ASPIRIN

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer with food or large amounts (240 mL) of water or milk to minimize gastric irritation.
Oral Solid Formulations
-Film-coated tablets: May help to reduce the unpleasant taste or aftertaste, burning in the throat, or difficulty in swallowing associated with uncoated tablets.
-Enteric-coated or extended-release tablets: Swallow whole; do not crush, cut, or chew. May help to reduce gastric irritation and/or symptomatic GI disturbances associated with uncoated tablets.
-Chewable tablets: May be chewed, crushed, and/or dissolved in a liquid, or swallowed whole, followed by approximately 120 mL of water, milk, or fruit juice immediately after administration.
-Capsules: Swallow whole; do not crush, cut, or chew.



Rectal Administration
-For use in patients unable to take or retain oral aspirin; however, absorption may be slow and incomplete. Do not use aspirin tablets rectally because they are likely to cause irritation and erosion of rectal mucosa.
-Instruct patient or caregiver on proper use of suppository.
-Prior to insertion, carefully remove the wrapper. Avoid excessive handling as to avoid melting of the suppository.
-If suppository is too soft to insert, chill in the refrigerator for 30 minutes or run cold water over it before removing the wrapper.
-Moisten the suppository with cool water prior to insertion.
-Have patient lie down on their side, usually in the Sim's lateral position to provide support and comfort.
-Apply gentle pressure to insert the suppository completely into the rectum, pointed end first, using a gloved, lubricated index finger.
-After insertion, keep the patient lying down to aid retention and gently hold the buttock cheeks close to keep the child from immediately expelling the suppository. The suppository must be retained in rectum to ensure complete absorption.

Central nervous system adverse effects reported with aspirin include agitation, cerebral edema, coma, confusion, dizziness, headache, lethargy, and seizures. Tinnitus and hearing loss may occur in patients receiving high-dose and/or long-term aspirin therapy. Discontinue aspirin if tinnitus or hearing loss occurs. These effects are early manifestations of salicylate toxicity. However, hearing loss has occurred in patients at low serum salicylate concentrations. Tinnitus and hearing loss are usually dose-related and reversible upon dose reduction or discontinuation. Tinnitus is commonly associated with salicylate concentrations more than 200 to 300 mcg/mL. Maximum hearing loss occurs most frequently at salicylate concentrations of 400 mcg/mL or more.

Gastrointestinal disturbances are the most common adverse events reported in children treated with aspirin. Most GI effects are mild and include nausea, vomiting, dyspepsia, abdominal pain, pyrosis (heartburn), and gastritis. Elevated hepatic enzymes have been commonly reported in children with rheumatic diseases treated with aspirin. Other gastrointestinal adverse effects reported with aspirin include anorexia, GI bleeding, and hepatitis. Aspirin may cause peptic ulcer.

Reye's syndrome has been reported with aspirin use. Aspirin may increase the risk of developing Reye's syndrome, a rare but serious disease which can follow flu or chicken pox in children and adolescents. Reye's syndrome has been reported in children of all ages; however, most of the reported cases have occurred in children 5 to 10 years. Data are not strong to support a dose-dependent association with Reyes's syndrome; however, a case-controlled study reported that patients who developed Reye's syndrome (n = 27) had received larger doses for a longer duration compared with controls who did not develop Reye's syndrome. Of the patients who developed Reye's syndrome, 67% were receiving more than 20 mg/kg/day of salicylates compared with only 22% of controls. Reye's syndrome is a multisystem disorder evidenced by persistent vomiting, altered sensorium, elevated hepatic enzymes, hypoprothrombinemia, hyperammonemia, convulsions, and encephalopathy.

Renal adverse effects reported with aspirin include interstitial nephritis, renal papillary necrosis, proteinuria, renal insufficiency and acute renal failure.

Dermatologic adverse reactions reported with aspirin include rash, pruritus, and purpura. Hypersensitivity reactions to aspirin are reported less frequently in children with a rate of approximately 0.3%. In children with asthma, aspirin sensitivity is approximately 5%.

Salicylates, such as aspirin, have dose-dependent effects on plasma uric acid concentrations. At low doses (1 to 2 g/day) decreased urate excretion and hyperuricemia may be seen. Intermediate salicylate doses (2 to 3 g/day) usually do not alter urate excretion, and high doses of salicylates (more than 3 g/day) induce uricosuria and lower plasma uric acid concentrations.

