Salicylates General Statement

[Section Outline]

GI Effects
Otic Effects
Hepatic Effects
Renal Effects
Cardiovascular Effects
Hematologic Effects
Dermatologic Effects
Sensitivity Reactions
Precautions and Contraindications
Pediatric Precautions
Geriatric Precautions
Pregnancy, Fertility, and Lactation

GI Effects

Adverse reactions to salicylates mainly involve the GI tract and include symptomatic GI disturbances, GI bleeding, and/or mucosal lesions (e.g., erosive gastritis, gastric ulcer). These reactions apparently occur more frequently with aspirin than with other currently available salicylates.

Symptomatic GI Disturbances

Symptomatic GI disturbances are manifested most frequently as dyspepsia, heartburn, epigastric distress, or nausea, and less frequently as vomiting, anorexia, or abdominal pain; these disturbances appear to occur more frequently with aspirin than with some other NSAIAs. Symptomatic GI disturbances reportedly occur in about 2-10% of healthy individuals receiving usual analgesic or antipyretic dosages of salicylates, in about 10-30% of patients receiving high dosages (e.g., greater than 3.6 g of aspirin daily), and in about 30-90% of patients with preexisting peptic ulcer, hemorrhagic gastritis, or duodenitis. Symptomatic GI disturbances frequently occur in the first few days of treatment with high dosages; although these disturbances disappear when therapy is discontinued, they also often subside despite continued treatment and without dosage adjustment. Centrally induced nausea and vomiting occur most often when the plasma salicylate concentration exceeds 270 mcg/mL, but nausea and vomiting may occur at lower concentrations as a result of local gastric irritation.

Symptomatic GI disturbances may be minimized by administering salicylates immediately after meals or with food, antacids, or a large quantity (240 mL) of water or milk. Alternatively, if symptomatic GI disturbances occur with an uncoated tablet, an enteric-coated tablet, extended-release tablet, or an oral solution of salicylate may be better tolerated. If burning in the throat or an unpleasant taste or aftertaste occurs with an uncoated tablet, a film-coated or enteric-coated tablet may be better tolerated. It has not been established that buffered aspirin tablets cause fewer symptomatic GI disturbances than uncoated plain aspirin tablets.

GI Bleeding

Occult GI bleeding, which occurs in most patients receiving salicylates (particularly aspirin), is usually painless and appears to be the result of a local action on GI mucosa. Occult GI blood loss with usual dosages of aspirin appears to be greater than that with usual dosages of most other NSAIAs. There appears to be no correlation between the incidence of salicylate-induced occult GI bleeding and symptomatic GI disturbances. Uncoated plain aspirin tablets in an oral dosage of 1-4.5 g daily produce a blood loss of 2-8 mL daily in about 70% of patients. However, about 10-15% of patients lose 10 mL or more of blood daily, which may result in iron deficiency anemia with long-term therapy; tolerance to salicylate-induced bleeding apparently does not occur. Unlike aspirin, usual oral dosages of salicylate salts or salsalate produce little or no GI blood loss.

The incidence and severity of GI bleeding are generally dose related. GI bleeding is not reduced by administration of salicylates with food. GI bleeding is less in patients with achlorhydria than in healthy individuals with normal gastric acid production, apparently because gastric acid is necessary to produce gastric mucosal injury. There is adequate evidence that sufficient buffering to decrease gastric acidity and increase the pH of gastric contents substantially reduces aspirin-induced GI blood loss; however, concomitant oral administration of high dosages of antacids is necessary to provide sufficient buffering capacity. (See Drug Interactions: Acidifying and Alkalinizing Agents.) It has not been established that the amounts of buffers contained in commercially available buffered aspirin tablets have any effect in reducing GI blood loss. However, GI blood loss is reduced with oral aqueous aspirin solutions. Although single oral doses of highly buffered aqueous aspirin solutions (e.g., Alka-Seltzer^®) cause little or no GI blood loss, multiple doses for 2-3 days do cause some GI bleeding; these solutions are not recommended for long-term therapy because of their high buffer and sodium content. Aspirin-induced GI blood loss also may be reduced with enteric-coated tablets, extended-release tablets, or by concomitant oral administration of a histamine H₂-receptor antagonist (e.g., cimetidine hydrochloride).

The risk of GI bleeding is increased in geriatric patients 60 years of age or older and in patients with a history of GI ulcers or bleeding, those receiving an anticoagulant or corticosteroid or taking multiple NSAIAs concomitantly, those consuming 3 or more alcohol-containing beverages daily, and those receiving excessive dosages or prolonged therapy.

In an FDA review of 41 reports of serious bleeding events (site unspecified but severe enough to require hospitalization) associated with use of OTC preparations containing aspirin in fixed combination with antacids (e.g., buffered effervescent tablets administered as oral solutions), 88% of the events occurred in patients with risk factors for bleeding.1035

Rarely, major upper GI bleeding may occur in patients receiving salicylates (particularly aspirin), regardless of the specific dosage form. A definite relationship between occult GI bleeding and major upper GI bleeding with aspirin therapy has not been established. Patients with active peptic ulcer or those who have recently had major upper GI bleeding do not experience greater occult blood loss after small doses of aspirin than do healthy individuals; however, these patients do have an increased risk of recurrent major bleeding. Most clinicians believe that aspirin and other salicylates can potentiate GI bleeding in patients with GI lesions.

In patients who have undergone tonsillectomy, severe bleeding from tonsillar blood vessels has been reported following topical application of aspirin via gargles or chewing gum tablets.

Mucosal Lesions

Salicylates (especially aspirin) can cause gastric mucosal damage with varying degrees of erythema, petechiae, submucosal bleeding, erosions, and/or ulceration, with or without bleeding, and even in the absence of GI symptoms. Aspirin and other salicylates may also reactivate latent gastric or duodenal ulcers. Although not clearly established, the incidence of gastric mucosal damage may be higher with aspirin than with other NSAIAs. The exact relationships between salicylate-induced gastric mucosal damage and occult GI bleeding or major upper GI bleeding remain to be clearly determined. Microscopic mucosal damage that accompanies endoscopically observed mucosal abnormalities usually resolves within several hours following a single oral dose of aspirin and can be reduced or prevented by concomitant oral administration of sodium bicarbonate (in amounts sufficient to buffer gastric contents) or a histamine ₂-receptor antagonist (e.g., cimetidine). However, with long-term aspirin therapy, many patients develop persistent gastric erythema and erosions and gastric ulcer (often in the distal antrum). Several studies using endoscopy have indicated that the incidence of aspirin-induced gastric erosions and ulceration is lower with enteric-coated tablets than with buffered or uncoated plain tablets; buffered tablets appear to provide little or no protection against gastric mucosal damage.

Although long-term aspirin therapy has not been clearly associated with the occurrence of duodenal ulceration, duodenal erythema and erosions have been reported to occur frequently in patients receiving aspirin; the incidence of duodenal mucosal damage appears to be lower with enteric-coated tablets than with buffered or uncoated plain tablets.

In patients who develop gastric or duodenal ulcers during treatment with salicylates, salicylate therapy is generally discontinued because of an increased risk of bleeding and/or ulcer perforation; occasionally, another NSAIA is substituted for the salicylate in these patients. However, gastric or duodenal ulcers 1 cm or less in diameter, which are induced by salicylates or other NSAIAs, may heal despite continued treatment with these agents when an oral histamine H₂-receptor antagonist (e.g., cimetidine) and high-dose antacid therapy are administered concomitantly. Although such regimens generally appear to be safe and effective, ulcer perforation has occurred in patients receiving a NSAIA and cimetidine concomitantly; further evaluation of these regimens is necessary.

Uncoated plain aspirin tablets allowed to remain in contact with mucous membranes of the mouth and aspirin chewing gum tablets have produced mucosal erosions and ulcerations of the mouth. Rectally administered aspirin suppositories may rarely cause rectal mucosal irritation, burning pain, rectal bleeding, diarrhea, and tenesmus.

Other Adverse GI Effects

Although a causal relationship has not been established, one case-control analysis suggests that NSAIAs may contribute to the formation of esophageal stricture in patients with gastroesophageal reflux.

Gastric accumulation of enteric-coated aspirin tablets, sometimes resulting in gastric ulceration or salicylate intoxication, has been reported in some patients with gastric outlet obstruction. Removal of accumulated enteric-coated aspirin tablets from the stomach by usual methods (e.g., emesis, gastric lavage) may be unsuccessful in these patients and surgery may be necessary. However, some clinicians have reported successful removal by gastric lavage using an isotonic sodium bicarbonate solution (containing 150 mEq/L) to dissolve the enteric coating and allow dissolution of the aspirin; 300 mL of the solution was instilled into the stomach via a nasogastric tube over 30 minutes and then removed by continuous nasogastric suction for 30 minutes, the regimen being repeated continuously for 24 hours.

Otic Effects

Tinnitus and hearing loss may occur in patients receiving large dosages of salicylates and/or long-term therapy. These effects are often the initial manifestations of chronic salicylate intoxication in adults. (See Chronic Toxicity: Manifestations.) Tinnitus and hearing loss are rarely noted by young children or patients with preexisting hearing impairment and are therefore usually not useful as indicators of early chronic intoxication in these patients.

Tinnitus and hearing loss are dose related, usually completely reversible (even after administration of large dosages for many years), and are more likely caused by actions on the inner ear than on the CNS. Patients receiving high dosages should be monitored periodically for tinnitus and hearing loss. Tinnitus usually develops only when the serum salicylate concentration exceeds 200 mcg/mL and generally occurs at a concentration of about 300 mcg/mL; however, it may develop only at higher concentrations in some patients. Tinnitus occurs infrequently in patients with preexisting hearing impairment, even at high serum salicylate concentrations (e.g., greater than 400 mcg/mL). Since serum salicylate concentrations of 200-300 mcg/mL are consistent with those considered necessary for anti-inflammatory effects, the occurrence of tinnitus in adults with inflammatory disease can indicate attainment of adequate concentrations, but only in those patients with normal hearing. Because tinnitus can occur over a wide range of concentrations, determinations of serum salicylate concentration are preferred as a guide to adjusting dosage. Tinnitus subsides gradually with reduction of salicylate dosage or usually within 24-48 hours after discontinuance of therapy.

Salicylate-induced hearing impairment involves bilateral loss of pure tone sensitivity for all sound frequencies. Hearing losses generally range from 20-40 decibels, occur initially at a serum salicylate concentration of about 200 mcg/mL, and increase with increasing concentrations. Maximum hearing loss occurs most frequently at a serum salicylate concentration of about 400 mcg/mL. Hearing loss is usually completely reversible, subsiding within 24-72 hours after discontinuance of therapy; rarely, permanent hearing loss has been reported.

Hepatic Effects

Salicylates occasionally cause acute, reversible hepatotoxicity, particularly in patients with juvenile arthritis, active systemic lupus erythematosus, rheumatic fever, or preexisting hepatic impairment. Therefore, hepatic function should be monitored in these patients. In addition, salicylate therapy has been associated in a few patients with hepatic injury consistent with chronic active hepatitis. Salicylate-induced hepatotoxicity is usually mild, but death or hepatic injury with encephalopathy has occurred in a few patients.

Hepatic injury usually consists of mild, focal, cellular necrosis, eosinophilic degeneration of hepatocytes, and portal inflammation; the exact mechanism is not known. Salicylate-induced hepatotoxicity is manifested principally as elevations in serum aminotransferase concentrations; elevations in serum alkaline phosphatase concentration occur occasionally. Rarely, serum bilirubin concentration may be elevated and/or serum prothrombin concentration may be decreased with a resultant increase in the PT. Although most patients are asymptomatic, some develop nausea, vomiting, anorexia, abdominal distress, loss of taste for cigarettes, liver tenderness, and/or hepatomegaly.

Hepatotoxicity has generally developed after 1-4 weeks of therapy and appears to be related to serum salicylate concentration, occurring principally at concentrations exceeding 200-250 mcg/mL; however, it may occur at lower concentrations. Elevated serum aminotransferase concentrations usually return to pretreatment values within 1-2 weeks after dosage reduction or discontinuance of salicylate therapy; however, they may be transient and return to pretreatment values despite continued therapy and without dosage adjustment.

It is usually not necessary to discontinue salicylate therapy in patients who develop hepatotoxicity, but dosage reduction may be advisable in patients who develop signs of hepatotoxicity and whose serum salicylate concentration exceeds 250 mcg/mL. Some clinicians recommend that the PT be measured periodically in patients with abnormal hepatic function test results and that salicylate therapy be discontinued if prolonged PT occurs.

Renal Effects

In usual dosages, salicylates rarely cause clinically important adverse renal effects. In overdosage, the drugs may cause a marked reduction in creatinine clearance or acute tubular necrosis with renal failure.

Although the exact mechanism(s) is not known, salicylates cause transient urinary excretion of renal tubular epithelial cells. Albuminuria, proteinuria, and urinary excretion of leukocytes and erythrocytes may also occur. Urinary excretion of renal tubular epithelial cells usually increases markedly in the first several days of continuous therapy and then subsides or continues at a low level with prolonged treatment. Salicylates have also been shown to cause urinary excretion of N -acetyl-β-glucosaminidase 2-4 hours after single doses equivalent in salicylate content to at least 1.95 g of aspirin; the mechanism is not known.

In patients with impaired renal function or systemic lupus erythematosus, aspirin may cause reversible (sometimes marked) decreases in renal blood flow and glomerular filtration rate; as a result, minimal water, sodium, and potassium retention may occur. These effects may also occur in patients with conditions predisposing to sodium and water retention (e.g., congestive heart failure, decompensated hepatic cirrhosis). However, aspirin may have less severe adverse renal effects than other currently available NSAIAs. Renal effects are usually rapidly reversed following discontinuance of aspirin therapy, but they may also subside despite continued treatment. Although these effects on renal function have not been reported to date with salicylates other than aspirin, other salicylates may cause similar effects.

Long-term therapy with aspirin alone or in combination with other analgesic-antipyretic agents (e.g., phenacetin) has been associated with analgesic nephropathy (renal papillary necrosis with subsequent chronic interstitial nephritis); however, evidence to date concerning aspirin alone is conflicting and a causal relationship remains to be clearly established. Several studies indicate that long-term aspirin or salicylate therapy rarely, if ever, causes substantial renal disease; however, some clinicians have reported a high incidence of renal papillary necrosis at autopsy in patients with rheumatoid arthritis who received long-term aspirin therapy. The exact mechanism(s) of renal damage is not known but may include renal medullary ischemia caused by inhibition of renal prostaglandin synthesis and/or a direct cytotoxic effect of the drugs or their metabolites. Further studies are needed to fully evaluate the effects of long-term salicylate therapy on the kidney and renal function.

