Nonsteroidal anti-inflammatory drugs (NSAIDs) possess antipyretic, analgesic and anti-inflammatory effects. They are frequently used in children and have numerous therapeutic indications, the most common ones being fever, postoperative pain and inflammatory disorders, such as juvenile idiopathic arthritis (JIA) and Kawasaki disease. Their major mechanism of action is through inhibition of prostaglandin biosynthesis by blockade of cyclo-oxygenase (COX). The disposition of most NSAIDs has been mainly studied in infants > or = 2 years of age. Compared with adults, the volume of distribution and clearance of NSAIDs such as diclofenac, ibuprofen (infants aged between 3 months and 2.5 years), ketorolac and nimesulide were increased in children. The elimination half-life was similar in children to that in adults. These pharmacokinetic differences might be clinically significant with the need for higher loading and/or maintenance doses in children. Ibuprofen, acetylsalicylic acid (ASA) and acetaminophen are the most frequently used agents for fever reduction in children. Over the past 20 years, because of the association between ASA use and Reye's syndrome, most of the interest has been directed toward ibuprofen and acetaminophen. In view of its comparable antipyretic efficacy, but superior tolerability profile, acetaminophen, when used appropriately with age-adapted formulations, should remain the first-line therapy in the treatment of childhood fever. At the moment, there is no scientific evidence to recommend simultaneous use of these two antipyretic drugs. Most NSAIDs provide mild to moderate analgesia, with the exception of ketorolac which has a strong analgesic activity. The analgesic efficacy of ketorolac, ketoprofen, diclofenac and ibuprofen in the treatment of postoperative pain has been mainly studied following a single dose, in children of > or = 1 year of age undergoing minor surgeries. In this setting, when used either alone or in adjunct to caudal or epidural anaesthesia, they were associated with an opioid-sparing effect and were well tolerated. With the exception of ketorolac use in children undergoing tonsillectomy, where controversy exists regarding the risk of postoperative haemorrhage, NSAIDs have not been associated with an increased risk of perioperative bleeding. NSAIDs are the first-line therapy in JIA. They appear to be equally effective and tolerated, with the exception of ASA which is associated with more adverse effects. ASA has been used for many years in the treatment of Kawasaki disease and is part of the standard modality of treatment in combination with intravenous gammaglobulins. More recently, lung inflammation associated with cystic fibrosis (CF) has become a new target for NSAIDs. Despite promising preliminary results with ibuprofen, numerous questions need to be answered before this new strategy becomes part of the conventional treatment of patients with CF. In summary, NSAIDs are effective in reducing fever, alleviating pain and reducing inflammation in children, with a good tolerance profile. Pharmacokinetic studies are needed to characterise the disposition of NSAIDs in very young infants in order to use them rationally. To date, no studies have been published on the disposition, tolerability and efficacy of specific COX-2 inhibitors in children. Further clinical experience with these agents in adults is warranted before undergoing trials with specific COX-2 inhibitors in children.

