Lecture 67

Question 1

distribution

Answer 1

• movement of a drug to and from the blood and various tissues of the body (fat, muscle, and brain) and the relative proportions of drug in those tissues
• D = C₀ × V_d
• volume of distribution (V_d) = extrapolated volume calculated from C₀ (NOT a physical volume)
• D = IV dose or total dose absorbed
• C₀ = determined from the graph by extrapolating the fit to the elimination phase to t = 0
• thus, C₀ ≠ concentration of IV dose at time 0

pg 1724

Question 2

The concentration of the drug in plasma is used to monitor therapeutic drug levels. Why?

Answer 2

Because the concentration of drug in the organ is often difficult to measure and it reflects the concentration in the body (one compartment)

pg 1725

Question 3

Following an intravenous dose, the drug experiences which of the following?

A. only distribution
B. distribution and elimination
C. elimination
D. absorption, distribution, and elimination

Answer 3

B. distribution and elimination

pg 1726

Question 4

drug distribution and total body water

Answer 4

• normal body weight = 70 kg
• total body water = 70% = 49 L
• extracellular = 26% = 18 L → plasma volume = 6% = 4 L → interstitial volume = 20% = 14 L
• intracellular = 44% = 31 L
• if volume of distribution is less than 4 L, drug is retained in plasma/vascular compartment
• between 4 L and 18 L, drug is restricted to extracellular fluid
• greater than 18 L, drug is distributed throughout total body

pg 1727-1728

Question 5

the plasma compartment

Answer 5

• drugs with large MW or those bind to plasma proteins are too large to move out through the endothelial slit junctions of capillaries
• thus, they are restricted within the vascular compartment

pg 1729

Question 6

A and B are two drugs of equal potencies. A is distributed among body tissues&raquo_space;> B. Which drug requires a higher initial dose?

A. A
B. B

Answer 6

• Since drug A is distributed more widely across body tissues, a larger initial dose is needed to achieve the same therapeutic concentration in the bloodstream as drug B.
• highly absorbed drug (high bioavailability) → needs LOWER dose
• highly distributed drug (high V_d) → needs HIGHER dose

pg 1730-1731

Question 7

extracellular fluid (ECF)

Answer 7

• lipophilic drugs with low MW move through the endothelial slit junctions of capillaries into the interstitial fluid but cannot enter the cells
• V_d is restricted to the ECF volume (~18 L)

pg 1732

Question 8

plasma protein binding

Answer 8

albumin:

• responsible for most drug binding
• only the free unbound drug is diffusing across membranes, binding with receptors and doing the action
• highly protein-bound drugs remain within the vasculature (low V_d)
• coadministration of 2 drugs can compete for the same binding sites → release more than expected and the plasma concentration of the free drug(s) is increased (therapeutic and/or toxic effects)
• need to adjust dosing of one or both to keep the free drug concentration in the therapeutic range

pg 1733

Question 9

A and B are 2 drugs of equal potencies. B is highly bound to albumin > A. Which drug requires a higher initial dose?

A. A
B. B

Answer 9

B needs a higher dose to establish a therapeutic plasma concentration

pg 1734-1735

Question 10

modeling the kinetics of drug distribution

Answer 10

• the drug distributes rapidly into other compartments
• after equilibrium between compartments, the drug is eliminated from circulation
• both drug distribution and elimination display 1st-order kinetics, on a semilogarithmic plot
• extrapolate the linear elimination back to time 0 to determine the initial plasma concentration
• plasma drug concentration decreases more slowly during the elimination phase because the drug’s “reservoir” in tissues allow it to circulate back into the blood to replace the drug that has been eliminated

pg 1736

Question 11

volume of distribution and body weight

Answer 11

• V_d depends upon body size and may be quoted as L/kg body weight (typically based on 70 kg ideal adult body weight)
• V_d = total dose administered / plasma concentration = D/C₀

pg 1737

Question 12

how do we assess V_d?

Answer 12

V_d is determined when drug distribution between the plasma and the tissues is at equilibrium → when the elimination phase is reached

pg 1738

Question 13

A 39-year-old female is given a dose (420 mg) of a drug X. The distribution curve of the drug is shown. What is the V_d of the drug?

