Continuing Education Activity

Salicylates have been available since the early 1900s. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, and monitoring, of salicylic acid, so providers can direct patient therapy in treating indicated conditions as part of the interprofessional team.

Objectives:

• Identify the mechanism of action of salicylic acid.
• Describe the potential adverse effects of salicylic acid.
• Review the numerous conditions where salicylic acid is therapeutically indicated.
• Explain the importance of improving care coordination amongst the interprofessional team to ensure the safe use of salicylic acid.

Indications

Salicylates have been derived from the willow tree bark. The Sumerians were noted to have used remedies derived from the willow tree for pain management as far back as 4000 years ago.[1] Hippocrates used it for managing pain and fever. He even utilized tea brewed from it for pain management during childbirth.

In a 1763 clinical trial, the first of its kind, Reverend Edward Stone studied the effects of willow bark powder for treating fever. About 100 years later, the effects of the willow bark powder were studied for acute rheumatism.

In 1828, Professor Johann Buchner used salicin, the Latin word for willow. Henri Leroux used it to treat rheumatism after isolating it in a crystalline form in 1829. In the 1800s, the Heyden Chemical Company was the first to mass-produce salicylic acid commercially. It was not until 1899 when a modified version named acetylsalicylic acid was registered and marketed by Bayer under the trade name aspirin.

Even though it has been available since the early 1900s, its real mode of action was not known until the late 1970s.

Some of the indications for aspirin use are as follows:[2][3]

• Angina pectoris
• Angina pectoris prophylaxis
• Ankylosing spondylitis
• Cardiovascular risk reduction
• Colorectal cancer
• Fever
• Ischemic stroke
• Ischemic stroke: Prophylaxis
• Myocardial infarction
• Myocardial infarction: prophylaxis
• Osteoarthritis
• Pain
• Revascularization procedures: prophylaxis
• Rheumatoid arthritis
• Systemic lupus erythematosus

Mechanism of Action

Aspirin is a cyclooxygenase-1 (COX-1) inhibitor. It is a modifier of the enzymatic activity of cyclooxygenase-2 (COX-2).[4] Unlike other NSAIDs (ibuprofen/naproxen), which bind reversibly to this enzyme, aspirin binding is irreversible.[5] It also blocks thromboxane A2 on platelets in an irreversible fashion preventing platelet aggregation.[6][7]

Researchers hypothesize that due to the blocking of the COX pathway, the arachidonic acids are shuttled into the lipoxygenase pathway. The production of anti-inflammatory lipoxins results from modifying prostaglandin-endoperoxide synthase (PTGS2), also called COX-2, that results in the production of lipoxins, most of which are anti-inflammatory. These compounds are called aspirin-triggered lipoxins, aspirin-triggered resolvins, and aspirin-triggered maresins.

Administration

Aspirin can be administered via the oral, rectal, and intravenous (IV) route.

It is available in different doses, the lowest being 81 mg, also called a baby aspirin.

• Tablet: 325 mg, 500 mg
• Delayed-release tablet: 81 mg, 325 mg, 500 mg, 650 mg
• Chewable: 81 mg
• Suppository: 60 mg, 120 mg, 200 mg, 300 mg, 600 mg
• Intravenous: 250 mg, 500 mg

Pharmacokinetics[8]

Aspirin absorption from the gastrointestinal (GI) tract depends on the formulation state. When consumed as a liquid preparation, it is rapidly absorbed as opposed to tablets. Its hydrolysis yields salicylic acid. Salicylic acid has a narrow therapeutic window. If maintained within that narrow range, it provides the appropriate anti-inflammatory effect.

The pKa of aspirin is 3.5. Most aspirin is mostly absorbed in the stomach. Aspirin absorption is pH sensitive at the level of the small intestine.

Salicylate elimination occurs through two pathways via the creation of salicyluric acid and salicyl phenolic glucuronide. Salicylic acid is renally cleared, which can be increased by raising the urinary pH. Medications like antacids can increase renal clearance as they raise urinary pH. It can cross the blood-placental barrier. It is also expressed in breast milk.