Cardiovascular Effects

Salicylates may cause moderate to severe noncardiogenic pulmonary edema, principally with chronic or acute intoxication. Salicylate-induced pulmonary edema may also be precipitated or aggravated by forced alkaline diuresis during the treatment of salicylate overdosage, but fluid volume overload is not necessary for its occurrence. It has been suggested that salicylates cause pulmonary edema by increasing alveolar capillary membrane permeability. Salicylate-induced noncardiogenic pulmonary edema appears to occur most frequently when the serum salicylate concentration exceeds 400 mcg/mL. It is usually manifested as diffuse bilateral infiltrates on chest radiographs, tachypnea or dyspnea, and hypoxemia, and is often associated with proteinuria and adverse neurologic effects such as lethargy or confusion. Patients receiving long-term salicylate therapy or those with a history of smoking appear to have an increased risk of developing pulmonary edema. Treatment of salicylate-induced pulmonary edema is generally supportive and includes measures to increase the excretion of salicylate; an adequate airway should be maintained and assisted pulmonary ventilation may be required. Following treatment, pulmonary edema generally resolves within 1-7 days.

In patients with rheumatic fever who have carditis, congestive heart failure and pulmonary edema may be precipitated with high dosages of salicylates, apparently as a result of increased circulating plasma volume and cardiac workload.

In one placebo-controlled study in a small number of patients with variant angina, aspirin therapy (2 g twice daily) was associated with an increased frequency of angina and an increased risk of exercise-induced angina.

Hematologic Effects

Although aspirin alters hemostasis through effects on platelet function and high dosages of salicylates can decrease hepatic synthesis of blood coagulation factors (see Pharmacology: Hematologic Effects), salicylates cause few hematologic reactions. Daily aspirin doses of 3-4 g may decrease the hematocrit and plasma iron concentration, and reduce erythrocyte life span. Since the effects of aspirin on platelets are irreversible, ingestion of aspirin or aspirin-containing preparations within 3-5 days of platelet donation generally precludes use of an individual donor as a sole source of platelet preparations for a thrombocytopenic recipient. However, ingestion of aspirin or aspirin-containing preparations does not preclude donation of whole blood. Since other currently available salicylates do not affect platelet aggregation, ingestion of these other salicylates does not preclude donation of platelets or whole blood.

Leukopenia, thrombocytopenia, pancytopenia, eosinopenia, agranulocytosis, aplastic anemia, purpura, eosinophilia associated with aspirin-induced hepatotoxicity, and disseminated intravascular coagulation have been reported rarely in patients receiving salicylates. Leukocytosis has occurred with salicylate overdosage. Increased perioperative and postoperative bleeding, hematomas, and ecchymoses have occurred in patients who ingested aspirin before and for several days after oral surgery. In addition, adverse hematologic effects have been reported in neonates whose mothers ingested aspirin before delivery. (See Cautions: Pregnancy, Fertility, and Lactation.)

Macrocytic anemia associated with folic acid deficiency has been reported in patients abusing analgesic-combination preparations containing aspirin and in patients with rheumatoid arthritis receiving high dosages of aspirin. In one patient, megaloblastic anemia was associated with long-term ingestion of a preparation containing aspirin, salicylamide, and caffeine.

In vitro, salicylates reduce adenosine triphosphate (ATP) concentrations and inhibit hexose-monophosphate shunt activity in erythrocytes of patients with pyruvate kinase deficiency. Although the clinical significance of these effects in vivo is not known, salicylates might cause or aggravate hemolysis in these patients.

Salicylates (especially aspirin) may cause or aggravate hemolysis in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency; however, this has not been clearly established. In a study in patients with G-6-PD deficiency, salicylate did not inhibit hexose-monophosphate shunt activity in erythrocytes from these patients in vitro, and oral doses of aspirin (50 mg/kg daily for 4 days) did not cause hemolysis; however, none of the patients in this study had chronic hemolysis. Some clinicians suggest that aspirin or other salicylates can probably be used safely in most patients with G-6-PD deficiency, but effects of the drugs in patients with rare variants of this enzyme deficiency remain to be fully evaluated.

Dermatologic Effects

Skin eruptions of a pustular acneiform nature may occur but are usually observed only in patients who have received salicylates continually for longer than 1 week or with overdosage. Erythematous, scarlatiniform, pruritic, eczematoid, or desquamative lesions, which rarely may be bullous or purpuric, have also been reported. Hemorrhage from mucous membranes may occur rarely. Rarely, aspirin has been associated with Stevens-Johnson syndrome and toxic epidermal necrolysis.

Sensitivity Reactions

Sensitivity reactions to aspirin may occur rarely; sensitivity reactions to other salicylates are extremely rare. Sensitivity reactions manifested principally as bronchospasm appear to be related mainly to inhibition of prostaglandin synthesis. The exact mechanism(s) of sensitivity reactions manifested principally as urticaria and/or angioedema has not been determined; although these reactions may be immune-mediated in some patients, IgE antibodies or specific antibodies have not been detected. If an aspirin (or salicylate) sensitivity reaction occurs, it usually develops within 3 hours of ingestion and is characterized as urticaria, angioedema, bronchospasm, severe rhinitis, or shock. Facial edema also has been reported with aspirin.836,838,839,840,841,842,843,844 Lacrimation, complete vasomotor collapse, and loss of consciousness may also occur. Although extremely rare, severe reactions resulting in death have occurred within minutes following ingestion of 325-650 mg of aspirin in individuals with known aspirin sensitivity. If a severe reaction occurs, the drug should be discontinued and the patient given appropriate treatment (e.g., epinephrine, corticosteroids, maintenance of an adequate airway, oxygen) as indicated.

Aspirin sensitivity appears to occur in about 0.3% of the general population, in about 20% of patients with chronic urticaria, in about 4% of patients with asthma, and in about 1.5% of patients with chronic rhinitis. Aspirin sensitivity also appears to occur more frequently in adults 30-60 years of age than in younger adults or children, and more frequently in females.

In patients with asthma, aspirin sensitivity is manifested principally as bronchospasm and is usually associated with the presence of nasal polyps; the association of aspirin sensitivity, asthma, and nasal polyps is known as the aspirin triad. In these patients, nasal symptoms usually precede asthma, and the onset of asthma may precede the development of aspirin sensitivity by many years. Mild to marked bronchospasm of variable duration may occur with oral doses of aspirin as small as 20-30 mg and usually develops within 15-30 minutes after ingestion of the drug.

In one study in patients with asthma, the capacity of aspirin and other NSAIAs to induce bronchospasm was directly correlated with the degree of in vitro inhibition of prostaglandin synthesis caused by the drugs. As an inhibitor of cyclooxygenase, aspirin may alter the synthesis of prostaglandin E (a bronchodilator) and prostaglandin F_2α (a bronchoconstrictor), resulting in a predominance of prostaglandin F_2α and bronchoconstriction. It has also been suggested that the inhibition of cyclooxygenase favors the formation of leukotrienes that contribute to bronchoconstriction. Patients with aspirin-induced bronchospasm are often cross-sensitive to other inhibitors of prostaglandin synthesis. Cross-sensitivity in these patients appears to occur most frequently with indomethacin, followed by ibuprofen, mefenamic acid, phenylbutazone, and sodium benzoate; therefore, these drugs and any NSAIA are generally contraindicated in patients with aspirin sensitivity and vice versa. Patients with aspirin-induced bronchospasm are usually not cross-sensitive to salicylate salts, salicylamide, or acetaminophen. Aspirin desensitization in aspirin-sensitive asthmatic patients has been reported; in some of these patients, cross-desensitization with indomethacin and other NSAIAs was demonstrated. However, continuous aspirin therapy appears to be necessary to maintain desensitization, which disappears gradually over several days when aspirin is withheld. Further evaluation is needed to determine the clinical implications of these findings.

In patients with chronic urticaria or chronic rhinitis, aspirin sensitivity is manifested principally as urticaria and/or angioedema, but bronchospasm and shock may also occur. Patients with aspirin sensitivity who generally have dermatologic reactions to the drug appear to have an increased risk of cross-sensitivity to salicylate salts or acetaminophen.

In general, about 10% of patients with aspirin sensitivity appear to be cross-sensitive to the dye tartrazine (FD&C yellow No. 5) and about 5% appear to be cross-sensitive to acetaminophen; since the incidence of cross-sensitivity to acetaminophen is low, some clinicians state that, if necessary, acetaminophen may be used instead of aspirin for analgesic-antipyretic effects in some patients with aspirin sensitivity.

The manufacturer of salsalate states that patients with aspirin sensitivity are not cross-sensitive to salsalate; although specific data are not available, the manufacturer suggests that patients who have sensitivity reactions to non-salicylate NSAIAs are probably not cross-sensitive to salsalate.

Precautions and Contraindications

Salicylates (particularly aspirin) should be used with caution in patients with active GI lesions (e.g., erosive gastritis, peptic ulcer) or with a history of recurrent GI lesions, since the drugs may cause or aggravate GI bleeding and/or ulcerations. Patients with ulcers or persistent or recurring stomach disorders (e.g., heartburn, stomach pain, dyspepsia) should contact their clinician prior to initiating therapy with aspirin.836,837,838,839,840,841,842,843,844 If salicylates must be administered, these patients should be closely monitored for signs of GI bleeding or ulcer perforation. For additional information on precautions associated with the use of salicylates in these patients, see Cautions: GI Effects. Use of enteric-coated salicylate preparations in patients with known or suspected gastric outlet obstruction should generally be avoided. When aspirin is used in fixed combination with dipyridamole, the cautions, precautions, and contraindications associated with dipyridamole must be considered in addition to those associated with aspirin.738

Patients should be informed that alcohol has a synergistic effect with aspirin in causing GI bleeding. The manufacturers caution that patients who generally consume 3 or more alcohol-containing drinks per day should ask their clinician whether to use salicylates (e.g., aspirin, choline salicylate, magnesium salicylate) or an alternative analgesic for self-medication since salicylates may increase the risk of GI bleeding.633,643,644,645,646,836,837,838,839,840,841,842,843,844 In addition, the manufacturers caution that patients who generally consume 3 or more alcohol-containing drinks per day should ask their clinician whether to use a salicylate (e.g., aspirin) in fixed combination with acetaminophen or an alternative analgesic for self-medication since aspirin in fixed combination with acetaminophen may increase the risk of GI bleeding and hepatotoxicity.633,643,644,645,646

Despite current warnings on OTC product labels, serious bleeding events continue to occur in patients receiving aspirin in fixed combination with antacids (e.g., buffered effervescent tablets administered as oral solutions) for self-medication .1035 FDA is evaluating whether additional actions are needed to address this safety concern.1035

Patients should discontinue aspirin and consult a clinician if they experience erythema or edema in the area being treated for pain or if new symptoms occur.836,837,838,839,840,841,842,843,844

Because of an increased risk of bleeding, salicylates (particularly aspirin) should be used with extreme caution, if at all, in patients with preexisting hypoprothrombinemia, vitamin K deficiency, thrombocytopenia, thrombotic thrombocytopenic purpura, or severe hepatic impairment, or in patients receiving anticoagulants (see Drug Interactions: Anticoagulants and Thrombolytic Agents). Since salicylates may cause or aggravate hemolysis in patients with pyruvate kinase deficiency or in patients with rare variants of G-6-PD deficiency, the drugs should probably be avoided in these patients. Most clinicians recommend that aspirin therapy be discontinued 5-7 days before surgery to prevent or minimize excessive perioperative bleeding; however, it has not been clearly established that patients receiving aspirin have substantially increased perioperative blood loss. Therapy with salicylates that do not affect platelet aggregation need not be discontinued before surgery.

Because of an increased risk of bleeding, aspirin is contraindicated in patients with bleeding disorders such as hemophilia, von Willebrand's disease, or telangiectasia. If salicylate therapy is considered necessary in patients with bleeding disorders, some clinicians suggest that salicylates which do not inhibit platelet aggregation (e.g., salicylate salts) may be used. Patients with bleeding disorders should contact their clinician prior to initiating therapy with aspirin for self-medication .836,837,839,840,841,842,843,844

Because of an increased risk of bleeding, chewing gum tablets or gargles that contain aspirin should be avoided for at least 1 week after tonsillectomy or oral surgery. In addition, tablets containing aspirin should not be chewed before swallowing for at least 1 week after tonsillectomy or oral surgery because of possible injury to oral tissues from prolonged contact with aspirin particles.

Salicylates should be used with caution in patients with impaired renal function and with extreme caution, if at all, in patients with advanced chronic renal insufficiency, since salicylate and its metabolites are excreted almost completely in the urine; in addition, these patients may have an increased risk of developing adverse renal effects.

Hematocrit and renal function should be monitored periodically in patients receiving prolonged salicylate therapy or high dosages since iron deficiency anemia or adverse renal effects may occur. Because of an increased risk of hepatotoxicity, hepatic function should also be monitored in patients with juvenile arthritis, active systemic lupus erythematosus, rheumatic fever, or preexisting hepatic impairment who are receiving high dosages of salicylates.

Because of the high sodium content, highly buffered aspirin solutions (e.g., Alka-Seltzer^®) should be used with extreme caution, if at all, in patients with congestive heart failure or other conditions in which a high sodium intake would be harmful; in addition, highly buffered aspirin solutions can result in alkalinization of the urine and enhance urinary excretion of salicylate. Salicylate salts containing magnesium or sodium should be avoided in patients in whom excessive amounts of these electrolytes might be harmful. Patients on a sodium-restricted diet should consult a clinician prior to initiating therapy with aspirin for self-medication .838,843,844

If corticosteroid dosage is decreased during salicylate therapy, it should be done gradually and patients should be observed for adverse effects, including adrenocortical insufficiency or symptomatic exacerbation of the inflammatory condition being treated. In addition, since corticosteroids may increase renal excretion of salicylate or induce its metabolism, reduction of salicylate dosage may be necessary when steroid therapy is discontinued. (See Drug Interactions: Corticosteroids.)

The possibility that the antipyretic and anti-inflammatory effects of NSAIAs may mask the usual signs and symptoms of infection or other diseases should be considered.

Some commercially available formulations of salicylates contain sodium bisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals. Some commercially available formulations of salicylates contain the dye tartrazine (FD&C yellow No. 5), which may cause allergic reactions including bronchial asthma in certain susceptible individuals. Although the incidence of tartrazine sensitivity is low, it frequently occurs in individuals who are sensitive to aspirin.

