Drug disease interactions: role of inflammatory mediators in disease and variability in drug response.

Expression of both pro- and anti-inflammatory mediators are influenced by various factors such as rheumatic diseases, myocardial infarction, angina, aging, obesity and pharmacotherapy. This has therapeutic consequences. Clearance of highly bound and efficiently metabolized drugs may be reduced in the presence of inflammation amounting to increased circulating drug concentration. In the meantime, various cardiovascular receptors are down-regulated in the presence of pro-inflammatory mediators. Consequently, conditions such as rheumatoid arthritis, aging and obesity results in reduced response to drugs such as verapamil despite increased drug concentration. The inflammatory response is a complex cascade of non-specific events resulting in excessive generation of inflammatory mediators such as cytokines, C-reactive protein and nitric oxide by cells of the innate (macrophages, monocytes, neutrophils) and adaptive (T-lymphocytes) arms of the immune system. T-lymphocytes secrete various pro- and anti-inflammatory cytokines during an inflammatory event. In general, two distinct subpopulations of these T-helper cells exist, anti-inflammatory Th2 and pro-inflammatory Th1. As a common rule, Th1 cytokines suppress Th2 and vice-versa. Hence, a balance of these activities is desired. Drugs such as antirheumatoid agents, angiotensin II blockers and hydroxymethyl-glutaryl-CoA reductase inhibitor (statin) may help to restore the Th1/Th2 balance. In general, at least for some conditions, the challenge of therapeutic drug monitoring will be more useful if expression of inflammatory mediators is also taken into account. In addition, some of the intersubject variation in pharmacotherapy and clinical trails may be attributed to variations in the inflammatory mediator's concentration. A detail list of conditions and drugs that influence expression of the inflammatory mediators are provided and potential therapeutic consequences are discussed.