GENERAL PRINCIPLES IN

PHARMACOLOGY
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General Principles in Pharmacology

How drug concentrations change in plasma.

The table (right) shows concentrations of a drug in

Plasma Drug Level
plasma at different times after giving the dose. Time (hours)
(µg/mL)
The concentration of a drug, call it C, changes as a 0 12
function of time (t) according to the relation:
1 10
C = f(t) 2 8

In the table the concentration of drug is decreasing 2 3 6

µg/mL every hour. To determine the rate of change of 4 4
drug concentrations we take the derivative of C and 5 2
express it as:
dC/dt = 2µg/mL/hr
The original relation for C is given by:
Figure 2.2 Shargel et al (2005)
C = f(t) = 12 -2t
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General Principles in Pharmacology

Rates and Orders of Reactions – Zero Order Reactions
Time (hr) [Drug] mg/mL
0 100
If the amount of drug C is decreasing at a constant time
2 95
interval, t, then the rate of disappearance of drug C is
4 90
expressed as:
6 85
𝑑𝑑𝑑𝑑
= -k0 8 80
𝑑𝑑𝑑𝑑
10 75
12 70
The term k0 is the zero-order rate constant and is
expressed in units of mass/time (e.g. mg/min). C0
110

Integration of this relation produces the expression: 100

Slope = -k0
90

[Drug] mg/mL
C = -k0t + C0 80

70

60
Where C0 is the amount of drug at t=0 (initial [drug]).
50
A graph of C versus t yields a straight line.
40
The y-intercept is equal to C0 and the slope is -k0. 0 2 4 6 8 10 12 14
Time (hr)
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General Principles in Pharmacology

Rates and Orders of Reactions – Zero Order Reactions
The zero-order rate constant, -k0 can be found by working out the slope of the line, or using the
equation.
If C0 = concentration of drug at time zero (t=0), this is 100mg/mL from the table.
And C = concentration of drug at time 4hr (t=4), this is 90 mg/mL from the table.

Then using the equation C = -k0t + C0

90 = -k04 + 100 Or you can calculate the slope, K0 this way:

90-100 = -4k0
K0 = 5mg/mL
-10 = -4k0 2hr
= 2.5 mg/mL hr
10/4 = k0

k0 = 2.5 mg/mL hr

So the drug is decreasing at the rate of 2.5 mg/mL hr.

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General Principles in Pharmacology

Rates and Orders of Reactions – First Order Reactions
[Drug] Log
Time (hr)
If the amount of drug C is decreasing at a rate that is proportional to the mg/mL [Drug]
amount of drug C remaining, then the rate of disappearance of drug C is
0 100.00 2.00
expressed as:
𝑑𝑑𝑑𝑑
= -kC 4 50.00 1.70
𝑑𝑑𝑑𝑑
8 25.00 1.40
Where k is the first-order rate constant with the units of time-1 (e.g. hr-1).
12 12.50 1.10
Integration of this relation produces:
16 6.25 0.80
C = C0e-kt
20 3.13 0.50
If you take the natural logarithm it becomes:
24 1.56 0.20
lnC = -kt + lnC0

It is easier to work in log10 so we can rewrite this as: Let us consider the table above as an example.

log10C = -kt/2.3 + log10C0

So, this is plotted as a straight line, with y-intercept C0 and slope = -k/2.3
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General Principles in Pharmacology

Rates and Orders of Reactions – First Order Reactions
We can graph the data in two ways:
In the top graph we can see how the drug concentration halves every 4 hours
120.00
(this is an exponential decline) when the axis scales are linear.
100.00
[Drug] mg/mL

80.00

60.00
In the bottom graph, which is a semilog plot, this relationship becomes a
40.00
straight line.
20.00

0.00 Now we can use the straight line to find the slope (or the rate constant of
0 5 10 15 20 25 30
Time (hr)
decline of drug).
2.50
The first-order rate constant is found by the product of the slope and 2.3:
2.00
log [Drug]

