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2 ESSENTIAL PHARMACOLOGY
mechanisms of action were not understood. In the modern era, as
we unravel the mechanisms of action of drugs, we find that the vast
majority of drugs used as medicines act not by creating novel processes
in the body, but instead by modulating existing signaling mechanisms in
the body. That is, they alter the internal “language” of the body, the roles
of hormones, neurotransmitters, and other signaling molecules. This is
the central theme of this book, which attempts to outline the principles
behind the current use of medicines and the development of new drugs
in the pharmaceutical industry.
The book has been written in the hope that it will be valuable for
readers at several levels. It may serve as a general introduction to phar-
macology and medicine for nonprofessionals who would like to have
a better understanding of the recommendations of their physicians
or pharmacists. It may serve to provide those involved in public pol-
icy with a better understanding of the promise and limitations of the
medical establishment and the pharmaceutical research enterprise. It
may provide a concise picture of the state of the art in pharmacology
for medical students, healthcare professionals, or practicing scientists
working in related disciplines. The presentation is intended to be at
a level that is comprehensible to anyone who has completed upper-
level high school or introductory college courses in mathematics and
natural sciences. Fortunately, this allows a fairly sophisticated presen-
tation of the material since the level and quality of science education
have increased tremendously in recent decades. The book may also be
particularly valuable for students who might want to consider a career
in basic pharmacology research or drug development.
3
A. In the most general sense, pharmacology is the study of the inter-
action of chemical agents with biological systems. In this book,
the emphasis will be on the human organism and its pathogens.
The chemical agents can be divided into:
1. Drugs – possessing potentially useful therapeutic actions
2. Poisons – possessing only undesirable and/or toxic actions
Although the book focuses only on the first class of agents, drugs,
it is important to remember that any drug, if used improperly,
may have toxic effects.
B. Pharmacology is a “bridge” science that integrates information
from other basic disciplines (biochemistry, physiology, anat-
omy, microbiology, etc.) in order to develop a rational approach
to therapy.
4 ESSENTIAL PHARMACOLOGY
C. Pharmacology is broadly divided into two distinct areas, with
similar- sounding names but very different meanings:
Pharmacokinetics– “what the body does to drugs” (includes
absorption, distribution, metabolism, and excretion of drugs).
Pharmacodynamics– “what drugs do to the body” (includes
descriptions of effects on organ systems, tissues, cells, endog-
enous molecules, as well as explanations for therapeutic and/
or toxic actions).
5
Chapter 3
Movement of Drugs to and
from Sites of Action
F
or physicians, a major objective is to deliver a given drug to
its therapeutic site of action in a patient. This is not a sim-
ple task, since the human body is designed to protect itself
from foreign compounds by providing barriers to the movement
of small molecules into the body as well as mechanisms to destroy
or remove foreign compounds. As drugs move to and from sites of
action in the body, they must cross a number of barriers and are
exposed to a number of irrelevant binding sites, as summarized in
Figure 3.1.
6 ESSENTIAL PHARMACOLOGY
There are a number of mechanisms involved in the movement of
drugs across barriers in the body. These include the following:
1. Passive diffusion: This is governed by Fick’s law, which
states that the flux of molecules through a barrier is deter-
mined by the concentration gradient of the drug through the
barrier and an intrinsic permeability coefficient reflecting the
physicochemical properties of the drug and of the compart-
ment or membrane it is passing through (F=– P × dc/dx, i.e.,
the flux or flow of drug (F) equals the permeability coefficient
(P) times the concentration gradient in the direction (x) of dif-
fusion (dc/dx)). This fundamental law works in favor of the
physician: the negative sign indicates that drugs always try to
move down their concentration gradient and thereby into all
parts of the body.
Locus of
action
"receptors"
Tissue
reservoirs
Bound
Free
Free
Bound
Systemic
circulation
Absorption
Free drug
Excretion
Bound drug Metabolites
Biotransformation
Schematic representation of the interrelationship of the absorption,
distribution, binding, biotransformation, and excretion of a drug and its
concentration at its locus of action.
SOURCE:-
th
edition, 1985. Figure 1.1 / with permission of McGraw Hill LLC.
