Aspirin

Aspirin or acetylsalicylic acid (acetosal) is a drug in the family of salicylates, often used as an analgesic (against minor pains and aches), antipyretic (against fever), and anti-inflammatory. It has also an antiplatelet (“blood-thinning”) effect and is used in long-term low-doses to prevent heart attacks.

Low-dose long-term aspirin irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation, and this blood-thinning property makes it useful for reducing the incidence of heart attacks. Aspirin produced for this purpose often comes in 75 or 81 mg dispersible tablets and is sometimes called “Junior aspirin” or “Baby aspirin.” High doses of aspirin are also given immediately after an acute heart attack. These doses may also inhibit the synthesis of prothrombin and may therefore produce a second and different anticoagulant effect.

Several hundred fatal overdoses of aspirin occur annually, but the vast majority of its uses are beneficial. Its primary undesirable side effects, especially in higher doses, are gastrointestinal distress (including ulcers and stomach bleeding) and tinnitus. Another side effect, due to its anticoagulant properties, is increased bleeding in menstruating women. Because there appears to be a connection between aspirin and Reye's syndrome, aspirin is no longer used to control flu-like symptoms or the symptoms of chickenpox in minors.

Aspirin was the first discovered member of the class of drugs known as non-steroidal anti-inflammatory drugs (NSAIDs), not all of which are salicylates, though they all have similar effects and a similar action mechanism.

How it works

In a piece of research for which he was awarded both a Nobel Prize in Physiology or Medicine in 1982 and a knighthood, John Robert Vane, who was then employed by the Royal College of Surgeons in London, showed in 1971 that aspirin suppresses the production of prostaglandins and thromboxanes. This happens because cyclooxygenase, an enzyme that participates in the production of prostaglandins and thromboxanes, is irreversibly inhibited when aspirin acetylates it. This makes aspirin different from other NSAIDS (such as diclofenac and ibuprofen), which are reversible inhibitors.

Prostaglandins are local hormones (paracrine) produced in the body and have diverse effects in the body, including but not limited to transmission of pain information to the brain, modulation of the hypothalamic thermostat, and inflammation. Thromboxanes are responsible for the aggregation of platelets that form blood clots. Heart attacks are primarily caused by blood clots, and their reduction with the introduction of small amounts of aspirin has been seen to be an effective medical intervention. The side-effect of this is that the ability of the blood in general to clot is reduced, and excessive bleeding may result from the use of aspirin.

More recent work has shown that there are at least two different types of cyclooxygenase: COX-1 and COX-2. Aspirin inhibits both of them. Newer NSAID drugs called COX-2 selective inhibitors have been developed that inhibit only COX-2, with the hope for reduction of gastrointestinal side-effects.

However, several of the new COX-2 selective inhibitors have been recently withdrawn, after evidence emerged that COX-2 inhibitors increase the risk of heart attack. It is proposed that endothelial cells lining the arteries in the body express COX-2, and, by selectively inhibiting COX-2, prostaglandins (specifically PGF2) are downregulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anti-coagulative effect of PGF2 is decreased, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, rendering them "useless": an important difference with reversible inhibitors.

Furthermore, aspirin has 2 additional modes of actions, contributing to its strong analgesic, antipyretic and antiinflammatory properties:

It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria.

It induces the formation of NO-radicals in the body that enable the white blood cells (leukocytes) to fight infections more effectively. This has been found recently by Dr. Derek W. Gilroy, winning Bayer's International Aspirin Award 2005.

Indications

Aspirin, as with many older drugs, has proven to be useful in many conditions. Despite its well-known toxicity it is widely used, since physicians are familiar with its properties. Indications for its use include:

Fever

Pain (especially useful for some forms of arthritis, osteoid osteoma, and chronic pain)

Migraine

Rheumatic fever (drug of choice)

Kawasaki's disease (along with IVIG)

Pericarditis

Coronary artery disease

o Acute myocardial infarction

In addition, aspirin is recommended (low dose, 75-81 mg daily) for the prevention of:

Myocardial infarction - in patients with either documented coronary artery disease or at elevated risk of cardiovascular disease

Stroke - as secondary prevention (ie. to prevent recurrence)

Dosage

For adults a maximum of 4000 mg per day, spread over at least 4 doses of at most 1000 mg. For children over 12 years old a maximum of 2000 mg, spread over at least 4 doses of at most 500 mg, with at least 4 hours between doses.

The correct dose of aspirin depends on the disease process that is being treated. For instance, for the treatment of rheumatic fever, doses near the maximal daily dose have been used historically. For the prevention of myocardial infarction in someone with documented or suspected coronary artery disease, doses as low as 75 mg daily (or possibly even lower) are sufficient.

Contraindications and warnings

Aspirin should be avoided by those known to be allergic to aspirin, ibuprofen or naproxen.

Caution should be exercised in those with asthma or NSAID-precipitated bronchospasm.

It is generally recommended that one seek medical help if symptoms do not improve after a few days of therapy.

Caution should be taken in patients with kidney disease, peptic ulcers, mild diabetes, gout or gastritis; manufacturers recommend talking to one's doctor before using this medicine.

Taking aspirin with alcohol increases the chance of gastrointestinal haemorrhage (stomach bleeding).

Children, including teenagers, are discouraged from using aspirin in cold or flu symptoms as this has been linked with Reye's syndrome.

Patients with hemophilia or other bleeding tendencies should not take salicylates.

