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Mechanism of Action
US Drug Names
Initially, 3 grams/day PO in divided doses. Target plasma salicylate concentrations range from 150 mcg/mL to 300 mcg/mL. The lowest effective dose should be used. Consider risks versus benefits in deciding optimal therapy, particularly in the older adult.
3 grams/day PO or less in divided doses. The lowest effective dose should be used. Other agents, such as acetaminophen, are preferred per clinical guidelines for the treatment of osteoarthritis, particularly for geriatric adults. 
325 to 650 mg PO every 4 hours as needed. Alternatively, 1,000 mg PO every 6 hours, as needed. Self-medication Max: 4 grams/day PO. Do not take for more than 10 days for pain or more than 3 days for fever unless directed by a physician. Use the lowest effective dose. In the geriatric adult, consider preferred alternatives, such as acetaminophen.
300 to 600 mg PR every 4 to 6 hours, as needed. Self-medication Max: 6 doses/day PR. Do not take for more than 10 days for pain or more than 3 days for fever unless directed by a physician. Use the lowest effective dose. In the geriatric adult, consider preferred alternatives, such as acetaminophen.
160 to 325 mg PO once daily starting within 24 to 48 hours of stroke symptom onset.  In patients with minor noncardioembolic ischemic stroke who did not receive a thrombolytic, use aspirin for first 21 days in combination with clopidogrel.  Aspirin is not recommended as a substitute for acute stroke treatment in patients eligible for thrombolytic therapy or mechanical thrombectomy.
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.
1 to 5 mg/kg/dose PO once daily. Aspirin is recommended for neonates with recurrent acute ischemic stroke.
80 to 100 mg/kg/day PO in 4 divided doses during the acute phase (often until patient has been afebrile for 24 to 72 hours, for up to 14 days), then decrease to 3 to 5 mg/kg/day PO once daily (Max: 325 mg/day) until 4 to 6 weeks after the onset of illness. High-dose IVIG (2 grams/kg IV as a single dose) should be given concurrently within 10 days of illness onset but as soon as possible after diagnosis. For those who develop coronary abnormalities, low-dose aspirin may continue indefinitely.     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 the 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 the ACCP and AHA clinical guidelines. However, moderate doses (30 to 50 mg/kg/day) are commonly used in Asia and Western Europe during the acute phase to minimize aspirin toxicity. There are no data to suggest either dose is superior.  Additionally, some data suggests low-dose aspirin (3 to 5 mg/kg/day or less than 10 mg/kg/day) is not inferior to high-dose aspirin (80 mg/kg/day or more than 10 mg/kg/day) in reducing the risk of CAA when given concomitantly with IVIG during the acute phase.
750 mg to 1000 mg PO 3 times per day, usually for 1 to 2 weeks for acute pericarditis, and usually a longer duration of 2 to 4 weeks for recurrent pericarditis, then tapered over 3 to 4 weeks. Treatment duration is dependent on resolution of symptoms and the normalization of markers of inflammation (e.g., C-reactive protein). Indomethacin or ibuprofen are commonly used NSAIDs with similar levels of evidence. The concomitant use of colchicine 1 mg to 2 mg PO on the first day of therapy followed by 0.5 mg to 1 mg PO daily for 3 months significantly reduced the recurrence rate and symptom persistence at 72 hours compared to aspirin alone.  
The role of aspirin as chemoprevention for colorectal cancer has yet to be determined. Doses of 325 mg or 81 mg PO once daily have been studied. Although observational studies have suggested a trend toward reduced risk, one randomized trial did not show any benefit of aspirin chemoprevention in otherwise healthy males. In a long-term study, adult males were randomized to receive aspirin 325 mg PO every other day was performed. Over 12 years of follow-up, random assignment to aspirin was associated with a relative risk of colorectal cancer of 1.03 (95% confidence interval, 0.83 to 1.28). A cost-effectiveness analysis found that aspirin prophylaxis was generally not cost-effective for persons who follow appropriate colorectal cancer screening programs (NOTE: results of this analysis were very sensitive to changes in assumptions regarding aspirin's effects). Randomized trials in patients with a history of colorectal cancer or adenomas have suggested a possible decreased risk in development of colorectal cancer. In patients with previous colorectal cancer randomized to receive either aspirin 325 mg PO once daily or placebo, one or more adenomas was found in significantly less patients in the aspirin group vs. the placebo group (17% vs. 27%). Aspirin appeared to delay the development of adenomas; however, the mean size of the adenomas and the proportion of patients with advanced adenomas did not differ between the groups. In another trial, patients with a recent history of adenomas were randomized to receive placebo, aspirin 81 mg, or aspirin 325 mg PO once daily. After a mean duration of 33 months, the incidence of 1 or more adenomas was 47% in the placebo group, 38% in those given aspirin 81 mg, and 45% in those given aspirin 325 mg. The rate of recurrence was significantly lower in the low-dose aspirin group as compared to placebo, but the higher dose of aspirin did not significantly reduce the recurrence rate.
