Chapter 4 - Pharmacokinetics

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Basic Concepts in Pharmacology: What You Need to Know for Each Drug Class, 6e
Chapter 4: Pharmacokinetics
INTRODUCTION
Pharmacokinetics is the mathematical description of the rate and extent of uptake, distribution, and elimination of drugs in the body.
VOLUME OF DISTRIBUTION
Volume of distribution (VD) is a calculation of the apparent volume in which a drug is dissolved.
This definition assumes that the drug is evenly distributed and that metabolism or elimination has not taken place. In reality, it does not correspond to
any real volume:
This equation is very easy to remember. Suppose you take 1000 mg of sugar and dissolve it into a beaker of water. After it has dissolved, you take a
sample of water (let’s say, 10 mL) and determine the concentration of sugar in that sample (e.g., 1 mg/mL). From this finding you can calculate the
volume of water in which the sugar was dissolved, as follows:
1 mg/mL = 1000 mg/volume of water
Thus,
In this case the volume was 1000 mL or 1 L. If you keep the units straight, the equation does not need to be memorized.
Try another one. Suppose 500 mg of “Newdrug” is administered to a medical student. The plasma concentration is 0.01 mg/mL. What is the volume of
distribution?*
The volume of distribution is rather large. Your selected medical student is not, however, a huge water balloon. The only explanation is that the drug is
hiding at some place in the body where it is not recorded by the measurement of plasma concentration. The drug could be lipid soluble and stored in
fat, or it could be bound to plasma proteins. As this example shows, the volume of distribution is a hypothetical volume and not a real volume.
The volume of distribution gives a rough accounting of where a drug goes in the body, especially if you have a feel for the various body fluid
compartments and their sizes (Figure 4–1). In addition, it can be used to calculate the dose of a drug needed to achieve a desired plasma
concentration.
FIGURE 4–1
The various body fluid compartments for a standard 70kg man are illustrated in this figure.
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FIGURE 4–1
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The various body fluid compartments for a standard 70kg man are illustrated in this figure.
*Answer: 50,000 mL or 50 L.
FIRSTORDER KINETICS
The order of a reaction refers to the way in which the concentration of drug or reactant influences the rate of a chemical reaction. For most drugs, we
need only consider firstorder and zeroorder.
Most drugs disappear from plasma by processes that are concentrationdependent, which results in firstorder kinetics. With firstorder
elimination, a constant percentage of the drug is lost per unit time. An elimination rate constant can be described.
The elimination rate constant is ke (units are 1/time). On a log plot, the curve is linear and the slope of the line is equal to ke/2.303. (The factor 2.303
converts from natural log to base 10 log units.)
The halflife (t1/2) is the period of time required for the concentration of a drug to decrease by onehalf.
The halflife, or t1/2, is shown graphically in Figure 4–2.
FIGURE 4–2
The determination of the halflife (t1/2) of a drug with firstorder kinetics is illustrated. The drug concentration is graphed against the time. The time it
takes for the concentration to decrease by 50% is indicated at two places on the curve. The t1/2 is the same for both determinations.
The halflife is constant and related to ke for drugs that have firstorder kinetics.
t1/2 = 0.693/ke
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The halflife is constant and related to ke for drugs that have firstorder kinetics.
t1/2 = 0.693/ke
Firstorder elimination rate
Clearance of a drug is different from the elimination rate.
Remember clearance? As explained in Chapter 3, it’s the volume of fluid cleared of a drug per unit time. In contrast, the elimination rate is the rate of
removal of drug with the units of weight per unit time. For drugs with firstorder kinetics, clearance and elimination rate are related, as shown in the
following equation:
For drugs with firstorder kinetics, the VD, t1/2, ke, and clearance are all interrelated.
ZEROORDER KINETICS
Drugs that saturate routes of elimination disappear from plasma in a non–concentrationdependent manner, which is zeroorder kinetics.
