Aspirin: a Non-Steroidal Anti-Inflammatory Drug
Aspirin was first used as a treatment for the disease in the 1890s when Felix Hoffmann used it to treat his father’s rheumatism. A German pharmaceutical company Bayer obtained a patent for the drug in 1899 and distributed it to physicians in powder form so they could use it to treat ill patients. Aspirin was sold in tablet form from 1915. Aspirin is a salicylate and is also known as acetylsalicylic acid. It has the chemical name 2-Acetoxybenzoic acid and the formula C9H8O4. The appearance of aspirin is white crystals or crystalline powder, it has no odour and tastes slightly bitter. It has a molecular weight of 180.16 gmol, a melting point of 140°C, a boiling point of 135°C and acid dissociation constant (pKa) of 3.49 at 25°C. Aspirin is a non-steroidal anti-inflammatory drug (NSAID) and is used for pain relief, to reduce inflammation and to lower high temperatures. It can also be used as an antiplatelet drug and due to its ability to inhibit platelet assembly can be used to prevent the formation of blood clots and helps prevent ischemic strokes and heart attacks.
Prostaglandins (PGs) are eicosanoids synthesised from arachidonic acid, catalysed by cyclo-oxygenase (COX-1 and COX-2) enzymes. Prostaglandins trigger the reactions that cause pain, fever and inflammation at the site of injury. Aspirin irreversibly reacts with COX-2 enzymes, inhibiting their function and stopping the production of prostaglandins. This reduction in prostaglandins leads to a reduction in pain and inflammation.
Thromboxane A2 (TXA2) is produced when arachidonic acid in platelets is metabolised by COX-1 enzymes. TXA2 is a lipid that is present in platelets and has a key role in their aggregation. The acetyl group in aspirin binds to a serine residue in COX-1 enzymes which leads to a reduction in prostaglandin production. It also inhibits the production of TXA2. This means that the blood becomes thinner and is unable to clump together and form clots. This is beneficial as it helps to prevent conditions like a stroke or pulmonary embolism.
COX-1 and COX-2 are similar in structure with 60% homology. Aspirin binds to serine 516 residue on the COX-2 active site and serine 530 residues on the COX-1 active site. COX-2 has a larger active site than COX-1, meaning that arachidonic acid is able to evade the aspirin molecule inactivating COX-2. Therefore, aspirin acts on COX-1 more than COX-2 and a higher dose is required for COX-2 inhibition.
Absorption- Aspirin is usually absorbed quickly in the stomach and small intestine when consumed orally. The aspirin is transported into the stomach by passive diffusion. The optimal pH for absorption in the stomach is between 2.15-4.10. Aspirin absorption happens at a faster rate in the intestines than in the stomach when the pH is between 3.5-6.5, and the stomach is unable to absorb aspirin at a pH of 6.5. Within the first 60 mins following consumption, half of the dose is hydrolysed to salicylic acid by esterases in the gastrointestinal (GI) tract. Plasma salicylate concentrations are best 1-2 hours after ingestion.
Distribution- Following absorption, aspirin is distributed throughout the body and binds to plasma proteins, primarily albumin. 80-95% of salicylic acid is bound to albumin. Salicylic acid reaches synovial fluid, cerebrospinal fluid, saliva and breast milk. Aspirin can bind to and acetylate DNA, hormones, haemoglobin and platelets.
Metabolism- Aspirin is hydrolysed in the plasma and becomes salicylic acid. Other issues are also involved, but most of the salicylate metabolism takes place in the liver. The substances produced after aspirin metabolism are “salicylic acid, salicylic acid, the ether or phenolic glucuronide and the ester or acyl glucuronide. A small portion is converted to gentisic acid and other hydroxybenzoic acids”.
Elimination- The removal of salicylates from the body occurs by alternative pathways of renal elimination and metabolite formation. Renal elimination through the kidney happens through first-order kinetics in a linear manner and is sensitive to urinary pH, organic acids and flow rate. The more basic the urine pH, the greater the excretion of salicylates will be. It can take up to two days for total elimination.
Like all drugs, excessive amounts of aspirin can become toxic. Normal amounts for a dose of aspirin are 81mg for a low dose, 325mg standard dose or 500mg for an extra-strong dose. The median lethal dose (LD50) of aspirin in humans is 1.0gkg. Consumption of >250mgkg of aspirin may cause moderate toxicity and >500mgkg of aspirin can cause potentially fatal toxicity. Salicylate toxicity can develop as a result of treatment for either acute illness or chronic illness. Symptoms of salicylate poisoning include vomiting, dehydration, sweating, increased respiratory rate and hyperventilation. There is also a disturbance in acid-base balance and hyperglycaemia, or hypoglycaemia may occur. Multiple systems can be harmed by salicylate toxicity, like the central nervous, pulmonary system and GI system. Chronic salicylate poisoning is more common in elderly patients and can sometimes be difficult to identify. There is a significant number of contraindications to why patients should not take aspirin, some of which are anaemia, Willebrand’s disease, stomach or intestinal ulcer, alcoholism and pregnancy. Anyone with salicylate or NSAID allergy should not take this drug.
In terms of future uses and research of aspirin, could it have a role to play in the fight against the Covid-19 pandemic? According to a study by Chow et al. aspirin may be beneficial to hospitalised Covid-19 patients in terms of needing mechanical ventilation or being admitted into the intensive care unit (ICU). Covid-19 is associated with thrombophilia in severe cases, so the antiplatelet effect of aspirin could potentially be advantageous. In a small investigation of 412 Covid-19 positive patients, 98 patients (23.7%) received aspirin and 314 patients (76.3%) did not. Of the patients who were taking aspirin, 35.7% required mechanical ventilation compared to 48.4% of non-aspirin patients. 38.8% of aspirin takers were admitted to ICU compared to 51% of non-aspirin takers. This is just a small sample of people, but it shows that aspirin could improve the condition of some of those severe cases of patients hospitalised with Covid-19. However, a randomised control trial with much larger sample size is necessary to see if there’s a clear association between aspirin use and a reduction in lung damage and mortality in Covid-19 patients. There is evidence from some studies to suggest that small daily doses of aspirin can also reduce the risk of developing certain cancers, mainly colorectal cancer. In a CAPP2 trial, an investigation was conducted with patients who had Lynch syndrome- a genetic disorder which increases the risk of colorectal and other cancers. Patients who were given aspirin had a 63% reduction in the risk of colorectal cancer development compared to the patients who were given a placebo. Other long-term cohort studies published in JAMA Oncology show that aspirin use ≥ 6 years was associated with a 19% decrease of colorectal cancer and a 15% reduced risk of developing any gastrointestinal cancer. The use of aspirin to reduce the risk of certain cancers may be an important approach for the future.