Pharmacodynamics

Almost 90% of COX inhibition can be achieved with the administration of 160 to 325 mg of aspirin. These effects last for about 7 to 10 days which usually corresponds with the lifespan of a platelet. Prostacyclin inhibition can be achieved with the use of higher doses. This inhibition occurs in the endothelial cells of blood vessels.

Adverse Effects

Aspirin has had multiple metanalyses, which suggest that aspirin reduces the risk of major adverse cardiovascular events in patients who have diabetes without cardiovascular disease while also causing a trend toward higher rates of bleeding and gastrointestinal complications.[9][10][11][12]

The most common side effect of aspirin is gastrointestinal upset ranging from gastritis to gastrointestinal bleeding.[13]

Hypersensitivity 

Hypersensitivity to NSAIDs is common among the general population. The rate is about 1% to 2%. Symptoms could be as mild as a simple rash to angioedema, and anaphylaxis. In patients with asthma or chronic rhinosinusitis, the prevalence of these allergic symptoms could be as high as 26%. If this is accompanied by nasal polyps and inflammation of the respiratory tract with eosinophils, it is called the aspirin triad. NSAID-exacerbated respiratory disease (NERD) is a new term associated with this syndrome due to upper and lower respiratory mucosal inflammation.

Reye Syndrome 

Reye syndrome, named after the Australian pathologist Dr. R.D. Reye was first described in 1963. It is a rare but fatal condition with an estimated mortality rate of between 30% to 45%. It is a form of encephalopathy secondary to fatty changes in an otherwise healthy liver. The clinical vignette of Reye syndrome constitutes a viral upper respiratory tract infection in children and concomitant administration of aspirin for the treatment of fever. It is thought that mitochondrial injury secondary to the preceding viral illness is the first hit to both the liver and the brain. Aspirin or similar compounds provide the second hit completing the syndrome. The incidence has dramatically decreased due to better awareness and the use of acetaminophen to manage fever in children instead of aspirin.[14]

Even though the association between aspirin and Reye syndrome exists, some authors argue that at the time of diagnosis, salicylate levels were not routinely checked, biopsies were not obtained, and genetic/inborn errors of metabolism were not ruled out.

Intracerebral Hemorrhage

Aspirin increases the risk of intracranial bleeding (RR = 1.65; 95% CI, 1.06 to 5.99) versus placebo.

Contraindications

People who are allergic to ibuprofen should not take aspirin as there is cross-reactivity. Patients who have asthma should be cautious if they have asthma or known bronchospasm associated with NSAIDs.

Aspirin increases the risk of GI bleeding in patients who already suffer from peptic ulcer disease or gastritis. The risk of bleeding is still present even without these conditions if there is concomitant alcohol consumption or if the patient is on warfarin. Patients who have inborn coagulopathies such as hemophilia should avoid all salicylates. Acquired diathesis, as in the setting of dengue or yellow hemorrhagic fever, should avoid the use of aspirin.

Patients who have glucose-6-phosphate dehydrogenase deficiency are at risk of acute intravascular hemolytic anemia. Many factors can precipitate these hemolytic episodes. Aspirin is one such known cause.

Avoid using aspirin in children who are suffering from a viral infection to avoid Reye syndrome.[14]

Monitoring

Therapeutic Index and Toxic Doses

Therapeutic drug levels for aspirin are 150 to 300 mcg/mL (salicylate).

Toxic Levels: Greater than 300 mcg/mL

Timing: 1 to 3 hours after the dose

Time to Steady State: 5 to 7 days

Plasma levels of aspirin can range from 3 to 10 mg/dL for therapeutic doses to as high as 70 to 140 mg/dL for acute toxicity. Due to delayed absorption of certain preparations, levels should be checked 4 hours after consumption and every subsequent 2 hours until maximum levels are reached.

Treatment needs to be individualized based on symptomatology as well as levels.

Aspirin levels do not need to be monitored in most cases. For certain diseases, serum creatinine at baseline, along with serum drug levels, if patients have adult or juvenile rheumatoid arthritis, Kawasaki disease, or arthritis/pleurisy.

