Article Figures & Data
Figures
- FIGURE 1.
Schematic of relationship between pharmacokinetics and pharmacodynamics (1).
- FIGURE 2.
Schematic of pharmacokinetics and absorption, distribution, metabolism, and excretion concept (A), and same schematic highlighting interplay between free and bound drug, and pathway from site of administration to site of action (B).
- FIGURE 3.
Schematics of equilibrium between drug concentration and plasma, well-perfused tissue, and poorly perfused tissue. Set of 3 schematics at top does not incorporate effects of metabolism or elimination but illustrate early equilibrium in well-perfused tissue (A) followed by period of concentration in poorly perfused tissues (A to B) before reaching equilibrium in all tissues and plasma (B). Set of 3 schematics at bottom provides phases as discrete intervals (straight line) and illustrates impact of elimination. (Adapted from (3).)
- FIGURE 4.
Schematic of 1-compartment model, 2-compartment model, and multicompartment model. Elimination rate constant reflects movement from one compartment or volume of distribution to another and can be calculated numerically. Schematically, rate constant may be represented in several ways. In multiple-compartment model, k5 and k6 have arrows of different sizes, indicating greater movement of drug to tissue compartment than from it. Likewise, for k7 and k8, double-head arrow with different sizes of arrowhead is used to represent relative k values. When drug transport between compartments is not reversible, single-head arrow is used (k9). Note that multiple methods would not be used on a single schematic as is done here.
- FIGURE 5.
Phase I and II metabolism of acetaminophen. Phase I hydroxylation results in toxic metabolite, with 3 forms of phase II metabolism converting metabolite to a form for urine excretion. Toxic interaction can occur, leading to liver necrosis and potential renal failure, especially with deleted hepatic glutathione. (Adapted from (13).)
- FIGURE 6.
Schematic of first-order and zero-order elimination. First-order elimination follows exponential trend and can be displayed with logarithmic y-axis to generate straight line (inset). Zero-order elimination removes constant amount of drug per unit time.
- FIGURE 7.
(A) Logarithmic/linear plot confirming single-compartment monoexponential curve (scenario 1). (B) Linear/linear and logarithmic/linear plots demonstrating interplay between absorption and elimination for scenario 2 (scenario 2). (C) Logarithmic/linear plots for raw data (dashed line) and for R (scenario 2). (D) Linear/linear and logarithmic/linear plots demonstrating interplay between absorption and elimination for scenario 3 (scenario 3). (E) Logarithmic/linear plots for raw data (dashed) and for elimination curve minus plasma curve (R) (solid line) (scenario 3).
Tables
Route Advantage Disadvantage Intranasal (e.g., antihistamine) Rapid delivery and immediate effect. High bioavailability. No first-pass metabolism. Avoids gastric environment. Local irritation. Limited to small doses and small range of drugs. Sublingual (e.g., nitroglycerin) Easy and convenient delivery. Rapid delivery and immediate effect. High bioavailability. No first-pass metabolism. Avoids gastric environment. Self-administration. Changes in absorption if swallowed, chewed, or taken after emesis. Oral/enteral (e.g., captopril) Easy, reliable, economic, convenient, painless, no infection risk. Self-administration. First-pass metabolism/elimination decreases bioavailability. Slow delivery and onset of action. Dose form needs to accommodate gastric environment (e.g., transit stomach intact for small-bowel absorption). Bioavailability can be influenced by changes in gut status (e.g., emesis, diarrhea, or constipation). Rectal (e.g., laxatives) Rapid delivery and immediate effect. High bioavailability. No first-pass metabolism. Avoids gastric environment. Suitable for patients with emesis or otherwise inappropriate oral route. Unpleasant form of administration, with bacteremia risk for immunocompromised patient. Altered absorption in diarrhea and constipation. Inhalation (e.g., albuterol) Rapid delivery and immediate effect. High bioavailability. No first-pass metabolism. Avoids gastric environment. Direct delivery to affected tissues. Self-administration. Local irritation. Limited to small doses and small range of drugs. May require special equipment and decreased efficacy with incorrect use. Intramuscular (e.g., morphine) Intermediate onset of action. Suitable for oil-based drugs. Easier (less skill) administration than intravenous. Local edema, irritation, or pain. Slower onset of action. Infection risk. Intravenous (e.g., furosemide) Rapid delivery and immediate effect. Is 100% bioavailable. No first-pass metabolism. Avoids gastric environment. Controlled drug delivery. Irritation or pain. Risk of infection. Solution must be dissolved well. Risk of embolism. Action not easily reversed. Rapid onset of toxicity. Subcutaneous (e.g., insulin) Slower absorption and onset of action. Suitable for oil-based drugs. Local edema, irritation, or pain. Small volumes. Slow onset of action. Infection risk. Transdermal (e.g., fentanyl) Easy, reliable, economic, convenient, painless. Enables slow and prolonged drug delivery. No first-pass metabolism. Avoids gastric environment. Self-administration. Slow onset of action. Local skin reactions can occur. Needs highly lipophilic drugs. Percutaneous (e.g., diclofenac/diclofenac sodium gel) Easy, reliable, economic, convenient, painless. Suitable for local effect. Slow onset of action. Local skin reactions can occur. Use Equation Definition Drug concentration C = C0 e−kt C = drug concentration at time t after C0 C0 = drug concentration at reference time k = elimination rate constant t = time between C and C0 Elimination rate constant k = ln2/T0.5 k = elimination rate constant ln2 = 0.693 T0.5 = half clearance time Volume of distribution V = amount in body (μg)/actual C0 V = volume of distribution Actual C0 = concentration at time of administration Area under curve AUC0–∞ = FD/Vk AUC0–∞ = area under curve (total drug dose) from time 0 to infinity F = fraction of drug absorbed D = dose V = volume of distribution k = elimination rate constant Clearance CL = k × V CL = clearance k = elimination rate constant V = volume of distribution Time to maximum concentration Tmax = (1/[ka − k]) ln (ka/k) Tmax = time to maximum concentration ka = absorption rate constant k = elimination rate constant Time (h) Plasma concentration (μg/L) 2 139.0 4 65.6 6 31.1 8 14.6 Time (min) Plasma concentration (U/L) 0 0 1 31.3 2 49.3 3 58.6 4 62.5 5 62.8 7 58.1 10 50.6 16 36.1 24 25.3 - TABLE 5
Use of Data for 7- to 24-Hour Stable Elimination Period to Calculate Elimination Rate Constant and Backproject Elimination Curve by Calculating Earlier Values (Bold) for Elimination Confounded by Absorption
Time (h) Plasma concentration (U/L) Elimination curve concentration R (elimination – plasma) 0 0 81.8 81.8 1 31.3 77.9 46.6 2 49.3 74.0 24.7 3 58.6 70.7 12.1 4 62.5 67.1 4.6 5 62.8 64.1 1.3 7 58.1 58.1 10 50.6 50.6 16 36.1 36.1 24 25.3 25.3 Time (h) Plasma concentration (μg/mL) 0 0 0.5 16.0 1 22.0 1.5 22.0 2 19.0 4 11.0 6 5.6 8 3.2 - TABLE 7
Use of Data for 2- to 8-Hour Stable Elimination Period to Calculate Elimination Rate Constant and Backproject Elimination Curve by Calculating Earlier Values (Bold) for Elimination Confounded by Absorption
Time (h) Plasma concentration (μg/mL) Elimination curve concentration R (elimination – plasma) 0 0 37.8 37.8 0.5 16 32.4 16.4 1 22 27.8 5.8 1.5 22 2 19 19 4 11 11 6 5.6 5.6 8 3.2 3.2