100 or 325 mg PO every other day, or alternately, 300 mg PO once daily.   Clinical practice guidelines classify aspirin as having inadequate or conflicting data to support or refute use for migraine prophylaxis.
Not a first line therapy. Limited data suggest that aspirin doses of 0.25 grams to 2 grams/day PO added to cromolyn have been useful in providing symptomatic relief in some refractory patients whose symptoms were not controlled by cromolyn or corticosteroids alone. The duration of therapy ranged from 2 to 8 weeks followed by gradual tapering.  
Available data are limited, and efficacy has not been established. Doses varying from 3 to 5 mg/kg/day PO (low dose) to 30 to 100 mg/kg/day PO (moderate to high dose) have been reported and are being used in combination with IVIG with or without methylprednisolone.     Although ranges are provided in clinical studies, the optimal duration of treatment or recommendations on dividing larger doses is not always described. However, when treating other conditions, high doses of aspirin are divided into 2 to 4 doses. At a minimum, low dose aspirin is recommended for patients with Kawasaki disease-like syndrome. In 1 institutional protocol, aspirin 20 to 25 mg/kg/dose every 6 hours (80 to 100 mg/kg/day) is recommended in patients with Kawasaki disease-like illness, evidence of excessive inflammation (ferritin more than 700 ng/mL, CRP more than 300 g/dL, or multisystem organ failure), or cardiac involvement. Once patients are afebrile for 24 hours or more, the aspirin dose is reduced to 3 to 5 mg/kg/day. Low dose aspirin (3 to 5 mg/kg/day; max 81 mg/day) has been recommended in patients with MIS-C and Kawasaki disease-like features and/or thrombocytosis (platelet count 450,000/microliter or more). Continuation is recommended until platelet count and coronary arteries are normal for at least 4 weeks after diagnosis with avoidance in patients with a platelet count of 80,000/microliter or less. Additionally, it is recommended that patients with coronary artery aneurysms and a maximal z-score of 2.5 to 10 be treated with low dose aspirin, whereas patients with a z-score of 10 or more be treated with low dose aspirin and therapeutic anticoagulation with enoxaparin or warfarin. In a prospective observational study, 21 patients received low dose aspirin 3 to 5 mg/kg/day in combination with IVIG. In retrospective studies and case series, 30 to 100 mg/kg/day PO (moderate to high dose) was usually administered initially, followed by 3 to 5 mg/kg/day PO (low dose).   In 1 study, moderate to high dose aspirin was continued until 48 hours after defervescence and then continued at a low dose for 8 weeks.
Most patients experience signs of acute salicylate toxicity when the total salicylate level is > 300 mcg/ml. In chronic salicylism, signs of toxicity may occur at lower concentrations (>= 150 mcg/ml).
Therapeutic monitoring must be taken in context of the ingestion details, such as the type of aspirin formulation ingested, the suspected quantity of ingestion, and other clinical factors, as delayed symptoms of toxicity have been reported. Enteric-coated aspirin formulations, pylorospasm, as well as structural abnormalities, such as pyloric stenosis, gastric outlet obstruction, and peptic ulcer disease, may increase the likelihood of delayed absorption of aspirin from the stomach and proximal small intestine, resulting in delayed toxicity following overdose.
Avoid aspirin in patients with severe hepatic insufficiency. Patients with any degree of hepatic disease are at increased risk of salicylate-induced adverse reactions.