Movement ofDrugs toand fromSites ofAction 7
2. Cell membranes present a hydrophobic lipid barrier through
which “greasy” drugs will pass more easily.
3. Aqueous pores in membranes permit rapid movement of
charged or hydrophilic molecules (e.g., capillary fenestrations).
4. Permeability may be enhanced by the association of the drug
with carrier proteins in membranes (e.g., the passive movement
of glucose into muscle down its concentration gradient).
5. Diffusion of hydrophobic substances in aqueous compartments
can be enhanced by binding to carrier proteins (e.g., hydropho-
bic drugs bound to serum albumin).
Some drugs that are similar in structure to endogenous molecules
(e.g., metabolites or hormones) may be moved across membranes
by active transport processes. This can occur against concentration
gradients, in the opposite direction to passive diffusion.
Some examples are as follows:
1. Absorption of glucose in intestines and renal tubules
2. Secretion in renal tubules and choroid plexus
3. Energy is often provided by a Na
+
gradient, proton pumps, or
cellular ATP
4. Endocytosis of proteins (e.g., IgG– toxin complexes)
For rapid distribution in the body, drugs must usually have some
hydrophobic character in order to cross membrane barriers while
also have sufficient hydrophilic character to remain soluble in
blood and tissue fluids. This paradox is resolved frequently in phar-
macology by designing drugs that are charged (and thus very hydro-
philic) part of the time and uncharged (and more hydrophobic) part
of the time. This occurs naturally if the drug is a weak acid or base
that picks up or releases the hydrogen ion (H
+
, also simply referred
to as a “proton”). However, the acid/base characteristics of a drug
8 ESSENTIAL PHARMACOLOGY
also have dramatic consequences on the distribution of the drug in
compartments in the body of different pH, as analyzed below.
1. First it is convenient to define an acid as a compound that becomes
negatively charged upon releasing a proton (HA <=> H
+
+ A
−
)
and a base as a compound that becomes neutral upon releasing
a proton (BH
+
<=> H
+
+ B). (As examples, think of carboxyl
groups– acids and amino groups– bases).
2. Ionized species are usually more water soluble (hydrophilic) and
poorly membrane permeant.
3. Unionized species are usually more lipid soluble and mem-
brane permeant.
4. The concentrations of the ionized and un- ionized forms present
in a body compartment at a given pH can be determined from
the Henderson– Hasselbalch equation. This is simply derived
from the definition of the dissociation constant for the acid
(orbase), K
a
, as follows:
HA <=> H
+
+ A
–
K
a
= [H
+
][A
–
]/[HA]
log K
a
= log [H
+
] + log [A
–
]/[HA]
pK
a
= pH– log [A
–
]/[HA]
The most useful form of this equation for calculation of drug
partition between compartments is
pH pK
AH
A
a
lo
g/
For a base (BH
+
<=> H
+
+ B), the same formulation applies:
pH − pK
a
=log[B]/[BH
+
]
Notice that in both cases the protonated species is on the
bottom of the ratio, and the ratio of concentration of the dif-
ferent forms is determined by how distant the pKa is from the
ambient pH of the solution.
The example below is for the partition of a weak acid
with a pKa of 4.4 (e.g., acetic acid) between gastric juice
Movement ofDrugs toand fromSites ofAction 9
(pH = 1.4) and plasma (pH = 7.4). It is essential to realize that
the concentration of the permeant species (HA) is equal in both
compartments (at equilibrium), and so we have set it equal
to one in both compartments for the calculation, but that the
total drug in each compartment is the sum of both species. At
pH 7.4,
log/[].][A HA 30
and
[]/[ ]A HA 10
3
, while at pH 1.4,
log/[] .][A HA
30
and [A
−
]/[HA]=10
−3
. Notice that the result
of the calculation is that the acidic drug is present (at equilib-
rium) at a concentration 1000- fold higher in the plasma than in
the stomach (Figure3.2).
For a similar calculation of the distribution of a basic
drug (e.g., pKa 8.4) across a membrane, we would assume the
uncharged form (B without the proton) would come to equal
concentration (1) on both sides of the membrane. The calcu-
lation would indicate that the total drug would be at a much
higher concentration (almost a millionfold higher!) in the acidic
environment of the stomach (Figure3.3).