Intracranial bleeding has been reported with aspirin use. This is rarely observed in children when aspirin is used alone, but the risk is significantly increased with concomitant use of other antithrombotics, anticoagulants, or thrombolytics.

At therapeutic doses, salicylates such as aspirin cause changes in acid/base balance and electrolytes resulting in respiratory alkalosis. In patients with normal renal and respiratory function, this is usually compensated for appropriately. Severe acid/base disturbances may occur during salicylate toxicity. Infants and children with salicylate toxicity rarely present clinically with respiratory alkalosis. As salicylate toxicity progresses, changes resembling metabolic acidosis are present (e.g., low blood pH, low plasma bicarbonate concentrations, and normal or nearly normal plasma PaCO2). In reality, a combination of respiratory acidosis and metabolic acidosis is present. Alterations in water and electrolyte balance also occur in salicylate toxicity. Dehydration due to salicylate-induced diaphoresis and hyperventilation occurs. Since more water than electrolytes are lost, dehydration is associated with hypernatremia. Other laboratory changes noted in salicylate toxicity include hyperglycemia or hypoglycemia (especially in children), ketonuria, hypokalemia, and proteinuria. Prolonged exposure to high doses of salicylates also causes hypokalemia through both renal and nonrenal losses. Hyperventilation occurs due to direct stimulation of the respiratory center in the medulla. At high salicylate plasma concentrations (350 mcg/mL or more), marked hyperventilation will occur, and at serum concentrations of about 500 mcg/mL, hyperpnea will be seen. At high or prolonged doses, salicylates also have a depressant effect on the medulla. Toxic doses of salicylates cause central respiratory depression as well as cardiovascular collapse secondary to vasomotor depression. Since enhanced CO2 production continues, respiratory acidosis occurs.

Overuse of drugs for treating acute headaches, including aspirin, may lead to medication overuse headache. Patients may experience migraine-like daily headaches or a significant increase in migraine attack frequency. Withdrawal of the overused drug and treatment of withdrawal symptoms (e.g., transient worsening of headache) may be necessary. Advise patients about the risks of medication overuse (e.g., use of a single agent or a combination of drugs for at least 10 days per month) and encourage them to keep a written record of headache frequency and drug use.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), a multi-organ hypersensitivity reaction, has occurred with NSAIDs. Some of these events have been life-threatening or fatal. DRESS typically presents as fever, rash, and/or lymphadenopathy in conjunction with other organ system involvement including hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Early manifestations such as fever and lymphadenopathy may be present without evidence of a rash. Discontinue the NSAID in patients presenting with such signs and symptoms in whom an alternative etiology cannot be identified.

Aspirin is contraindicated in patients with salicylate hypersensitivity or NSAID hypersensitivity. Aspirin is also contraindicated in patients with the syndrome of asthma, rhinitis, and nasal polyps; aspirin may cause severe urticaria, angioedema, or bronchospasm in these patients.

Aspirin is contraindicated in children for viral infection, with or without fever, because of the risks of Reye's syndrome. Do not use aspirin in children recovering from varicella infection or influenza. If children are receiving chronic aspirin therapy, aspirin should be discontinued immediately if a fever develops, and not resumed until diagnosis confirms that the febrile viral illness has run its course and the absence of Reye's syndrome. After varicella vaccination, aspirin use should generally be avoided for 6 weeks. Children receiving long-term aspirin therapy should receive the annual influenza vaccine.

Avoid aspirin in patients with active peptic ulcer disease due to the risk for gastric ulceration and bleeding. Aspirin increases bleeding risk; risk factors for bleeding include the use of other drugs that increase the risk of bleeding (e.g., anticoagulant therapy, antiplatelet agents, NSAID therapy), inherited (hemophilia, von Willebrand's disease) or acquired (liver disease) coagulopathy, alcoholism, and age 60 years and older. Neonates have a slower clearance of aspirin and therefore are at higher risk for bleeding.

Avoid aspirin in patients with severe hepatic insufficiency. Hepatic disease increases the risk for bleeding.

Avoid aspirin in patients with severe renal failure (i.e., GFR less than 10 mL/minute).

