Antiinflammatory, Antipyretic

Description: Aspirin, the salicylic ester of acetic acid, is used for its analgesic, antiinflammatory, antipyretic, and antithrombotic effects. Once in the body, it is hydrolyzed to salicylate, which is also active. Aspirin is has been shown to have antiinflammatory and analgesic effects roughly equivalent to those of many NSAIDs. Aspirin is the preferred agent in treating pain and inflammation associated with juvenile arthritis, rheumatoid arthritis, and osteoarthritis and is the preferred salicylate in the treatment of fever, pleurisy, arthritis, and pericarditis in patients with systemic lupus erythematosus (SLE). Because of its antithrombotic and antiinflammatory effects, aspirin is useful in preventing or reducing the risk of myocardial infarction and recurring transient ischemic attacks (TIAs), and is considered to be the drug of choice for treating Kawasaki syndrome (mucocutaneous lymph node syndrome). In 1995, the results of a large-scale study of nurses revealed a small but significant trend showing long-term (e.g., " 10 years) regular consumption of aspirin may lower the risk of developing colorectal cancer. Aspirin was introduced into medicine in 1899 and was officially approved by the FDA in 1939.

Mechanism of Action: Aspirin interferes with prostaglandin synthesis by irreversibly inhibiting cyclooxygenase, unlike some NSAIDs that produce similar effects that are reversible and shorter-lived. Antipyretic effects of aspirin are a result of inhibition of prostaglandin synthesis in the hypothalamus. Aspirin also may enhance peripheral vasodilation and sweating. Antiinflammatory action is believed to be caused by peripheral inhibition of prostaglandin synthesis, but aspirin may also inhibit the action and synthesis of other mediators of inflammation. Inhibition of cyclooxygenase within platelets 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.

Today, aspirin is probably used more often for its antiplatelet effects than for its analgesic or antiinflammatory actions. 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, and fibrin is formed, utimately generating a thrombus. While aspirin is known to inhibit localized platelet aggregation secondary to blocking thromboxane-AA synthesis, aspirin has little effect on thrombin- induced platelet aggregation. It is thought that thrombin- mediated occlusion is responsible for ischemia during the acute phase of unstable angina. Since heparin does inhibit thrombin- induced aggregation, this may explain why heparin alone and anticoagulation combined with aspirin were both found more effective than aspirin alone in preventing MI 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.

Pharmacokinetics: Aspirin 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 æg/ml are required for analgesia, and concentrations of roughly 150- 300 æg/ml are necessary for antiinflammatory effects. Tinnitus can occur when salicylate concentrations reach 300 æg/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 æg/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.

CONTRAINDICATIONS/PRECAUTIONS: 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.

Because there is a risk of gastrointestinal hemorrhage occurring in patients with gastric ulcer, aspirin should be avoided in patients with peptic ulcer disease.

Aspirin inhibits platelet aggregation and increases bleeding time. Aspirin should be administered cautiously to hemophiliac patients and other patients with bleeding disorders. Aspirin should be discontinued at least 1 week before surgery to minimize postoperative bleeding.

Intramuscular injections should be administered cautiously to patients receiving aspirin. IM injections may cause bleeding, bruising, or hematomas due to platelet effects secondary to aspirin therapy.

Liver function should be monitored in patients receiving large doses (e.g., for rheumatoid arthritis) or 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.

In some patients, even normal doses can cause urticaria. Asthmatic symptoms can occur, especially in patients with nasal polyps. Patients with a tartrazine dye hypersensitivity should avoid aspirin.

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.

DRUG INTERACTIONS: 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 and warfarin may be used together, however, if aspirin is administered before warfarin therapy is begun. In addition, 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.

Large doses of aspirin can decrease blood glucose levels and could enhance the effect of oral hypoglycemics.

The activity of probenecid at the nephron membrane is antagonized by salicylates.

Although there is controversy regarding the ulcerogenic potential of corticosteroids (e.g., prednisone) alone, concomitant administration of corticosteroids and aspirin can increase the GI toxicity of aspirin. Similarly, the use of aspirin together with NSAIDs (e.g., indomethacin and others) can lead to additive GI toxicity.

Aspirin delays the renal elimination of methotrexate and therefore increases its toxicity. Due to the seriousness of this interaction, aspirin should never be given to a patient receiving high-dose methotrexate.

Aspirin in large doses can displace phenytoin from protein-binding sites, although the clinical effect appears to be minor.

Routine consumption of ethanol and aspirin can increase the risk of developing gastric irritation.

ADVERSE REACTIONS: Nausea/vomiting, dyspepsia, and other gastric distress can be reduced if aspirin is taken with food or a full glass of water. These effects occur less frequently during analgesic doses than after anti-rheumatic doses. 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. GI bleeding is more common with aspirin than with other salicylates and is not reduced by administering aspirin with food. 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.

Tinnitus is dose-related and usually is completely reversible. Tinnitus is most commonly seen when serum salicylate concentrations exceed 300 æg/ml, but this side effect may not be detected in patients with preexisting hearing deficits.

Bronchospasm can occur in patients with preexisting nasal polyps when given aspirin. This reaction can include urticaria and angioedema. Aspirin hypersensitivity, however, is uncommon.

