Acetylsalicylic Acid

Acetylsalicylic acid (ASA), or aspirin, is an NSAID that is one of the best-known drugs in the world. It is also one of the oldest - people have known since the time of Hippocrates that willow bark, from which ASA is derived, was effective at treating fevers and pains.

Uses

Acetylsalicylic acid has many uses. These include:

 

Mechanism

ASA is a irreversible, nonselective inhibitor of cyclooxygenases COX1 and COX2, preventing eicosanoid synthesis.

 

ASA also intereferes with chemical mediators of the kallikrein system, inhibiting granulocyte adherence to damage vasculature, stabilizing lysozomes, and inhibiting migration of PMNs and macrophages.

 

ASA acts at peripheral sites of inflammation, as well, most likely, at subcortical regions, to reduce pain.

 

ASA reduces fever, likely by direct inhibition of COX and secondary prevention of IL-1 release from macrophages during inflammation. Superficial vasodilation, and accompanying sweating, assists in lowering body temperature.

 

ASA prolongs bleeding time, doubling it if given for one week. This is due to inhibition of platelet synthesis of thromboxane A2. TXA2 causes platelets to change shape, degranulate, and aggregate during hemostasis. ASA's period of action is 8-10 days - similar to the life span of a platelet - due to its irreversible action.

 

 

 

Dose and Half Life

Salicylates are rapidly absorbed through the stomach and small intestine, with peak plasma levels within 1-2 hours. Aspirin is rapidly hydrolyzed to acetic acid and salicylate by esterases in the tissue and blood.

As doses increase, elimination half-life increases from 3-5 hours for 600 mg/day to 12-16 hours for dosages greater than 3.6g/day.

 

Standard dosing is as follows:

Usual dose may be repeated every 4 hours, or small doses (0.3g) every three hours. Because of long half-lives, frequent dosing is not required when daily doses of 4 g or more are taken, and total dose can be divided by three and taken following meals.

 

 

Adverse Drug Reactions

 

Gastrointestinal effects, such nausea are among the most common side effects, but can be mitigated by taking with meals followed by a glass of water or antacids.

 

Gastritis, ulceration, and gastric bleeding are more serious and can be due to direct irritation or systemic effects of prostaglandin inhibition. A 3 ml increase in fecal blood loss is common, but often declines over weeks with mucosal adaptation. Proton-pump inhibitors or misoprostol, but not H2 blockers, reduce the likelihood of gastrointestinal toxicity.

 

Systemic toxicity - Like other NSAIDs, aspirin can also cause liver enzyme elevation, decreased renal function, bleeding, rashes, and asthma. Hypersensitivity ('allergy') due to arachidonic acid shunt and leukotriene production can lead to bronchospasm, hypotension/shock.

 

Chronic toxicity is possible, especially in the elderly. Salicylism can occur at higher doses, and is characterized by vomiting, tinnitus, decreased hearing, and vertigo.

 

Reye's syndrome can occur in children with influenza. While the effect of ASA is in doubt (Hurwitz, 1987, 1989), acetominophen is a safter choice.

 

Overdose

Overdose, which is often accidental, can be life-threatening. It is potentially toxic at >150 mg/kg, with serious toxicity occurring with doses of 300-500 mg/kg.

 

Early after toxic dosing, direct stimulation of the respiratory centre in the medulla leads to hyperventilation, acute respiratory alkalosis and increased O2 consumption. Later, increasing anion gap metabolic acidosis occurs first as a mixed disorder, then pure as respiratory depression begins. Toxic doses can also cause glucose intolerance and cardiotoxicity.

 

Ventilatory assistance may be required, with sodium bicarbonate infusions to alkanize the urine and increase the amount of salicylate excretion.

 

 

Contraindications and Drug Interactions

 

Metabolism and Excretion

Ingested salicylate may be excreted unchanged, but metabolic pathways become overwhelmed when total body load exceeds 600 mg.

Alkalinization of the urine increases rate of excretion.