A specific salicylate preparation is contraindicated in patients with known hypersensitivity to that preparation or any of the ingredients in the formulation and should be used with extreme caution, if at all, in patients with known hypersensitivity to salicylates. The commercially available preparation containing aspirin in fixed combination with extended-release dipyridamole is contraindicated in patients with hypersensitivity to dipyridamole, aspirin, or any other ingredient in the formulation.738 Aspirin generally is contraindicated in patients in whom sensitivity reactions (e.g., urticaria, angioedema, bronchospasm, severe rhinitis, shock) are precipitated by any NSAIA and vice-versa, although the drugs have occasionally been used in aspirin- or NSAIA-sensitive patients who have undergone desensitization. Patients with known aspirin sensitivity should be warned to avoid aspirin and aspirin-containing preparations. If an allergic reaction with aspirin occurs, a clinician should be contacted immediately.836,838,839,840,841,842,843,844 Patients with asthma should consult their clinician prior to initiating therapy with aspirin.836,837,838,839,840,841,842,843,844 (See Cautions: Sensitivity Reactions.)

Pediatric Precautions

Salicylates should be used with caution in pediatric patients who are dehydrated, since these patients are especially susceptible to salicylate intoxication.

Safety and efficacy of magnesium salicylate in children younger than 12 years of age have not been established. Safety and efficacy of salsalate in children have not been established.

The safety and efficacy of the commercially available preparation containing aspirin in fixed combination with extended-release dipyridamole have not been established in children.738

Reye's Syndrome

Use of salicylates (almost exclusively aspirin) in children with varicella infection or influenza-like illnesses reportedly is associated with an increased risk of developing Reye's syndrome;166,167,168,169,468,538,549,638 however, a causal relationship has not been established.169,466,469,470,529,550 In several initial epidemiologic studies, children with varicella or influenza-like illnesses who developed Reye's syndrome appeared to receive salicylates more frequently during their antecedent illness than those who did not develop the syndrome;166,167,169,468 however, the methodology and results of some of these studies have been questioned.469,470,529 Subsequent epidemiologic studies designed and implemented by the US Public Health Service Reye Syndrome Task Force found a strong association between development of the syndrome and ingestion of salicylates (almost exclusively aspirin) during the antecedent illness.538,549,578 Most evidence to date, including a decline in the use of aspirin in children accompanied by a continuing decline in reported cases of Reye's syndrome, strongly supports such an association,166,167,168,169,468,537,538,549,551,552,553,554,578 but some data do not550 and some controversy still remains.469,470,529,550 Whether an increased risk of developing the syndrome is associated with aspirin only or with all salicylates has not been adequately evaluated.549,554,578

The exact pathogenesis of Reye's syndrome and the potential role of aspirin and other salicylates in its pathogenesis remain to be determined. 169,467,550,554 The syndrome has occurred in children who did not receive salicylates and in children who received other medications.166,167,168,169,466,467,468,470,538,549

Because of the evidence to date, the US Surgeon General, the American Academy of Pediatrics Committee on Infectious Diseases, the US Food and Drug Administration (FDA), and other authorities currently advise that salicylates not be used in children and teenagers with varicella or influenza, unless directed by a clinician. 466,467,554,638,836,837,838,839,840,841,842,843,844 Use of salicylates also generally should be avoided in children and teenagers with suspected varicella or influenza and during presumed outbreaks of influenza, since diagnosis of these diseases may be impossible to establish accurately during the prodromal period;466 similarly, salicylates should not be used in the management of viral infections in children or adolescents because of the possibility that the infection may be one associated with an increased risk of Reye's syndrome.646 If antipyretic medication is considered necessary in children or teenagers with known or suspected varicella or influenza or other viral illness, acetaminophen may be used.554,638 It is not known whether Reye's syndrome may occur in children who receive salicylates following vaccination with varicella virus vaccine live.638 (See Drug Interactions: Varicella Virus Vaccine Live.)

Geriatric Precautions

Geriatric individuals receiving salicylates are more likely than younger individuals to experience adverse effects secondary to age-related decline in renal function and/or increased use of concomitant drug therapy. The risk of GI bleeding is increased in geriatric patients 60 years of age or older. (See Cautions: GI Effects.)

Salicylates are highly protein bound and can be displaced from binding sites by other protein-bound drugs. Because geriatric patients are more likely to be taking multiple drugs than younger patients, geriatric patients are at increased risk of drug interactions mediated by alterations in protein binding (i.e., decrease in protein binding of salicylate and increased concentrations of unbound salicylate). (See Drug Interactions: Protein-bound Drugs.)

Pregnancy, Fertility, and Lactation

Pregnancy

Although safe use of salicylates during pregnancy has not been established, there is evidence indicating that aspirin is the most frequently used drug during pregnancy either as a single entity or in combination with other drugs. Salicylates have been shown to be teratogenic and embryocidal in animals. In humans, a slight positive association between chronic maternal salicylate ingestion during pregnancy and congenital abnormalities has been reported in some studies, but other studies have found no association. In some studies, chronic maternal salicylate ingestion has also been associated with decreased fetal birth weight; an increased incidence of stillbirth, neonatal mortality, antepartum and postpartum maternal hemorrhage, and complicated deliveries; and prolongation of gestation and spontaneous labor. There have been several reports of adverse hematologic effects (e.g., subconjunctival hemorrhage, hematuria, purpura, petechiae, cephalhematoma) in neonates whose mothers had ingested aspirin before delivery, and at least 2 reports of neonatal salicylate intoxication secondary to salicylate accumulation in utero. In one study, maternal ingestion of aspirin during the week before delivery was associated with an increased incidence of intracranial hemorrhage in premature neonates. In addition, it has been suggested that premature closure of the ductus arteriosus secondary to maternal salicylate ingestion may be one cause of persistent pulmonary hypertension in some infants.

Maternal and fetal hemorrhagic complications observed with maternal ingestion of large doses (e.g., 12-15 g daily) of aspirin594,595,597,611,612 generally have not been observed in studies in which low doses (60-150 mg daily) of the drug were used for prevention of complications of pregnancy† (e.g., preeclampsia, recurrent spontaneous abortions, prematurity, intrauterine growth retardation, stillbirth, low birthweight), including those associated with autoimmune disorders such as antiphospholipid syndrome, poor paternal blocking antibody production, or systemic lupus erythematosus.594,595,596,597,598,599,600,601,605,626,627,629,630,631,632,649 (See Uses: Complications of Pregnancy, in Aspirin 28:08.04.24.) Although current evidence indicates that low dosages of aspirin can be used safely during pregnancy,594,595,596,597,598,599,600,601,603,604,605,608,610,626,627,628,631,649 the possibility of maternal and/or fetal complications (e.g., bleeding) should be considered.648,649 At least one case of fatal cerebral hemorrhage has been reported in a woman who was receiving prophylactic therapy with aspirin, heparin, and immune globulin despite no history of recurrent pregnancy loss nor antiphospholipid antibodies; this woman was found to have had a congenital arteriovenous malformation as a predisposing risk for hemorrhage.648

Salicylates should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. The drugs (particularly aspirin) generally should be avoided during the last 3 months (although low dosages have been useful in the prevention of preeclampsia during this period) of pregnancy (especially during the 1-2 weeks before delivery). Similarly, aspirin in fixed combination with extended-release dipyridamole should be avoided in the third trimester of pregnancy.738

If maternal ingestion of aspirin occurs within 1-2 weeks of delivery, the neonate should be closely evaluated for the presence of bleeding.

Fertility

In animals, aspirin has been shown to cause testicular atrophy and inhibit spermatogenesis. Although the effect on fertility is not known, aspirin has been shown to decrease seminal fluid concentrations of prostaglandins E and F in healthy men.

Lactation

Since salicylates are distributed into milk in low concentrations, the drugs should be administered with caution to nursing women. However, maternal consumption of high salicylate dosages potentially may result in adverse effects (e.g., rash, platelet abnormalities, bleeding) in nursing infants.646 At least one case of salicylate toxicity in an infant has been attributed to breast-feeding;649 however, some experts consider it unlikely that ingestion of breast milk alone could have resulted in the serum salicylate concentration reported in the infant.649 In general, nursing should be discontinued during long-term salicylate therapy with high dosages; however, some clinicians state that occasional single doses of salicylates in nursing women appear to be of little risk to nursing infants.

Drug Interactions ⬆ ⬇

[Section Outline]

Protein-bound Drugs
Anticoagulants
Thrombolytic Agents
Uricosuric Agents
Antidiabetic Agents
Corticosteroids
Methotrexate
Acidifying and Alkalinizing Agents
Alcohol
Nonsteroidal Anti-inflammatory Agents
Salicylates
Anticonvulsants
Diuretics
Tetracyclines
Angiotensin-converting Enzyme Inhibitors
Varicella Virus Vaccine Live
Other Drugs

Numerous drug interactions involving salicylates have been reported but few appear to be clinically important. The salicylate interactions that many clinicians consider to be the most important include those with anticoagulants and thrombolytic agents, uricosuric agents, sulfonylureas, corticosteroids, and methotrexate.

Protein-bound Drugs

Because salicylate is highly protein bound, it could be displaced from binding sites by, or could displace from binding sites, other protein-bound drugs such as oral anticoagulants, sulfonylureas, hydantoins, penicillins, and sulfonamides; salicylates could also theoretically displace bilirubin in neonates, resulting in hyperbilirubinemia. Patients receiving salicylates with any of these drugs should be observed for adverse effects. The acetylation of albumin by aspirin could alter protein binding of other drugs; acetylated albumin has been shown to have a higher affinity for phenylbutazone.

Anticoagulants

Salicylates may enhance the hypoprothrombinemic effect of warfarin and other oral anticoagulants and increase the risk of bleeding complications with these agents; several mechanisms may be involved. However, low-dose aspirin (e.g., 75-100 mg daily) may be used in combination with heparin or oral anticoagulants for therapeutic benefit (i.e., additive antithrombotic effects) in selected patients at high risk for thromboembolism (e.g., patients with prosthetic mechanical heart valves).694,1008

Although salicylates can cause a dose-dependent hypoprothrombinemia, clinical data are conflicting regarding salicylate enhancement of oral anticoagulant-induced hypoprothrombinemia. In several studies in patients receiving warfarin or other oral anticoagulants, the PT was not affected when aspirin was administered concurrently in dosages up to 3 g daily for 3-14 days. However, in one study in which either a lower or a higher aspirin dosage (1.95 or 3.9 g daily, respectively) was administered concurrently, the PT was substantially increased; patients receiving the higher aspirin dosage also had signs of bleeding. Therefore, it appears that high dosages of salicylates (e.g., greater than 3 g of aspirin daily) may enhance the hypoprothrombinemic effect of oral anticoagulants when administered concurrently. At lower dosages, salicylates may not affect oral anticoagulant-induced hypoprothrombinemia and occasional low doses of salicylates (other than aspirin) can probably be used with caution in patients receiving anticoagulants; however, salicylates should generally be avoided in these patients since they also cause GI bleeding. Patients with preexisting hepatic impairment may have an increased risk of bleeding if salicylates and oral anticoagulants are administered concomitantly. Since aspirin also inhibits platelet aggregation, it should be used with caution in patients receiving anticoagulants. Patients receiving anticoagulants should consult a clinician prior to initiating therapy with aspirin for self-medication .836,837,838,839,840,841,842,843,844 If salicylates are indicated for other than their antithrombotic effects in patients receiving anticoagulants, salicylates (e.g., salicylate salts) that do not affect platelet aggregation are preferred to aspirin. In addition, the lowest effective salicylate dosage should be used, the PT should be determined frequently and anticoagulant dosage adjusted accordingly, and patients should be observed closely for adverse effects.

Because aspirin inhibits platelet aggregation and causes GI bleeding, it should be used with caution in patients receiving heparin. Although further documentation is necessary, severe bleeding complications have been reported in some patients with hip fractures who received aspirin in conjunction with heparin as prophylaxis for deep-vein thrombosis.

Thrombolytic Agents

Aspirin has been administered concomitantly with and/or after therapy with thrombolytic agents (e.g., streptokinase, alteplase) to prevent coronary artery reocclusion and/or reinfarction in patients with acute myocardial infarction.579,580,581,582,583,584,585,586,587,588,589,590 Concomitant administration of low dosages of aspirin with IV streptokinase therapy has been associated with additive reductions in mortality compared with those attributed to streptokinase therapy alone.579 Although concurrent therapy with aspirin and streptokinase was associated with an increased risk of major bleeding (including a slight increase in the incidence of confirmed intracranial hemorrhage during the first days of therapy) compared with placebo, such therapy appeared to be associated with only a slight increase in minor bleeding complications and no overall increase in serious bleeding episodes compared with streptokinase alone.579 Concomitant administration of low dosages of oral aspirin and IV heparin with IV alteplase therapy also has been associated with a substantial reduction in acute post-myocardial infarction mortality compared with placebo, but this regimen was accompanied by an apparent increased risk of bleeding complications, notably intracranial hemorrhage.589,590 Use after thrombolysis of drugs that affect platelet function should be individualized since these drugs may increase the risk of bleeding complications580,583,587,588,591 and have not been shown to be unequivocally effective to date.583,591,592,593 Further study is needed to elucidate the contribution of anticoagulant and/or platelet-aggregation inhibitor (e.g., aspirin) therapies to mortality reduction and the incidence of hemorrhagic complications observed in patients receiving these agents concomitantly with thrombolytic therapy.589

Uricosuric Agents

The uricosuric effects of salicylates and phenylbutazone, probenecid, or sulfinpyrazone are antagonistic; therefore, salicylates are generally contraindicated during uricosuric therapy. Although the exact mechanism(s) of the interaction has not been established, it appears to involve competition for active renal tubular transport; salicylates may also displace these agents from protein-binding sites. Salicylate-induced uricosuria is inhibited by usual doses of any of these agents. However, probenecid-induced uricosuria appears to be inhibited principally when the serum salicylate concentration exceeds 50 mcg/mL; therefore, occasional doses of salicylates for analgesia or antipyresis in patients receiving probenecid may be insufficient to produce a clinically important interaction. Although high single doses (e.g., greater than 3 g of sodium salicylate) of salicylates inhibit sulfinpyrazone-induced uricosuria, the effect of lower doses has not been determined. Frequent doses of salicylates for analgesia or antipyresis in patients receiving sulfinpyrazone as a uricosuric should probably be avoided. Patients receiving uricosuric agents should consult a clinician prior to initiating therapy with aspirin for self-medication .836,837,838,839,837,840,841,842,843 Sulfinpyrazone decreases the renal excretion of salicylate, apparently as a result of preferential tubular secretion of sulfinpyrazone.

