Aspirin

Aspirin, also known as acetylsalicylic acid (ASA), is a generic non-steroidal anti-inflammatory drug and antiplatelet agent. It is one of the most-widely if not the most commonly used drug in the world and is listed on the WHO Model List of Essential Medicines ^1-4. It is used as an over-the-counter medication for pain relief and to reduce fever and inflammation and serves as a secondary preventive agent and reduces the risk of death in cardiovascular disease ^1,2. 

Terminology

Chemically the agent is known as acetylsalicylic acid, although its systematic IUPAC name is aspirin.

Other names include:

• acetylsalicylate
• 2-acetoxybenzoic acid
• o-acetylsalicylic acid

Clinical usage

Aspirin is an effective analgesic, antipyretic and anti-inflammatory agent ^3,4. It also has an antithrombotic effect by inhibiting platelet function and low-dose aspirin has a central role in antiplatelet therapy in the setting of acute and chronic coronary syndromes. Clinical uses are as follows ^3-10:

• mild to moderate pain
  • headache
  • increased risk of GI bleeding compared to ibuprofen
  • ineffective for muscle cramps, gastric distension, skin irritation
• inflammation
  • acute and/or long term
  • rheumatoid arthritis
  • rheumatic fever
• cardiovascular disease ^2-4
  • secondary prevention of major adverse cardiovascular events
  • primary prevention (controversial)
• cancer prevention
  • low-dose aspirin reduces the risk of colorectal cancer ⁹ and slightly the risk of endometrial cancer, breast cancer and prostate cancer
• preeclampsia prevention

Contraindications

Contraindications against using acetylsalicylic acid include:

• allergy against aspirin or other non-steroidal anti-inflammatory drugs 
• salicylate intolerance
• asthma and NSAID-induced bronchospasm
• acute gastrointestinal bleeding or peptic ulcer disease
• bleeding disorders
• hepatic failure or renal failure
• cardiac decompensation
• 3rd trimester of pregnancy
• concurrent usage of ≥15 mg methotrexate per week

Cautions have to be taken under the following conditions

• hypersensitivity to other analgesics or anti-inflammatory agents
• glucose-6-phosphate dehydrogenase insufficiency
• dengue (bleeding tendency)
• kidney disease, hyperuricaemia, gout (decreased excretion of uric acid)
• upcoming surgery

Side effects

Due to its antiplatelet effects aspirin is associated with increased bleeding especially in higher doses or with chronic use. Care has to be taken in the application of children and adolescents.  Side effects include the following:

• gastrointestinal symptoms including reflux, nausea, vomiting, abdominal pain
• hypersensitivity
• increased risk of bleeding 
  • gastrointestinal bleeding (especially in conjunction with COX-2 inhibitors)
  • cerebral haemorrhage/cerebral microbleeds
  • postoperative bleeding
• gastrointestinal ulcers
• tinnitus (large doses)
• Reye syndrome (in children - acute encephalopathy and fatty liver) ¹¹
• hyperkalaemia due to hyporenimic hypoaldosteronic state
• haemolytic anaemia

Toxicity

Acute salicylate or aspirin toxicity is generally considered at a dose >150 mg/kg of body mass and can cause respiratory alkalosis with consecutive metabolic acidosis ¹¹. Fluid electrolyte and acid-base imbalance have been grouped into different phases:

• stage 1 (<12 hrs)
  • hyperventilation from respiratory stimulation 
  • respiratory alkalosis and compensatory alkaluria
  • renal excretion of potassium and sodium bicarbonate
• stage 2 (12-24 hrs)
  • continued respiratory alkalosis 
  • paradoxical aciduria
• stage 2 (>24 hrs in adolescents and adults or 4-6 hrs in infants)
  • progressive metabolic acidosis 
  • hypokalaemia
  • dehydration

Acute overdose is associated with a mortality of approximately 2%. Chronic overdose has significantly higher mortality of up to 25% ¹¹.

Treatment and prognosis

Since there is no antidote for salicylate poisoning, treatment focuses on supportive measures with fluid resuscitation (e.g. dextrose 5%) and gastric decontamination as well as airway maintenance and adequate oxygenation ¹².

Gastric decontamination is achieved by the administration of repeated doses of activated charcoal in order to absorb salicylates within the gastrointestinal tract.

