaglandins responsible for inhibiting acid secretion and partially protecting the mucosa is halted. The prevention of acid secretion inhibition causes side effects such as dyspepsia, and in severe cases ulceration and gastric bleeding. Nausea, vomiting and diarrhoea are also common. [xii] Because of this, it is recommended that aspirin should be taken with food/milk, but this only limits the side effects, not completely prevent them. Those with a high risk of serious gastrointestinal side effects are often advised to take selective COX-2 inhibitors instead, as the inhibition of COX-2 doesn't affect the GI system like COX-1 does.
Aspirin cannot be given to children under 16 years old. This is because there is a suspected link between aspirin use and Reye's syndrome. This is a possibly fatal condition that generally follows a viral illness, and includes both liver disorder and encephalopathy .It is unknown currently why aspirin use can lead to Reye's. Another group of people that are advised against the use of aspirin are those with aspirin sensitive asthma. Those who take aspirin with this condition suffer from airway obstruction, as well as congestion in the nose. A reason for this response has yet to be confirmed; however, it has been suggested that the increase in leukotriene levels after taking aspirin could cause the side effect. Because the arachidonic acid isn't made into prostaglandins, as the COX-1 enzyme is inhibited, it is made into leukotrienes. These are known to be involved in the cause of asthsma. [xiii]
Along with aspirin, Paracetamol is one of the most commonly used painkillers. Like aspirin, it provides analgesic and antipyretic effects. However, it does not seem provide a noticeable anti-inflammatory effect. This is because it only very weakly inhibits COX-2. The mechanism of action of paracetamol isn't currently understood. It is believed that it inhibits cyclo-oxygenase 3, which in turn prevents the synthesis of certain prostaglandins. Another possible mechanism is that paracetamol prevents prostaglandin synthesis by reducing peroxide tone. [xiv] Because peroxides are needed as cofactors for the action of COX, this prevents the production of prostaglandins in areas of low peroxide concentration.
Paracetamol is very popular because it can be used in children as well as adults, as there is no link to Reye's syndrome. In addition to this, there are few gastrointestinal side effects, due to the limited inhibition of COX-1 and COX-2, causing little to no effects to the useful jobs of these enzymes, including acid secretion inhibition. .
One major issue with paracetamol is its effect in high dosages. When paracetamol is metabolised in the body, a toxic metabolite, NAPQI, is produced. This can be very damaging to the liver and can cause liver failure through both acute and chronic overdose. Because of this, people that have hepatic issues are cautioned against the drug's use.
Ibuprofen, a derivative of propionic acid, is popular because of the availability of low strengths over the counter. In addition to this, ibuprofen causes fewer side effects than aspirin, and some patients find it more effective for their pain relief. Its ability to reduce pain is similar in strength to paracetamol, but it has an advantage over paracetamol as it can also reduce inflammation. This makes it a popular choice for those with sports injuries and muscular pain. Unlike aspirin, it is a reversible cyclo-oxygenase inhibitor. Instead of covalently bonding with the enzyme, it acts as a competitive inhibitor.