CrCl less than 10 mL/minute: Avoid analgesic doses. Use of low-dose aspirin for primary and secondary prevention of atherosclerotic events in patients with cardiovascular disease is recommended.
Avoid analgesic doses. Use of low-dose aspirin for primary and secondary prevention of atherosclerotic events in patients with cardiovascular disease is recommended. If use is necessary, doses should be administered after hemodialysis; aspirin is 50% to 100% dialyzable.
Continuous ambulatory peritoneal dialysis (CAPD)
Avoid analgesic doses. Use of low-dose aspirin for primary and secondary prevention of atherosclerotic events in patients with cardiovascular disease is recommended.
Continuous renal replacement therapy (CRRT)
No dosage adjustment needed; monitor serum salicylate concentrations if possible.
Aspirin is an oral and rectal nonsteroidal antiinflammatory drug (NSAID) indicated for the temporary relief of minor aches and pains associated with headache, backache, muscular aches, a cold, toothache, minor pain of arthritis, premenstrual and menstrual cramps, to reduce the risk of death and myocardial infarction (MI) in patients with chronic coronary artery disease, such as patients with a history of MI or angina pectoris or chronic stable angina, and to reduce the risk of death and recurrent stroke in patients who have had an ischemic stroke or transient ischemic attack (TIA). Aspirin increases the risk of bleeding and may cause gastric ulceration and bleeding. Reye's syndrome, a potentially fatal disease, has been associated with aspirin use after active varicella infection or other viral illnesses in children; hence, aspirin use is children is primarily limited to the treatment of Kawasaki disease, for thrombosis prophylaxis, particularly in those with congenital heart disease after cardiac surgery, and for the treatment and secondary prevention of arterial ischemic stroke. Guidelines for the treatment of juvenile idiopathic arthritis in children no longer 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. Observational studies have suggested that aspirin reduces the risk of colorectal cancer. However, long-term follow-up of the randomized Physicians' Health Study found no association between aspirin use and colorectal cancer. In contrast, randomized trials have shown that aspirin reduces the risk of recurrent adenomas in persons with a history of colorectal cancer or adenomas. The role of aspirin in the chemoprevention of colorectal cancer, either as primary or secondary prophylaxis, has not been determined.
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Symptomatic GI disturbances occur in 2% to 10% of individuals receiving normal doses of aspirin for analgesia or pyrexia, 10% to 30% of individuals receiving doses more than 3.6 grams/day, and 30% to 90% of patients with preexisting GI disease. Nausea, dyspepsia, abdominal pain, pyrosis (heartburn), gastritis and other common symptoms of gastric distress can be reduced if aspirin is taken with food or a full glass of water. In patients receiving chronic aspirin therapy, preventative agents, such as proton pump inhibitors or H2-antagonists may be needed for protective effect on the gastric mucosa. Diarrhea or constipation may also occur. Melena, hemorrhoids, and rectal hemorrhage have occurred with aspirin therapy. Rare cases of esophagitis have been reported in patients receiving aspirin. Aspirin-induced esophagitis is characterized by sudden onset odynophagia, retrosternal pain, and dysphagia. Severe complications such as GI perforation, esophageal ulceration, esophageal stricture, and GI bleeding, have been reported rarely. Risk factors for aspirin-induced esophageal effects include taking the medication without water and at night. Symptoms usually resolve within days to weeks after stopping the medication. Penetration of the gastric or esophageal mucosal cell by unionized molecules is 1 mechanism by which aspirin causes mucosal damage. Raising the intragastric pH increases the amount of aspirin in the unionized form, and some data indicate that agents such as cimetidine or antacids can reduce mucosal injury from aspirin. Chronic aspirin therapy may induce peptic ulcer disease. Gastric or peptic ulcers up to 1 cm in diameter induced by salicylates may heal despite continued therapy when oral cimetidine or high dose antacids are used concomitantly. Duodenal mucosal damage appears to be less common when enteric-coated tablets are used when compared with buffered or uncoated tablets. GI bleeding or erosive gastritis can be minor or life-threatening and may result from a combination of direct irritant action on the stomach mucosa and an increased bleeding time. In general, the severity of GI bleeding with aspirin is dose-related. Occult GI bleeding occurs in many patients and is not necessarily correlated with GI distress. While the amount of blood lost is usually not significant, blood loss can result in iron deficiency anemia. Patients taking aspirin in large doses (more than 15 tablets per week) or regularly (4 days/week or more) are at increased risk of GI bleeding or gastric ulceration. GI bleeding is more common with aspirin than with other salicylates and is not reduced by administering aspirin with food.