Some sources recommend that patients with hyperthyroidism avoid aspirin because it elevates T4 levels.

Pets-- aspirin may be used in cats, but only under a veterinarian's strict supervision, as aspirin has a biological half-life of 3 days in cats (cats have trouble breaking down aspirin). Dogs may also use aspirin under a vet's strict supervision, though dogs are more susceptible to aspirin-caused GI bleeds than humans. Aspirin is generally not recommended for pets, though, as there are much safer alternatives for pain relief, and aspirin interacts with several other drugs including cortisones, digoxin, some antibiotics, Phenobarbital and furosemide (Lasix).

Common side-effects

Gastrointestinal complaints (stomach upset, dyspepsia, heartburn, small blood loss). To help avoid these problems, it is recommended that aspirin be taken at or after meals. Undetected blood loss may lead to hypochromic anaemia.

Severe gastrointestinal complaints (gross bleeding and/or ulceration), requiring discontinuation and immediate treatment. Patients receiving high doses and/or long-term treatment should receive gastric protection with high-dosed antacids, ranitidine or omeprazole.

Frequently, central effects (dizziness, tinnitus, hearing loss, vertigo, centrally mediated vision disturbances, and headaches). The higher the daily dose is, the more likely it is that central nervous system side effects will occur.

Sweating, seen with high doses, independent from antipyretic action

Long-term treatment with high doses (arthritis and rheumatic fever): often increased liver enzymes without symptoms, rarely reversible liver damage. The potentially fatal Reye's syndrome may occur, if given to paediatric patients with fever and other signs of infections. The syndrome is due to fatty degeneration of liver cells. Up to 30 percent of those afflicted will eventually die. Prompt hospital treatment may be life-saving.

Chronic nephritis with long-term use, usually if used in combination with certain other painkillers. This condition may lead to chronic renal failure.

Prolonged and more severe bleeding after operations and post-traumatic for up to 10 days after the last aspirin dose. If one wishes to counteract the bleeding tendency, fresh thrombocyte concentrate will usually work.

Skin reactions, angioedema, and bronchospasm have all been seen infrequently.

Overdose

Aspirin overdose can be acute or chronic. In acute poisoning, a single large dose is taken; in chronic poisoning, supratherapeutic doses are taken over a period of time. Acute overdose has a mortality rate of 2%. Chronic overdose is more commonly lethal with a mortality rate of 25%; chronic overdose may be especially severe in children.

Symptoms

Aspirin overdose has potentially serious consequences, sometimes leading to significant morbidity and mortality. Patients with mild intoxication frequently have nausea and vomiting, abdominal pain, lethargy, tinnitus, and dizziness. More significant symptoms occur in more severe poisonings and include hyperthermia, tachypnea, respiratory alkalosis, metabolic acidosis, hypokalemia, hypoglycaemia, hallucinations, confusion, seizure, cerebral oedema, and coma. The most common cause of death following an aspirin overdose is cardiopulmonary arrest usually due to pulmonary oedema.

Toxicity

The toxic dose of aspirin is generally considered greater than 150 mg per kg of body mass. Moderate toxicity occurs at doses up to 300 mg/kg, severe toxicity occurs between 300 to 500 mg/kg, and a potentially lethal dose is greater than 500 mg/kg. This is the equivalent of many dozens of the common 325 mg tablets, depending on body weight. Please note that children cannot tolerate as much aspirin per unit body weight as adults can, even when aspirin is indicated. Label-directions should be followed carefully.

Treatment

All overdose patients must be taken to a hospital immediately. Contrary to the urban legend, one can die from ingesting a bottle of pills, even if they are subsequently thrown up.

Initial treatment of an acute overdose includes gastric decontamination of the patient. This is achieved by administering activated charcoal which adsorbs the aspirin in the gastrointestinal tract, stomach pumps are no longer routinely used in the treatment of poisonings but are sometimes considered if the patient has ingested a potentially lethal amount up to 1 hour previously. Repeated doses of charcoal have been proposed to be beneficial in aspirin overdose.[9] A study performed found that repeat dose charcoal might not be of significant value. However, most toxicologists will administer additional charcoal if serum salicylate levels are increasing.

Patients are monitored until their peak salicylate blood level has been determined. Blood levels are usually performed 4 hours after ingestion and then every 2 hours after that to determine the maximum level. Maximum levels can be used as a guide to toxic effects expected.

There is no antidote to salicylate poisoning. Frequent blood work is performed to check metabolic, salicylate, and blood sugar levels; arterial blood gas assessments are performed to test for respiratory alkalosis and metabolic acidosis. Patients are monitored and often treated according to their individual symptoms, patients may be given intravenous potassium chloride to counteract hypokalemia, glucose to restore blood sugar levels, benzodiazepines for any seizure activity, fluids for dehydration, and importantly sodium bicarbonate to restore the blood's sensitive pH balance. Sodium bicarbonate also has the effect of increasing the pH of urine, which in turn increases the elimination of salicylate. Additionally, haemodialysis can be implemented to enhance the removal of salicylate from the blood. haemodialysis is usually used in severely poisoned patients; for example, patients with significantly high salicylate blood levels, significant neurotoxicity (agitation, coma, convulsions), renal failure, pulmonary oedema, or cardiovascular instability are hemodialyzed. haemodialysis also has the advantage of restoring electrolyte and acid-base abnormalities; haemodialysis is often life-saving in severely ill patients.

If the overdose was intentional, the patient should undergo psychiatric evaluation, as with any suicide attempt.