Aspirin

Also known as Aspirin, acetylsalicylic acid (ASA) is a commonly used drug for the treatment of pain and fever due to various causes. Acetylsalicylic acid has both anti-inflammatory and antipyretic effects. This drug also inhibits platelet aggregation and is used in the prevention of blood clots stroke, and myocardial infarction (MI) .

Interestingly, the results of various studies have demonstrated that long-term use of acetylsalicylic acid may decrease the risk of various cancers, including colorectal, esophageal, breast, lung, prostate, liver and skin cancer . Aspirin is classified as a non-selective cyclooxygenase (COX) inhibitor and is available in many doses and forms, including chewable tablets, suppositories, extended release formulations, and others .

Acetylsalicylic acid is a very common cause of accidental poisoning in young children. It should be kept out of reach from young children, toddlers, and infants .

Aspirin is a salicylate used to treat pain, fever, inflammation, migraines, and reducing the risk of major adverse cardiovascular events.

Pain, fever, and inflammation

Acetylsalicylic acid (ASA), in the regular tablet form (immediate-release), is indicated to relieve pain, fever, and inflammation associated with many conditions, including the flu, the common cold, neck and back pain, dysmenorrhea, headache, tooth pain, sprains, fractures, myositis, neuralgia, synovitis, arthritis, bursitis, burns, and various injuries. It is also used for symptomatic pain relief after surgical and dental procedures .

The extra strength formulation of acetylsalicylic acid is also indicated for the management migraine pain with photophobia (sensitivity to light) and phonophobia (sensitivity to sound).

Other indications

ASA is also indicated for various other purposes, due to its ability to inhibit platelet aggregation. These include:

Reducing the risk of cardiovascular death in suspected cases of myocardial infarction (MI) .

Reducing the risk of a first non-fatal myocardial infarction in patients, and for reducing the risk of morbidity and mortality in cases of unstable angina and in those who have had a prior myocardial infarction .

For reducing the risk of transient ischemic attacks (TIA) and to prevent atherothrombotic cerebral infarction (in conjunction with other treatments) .

For the prevention of thromboembolism after hip replacement surgery .

For decreasing platelet to platelet adhesion following carotid endarterectomy, aiding in the prevention of transient ischemic attacks (TIA) .

Used for patients undergoing hemodialysis with a silicone rubber arteriovenous cannula inserted to prevent thrombosis at the insertion site .

Important note regarding use of the extended-release formulation

In the setting of acute myocardial infarction, or before percutaneous interventions, the extended-release form of acetylsalicylic acid should not be used. Use immediate-release formulations in scenarios requiring rapid onset of action . The extended-release form is taken to decrease the incidence of mortality and myocardial infarction (MI) for individuals diagnosed with chronic coronary artery disease (CAD), including patients with previous myocardial infarction (MI) or unstable angina or with chronic stable angina. Additionally, the extended-release form is used to decrease the risk of death and recurrent episodes of stroke in patients with a history of stroke or TIA .

• Acute Coronary Syndrome (ACS)
• Anxiety
• Arthritis
• Atherothrombotic cerebral infarction
• Cardiovascular Disease (CVD)
• Cardiovascular Events
• Cardiovascular Mortality
• Colorectal Adenomas
• Colorectal Cancers
• Common Cold
• Coronary artery reocclusion
• Death
• Dyspeptic signs and symptoms
• Fever
• Flu Like Symptom
• Flu caused by Influenza
• Headache
• Heterozygous Familial Hypercholesterolemia
• Inflammation
• Juvenile Idiopathic Arthritis (JIA)
• Kawasaki Syndrome
• Major Adverse Cardiovascular and Cerebrovascular Events (MACCE)
• Migraine
• Morbidity
• Mucocutaneous Lymph Node Syndrome
• Muscle Contraction
• Myocardial Infarction
• Myocardial Infarction (MI)
• first occurrence
• Neuralgia
• Pain
• Pain caused by Common Cold
• Pain
• Menstrual
• Pericarditis
• Polycythemia Vera (PV)
• Preeclampsia
• Rheumatic Pain
• Rheumatism
• Rheumatoid Arthritis
• Rhinosinusitis
• Severe Pain
• Soreness
• Muscle
• Spondyloarthropathies
• Stroke
• Systemic Lupus Erythematosus (SLE)
• Tension Headache
• Thromboembolism
• Toothache
• Transient Ischemic Attack
• Venous Thromboembolism
• Acute Inflammation
• Atherothrombotic events
• Death by myocardial infarction
• Moderate Pain
• Thrombotic events
• Antiplatelet Therapy
• Hemodialysis Treatment
• Secondary Prevention