Tinnitus (1% or less) and hearing loss may occur in patients receiving high-dose and/or long-term aspirin therapy. 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.  The association of hearing loss and regular analgesic therapy (including aspirin) was prospectively assessed over 18 years in a study of 26,917 male patients 40 to 74 years of age at study enrollment. During 369,079 person-years of follow-up, 3,488 cases of hearing loss were reported. After adjustment for confounders, the hazard ratio (HR) for aspirin associated hearing loss was 1.12 (95% CI 1.04 to 1.2, p = 0.005) in patients who were regular users of the drug (2 times weekly or more) compared to those with less use. Men who used aspirin regularly for 1 to 4 years were 28% (17% to 40%) more likely to develop hearing loss than those without regular use; the risk of hearing loss did not further increase with longer duration of use. Regular users of aspirin less than 60 years of age were 33% more likely to experience hearing loss compared to non-regular users; no association occurred in those 60 years and older. This study does suggest association; however, data are based on patient reporting of the outcomes. Information regarding noise exposure and analgesic doses was not provided. Conversely, a similar prospective analysis conducted over 14 years in 62,261 women did not demonstrate an independent association of aspirin therapy with hearing loss. Salicylate ototoxicity may result from damage to the cochlea or auditory nerve through multiple mechanisms, including reduced cochlear blood flow, impairment of outer hair cell function, or inhibition of prostaglandin-forming cyclooxygenase. Counsel patients to report any symptoms of ototoxicity to a health care provider, as dosage adjustments may be needed.
Anaphylactoid reactions, including angioedema, laryngeal edema, and acute bronchospasm, may occur with aspirin therapy. Most allergic reactions occur within minutes and almost always within an hour of ingestion, although delayed reactions have been noted. Aspirin hypersensitivity may manifest as a respiratory reaction including rhinitis and/or asthma or with urticaria and angioedema. Aspirin hypersensitivity, however, is uncommon and occurs in only 0.3% of the general population. Patients with chronic urticaria have the highest incidence (20%), followed by patients with asthma (4%) and patients with chronic rhinitis (1.5%). Sensitivity is manifested primarily as bronchospasm in asthmatic patients and is most commonly associated with nasal polyps. The correlation of aspirin hypersensitivity, asthma, and nasal polyps is known as the aspirin triad. Hypersensitivity reactions are more common with aspirin than other salicylates. Patients sensitive to aspirin may develop cross-sensitivity to other analgesics, NSAIDs, and azo dyes such as tartrazine. Acetaminophen and other salicylate salts are not cross-sensitive and may be used cautiously in patients with aspirin-induced asthma.
Salicylates, such as aspirin, may cause reversible hepatotoxicity primarily manifested as mild focal hepatic necrosis and portal hypertension with elevated hepatic enzymes (usually transaminases) and hyperbilirubinemia. Transaminase elevations have been commonly reported in children with rheumatic diseases treated with aspirin.  Jaundice has been reported in some patients. Rarely, salicylates are associated with hypoprothrombinemia resulting in a prolonged prothrombin time and chronic hepatitis. Usually salicylate-induced hepatotoxicity is mild, but in some cases fatalities or hepatic encephalopathy have occurred. The occurrence of these events appears to be dose and duration related. 
Reye's syndrome, a potentially fatal disease, has been associated with aspirin use in children after active varicella infection or other viral illnesses.   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 of age. 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.  
