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Pharmacokinetics and pharmacodynamics in critically ill patients

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Abstract

The rapidly changing physiology of critically ill patients causes variations in the absorption, distribution, metabolism, excretion, and pharmacodynamic effect of drugs used to treat these patients. Alterations in fluid status, cardiac, renal and hepatic function, and circulating serum proteins necessitate increased attention to drug selection and dosage modification. Cardiac failure results in decreased absorption, metabolism, and excretion of drugs while renal failure results in parent drug and metabolite accumulation, increases in unbound drug, and changes in distribution volume. The changes in hepatic blood flow and protein binding, and decreases in hepatocellular mass and enzyme function that occur in hepatic failure may alter the clearance of several drugs. Serum drug concentrations are helpful in defining the pharmacokinetics and ultimately the pharmacodynamic effect of the drugs used in critically ill patients. The serum drug concentrations must be interpreted in association with their pharmacodynamic effect and the clinical situation. Adjusting drug therapy based on pharmacokinetic principles is discussed in detail with specific suggestions for dosage modifications in renal and hepatic failure.

Résumé

Le changement rapide de l'état physiologique des malades dont l'état est critique provoque des variations dans l'absorption, la distribution, le métabolisme, l'excrétion et l'effet pharmacodynamique des médicaments. Des modifications dans l'état des liquides circulants, de la fonction cardiaque, rénale et hépatique, dans les protéines circulantes dans le sérum, imposent une attention toute particulière pour sélectionner les drogues utilisées et modifier leur posologie. La défaillance du coeur entraîne une diminution de l'absorption, du métabolisme et de l'excrétion des agents médicamenteux. La défaillance du rein entraîne l'accumulation des metabolites et des drogues parentes, augmente l'absence de fixation des médicaments et modifie le volume de la distribution. Les modifications de la circulation du sang dans le foie et de la liaision protéique, les diminutions de la masse cellulaire hépatique et de la fonction enzymatique qui se manifestent dans la défaillance hépatique peuvent modifier la clairance de plusieurs médicaments. La mesure des concentrations du médicament dans le sérum permet de définir les données pharmacocinétiques et en définitive l'effet pharmaco-dynamique des médicaments employés chez le malade en état critique. Les concentrations du médicament dans le sérum doivent être interprétées en association avec leur effet pharmaco-dynamique et l'état clinique du malade. Le traitement médicamenteux adapté en fonction de ces principes pharmacocinétiques est discuté en détail par les auteurs qui présentent des suggestions spécifiques pour modifier la posologie en cas de défaillance rénale ou hépatique.

Resumen

La rapidamente cambiante fisiología de los pacientes en estado crítico causa variaciones en la absorción, distribution, metabolismo, y efecto farmacodinámico de las drogas utilizadas en su tratamiento. Las alteraciones en el estado de los líquidos corporales, en la función cardfaca, renal, y hepática, y en las proteínas séricas circulantes, hacen necesaria una mayor atención a la selectión de las drogas y a las modificaciones de dosificación. La falla cardiaca resulta en disminución en la absorcion, metabolismo, y excreción de las drogas, en tanto que la falla renal resulta en la acumulación del fármaco y de sus metabolitos, incrementa el nivel de droga no ligada, y produce cambios en la distribución volumétrica. Los cambios en el flujo hepático y en la ligadura proteica, junto con las disminuciones en la masa hepatocelular y en la función enzimática que ocurren en la falla hepática pueden alterar la depuración de ciertas drogas. La determinación de las concentraciones séricas de las drogras son de utilidad en la definición de la farmacocinética y por ende del efecto farmacodinámico de las drogas que se utilizan en pacientes en estado crítico. Las concentraciones séricas a su vez deben ser interpretadas, a la luz de su efecto farmacodinámico y de la situation clínica. Se discute en detalle el ajuste de la terapia basado en principios farmacocinéticos y se hacen sugerencias específicas para la modificatión de las dosis en presencia de falla renal y hepática.

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Authors and Affiliations

  1. University of Minnesota College of Medicine, Minneapolis, Minnesota, USA

    Henry J. Mann Pharm.D., David W. Fuhs M.S., Pharm.D. & Frank B. Cerra M.D.

  2. University of Minnesota Hospital Departments of Pharmaceutical Services and Surgery, Minneapolis, Minnesota, USA

    Henry J. Mann Pharm.D., David W. Fuhs M.S., Pharm.D. & Frank B. Cerra M.D.

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Mann, H.J., Fuhs, D.W. & Cerra, F.B. Pharmacokinetics and pharmacodynamics in critically ill patients. World J. Surg. 11, 210–217 (1987). https://doi.org/10.1007/BF01656404

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