This type of distribution has practical implications. For example,
basic drugs that are toxins (e.g., strychnine) can be removed from
Weak acid pKa = 4.4
pH − pKa = log
Total drug
Gastric juice
pH = 1.4
pH 7.4 plasma
==
[AH]
HA
1 1000
H
+
+ A
−
[A
−
]
[AH]
[A
−
]
1.001
1001
1000
= 1000
7.4−4.4 = 3.0
pH − pKa = log
[AH]
[A
−
]
[AH]
[A
−
]
= .001
1.4−4.4 = −3.0
HA
1
.001
H
+
+ A
−
Plasma
Gastric juice
Calculation of the distribution of a weak acid across a semipermeable
10 ESSENTIAL PHARMACOLOGY
the body by lavage of the stomach with an acidic solution. The
acidic compartment of the stomach acts as a “pump” to extract
the basic toxin from the bloodstream.
It is a helpful mnemonic to remember that “Opposites
Attract,” i.e., acidic drugs accumulate in the more basic com-
partments and basic drugs accumulate in the more acidic
compartments.
5. Effect of pH on drug absorption and urinary excretion.
(a) In principle, acidic drugs would be expected to be absorbed
more readily from the stomach than the intestine because
the low pH of the stomach results in a higher concentration
of uncharged (protonated) drug. However, the absorptive
surface area of the intestine is so much greater that most
drugs are primarily absorbed from the intestine.
(b) Acids are more rapidly excreted by the kidney as urinary pH
is increased (e.g., by administering sodium bicarbonate to
the patient) because the rate of tubular reabsorption of the
charged drug (A
–
) decreases. Because of the large surface
area of the kidney tubules, the distribution of a drug that
is undergoing passive diffusion approaches equilibrium, so
Weak base pKa = 8.4
pH − pka = log
Ratio of total drug
Gastric
juice = 1.4
pH 7.4
plasma
Gastric juice
==
[BH
+
]
BH
+
10 1
B + H
+
[B]
[BH
+
]
[B]
11
10
7
+1
9.1 ×10
5
= 0.1
7.4−8.4 = −1
pH − pka = log
[BH
+
]
[B]
[BH
+
]
[B]
= 10
−7
1.4−8.4 = −7
BH
+
10
7
1
B + H
+
Plasma
Calculation of the distribution of a weak base across a
Movement ofDrugs toand fromSites ofAction 11
the rules derived above regarding the distribution of drugs
between compartments also apply.
(c) Conversely, bases will be more rapidly excreted as urinary
pH is decreased, thereby increasing the charged form of the
base (BH
+
) in the kidney tubules. This can be accomplished
by administering ammonium chloride, or – as a practical
matter – acidic cranberry juice. Drug enforcement agents
have been known to drink cranberry juice prior to entering
illicit labs manufacturing basic drugs like amphetamines in
order to enhance excretion of the drugs in the kidney after they
are inhaled in the environment of the lab.
6. To understand the behavior of a given drug, you must determine
if it is an acid or a base. Usually this can be determined from the
structure.
(a) Easy: compounds that contain carboxylate, phosphate, or
sulfate moieties (acids), and amino N functions (primary,
secondary, or tertiary) (bases).
(b) Not so easy: compounds that contain N in ureide or sulfona-
mide structures; these are acids (release H
+
) as shown.
Ureide structure (uric acid, barbiturates, phenytoin)
R
1
R
2
R
3
HO
NN
Sulfonamide structure
C
O
O
RNH
2
S
O
O
−
RNH + H
+
S
R
1
R
2
R
3
OH
NN
CR
1
R
2
R
3
O
−
NN
H
+
+
C
(c) Note that ordinary amides (e.g., peptide bonds) do not ionize
at physiological pH, and so may diffuse readily through mem-
branes. But quaternary amines, e.g., acetylcholine, are ion-
ized at all pH values and so cannot pass through membranes.
Additional examples are provided in Figure 3.4.
Amides Peptide bonds Quaternary amines
CH
3
CH
3
CH
3
N
+
R
O
RNH
2
CR
1
HO
CR
2
N