CONCEPTS IN CLINICAL PHARMACOKINETICS PDF
University of Cincinnati. Cincinnati, Ohio. Concepts in Clinical. Pharmacokinetics. SIXTH EDITION. American Society of Health-System Pharmacists®. Bethesda. Concepts in Clinical Pharmacokinetics has helped thousands of students and practitioners through five editions by Download the PDF (pages ). This programmed manual presents basic pharmacokinetic concepts and Although the fourth edition of Concepts in Clinical Pharmacokinetics.
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However, the hepatic clearance of drugs with high extraction ratios does not change much when protein binding displacement or enzyme induction or inhibition occurs due to drug interactions. Examples of drugs with high hepatic extraction ratios are lidocaine, morphine, and most tricyclic antidepressants.
However, it is rare to know the exact volume of distribution for a patient because it is necessary to administer a dose on a previous occasion in order to have computed the volume of distribution.
Thus, usually an average volume of distribution measured in other patients with similar demographics age, weight, gender, etc. Because of this, most patients will not actually attain steady state after a loading dose, but, hopefully, serum drug concentrations will be high enough so that the patient will experience the pharmacological effect of the drug.
The volume of distribution is a hypothetical volume that relates drug serum concentrations to the amount of drug in the body. Thus, the dimension of volume of distribution is in volume units, such as L or mL. In this case, one beaker, representing a patient with a small volume of distribution, contains 10 L while the other beaker, representing a patient with a large volume of distribution, contains L. This situation would not be acceptable for many clinical situations where a quick onset of action is needed.
Since the volume of distribution is not known for a patient before a dose is given, clinicians use an average volume of distribution previously measured in patients with similar demographics and disease states to compute loading doses. In these cases, it still takes 3—5 half-lives to reach steady-state, but therapeutic drug concentrations are achieved much sooner than giving the drug by intravenous infusion only.
The physiologic determinates of volume of distribution are the actual volume of blood VB and size measured as a volume of the various tissues and organs of the body VT.
Therefore, a larger person, such as a kg football player, would be expected to have a larger volume of distribution for a drug than a smaller person, such as a kg grandmother.
How the drug binds in the blood or serum compared to the binding in tissues is also an important determinate of the volume of distribution for a drug. For example, the reason warfarin has such a small volume of distribution is that it is highly bound to serum albumin so that the free fraction of drug in the blood fB is very small. An example is how the volume of distribution changes when plasma protein binding drug interactions occur.
When the same data is plotted on a semilogarithmic axis, serum concentrations decrease in a linear fashion after drug absorption and distribution phases are complete Figure This part of the curve is known as the elimination phase. The half-life describes how quickly drug serum concentrations decrease in a patient after a medication is administered, and the dimension of half-life is time hour, minute, day, etc.
Another common measurement used to denote how quickly drug serum concentrations decline in a patient is the elimination rate constant ke. If this data is plotted on rectilinear axes, serum concentrations decline in a curvilinear fashion in both cases. When the drug is given orally, serum concentrations initially increase while the drug is being absorbed and decline after drug absorption is complete.
If this data is plotted on semilogarithmic axes, serum concentrations decline in a straight line in both cases. This same data set is plotted in Figure on rectilinear axes. The half-life is important because it determines the time to steady state during the continuous dosing of a drug and the dosage interval.
The approach to steady-state serum concentrations is an exponential function. It should be noted that the half-life for a drug in a patient is not usually known, but is estimated using values previously measured during pharmacokinetic studies conducted in similar patients. The dosage interval for a drug is also determined by the half-life of the medication. During drug development, it is very common to use the drug half-life as the initial dosage interval for the new drug compound until the pharmacodynamics of the agent can be determined.
The half-life and elimination rate constant for a drug can change either because of a change in clearance or a change in the volume of distribution. Because the values for clearance and volume of distribution depend solely on physiological parameters and can vary independently of each other, they are known as independent parameters.
The clinical implication of Michaelis-Menten pharmacokinetics is that the clearance of a drug is not a constant as it is with linear pharmacokinetics, but is concentration- or dose-dependent.
This is the reason concentrations increase disproportionately after a dosage increase. However, since clearance is dose- or concentration-dependent, half-life also changes with dosage or concentration changes.
Under steady-state conditions the rate of drug administration equals the rate of drug removal. When the therapeutic range for a drug is far above the Km value for the enzyme system that metabolizes the drug, the rate of metabolism becomes a constant equal to Vmax.
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Clinical Pharmacokinetics: Concepts and Applications
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However, the hepatic clearance of drugs with high extraction ratios does not change much when protein binding displacement or enzyme induction or inhibition occurs due to drug interactions.
This part of the curve is known as the elimination phase. However, even in these cases saturable drug metabolism can occur in drug overdose cases where the drug concentration far exceeds the therapeutic range for the medication.
The detailed syllabus is in pdf format below.
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