Description: Aspirin, the salicylic ester of acetic acid, is used for its analgesic, antiinflammatory, antipyretic, and antithrombotic effects. The antiinflammatory and analgesic effects of aspirin are roughly equivalent to those of many other NSAIDs. The use of aspirin in children is primarily limited to the treatment of Kawasaki disease, for thrombosis prophylaxis, particularly in children with congenital heart disease following cardiac surgery, and for the treatment and secondary prevention of arterial ischemic stroke (AIS). Reye's syndrome, a potentially fatal disease, has been associated with aspirin use following active varicella infection or other viral illnesses in children. Since this association, aspirin use has declined significantly and other NSAIDs and acetaminophen have replaced aspirin for mild analgesia and fever in children. Clinical guidelines for the treatment of juvenile idiopathic arthritis do not recommend aspirin as a treatment option due to the availability of other NSAIDs (i.e., ibuprofen, naproxen) that are just as effective, safer, and better tolerated. Aspirin is an OTC drug and is labeled for use as an analgesic in children >= 12 years of age ; however, aspirin is used off-label in children as young as neonates for its antiplatelet effects.

General dosing information
-Dosage is typically rounded to the nearest 20.25 mg increment (e.g., one-fourth of an 81 mg tablet) based on measurable tablet size.


For the treatment of acute ischemic stroke*:
Oral dosage:
Neonates: 1 to 5 mg/kg/dose PO once daily. Aspirin is recommended for neonates with recurrent acute ischemic stroke.
Infants, Children, and Adolescents: 1 to 5 mg/kg/dose PO once daily. If dissection and cardioembolic causes are excluded, continue aspirin for a minimum of 2 years. Transition to clopidogrel, LMWH, or warfarin in those who have recurrent acute ischemic stroke (AIS) or transient ischemic attacks. For acute AIS due to non-Moyamoya vasculopathy, continue aspirin for 3 months; guide ongoing antithrombotic therapy with repeat cerebrovascular imaging.

For secondary stroke prophylaxis* in patients who have had an ischemic stroke or transient ischemic attack (TIA):
Oral dosage:
Neonates: 1 to 5 mg/kg/dose PO once daily. Aspirin is recommended for neonates with recurrent acute ischemic stroke.
Infants, Children, and Adolescents: 1 to 5 mg/kg/dose PO once daily for a minimum of 2 years. Transition to clopidogrel, LMWH, or warfarin in those who have recurrent acute ischemic stroke or transient ischemic attacks.

For arterial thromboembolism prophylaxis* (i.e., thrombosis prophylaxis*), including primary prophylaxis after cardiac surgery*:
NOTE: Dosing recommendations are based on extrapolation from adult data.
-for general antiplatelet therapy and thromboprophylaxis*:
Oral dosage:
Neonates: 1 to 5 mg/kg/dose PO once daily.
Infants, Children, and Adolescents: 1 to 5 mg/kg/dose (Max: 81 to 325 mg/dose) PO once daily.
-for postoperative thromboprophylaxis* in patients undergoing Blalock-Taussig (BT) shunt placement*, Glenn procedure*, Norwood procedure*, Sano procedure*, or Fontan procedure*:
Oral dosage:
Neonates: 1 to 5 mg/kg/dose PO once daily. Higher doses (up to 15 mg/kg/day) have been reported. A flat dose of 40 mg/day PO was described in a retrospective review evaluating thrombosis after modified BT shunt placement in 207 patients, 162 (78%) which were neonates, with a mean weight of 3.1 +/- 0.8 kg.
Infants and Children: 1 to 5 mg/kg/dose (Max: 81 to 325 mg/day) PO once daily. Higher doses (up to 10 mg/kg/day) have been reported. There was no significant difference in thrombosis rate at 2 years in patients receiving warfarin or aspirin (24% vs. 14%, p = 0.45) in a multicenter, randomized control trial of 111 children after Fontan surgery. Although not statistically significant, the incidence of thrombosis was 9% in patients receiving aspirin (n = 34) compared to 2% in patients receiving rivaroxaban (n = 64) for thromboprophylaxis post-Fontan procedure in a randomized, multicenter, open-label study.
-for postoperative thromboprophylaxis* in patients undergoing atrial or ventricular septal defect repair*:
Oral dosage:
Infants, Children, and Adolescents: 1 to 5 mg/kg/dose (Max: 81 to 325 mg/dose) PO once daily; begin 1 to several days before device implantation and continue for at least 6 months. Higher doses (up to 10 mg/kg/day) have been reported.
-for thromboprophylaxis* in patients with ventricular assist devices (VADs)*:
Oral dosage:
Infants, Children, and Adolescents: 1 to 5 mg/kg/dose PO once daily; begin within 72 hours of VAD placement. Use in combination with heparin (begun 8 to 48 hours after implantation) and with or without dipyridamole.