Toxicity

Patients who have aspirin toxicity can have a myriad of symptoms. Symptoms of mild toxicity can be but are not limited to tinnitus, dizziness, lethargy, nausea, and vomiting.[15] For more severe toxicity, the signs and symptoms include hyperthermia, tachypnea leading to respiratory alkalosis, high anion gap metabolic acidosis, hypokalemia, hypoglycemia, seizures, coma, and cerebral edema. Death commonly occurs due to cardiopulmonary edema secondary to pulmonary edema.[16][17]

Treatment for salicylate toxicity is based on salicylate concentration, acid-base status, volume status, electrolytes, GI decontamination, airway protection, and respiratory status, and enhanced elimination.[18]

The acuity of exposure, type of formulations, co-ingestions, comorbidities, and clinical status of the patient can affect salicylate levels in serum. Of all of these, particularly acid-base status can influence how the drug is handled by the body the most. Hence, initial and subsequent levels are recommended to assess trajectory. Different laboratories may report salicylate levels differently. One must pay attention to salicylate concentration units. The conversion is as follows:

• 100 milligrams per deciliter (mg/dL) equals
• 1000 milligrams per liter (mg/L), or
• 7.24 millimoles per liter (mmol/L) 

One must draw serial salicylate levels to show that the levels are declining and thus also establishing a reduction in absorption.

Aspirin causes high anion gap metabolic acidosis and respiratory alkalosis. The high anion gap comes from the addition of salicylic acid as well as the generation of lactic acid (due to the uncoupling of oxidative phosphorylation causing anaerobic respiration). Respiratory alkalosis is due to direct stimulation of the respiratory center. Acidemia worsens symptomology. Salicylate exists in the blood in both ionized as well as uncharged forms. Acidemia shifts salicylate from its ionized to unionized forms making it more lipophilic and allowing increased penetration into the central nervous system (CNS). Volume status and electrolyte monitoring are paramount as brain glucose utilization increases in the setting of aspirin toxicity, even when serum glucose levels are normal. Hypokalemia worsens acidemia, and hence, supplementation may be required.

Alkalization of the urine can be achieved via a bicarbonate drip (3 ampules of 50 meq/50 ml for a total of 150 meq in 1000 ml of D5W). However, this may worsen hypokalemia, and hence, special attention to potassium supplementation is required.

Activated charcoal and/or bowel irrigation are recommended in both acute and chronic ingestion because of the extended-release preparations available on the market. In the setting of worsening mental status, one must exercise caution to avoid aspiration pneumonia.

Airway protection might be required in the setting of worsening mental status or acute injury to the lung.

Maintaining an alkaline pH is important to avoid CNS toxicity. This can be achieved by increasing minute ventilation to avoid carbon dioxide (CO2) retention. Bicarbonate drips can be used to achieve a pH of no greater than 7.5 during the intubation process.

Hemodialysis is an efficient treatment of salicylate toxicity. Once the protein-bound fraction is saturated, removal of the free fraction is effective through dialysis. Due to this efficiency, the clearance of salicylate is reduced to hours rather than days.

Peritoneal dialysis does not efficiently remove salicylate.

Indications for hemodialysis are as follows:[19]

• Aspirin levels in acute ingestions of 100 mg/dL with or without symptoms
• Aspirin levels in chronic ingestions 40 mg/dL with or without symptoms
• Any neurotoxicity (tinnitus, coma, seizures) with any level
• Renal failure (as the drug needs to be cleared by the kidney)
• Acute pulmonary edema
• Cardiovascular compromise, including volume overload

Hemodialysis does not only clear the drug from circulation but also restores the internal acid-base and electrolyte balance.

Enhancing Healthcare Team Outcomes

Aspirin is available over the counter and is commonly involved in pediatric overdoses. The medication should be kept in a closed cabinet away from the reach of children. Given its wide availability, potential adverse effects, therapeutic uses, and potential interactions, all interprofessional healthcare team members should be aware of when patients are using aspirin and monitor and counsel the patient to optimize therapeutic outcomes and prevent any potential adverse effects of salicylic acid. This interprofessional team includes all clinicians (MDs, DOs, NPs, PAs), nurses, and pharmacists, all of whom need to have access to the same patient information and coordinate their activities, and openly share information so the patient receives the best possible healthcare, including how aspirin is used. [Level 5]