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Clinical Implications of Drug Distribution Digoxin accesses its cardiac site of action slowly, over a distribution phase of several hours. Thus, after an intravenous dose, plasma levels fall, but those at the site of action increase over hours. Only when distribution is near-complete does the concentration of digoxin in plasma reflect pharmacologic effect. For this reason, there should be a 6–8 h wait after administration before plasma levels of digoxin are measured as a guide to therapy. Animal models have suggested, and clinical studies are confirming, that limited drug penetration into the brain, the "blood-brain barrier," often represents a robust. | Chapter 005. Principles of Clinical Pharmacology Part 4 Clinical Implications of Drug Distribution Digoxin accesses its cardiac site of action slowly over a distribution phase of several hours. Thus after an intravenous dose plasma levels fall but those at the site of action increase over hours. Only when distribution is near-complete does the concentration of digoxin in plasma reflect pharmacologic effect. For this reason there should be a 6-8 h wait after administration before plasma levels of digoxin are measured as a guide to therapy. Animal models have suggested and clinical studies are confirming that limited drug penetration into the brain the blood-brain barrier often represents a robust P-glycoprotein-mediated efflux process from capillary endothelial cells in the cerebral circulation. Thus drug distribution into the brain may be modulated by changes in P-glycoprotein function. Loading Doses For some drugs the indication may be so urgent that the time required to achieve steady-state concentrations may be too long. Under these conditions administration of loading dosages may result in more rapid elevations of drug concentration to achieve therapeutic effects earlier than with chronic maintenance therapy Fig. 5-4 . Nevertheless the time required for true steady state to be achieved is still determined only by elimination half-life. This strategy is only appropriate for drugs exhibiting a defined relationship between drug dose and effect. Disease can alter loading requirements in congestive heart failure the central volume of distribution of lidocaine is reduced. Therefore lower-than-normal loading regimens are required to achieve equivalent plasma drug concentrations and to avoid toxicity. Rate of Intravenous Administration Although the simulations in Fig. 5-2 use a single intravenous bolus this is very rarely appropriate in practice because side effects related to transiently very high concentrations can result. Rather drugs are more usually administered .