For the treatment of Kawasaki disease*:
Oral dosage (high-dose):
Infants, Children, and Adolescents: 80 to 100 mg/kg/day PO in 4 divided doses during the acute phase, then decrease dose to 3 to 5 mg/kg/day PO once daily (Max: 325 mg/day) for at least 4 to 6 weeks after the onset of illness. Duration of high-dose aspirin varies in clinical practice; while many clinicians reduce the aspirin dose after the patient is afebrile for 24 to 72 hours, others continue high-dose aspirin until day 14 of illness and at least 48 to 72 hours after cessation of fever. There is also debate over the optimal dose of aspirin in the acute phase of treatment. High-dose is recommended in guidelines. However, moderate doses are commonly used during the acute phase to minimize aspirin toxicity. There are no data to suggest either dose is superior. Additionally, some data suggest low-dose aspirin is not inferior to high-dose aspirin in reducing the risk of coronary artery aneurysms when given concomitantly with IVIG during the acute phase.
Oral dosage (moderate-dose):
Infants, Children, and Adolescents: 30 to 50 mg/kg/day PO in 4 divided doses during the acute phase, then decrease dose to 3 to 5 mg/kg/day PO once daily (Max: 325 mg/day) for at least 4 to 6 weeks after the onset of illness. There is debate over the optimal dose of aspirin in the acute phase of treatment. High-dose is recommended in the guidelines. However, moderate doses are commonly used during the acute phase to minimize aspirin toxicity. There are no data to suggest either dose is superior.
Oral dosage (low-dose):
Infants, Children, and Adolescents: 3 to 10 mg/kg/day PO once daily (Max: 325 mg/day) for at least 4 to 6 weeks after the onset of illness. For those who develop coronary abnormalities, low-dose therapy may continue indefinitely. Some data suggest low-dose aspirin is not inferior to high-dose aspirin in reducing the risk of coronary artery aneurysms when given concomitantly with IVIG during the acute phase.

For the management of multisystem inflammatory syndrome in children (MIS-C) post SARS-CoV-2 exposure*:
Oral dosage:
Infants, Children, and Adolescents: 3 to 5 mg/kg/dose (Max: 81 mg) PO once daily for all patients without risk factors for bleeding. Continuation is recommended until platelet count is normalized and normal coronary arteries are confirmed at least 4 weeks after diagnosis. Avoid use in patients with active bleeding, significant bleeding risk, and/or a platelet count of 80,000/microliter or less. Patients with coronary artery aneurysms and a maximal z-score of 2.5 to 10 should be treated with low dose aspirin, whereas patients with a z-score of 10 or more should be treated with low dose aspirin and therapeutic anticoagulation with enoxaparin for at least 2 weeks before transitioning to warfarin. Patients with an ejection fraction (EF) less than 35% should receive low dose aspirin and therapeutic anticoagulation until EF exceeds 35%. Patients with documented thrombosis should receive low dose aspirin and therapeutic anticoagulation for 3 months, pending thrombosis resolution.

Therapeutic Drug Monitoring:
Most patients experience signs of acute salicylate toxicity when the total salicylate concentration is more than 300 mcg/mL. In chronic salicylism, signs of toxicity may occur at lower concentrations (150 mcg/mL or more).

Maximum Dosage Limits:
Aspirin dosage must be individualized and is highly variable depending on the indication, coexisting conditions, and on patient response.
-Neonates
5 mg/kg/day PO for antiplatelet therapy (usual maximum); however, doses up to 15 mg/kg/day PO have been used for thrombosis prophylaxis.
-Infants
5 mg/kg/day PO for antiplatelet therapy (usual maximum); however, doses up to 10 mg/kg/day PO have been used for thrombosis prophylaxis. 100 mg/kg/day PO during febrile phase of Kawasaki disease.
-Children
5 mg/kg/day (Max: 81 to 325 mg/day) PO for antiplatelet therapy (usual maximum); however, doses up to 10 mg/kg/day PO have been used for thrombosis prophylaxis. 100 mg/kg/day PO during febrile phase of Kawasaki disease.
-Adolescents
5 mg/kg/day (Max: 81 to 325 mg/day) PO for antiplatelet therapy (usual maximum); however, doses up to 10 mg/kg/day PO have been used for thrombosis prophylaxis. 100 mg/kg/day PO during febrile phase of Kawasaki disease.