Antidiabetic Agents

The hypoglycemic effect of sulfonylureas (e.g., chlorpropamide, tolbutamide) may be enhanced by salicylates. Although this effect occurs principally with high salicylate dosages, it may occur with serum salicylate concentrations less than 100 mcg/mL. The exact mechanisms of the interaction are not known, but the ability of salicylates to decrease blood glucose concentration in diabetics may be involved. In vitro studies indicate that salicylates displace chlorpropamide and tolbutamide from protein-binding sites. In addition, salicylates may interfere with the renal tubular secretion of chlorpropamide, resulting in increased serum concentrations of the sulfonylurea. Further evaluation of the interaction between salicylates and sulfonylureas is needed. Patients receiving antidiabetic agents should consult a clinician prior to initiation of aspirin for self-medication .836,837,839,840,838,841,842,843,844 If salicylates and sulfonylureas are administered concurrently, caution should be exercised. Patients receiving both drugs should be observed closely for signs and symptoms of hypoglycemia and appropriate dosage reduction of either drug should be made accordingly. If reduction in sulfonylurea dosage is necessary when salicylate therapy is initiated, an increase in sulfonylurea dosage may be necessary when salicylate therapy is discontinued. It is not known whether salicylates have similar effects on insulin.

Although the exact mechanism(s) is not known, aspirin appears to inhibit the flush effect induced by alcohol in some patients receiving chlorpropamide.

Corticosteroids

Serum salicylate concentrations may decrease when corticosteroids are administered concomitantly. Likewise, when corticosteroids are discontinued in patients receiving salicylates, serum salicylate concentration may increase; salicylate intoxication has been precipitated rarely. Several mechanisms may be involved in this interaction. In one study in healthy individuals and in patients with polyarthritis who received both drugs concomitantly, corticosteroids increased the renal clearance of salicylate, possibly by increasing glomerular filtration rate. Corticosteroids may also induce the metabolism of salicylate. Salicylates and corticosteroids should be used concurrently with caution. Patients with receiving antiarthritic agents should consult a clinician prior to initiating therapy with aspirin for self-medication .836,837,838,839,837,840,841,842,843 Patients receiving both drugs should be observed closely for adverse effects of either drug. It may be necessary to increase salicylate dosage when corticosteroids are administered concurrently or decrease salicylate dosage when corticosteroids are discontinued in patients receiving salicylates.

Methotrexate

Limited clinical data indicate that concurrent administration of salicylates and methotrexate may result in increased serum concentrations of methotrexate and thereby increase the risk of methotrexate toxicity. Salicylates displace methotrexate from plasma protein binding sites and decrease renal excretion of methotrexate by competing with and inhibiting renal tubular secretion of the antineoplastic agent. Several patients receiving both drugs reportedly developed severe pancytopenia; a few of these patients died. Since methotrexate has a low therapeutic index and may produce serious adverse effects, salicylates should be used with extreme caution, if at all, in patients receiving the drug. Geriatric patients and patients with impaired renal function may be at particular risk. If the drugs are administered concurrently, patients should be carefully monitored for signs of adverse effects of methotrexate. Patients receiving methotrexate should be warned to avoid nonprescription preparations containing salicylates.

Acidifying and Alkalinizing Agents

Since the urinary excretion of salicylate is markedly pH dependent (see Pharmacokinetics: Elimination), concurrent administration of drugs that increase or decrease urine pH may increase or decrease urinary excretion of salicylate, respectively.

In patients receiving high dosages of salicylates, urinary acidifying agents (e.g., ammonium chloride) may increase renal tubular reabsorption of salicylate and possibly increase serum salicylate concentrations. However, if urine is acidic before administration of an acidifying agent, the increase in serum salicylate concentration is likely to be minimal; a substantial increase is likely only in patients who have an initial urine pH greater than 6.5.

Concurrent administration of high dosages of antacids (e.g., 4 g of sodium bicarbonate or at least 60-120 mL of aluminum and magnesium hydroxides suspension daily), or highly buffered aspirin solutions (e.g., Alka-Seltzer^®) may increase urine pH and decrease serum salicylate concentrations by decreasing renal tubular reabsorption of salicylate. Although substantial reductions in serum salicylate concentration caused by concomitant antacid therapy have occasionally been reported, a quantitative reduction in serum salicylate concentration cannot be routinely predicted. Patients receiving high dosages of salicylates should be monitored for alterations in serum salicylate concentration if antacid therapy is initiated or discontinued, and salicylate dosage adjusted accordingly when necessary. Except for highly buffered tablets for preparation of an oral solution (Alka-Seltzer^®), the amounts of buffer contained in other commercially available solid dosage forms of salicylates are insufficient to alter urine pH.

Carbonic anhydrase inhibitors (e.g., acetazolamide) may also increase urine pH and should generally be avoided in patients receiving high dosages of salicylates. More importantly, however, carbonic anhydrase inhibitors may induce metabolic acidosis and thereby enhance salicylate penetration into the CNS and other tissues, possibly resulting in salicylate intoxication. Likewise, use of a carbonic anhydrase inhibitor to alkalinize the urine in patients with salicylate overdosage may precipitate metabolic acidosis and lead to severe complications. (See Acute Toxicity: Treatment.) There is evidence from pharmacokinetic studies that salicylates competitively inhibit protein binding of acetazolamide and substantially reduce plasma clearance of the drug, probably by competitively inhibiting renal tubular secretion of the carbonic anhydrase inhibitor.555 These results and well-documented case reports of toxicity during concomitant administration of acetazolamide and salicylates suggest that the observed toxicity potentially may result from either drug or both, and not necessarily just from the salicylate.555

Alcohol

Concomitant ingestion of salicylates (particularly aspirin) and alcohol generally should be avoided since alcohol increases the incidence and severity of salicylate-induced GI bleeding and increases the risk of gastric mucosal erosions and ulceration. In one study, alcohol reportedly enhanced aspirin-induced prolongation of bleeding time in healthy individuals when ingested concomitantly or within at least 36 hours after a single dose of aspirin; the aspirin-induced prolongation of bleeding time was not potentiated when alcohol was ingested 12 hours before the dose of aspirin, and alcohol did not potentiate the effects of aspirin on platelet aggregation. Although further documentation is necessary, some clinicians have suggested that use of aspirin within 8-10 hours of heavy alcohol ingestion should be avoided when possible. The manufacturers caution that patients who generally consume 3 or more alcohol-containing drinks per day should ask their clinician whether to use oral salicylates (e.g., aspirin, choline salicylate, magnesium salicylate) or an alternative analgesic for self-medication since salicylates may increase the risk of GI bleeding.633,643,644,645,646 In addition, the manufacturers caution that patients who generally consume 3 or more alcohol-containing drinks per day should ask their clinician whether to use a salicylate (e.g., aspirin) in fixed combination with acetaminophen or an alternative analgesic for self-medication since salicylates in fixed combination with acetaminophen may increase the risk of GI bleeding and hepatotoxicity.633,643,644,645

Nonsteroidal Anti-inflammatory Agents

Salicylates should be used cautiously with non-salicylate NSAIAs. Salicylates appear to have various pharmacokinetic interactions with many other NSAIAs; however, these interactions appear to have little or no clinical importance. Although most of the interactions with other NSAIAs have been studied or detected during concurrent administration of aspirin, the salicylate moiety is probably responsible for the interactions.

Concurrent administration of aspirin may decrease plasma concentrations of diflunisal, fenoprofen, ibuprofen, indomethacin, piroxicam, meclofenamate, and possibly naproxen and the active sulfide metabolite of sulindac; plasma concentrations of free tolmetin may be slightly increased. Aspirin appears to decrease plasma concentrations of indomethacin by decreasing the efficiency of its GI absorption and its renal clearance, and by increasing its biliary clearance. Aspirin apparently decreases GI absorption of meclofenamate sodium. Although the mechanisms of interaction with many of the other NSAIAs remain to be clearly established, salicylates may displace these agents from protein-binding sites, thereby increasing their metabolism and/or excretion. In general, salicylate pharmacokinetics are not affected by other NSAIAs.

Although the pharmacokinetic interactions appear to be of little or no clinical importance, many clinicians recommend that salicylates not be used in conjunction with other NSAIAs, since it has not been established that combination therapy is more efficacious than the individual agents alone and the potential for adverse effects (particularly GI and renal effects) may be increased.

Ibuprofen can antagonize the irreversible inhibition of platelet aggregation induced by aspirin and therefore may limit the cardioprotective effects of aspirin in patients with increased cardiovascular risk.788 Administration of 400 mg of ibuprofen 3 times daily in patients receiving aspirin 81 mg daily blocked the aspirin-induced inhibition of platelet cyclooxygenase-1 activity as well as the impairment of platelet aggregation achieved with aspirin during prolonged dosing.788 Administration of aspirin 2 hours before the morning dose of ibuprofen failed to circumvent the interaction with such multiple-dose administration, although such dose timing did effectively obviate the interaction when only single doses of each drug were administered.788

The US Food and Drug Administration (FDA) recommends that patients taking a single dose of ibuprofen 400 mg for self-medication in conjunction with immediate-release, low-dose aspirin therapy be advised to administer the ibuprofen dose at least 8 hours before or at least 30 minutes after administration of aspirin.858,859 Data currently are insufficient to support recommendations regarding the timing of ibuprofen administration relative to that of enteric-coated, low-dose aspirin.858,859 The occasional use of ibuprofen is likely to be associated with minimal risk of attenuating the effects of low-dose aspirin.858 FDA states that other NSAIAs that are used for self-medication (e.g., ketoprofen, naproxen) should be viewed as having the potential to interfere with the antiplatelet effect of aspirin unless data are available that indicate otherwise.858,859 In one study, concomitant administration of naproxen (500 mg) and low-dose aspirin (100 mg) interfered with the antiplatelet effect of aspirin.859,860 Whether ketoprofen interferes with the antiplatelet effect of aspirin has not been investigated.858,859 Use of alternative analgesics that do not interfere with the antiplatelet effect of low-dose aspirin (e.g., acetaminophen, opiates) should be considered for patients at high risk of cardiovascular events.858,859 Labeling for prescription NSAIAs states that concomitant use of NSAIAs with aspirin is not recommended because of the potential for increased adverse effects.861 Limited data indicate that administration of diclofenac sodium delayed-release tablets (75 mg twice daily) does not inhibit the antiplatelet effect of aspirin (81 mg daily).788

Salicylates

Patients receiving long-term salicylate therapy should be warned to avoid nonprescription preparations containing salicylates to prevent salicylate accumulation and potential toxicity. Results of several studies suggest that repeated doses or maximum recommended dosages of bismuth subsalicylate-containing antidiarrheal preparations (e.g., Pepto-Bismol^®) could potentially lead to salicylate intoxication in patients receiving concurrent salicylate therapy.

Anticonvulsants

At high dosages, salicylate appears to displace phenytoin from protein-binding sites; however, it is unlikely that this interaction is clinically important since the increase in serum concentration of free phenytoin is apparently small and transient. However, because the fraction of total drug in serum as free phenytoin is increased, therapeutic effects of phenytoin may be associated with lower than usual total serum phenytoin concentrations in patients receiving both drugs.

Salicylates (particularly aspirin) and valproic acid should be administered concurrently with caution. When aspirin and valproic acid were administered concurrently in one study in children with epilepsy, salicylate apparently displaced valproic acid from serum albumin; the serum concentration and elimination half-life of both free and total valproic acid were increased. Salicylate also appeared to alter the metabolism of valproic acid. Although further evaluation of this interaction is needed, the results of this study suggest that concomitant use of salicylates and valproic acid might result in increased serum concentrations of free valproic acid and thereby increase the risk of adverse effects of the anticonvulsant. In addition to this potential interaction, both salicylates (particularly aspirin) and valproic acid may affect coagulation and their combined use may increase the risk of bleeding complications. If the drugs are administered concurrently, patients should be carefully monitored for adverse effects.

Diuretics

Aspirin has been shown to slightly reduce the natriuretic effect of spironolactone in healthy individuals, possibly by reducing active renal tubular secretion of canrenone, the active metabolite of spironolactone; the antihypertensive effect of spironolactone and its effect on urinary potassium excretion in hypertensive patients are apparently not affected. Until more clinical data are available on this potential interaction, patients receiving both drugs should be monitored for signs and symptoms of decreased clinical response to spironolactone.

Although reports are conflicting, aspirin appears to attenuate the diuretic effect of furosemide, possibly by competing with and inhibiting renal tubular secretion of furosemide. The clinical importance of this potential interaction has not been established; further evaluation is necessary.

Tetracyclines

Because tetracyclines readily chelate divalent and trivalent cations such as aluminum or magnesium, concurrent administration of buffered salicylate preparations containing such cations (e.g., Bufferin^®), or concurrent administration of salicylate salts containing magnesium, may decrease absorption of oral tetracyclines. Therefore, such salicylate preparations should be given at least 1 hour before or after the tetracycline.