A. 25 L
B. 35 L
C. 15 L
D. 45 L

Answer 13

V_d = total dose administered / plasma concentration = D/C₀

V = 420 mg / 12 mg/L = 35 L (B)

pg 1739-1740

Question 14

clinical applications: therapeutic dosing and frequency

Answer 14

accumulation to steady state → when 100 mg of drug are given every half-life, it takes roughly 4 half-lives to reach steady state (keeps the drug level within therapeutic window)

pg 1741

Question 15

After a person ingests an overdose of an opioid analgesic, the plasma drug concentration is found to be 32 mg/L. How long will it take to reach a safe plasma concentration of 2 mg/L if the drug’s half-life is 6 hours?

A. 12 hours
B. 24 hours
C. 48 hours
D. 72 hours
E. 1 week

Answer 15

B. 24 hours

pg 1742

Question 16

steady-state concentration

Answer 16

• steady-state concentration is achieved when the rate of drug input = drug output
• when using therapeutic dosing, the first dose may not reach therapeutic level; requires 4 t_1/2 to remain in therapeutic window
• using a loading dose (greater than maintenance dose) eliminates the need for those 4 t_1/2 by providing enough drug to attain steady state at therapeutic level after only 1 or 2 doses of drug
• excessive dosing frequency accumulates drug = toxicity
• insufficient dosing frequency = subtherapeutic steady state concentration
• need to maintain the peak plasma concentration below toxic and the trough concentration above minimum effective concentration

pg 1743

Question 17

example of steady state concentration

Answer 17

• same average C_ss is achieved via 3 different doses and dosing intervals
• frequent small doses is inconvenient
• infrequent large doses lead to fluctuation which leads to toxic peaks and subtherapeutic troughs
• continuous infusion is best for steady state

pg 1744

Question 18

dose adjustments to switch from oral to intravenous

Answer 18

• dose_new = (dose_current × bioavailability_current) ÷ bioavailability_new
• dose_ORAL = (dose_IV × bioavailability_IV) ÷ bioavailability_ORAL

pg 1745

Question 19

A 52-year-old man presents to the office for routine follow up. Currently, he is under treatment for HTN and CHF with 20 mg furosemide IV. His BP is under acceptable control, and he has no symptoms of heart failure at present. The physician decided to prescribe an oral furosemide, bioavailability = 50% for him. What will be the value of the oral dose?

A. 25 mg
B. 35 mg
C. 40 mg
D. 41 mg

Answer 19

dose_oral = (20 mg)(100%)/(50%) = 40 mg (C)

pg 1746

Question 20

loading dose (LD)

Answer 20

• loading dose is given to achieve therapeutic levels of the drug at steady state
• the distribution then decreases it
• loading dose depends on V_d and is generally 2-3x maintaining dose
• LD = V_d × C_ss

pg 1747

Question 21

maintenance dose (MD)

Answer 21

• once steady state is met, maintenance doses are needed
• maintenance dose depends on drug clearance (Cl)
• MD = Cl × C_ss

pg 1748

Question 22

Lidocaine has a V_d = 77 L. The C_ss is 3.5 mg/L, needed to control ventricular arrhythmias. What is the appropriate LD?

Answer 22

LD = 77 L x 3.5 mg/L = 269.5 mg

pg 1749

Question 23

A 45-year-old male weighs 70 kg and his volume of distribution is 0.25 L/kg for drug X. The plasma concentration at steady state = 2.5 mg/L and the clearance rate is 25 L/hr. What is the loading dose for drug X?

A. 43.75 mg
B. 53.75 mg
C. 33.75 mg
D. 40.75 mg

Answer 23

LD = V_d × C_ss
LD = (0.25 L/kg)(70 kg)(2.5 mg/L)
LD = 43.75 mg (A)

pg 1750-1751

Question 24

A 45-year-old male weighs 70 kg and his volume of distribution is 0.25 L/kg for drug X. The plasma concentration at steady state = 2.5 mg/L and the clearance rate is 25 L/hr. What is the maintenance dose for drug X?

A. 37.5 mg
B. 62.5 mg
C. 33.5 mg
D. 43.7 mg

Answer 24

MD = Cl × C_ss
MD = (25 L/hr)(2.5 mg/L) = 62.5 mg (B)

pg 1752-1753