Intravenous administration of sodium bicarbonate aids in the renal clearance of salicylates by plasma and urine alkalinization. Salicylate toxicity requires dialysis in the following indications ¹³:

• salicylate level higher than 90 mg/dL
• severe acid-base imbalance
• acute respiratory distress syndrome
• severe cardiac toxicity
• neurological signs and symptoms suggesting cerebral involvement
• failure of standard treatment approaches 
• a persistent rise in serum salicylate levels despite alkalinization and multiple doses of activated charcoal
• fluid overload and intolerance to fluid resuscitation 

Interactions

Medications that have interactions or enhance the effect and probability of intoxication or gastrointestinal bleeding of acetylsalicylic acid include:

• anticoagulants (warfarin, coumadin etc.)
• platelet inhibitors (clopidogrel/ticlopidine)
• other anti-inflammatory agents
• corticosteroids
• alcohol
• digoxin
• antidiabetics
• methotrexate
• valproic acid
• acetazolamide
• ammonium chloride
• tolbutamide
• chlorpropamide
• probenecid
• phenytoin

The antiplatelet effect of aspirin might be reduced by other non-steroidal anti-inflammatory drugs.

Pharmacology

Pharmacodynamics

Aspirin acts as an acetylating agent on two types of the cyclooxygenase enzyme. It irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2, thus suppressing the synthesis of thromboxane and prostaglandins. Mechanisms of action are dose-dependent. 

The antithrombotic property of aspirin occurs already at low doses (75-81 mg per day) mainly targeting COX-1 affecting the synthesis of thromboxane A2 ⁶:

• irreversible inhibitory effect on platelet aggregation
• blockage of the formation of thromboxane A₂ in platelets
• persists during the whole lifetime of the affected platelet (10 days)

An analgesic and antipyretic effect can be achieved with an intermediate dose with an effect on both COX-1 and COX-2 and inhibition of prostaglandin synthesis. An anti-inflammatory effect requires higher doses ^5,6.

Beyond its anti-inflammatory, analgesic and antiplatelet mechanisms, acetylsalicylic acid is considered to be anti-cancerogenic and anti-proliferative on vascular smooth muscle cells.

Pharmacokinetics

Low-dose aspirin is typically administered at doses 75-150 mg for cardiovascular disease prevention with doses as low as 30 mg already showing a significant inhibitory effect on thrombocyte aggregation ³.

The recommended dosage as an analgesic varies between countries and is in the range of 300-1000 mg per application and up to a maximum of 1,5 or 3 g per day for children or adults ^1-4.

After oral administration acetylsalicylic acid is quickly absorbed through the stomach and more slowly in the small intestine. At higher doses or during overdosing it is absorbed more slowly due to the formation of concretions and plasma levels might even rise after 24 hrs. 

Protein binding in the blood is concentration-dependent with approximately 50–80% of salicylate bound to albumin and the rest remaining ionised and active. 

The largest proportion of therapeutic doses of salicylic acid (ca. 80%) is metabolised in the liver to salicyluric acid and with glucuronic acid to other metabolites. 

Excretion of salicylates and metabolites occurs mainly by the kidneys that become increasingly important as metabolic pathways become saturated with higher doses or toxicity.

Small doses are eliminated with a half-life of approximately 2.0-4.5 hrs, whereas in larger doses the elimination half-life increases to 15-30 hrs.

History and etymology

Salicylates in the form of willow leaves (genu Salix) have been used as medicine for more than three millennia. Hippocrates already referred to their antipyretic properties and the first record of use as an analgesic the Ebers papyrus goes back to 1534 BC ^12,13.

An unstable compound of acetylsalicylic acid was first produced by the French chemist Charles Frédéric Gerhardt by combining sodium salicylate with acetyl chloride in 1853 ^12,13.

In 1897 the German scientists Felix Hoffmann, Arthur Eichengrün and Heinrich Dreser from the drug and dye company Bayer started to investigate acetylsalicylic acid as a replacement for common salicylates and found a new way to synthesise it ^12,13.

In 1899 Bayer branded the new synthesised Aspirin and sold it globally. In the meantime, the trademark has been lastly Bayer in many countries and it is available as a generic drug.

The discovery of its action mechanism on prostaglandins and its antithrombotic effects on platelets were discovered by the British pharmacologist John Vane and the Swedish Bengt Samuelsson who both shared a Nobel prize for Medicine of Physiology in 1982 also with Sune Bergstrom (who discovered the prostaglandins) ^12,13.

With the development of paracetamol in 1956 and ibuprofen in 1962, the popularity of aspirin declined until the 1980s, when its use in the prevention of cardiovascular events was shown. This lead to a revival in sales for that purpose in particular during the last two decades ^12,13.

Since 1977 acetylsalicylic acid has been listed as an indispensable drug on the WHO Model List of Essential Medicines ¹.