Aspirin’s cardiovascular benefits are now widely recognized, and over the years, in increasing amount of evidence has been accumulating, suggesting that regular aspirin use may also reduce the risk of developing certain cancers. The mechanism which instigate this are not fully understood, but there are several interesting hypotheses. One is that aspirin causes cancer cells to self-destruct through a process called apoptosis, as it is a result of the combination of cancer cells and salicylate. It is believed that cancer develops when apoptosis is impaired, and salicylate is thought to correct this through various effects on both COX and non-COX pathways.
Recent evidence has also suggested that as well as preventing pain, heart disease and cancer, aspirin may also prevent Alzheimer’s disease, by approximately 10%. Although the exact cause of Alzheimer’s disease is still unclear, one suggestion is that the inflammation in the brain responsible for some of the mental deterioration. If proven to be correct, it may simply be aspirin’s anti-inflammatory response which reduces the effects of Alzheimer’s disease. If so, then most other drugs of the NSAID’s class would also have the same effect. The evidence that long-term low dosage aspirin use reduces the levels of C-reactive protein in the blood, supports this idea, as C-reactive protein is a marker for inflammation. Another property of salicylate is its anti-oxidant effect that neutralizes free-radicals which harm tissue. These free-radicals are produces as a result of certain metabolic reactions that take place in the body. They have been associated with many serious illnesses, such as cancer and Alzheimer’s disease.
Many people believe that aspirin is so effective as salicylate should originally be a part of a healthy balanced diet. This is supported by the fact that many plant species release salicylate as a defence mechanism. Therefore, fruit and vegetables that are prone to this chemical release are more resistant to damage and disease. This is also supported by the fact that people who consume large amounts of fruit and vegetables have lower levels of heart disease and certain cancers.
In this day and age however, people do not consume the daily requirement of fruit and vegetables. Worse still, the salicylate content of fruit and vegetables is likely to be less then it used to be. Throughout history people have grown there own vegetables or bought them form local sellers. As the level of pests, diseases and physical damage to the fruit and vegetables has decreased, so to have the levels of salicylate within them.
However, although aspirin has labelled itself as “the wonder drug for all manner of diseases”, there are a number of problems that are associated with its use.
As with almost all chemicals, the body has ways of getting rid of aspirin. In this case, the liver, stomach, and other organs change aspirin to salicylic acid. This chemical then gets altered in the liver in a slow and gradual process, attaching a number of other complex chemical onto the salicylic acid so that the kidneys can filter it out of the blood and send it to the excretory organs in the urine. This whole process takes approximately four to six hours, so another pill must be taken accordingly for the effect to last. This may become tedious after a certain amount of time.
The problem with the fact that aspirin travels through the entire bloodstream is that the body needs prostaglandins for a number of reasons, such as in the stomach. COX 1 enzymes produce a substance that maintains the thickness of the lining of the stomach. As aspirin inhibits COX 1 pathways, the lining of the stomach decreases in thickness, allowing the acidic digestive juice to irritate it, thus causing severe stomach pains. The same can be said for COX 2 enzymes, which are needed in areas such as the brain and kidney. If large doses of aspirin are taken, then the normal processes that occur in these organs may be disrupted. It is for this reason that other drugs have been created to have a similar effect as aspirin but without the side effects. One prime example is paracetamol, which will be explained in detail later.
There are many campaigns to boost the appropriate uptake of low dosage aspirin. However, it is important to note whether the decision has been made on whether benefit exceeds risk.
The diagram above shows the molecular structure of aspirin
Paracetamol relieves pain and fever in adults and children, and it is the most widely accepted medicine for this purpose. It is used mainly for it’s pain relieving qualities, either as a medicine prescribed by a doctor or it can be purchased as an over-the-counter medicine both in retail pharmacies or grocery stores.
There are virtually no groups of people who should not take paracetamol, and interactions with other treatments are not a problem. When taken at the recommended dosage, there are virtually no side-effects.
Its pain relief and fever relief effects are similar to those of aspirin and it works in a similar, though not identical, way. Unlike aspirin, however, increasing the dose does not result in clinically useful anti-inflammatory activity. Paracetamol is therefore not of value for reducing inflammation in the treatment of chronic rheumatic diseases as are the non-steroidal anti-inflammatory drugs like aspirin. Nevertheless, paracetamol does provide useful pain relief and is considered the first line treatment in osteoarthritis.
Paracetamol can be combined with decongestant ingredients to help relieve the symptoms of the common cold, influenza and sinusitis by relieving headache, general aches, nasal congestion and fever.
Paracetamol and its combinations are mainly available as tablets for immediate consumption or for dissolving in water before consumption. It is suitable for all age groups including the very young for whom it may be used following immunisation procedures, and it is available in liquid formulations for young children
Paracetamol has been compared to aspirin in many different ways:
- Its analgesic (pain relief) and antipyretic (fever relief) effects are comparable to those of aspirin.
- There are virtually no groups of people who should not take it.
- Interactions with other treatments are not a problem.
- At the recommended dosage there are virtually no side-effects.
