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Aspirin, the salicylic ester of acetic acid, was introduced into medicine in 1899 and is used for its analgesic, antiinflammatory, antipyretic, and antithrombotic effects. Once in the body, it is hydrolyzed to salicylate, which is also active. The antiinflammatory and analgesic effects of aspirin are roughly equivalent to those of many NSAIDs. Aspirin is used in the treatment of many inflammatory and autoimmune conditions such as juvenile arthritis, rheumatoid arthritis, and osteoarthritis. Because of its antithrombotic effects, aspirin is useful in preventing or reducing the risk of myocardial infarction and recurring transient ischemic attacks (TIAs). Aspirin was officially approved by the FDA in 1939. During most of this century, it was mainly used for its antiinflammatory and analgesic properties. In the 1980s, its ability to inhibit platelet aggregation was realized and it became an important antithrombotic agent. More recently, it has been shown that long-term (e.g., >= 10 years) regular consumption of aspirin may lower the risk of developing colorectal cancer. It is now thought that aspirin may possess antiproliferative actions. A sustained-release aspirin (Asacard) was approved for use in the UK in February 1998; phase I studies on this product were initiated in the US also in February 1998.
Mechanism of Action:
Classically, aspirin is known to possess analgesic, antiinflammatory, antiplatelet, and antipyretic properties. Biochemically, aspirin acetylates proteins. This is how aspirin interferes with arachidonate metabolism. Most pharmacology texts state that aspirin interferes with prostaglandin synthesis by irreversibly inhibiting cyclooxygenase, one of two major enzymes that act upon arachidonic acid. Cyclooxygenase exists in 2 isozymes: cyclooxygenase-1 or COX-1 and cyclooxygenase-2 or COX-2. These isozymes are encoded by different genes, reside in different sites (i.e., COX-1 occurs in endoplasmic reticulum, COX-2 is found in the nuclear envelope), and, not surprisingly, have different functions. COX-1 may be more important for hormonal regulation, hemostasis, and thrombosis, while COX-2 may be more important in the inflammatory response. Aspirin acetylates serine in both isozymes. Acetylated COX-1 can no longer generate prostaglandins. Acetylated COX-2, however, retains the ability to generate metabolites of arachidonic acid that are thought to possess antiproliferative effects. This latter mechanism may explain why aspirin has been found effective in reducing the risk of colorectal cancer. Since virtually all tissues can produce eicosanoids, the effects of aspirin are many and diverse. Non-salicylate NSAIDs also inhibit both isozymes of cyclooxygenase (i.e., COX-1 and COX-2), however the effects of these drugs are reversible and shorter-lived than the effects of aspirin. Finally, the effects of aspirin on platelet aggregation occur at doses much lower than those required for an antiinflammatory effect. Aspirin does not inhibit the actions of lipoxygenases, the other major enzyme class that acts on arachidonic acid.
Platelet-derived COX-1 (i.e., cyclooxygenase-1) generates thromboxane A2, a potent vasoconstrictor and platelet agonist. In contrast, endothelial cell COX-1 generates prostacyclin which possesses vasodilatory and antiplatelet actions. Platelet COX-1 is more sensitive than endothelial cell COX-1 is to this effect of aspirin and this distinction explains the recommendation for using very low doses of aspirin to retard platelet aggregation. Inhibiting platelet COX-1 without diminishing endothelial cell COX-1 is desirable in patients with coronary artery disease. Inhibition of platelet COX-1 results in decreased platelet aggregation, leading to a prolonged bleeding time. Hemostatic effects return to normal roughly 36 hours after the last dose of the drug.
The initiating event in unstable angina is thought to be rupture of an atherosclerotic plaque in the vessel wall. Platelet activation results, thrombin is generated, fibrin is formed, and ultimately a thrombus is produced. While aspirin is known to inhibit localized platelet aggregation secondary to its ability to block thromboxane-A2 synthesis, aspirin has little effect on thrombin-induced platelet aggregation, the mechanism thought to be responsible for ischemia during the acute phase of unstable angina. Aspirin, however, is nonetheless recommended for chronic administration in patients with a known history of coronary artery disease. More recently, it has been proposed that the beneficial effect of aspirin in MI prophylaxis might be related to its ability to reduce circulating levels of C-reactive protein. In very high and toxic doses, aspirin also exerts a direct inhibitory effect on vitamin K-dependent hemostasis. Prothrombin synthesis is impaired, resulting in hypoprothrombinemia.