Hepatotoxicity, presenting as hepatitis, is a dose-related reaction and is usually reversible after discontinuation of aspirin therapy. In addition, administration of salicylates to children with viral illnesses has been suspected of causing Reye's syndrome, a multisystem disorder evidenced by persistent vomiting, altered sensorium, elevated hepatic enzymes, hypoprothrombinemia, and hyperammonemia.

Dermatologic reactions can also occur, but these are uncommon. These reactions include urticaria, purpura, maculopapular rash, and erythema nodosum.

Although uncommon, aspirin has been associated with interstitial nephritis and thrombocytopenia.

PATIENT INFORMATION:

What do aspirin tablets or capsules do?

Aspirin (Ascription^TM , Aspergum^TM , Bayer^TM , Bufferin^TM , Easprin^TM , Ecotrin^TM , Empirin^TM , Genprin^TM , Zorprin^TM ) affects the body in several ways; it eases symptoms of fever, pain, and inflammation (swelling and redness) and reduces the ability of the blood to clot. Aspirin relieves the mild to moderate discomfort caused by a variety of conditions including arthritis, headaches, infections, menstrual cramps or pain, minor injuries, and other conditions. It can also be part of a total treatment aimed at reducing the risk of heart attacks or stroke. Generic aspirin is available as tablets or capsules. They can be enteric-coated, extended-release, chewable, or effervescent.

What should my doctor, dentist, or pharmacist know before I take aspirin?

They need to know if you have any of these conditions:

• bleeding or clotting problems
• kidney disease
• liver disease
• nasal polyps
• receiving intramuscular injections
• skin problems
• stomach ulcers
• viral illness, such as flu, or chickenpox
• vitamin K deficiency
• an unusual or allergic reaction to aspirin, tartrazine dye, other medicines, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding

How should I take this medicine?

Take aspirin tablets or capsules by mouth. Follow the directions on the prescription label.

• Swallow regular tablets or capsules with a drink of water.
• Extended-release tablets or capsules must be swallowed whole; do not crush or chew.
• Chewable tablets can be chewed, crushed, mixed in a drink, or swallowed whole. Always follow the dose with a drink of water or other beverage.
• Dissolve effervescent tablets in a glass of water. Drink all the contents of the glass as soon as the contents have dissolved and stopped fizzing.

If aspirin upsets your stomach, take the tablets with food or milk. Take your doses at regular intervals. Do not take your medicine more often than directed.

Special precautions for use in children: Aspirin is not for children under 16 years old who have chickenpox or influenza (flu-like symptoms). If you are unsure do not give to children without advice from your doctor or pharmacist. Do not give children under 12 years old more than 5 doses a day.

What if I miss a dose?

If you are taking aspirin on a regular schedule and miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses.

What other medicines can interact with aspirin?

• alcohol
• antiinflammatory drugs (NSAIDs such as ibuprofen)
• blood thinners
• hormones such as prednisone or cortisone
• medicines for diabetes that are taken by mouth
• methotrexate
• phenytoin
• probenecid

Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.

What side effects may I notice from taking aspirin?

Serious side effects with aspirin include:

• black, tarry stools
• confusion
• difficulty breathing, wheezing
• dizziness, drowsiness
• ringing in the ears
• seizures (convulsions)
• skin rash
• stomach pain
• unusual bleeding or bruising, red or purple spots on the skin
• vomiting up blood, or what looks like coffee grounds

Call your doctor as soon as you can if you get any of these side effects.

Minor side effects with aspirin include:

• diarrhea
• nausea, vomiting
• reduced amount of urine passed
• stomach gas, heartburn

Let your doctor know about these side effects if they do not go away or if they annoy you.

What do I need to watch for while I take aspirin?

Check with your doctor if you are treating yourself for a pain that does not go away after 10 days; and for a fever that does not go away after 3 days or keeps coming back. Only take aspirin to prevent heart attacks or blood clotting if prescribed by your doctor. Many non-prescription medicines contain aspirin as an ingredient. To prevent accidental aspirin overdose, read labels carefully and do not take more than one product that contains aspirin.

If you have had surgery do not take aspirin for 5 days, unless your doctor tells you to. Aspirin can interfere with your body's ability to stop bleeding.

If you are diabetic, aspirin may alter your blood sugar levels. Check with your doctor before you change your diet or the dose of your diabetic medicine.

Aspirin can irritate your stomach. Drinking alcohol and smoking cigarettes can make this irritation worse and may cause ulcers or bleeding problems. Ask your doctor or pharmacist for help to stop smoking or drinking. Do not lie down for 30 minutes after taking aspirin to prevent irritation to your throat.

Where can I keep my medicine?

Keep out of the reach of children in a container that small children cannot open. Even small doses of aspirin can be dangerous to small children and pets.

Store at room temperature, between 15 and 30C (59 and 86F). Heat and moisture can cause aspirin to break down, becoming inactive and possibly dangerous to use. Do not use products that have a strong vinegar smell; throw the away them at once.

The P-I-E-N-O Parkinsn's List Drug Database Index

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