Dermatologic reactions are uncommon; usually reported in patients who receive salicylate therapy for more than 1 week continually or with overdosage. These reactions include acneiform rash, erythema nodosum, maculopapular rash, pruritus, purpura, and urticaria. Rarely, aspirin has been associated with Stevens-Johnson syndrome and toxic epidermal necrolysis. Aspirin (acetylsalicylic acid) has been associated with acute generalized exanthematous pustulosis (AGEP). The nonfollicular, pustular, erythematous rash starts suddenly and is associated with fever above 38 degrees C. Drugs are the main cause of AGEP. A period of 2 to 3 weeks after an inciting drug exposure appears necessary for a first episode of AGEP; unintentional reexposure may cause a second episode within 2 days.
Aspirin therapy causes platelet dysfunction by inhibiting platelet aggregation resulting in a prolonged bleeding time; this effect is a common and expected pharmacologic effect of the drug leading to drug efficacy.  Infrequently this effect on platelet aggregation may result in minor bleeding episodes such as epistaxis (3% or less) or hematoma or gingival bleeding (1% or less) in clinical use, either alone or in combination with other medications. Leukopenia, pancytopenia, thrombocytopenia, agranulocytosis, aplastic anemia, and disseminated intravascular coagulation (DIC) have been reported rarely with salicylates. Leukocytosis has occurred in patients with salicylate overdose. If hemolytic anemia occurs in patients receiving aspirin, it almost always occurs in G6PD-deficient individuals. It appears that aspirin can induce hemolysis at therapeutic concentrations if other oxidative stressors are present. Otherwise, hemolysis only occurs at much higher concentrations.
With chronic, high-dose aspirin use, analgesic abuse, or salicylate overdose, a marked reduction in creatinine clearance, renal papillary necrosis, interstitial nephritis, or renal tubular necrosis with renal failure (unspecified) may be seen; however, in usual doses, salicylates rarely cause clinically significant renal effects in patients with normal renal function. Salicylates may cause transient urinary excretion of renal tubular epithelial cells, azotemia, albuminuria, and proteinuria.
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 large doses of salicylates (more than 3 g/day) induce uricosuria and lower plasma uric acid concentrations. Small doses of salicylates can block the effects of probenecid and other uricosuric agents that decrease the tubular reabsorption of uric acid.
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 levels, 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 loss, 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), 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.  
Moderate-to-severe noncardiogenic pulmonary edema may occur during aspirin associated acute or chronic salicylic acid toxicity. 
Intracranial bleeding may occur in patients at risk who are taking aspirin. Intracranial bleeding is rarely observed when aspirin is used in lower doses for prophylactic purposes. One trial reported an incidence of 0.4% in patients treated with 50 mg/day aspirin vs. 0.4% for placebo in patients being evaluated for stroke prophylaxis. The risk is significantly increased with concomitant use of other antithrombotics, anticoagulants, or thrombolytics.
Overuse of drugs for treating acute migraines, including aspirin, ASA, may lead to headache exacerbation (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. Patients should be informed of 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 encouraged to keep a written record of headache frequency and drug use.
Dizziness, drowsiness, headache, lightheadedness, and lethargy may be signs of salicylism, mild salicylate toxicity. Other symptoms of salicylism include uncontrollable flapping movements of the hands, increased thirst, and visual impairment. In severe aspirin overdose, seizures, hallucinations, severe nervousness, excitement, confusion, wheezing or shortness of breath, and unexplained fever may occur. In young children, the only signs of overdose may be behavioral changes.  
Aspirin use is contraindicated in patients with hypersensitivity to other medications for pain or fever, including those with salicylate hypersensitivity or NSAID hypersensitivity. The risk of cross-sensitivity with other nonsteroidal antiinflammatory drugs is significantly greater with aspirin than other salicylates. Patients with nasal polyps or with allergic reactions (e.g. urticaria) to aspirin are at risk of developing bronchoconstriction or anaphylaxis and should not receive aspirin. Patients with asthma are at risk of developing severe and potentially fatal exacerbations of asthma after taking aspirin. Aspirin should be avoided in asthmatics with a history of aspirin-induced acute bronchospasm.
In patients with gout, salicylates such as aspirin may increase serum uric acid levels, resulting in hyperuricemia, and interfere with the efficacy of uricosuric agents.
Aspirin has been associated with the occurrence of Reye's syndrome when given to children with varicella (i.e., chickenpox) or influenza. Although a causal relationship has not been confirmed, most authorities advise against the use of aspirin in children with varicella, influenza, or other viral infection. 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.