The antiinflammatory action of aspirin is believed to be a result of peripheral inhibition of prostaglandin synthesis, but aspirin may also inhibit the action and synthesis of other mediators of inflammation. Aspirin acetylates both COX-1 and COX-2. It is thought that COX-2 is the more important pathway for the inflammatory response since COX-2 is inducible in settings of inflammation by cytokines. Inhibition of COX-2 by aspirin depresses the production of prostaglandins of the E and F series. These prostaglandins induce vasodilation and increase tissue permeability, which, in turn, promote the influx of fluids and leukocytes. Ultimately, the classic symptoms of inflammation result: swelling, redness, warmth, and pain. Aspirin can not only decrease capillary permeability (which reduces swelling and the influx of inflammatory mediators), but it can also reduce the release of destructive enzymes from lysozymes.
The analgesic property of aspirin is thought to be mainly a result of peripheral actions but direct effects on the CNS are possible.
Antipyretic effects of aspirin are a result of inhibition of prostaglandin synthesis in the hypothalamus but may also be a result of aspirin-induced peripheral vasodilation and sweating.
Even though aspirin acetylates COX-2 (e.g., cyclooxygenase-2), acetylated COX-2 retains the ability to metabolize arachidonic acid to produce the monohydroxy fatty acid 15R-hydroxyeicosatetraenoic acid (15R-HETE). Hydroxy fatty acids are thought to have antiproliferative effects. It is unclear if aspirin's prostaglandin-reducing effect contributes to its antitumor activity.
Salicylates act on the renal tubules to affect uric acid excretion. In lower doses (e.g., 1-2 g/day), salicylates inhibit the active secretion of uric acid into the urine via the proximal tubules. At high doses (> 5 g/day), salicylates inhibit the tubular reabsorption of uric acid, resulting in a uricosuric effect. Uric acid secretion is not changed at intermediate dosages. While once used for their uricosuric properties, salicylates have been replaced by other agents for this purpose.
In the treatment of vernal conjunctivitis, aspirin prevents the formation of prostaglandin D2, a secondary mast cell mediator of allergic conditions. Finally, at high-therapeutic and at toxic doses, aspirin can affect oxidative phosphorylation, however, this action is insignificant at lower doses. Single doses of aspirin do not exert detrimental effects on exercise metabolism or exercise performance.
Aspirin is usually administered orally in adults, but can be given rectally as suppositories in children. It is rapidly absorbed from the gastrointestinal tract, although its intragastric concentration and the pH of gastric contents influence the rate of absorption. Also, larger doses take longer to dissolve. Aspirin is partially hydrolyzed to salicylate on the first pass through the liver and is widely distributed into most body tissues. Aspirin is poorly bound to plasma proteins, but it should be used cautiously in patients already receiving other highly protein-bound drugs such as warfarin (see Drug Interactions).
Following oral administration and depending on dosage form, salicylate can be present in serum within 5-30 minutes, and peak serum concentrations are attained within 0.25-2 hours. Steady-state salicylate serum concentrations are similar after administration of plain, uncoated tablets and enteric-coated tablets. Serum salicylate concentrations of at least 100 Ķg/ml are required for analgesia, and concentrations of roughly 150-300 Ķg/ml are necessary for antiinflammatory effects. Tinnitus can occur when salicylate concentrations reach 300 Ķg/ml, and this can be used as a monitoring parameter in patients with normal hearing. Severe toxic side effects can occur at concentrations greater than 400 Ķg/ml.
Aspirin is 99% metabolized to salicylate and other metabolites. The elimination half-life of aspirin in plasma is about 15-20 minutes. Salicylate, but not aspirin itself, undergoes Michaelis-Menten (saturable) kinetics. At low doses, the elimination is first-order and the half-life remains constant at 2-3 hours; however, at higher doses, the enzymes responsible for metabolism become saturated and the apparent half-life can increase to 15-30 hours. Because of this, 5-7 days may be required before a steady-state concentration is reached. Salicylate and its metabolites are excreted primarily by the kidneys. Almost all of an ingested dose is excreted in the urine. About 75% of the aspirin and sodium salicylate found in the urine is comprised of salicyluric acid, while about 15% is in the form of mono- and diglucuronides. The remaining 10% consists of free salicylate. The excretion of salicylate (but not other metabolites) is enhanced by alkalinization of the urine.