Metabolism in the liver, which involves specific enzymes, is one of the most important factors that contribute to a drug having zeroorder kinetics. The
most common examples of drugs that have zeroorder kinetics are aspirin, phenytoin, and ethanol. Many drugs will show zeroorder kinetics at high,
or toxic, concentrations.
For drugs with zeroorder kinetics, a constant amount of drug is lost per unit time. The halflife is not constant but depends on the concentration.
The higher the concentration, the longer the t1/2. This is illustrated in Figure 4–3. Because the t1/2 changes as the drug concentration declines, the zero
order t1/2 has little practical significance.
FIGURE 4–3
A drug showing zeroorder elimination kinetics is illustrated here. On the left, the drug concentration is plotted on a linear scale and on the right, on a
logarithmic scale. Notice that drugs with zeroorder kinetics show a straight line on the linear scale. Try calculating the halflife of this drug in at least
two different places. Do you get the same value?
FIGURE 4–3
A drug showing zeroorder elimination kinetics is illustrated here. On the left, the drug concentration is plotted on a linear scale and on the right, on a
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logarithmic scale. Notice that drugs with zeroorder kinetics show a straight line on the linear scale. Try calculating the halflife of this drug in at least
two different places. Do you get the same value?
Zeroorder kinetics is also known as nonlinear or dosedependent kinetics.
You will see the terms zeroorder, nonlinear, and dosedependent used interchangeably in the medical literature. The term dosedependent refers to
drugs that are firstorder at lower doses and switch to zeroorder at higher doses (often in the therapeutic range). Therefore, the kinetics of these
drugs are dosedependent. Nonlinear refers to the fact that drugs with zeroorder kinetics do not show a linear relationship between drug dose and
plasma concentration.
STEADYSTATE CONCENTRATION
With multiple dosing, or a continuous infusion, a drug will accumulate until the amount administrated per unit time is equal to the amount
eliminated per unit time. The plasma concentration at this point is called the steadystate concentration (Css).
Rarely are drugs given as a single dose. Normally repeated doses are given, and sometimes drugs are given as a continuous intravenous (IV) infusion.
When a drug is given as a continuous infusion, it will increase in concentration in the blood until the rate of elimination is equal to the infusion rate
(Figure 4–4).
FIGURE 4–4
A continuous intravenous (IV) infusion of a drug was started at the beginning point of the graph. The concentration of the drug in the plasma was
followed over time. When the amount delivered in a unit of time is equal to the amount eliminated in the same time unit, the plasma concentration is
said to have reached steady state.
Let’s consider a patient who has no drug in his system. You start an IV infusion at 100 mg/min. At first the plasma level will be low and the infusion rate
will be greater than the elimination rate. The plasma level will rise relatively quickly. Remember that the elimination rate is proportional to the plasma
concentration of the drug, so as the concentration rises so does the elimination rate. As the elimination rate increases with the increasing plasma
concentration, the rate of increase in the plasma level will slow down. At steady state, the infusion rate and the elimination rate are equal.
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Let’s consider a patient who has no drug in his system. You start an IV infusion at 100 mg/min. At first the plasma level will be low and the infusion rate
will be greater than the elimination rate. The plasma level will rise relatively quickly. Remember that the elimination rate is proportional to the plasma
concentration of the drug, so as the concentration rises so does the elimination rate. As the elimination rate increases with the increasing plasma
concentration, the rate of increase in the plasma level will slow down. At steady state, the infusion rate and the elimination rate are equal.
For an IV infusion,
Notice the direct relationship between Css and the infusion rate (assuming clearance is constant). If we double the infusion rate, the Css doubles.
There is also a concentration at steady state for repeated doses. Some textbooks call this an average concentration (Cav). With multiple dosing
schedules, we normally assume that early doses of the drug do not affect the pharmacokinetics of subsequent doses. Generally, we also give equal
doses at equal time intervals.
Repeated dosing is associated with peak and trough plasma concentrations.