1.50
Slope = -k = log y2 – log y1 OR k = 0.693 = 0.693 = 0.173hr-1
1.00 2.3 x2 – x1 t½ 4
0.50

0.00
-k = 2.3 (log 50 – log 100) = 0.173 hr-1
0 5 10 15 20 25 30 4–0
Time (hr)
So either method will work to find k.
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General Principles in Pharmacology

One Compartment Open Model
The rate of elimination of most drugs from the body is a first-order process. So the rate of
elimination is dependent on the amount of drug present in the body. The elimination rate
constant, k has the units of time-1 (e.g. hour -1)
Generally the drug is measured in the blood (can’t really measure it in the tissues).

For complete removal of the drug from the body, there are 2 main processes involved:

 Metabolism (where the liver biotransforms the drug for excretion)

 Elimination (where usually the kidneys remove the drug in urine)

We can write this as: k = km + ke

km is the first order rate constant for the metabolism of the drug
ke is the first order rate constant for the elimination of the drug

So when we use k we need to remember that there really are 2 parts to it.
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General Principles in Pharmacology

One Compartment Open Model
If we use a simple model for human body tissues, we can estimate how much drug is in the body at any
given time after it has been administered.

The simplest model is to assume the human body behaves like one big compartment with the drug
dissolved in all of it at once and equally distributed through it.

This is also an open mode, because we can add drug to it, and drug can leave it (elimination). So the
[drug] in the body will decrease over time after stopping administration of it.

IV k
DB, VD Elimination
Dose

Where DB is the amount of drug in the body

VD is the volume of distribution of the body
k is the elimination rate constant
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General Principles in Pharmacology

One Compartment Open Model
This model shows that the rate of elimination of drug in the body is a first-order process depending on the
overall elimination rate constant, k, and the amount of drug in the body, DB, remaining at any given time, t.
𝐷𝐷𝐵𝐵0
Mathematically it looks like this:
100

𝑑𝑑𝑑𝑑𝐵𝐵
= -kDB
𝑑𝑑𝑑𝑑

Drug in body (DB)

−𝑘𝑘𝑘𝑘
Integration of this produces: Slope =
2.3
10

DB = 𝐷𝐷𝐵𝐵0 𝑒𝑒 −𝑘𝑘𝑘𝑘

If we take the logarithm it becomes:

1
−𝑘𝑘𝑘𝑘
log DB = + log 𝐷𝐷𝐵𝐵0 0 1 2 3 4 5
2.3 Time

𝐷𝐷𝐵𝐵0 is the amount of drug initially in the body

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General Principles in Pharmacology

One Compartment Open Model
Now we need to consider the apparent volume of distribution of drug in the body (VD).

In general a drug introduced into the body will equilibrate into most tissues very quickly, but it does depend
on a few things:
 How the drug is taken (oral, IV, IM, patch, inhaled, etc.)
 How easily it moves into the tissue cells (so how lipophilic it is to go through cell
membranes)

Since we never really know how well the drug has distributed into the tissues, we talk about the apparent
volume of distribution.

Also, we can’t just sample any tissue in the body, rather we sample convenient fluids like blood and urine.

Usually we can assume the volume of distribution from the plasma concentration (CP) and it is related to VD
this way:

DB = VD x CP

So the concentration of drug in the body (DB) is equal to the volume of distribution (VD) times the plasma
concentration (CP).
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General Principles in Pharmacology

One Compartment Open Model
CP0
If we rearrange the equation to isolate VD it becomes:
100
𝐷𝐷𝐵𝐵
VD = 𝐶𝐶𝑃𝑃

Plasma Level (Cp)

Since we are interested in plasma concentration after giving
a certain dose of drug we can rewrite this as: 10
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝐷𝐷𝐵𝐵0
VD = =
𝐶𝐶𝑃𝑃0 𝐶𝐶𝑃𝑃0

So we need to determine the plasma concentration at t=0

(instantly after the dose was given), so CP0 , which we can’t 1
0 1 2 3 4 5 6 7 8 9 10
actually measure. But we can measure plasma Time
concentration over time.
In the graph (right) Cp has been plotted against time. Since
this is a straight line (semi-log plot), we can extrapolate
back to t=0 to find out CP0 .