For the treatment of acute-onset headache pain including migraine:
Adults: 900 mg PO at the onset of the migraine has been recommended. When metoclopramide was administered concomitantly to overcome gastric stasis that occurs during a migraine attack, aspirin 900 mg PO.
WARNING: Acute overdoses of Aspirin are toxic and. Furthermore, Aspirin and other OTC (over the counter) medications are too weak for addressing moderate or severe Migraine pain and MUST be avoided as this practice can lead to painful Rebound headaches. Rebound headache a trigger, or re-trigger Migraines leading to chronic daily headache. Do not exceed recommended daily dosage.
NOTE: If Aspirin is not effective for your Migraine pain, discuss a more appropriate pain management medication with your physician.
For the treatment of rheumatoid arthritis or osteoarthritis in adults:
Adults: 2.6-5.4 g PO per day in 4 or more divided doses.
For the treatment of juvenile rheumatoid arthritis (JRA):
Oral or rectal dosage:
Children weighing 25 kg or less: 60-90 mg/kg/day PO or PR in divided
For the treatment of mild pain or fever:
Oral or rectal dosage:
Adults: 325-650 mg PO or PR every 4 hours, as needed.
For stroke prophylaxis:
Adults: A dose of 650 mg PO bid or 325 mg PO qid is commonly used, however, substantial controversy exists regarding the appropriate dose of aspirin in this setting. In 1991, The Dutch TIA Trial Study Group published results of a comparison of 2 doses of aspirin (e.g., 30 mg PO once daily vs 283 mg PO once daily) and found that the lower dose was no less effective than the higher dose. However, this study was criticized by one reader since it was not clear that aspirin provided benefit at either dose.
Adults: The efficacy of aspirin to prevent stroke in patients with atrial fibrillation is not clear. The Stroke Prevention in Atrial Fibrillation (SPAF) study found a dose of 325 mg PO enteric-coated aspirin once daily to be effective but a lower dose of 75 mg/day was not beneficial in the Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation (AFASAK) study. This latter study, however, enrolled fewer patients and confidence intervals were wide. In 1993, the European Atrial Fibrillation Trial Study Group showed that aspirin 300 mg/day was slightly better than placebo, but these results were not statistically significant. Although anticoagulation with warfarin (INR 2.5-4.0) was superior to aspirin, the authors concluded aspirin could be used in lieu of warfarin when warfarin anticoagulation is contraindicated.
For arterial thromboembolism prophylaxis in combination with warfarin in patients with prosthetic heartvalves:
Adults: NOTE: Warfarin is considered the primary agent for prevention of systemic embolism in recipients of mechanical heart valves - therapy with antiplatelet agents alone is not effective. A randomized, double-blind, placebo-controlled study, published in 1993, demonstrated that the addition of enteric-coated, slow-release aspirin 100 mg/day PO to warfarin provided better reduction of morbidity and mortality than warfarin alone (i.e., warfarin plus placebo). The combination of warfarin with aspirin was also associated with an increased risk of bleeding as compared to warfarin alone.
For the treatment of an evolving acute myocardial infarction:
Adults: The American College of Chest Physicians, the American College of Cardiology, and the American Heart Association all recommend that 160-325 mg non-enteric-coated aspirin be chewed and swallowed as soon as possible after the diagnosis of acute MI is made and repeated once daily indefinitely, regardless if thrombolytic therapy will be given. If heparin is to be given, aspirin should be used concomitantly; if warfarin is to be given, aspirin should be withheld until the course of therapy has been completed.
