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The Influence of Cardiovascular Physiology on Dose/Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Relationships

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Abstract

Inter- and intraindividual variability in the relationship between dose and clinical — or pharmacodynamic — response of a drug can be analysed in two steps: firstly, by considering the plasma pharmacokinetic response to a given dose and, secondly, by the connection between both pharmacokinetic and pharmacodynamic responses.

As the cardiovascular system is the means of transport of endogenous and exogenous substances, blood flow fraction destined to each organ determines the relative mass of solute in plasma, which is constantly in contact with the tissue. Hence, not only the rate but also the extent of drug transfer would be increased when tissues are irrigated by a higher fraction of cardiac output.

Aging and circadian rhythms present similar cardiac output distribution patterns when moving from young to aged adult and from nocturnal to diurnal hours. These two changes lead to an increased blood flow delivery to the extra-splanchnic-renal region in the elderly and in the morning, but with a decreased cardiac output in aged individuals and an increased one during the day.

This scenario allows us to forecast substance concentrations outside the blood vessels, which are responsible for the extent of drug elimination and the intensity of drug effect. So available data on disposition and pharmacodynamics of drugs might be explained from another point of view that challenges current knowledge. Furthermore, the administration of cardiovascular active drugs might reverse the chronological sequence between pharmacokinetic and pharmacodynamic responses, since they could modify blood flow distribution.

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Acknowledgements

We acknowledge the Institutional Agreement between the Faculties of Medicine and Chemistry that enables us to work in the Pharmacy Department and in the Therapeutic Drug Monitoring Service at the University Hospital “Dr Manuel Quintela”. No sources of funding were use to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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  1. Pharmacology and Biopharmaceutics, Faculty of Chemistry, University of the Republic of Uruguay, CC 1157, 11800, Montevideo, Uruguay

    Pietro Fagiolino, Rosa Eiraldi & Marta Vázquez

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  1. Pietro Fagiolino
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  2. Rosa Eiraldi
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Correspondence to Pietro Fagiolino.

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Fagiolino, P., Eiraldi, R. & Vázquez, M. The Influence of Cardiovascular Physiology on Dose/Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Relationships. Clin Pharmacokinet 45, 433–448 (2006). https://doi.org/10.2165/00003088-200645050-00001

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