Angiotensin-converting Enzyme Inhibitors

Because angiotensin-converting enzyme (ACE) inhibitors may promote kinin-mediated prostaglandin synthesis and/or release, concomitant use of drugs that inhibit prostaglandin synthesis and release, including salicylates, may reduce the blood pressure response to ACE inhibitors (e.g., captopril, enalapril).752,753 In addition, salicylates (e.g., aspirin) can attenuate the hemodynamic actions of ACE inhibitors in patients with congestive heart failure.752,753 Because ACE inhibitors share and enhance the effects of the compensatory hemodynamic mechanisms of heart failure, with aspirin interacting with the compensatory mechanisms rather than with a given ACE inhibitor per se, these desirable mechanisms are particularly susceptible to the interaction and a subsequent potential loss of clinical benefits.752 As a result, the more severe the heart failure and the more prominent the compensatory mechanisms, the more appreciable the interaction between aspirin and ACE inhibitors.752 Even if optimal dosage of an ACE inhibitor is used in the treatment of congestive heart failure, the potential cardiovascular and survival benefit may not be seen if the patient is receiving aspirin concomitantly.753

In several multicenter studies, concomitant administration of a single 350-mg dose of aspirin in patients with congestive heart failure inhibited favorable hemodynamic effects associated with ACE inhibitors, attenuating the favorable effects of these drugs on survival and cardiovascular morbidity.752,753,754 However, these findings have not been confirmed by other studies.751,752,753 In one retrospective analysis of pooled data, patients who received an ACE inhibitor concomitantly with aspirin (160-325 mg daily) during the acute phase following myocardial infarction had proportional reductions in 7- and 30-day mortality rates comparable to patients who received an ACE inhibitor alone.751,752 Some clinicians have questioned the results of this study because of methodologic concerns (e.g., unsubstantiated assumptions about aspirin therapy [dosage, time of initiation, duration]; disparate distribution of patients).751,752

Although it has been suggested that patients requiring long-term management of heart failure avoid the concomitant use of ACE inhibitors and aspirin (and perhaps substitute another platelet-aggregation inhibitor [e.g., clopidogrel, ticlopidine] for aspirin),752 many clinicians state that existing data are insufficient to recommend a change in the current prescribing practices of clinicians concerning the use of aspirin in patients receiving therapy with an ACE inhibitor.753

Varicella Virus Vaccine Live

Because of the association between Reye's syndrome, natural varicella infection, and salicylates (see Reye's Syndrome under Cautions: Pediatric Precautions), the manufacturer of varicella virus vaccine live recommends that individuals who receive the vaccine avoid use of salicylates for 6 weeks following vaccination.756 However, an association between Reye's syndrome, administration of varicella virus vaccine live, and use of salicylates has not been established and the syndrome has not been reported to date in recipients of the vaccine.638 For children who are receiving long-term salicylate therapy, the American Academy of Pediatrics (AAP) suggests that the theoretical risks associated with the vaccine be weighed against the known risks of the wild-type virus.638 The ACIP states that, since the risk for serious salicylate-associated complications is likely to be greater in children in whom natural varicella disease develops than in children who receive the vaccine containing attenuated virus, children who have rheumatoid arthritis or other conditions requiring therapeutic salicylate therapy probably should receive varicella virus vaccine live in conjunction with subsequent close monitoring.757

Other Drugs

Salicylates should be used cautiously, if at all, with other drugs that might potentiate the adverse GI effects.

Concurrent administration of salicylates and pyrazinamide may prevent or reduce hyperuricemia which usually occurs with pyrazinamide therapy.

Although there are apparently no published reports to date, the possibility that concurrent administration of salicylates and antiemetics (including antihistamines and phenothiazines) might mask the symptoms of salicylate-induced otic effects should be considered.

Other Information ⬆ ⬇

[Section Outline]

Pathogenesis
Manifestations
Treatment
Pathogenesis
Manifestations
Treatment
Analgesic Effect
Anti-inflammatory Effect
Antipyretic Effect
Hematologic Effects
Genitourinary and Renal Effects
GI Effects
Cardiovascular Effects
Metabolic Effects
Absorption
Distribution
Elimination
Chemistry
Stability

Laboratory Test Interferences

At dosages equivalent in salicylate content to 2.4 g or more of aspirin daily, salicylates may cause false-negative results in urinary glucose determinations using glucose oxidase reagent (e.g., Clinistix^®, Tes-Tape^®) and false-positive results in urinary glucose determinations using the cupric sulfate method (Benedict's solution, Clinitest^®). Gentisic acid, a salicylate metabolite, may be responsible for false-negative results with glucose oxidase reagent since it is a potent reducing agent. Although salicylates are generally considered not to substantially affect glucose tolerance tests, some clinicians have reported that 3 g of aspirin daily results in a slightly increased oral glucose tolerance in healthy individuals and in patients with type 2 (non-insulin-dependent) diabetes mellitus.

Salicylates interfere with the Gerhardt test for acetoacetic acid by reacting with ferric chloride to produce a reddish color which, unlike the color produced by acetoacetic acid, persists after boiling.

Salicylates may produce falsely increased or decreased results in urinary vanillylmandelic acid (VMA) determinations, depending on the method used; with the Pisano method, urinary VMA may be falsely decreased. Salicylates should be avoided before and during urine collections for VMA determinations.

Aspirin has been shown to interfere with urinary 5-hydroxyindoleacetic acid (5-HIAA) determinations that use a fluorescent method.

Salicylates may decrease urinary excretion of phenolsulfonphthalein by competing for renal tubular secretion with the diagnostic agent. Therefore, the phenolsulfonphthalein excretion test should not be performed in patients receiving salicylates.

Although the evidence is somewhat conflicting, salicylates probably do not interfere with urinary 17-hydroxycorticosteroid determinations using the Porter-Silber method or with urinary 17-ketosteroid determinations using the Zimmerman color reaction. However, high dosages may cause false decreases in urinary 17-hydroxycorticosteroid determinations which utilize β-glucuronidase to hydrolyze the steroid glucuronides before extraction.

Concurrent administration of aspirin with xylose reportedly reduces urinary excretion of the sugar; the exact mechanism is not known.

At high dosages, salicylates competitively bind to thyroxine-binding globulin and thyroxine-binding prealbumin. As a result, serum protein-bound iodine is decreased; total serum concentrations of thyroxine and triiodothyronine are decreased while the unbound fractions of these hormones are increased. Secretion of thyrotropin, induced by exogenous administration of synthetic thyrotropin-releasing hormone (protirelin), is decreased in patients receiving salicylates, apparently as a result of the increased unbound fraction of thyroid hormones. Resin triiodothyronine uptake may be unchanged or slightly increased in patients receiving salicylates. Although reports are conflicting, 24-hour thyroid uptake of iodine 131 may be reduced following high dosages of salicylates.

Salicylates may falsely increase serum uric acid concentrations determined by colorimetric methods; serum uric acid concentrations determined by the uricase method are not affected.

Salicylates may completely interfere with or falsely decrease plasma theophylline concentrations determined by the Schack and Waxler method.

Acute Toxicity

Pathogenesis

Acute salicylate overdosage results from ingestion of a single toxic dose. The acute lethal dose of salicylate varies with the specific preparation ingested. Death has occurred in adults who ingested single 10- to 30-g doses of aspirin or sodium salicylate, but one patient survived after ingestion of 130 g of aspirin. In salicylate overdosage resulting from acute ingestion, little or no toxicity generally occurs in individuals ingesting less than 150 mg/kg, mild to moderate toxicity in those ingesting 150-300 mg/kg, severe toxicity in those ingesting 300-500 mg/kg, and potentially lethal toxicity in those ingesting greater than 500 mg/kg.

The pathophysiology of salicylate overdosage is complex because of the variety of toxic effects produced and their resultant manifestations. The principal toxic effects are extensions of pharmacologic actions and include local GI irritation, direct CNS stimulation of respiration, uncoupling of oxidative phosphorylation, altered glucose metabolism through inhibition of Krebs cycle enzymes, stimulation of gluconeogenesis and lipid metabolism, increased tissue glycolysis, inhibition of amino acid metabolism, and interference with hemostatic mechanisms.

Manifestations

Acute salicylate overdosage produces manifestations similar to those of chronic intoxication, but the effects are often more pronounced and occur in more rapid succession.

Ingestion may cause mild burning pain in the throat and stomach; vomiting, particularly in infants and children, usually begins within 1-8 hours. An asymptomatic interval of several hours may follow these initial manifestations.

In addition to manifestations of chronic intoxication, oliguria or acute renal failure, hyperthermia, restlessness, irritability, garrulity, incoherent speech, apprehension, vertigo, asterixis, tremor, diplopia, confusion, disorientation, delirium, mania, hallucinations, EEG abnormalities, generalized seizures, lethargy, and coma may occur; toxic encephalopathy resembling chorea may also occur. The mental disturbances, sometimes referred to as salicylate jag, resemble alcoholic intoxication without euphoria. Pulmonary edema, skin eruptions (see Cautions: Dermatologic Effects), and pancreatitis occur less frequently. Hemorrhagic complications (e.g., petechiae in skin and mucous membranes, GI bleeding, perforated peptic ulcer) or a syndrome resembling inappropriate secretion of antidiuretic hormone (SIADH) occurs rarely. As salicylate intoxication progresses, CNS stimulation is replaced by CNS depression manifested as stupor and coma; respiratory insufficiency and cardiovascular collapse follow, sometimes with asphyxial seizures. Death usually occurs during coma and results from respiratory failure or cardiovascular collapse.

The principal physiologic manifestations of salicylate overdosage are acid-base and electrolyte disturbances, dehydration, hyperpyrexia, and hyperglycemia or hypoglycemia. As with high dosages, single toxic doses of salicylate produce respiratory stimulation by peripheral and central mechanisms, resulting in hyperventilation, hypocapnea, and respiratory alkalosis; compensation for the respiratory alkalosis occurs rapidly. (See Pharmacology: Metabolic Effects.) Hyperventilation usually occurs when the serum salicylate concentration exceeds 350 mcg/mL and begins within 6-12 hours after ingestion of a single toxic dose. Marked hyperpnea usually occurs at a serum concentration of about 500 mcg/mL.

Metabolic acidosis usually follows compensation of respiratory alkalosis; occasionally, respiratory acidosis also occurs, usually only when intoxication progresses and respiration is centrally depressed or when a CNS depressant has been ingested concomitantly. Metabolic acidosis develops principally from accumulation of organic acids (pyruvic, lactic, acetoacetic, and amino acids) secondary to salicylate interference with carbohydrate and amino acid metabolism and increased lipid metabolism; inorganic phosphoric and sulfuric acids also accumulate secondary to salicylate-induced renal impairment. Depletion of buffer capacity as a result of the initial compensatory increase in renal excretion of bicarbonate also contributes to development of metabolic acidosis. Depending on the relative contributions of the metabolic effects, either alkalemia or acidemia and either alkaluria or aciduria may be observed. Early in the course of acute intoxication in most adults and with mild to moderate intoxication in older children, respiratory alkalosis alone or with alkaluria may be present. In adults, alkalemia occurs often and may persist, but a mixed acid-base disturbance (usually metabolic acidosis and respiratory alkalosis) appears to occur most frequently. With acute intoxication in children, metabolic acidosis and respiratory alkalosis are usually present, with acidosis and acidemia predominating. Until adequate salicylate removal from the GI tract has been accomplished, the likelihood of acidosis increases with time elapsed since the ingestion; severe acidosis may not occur for 12-24 hours after acute ingestion.

In general, severity of acidosis increases with decreasing a metabolic acidosis apparently predominates in young children because they are more susceptible to development of ketosis. The severity of acidosis also generally increases with increasing severity of intoxication and vice versa. Acidosis and acidemia increase the severity of intoxication by enhancing salicylate penetration into the CNS and other tissues (see Pharmacokinetics: Distribution); increased CNS concentrations of salicylate appear to be directly related to CNS dysfunction and death. Therefore, the greater severity of intoxication observed in young children appears to be due in part to the increased frequency and severity of acidosis in these patients. In adults, severe acidosis is associated with impaired consciousness and a poor prognosis.

Toxic effects that result in acid-base disturbances also cause alterations of fluid and electrolyte balance. Increased metabolism and heat production increase cutaneous insensible losses, principally of water, but also of sodium as a result of sweating. During compensation of initial respiratory alkalosis, renal excretion of bicarbonate is accompanied by increased renal excretion of sodium, potassium, and water. As intoxication progresses and metabolic acidosis develops, organic aciduria increases the solute load excreted by the kidney and is also accompanied by increased renal excretion of sodium, potassium, and water. The resultant dehydration and electrolyte imbalance may be enhanced by decreased fluid intake and vomiting, and hyperventilation (increased pulmonary insensible water loss). Electrolyte losses lead to total body depletion of sodium and potassium. However, hypernatremia is usually observed due to dehydration; hyponatremia is uncommon and associated with inappropriate fluid retention (SIADH). Hypokalemia is also usually observed; even if serum potassium concentration is normal, total body potassium depletion is likely. In general, water loss may be as great as 2-3 L/m² with moderate intoxication and 4-6 L/m² with severe intoxication. Oliguria may occur as a result of severe dehydration. Anuria or acute renal failure usually accompanies severe shock, hemorrhage, or cardiovascular collapse.

Hyperthermia, sometimes with rectal temperature as high as 40.5-42.2°C, is secondary to impaired oxidative phosphorylation and the consequent increase in heat production by body tissues. In toxic doses, salicylates appear to decrease efficiency of normal body cooling mechanisms; dehydration enhances this effect. When hyperthermia is present, it contributes to dehydration.

Altered glucose metabolism may result in hyperglycemia or hypoglycemia. Hyperglycemia usually occurs early in the course of intoxication as a result of interference with tissue utilization of glucose. Blood glucose concentration usually does not exceed 200 mg/dL but glucosuria may occur; hyperglycemia may persist for a few hours to a few days. Salicylate-induced hyperglycemia associated with coma, ketoacidosis, dehydration, and hyperventilation closely simulates diabetic ketoacidosis. Eventually, hypoglycemia may occur as a result of glucose depletion. Hypoglycemia may be life-threatening and is most likely to occur in infants or late in the course of intoxication. CNS hypoglycemia may occur despite the absence of systemic hypoglycemia and should be considered in children with seizures, coma, or cardiovascular collapse.

Treatment

In the treatment of acute salicylate intoxication, intensive symptomatic and supportive therapy should be instituted immediately. Treatment consists principally of removal of salicylate from the GI tract and prevention of further absorption; correction of fluid, electrolyte, and acid-base disturbances; and measures to enhance salicylate elimination.

Assessment of Severity of Intoxication

In acute ingestions, severity of intoxication can be estimated by assessing the amount reported to be ingested, by evaluating the clinical condition of the patient, and by measuring serum salicylate concentration.

Since the apparent volume of distribution of salicylate appears to increase with increasing doses, a specific serum salicylate concentration following acute ingestion of large doses may reflect a higher amount of salicylate in the body than the same serum concentration attained following ingestion of smaller doses; therefore, toxic effects may be more severe than generally anticipated, depending upon the ingested dose.

In overdosage with massive doses, serum salicylate concentration may continue to increase for up to 24 hours. In overdosage with enteric-coated or extended-release salicylate preparations, absorption may be delayed and serum salicylate concentration may continue to increase up to 72 hours after the ingestion. In the event that a serum concentration cannot be obtained or a preliminary estimate is desired, a Phenistix^® reagent strip (as used in the diagnosis of phenylketonuria) may be dipped into separated plasma or serum obtained from the intoxicated individual; the reagent strip generally gives a tan color with salicylate concentrations less than 400 mcg/mL, a darker brown color with concentrations of 400-900 mcg/mL, and a purple color with concentrations exceeding 900 mcg/mL.