For myocardial infarction prophylaxis:
Adults: Some clinicians have recommended patients at high risk of myocardial infarction take a single oral or rectal dose of aspirin at the first sign of chest pain unresponsive to sublingual nitroglycerin, however, a specific dose of aspirin has not been established. Aspirin doses of 325 mg PO bid and 162.5 mg PO once daily have been studied for the acute treatment of unstable angina. In healthy men, several combinations of loading and maintenance doses were studied; a loading dose of 300 mg PO, followed by 40 mg/day PO was found optimum to inhibit platelet aggregation and thromboxane synthesis. Aspirin, however, may not be as effective for unstable angina as therapeutic anticoagulation. A comparison of aspirin 325 mg PO bid versus therapeutic heparin to prevent acute MI, initiated within an average of 8.3 hrs of symptoms, showed that myocardial infarction occurred in significantly fewer patients receiving heparin than in the group receiving aspirin. A separate study demonstrated that aspirin 162.5 mg PO once daily with therapeutic anticoagulation was more effective than aspirin 162.5 mg PO once daily without anticoagulation in patients with unstable angina. Therapy was initiated within 48 hrs of onset of chest pain and continued for 12 weeks in both study groups. Total ischemic events were less in the combination therapy group than in the aspirin-only group at both 14 days and 12 weeks although this difference was not statistically significant at 12 weeks. A meta-analysis published in 1996 revealed that combining therapeutic heparin with aspirin was better than aspirin alone. The doses of aspirin in the 6 studies included in the meta-analysis ranged from 75 mg PO once daily to 325 mg PO bid.
Adults: 160-325 mg PO once daily is recommended by the American College of Cardiology and the American Heart Association. In July 1996, the FDA proposed an amendment to labeling for aspirin to include the use of aspirin post-myocardial infarction. A dose of 162.5 mg PO once daily is recommended, beginning once a myocardial infarction is determined and continuing for 30 days. NOTE: While the optimal dose of aspirin for this condition has yet to be established, a study found aspirin 75 mg/day more effective than placebo in reducing nonfatal myocardial infarctions and vascular events. There was also a trend toward fewer sudden deaths in the aspirin group.
Adults: Antiplatelet therapy was compared to anticoagulation in patients receiving aspirin for placement of a coronary artery stent following PTCA (i.e., ticlopidine plus aspirin was compared to phenprocoumon plus aspirin). Cardiac events and hemorrhagic complications were both lower in the ticlopidine-aspirin group. The aspirin dose in this 4-week study was 100 mg PO bid.
Patients with renal impairment:
Aspirin has been associated with the occurrence of Reye's syndrome when given to children with varicella (chickenpox) or influenza (flu). Although a causal relationship has not been confirmed, most authorities advise against the use of aspirin in children with chickenpox, flu, or other viral infection. If children are receiving chronic aspirin therapy, aspirin should be discontinued immediately if a fever develops, and not resumed until diagnosis confirms that the febrile illness has run its course and absence of Reye's syndrome.
Aspirin inhibits platelet aggregation and, in high doses, affects vitamin K-dependent coagulation. The combination of its effects on hemostasis with its potential for causing GI mucosal damage, there is a risk of gastrointestinal injury or bleeding in patients who receive aspirin. Because of this, aspirin should be avoided or used cautiously in patients with peptic ulcer disease or underlying anemia. Since aspirin inhibits platelet aggregation and increases bleeding time, aspirin should be administered cautiously to patients with preexisting thrombocytopenia, hemophilia or other coagulopathy. It should also be avoided in patients with aplastic anemia or pancytopenia or other forms of bone marrow depression. Aspirin should be discontinued at least 1 week before surgery to minimize postoperative bleeding. Finally, intramuscular injections should be administered cautiously to patients receiving aspirin. IM injections may cause bleeding, bruising, or hematomas due to aspirin-induced inhibition of platelet aggregation.
Because salicylates may cause or aggravate hemolysis in patients with G6PD deficiency, some reference texts state that aspirin should be used cautiously in these patients. If hemolytic anemia occurs in patients receiving aspirin, it almost always occurs in G6PD-deficient individuals. It appears that aspirin can induce hemolysis at therapeutic concentrations if other oxidative stressors are present. Otherwise, hemolysis only occurs at much higher concentrations.