Patients with Hepatic Impairment Dosing
Avoid aspirin in patients with severe hepatic insufficiency. Patients with any degree of hepatic disease are at increased risk of salicylate-induced adverse reactions.

Patients with Renal Impairment Dosing
CrCl less than 10 mL/minute/1.73 m2: Avoid regular- or high-dose aspirin. While pediatric-specific recommendations are not available, low-dose aspirin therapy is recommended for the prevention of atherosclerotic events in adults patients with cardiovascular disease. Similar consideration of benefits and risks should be made for pediatric patients who would typically receive low-dose aspirin therapy for chronic cardiovascular conditions.

Intermittent hemodialysis
Avoid regular- or high-dose aspirin. While pediatric-specific recommendations are not available, low-dose aspirin therapy is recommended for the prevention of atherosclerotic events in adults patients with cardiovascular disease. Similar consideration of benefits and risks should be made for pediatric patients who would typically receive low-dose aspirin therapy for chronic cardiovascular conditions. If use is necessary, doses should be administered after hemodialysis; aspirin is 50% to 100% dialyzable.

Continuous ambulatory peritoneal dialysis (CAPD)
Avoid regular- or high-dose aspirin. While pediatric-specific recommendations are not available, low-dose aspirin therapy is recommended for the prevention of atherosclerotic events in adults patients with cardiovascular disease. Similar consideration of benefits and risks should be made for pediatric patients who would typically receive low-dose aspirin therapy for chronic cardiovascular conditions.

Continuous renal replacement therapy (CRRT)
No dosage adjustment needed; monitor serum salicylate concentrations if possible and clinically appropriate.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: The activity of aspirin is due to its ability to inhibit cyclooxygenase (COX). Cyclooxygenase is responsible for the conversion of arachidonic acid to prostaglandin G2 (PGG-2), the first step in prostaglandin synthesis and precursor to prostaglandins of the E and F series. Cyclooxygenase exists in 2 isozymes: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). In vivo, aspirin is hydrolyzed to salicylic acid and acetate. However, hydrolysis is not required for aspirin activity. Aspirin irreversibly inhibits COX by acetylation of a specific serine moiety (serine 530 of COX-1 and serine 516 of COX-2). Aspirin is about 170-times more potent in inhibiting COX-1 than COX-2. In comparison, salicylic acid has little or no ability to inhibit COX in vitro despite inhibiting prostaglandin synthesis at the site of inflammation in vivo. The exact mechanism of prostaglandin inhibition by salicylic acid is unclear; however, salicylates produce the majority of classic NSAID effects. Theories regarding the potential mechanism for salicylic acid include inactivation of transcriptional regulatory proteins (e.g., NF-kappaB), which regulate the expression of inflammatory proteins. Aspirin appears to inhibit COX through two pathways and seems to have a different mechanism of action than other salicylates. Aspirin does not inhibit the peroxidase activity of COX and does not suppress leukotriene synthesis by lipoxygenase pathways.

Antithrombotic Actions
Aspirin-induced inhibition of thromboxane A2 (TXA2) and prostacyclin (PGI-2) has opposing effects on hemostasis. TXA2 is a potent vasoconstrictor and platelet agonist, while PGI-2 inhibits platelet aggregation and vascular smooth muscle contraction. However, data suggest that the effects of aspirin-induced TXA2 inhibition predominate clinically. This may be due to the ability of vascular endothelial cells to regenerate new COX and recover normal function, while COX inhibition in platelets is irreversible due to the limited amount of mRNA and protein synthesis in these cells. This distinction also allows for the use of very low doses of aspirin to retard platelet aggregation. The antithrombotic actions of aspirin are primarily mediated by COX-1 inhibition; COX-1 produces TXA2. Aspirin may also inhibit platelet activation by neutrophils. The antiplatelet effects of aspirin result in a prolonged bleeding time, which returns to normal roughly 36 hours after the last dose of the drug. Antiplatelet effects occur before acetylsalicylic acid is detectable in the peripheral blood due to exposure of platelets in the portal circulation. In very high and toxic doses, aspirin also exerts a direct inhibitory effect on vitamin K-dependent hemostasis by inhibiting the synthesis of vitamin K-dependent clotting factors. Prothrombin synthesis is impaired, resulting in hypoprothrombinemia.

