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Chapter 8. Principles of Pharmacokinetics and Pharmacodynamics

C. Lindsay DeVane, Pharm.D.
DOI: 10.1176/appi.books.9781585623860.408715

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Excerpt

Pharmacokinetics is defined as the study of the time course of drugs and their metabolites through the body. Pharmacodynamics is defined as the study of the time course and intensity of pharmacological effects of drugs. A convenient lay description of these terms is that pharmacokinetics describes what the body's physiology does to a drug, and pharmacodynamics describes what a drug does to the body. Although clinicians are more interested in drug effects than drug concentrations, these disciplines are closely connected. Pharmacokinetic and pharmacodynamic variability is a major determinant of the dose–effect relationship in patients (Figure 8–1). There is increasing recognition that genetic variability—in the form of polymorphic genes controlling the transcription of proteins involved in drug-metabolizing enzymes, drug transporters, and drug targets—is a substantial determinant of pharmacokinetic and pharmacodynamic variability. An integrated knowledge of these areas is essential in the drug development process and can be instrumental in individualizing dosage regimens for specific patients.

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FIGURE 8–1. Pharmacokinetic and pharmacodynamic variability as determinants of the dose–effect relationship.

FIGURE 8–2. Predicted plasma concentration curves following single doses of a drug by rapid intravenous injection (I), a dosage form with complete bioavailability (II), a dosage form with reduced bioavailability (III), and an extended-release dosage form that reduces the rate but not the completeness of absorption (IV).MEC = minimal effective concentration.

FIGURE 8–3. Predicted concentration of a drug in plasma and tissue following a rapid intravenous injection.MEC = minimal effective concentration.

FIGURE 8–4. Effect of protein binding on distribution of drug between plasma and tissue.

FIGURE 8–5. Accumulation of drug during multiple dosing.It takes four to five half-lives (4–5 t1/2) to achieve initial steady state (Cpss) on a constant dosage regimen, to achieve a new steady state after an increase in dosage, or to wash out drug from the body after discontinuation. The average steady-state concentration lies somewhere between the peaks and troughs of drug concentration during a dosage interval.

FIGURE 8–6. Predicted plasma concentration changes from administering either a selected dose (D) every 24 hours (D q24h), twice the dose every 24 hours (2D q24h), or the original dose every 12 hours (D q12h).MEC = minimal effective concentration.

FIGURE 8–7. The sigmoid maximum effect (Emax) pharmacodynamic model relates concentration (C) to intensity of effect (E).EC50 is the concentration that produces half of the Emax, and n is an exponent that relates to the shape of the curve.

FIGURE 8–8. Concentration–effect curves for a drug that produces a therapeutic effect and mild (A) and severe (B) toxicity.The concentration is shown for a therapeutic effect that produces 50% of the maximum effect (EC50).

FIGURE 8–9. Theoretical relationships of drug concentration versus intensity of effect.Drug concentration changes occur in the direction of the arrow. Effects superimposable on concentration changes (A) suggest a direct and reversible interaction between drug and receptor, a clockwise hysteresis curve (B) suggests the development of tolerance, and a counterclockwise curve (C) suggests an indirect effect or the presence of an active metabolite.

FIGURE 8–10. Theoretical frequency histograms of the distribution of the metabolic ratio of a model substrate showing a unimodal distribution among a population of normal or extensive metabolizers (A) and a bimodal distribution among a population including poor metabolizers and ultrarapid metabolizers (B).

FIGURE 8–11. Predicted plasma concentration changes from the coadministration of an inducer of the metabolism of drug A.

FIGURE 8–12. Predicted plasma concentration changes from the coadministration of an inhibitor of the metabolism of drug A.
Table Reference Number
TABLE 8–1. Substrates, inhibitors, and inducers of the major human liver cytochrome P450 (CYP) enzymes involved in drug metabolism
Table Reference Number
TABLE 8–2. Some genetically determined variations influencing drug pharmacokinetics
Table Reference Number
TABLE 8–3. Comparison of average immunoquantified levels of the various cytochrome P450 (CYP) enzymes in liver microsomes, with their estimated participation in drug metabolism
Table Reference Number
TABLE 8–4. Newer antidepressants and cytochrome P450 (CYP) enzyme inhibitory potential

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Sample questions:
1.
Taking medications with meals will usually decrease the rate of drug absorption, leading to a decreased peak plasma concentration and prolonged time to reach the maximum plasma concentration. For which of the following selective serotonin reuptake inhibitor antidepressants does food increase plasma concentrations and shorten the time to reach the maximum plasma concentration?
2.
Which of the following cytochrome P450 (CYP) enzymes is found in high concentrations in the luminal epithelium of the small intestine and leads to extensive presystemic metabolism?
3.
Which of the following terms is defined as maintaining a stable clearance across the usual dosage range?
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