With repeated dosing, the concentration fluctuates around a mean (steadystate value) with peak and trough values. Here, steady state is achieved
when the dose administered and the amount eliminated in a given dosing interval is the same (Figure 4–5). The goal is to have the concentration
remain within the therapeutic window, where it is effective, but not toxic. Sometimes this is not the case with a chosen dosing schedule. Either the peak
reaches into the toxic range, in which case the patient experiences side effects, or the trough drops too low and the drug is no longer effective. Both of
these problems can be solved by adjusting the dose and dosing schedule.
FIGURE 4–5
This graph shows the change in concentration with repeated doses. Peak and trough levels are indicated, as well as the steadystate concentration (or
average concentration).
TIME NEEDED TO REACH STEADY STATE
So far we’ve focused on the concentration at steady state. Now let’s consider the time it takes to reach this steadystate concentration.
The time needed to reach steady state depends only on the halflife of the drug. Ninety percent of steady state is reached in 3.3 halflives.
There is a good bit of math behind these numbers, which you can read about elsewhere if you want. Remember that to have a halflife, the drug has to
follow firstorder elimination kinetics.
The bottom line is that during each halflife, 50% of the change from the starting point to Css is achieved. After one halflife, we gain 50% of the Css. We
have 50% of the distance remaining. In the next halflife, we will gain 50% of this remaining distance, or 1/2 of 50%, which is 25%. So, after two half
lives, we will be 75% of the way to steady state. If you repeat this several times, you can generate Table 4–1. Notice that after five halflives, we are still
The time needed to reach steady state depends only on the halflife of the drug. Ninety percent of steady state is reached in 3.3 halflives.
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There is a good bit of math behind these numbers, which you can read about elsewhere if you want. Remember that to have a halflife, the drug has to
follow firstorder elimination kinetics.
The bottom line is that during each halflife, 50% of the change from the starting point to Css is achieved. After one halflife, we gain 50% of the Css. We
have 50% of the distance remaining. In the next halflife, we will gain 50% of this remaining distance, or 1/2 of 50%, which is 25%. So, after two half
lives, we will be 75% of the way to steady state. If you repeat this several times, you can generate Table 4–1. Notice that after five halflives, we are still
approaching steady state.
TABLE 4–1
Percentage of Steady State (C s s) Achieved after Every HalfLife (t 1 / 2)
No. of t 1 / 2 % C s s
1 50
2 75
3 88
3.3 90
4 94
5 97
When asked the question, how long does it take to get to steady state, some sources accept 3.3 halflives (90% of Css), whereas others use 4 halflives
(94% of Css), and still others accept 5 halflives (97% of Css). Check your textbook or lecture notes.
LOADING DOSE
If the halflife of a drug is relatively long, such as ~6 days for digitoxin, it will take quite a long time for the drug concentration to reach steady state
(about four times the halflife). For digitoxin, this would take over 3 weeks. Sometimes the patient can’t wait that long for the therapeutic effect to
occur. In these instances, a loading dose is used.
A loading dose is a single large dose of a drug that is used to raise the plasma concentration to a therapeutic level more quickly than would occur
through repeated smaller doses.
A single dose of a drug can be given that will result in the desired plasma concentration. This dose is called a loading dose if followed by repeated
doses or a continuous infusion that will maintain the plasma concentration at the desired level (termed maintenance doses).
As you can see in Figure 4–6, as the concentration begins to decline after the loading dose, the concentration contributed by the continuous infusion
begins to increase.
FIGURE 4–6
In A, the change in drug concentration as a function of time after an intravenous (IV) bolus is presented. In B, the change in drug concentration as a
function of time after the start of a continuous IV infusion is presented. In C, both the bolus and the continuous infusion are given at time 0. The IV
bolus is the loading dose. Notice how quickly the plasma concentration reaches the steadystate concentration with this technique.
FIGURE 4–6
In A, the change in drug concentration as a function of time after an intravenous (IV) bolus is presented. In B, the change in drug concentration as a
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function of time after the start of a continuous IV infusion is presented. In C, both the bolus and the continuous infusion are given at time 0. The IV
bolus is the loading dose. Notice how quickly the plasma concentration reaches the steadystate concentration with this technique.

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