Anti-inflammatory Actions
The anti-inflammatory action of aspirin is believed to be a result of peripheral inhibition of COX-1 and COX-2, but aspirin may also inhibit the action and synthesis of other mediators of inflammation. It is thought that COX-2 is the more important pathway for the inflammatory response since COX-2 is inducible in settings of inflammation by cytokines. Inhibition of COX-2 by aspirin suppresses the production of prostaglandins of the E and F series. These prostaglandins induce vasodilation and increase tissue permeability, which, in turn, promotes the influx of fluids and leukocytes. Ultimately, the classic symptoms of inflammation result: swelling, redness, warmth, and pain. Aspirin does not only decrease capillary permeability (which reduces swelling and the influx of inflammatory mediators), but it can also reduce the release of destructive enzymes from lysozymes.

Analgesic Actions
Salicylates are effective in cases where inflammation has caused sensitivity of pain receptors (hyperalgesia). It appears prostaglandins, specifically prostaglandins E and F, are responsible for sensitizing the pain receptors; therefore, salicylates have an indirect analgesic effect by inhibiting the production of further prostaglandins and do not directly affect hyperalgesia or the pain threshold. Salicylates may also interfere with pain perception centrally by activity within the hypothalamus. The total serum salicylate concentrations associated with analgesic activity are 30 to 100 mcg/mL.

Antipyretic Actions
Salicylates promote a return to a normal body temperature set point in the hypothalamus by suppressing the synthesis of prostaglandins, specifically PGE-2, in circumventricular organs in and near the hypothalamus. Salicylates rarely decrease body temperature in afebrile patients. Paradoxically, toxic doses of salicylates may increase body temperature by increasing oxygen consumption and metabolic rate. The total serum salicylate concentrations associated with antipyretic activity are 30 to 100 mcg/mL.

Gastrointestinal Effects
Adverse gastrointestinal effects from salicylates may be mediated through decreased prostaglandin synthesis due to inhibition of COX-1. A direct irritant effect on gastric mucosa may also be involved. Salicylates increase the permeability of the gastric mucosa to cations, thus increasing the entry of acid into the mucosa. Salicylates are also known to stimulate the chemoreceptor trigger zone, resulting in nausea and vomiting.

Respiratory Effects
The respiratory effects of salicylates lead to acid/base changes and alterations in electrolyte and water balance. Salicylates stimulate respiration directly and indirectly resulting in respiratory alkalosis. This is caused by a salicylate-induced increase in oxygen consumption, primarily in skeletal muscle, leading to increased carbon dioxide production and respiratory stimulation. Increased alveolar ventilation balances the increased carbon dioxide production; therefore, plasma carbon dioxide (PaCO2) does not change. Salicylate-induced respiratory alkalosis is compensated for by increasing renal excretion of bicarbonate, which is accompanied by increased sodium and potassium excretion. The serum bicarbonate level is then lowered and the serum pH returns to normal (i.e., compensated respiratory alkalosis). However, if the respiratory response to hypercapnia has been depressed (e.g., administration of a barbiturate or opiate agonist), salicylates will cause a significant increase in PaCO2 and respiratory acidosis. Hyperventilation also occurs due to direct stimulation of the respiratory center in the medulla. At high salicylate plasma concentrations (350 mcg/mL or more), marked hyperventilation will occur, and at serum concentrations of about 500 mcg/mL, hyperpnea will be seen. Finally, at high-therapeutic and at toxic doses, aspirin can affect oxidative phosphorylation, however, this action is insignificant at lower doses. Other changes in acid-base status (e.g., metabolic and respiratory acidosis) and electrolyte and water balance (hypokalemia, hypernatremia, dehydration) may be seen during salicylate intoxication.

Renal Effects
In addition to changes in sodium and fluid status secondary to acid/base changes, salicylates may decrease renal blood flow and glomerular filtration rate, which may be accompanied by water and potassium retention, in sodium-restricted patients and patients with impaired renal function or hypovolemic states. Changes in renal function are due to inhibition of renal prostaglandin synthesis, which increase renal blood flow and maintain normal renal function. Salicylate-induced renal effects are uncommon in patients with normal renal function.

Uricosuric Effects
Salicylates act on the renal tubules to affect uric acid excretion. Lower doses (e.g., 1 to 2 g/day) of salicylates inhibit the active secretion of uric acid into the urine via the proximal tubules. However, high doses (more than 3 g/day) of salicylates inhibit the tubular reabsorption of uric acid, resulting in a uricosuric effect. Uric acid secretion is not changed at intermediate dosages. While once used for their uricosuric properties, other agents have replaced salicylates for this purpose.