Effects on pain and fever

Acetylsalicylic acid disrupts the production of prostaglandins throughout the body by targeting cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) . Prostaglandins are potent, irritating substances that have been shown to cause headaches and pain upon injection into humans. Prostaglandins increase the sensitivity of pain receptors and substances such as histamine and bradykinin. Through the disruption of the production and prevention of release of prostaglandins in inflammation, this drug may stop their action at pain receptors, preventing symptoms of pain. Acetylsalicylic acid is considered an antipyretic agent because of its ability to interfere with the production of brain prostaglandin E1. Prostaglandin E1 is known to be an extremely powerful fever-inducing agent .

Effects on platelet aggregation

The inhibition of platelet aggregation by ASA occurs because of its interference with thromboxane A2 in platelets, caused by COX-1 inhibition. Thromboxane A2 is an important lipid responsible for platelet aggregation, which can lead to clot formation and future risk of heart attack or stroke .

A note on cancer prevention

ASA has been studied in recent years to determine its effect on the prevention of various malignancies . In general, acetylsalicylic acid is involved in the interference of various cancer signaling pathways, sometimes inducing or upregulating tumor suppressor genes . Results of various studies suggest that there are beneficial effects of long-term ASA use in the prevention of several types of cancer, including stomach, colorectal, pancreatic, and liver cancers . Research is ongoing.

Acetylsalicylic acid (ASA) blocks prostaglandin synthesis. It is non-selective for COX-1 and COX-2 enzymes . Inhibition of COX-1 results in the inhibition of platelet aggregation for about 7-10 days (average platelet lifespan). The acetyl group of acetylsalicylic acid binds with a serine residue of the cyclooxygenase-1 (COX-1) enzyme, leading to irreversible inhibition. This prevents the production of pain-causing prostaglandins. This process also stops the conversion of arachidonic acid to thromboxane A2 (TXA2), which is a potent inducer of platelet aggregation . Platelet aggregation can result in clots and harmful venous and arterial thromboembolism, leading to conditions such as pulmonary embolism and stroke.

It is important to note that there is 60% homology between the protein structures of COX-1 and COX-2. ASA binds to serine 516 residue on the active site of COX-2 in the same fashion as its binding to the serine 530 residue located on the active site of COX-1. The active site of COX-2 is, however, slightly larger than the active site of COX-1, so that arachidonic acid (which later becomes prostaglandins) manages to bypass the aspirin molecule inactivating COX-2 . ASA, therefore, exerts more action on the COX-1 receptor rather than on the COX-2 receptor . A higher dose of acetylsalicylic acid is required for COX-2 inhibition .

Absorption is generally rapid and complete following oral administration but absorption may be variable depending on the route, dosage form, and other factors including but not limited to the rate of tablet dissolution, gastric contents, gastric emptying time, and gastric pH .

Detailed absorption information

When ingested orally, acetylsalicylic acid is rapidly absorbed in both the stomach and proximal small intestine. The non-ionized acetylsalicylic acid passes through the stomach lining by passive diffusion. Ideal absorption of salicylate in the stomach occurs in the pH range of 2.15 - 4.10. Intestinal absorption of acetylsalicylic acid occurs at a much faster rate. At least half of the ingested dose is hydrolyzed to salicylic acid in the first-hour post-ingestion by esterases found in the gastrointestinal tract. Peak plasma salicylate concentrations occur between 1-2 hours post-administration .

This drug is distributed to body tissues shortly after administration. It is known to cross the placenta. The plasma contains high levels of salicylate, as well as tissues such as spinal, peritoneal and synovial fluids, saliva and milk. The kidney, liver, heart, and lungs are also found to be rich in salicylate concentration after dosing. Low concentrations of salicylate are usually low, and minimal concentrations are found in feces, bile, and sweat .

50% to 90% of a normal therapeutic concentration salicylate (a main metabolite of acetylsalicylic acid ) binds plasma proteins, particularly albumin, while acetylsalicylic acid itself binds negligibly . Acetylsalicylic acid has the ability to bind to and acetylate many proteins, hormones, DNA, platelets, and hemoglobin .