Aspirin can induce gastric or intestinal ulceration that can occasionally be accompanied by iron-deficiency anemia or other anemia from the resultant blood loss. Aspirin should be used cautiously, if at all, in patients with a history of or active GI disease including erosive gastritis, esophagitis, GI bleeding, peptic ulcer disease, or previous NSAID-induced bleeding. Such patients should be monitored closely, with special caution in tobacco smoking patients or in patients with alcoholism. All patients receiving chronic treatment should be routinely monitored for potential GI ulceration and bleeding. In patients who develop gastric or duodenal ulcers during aspirin treatment, the drug should be discontinued due to an increased risk of bleeding and/or perforation. In addition, patients should not self-medicate with aspirin if they consume 3 or more alcoholic beverages per day because of the potential increased risk for GI bleeding. In patients with anemia, this condition may be exacerbated during aspirin therapy due to GI blood loss. Hematocrit should be monitored periodically in patients receiving prolonged or high-dose aspirin therapy since iron deficiency anemia may occur. Traditionally, aspirin has been recommended to be discontinued for a time interval (e.g., 1 week) prior to surgery to minimize postoperative bleeding. However, data presented at the 2003 meeting of the American College of Chest Physicians indicates a risk of increased coronary events with abrupt discontinuation of aspirin in patients with pre-existing coronary artery disease. Patients with stable coronary disease developed acute coronary events within one week of stopping aspirin therapy; these events included unstable angina and myocardial infarction. Until the results of this trial are published and/or consensus recommendations are available, the decision whether to discontinue aspirin therapy abruptly should include a careful evaluation of the overall risks and benefits given the patient's coexisting conditions and the type of surgery or procedure. The use of aspirin is generally not recommended in patients expected to require CNS surgery due to the increased risk of perioperative bleeding.
Since even low doses of aspirin inhibit platelet aggregation and increase bleeding time, aspirin should be used cautiously in patients with coagulopathy, hemophilia, pre-existing thrombocytopenia, thrombotic thrombocytopenic purpura (TTP), or in patients receiving anticoagulant therapy or thrombolytic therapy. Medical evaluation of the potential risks versus benefits of aspirin therapy is needed in patients with aplastic anemia, agranulocytosis, or pancytopenia. Aspirin should be used with caution in patients with immunosuppression or neutropenia following myelosuppressive chemotherapy. Aspirin may mask signs of infection, such as fever and pain, in patients with bone marrow suppression.
Avoid aspirin in patients with potential for intracranial bleeding (e.g., subarachnoid aneurysm, head trauma, increased intracranial pressure) because of the possibility of interference with platelet function.
Because salicylates may cause or aggravate hemolysis in patients with G6PD deficiency, some reference texts state that aspirin should be used cautiously in these patients. If hemolytic anemia occurs in patients receiving aspirin, it almost always occurs in G6PD-deficient individuals. Otherwise, hemolysis only occurs at high concentrations.
Intramuscular injections should be administered cautiously to patients receiving aspirin. IM injections may cause bleeding, bruising, or hematomas due to aspirin-induced inhibition of platelet aggregation.
Liver function should be monitored in patients receiving large doses of aspirin (e.g., for treatment of Kawasaki disease, rheumatoid arthritis) or in patients with preexisting hepatic disease or impairment in order to prevent reversible, dose-dependent hepatotoxicity. Large doses also can cause hypoprothrombinemia, which can be reversed by vitamin K. Patients with vitamin K deficiency should be closely monitored if taking large doses of aspirin.