Risks and benefits of nonsteroidal anti-inflammatory drugs in children: a comparison with paracetamol.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs. Drug interactions with this class of compounds are frequently reported and can be pharmacokinetic and/or pharmacodynamic in nature. The pharmacokinetic interactions can be divided into 3 classes: (1) drugs affecting the pharmacokinetics of an NSAID. (2) an NSAID interfering with the pharmacokinetics of another NSAID and (3) NSAIDs altering the pharmacokinetics of another drug. Although the pharmacokinetics of some NSAIDs may be significantly affected by the concurrent administration of certain other drugs (including other NSAIDs), this type of interaction only occasionally leads to serious complications. Concurrent administration of antacids or sucralfate may delay the rate of oral absorption of NSAIDs but generally has little effect on the extent. Use of antacids increases urinary pH, leading to increased renal excretion of unchanged salicylic acid and decreased plasma concentrations of this antirheumatic agent. The H2-receptor blocking agent cimetidine inhibits the oxidative metabolism of many concurrently administered drugs, including certain NSAIDs. Probenecid inhibits the renal secretion of drug glucuronides and this will lead to accumulation in plasma of those NSAIDs eliminated primarily by the formation of labile acyl glucuronides such as naproxen, ketoprofen, indomethacin, carprofen. Cholestyramine decreases the oral absorption of many concurrently administered drugs, including NSAIDs. It may also decrease plasma concentrations of those NSAIDs undergoing enterohepatic circulation (e.g. piroxicam, tenoxicam) by interrupting the enterohepatic cycle. Corticosteroids stimulate the clearance of salicylic acid, leading to low plasma salicylate concentrations. Plasma concentrations of many NSAIDs are significantly reduced when the NSAID is coadministered with aspirin. The clinical relevance of most of these interactions is not well established. However, in those cases where the interaction results in elevated plasma concentrations of the NSAID, special caution should be exercised to avoid excessive accumulation of the NSAID especially in elderly and/or very sick patients who may be more sensitive to the more serious gastroduodenal and renal side-effects of these agents. By virtue of their pharmacokinetic and pharmacodynamic properties, NSAIDs may significantly affect the disposition kinetics of a number of other drugs. They can displace other drugs from their plasma protein binding sites, inhibit their metabolism or interfere with their renal excretion. If the affected drug has a narrow therapeutic index, the interaction may be clinically significant. The pyrazole NSAIDs (phenylbutazone, oxyphenbutazone, azapropazone) inhibit the metabolism of many drugs such as the coumarin anticoagulants, oral antidiabetics and anticonvulsants such as phenytoin. Salicylates displace oral anticoagulants from their plasma protein binding sites.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetic drug interactions with nonsteroidal anti-inflammatory drugs.

The nonsteroidal anti-inflammatory drugs (NSAIDs) are very commonly prescribed, especially in the elderly population. In many countries more than 10 different NSAIDs are available. As the older pyrazole compounds like phenylbutazone, oxyphenbutazone and azapropazone are most prone to pharmacokinetic interactions, the use of these compounds should be avoided where possible. Acidic NSAIDs interact with bile acid-binding resins, resulting in decreased concentrations of NSAIDs in the blood. In earlier reports it was suggested that the absorption of NSAIDs was affected by antacids and sucralfate. More recently, it was shown that there is delayed absorption of these drugs, but there is no difference in the extent of absorption. Only salicylates had their urinary secretion enhanced by antacids, which increase the urinary pH to values > 7. Histamine H2-receptor antagonists can be combined safely with NSAIDs. The concomitant administration of probenecid increased the blood concentration of NSAIDs, so an enhanced anti-inflammatory effect can be expected when these 2 drugs are combined. More importantly, NSAIDs can cause pharmacokinetic drug-drug interactions with other drugs. As can be expected, interactions with drugs that have a small therapeutic window are most likely to be of clinical significance. For example, lithium, medium to high dose methotrexate and, to a lesser extent, cyclosporin may be affected by concomitant administration of an NSAID. Aspirin (acetylsalicylic acid) and/or pyrazoles interact with oral anticoagulants, oral antihyperglycaemic agents and the anticonvulsants phenytoin and valproic acid (sodium valproate). Elevation of blood concentrations of these agents can be potentially dangerous. Similarly, NSAIDs interact with digoxin. This interaction is most likely to occur in the elderly, in neonates or in patients with renal impairment. Indomethacin can influence the blood concentrations of aminoglycosides in neonates. Unfortunately, this effect seems unpredictable, so practical therapeutic recommendations cannot be made. When NSAIDs are combined with salicylates or diflunisal, the blood concentrations of the salicylate or diflunisal may increase. However, the clinical relevance of this increase in drug concentration seems to be of minor importance. Gastrointestinal bleeding caused by NSAIDs is the most dangerous when it results from a mixed pharmacokinetic/pharmacodynamic interaction; however, patients are also at risk when pharmacodynamic interactions only are involved.