Measures to Reduce Salicylate Absorption

In acute overdosage, the stomach should be emptied immediately, preferably by ipecac syrup-induced emesis if the patient is alert, or by gastric lavage. These procedures are generally effective up to 3-4 hours after an acute ingestion and may be effective for up to 10 hours following ingestion of massive doses. If the patient is comatose, having seizures, or has lost the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of vomitus. Activated charcoal should be administered since it is extremely effective in reducing salicylate absorption. Activated charcoal is usually administered as an aqueous suspension; adults are usually given 50-100 g and children 30-60 g or 0.5-1 g/kg. Activated charcoal should not be administered before induction of emesis with ipecac syrup since the emetic is inactivated by activated charcoal. Administration of a saline cathartic (e.g., magnesium citrate, sodium sulfate) is also usually recommended, with repeated administration until the activated charcoal has been passed rectally. However, the efficacy of saline catharsis in salicylate overdosage remains to be clearly determined. Results of several studies in healthy individuals suggest that saline catharsis in combination with activated charcoal does not further decrease GI absorption of salicylate compared to activated charcoal alone; however, studies in acutely intoxicated patients are needed.

Fluid and Electrolyte Therapy

If hyperthermia and/or dehydration have developed, initial treatment should be directed to their correction and maintenance of normal renal function. Patients with a rectal temperature greater than 40°C should be cooled by cooling devices or by sponging with tepid water. Appropriate fluid and electrolyte therapy should be administered promptly, based on evaluation of the patient's fluid, acid-base, and electrolyte status. Arterial pH and blood gases (Po₂, pCO₂, and total CO₂); serum sodium, potassium, chloride, bicarbonate, and creatinine concentrations; and blood glucose concentration and BUN should be determined immediately. Urinary output should be monitored hourly. The PT should also be monitored. Determinations of acid-base and electrolyte status and renal function should be performed frequently during treatment to guide therapy.

In patients with mild intoxication who have adequate urine output and do not vomit severely, fluids should be administered orally every hour up to a total of 100 mL/kg in the first 24 hours. In more severely intoxicated patients, IV fluid and electrolyte therapy is necessary; fluid requirements usually range from 2-6 L/m² in the first 24 hours. Patients are usually rehydrated initially with an IV solution containing 5-10% dextrose (to prevent hypoglycemia) with 75 mEq of sodium, 50 mEq of chloride, and 25 mEq of bicarbonate per liter; if metabolic acidosis is not present, the bicarbonate is replaced by chloride. This solution is usually administered at a rate of 10-20 mL/kg per hour for 1-2 hours; patients in shock may require more rapid fluid administration. Acidemia should be corrected as rapidly as possible to minimize entry of salicylate into the CNS and other tissues. Just as acidemia enhances intracellular movement of salicylate, correction of acidemia and/or maintenance of an alkaline serum pH facilitate movement of salicylate from intracellular sites to plasma and ultimately to urine. If acidosis is severe (serum pH less than 7.15), patients should receive additional IV sodium bicarbonate, 1-2 mEq/kg every 1-2 hours, as necessary. Potassium is added to IV fluids to replace losses only after it has been determined that renal function is adequate; potassium replacement may be necessary to accomplish alkalinization of the urine. Patients should be monitored by ECG and serum potassium determinations during potassium replacement. Subsequent hydration is usually performed with an IV solution containing 5-10% dextrose with 40 mEq of sodium, 35 mEq of potassium, 50 mEq of chloride, and 20 mEq of bicarbonate per liter; if acidosis persists, an additional 15 mEq of sodium bicarbonate is usually added to each liter. This solution is usually administered at a rate of 4-8 mL/kg per hour until the serum salicylate concentration is less than 300 mcg/mL, which may require several hours to several days. Thereafter, IV hydration is continued as necessary, usually with a solution containing 5% dextrose with 25 mEq each of sodium and chloride and 20 mEq each of potassium and bicarbonate per liter; this solution is usually administered at a rate of 2-3 mL/kg per hour.

Other Supportive Therapies

If severe hypotension and/or manifestations of hemorrhagic complications (e.g., petechiae) are initially present, whole blood transfusions (10-15 mL/kg over 1 hour) may be necessary. Plasma transfusions may be beneficial, especially if shock develops. Although routine administration of vitamin K has been suggested in salicylate intoxication, the drug is usually administered only if hemorrhagic complications occur or if the PT is prolonged. Patients with respiratory depression may require assisted pulmonary ventilation and oxygen. CNS depressants (e.g., barbiturates, narcotics) should not be administered to counter salicylate-induced hyperventilation since they may lead to respiratory acidosis and coma. Seizures may usually be controlled by IV administration of a benzodiazepine (e.g., diazepam) or short-acting barbiturate; a short-acting skeletal muscle relaxant (e.g., succinylcholine), assisted pulmonary ventilation, and oxygen may occasionally be necessary.

Measures to Enhance Salicylate Elimination

Although reduction of hyperthermia and appropriate IV fluid and electrolyte therapy constitute adequate treatment for many patients, therapeutic measures (e.g., forced alkaline diuresis, hemodialysis) to enhance salicylate elimination may also be useful and/or necessary, depending on severity of intoxication. Forced alkaline diuresis with IV sodium bicarbonate (and IV furosemide when necessary) may be employed since alkalinization of the urine to pH 7.5 or greater, with maintenance of sufficient urine flow, greatly enhances the rate of urinary salicylate excretion. (See Pharmacokinetics: Elimination.) Sodium bicarbonate should not be given orally since it might enhance absorption of salicylate. Forced alkaline diuresis is often employed when the serum salicylate concentration exceeds 500 mcg/mL 6 hours after the ingestion and the patient's condition indicates severe intoxication. However, dehydration must be corrected before the procedure is employed. Forced alkaline diuresis with sodium bicarbonate should be performed with caution, particularly in infants, or in older children and adults with respiratory alkalosis; hypernatremia, pulmonary edema, and severe alkalosis (possibly with tetany and/or hypokalemia) may occur. If forced alkaline diuresis is employed, sufficient urinary output must be maintained, urine and serum pH must be carefully monitored, and dosage of sodium bicarbonate adjusted accordingly; for optimum results, urine pH of 7.5 or greater and serum pH of 7.5 should be maintained. In most children, even high doses of sodium bicarbonate may not produce a sufficiently alkaline urine because the degree of inorganic acid production and resultant aciduria cannot be adequately compensated; in addition, alkalinization of the urine may not be accomplished until potassium depletion is corrected.

Following correction of acidemia with sodium bicarbonate, acetazolamide has been used as an adjunct to alkalinize the urine; however, its use is dangerous and generally not recommended since it may precipitate metabolic acidosis and lead to severe complications. (See Drug Interactions: Acidifying and Alkalinizing Agents.) Therefore, if acetazolamide is used at all, it should probably be used only in adults with respiratory alkalosis and only under the supervision of clinicians experienced in the use of the drug in salicylate overdosage. Some clinicians have also suggested that tromethamine may be useful in patients with severe, refractory metabolic acidosis or in patients in whom sodium restriction is necessary; however, tromethamine should be used with extreme caution, if at all, since the drug produces intracellular as well as extracellular alkalinization and may therefore increase CNS and tissue concentrations of salicylate.

The most effective measures for removal of salicylate from the body are hemodialysis or hemoperfusion in adults and older children, and peritoneal dialysis or exchange transfusions in young children and infants; however, these measures are rarely necessary. Most clinicians reserve these measures for patients with serum salicylate concentrations of 900-1300 mcg/mL or higher 6 hours after an ingestion, unresponsive acidosis (pH less than 7.1), impaired renal function or renal failure, pulmonary edema, persistent CNS manifestations (e.g., seizures, coma), progressive deterioration despite appropriate therapy, or preexisting disease that prohibits usual therapeutic measures. If any of these conditions occurs, hemodialysis may be useful regardless of serum salicylate concentration. Hemodialysis and hemoperfusion are considered to be equally effective in removing salicylate, but hemodialysis is preferred to hemoperfusion since acid-base and electrolyte disturbances are corrected more rapidly with hemodialysis. In patients with severe intoxication, peritoneal dialysis and exchange transfusions may be instituted while preparations for hemodialysis or hemoperfusion are undertaken. If peritoneal dialysis is employed, 50 g of albumin should be added to each liter of dialysate; binding of salicylate to albumin enhances the efficiency of peritoneal dialysis.

Chronic Toxicity

Since the pathophysiology, manifestations, and treatment of chronic salicylate intoxication are similar to those of acute salicylate intoxication, the Acute Toxicity section should be consulted for additional information.

Pathogenesis

Chronic salicylate intoxication, also known as salicylism, results from high dosages or from prolonged therapy with high dosages. Some clinicians believe that chronic intoxication is generally associated with ingestion of dosages greater than 100 mg/kg daily for 2 days or longer. Severe chronic intoxication has often occurred in infants who were dehydrated as a result of fever and/or illness, and is best prevented by generally avoiding use of salicylates for antipyresis in infants or by limiting dosage in these patients.

Manifestations

Chronic intoxication is manifested principally as tinnitus, hearing loss, dimness of vision, headache, dizziness, mental confusion, lassitude, drowsiness, sweating, thirst, hyperventilation, increased heart rate, nausea, vomiting, and occasionally diarrhea; however, if intoxication is severe, other manifestations associated with acute intoxication may occur. Chronic salicylate intoxication is sometimes not readily recognized since a preexisting disease or concomitant illness may produce signs and symptoms (e.g., nausea, vomiting, tachypnea, disorientation) that are similar to those of salicylate intoxication.

Tinnitus and hearing loss are the most frequent manifestations of chronic intoxication in adults. (See Cautions: Otic Effects.) In children, the most frequent manifestations are hyperventilation or CNS effects such as giddiness, drowsiness, or behavioral changes; these effects usually occur at serum salicylate concentrations greater than 300 mcg/mL.

The onset of hyperventilation is usually insidious. With chronic intoxication, metabolic acidosis and respiratory alkalosis are usually present, with acidosis and acidemia predominating. Acidosis is usually more severe with chronic intoxication than with ingestion of a single toxic dose. Hypoglycemia, which may be life-threatening, is also likely to occur.

Treatment

Usually only evaluation of the clinical condition of patients with chronic intoxication is useful in determining the severity of intoxication. Serum salicylate concentrations may be determined but are not as useful in estimating the severity; severe symptomatology has been associated with concentrations as low as 150 mcg/mL.

When chronic intoxication is mild, dosage reduction or discontinuance of salicylates, in conjunction with symptomatic and supportive therapy, usually constitutes adequate treatment. When intoxication is more severe, salicylates are discontinued and intensive symptomatic and supportive therapy, as in the treatment of acute salicylate intoxication, should be instituted immediately. Patients who experience hearing loss of tinnitus during aspirin therapy should discontinue therapy and consult a clinician.836,837,838,839,840,841,842,843,844 Hemodialysis may be particularly useful in chronically intoxicated patients with high serum salicylate concentrations. Regardless of serum salicylate concentration, hemodialysis may also be especially useful in those with unresponsive acidosis (pH less than 7.1), impaired renal function or renal failure, pulmonary edema, persistent CNS manifestations (e.g., seizures, coma), progressive deterioration despite appropriate therapy, or preexisting disease that prohibits usual therapeutic measures.

Pharmacology

Salicylates mainly exhibit analgesic, anti-inflammatory, and antipyretic activity. These effects appear to result principally from the salicylate moiety. Although aspirin hydrolyzes to salicylate and acetate, it does not require hydrolysis to produce its effects; in addition, aspirin appears to have some pharmacologic effects that are distinct from those of salicylate. The ability of aspirin to acetylate proteins results in some effects, such as inhibition of platelet aggregation, which other currently available salicylates do not exhibit. (See Pharmacology in Aspirin 28:08.04.24.)

The exact mechanisms have not been clearly established, but many actions (e.g., analgesic, anti-inflammatory) of salicylates appear to be associated principally with inhibition of prostaglandin synthesis. Aspirin inhibits the synthesis of prostaglandins in body tissues by irreversibly acetylating and inactivating cyclooxygenase; at least 2 isoenzymes, cyclooxygenase-1 (COX-1) and -2 (COX-2) (also referred to as prostaglandin G/H synthase-1 [PGHS-1] and -2 [PGHS-2], respectively), have been identified that catalyze the formation of prostaglandins in the arachidonic acid pathway. Salicylate only minimally inhibits cyclooxygenase in vitro but is as active as aspirin in vivo in decreasing prostaglandin synthesis. Salicylate may be a reversible inhibitor of cyclooxygenase, but this has not been clearly established. Inhibition of prostaglandin synthesis by aspirin and salicylate may also involve other mechanisms.

Although aspirin and other salicylates inhibit cyclooxygenase and thereby decrease production of prostaglandins, they apparently do not inhibit lipoxygenase, an enzyme involved in the formation of 12-hydroperoxyarachidonic acid (12-HPETE) and leukotrienes from arachidonic acid. Since cyclooxygenase and lipoxygenase appear to compete for the metabolism of arachidonic acid, the inhibition of cyclooxygenase by aspirin and other salicylates may actually result in increased formation of 12-HPETE and leukotrienes. In platelets, 12-HPETE increases lipoxygenase activity (thereby increasing its own formation) and inhibits cyclooxygenase. Therefore, in the presence of salicylate, increased formation of 12-HPETE via lipoxygenase may contribute to the inhibition of cyclooxygenase. In addition, high concentrations of aspirin or salicylate have been reported to reversibly inhibit the conversion of 12-HPETE to 12-hydroxyarachidonic acid (12-HETE) via peroxidase. By inhibiting this conversion, salicylates may also increase concentrations of 12-HPETE and thereby indirectly inhibit cyclooxygenase. However, further evaluation of these effects is needed.

Analgesic Effect

The analgesic effect of salicylates may result from inhibition of prostaglandin synthesis. Prostaglandins appear to sensitize pain receptors to mechanical stimulation or to other chemical mediators (e.g., bradykinin, histamine). Since salicylates do not directly alter the pain threshold or prevent pain caused by exogenous or previously synthesized endogenous prostaglandins, the drugs may produce analgesia by inhibiting the formation of prostaglandins involved in pain. The analgesic effect of salicylates appears to result from mainly a peripheral action, but the drugs may also have similar activity and/or other mechanisms of action in the CNS, possibly in the hypothalamus. In addition, the anti-inflammatory effect of the drugs may contribute to their analgesic effect. There is no evidence that long-term therapy with salicylates results in tolerance to or physical dependence on the drugs.