Salicylates should be used with caution in patients with renal impairment; regular-dose aspirin should be avoided in patients with advanced, chronic renal failure since salicylic acid and its metabolites are excreted in the urine.  Although data are limited in patients with chronic kidney disease, use of low-dose aspirin for primary and secondary prevention of atherosclerotic events in patients with concomitant cardiovascular disease is recommended. Observational data of dialysis patients who received aspirin following myocardial infarction (MI) indicate that, similar to the general population, aspirin use is associated with a reduction in post-MI mortality.  Even though cardiovascular disease is prevalent among patients with chronic kidney disease, data indicate aspirin for the primary and secondary prevention of atherosclerotic events is underutilized in hemodialysis patients. Salicylates should be used cautiously in patients with renal disease or systemic lupus erythematosus (SLE) due to the risk of decreased glomerular filtration rate in these patients. In addition, patients with renal impairment may be at increased risk of developing salicylate-induced nephrotoxicity. In a case-controlled study of patients with early renal failure, the regular use of aspirin (without acetaminophen) was associated with a risk of chronic renal failure that was 2.5-times as high as that for non-aspirin users. The risk increased significantly with increasing cumulative lifetime dose and increasing average dose during periods of regular use; duration of therapy was not associated with increased risk. When aspirin was given regularly in analgesic doses (more than 500 g per year during periods of regular use) the odds ratio for chronic renal failure was 3.5 (95% confidence interval 1.4 to 8). Low-dose aspirin use for cardiovascular prophylaxis was not significantly associated with the development of renal failure. In this study, it appears that pre-existing renal disease or systemic disease is a required precursor to the development of analgesic-induced renal failure; patients without preexisting renal disease who used analgesics had only a small risk of developing end-stage renal disease. Renal function should be monitored periodically in patients receiving prolonged or high-dose salicylate therapy.
Aspirin, ASA should be used with caution in the geriatric patient. Care should be taken in dose selection and the lowest effective dose should be used. Elderly patients should be monitored for the development of pedal edema, rales, blood pressure elevation, or changes in creatinine or BUN levels. Monitoring of stool for occult blood, serum potassium levels, and a complete blood count should be considered at baseline and periodically during chronic use of aspirin, ASA. According to the Beers Criteria, aspirin is considered a potentially inappropriate medication (PIM) in geriatric patients. Aspirin may cause new or worsening gastric or duodenal ulcers, and there is an increased risk of GI bleeding and peptic ulcer disease in high-risk groups including those above 75 years of age, or those taking oral or parenteral corticosteroids, anticoagulants, or antiplatelet medications. The Beers panel recommends avoiding chronic use of aspirin doses more than 325 mg/day in high-risk patients unless other alternatives are not effective and the patient can take a gastroprotective agent. Aspirin doses above 325 mg/day should be avoided in patients with a history of gastric or duodenal ulcers unless other alternatives are not effective and the patient can take a gastroprotective agent. The use of a gastroprotective agent, like a proton-pump inhibitor or misoprostol, reduces but does not eliminate, GI risks. The risk of ulcers, gross bleeding, or perforation is cumulative with continued use. Use caution when aspirin is used for the primary prevention of cardiac disease and colorectal cancer in adults 70 years of age and older. Several studies suggest a lack of net benefit when used for primary prevention in older adults with cardiac risk factors, but the evidence is not conclusive. Aspirin is generally indicated for secondary prevention in older adults with established cardiac disease. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, reserve the use of aspirin for symptoms or inflammatory conditions for which lower risk analgesics (e.g., acetaminophen) have either failed or are not clinically indicated. Aspirin may cause GI bleeding in patients with a prior history of, or with increased risk for, GI bleeding, or may worsen renal failure, increase blood pressure, or exacerbate heart failure. According to OBRA, low-dose aspirin (81 to 325 mg/day) may be appropriate as a prophylactic treatment for cardiac events such as myocardial infarction or stroke. Monitor closely for bleeding when aspirin is used in doses greater than 325 mg/day with another NSAID or when used with other platelet inhibitors or anticoagulants. Aspirin can increase the risk of adverse effects from NSAIDs or COX-2 inhibitors on the GI tract. Some NSAIDs, such as ibuprofen, may reduce the cardioprotective effect of aspirin.
Caution is advised with aspirin use in sodium-restricted patients or patients with hypovolemic states (e.g., ascites, dehydration, heart failure, hypertension, or hypovolemia) as they may be more susceptible to adverse renal effects of salicylate therapy. Patients with sodium-retaining states, such as congestive heart failure or renal failure, should avoid sodium-containing buffered aspirin preparations because of their high sodium content.
