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Pharmacologic Principles for Combination Therapy

Department of Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska

Correspondence and requests for reprints should be addressed to Myron L. Toews, Ph.D., Professor, Department of Pharmacology, University of Nebraska Medical Center, 985800 Nebraska Medical Center, Omaha, NE 68198–5800. E-mail: mtoews{at}unmc.edu

This article discusses the pharmacologic basis for understanding the therapeutic actions of drugs, particularly for their use in combinations. The focus is on principles underlying combination therapy in general, including examples from diseases other than chronic obstructive pulmonary disease (COPD). Pharmacodynamic aspects of drug action are covered, with an emphasis on recent advances in the understanding of drug–receptor interactions and of drug agonism. Pharmacokinetics and drug-induced adaptive changes in receptors and cell signaling pathways are summarized, emphasizing their importance for potential combination therapies aimed at prolonging drug action. An organizational framework for three different approaches to combination therapy is then proposed; the molecular rationales for each approach are described together with classic examples from other diseases, and then their application to combination therapy in COPD is discussed. Finally, terminology for the independent and interactive effects of drug combinations is discussed, and approaches to the quantitative analysis and visual display of the effects of drug combinations are introduced. The basic principles reviewed here provide the pharmacologic foundation for subsequent articles in this issue that address the combinations in current use for COPD, and they point to novel strategies for potential future approaches to combination therapy in COPD.

Key Words: desensitization • dose–response curves • drug–receptor interactions • pharmacodynamics • pharmacokinetics • synergism