Liver function should be monitored in patients receiving large doses of aspirin (e.g., for treatment of rheumatoid arthritis) or in patients with preexisting hepatic disease in order to prevent reversible, dose-dependent hepatotoxicity. Large doses also can cause hypoprothrombinemia, which can be reversed by vitamin K. Similarly, patients with renal insufficiency, renal failure, or vitamin K deficiency should be closely monitored if taking large doses of aspirin.
Patients with a tartrazine dye hypersensitivity or aspirin hypersensitivity should avoid aspirin. Patients with aspirin-induced nasal polyps or with allergic reactions (e.g. urticaria) to aspirin are at risk of developing bronchoconstriction or anaphylaxis and should not receive aspirin. Patients with asthma are at risk of developing severe and potentially fatal exacerbations of asthma after taking aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs). Aspirin and other NSAIDs should be avoided in asthmatics with a history of aspirin-induced bronchoconstriction.
Aspirin recently was studied as an agent to prevent preeclampsia in women who were 13--26 weeks pregnant. Its efficacy in preventing preeclampsia was only marginal, and a higher risk of developing abruptio placentae was seen. There were no differences between groups in birth weight or rates of fetal growth retardation, neonatal bleeding, or postpartum hemorrhage. Nevertheless, aspirin is classified as pregnancy category C during the first and second trimesters and should be used cautiously. Aspirin has also been found to increase the risk of perinatal mortality, intrauterine growth retardation, and postmaturity syndrome (fetal damage or death due to decreased placental function in prolonged pregnancy). In addition, studies have indicated that regular use of aspirin late in pregnancy may result in constriction or premature closure of the fetal ductus arteriosus. Due to the risks involved, aspirin should be considered pregnancy category D during the third trimester of pregnancy. Salicylates are excreted into breast milk and could cause adverse effects in infants. The occasional use of aspirin at recommended dosage poses little danger to the nursing infant. However, breast-feeding should be avoided during prolonged high-dose aspirin therapy.
Several interactions occur between acetazolamide and aspirin. Salicylates displace acetazolamide from plasma protein binding sites and also decrease acetazolamide renal excretion. Conversely, acetazolamide may increase the renal elimination of salicylates by increasing urinary pH. Aspirin can precipitate acetazolamide CNS toxicity, however, the effects of acetazolamide on aspirin may not be clinically significant.
The risk of bleeding is increased if aspirin is administered to patients already receiving anticoagulants. Aspirin can displace warfarin from protein-binding sites and can increase the risk of bleeding during heparin or warfarin therapy because of its effect on platelet aggregation. Aspirin-induced GI bleeding may be worse in anticoagulated patients. Also, aspirin, in high-doses, has a hypoprothrombinemic effect. Aspirin and warfarin may be used together, however, if aspirin is administered before warfarin therapy is begun. Combination therapy with both aspirin and warfarin has been shown to reduce mortality compared to warfarin therapy alone in patients with artificial heart valves. The anticoagulant effect of heparin can be potentiated by aspirin however these two agents are often used together in the treatment of acute myocardial infarction. Regarding thrombolytic agents, while the risk of bleeding is increased if aspirin is coadministered, it is likely that a high percentage of patients who receive thrombolytic agents will be already receiving aspirin.
Concomitant ingestion of ethanol and aspirin increases the risk of developing gastric irritation and GI mucosal bleeding. Both agents are mucosal irritants and aspirin decreases platelet aggregation. Routine ingestion of ethanol and aspirin can cause significant GI bleeding which may or may not be overt. Even occasional concomitant use of these two agents should be avoided. Chronic alcoholism is often associated with hypoprothrombinemia and this condition increases the risk of aspirin-induced bleeding. The action of either agent on the pharmacokinetics of the other is unclear at this time.
Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood sugar. This mechanism may explain how salicylates can potentiate the clinical effects of sulfonylures, however, displacement of sulfonylureas from protein binding sites has also been reported. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents.
Drugs that inhibit prostaglandin synthesis appear to interact with some, but not all, ACE inhibitors. Indomethacin has been shown to blunt the hypotensive effect of captopril in normal volunteers and patients withhypertension. Aspirin and other salicylates should also be expected to interfere with the antihypertensive effects of captopril.