Anti-inflammatory Effect

Due in part to the complexity of the inflammatory response, the exact mechanisms of the anti-inflammatory effect of salicylates have not been fully elucidated. Since prostaglandins appear to mediate many inflammatory effects and have been shown to directly produce many of the signs and symptoms of inflammation, the anti-inflammatory effect of salicylates may be due in part to inhibition of prostaglandin synthesis and release during inflammation. The anti-inflammatory effect of salicylates and other NSAIAs generally appears to be positively correlated with their ability to inhibit prostaglandin synthesis; however, the relative contributions of this and other mechanisms of action remain to be determined.

Although aspirin and other salicylates inhibit cyclooxygenase and thereby decrease production of prostaglandins, they apparently do not inhibit the formation of leukotrienes. The exact roles of leukotrienes in inflammation have not been fully elucidated, but they may contribute to the inflammatory response. Inhibition of cyclooxygenase by aspirin and other salicylates, while reducing prostaglandin synthesis and release, may actually result in the increased formation of leukotrienes. However, the clinical importance of such an effect remains to be determined.

Although high concentrations of aspirin or salicylate have been reported to reversibly inhibit the conversion of 12-HPETE to 12-HETE, a compound that appears to be a chemotactic stimulus for polymorphonuclear leukocytes, it is not clear whether salicylates enhance or inhibit migration of leukocytes into inflamed tissue. Salicylates have been shown to stabilize lysosomal membranes in vitro; therefore, they may prevent the release of lysosomal substances which contribute to inflammation. The anti-inflammatory action of the drugs may also involve effects on other cellular and immunologic processes in mesenchymal and connective tissues. Salicylates may inhibit lymphocyte activation, and by inhibiting cyclooxygenase, salicylates and other NSAIAs may interfere with prostaglandin-mediated formation of autoantibodies that are involved in the inflammatory process. High serum concentrations of salicylates may also suppress antigen-antibody reactions, but the contribution of this effect to the anti-inflammatory action of salicylates has not been established. Although the mechanism is not known, salicylates have been shown to enhance monocyte-mediated cytotoxicity and thereby increase antigen removal. Salicylates may also alter the composition, synthesis, and metabolism of connective tissue mucopolysaccharides related to the ground substance that helps prevent spread of inflammation.

Antipyretic Effect

Salicylates lower body temperature in patients with fever; the drugs rarely decrease body temperature in afebrile patients. Salicylates decrease body temperature principally by inhibiting the synthesis and release of prostaglandins that mediate the effect of endogenous pyrogen in the hypothalamus; however, other mechanisms may be involved. Although heat production is not directly inhibited by salicylates, centrally mediated dilation of peripheral blood vessels and sweating enhance dissipation of heat. Paradoxically, toxic doses of salicylates may increase body temperature by increasing oxygen consumption and metabolic rate, apparently as a result of salicylate-induced uncoupling of oxidative phosphorylation.

Hematologic Effects

Aspirin, but not other currently available salicylates, inhibits platelet aggregation and prolongs bleeding time. (See Pharmacology: Hematologic Effects, in Aspirin 28:08.04.24.)

Salicylates alter the hepatic synthesis of blood coagulation factors VII, IX, and X, apparently by interfering with the action of vitamin K; this effect appears to be dose-dependent and occurs principally when serum salicylate concentration exceeds 300 mcg/mL. At usual dosages (e.g., 1.3-6 g of aspirin daily), the prothrombin time (PT) may rarely be increased by 2-3 seconds; larger increases in the PT may occur at higher dosages or in patients with fever or increased metabolic rate. The increased PT is due mainly to a deficiency in factor VII and can be reversed by administration of phytonadione (vitamin K₁) or discontinuance of salicylate therapy; in some patients, the PT may return to normal even if salicylate therapy is continued.

Although salicylates usually do not alter the leukocyte or erythrocyte count, the drugs may decrease leukocytosis and erythrocyte sedimentation rate in patients with rheumatic fever; the mechanisms of these effects are not known. Although reports are conflicting, salicylates also apparently increase fibrinolysis, possibly by enhancing the fibrinolytic action of leukocytes.

Genitourinary and Renal Effects

Salicylates produce various effects on the uterus, apparently by inhibiting prostaglandin synthesis. Prostaglandins E₂ and F_2α increase the amplitude and frequency of uterine contractions in pregnant women; current evidence suggests that primary dysmenorrhea is also mediated by these prostaglandins. In some patients with primary dysmenorrhea, salicylate therapy has produced analgesic effects and has been associated with decreased synthesis of prostaglandin F_2α. Administration of salicylates during late pregnancy may prolong gestation and labor by inhibiting the formation of prostaglandins involved in these processes.

Salicylates have dose-related effects on urinary excretion of uric acid. In large dosages (e.g., 1.3 g of aspirin 4 times daily), salicylates enhance urinary excretion of uric acid and decrease serum uric acid concentration by inhibiting reabsorption of uric acid in the proximal renal tubule. Intermediate dosages (e.g., 650 mg to 1 g of aspirin 3 times daily) inhibit secretion of uric acid in the distal renal tubule but only slightly inhibit its reabsorption; therefore, urinary uric acid excretion is usually not altered. Low dosages (e.g., 325 mg of aspirin 3 times daily or less) inhibit renal tubular secretion of uric acid and therefore may decrease urinary uric acid excretion and increase serum uric acid concentration. In general, serum uric acid concentrations are increased when plasma salicylate concentrations are less than 100 mcg/mL and decreased when plasma salicylate concentrations are greater than 100 mcg/mL. Salicylates antagonize the activity of other uricosuric agents. (See Drug Interactions: Uricosuric Agents.)

Although salicylates generally do not alter renal function in healthy individuals, aspirin has been reported to cause reversible (sometimes marked) decreases in renal blood flow and glomerular filtration rate (which may be accompanied by minimal water, sodium, and potassium retention) in sodium-restricted, otherwise healthy individuals and in patients with impaired renal function, systemic lupus erythematosus, or other conditions predisposing to sodium and water retention. (See Cautions: Renal Effects.) These effects appear to be associated with inhibition of renal synthesis of prostaglandins such as prostaglandin E₂ and prostacyclin (epoprostenol, PGI₂); these prostaglandins increase renal blood flow and help to maintain renal function. Aspirin-induced renal impairment has been directly correlated with decreased urinary excretion of immunoreactive prostaglandin E. In addition, aspirin has been associated with analgesic nephropathy. (See Cautions: Renal Effects.)

GI Effects

Salicylates (especially aspirin) can cause gastric mucosal damage which may result in ulceration and/or bleeding. (See Cautions: GI Effects.) The damage is generally believed to be the result of a local action; however, IV administration of salicylates has also been reported to cause gastric mucosal lesions and bleeding.

The mechanism of salicylate-induced gastric mucosal damage is complex. Gastric mucosal effects have been attributed to inhibition of the synthesis of prostaglandins produced by COX-1. Salicylates appear to selectively increase permeability of the gastric mucosa to cations, and thus, enhance back diffusion of hydrogen ions; the increased entry of acid into the mucosa causes cellular damage. The resultant cellular damage leads to additional alterations in gastric mucosal permeability. Salicylates may also alter mucosal permeability by disrupting metabolism in gastric mucosal cells.

Salicylates cause nausea and vomiting as a result of local gastric irritation and/or by CNS stimulation.

Cardiovascular Effects

Salicylates generally have no direct cardiovascular effects; however, large single doses (e.g., 2.4 g of aspirin) may result in dilation of peripheral blood vessels by a direct effect on smooth muscle. In patients receiving large dosages of salicylates, such as those with rheumatic fever, circulating plasma volume may increase by about 20% (with resultant hemodilution) and cardiac workload and output may also increase. The increase in plasma volume may be due to sodium and water retention secondary to salicylate-induced renal impairment. In overdosage, salicylates may directly suppress cardiac conduction and may cause circulatory depression and possibly collapse, both directly and through central vasomotor paralysis.

Metabolic Effects

In high dosages (e.g., greater than 6 g of aspirin daily) or in the initial phase of overdosage, salicylates produce respiratory stimulation by peripheral and central mechanisms, with resultant changes in acid-base balance and electrolytes. Peripherally, salicylates uncouple oxidative phosphorylation, principally in skeletal muscle; the resultant increased production of carbon dioxide stimulates alveolar ventilation so that carbon dioxide tension is not changed. This increase in alveolar ventilation is characterized as an increase in depth of respiration and a slight increase in rate of respiration. As salicylates enter the CNS, the drugs directly stimulate the respiratory center in the medulla, resulting in marked hyperventilation that is characterized as an increase in depth of respiration and a pronounced increase in rate of respiration. Plasma carbon dioxide tension decreases, and intracellular and extracellular respiratory alkalosis develops. Compensation for respiratory alkalosis occurs rapidly and includes increased renal excretion of bicarbonate, sodium, potassium, and water; as a result, plasma bicarbonate concentration is decreased and blood pH returns toward normal. If substantial potassium depletion occurs, the kidneys retain potassium and excrete hydrogen ions instead, regardless of blood pH; therefore, a paradoxical aciduria can occur in the presence of salicylate-induced systemic alkalosis. These changes in acid-base balance and electrolytes are most often observed in adults receiving high dosages; more severe alterations in acid-base balance (e.g., metabolic acidosis) and electrolytes generally occur only in overdosage.

Salicylates produce a variety of other metabolic effects. The effects on carbohydrate metabolism are complex and involve numerous mechanisms, often with opposing results on blood glucose concentration. High dosages may cause hyperglycemia and glycosuria by interfering with tissue utilization of glucose; however, blood glucose concentration may be decreased in diabetics. It has been suggested that this effect in diabetics may result from increased uptake of glucose by muscle, increased rate of tissue glycolysis, and decreased synthesis of glucose from non-carbohydrate precursors, all of which may be due in part to uncoupling of oxidative phosphorylation. It has also been suggested that salicylates stimulate insulin secretion. In high dosages, or with long-term therapy or overdosage, salicylates eventually decrease aerobic metabolism of glucose and cause depletion of liver and muscle glycogen; hypoglycemia may occur. Depletion of liver glycogen may be caused by an increased rate of glycogenolysis and a decreased rate of glycogen synthesis; these effects may also be related to the uncoupling action of salicylates. In vitro studies have shown that salicylates also inhibit aldose reductase, the enzyme that catalyzes the formation of sorbitol. In overdosage, salicylates decrease synthesis and increase catabolism of proteins which results in a negative nitrogen balance characterized as aminoaciduria. Salicylates may also decrease fatty acid synthesis, increase metabolism of fatty acids and oxidation of ketone bodies, and decrease plasma concentrations of phospholipids and free fatty acids. With a dosage equivalent in salicylate content to at least 5 g of aspirin daily, plasma concentrations of cholesterol may be decreased.

Salicylates inhibit uptake of ascorbic acid by leukocytes and platelets. As a result, leukocyte and plasma concentrations of ascorbic acid are decreased to concentrations slightly higher than those associated with tissue depletion of the vitamin; however, there is no evidence to date that salicylate therapy precipitates ascorbic acid deficiency. Although concomitant administration of ascorbic acid supplements increases plasma ascorbic acid concentrations, leukocyte ascorbic acid concentrations are not increased and tissue stores of the vitamin may not be increased. Therefore, routine administration of ascorbic acid supplements to patients receiving salicylates is not warranted; however, patients receiving high dosages of salicylates who exhibit any signs or symptoms of ascorbic acid deficiency should be evaluated for such a deficiency.

Aspirin has been shown to inhibit osteolytic activity of human breast carcinoma in vitro, apparently by inhibiting the synthesis of prostaglandins that may mediate this activity. Supporting evidence for this effect and its mechanism has been obtained in patients with certain types of solid tumors (e.g., lung carcinoma) who developed hypercalcemia; in some of these patients, aspirin therapy has resulted in normalization of serum calcium concentrations and has been associated with a reduction in the urinary excretion of a metabolite of prostaglandin E.

Toxic doses of salicylates may stimulate corticosteroid secretion by the adrenal cortex through an effect on the hypothalamus and may transiently increase plasma concentrations of free corticosteroids by displacement from plasma proteins; however, the anti-inflammatory action of salicylates is not dependent on these effects.

Pharmacokinetics

Absorption

In general, salicylates are rapidly and well absorbed from the GI tract following oral administration. Although some absorption occurs from the stomach, salicylates are absorbed primarily from the upper small intestine via passive diffusion of un-ionized molecules (e.g., salicylic acid).

The rate of absorption of an orally administered salicylate depends on many factors, including dosage form and its formulation characteristics, gastric and intestinal pH, gastric emptying time, and the presence of food in the GI tract. The rate of absorption is generally most rapid with effervescent and noneffervescent aqueous solutions, followed by uncoated tablets (plain or with buffers) or film-coated tablets, and capsules; however, clinically significant therapeutic differences between these dosage forms or specific preparations have not been established. The rate of absorption is slowest for enteric-coated tablets, followed by extended-release tablets.

Dissolution is usually the rate-limiting process in the absorption of tablets containing salicylate; however, the in vitro dissolution rate of a specific preparation does not necessarily reflect the in vivo absorption rate. Dissolution depends on several factors such as pH in the GI tract and formulation characteristics of the preparation. An increase in gastric pH (e.g., as a result of concomitant administration of an antacid) enhances dissolution by increasing solubility of salicylate, but it may also decrease gastric absorption by increasing the degree of ionization of salicylate and decreasing gastric emptying time. The buffers contained in buffered aspirin tablets may increase pH in the microenvironment of aspirin particles and thereby increase solubility of the drug in surrounding GI fluids; as a result, the dissolution rate of the tablets may be increased. (See Pharmacokinetics: Absorption, in Aspirin 28:08.04.24.) Although the increased pH in the small intestine also increases dissolution and degree of ionization of salicylate, the high degree of ionization does not appear to limit the absorption of salicylate from the small intestine, probably because of the large surface area of the small intestine.

Other formulation characteristics of tablets (e.g., particle size, compression pressure) may have varied effects on the rate of absorption. In general, the smaller the particle size, the faster the absorption rate since the resultant increase in surface area of dissolving drug enhances the rate of dissolution. Since enteric-coated tablets are formulated to resist dissolution in the stomach and thereby lessen gastric irritation, the rate of absorption from this dosage form is usually decreased compared to uncoated tablets. Absorption of aspirin from extended-release tablets is delayed and prolonged. Since salicylates are absorbed primarily from the upper small intestine, the rate of absorption is generally slower when gastric emptying time is increased, and faster when gastric emptying time is decreased (e.g., by metoclopramide or when gastric pH is increased by concomitant administration of an antacid). Gastric emptying time may be partially dependent on salicylate dosa in overdosage, there is some evidence that salicylates may remain in the stomach for as long as 10 hours if not removed. Food delays absorption and decreases the rate, but not the extent, of absorption of orally administered salicylates.

