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...
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Chapter 005. Principles of Clinical Pharmacology (Part 4) Chapter 005. Principles of Clinical Pharmacology (Part 4) Clinical Implications of Drug Distribution Digoxin accesses its cardiac site of action slowly, over a distribution phaseof several hours. Thus, after an intravenous dose, plasma levels fall, but those atthe site of action increase over hours. Only when distribution is near-completedoes the concentration of digoxin in plasma reflect pharmacologic effect. For thisreason, there should be a 6–8 h wait after administration before plasma levels ofdigoxin are measured as a guide to therapy. Animal models have suggested, and clinical studies are confirming, thatlimited drug penetration into the brain, the blood-brain barrier, often represents arobust P-glycoprotein–mediated efflux process from capillary endothelial cells inthe cerebral circulation. Thus, drug distribution into the brain may be modulatedby changes in P-glycoprotein function. Loading Doses For some drugs, the indication may be so urgent that the time required toachieve steady-state concentrations may be too long. Under these conditions,administration of loading dosages may result in more rapid elevations of drugconcentration to achieve therapeutic effects earlier than with chronic maintenancetherapy (Fig. 5-4). Nevertheless, the time required for true steady state to beachieved is still determined only by elimination half-life. This strategy is onlyappropriate for drugs exhibiting a defined relationship between drug dose andeffect. Disease can alter loading requirements: in congestive heart failure, thecentral volume of distribution of lidocaine is reduced. Therefore, lower-than-normal loading regimens are required to achieve equivalent plasma drugconcentrations and to avoid toxicity. Rate of Intravenous Administration Although the simulations in Fig. 5-2 use a single intravenous bolus, this isvery rarely appropriate in practice because side effects related to transiently veryhigh concentrations can result. Rather, drugs are more usually administered orallyor as a slower intravenous infusion. Some drugs are so predictably lethal wheninfused too rapidly that special precautions should be taken to prevent accidentalboluses. For example, solutions of potassium for intravenous administration >20meq/L should be avoided in all but the most exceptional and carefully monitoredcircumstances. This minimizes the possibility of cardiac arrest due to accidentalincreases in infusion rates of more concentrated solutions. While excessively rapid intravenous drug administration can lead tocatastrophic consequences, transiently high drug concentrations after intravenousadministration can occasionally be used to advantage. The use of midazolam forintravenous sedation, for example, depends upon its rapid uptake by the brainduring the distribution phase to produce sedation quickly, with subsequent egressfrom the brain during the redistribution of the drug as equilibrium is achieved. Similarly, adenosine must be administered as a rapid bolus in the treatmentof reentrant supraventricular tachycardias (Chap. 226) to prevent elimination byvery rapid (t1/2 of seconds) uptake into erythrocytes and endothelial cells beforethe 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. Sinceonly unbound (free) drug can distribute to sites of pharmacologic action, drugresponse is related to the free rather than the total circulating plasma drugconcentration. Clinical Implications of Altered Protein Binding For drugs that are normally highly bound to plasma proteins (>90%), smallchanges in the extent of binding (e.g., due to disease) produce a large change inthe 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 isincreased in a range of common conditions, including myocardial infarction,surgery, neoplastic disease, rheumatoid arthritis, and burns. This increased bindingcan lead to reduced pharmacologic effects at therapeutic concentrations of totaldrug. Conversely, conditions such as hypoalbuminemia, liver disease, and renaldisease can decrease the extent of drug binding, particularly of acidic and neutraldrugs, such as phenytoin. Here, plasma concentration of free drug is increased, sodrug efficacy and toxicity are enhanced if total (free + bound) drug concentrationis used to monitor therapy. Clearance When drug is eliminated from the body, the amount of drug in the bodydeclines over time. An important approach to quantifying this reduction is toconsider that drug concentration at the beginning and end of a time period areunchanged, and that a specific volume of the body has been cleared of the drugduring that time period. This defines clearance as volume/time. Clearance includesboth drug metabolism and excretion. Clinical Implications of Altered Clearance