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 orally or as a slower intravenous infusion. Some drugs are so predictably lethal when infused too rapidly that special precautions should be taken to prevent accidental boluses. For example, solutions of potassium for intravenous administration >20 meq/L should be avoided in all but the most exceptional and carefully monitored circumstances. This minimizes the possibility of cardiac arrest due to accidental increases in infusion rates of more concentrated solutions. While excessively rapid intravenous drug administration can lead to catastrophic consequences, transiently high drug concentrations after intravenous administration can occasionally be used to advantage. The use of midazolam for intravenous sedation, for example, depends upon its rapid uptake by the brain during the distribution phase to produce sedation quickly, with subsequent egress from the brain during the redistribution of the drug as equilibrium is achieved. Similarly, adenosine must be administered as a rapid bolus in the treatment of reentrant supraventricular tachycardias (Chap. 226) to prevent elimination by very rapid (t 1/2 of seconds) uptake into erythrocytes and endothelial cells before the drug can reach its clinical site of action, the atrioventricular node. Plasma Protein Binding Many drugs circulate in the plasma partly bound to plasma proteins. Since only unbound (free) drug can distribute to sites of pharmacologic action, drug response is related to the free rather than the total circulating plasma drug concentration. Clinical Implications of Altered Protein Binding For drugs that are normally highly bound to plasma proteins (>90%), small changes in the extent of binding (e.g., due to disease) produce a large change in the amount of unbound drug, and hence drug effect. The acute-phase reactant 1 - acid glycoprotein binds to basic drugs, such as lidocaine or quinidine, and is increased in a range of common conditions, including myocardial infarction, surgery, neoplastic disease, rheumatoid arthritis, and burns. This increased binding can lead to reduced pharmacologic effects at therapeutic concentrations of total drug. Conversely, conditions such as hypoalbuminemia, liver disease, and renal disease can decrease the extent of drug binding, particularly of acidic and neutral drugs, such as phenytoin. Here, plasma concentration of free drug is increased, so drug efficacy and toxicity are enhanced if total (free + bound) drug concentration is used to monitor therapy. Clearance When drug is eliminated from the body, the amount of drug in the body declines over time. An important approach to quantifying this reduction is to consider that drug concentration at the beginning and end of a time period are unchanged, and that a specific volume of the body has been "cleared" of the drug during that time period. This defines clearance as volume/time. Clearance includes both drug metabolism and excretion. Clinical Implications of Altered Clearance . 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. 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,. 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