How aspirin, paracetamol and NSAIDs work
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Prostaglandin Synthesis |
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Prostaglandins & Pain |
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Prostaglandins & Inflammation |
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Prostaglandins & Fever |
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Prostaglandins & the Stomach |
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The Action of Minor Analgesics |
Prostaglandin Synthesis
Prostaglandins are normally present in very low concentrations throughout the healthy body. However, when a cell is damaged, such as by mechanical trauma or infection, it produces much higher local concentrations of prostaglandins. The process by which prostaglandins are synthesised is known as the arachidonic acid cascade. Damage to cells causes the release of arachidonic acid from the cell membrane, which is converted to endoperoxides by the enzyme cyclo-oxygenase. Endoperoxides are then converted to a series of substances, the most important of which, in the context of pain, are the prostaglandins.
Prostaglandins - arachidonic acid cascade
Prostaglandins and Pain
Tissue injury caused by excessive heat, cold, pressure or trauma results in the localised formation of prostaglandins. This surge of prostaglandins leads to the release of other biochemical substances including bradykinin. Bradykinin acts on nociceptors to amplify pain impulses. In addition, prostaglandins lower the threshold of the nerve endings, making them more sensitive to bradykinin, thus enhancing the painful stimulus.
Effects of prostaglandins - pain
Prostaglandins and Inflammation
Inflammation occurs as a defensive reaction to physical damage. This can be caused by infections, and mechanical or chemical trauma. The initial response is the release of mediators responsible for local vasodilation and vascular permeability (histamine and 5-hydroxy tryptamine). This is followed by the production of prostaglandins and bradykinin, which exacerbate the histamine effects.
The main result is one of increased blood flow to the area of damaged tissue. This causes the cardinal signs of inflammation:
• heat
• redness
• swelling
• pain.
The heat and redness are directly due to increased blood flow. Swelling of the tissues occurs due to fluid escaping from the capillaries into the interstitial spaces, causing inflammation and pain by pressure on nociceptors. The pain and swelling may become so severe that a fifth sign, loss of function, occurs. Whereas higher doses of NSAIDs, such as aspirin and ibuprofen, relieve inflammation, paracetamol has little effect.
Effects of prostaglandins - inflammation
Prostaglandins and Fever
When bacterial and viral infections cause tissue damage, phagocytes invade the area to engulf the bacteria or virus. Pyrogens are released into the blood stream and transported to the brain. There they stimulate production of prostaglandins in the hypothalamus. The prostaglandins act on the temperature-regulating centre in the hypothalamus, causing the body’s ‘thermostat’ to be reset at a higher temperature. Body temperature then rises from normal to the new level and the patient suffers pyrexia or fever.
The mechanisms by which the body temperature is raised include:
• vasoconstriction in the skin reducing heat loss
• an increase in metabolic rate via adrenaline release
• an increase in muscle tone
• shivering
• piloerection.
A temperature of over 37°C is indicative of pyrexia and is believed to be a protective response to infection – the raised temperature adversely affects the infecting organism. However, if the body temperature is too high for a prolonged period and is not reduced either by anti-pyretic drugs, or by physical means (e.g. cold compress application), irreparable tissue damage may occur.
Effects of prostaglandins - fever
Prostaglandins and the Stomach
Prostaglandins in the stomach increase the production of mucus and bicarbonate and help preserve the integrity of the mucus-bicarbonate barrier. This barrier protects the gastric mucosa from the corrosive effects of acid, pepsin and bile.
Effects of prostaglandins - gastroprotection
The Action of Minor Analgesics
Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, and other drugs such as paracetamol, inhibit the enzyme cyclo-oxygenase and thereby reduce the synthesis of prostaglandin substances that act centrally to produce pain, and peripherally to cause inflammation and stimulate secretion of protective gastric mucus.
Whereas the NSAIDs, including aspirin, reduce prostaglandin synthesis both in the central nervous system and peripherally, there is evidence to suggest that paracetamol principally acts centrally, with limited peripheral activity. This may account for its lack of significant anti-inflammatory effects with increased dose, and its association with fewer gastrointestinal side effects compared with solid asprin, the effects of which in some susceptible people can lead to dyspepsia and sometimes ulcers.
Unlike paracetamol, aspirin is unique in its irreversible inhibition of available cyclo-oxygenase. The enzyme is regenerated over time, except in platelets. This aspirin-specific effect and its importance in reducing the risks of heart attack and stroke is explained in the Anti-Platelet section.