Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications by Rowland Malcolm & Tozer Thomas N

Author:Rowland, Malcolm & Tozer, Thomas N. [Rowland, Malcolm]
Language: eng
Format: azw3
Publisher: Lippincot (Wolters Kluwer Health)
Published: 2012-04-30T16:00:00+00:00

CARDIOVASCULAR DISEASES

Circulatory disorders, which include shock, malignant hypertension, and congestive cardiac failure, are generally characterized by diminished vascular perfusion to one or more parts of the body. Because blood flow may influence drug absorption, distribution, and elimination, it is not surprising that the pharmacokinetics of drugs may be altered in circulatory disorders.

A diminished perfusion of absorption sites (e.g., gastrointestinal tract and muscle) with associated protracted and erratic drug absorption, tends to be seen in patients with depressed cardiovascular states; it may be necessary to give the drug intravenously if a prompt response is desired. However, in these conditions, the kinetics of distribution is also affected, with perfusion to many organs diminished. Exceptions are the brain and the myocardium, which consequently receive an increased fraction of an intravenous (i.v.) bolus dose, particularly in the earlier moments. For centrally acting and cardioactive agents, the rate of administration of a bolus dose to patients with circulatory depression must be tempered if the risk of toxicity is to be reduced. In these depressed circulatory states, cardiac output and therefore hepatic blood flow and, to a much lesser extent, renal blood flow are also reduced. Thus, a decrease in clearance of highly extracted drugs is expected. Evidence supporting this concept is illustrated in Fig. 15-4 by a strong positive correlation between the clearances of lidocaine, a drug eliminated hepatically by metabolism, and indocyanine green, a diagnostic agent rapidly picked up by active transporters within the liver, and excreted into bile, in patients with varying degrees of congestive cardiac failure. Both indocyanine green and lidocaine are high hepatic extraction ratio drugs whose clearances should therefore reflect a diminished hepatic blood flow. Notice in Fig. 15-4 the almost 16-fold variation in clearance of both lidocaine and indocyanine green. This range is almost certainly greater than the range of hepatic blood flows in these patients. The hepatic flow, usually about 18 mL/min per kilogram, is unlikely to fall to a value as low as 2 mL/min per kilogram, because severe anoxia is expected to result at even higher flow rates. Hepatocellular metabolism and transport are most probably also depressed when perfusion is severely diminished; this would further depress the clearances of both lidocaine and indocyanine green. Exposure to lidocaine is increased in patients with congestive cardiac failure, and the risk of toxicity is therefore increased.

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