Sections in this chapter:
 Key Concepts
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Key Concepts
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 Clinical pharmacokinetics is the discipline that describes the absorption, distribution, metabolism, and elimination of drugs in patients requiring drug therapy. Clearance is the most important pharmacokinetic parameter because it determines the steady-state concentration for a given dosage rate. Physiologically, clearance is determined by blood flow to the organ that metabolizes or eliminates the drug and the efficiency of the organ in extracting the drug from the bloodstream. The volume of distribution is a proportionality constant that relates the amount of drug in the body to the serum concentration. The volume of distribution is used to calculate the loading dose of a drug that will immediately achieve a desired steady-state concentration. The value of the volume of distribution is determined by the physiologic volume of blood and tissues and how the drug binds in blood and tissues. Half-life is the time required for serum concentrations to decrease by one-half after absorption and distribution are complete. It is important because it determines the time required to reach steady state and the dosage interval. Half-life is a dependent kinetic variable because its value depends on the values of clearance and volume of distribution. The fraction of drug absorbed into the systemic circulation after extravascular administration is defined as its bioavailability. Most drugs follow linear pharmacokinetics, whereby steady-state serum drug concentrations change proportionally with long-term daily dosing. Some drugs do not follow the rules of linear pharmacokinetics. Instead of steady-state drug concentration changing proportionally with the dose, serum concentration changes more or less than expected. These drugs follow nonlinear pharmacokinetics. Pharmacokinetic models are useful to describe data sets, to predict serum concentrations after several doses or different routes of administration, and to calculate pharmacokinetic constants such as clearance, volume of distribution, and half-life. The simplest case uses a single compartment to represent the entire body. Factors to be taken into consideration when deciding on the best drug dose for a patient include age, gender, weight, ethnic background, other concurrent disease states, and other drug therapy. Cytochrome P450 is a generic name for the group of enzymes that are responsible for most drug metabolism oxidation reactions. Several P450 isozymes have been identified, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. The importance of transport proteins in drug bioavailability and elimination is now better understood. The principal transport protein involved in the movement of drugs across biologic membranes is P-glycoprotein. P-glycoprotein is present in many organs, including the GI tract, liver, and kidney. When deciding on initial doses for drugs that are renally eliminated, the patient's renal function should be assessed. A common, useful way to do this is to measure the patient's serum creatinine concentration and convert this value into an estimated creatinine clearance (CrClest). For drugs that are eliminated primarily by the kidney ( 60% of the administered dose), some agents will need minor dosage adjustments for CrClest between 30 and 60 mL/min (0.50 and 1.00 mL/s), moderate dosage adjustments for CrClest between 15 and 30 mL/min (0.25 and 0.50 mL/s), and major dosage adjustments for CrClest less than 15 mL/min (0.25 mL/s). Supplemental doses of some medications also may be needed for patients receiving hemodialysis if the drug is removed by the artificial kidney or for patients receiving hemoperfusion if the drug is removed by the hemofilter. When deciding on initial doses for drugs that are hepatically eliminated, the patient's liver function should be assessed. The Child-Pugh score can be used as an indicator of a patient's ability to metabolize drugs that are eliminated by the liver. In the absence of specific pharmacokinetic dosing guidelines for a medication, a Child-Pugh score equal to 8 or 9 is grounds for a moderate decrease ( 25%) in the initial daily drug dose for agents that are metabolized primarily hepatically (60%), and a score of 10 or greater indicates that a significant decrease in the initial daily dose (50%) is required for drugs that are metabolized mostly hepatically. For drugs that exhibit linear pharmacokinetics, steady-state drug concentration (Css) changes proportionally with dose (D). To adjust a patient's drug therapy, a reasonable starting dose is administered for an estimated three to five half-lives. A serum concentration is obtained, assuming that it will reflect Css. Independent of the route of administration, the new dose (Dnew) needed to attain the desired Css(Css,new) is calculated as Dnew = Dold(Css,new /Css,old), where Dold and Css,old are the old dose and old Css, respectively. If it is necessary to determine the pharmacokinetic constants for a patient to individualize his or her dose, a small pharmacokinetic evaluation is conducted in the individual. Additionally, Bayesian computer programs that aid in the individualization of therapy are available for many different drugs. Pharmacodynamics is the study of the relationship between the concentration of a drug and the response obtained in a patient. If pharmacologic effect is plotted against concentration for most drugs, a hyperbola results with an asymptote equal to the maximum attainable effect.
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