- It is suitable for small children and the elderly.
- It can be taken by those sensitive to aspirin.
- It is well tolerated by people with peptic ulcers.
Over a century after it was first discovered, scientists are now learning what the mechanism of action is that makes paracetamol such an effective and useful drug. It now appears that paracetamol has a highly targeted action in the brain, blocking an enzyme involved in the transmission of pain.
As with many medicines, the effectiveness of paracetamol was discovered without knowing how it works. Its mode of action was known to be different to other pain relievers, but although it produces pain relief throughout the body the exact mechanism was not clear.
The production of prostaglandins is part of the body's inflammatory response to injury. As mentioned previously, the inhibition of prostaglandin production around the body by blocking the enzymes known as COX 1 and COX 2 has long been known to be the mechanism of action of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. However, their action in blocking COX 1 is known to be responsible for also causing the unwanted gastrointestinal side effects associated with these drugs.
Paracetamol has no significant action on COX 1 and COX 2, which left its mode of action a mystery but did explain its lack of anti-inflammatory action and also, more importantly, its freedom from gastrointestinal side effects typical of NSAIDs.
Early studies had suggested that the fever reducing action of paracetamol was due to activity in the brain while its lack of any clinically useful anti-inflammatory action was consistent with a lack of prostaglandin inhibition in the body.
However, recent research has shown the presence of a new, previously unknown cyclooxygenase enzyme COX 3, found in the brain and spinal cord, which is selectively inhibited by paracetamol, and is distinct from the two already known COX 1 and COX 2 enzymes. It is now believed that this selective inhibition of the enzyme COX 3 in the brain and spinal cord explains the effectiveness of paracetamol in relieving pain and reducing fever without having unwanted gastrointestinal side effects.
The recommended adult dose of paracetamol is two 500 mg tablets, with four hours between doses, and no more than eight tablets in twenty-four hours. If this recommended dose is adhered to, there are no toxic effects, even in prolonged or habitual use. Paracetamol does not accumulate in the body following normal doses. It is not absorbed any more rapidly or slowly than other highly popular pain relieving medicines and does not leave the stomach at a different rate.
Paracetamol however, also has its problems. Overdoses have been relatively comon with this specific drug. As paracetamol is a potent drug that is available without prescription, it is often used in suicide attempts, and in this respect it is potentially more dangerous than other over-the-counter drugs such as aspirin. This is because paracetamol overdoses often cause liver failure, and there have been many cases where attempted suicides have awakened from an overdose and changed their minds, yet still died a few days later from liver damage. In substantial overdose liver damage is likely to occur assuming the patient does not receive treatment.
Publicity has been given to death by 'accidental' overdose. It is difficult to see how a person can take a dose of paracetamol that is sufficient to be fatal without being aware of it. However, research with patients who have overdosed shows that overdoses are taken deliberately, and in a majority death was the intended outcome. In a proportion, although the overdose was deliberate, induced illness or self harm rather than death was the intended outcome.
Paracetamol is primarily metabolised by the liver. Most of it is combined with glucuronide and sulphate, which account for about 90% of the dose excreted. About 5% of the dose is excreted unchanged and a further 5% is oxidised to a quinine imine, which is then combined with glutathione and metabolised on to cysteine and other compounds which are safely excreted.
Paracetamol and its two primary metabolites are remarkably safe compounds, and the toxicity of paracetamol arises only through the 5% that is oxidised. The immediate oxidation metabolite, quinine imine, is a highly reactive substance that normally combines with glutathione. As the dose of paracetamol increases, the quantity of quinine imine produced increases too. There then comes a point where the glutathione stores in the liver have been completely used up and the rate of production of new glutathione cannot keep up with the rate of production of the quinine imine. It is at this point that the quinine imine attaches to liver protein and causes liver injury. It cannot be eliminated and begins to react with cellular proteins and nucleic acids in the liver, eventually causing irreparable damage.
The time required for the liver to become depleted of glutathione, and for the quinine imine to build up and cause fatal liver damage, is three to four days. During the early stages of this process, there may be few overt symptoms, and it is important that in cases of suspected overdose the patient does not wait for symptoms to appear before seeking medical help. It is estimated that liver injury may begin to occur at a single dose of paracetamol of 15g (30 standard tablets) or over.
Treatment of overdose consists of skilled hospital management of the patient, including where necessary the administration of an antidote, n-acetylcysteine or methionine, which are administered intravenously. The antidote restores the liver's capacity to produce glutathione for combination with the quinine imine, and appears to have further protective effects on the liver. A new formulation of paracetamol is now being marketed in the UK which incorporates methianine, such that the drug carries its own antidote with it.
The administration of antidote within twelve hours of overdose is highly effective and is able to remove the risk of liver injury. Antidote therapy is also very effective up to twenty-four hours and there is evidence for benefit from antidote administration up to forty-eight hours following overdose
Although both aspirin and paracetamol seem to have their problems, they both help a vast number of people from certain illnesses and pains, and there is no doubt that these drugs do benefit more people then harm.