Salicylates primarily alter acid-base balance by causing metabolic acidosis and respiratory alkalosis, either alone or mixed. The respiratory effects of salicylates, such as aspirin, may contribute to serious acid/base imbalance in patients with underlying acid/base disorders (e.g., metabolic acidosis, metabolic alkalosis, respiratory acidosis, or respiratory alkalosis) or in overdose situations. Patients who are unable to compensate for salicylate-induced metabolic acidosis (i.e., respiratory response to CO2 is depressed) may develop respiratory acidosis and increased levels of plasma CO2.
Avoid aspirin use during the third trimester of pregnancy (starting at 30 weeks of gestation) due to the risk of premature closure of the fetal ductus arteriosus and persistent pulmonary hypertension in the neonate. If NSAID treatment is deemed necessary between 20 to 30 weeks of pregnancy, limit use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NSAID treatment extends beyond 48 hours. Discontinue the NSAID if oligohydramnios occurs and follow up according to clinical practice. These recommendations do not apply to low-dose 81 mg aspirin prescribed for certain conditions in pregnancy. Use of NSAIDs around 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. Salicylates have also been associated with alterations in maternal and neonatal hemostasis mechanisms, decreased birth weight, and perinatal mortality. Avoid aspirin 1 week prior to and during labor and obstetric delivery because it can result in excessive blood loss at delivery. Prolonged gestation and labor due to prostaglandin inhibition have been reported.
Salicylates are excreted into breast milk and could cause adverse effects in infants. Mean peak breast milk concentrations of salicylate in 6 nursing mothers after aspirin doses of 500, 1,000, and 1,500 mg were 5.8, 15.8, and 38.8 mg/L, respectively. Salicylate concentrations were detectable in breast milk within 1 hour of dosing and reached maximum concentration within 2 to 6 hours. Previous American Academy of Pediatrics (AAP) recommended that aspirin be used cautiously during breast-feeding. Alternative analgesics and antipyretics considered to be usually compatible with breast-feeding by the AAP include acetaminophen and ibuprofen.
Clearance of aspirin is slower in neonates, potentially placing them at risk for bleeding for longer periods of time. If a neonate is also receiving indomethacin, then additive antiplatelet effects should be considered.
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 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 antiinflammatory 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 concentration 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.
Aspirin is administered orally or rectally. Salicylic acid is widely distributed with high concentrations in the liver and kidney. During chronic administration, salicylate concentrations in the fetus may be higher than those in the mother. Aspirin is poorly protein-bound as compared to salicylic acid. However, aspirin may acetylate albumin, resulting in changes 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 of 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 and drug transporters: none
Aspirin is absorbed orally via passive diffusion as unchanged drug and as hydrolyzed salicylic acid from the upper intestine and partly from the stomach. Approximately 70% of an aspirin dose reaches the circulation unchanged; the remaining 30% is hydrolyzed to salicylic acid during absorption by esterases in the GI tract, plasma, or liver. The rate of absorption is dependent upon many factors including oral formulation, gastric and intestinal pH, gastric emptying time, and the presence of food. Aspirin is rapidly absorbed after oral administration, and bioavailability of regular aspirin in adults is approximately 40% to 50%. Effervescent and soluble tablets are most rapidly absorbed, followed by uncoated or film-coated tablets, and then enteric-coated tablets and extended-release formulations. The absorption from enteric-coated tablets and sustained-release preparations is delayed and bioavailability is significantly lower compared with regular aspirin.   Peak plasma salicylate concentrations occur in approximately 30 to 60 minutes for effervescent tablets, 45 to 120 minutes for film-coated tablets, 4 to 12 hours for extended-release tablets, and 8 to 14 hours for enteric-coated tablets. Food decreases the rate, but not the extent, of absorption. Salicylic acid is more ionized as the pH increases; however, a rise in pH increases the solubility of ionized salicylic acid and increases the dissolution of aspirin tablets. The overall effect of increased pH is an increase in absorption. Time to peak aspirin concentrations is 15 to 240 minutes depending upon the formulation. Plasma aspirin concentrations decrease as salicylic acid concentrations increase. Steady-state salicylate serum concentrations are similar after administration of plain, uncoated tablets and enteric-coated tablets.
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.
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.
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.
Neonates would be expected to have a slower clearance of aspirin due to their immature hepatic function. 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.
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.
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