So knowing the dose DB0 and the plasma concentration CP0

we can calculate the volume of distribution (VD).
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General Principles in Pharmacology

One Compartment Open Model
Significance of the volume of distribution (VD)

Why do we bother with this?

Some drugs move into tissues more easily than others. Particularly fat soluble drugs which can move into
the fat tissue of the body.

Other drugs are bound to blood serum proteins and more remains in the circulation, rather than moving into
the tissues.

Once a drug moves into the blood it generally gets transported into the tissues in capillary beds. But how
much of it actually gets there will depend on its lipid solubility.

Also some targeted medicines accumulate in specific tissues.

e.g. Radioactive Iodine used for thyroid diseases will move from the blood and only really into the thyroid
gland.

This changes the dose required because the volume of distribution in the final tissue is very different.
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General Principles in Pharmacology

One Compartment Open Model

Clearance
Clearance of a drug is a measure of drug elimination from the body as a whole ( so it includes the
biotransformation (or metabolism) in the liver and the excretion by the kidneys or any other route.

i.e. It is the volume of plasma fluid volume cleared of drug per unit time.

Example
Let’s say a drug dose of 100mg is given to a patient in a volume of 10mL. So the concentration of the drug
dose
is: 100mg/10mL = 10mg/mL

The volume eliminated might be 1 mL/min of this drug. The concentration eliminated might be 10mg/min.

The only way to test this is to measure drug concentration in the urine over time. Then you can calculate the
clearance of the drug from the body.
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General Principles in Pharmacology

One Compartment Open Model
Some assumptions about clearance of a drug include:

 Plasma volume remains constant over time (water is absorbed by gut and reabsorbed by kidneys)
 Blood flow through the kidneys is constant ( average is 120 mL/min in a healthy adult).
 The rate of drug removal is dependent on the plasma concentration, so it is a first-order process.

Thinking back to drug in the body (DB) we can produce a mathematical relation for clearance (Cl).

𝑑𝑑𝑑𝑑𝐵𝐵
= -kCPVD
𝑑𝑑𝑑𝑑
If we divide both sides by CP we get:
𝑑𝑑𝑑𝑑𝐵𝐵/𝑑𝑑𝑑𝑑 −𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘
=
𝐶𝐶𝑃𝑃 𝐶𝐶𝑃𝑃

𝑑𝑑𝑑𝑑𝐵𝐵/𝑑𝑑𝑑𝑑
Which becomes: = -kVD = Cl k and VD are both constants
𝐶𝐶𝑃𝑃

dDB/dt is rate of drug removal from the body (mg/hr), CP is plasma drug concentration (mg/L), k is first order
rate constant (1/hr or hr-1) and VD is volume of distribution (L). So clearance has units L/hr. (i.e. volume /time)
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General Principles in Pharmacology

One Compartment Open Model
Clearance and volume of distribution ratio Cl/VD
𝑑𝑑𝑑𝑑𝐵𝐵 /𝑑𝑑𝑑𝑑
Finally, for the previous expression: = -kVD = Cl
𝐶𝐶𝑃𝑃

It follows that k = Cl/VD

This is useful to know when we are dealing with real patients and determining how much drug has cleared
from the body.
The One-Compartment Model Equation in terms of Cl and VD

The change in plasma concentration is described by the general relation:

CP = CP0 e-kt substitute Cl/VD for k

OR CP = D0/VD e-(Cl/V )t D since D0 (Dose) = CP/VD

This relation is used in clinical pharmacy. VD and Cl are well documented for the population and plugged into
the equation. The initial dose is known and the time, the plasma concentration can be measured.