Pharmacokinetics: Aspirin is administered orally or rectally. Salicylic acid is widely distributed with high concentrations in the liver and kidney. Aspirin is poorly protein-bound as compared to salicylic acid. However, aspirin may acetylate albumin, resulting in changes in the ability of albumin to bind other drugs. Protein binding of salicylic acid to albumin varies with serum salicylate and albumin concentrations. At salicylate concentrations of 100 mcg/mL or less, salicylic acid is 90% to 95% protein bound; approximately 70% to 85% protein-bound at 100 to 400 mcg/mL; and only 20% to 60% protein-bound at serum concentrations more than 400 mcg/mL. Patients with low serum albumin have higher free salicylate concentrations.

Aspirin has a half-life of 15 to 20 minutes in adults as it is rapidly hydrolyzed by the liver to salicylic acid. Salicylic acid is primarily metabolized in the liver. Metabolites include salicyluric acid (glycine conjugate), the ether or phenolic glucuronide, and the ester or acyl glucuronide. In addition, a small amount is metabolized to gentisic acid (2,5-dihydroxybenzoic acid) and 2,3-dihydroxybenzoic and 2,3,5-dihydroxybenzoic acids. Salicyluric acid and salicyl phenolic glucuronide are formed via saturable enzyme pathways, and therefore, exhibit non-linear pharmacokinetics. The elimination half-life of salicylic acid varies with dosage. After a single low dose, the serum half-life of salicylic acid is 2 to 3 hours but can increase to 12 hours with anti-inflammatory doses and up to 15 to 30 hours after overdoses. Because of decreased serum protein binding, the effect of increasing doses is more pronounced on free salicylate concentrations than total salicylate concentrations. Approximately 80% to 100% of the salicylic acid from a single salicylate dose is excreted within 24 to 72 hours in the urine as free salicylic acid (10%), salicyluric acid (75%), salicylic phenolic (10%) and acyl (5%) glucuronides, and gentisic acid (less than 1%). The excretion of free salicylic acid is variable and depends upon the dose and the urinary pH. In alkaline urine, more than 30% of the dose may be eliminated as free salicylic acid, but in acidic urine, only about 2% is eliminated as free salicylic acid.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Oral Route
Aspirin is rapidly absorbed following oral administration and bioavailability of regular aspirin in adults is approximately 40% to 50%. However, the absorption from enteric-coated tablets and sustained-release preparations is delayed and bioavailability is significantly lower compared with regular aspirin. Platelet function inhibition is seen within 1 hour in adults. Peak concentrations are achieved approximately 2 hours after administration in children.

Other Route(s)
Rectal Route
The bioavailability of aspirin after rectal administration in adults has been reported to be 20% to 40%. Peak concentrations are reached approximately 4 hours after rectal administration in adults. Limited pharmacokinetic data in 8 children (5 to 9 years) revealed that the absorption of aspirin was very slow after rectal administration and was highly dependent on retention time. In children that retained the suppository for 5 hours or less, urinary recovery was 54% to 64%. Therefore, aspirin given rectally may not attain effective serum concentrations.


-Special Populations
Pediatrics
Neonates
Pharmacokinetic data are unavailable in neonates. Aspirin is primarily metabolized in the liver. Neonates would be expected to have slower clearance of aspirin due to their immature hepatic function.

Children
Pharmacokinetic data are very limited in children. Data from 10 children (2 to 7 years) who received aspirin revealed a mean elimination half-life for salicylic acid of 3.4 hours. This is similar to what has been reported in adults.

Hepatic Impairment
Pharmacokinetic data are unavailable in patients with hepatic impairment; however, aspirin is extensively metabolized in the liver and patients with hepatic impairment may have decreased elimination.

Renal Impairment
Pharmacokinetic data are unavailable in patients with renal impairment. Aspirin is renally excreted and patients with renal impairment may have decreased elimination. Aspirin is 50% to 100% hemodialyzable.

Other
Kawasaki disease
The pharmacokinetics of aspirin are altered in children with Kawasaki disease. These patients have been shown to achieve lower salicylate concentrations compared with healthy children receiving the same aspirin dose due to a combination of impaired bioavailability and/or increased clearance.