In the kidney, salicylates undergo filtration, secretion, and reabsorption. It is well documented that as urinary pH increases, the renal excretion of salicylates increases dramatically. This effect on salicylate excretion is clinically significant not only for sodium bicarbonate but also for antacids such as magnesium-aluminum hydroxide. Substantial decreases in salicylate serum concentrations may result from concomitant administration of antacids, particularly when salicylates are administered in high doses. Antacids do not appear to affect the bioavailability of aspirin, but may cause earlier release of aspirin from enteric-coated products. Conversely, acidification of the urine by ammonium chloride may increase salicylate serum concentrations by increasing tubular reabsorption of salicylate, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
In the kidney, salicylates undergo filtration, secretion, and reabsorption. Tubular secretion also affects the clearance of other drugs and endogenous substances into the urine. Salicylates may affect tubular secretion when administered in high doses. The hyperuricemic action of salicylates and antagonism of the uricosuric action of probenecid are both more likely to occur at higher salicylate serum concentrations. Aspirin has been shown to inhibit the active tubular secretion of canrenone, the active metabolite of spironolactone, however, this effect on canrenone pharmacokinetics did not compromise the clinical action of spironolactone significantly. Thus, drug interactions of this type may depend largely on salicylate doses and the resulting serum concentrations. Salicylates may antagonize either the effect of drugs on tubular secretion or the ability of tubular secretion to deliver another drug to its site of action.
While there is controversy regarding the ulcerogenic potential of corticosteroids (e.g., prednisone and others) alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin. Although studies involving aspirin were not included, a meta-analysis published in 1991 revealed that concomitant use of corticosteroids increased the risk of adverse GI events due to NSAIDs. Combinations of aspirin with corticosteroids may be just as likely as combinations of nonsalicylate NSAIDs with corticosteroids to cause gastric mucosal injury since aspirin has been shown to cause more gastropathy than nonsalicylate NSAIDs independent of a contributing effect of corticosteroids. The use of aspirin together with nonsalicylate NSAIDs (e.g., indomethacin and others) can lead to additive GI toxicity. Aspirin has been shown to reduce plasma concentrations of many nonsalicylate NSAIDs however, this pharmacokinetic interaction may not be significant. Corticosteroids or NSAIDs should be used cautiously in patients receiving aspirin.
Renal excretion of unmetabolized drug is the major route of elimination of methotrexate. Filtration, tubular secretion, and tubular reabsorption are all involved and all three processes are also involved in aspirin excretion. Aspirin delays the renal elimination of methotrexate, perhaps by interfering with tubular secretion. Due to the potential seriousness of this interaction, aspirin should never be given to a patient receiving high-dose methotrexate. Many rheumatologists, however, use these drugs together safely since methotrexate is used in low doses for the treatment of rheumatic conditions.
Niacin, vitamin B3, is known to cause cutaneous flushing at doses greater than the RDA. This cutaneous vasodilation is thought to be mediated by prostacyclin. Pretreatment with aspirin inhibits this unpleasant adverse effect of high-dose niacin.
Aspirin in large doses can displace phenytoin from protein-binding sites, although the clinical effect appears to be minor. It is possible that the reduction in phenytoin protein binding is offset by a corresponding increase in clearance of free phenytoin.
Salicylates exert several effects on valproic acid pharmacokinetics. Salicylates can displace valproic acid from protein binding sites and may inhibit valproic acid hepatic metabolism. Both mechanisms increase serum valproic acid concentrations and valproic acid toxicity has been noted shortly after the addition of aspirin. Patients should be monitored for valproic acid toxicity if aspirin is added or for loss of anticonvulsant effect if aspirin is discontinued during valproic acid therapy.
Symptomatic GI disturbances occur in 210% of healthy individuals receiving normal doses of aspirin for analgesia or fever, 1030% of individuals receiving doses greater than 3.6 grams/day, and 3090% of patients with preexisting peptic ulcer gastritis or duodenitis. Nausea/vomiting, dyspepsia, abdominal pain and other gastric distress can be reduced if aspirin is taken with food or a full glass of water. Penetration of the gastric mucosal cell by unionized molecules is necessary for aspirin to cause damage. Raising the intragastric pH increases the amount of aspirin in the unionized form, and some data indicate that agents such as cimetidine or antacids can reduce mucosal injury from aspirin. Gastric or duodenal ulcers up to 1 cm in diameter induced by salicylates may heal despite continued therapy when oral cimetidine or high dose antacids are used concomitantly. Duodenal mucosal damage appears to be less common when enteric-coated tablets are used when compared with buffered or uncoated tablets.