Pharmacokinetic-Pharmacodynamic Drug Interactions with Nonsteroidal Anti-Inflammatory Drugs

Background:Use of oral anticancer agents is gaining wide acceptance in the treatment of cancer. However, patients receiving oral therapy are at high risk for drug–drug interactions (DDIs).Objective:To create a drug profile for each clinically significant DDI involving selected oral anticancer agents and evaluate the agreement between 2 commonly used DDI compendia: Drug Interaction Facts (DIF) 2008 and Micromedex DRUGDEX.Methods:DDI profiles were developed based on primary and tertiary literature reviews. DIF 2008 and Micromedex DRUGDEX were compared to assess the consistency of listings, severity, and scientific evidence ratings of DDIs involving the oral anticancer agents that were selected. The Spearman correlation test was used to assess the correlation of the severity ratings between the 2 compendia.Results:A total of 184 DDIs were identified. A DDI profile was created for 40 of these that met the predetermined criteria for clinically significant interactions. The comparative assessment showed inconsi...

Clinically Significant Drug-Drug Interactions Between Oral Anticancer Agents and Nonanticancer Agents : Profiling and Comparison of Two Drug Compendia

Aspirin (acetylsalicylic acid) is metabolically converted to salicyclic acid by the action of carboxylesterases. Although metabolic drug interactions involving aspirin are theoretically possible, there appear to have been no studies to date which have shown conclusively that aspirin hydrolysis is altered by coadministered drugs. However, a number of treatments are known to affect the rate or extent of aspirin absorption, including activated charcoal, antacids, cholestyramine and metoclopramide. Caffeine and metoprolol have been reported to increase peak salicylic acid concentration following aspirin administration, and coadministration of dipyridamole and aspirin results in higher plasma aspirin concentrations. The mechanism(s) responsible for these latter observations remains unknown. Salicylic acid is extensively bound to plasma albumin, and many of the reported drug interactions involve displacement of the coadministered drug from plasma protein. Protein binding displacement appears to be the basis of salicylic acid interactions with diclofenac, flurbiprofen, ibuprofen, isoxicam, ketoprofen, naproxen, phenytoin and tolmetin. Following displacement of these agents increased clearance of total drug occurs, and consequently the plasma concentration of total drug decreases. Although generally not measured, unbound concentration of the interacting drug should not be markedly altered. Salicylic acid also increases total plasma clearance of fenoprofen but, unlike the interactions with the other propionic acid non-steroidals, plasma protein binding displacement does not appear to be involved. Induction of fenoprofen metabolism is a possibility, although there is no firm evidence from other studies that salicylate is able to induce the metabolism of coadministered drugs. Since salicylic acid is extensively metabolised, it is not surprising that it is able to inhibit the metabolism of certain coadministered drugs and chemicals, an effect which has been reported for salicylamide, valproic acid, m-xylene, and zomepirac. The interactions with salicylamide, m-xylene and zomepirac are probably competitive in nature since mutual inhibition of salicylic acid metabolism occurs. There is an additional component of protein binding displacement in the interactions with valproic acid and zomepirac, resulting in increased unbound drug concentration. Certain coadministered drugs (or chemicals) may alter the metabolism of salicylic acid; inhibition of its metabolism has been demonstrated following treatment with benzoic acid, salicylamide, m-xylene, zomepirac and possibly cimetidine. In contrast, salicylic acid elimination is enhanced in oral contraceptive steroid users and by corticosteroid treatment. Oral contraceptive steroids induce both salicylic acid glucuronidation and salicylurate formation. Induction of metabolism has also been proposed to account for the effects of corticosteroids, but this is still to be proven.(ABSTRACT TRUNCATED AT 400 WORDS)

Drug interactions involving aspirin (acetylsalicylic acid) and salicylic acid.

Determinants of low serum concentrations of salicylates in patients with Kawasaki disease

In an 11-year-old child with juvenile rheumatoid arthritis (JRA), the addition of prednisone caused a significant decrease in salicylate serum concentrations. A pharmacokinetic assessment suggested that these changes were not the result of altered compliance or impaired absorption of salicylate but rather an increase in salicylate clearance induced by the corticosteroid.

David Suria

Papers

Determinants of low serum concentrations of salicylates in patients with Kawasaki disease

Corticosteroids-salicylate interaction in a case of juvenile rheumatoid arthritis.