In general, solid oral dosage forms of aspirin are 80-100% absorbed. Although well-designed bioavailability studies are generally lacking, solid oral dosage forms of most other salicylates also appear to be 80-100% absorbed. Oral aqueous solutions of aspirin or other salicylates appear to be completely absorbed. There is some evidence that absorption of salicylate following oral administration may be substantially impaired or is highly variable during the febrile phase of Kawasaki disease. Following rectal administration, salicylates are slowly and variably absorbed; the extent of absorption increases with increasing rectal retention time. Methyl salicylate, salicylic acid, and trolamine salicylate are rapidly and well absorbed percutaneously following topical application.

Salicylates are detected in serum within 5-30 minutes after oral administration of rapidly absorbed dosage forms (e.g., aqueous solutions, uncoated or film-coated tablets), and peak serum salicylate concentrations are usually attained within 0.25-2 hours, depending on dosage form and specific formulation. Although some rapidly absorbed dosage forms (e.g., aqueous solutions) may produce slightly higher peak serum salicylate concentrations than others (e.g., uncoated tablets), clinically significant therapeutic differences between such dosage forms or between specific preparations have not been established. However, if a rapid response is required (e.g., analgesic effect), the more slowly absorbed dosage forms (i.e., enteric-coated tablets, extended-release tablets) should not be used.

In general, analgesic and antipyretic effects of single oral doses of rapidly absorbed salicylates begin within 30 minutes, peak at 1-3 hours, and persist for 3-6 hours. Following rectal administration of aspirin as a suppository, the antipyretic effect generally begins within 1-2 hours, peaks at 4-5 hours, and may persist 7 or more hours. In patients with inflammatory diseases, the onset of anti-inflammatory effect generally occurs within 1-4 days of continuous oral salicylate therapy. The time required to achieve optimum anti-inflammatory effect depends principally on the attainment and maintenance of adequate serum salicylate concentrations; several weeks or longer may be required in some patients.

Onset, intensity, and duration of analgesic, antipyretic, and anti-inflammatory effects of single doses of salicylates do not directly coincide with the time course of serum salicylate concentrations; however, these effects appear to be related to total (protein-bound and free) serum salicylate concentration. The usual total serum salicylate concentration associated with analgesia and antipyresis is 30-100 mcg/mL. The usual total serum salicylate concentration required for anti-inflammatory effect is 150-300 mcg/mL; however, in the treatment of rheumatic fever, many clinicians believe a total serum salicylate concentration of 250-350 mcg/mL is associated with optimum therapeutic effects. Although many adverse effects are not well correlated with serum salicylate concentrations, most patients experience toxicity when the total serum salicylate concentration exceeds 300-350 mcg/mL. Because of large interindividual and intraindividual variations in the saliva to serum salicylate concentration ratio, salivary salicylate concentrations are generally not useful.

There is limited evidence from animal studies that the pharmacologic effects of salicylates are produced by free salicylate; however, serum concentrations of free salicylate are technically difficult to obtain and have not been clearly correlated with therapeutic effects. Measurements of serum free salicylate concentration may be useful in some patients with documented or suspected alterations in salicylate protein-binding (e.g., patients with extremely low serum albumin concentrations).

Distribution

Salicylates are rapidly distributed throughout extracellular fluid and into most body tissues and fluids, with high concentrations in the liver and kidneys. During absorption from the stomach, salicylate concentrations in gastric mucosal cells may be 15-20 times higher than concentrations within the gastric lumen. Salicylate can be detected in synovial, peritoneal, and cerebrospinal fluids.

The apparent volume of distribution of salicylate is generally 0.15-0.2 L/kg at usual therapeutic concentrations but may be higher in neonates. The volume of distribution appears to increase with increasing doses and/or serum concentration of salicylate. This increase with increasing doses and/or serum concentration may be due in part to decreased binding of salicylate to serum proteins. The volume of distribution is decreased in patients with decreased serum albumin concentrations and is also affected by plasma and tissue pH.

Distribution of salicylate occurs principally by pH-dependent processes; studies in animals have shown that the tissue-to-plasma distribution ratio of salicylate is increased when plasma pH is greater than that of tissue and decreased when plasma pH is less than that of tissue. Since a large fraction of salicylate in blood is ionized at normal pH, it usually crosses the blood-brain barrier slowly. However, when blood pH is decreased from 7.4 to 7.2, the amount of un-ionized salicylate in blood increases about twofold. Since acidosis often occurs in salicylate overdosage, pH-dependent distribution of salicylate into the CNS and other tissues must be considered. Salicylate is actively transported out of CSF across the choroid plexus by a low-capacity, saturable process.

Salicylate is rapidly distributed into synovial fluid. The principal mechanism of distribution from blood into synovial fluid appears to be passive diffusion. Following single oral doses, salicylate concentrations attained in synovial fluid are about 50-75% of peak serum concentrations. At steady-state, free salicylate concentrations in synovial fluid and serum are approximately equal; however, the total salicylate concentration in synovial fluid is slightly less than in serum because of decreased protein binding of salicylate in synovial fluid.

Salicylate is variably bound to serum proteins, mainly albumin. The fraction bound to serum proteins depends on both the serum salicylate and serum albumin concentrations; even with comparable serum albumin concentrations at a specific serum salicylate concentration, there are interindividual differences in the amount of drug bound. In healthy individuals, salicylate is approximately 90-95% bound to serum proteins at serum salicylate concentrations up to 100 mcg/mL; approximately 70-85% bound to serum proteins at serum salicylate concentrations of 100-400 mcg/mL; and possibly as little as 25-60% bound to serum proteins at higher serum salicylate concentrations. As a result of decreased serum albumin concentrations, serum protein binding of salicylate is decreased and the free fraction is increased in pregnant women, neonates, anephric patients, patients with impaired renal function, and patients with inflammatory diseases. In pregnant women, anephric patients, and patients with impaired renal function, salicylate may be displaced from serum proteins by accumulating endogenous compounds. Protein binding of salicylate is lower in synovial fluid than in serum, possibly as a result of decreased concentrations of albumin in synovial fluid and/or decreased affinity of salicylate for binding sites on synovial fluid proteins.

Salicylate readily crosses the placenta and fetal serum salicylate concentrations may exceed maternal serum concentrations. During chronic oral administration, salicylate may be distributed throughout fetal tissues in concentrations higher than those in the mother.

Salicylate is distributed into milk; however, the extent of distribution into milk is not clearly established. In one study, peak concentrations of salicylate in milk were only 2-5% of peak maternal plasma concentrations. In another study, peak salicylate concentrations in milk were 170-480 mcg/mL at 5-8 hours following maternal ingestion of a single 650-mg dose of aspirin; concurrent maternal plasma concentrations were not reported.

Elimination

Salicylate is metabolized principally in the liver by the microsomal enzyme system. Salicylate is predominantly conjugated with glycine to form salicyluric acid (salicylurate). Salicylate is also conjugated with glucuronic acid to form salicyl phenolic glucuronide and salicyl acyl glucuronide. In addition, small amounts of salicylate are hydroxylated to form 2,5-dihydroxybenzoic acid (gentisic acid), 2,3-dihydroxybenzoic acid, and 2,3,5-trihydroxybenzoic acid. Gentisuric acid, formed either by conjugation of gentisic acid with glycine or by hydroxylation of salicyluric acid, has also been identified as a minor metabolite. Of the salicylate metabolites, only gentisic acid appears to be active; although gentisic acid is a potent inhibitor of prostaglandin synthesis, its contribution to the clinical effects of salicylate is generally considered insignificant because only small amounts are formed. Salicyluric acid and salicyl phenolic glucuronide are formed by capacity-limited (saturable) processes which can be characterized by Michaelis-Menten kinetics. Other salicylate metabolites appear to be formed by first-order processes.

As a result of the capacity-limited processes, steady-state serum salicylate concentrations increase more than proportionally with increasing doses. The time required to attain steady-state concentrations also increases with increasing doses since the apparent serum half-life of salicylate increases with increasing serum salicylate concentration. With low doses (e.g., 325 mg of aspirin), elimination of salicylate is a first-order process and serum salicylate half-life is approximately 2-3 hours; however, with higher doses, elimination of salicylate is capacity limited and the apparent serum salicylate half-life may increase to 15-30 hours. Because of decreased serum protein binding, the effect of increasing doses is more pronounced on the free serum salicylate concentration than on the total serum salicylate concentration. However, in healthy adults, it has been shown that total serum salicylate clearance remains relatively constant at serum salicylate concentrations of 100-300 mcg/mL. The following pharmacokinetic parameters for adults, expressed in concentrations of salicylate and amounts of salicylate metabolized, have been reported for the Michaelis-Menten variables that characterize the capacity-limited metabolism of salicylate: the Michaelis-Menten constant (K_m) for salicyluric acid formation is approximately 5 mg/L; the maximum rate (V_max) of salicyluric acid formation is approximately 800-900 mcg/kg per hour (but may increase with long-term therapy, possibly as a result of enzyme induction); the Michaelis-Menten constant (K_m) for salicyl phenolic glucuronide formation is approximately 9 mg/L; and the maximum rate (V_max) of salicyl phenolic glucuronide formation is approximately 400 mcg/kg per hour. Specialized references should be consulted for more specific information on salicylate pharmacokinetics.

Genetically determined differences in salicylate metabolism have been reported. There is some evidence that salicylate may induce its own metabolism, as suggested by increased formation of salicyluric acid and decreased serum salicylate concentrations during long-term therapy. Although not clearly established, it has been reported that salicylate is eliminated more slowly by women. The elimination rate of salicylate is reduced in neonates compared to adults, apparently because neonatal metabolic and excretory pathways are incompletely developed; however, prolonged fetal exposure to salicylate resulting from chronic maternal ingestion of salicylate during pregnancy may increase the rate of development of fetal mechanisms of salicylate elimination.

Salicylate and its metabolites are rapidly and almost completely excreted in urine. Trace amounts of salicylate are also excreted in sweat, saliva, and feces. In patients with normal renal function, 80-100% of a single dose is excreted in the urine within 24-72 hours. The relative amounts of salicylate and its metabolites excreted in the urine are extremely variable, being dependent on the dose administered and urine pH. Following a single oral dose of salicylate of less than 10 mg/kg in patients with normal renal function, about 10% of the dose is excreted in urine as unchanged salicylate, 75% as salicyluric acid, 10% as salicyl phenolic glucuronide, 5% as salicyl acyl glucuronide, and less than 1% as gentisic acid and gentisuric acid. With higher single doses or long-term therapy, the proportions excreted in urine as unchanged salicylate, salicyl acyl glucuronide, and gentisic acid generally increase as a result of capacity-limited formation of salicyluric acid and salicyl phenolic glucuronide.

Unchanged salicylate and its metabolites are excreted in the urine via glomerular filtration and renal tubular secretion; since unchanged salicylate also undergoes renal tubular reabsorption, its urinary excretion is markedly pH dependent. As urine pH increases from 5 to 8, the urinary excretion rate of salicylate is greatly increased and the fraction of a single dose excreted in the urine as unchanged salicylate may increase from 5-10% to 85%. Therefore, concomitant administration of drugs that alter urine pH may have substantial effects on serum salicylate concentrations. (See Drug Interactions: Acidifying and Alkalinizing Agents.)

In patients with normal renal function, salicylate metabolites are excreted in the urine as rapidly as they are formed. Although anephric patients appear to eliminate small doses of salicylate (e.g., 650 mg of sodium salicylate) as rapidly as healthy individuals, the pharmacokinetics of salicylate in patients with severe renal impairment have not been clearly established and salicylates are usually avoided in these patients.

Salicylate and its metabolites are readily removed by hemodialysis and, to a lesser extent, by peritoneal dialysis.

Chemistry and Stability

Chemistry

Salicylates are nonsteroidal anti-inflammatory agents (NSAIAs) that are synthetic derivatives of salicylic acid. The drugs hydrolyze or dissociate to salicylate (ionized salicylic acid) in vivo. Salicylic acid is not used systemically because of its severe irritating effect on GI mucosa and other tissues; therefore, better tolerated chemical derivatives have been prepared for systemic use.

The pharmacologic actions of salicylates appear to result principally from the salicylate moiety. The carboxyl group and an adjacent hydroxyl group on salicylic acid are necessary for activity; either or both groups may have substituents. The currently available salicylates are either esters of organic acids derived by substitution at the hydroxyl group of salicylic acid, or esters or salts of salicylic acid derived by substitution at the carboxyl group. Aspirin, the prototype of the salicylates, is the salicylate ester of acetic acid; the drug hydrolyzes to salicylate and acetate. Salsalate is the salicylate ester of salicylic acid; the drug hydrolyzes to 2 molecules of salicylate. Many commercially available salicylate preparations contain salts of salicylic acid (e.g., choline salicylate, magnesium salicylate, sodium salicylate, trolamine salicylate) which dissociate to form salicylate. Although related to the salicylates structurally and pharmacologically, diflunisal, salicylamide, and probably sodium thiosalicylate are not hydrolyzed to salicylate; therefore, these drugs are not considered true salicylates and are not included in this discussion.

Salicylic acid occurs as white crystals, usually in fine needles, or as a fluffy, white, crystalline powder. The drug has a sweetish taste and an acrid aftertaste and is slightly soluble in water and freely soluble in alcohol. The synthetic form is white and odorless; when prepared from natural methyl salicylate, the drug may have a slightly yellow or pink tint and a faint, mint-like odor. Salicylic acid has pK_as of 2.97 and 13.4. Most salicylates occur as white, crystalline powders and are practically insoluble to very soluble in water and soluble to freely soluble in alcohol.

Stability

Aqueous solutions of salicylates slowly darken in color due to oxidation; however, the color change appears to have no effect on efficacy or toxicity. Darkening of solutions of salicylates is delayed by the presence of 0.1% of sodium bisulfite, sodium sulfite, sodium thiosulfate, or sodium hypophosphite, or 0.5% sodium citrate. Addition of mineral acids to aqueous solutions of salicylates results in precipitation of salicylic acid.

AHFS^® Drug Information. © Copyright, 1959-2024, Selected Revisions September 16, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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section name header

Introduction ⬇

AHFS Class:

Associated Monographs

Uses ⬆ ⬇

Dosage and Administration ⬆ ⬇

Cautions ⬆ ⬇

Drug Interactions ⬆ ⬇

Other Information ⬆ ⬇

Copyright ⬆ ⬇

References ⬆