Persistence of NSAIDs at effect sites and rapid disappearance from side-effect compartments contributes to tolerability

ABSTRACT

Background: Non-steroidal, anti-inflammatory drugs (NSAIDs) are still the most widely used drugs worldwide. The introduction of selective cyclooxygenase (COX)‐2 inhibitors has led to compounds which appear less damaging to the gastrointestinal tract, but possibly more risky to the cardiovascular system than older drugs. None has as yet reached OTC-status.

Objective: This situation necessitates an analysis of the characteristics of those older ones which – due to their relative safety – have achieved over-the-counter (OTC) status.

Design: The pharmacodynamic and pharmacokinetic characteristics of non-selective COX inhibitors in OTC use were obtained from the literature by systematic search, examined and used to construct a coherent hypothesis why they achieved OTC status, i.e. effectiveness and relative safety at low doses.

Results: Pharmacodynamic (COX‐2 preferential, but not selective inhibition) and, more importantly, pharmacokinetic characteristics of some of the older compounds may make them particularly safe drugs if used at low (OTC) doses with treatment limited to a few days of intake. The reason why some NSAIDs are particularly active while being relatively free from side-effects may be due to their specific biodistribution and metabolism, leading to drug accumulation and persistence in inflamed tissue (effect compartment) together with fast clearance from the central compartment, including blood, vascular wall, heart and kidney, i.e., possible side-effect compartments.

Conclusion: This specific pharmacokinetic behavior of some non-selective COX inhibitors, such as diclofenac and ibuprofen, may explain why these widely used, non-steroidal, anti-inflammatory compounds are relatively well suited for OTC use and why some are more appropriate for the therapy of certain pain conditions than others.

Key words: :

• COX-2
• Diclofenac
• Ibuprofen
• Mode of action
• Pharmacokinetics
• Tissue accumulation