PHARMACOKINETIC-PHARMACODYNAMIC DRUG-INTERACTIONS WITH NONSTEROIDAL ANTIINFLAMMATORY DRUGS

The nonsteroidal anti-inflammatory drugs (NSAIDs) are very commonly pr escribed, especially in the elderly population. In many countries more than 10 different NSAIDs are available. As the older pyrazole compoun ds like phenylbutazone, oxyphenbutazone and azapropazone are most pron e to pharmacokinetic interactions, the use of these compounds should b e avoided where possible. Acidic NSAIDs interact with bile acid-bindin g resins, resulting in decreased concentrations of NSAIDs in the blood . In earlier reports it was suggested that the absorption of NSAIDs wa s affected by antacids and sucralfate. More recently, it was shown tha t there is delayed absorption of these drugs, but there is no differen ce in the extent of absorption. Only salicylates had their urinary sec retion enhanced by antacids, which increase the urinary pH to values > 7. Histamine H-2-receptor antagonists can be combined safely with NSAI Ds. The concomitant administration of probenecid increased the blood c oncentration of NSAIDs, so an enhanced anti-inflammatory effect can be expected when these 2 drugs are combined. More importantly, NSAIDs ca n cause pharmacokinetic drug-drug interactions with other drugs. As ca n be expected, interactions with drugs that have a small therapeutic w indow art most likely to be of clinical significance. For example, lit hium, medium to high dose methotrexate and, to a lesser extent, cyclos porin may be affected by concomitant administration of an NSAID. Aspir in (acetylsalicylic acid) and/or pyrazoles interact with oral anticoag ulants, oral antihyperglycaemic agents and the anticonvulsants phenyto in and valproic acid (sodium valproate). Elevation of blood concentrat ions of these agents can be potentially dangerous. Similarly, NSAIDs i nteract with digoxin. This interaction is most likely to occur in the elderly, in neonates or in patients with renal impairment. Indomethaci n can influence the blood concentrations of aminoglycosides in neonate s. Unfortunately, this effect seems unpredictable, so practical therap eutic recommendations cannot be made. When NSAIDs are combined with sa licylates or diflunisal, the blood concentrations of the salicylate or diflunisal may increase. However, the clinical relevance of this incr ease in drug concentration seems to be of minor importance. Gastrointe stinal bleeding caused by NSAIDs is the most dangerous when it results from a mixed pharmacokinetic/pharmacodynamic interaction; however, pa tients are also at risk when pharmacodynamic interactions only are inv olved.