Excretion of salicylates occurs mainly through the kidney, by the processes of glomerular filtration and tubular excretion, in the form of free salicylic acid, salicyluric acid, and, additionally, phenolic and acyl glucuronides .

Salicylate can be found in the urine soon after administration, however, the entire dose takes about 48 hours to be completely eliminated. The rate of salicylate is often variable, ranging from 10% to 85% in the urine, and heavily depends on urinary pH. Acidic urine generally aids in reabsorption of salicylate by the renal tubules, while alkaline urine increases excretion .

After the administration of a typical 325mg dose, the elimination of ASA is found to follow first order kinetics in a linear fashion. At high concentrations, the elimination half-life increases .

The half-life of ASA in the circulation ranges from 13 - 19 minutes. Blood concentrations drop rapidly after complete absorption. The half-life of the salicylate ranges between 3.5 and 4.5 hours .

The clearance rate of acetylsalicylic acid is extremely variable, depending on several factors . Dosage adjustments may be required in patients with renal impairment . The extended-release tablet should not be administered to patients with eGFR of less than 10 mL/min .

Lethal doses

Acute oral LD50 values have been reported as over 1.0 g/kg in humans, cats, and dogs, 0.92 g/kg - 1.48 g/kg in albino rats, 1.19 g/kg in guinea pigs, 1.1 g/kg in mice, and 1.8 g/kg in rabbit models .

Acute toxicity

Salicylate toxicity is a problem that may develop with both acute and chronic salicylate exposure . Multiple organ systems may be affected by salicylate toxicity, including the central nervous system, the pulmonary system, and the gastrointestinal system. Severe bleeding may occur. In the majority of cases, patients suffering from salicylate toxicity are volume-depleted at the time of presentation for medical attention. Fluid resuscitation should occur immediately and volume status should be monitored closely. Disruptions in acid-base balance are frequent in ASA toxicity .

The acute toxicity of acetylsalicylic in animals has been widely studied. The signs of poisoning in rats from lethal doses are mild to severe gastroenteritis, hepatitis, nephritis, pulmonary edema, encephalopathy, shock and some toxic effects on other organs and tissues. Mortality has been observed following convulsions or cardiovascular shock. An important differentiating property between various animal species is the ability to vomit toxic doses. Humans, cats and dogs have this ability, but rodents or rabbits do not .

Chronic toxicity and carcinogenesis

Chronic ASA toxicity is frequently accompanied by atypical clinical presentations that may be similar to diabetic ketoacidosis, delirium, cerebrovascular accident (CVA), myocardial infarction (MI) or cardiac failure. Plasma salicylate concentrations should be measured if salicylate intoxication is suspected, even if there no documentation available to suggest ASA was ingested. In older age, nephrotoxicity from salicylates increases, and the risk of upper gastrointestinal hemorrhage is increased, with higher rates of mortality . It is also important to note that ASA toxicity may occur even with close to normal serum concentrations. Prevention of chronic ASA includes the administration of smallest possible doses, avoidance of concurrent use of salicylate drugs, and therapeutic drug monitoring. Renal function should be regularly monitored and screening for gastrointestinal bleeding should be done at regular intervals .

Chronic toxicity studies were performed in rodents. ASA was administered at doses measured to be 2 to 20 times the maximum tolerated clinical dose to mice for up to one year. Negative dose-related effects were seen. These include decreased mean survival time, decreased number of births and progeny reaching an appropriate age for weaning. No evidence of carcinogenesis was found in 1-year studies . At daily doses of 0.24 g/kg/day given for 100 days to albino rats, ASA led to signs to excessive thirst, aciduria, diuresis, drowsiness, hyperreflexia, piloerection, changes in respiration, tachycardia, followed by soft stools, epistaxis, sialorrhea, dacryorrhea and mortality during hypothermic coma in the second study month .

Use in pregnancy and lactation

While teratogenic effects were observed in animals nearly lethal doses, no evidence suggests that this drug is teratogenic in humans . It is advisable, however, to avoid ASA use the first and second trimester of pregnancy, unless it is clearly required. If acetylsalicylic acid containing drugs are ingested by a patient attempting to conceive, or during the first and second trimester of pregnancy, the lowest possible dose at the shortest possible duration should be taken . This drug is contraindicated in the 3rd trimester of pregnancy .

• Avoid alcohol. Alcohol increases the risk of gastrointestinal bleeding.
• Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.
• Take after a meal. This reduces irritating gastrointestinal effects.
• Take with a full glass of water.