GI bleeding can be minor or life-threatening and may result from a combination of direct irritant action on the stomach mucosa and a prolonged bleeding time. In general, the severity of GI bleeding with aspirin is dose-related. Occult GI bleeding occurs in many patients and is not necessarily correlated with GI distress. While the amount of blood lost is usually not significant, blood loss can result in iron deficiency anemia. GI bleeding is more common with aspirin than with other salicylates and is not reduced by administering aspirin with food. Blood loss, however, may be reduced by using enteric-coated or sustained-release products or by administering cimetidine concomitantly.
Tinnitus, hearing loss, and dizziness are an indication that blood salicylate concentrations are reaching or exceeding the upper limit of the therapeutic range. Tinnitus is commonly seen when serum salicylate concentrations exceed 300 Ķg/ml, but this side effect may not be detected in patients with preexisting hearing deficits. Tinnitus is dose-related and is usually completely reversible.
Patients with aspirin hypersensitivity can develop symptoms within 3 hours of ingestion. Aspirin hypersensitivity, however, is uncommon and occurs in only 0.3% of the general population. Patients with chronic urticaria have the highest incidence (20%), followed by patients with asthma (4%) and patients with chronic rhinitis (1.5%). Symptoms include urticaria, angioedema, bronchospasm, severe rhinitis and shock. Sensitivity is manifested primarily as bronchospasm in asthmatic patients and is most commonly associated with nasal polyps. The correlation of aspirin hypersensitivity, asthma, and nasal polyps is known as the aspirin triad.
Hepatotoxicity, presenting as hepatitis is a dose-related reaction and is usually reversible after discontinuation of aspirin therapy. Hepatic injury consists of mild, focal, cellular necrosis, eosinophilic degeneration of hepatocytes and portal inflammation, but the pharmacologic mechanism is not known. Hepatotoxicity is usually manifested as elevated hepatic enzymes and is usually mild; death or hepatic injury with encephalopathy, however, has occurred. The administration of salicylates to children with viral illnesses has been suspected of causing Reye'ssyndrome, a multisystem disorder evidenced by persistent vomiting, altered sensorium, elevated hepatic enzymes, hypoprothrombinemia, and hyperammonemia.
Aspirin may cause reversible decreases in renal blood flow and glomerular filtration rate in patients with impaired renal function or SLE. Although controversial, long-term therapy with aspirin has been associated with analgesic nephropathy characterized by renal papillary necrosis and interstitial nephritis. The pharmacologic mechanism of renal toxicity is not clear, but may be a result of medullary ischemia caused by the inhibition of renal prostaglandin synthesis or a direct cytotoxic effect. In overdose, aspirin has been reported to cause a reduction in creatinine clearance or acute tubular necrosis with renal failure. Although the pharmacologic mechanism is not known, aspirin has been reported to cause the urinary excretion of renal tubular epithelial cells, albuminuria, proteinuria and urinary excretion of leukocytes and erythrocytes. In usual doses, aspirin rarely causes important renal effects.
Dermatologic reactions to aspirin can occur, but these are uncommon. These reactions include urticaria, purpura, maculopapular rash, and erythema nodosum. Rarely, aspirin has been associated with Stevens-Johnson syndrome and toxic epidermal necrolysis.
Hematologic toxicity to aspirin has been reported. According to Myler's Side Effects of Drugs, thrombocytopenia secondary to aspirin was described in 27% of 95 reports of aspirin-induced blood disorders. Aplastic anemia and agranulocytosis were reported in 13.6% and 10%, respectively.
Salicylates can affect uric acid secretion and reabsorption by the kidney. Low doses (i.e., 12 g/day) inhibit tubular uric acid secretion and could cause hyperuricemia. Moderate doses (i.e., 23 g/day) have no effect on uric acid secretion or reabsorption, and high doses (i.e., >5 g/day) may increase uric acid secretion and decrease plasma uric acid concentration.
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