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12 ESSENTIAL PHARMACOLOGY
Answer key: Aspirin: acid due to the carboxyl group. Hepa-
rin: acid due to sulfate and carboxyl groups. Pyridoxal phos-
phate: acid due to phosphate group. Histamine: base due
to amino group. Norepinephrine: base due to amino group.
Atropine: base due to nitrogen that can pick up a proton. Uric
acid: acid due to ureide group. Sulfanilamide: acid due to sul-
fonamide group, which becomes negative upon releasing a
COOH
CHC
O
O
Uric acid
Phenytoin Barbituates
General formula:
H
N
NC
C
2
3
5
O(or S ) †
C
R
5a
R
3
R
5b
NH
O
O
O
O
H
N
HN
NH
N
H
7
8
9
6
3
4
5
2
1
N
7
6
O
NCH
3
CH
2
CH
2
NH
2
CH
2
OH
SO
2
NH
2
14
POCH
2
O
HO
HO
CHO
HOCHCH
2
NHCH
3
OH
OH
OH
HN N
OCOCH
3
O
−
CO
OH
O
O
OSO
3
–
SO
3
–
NH
OSO
3
–
O
O
O
HO
CH
2
Aspirin
Heparin
Histamine
Atropine Sulfanilamide
EpinephrinePyridoxal phosphate
CH
3
H
2
N
NC
O
H
O
(Answers are provided below).
Movement ofDrugs toand fromSites ofAction 13
proton (as shown in the text above). The amino group on the
ring does not titrate at physiological pH. Phenytoin: acid due
to ureide structure that can release a proton as shown in the
text above. (Teaching Exercise designed by Theodore W. Rall,
University of Virginia.)
(d) The names of parenteral drug preparations formulated
for intravenous injection can provide a practical clue as to
whether the drug acts as an acid or a base because these
are typically water- soluble salts made by titrating the acid
or base form of the drug. For example, morphine sulfate is
the salt formed by adding sulfuric acid to morphine, the
base. Remember that sulfate is negatively charged, so the
morphine must be positively charged, like our “generic”
base BH
+
, so that the compound is neutral overall. Pheny-
toin sodium is the salt formed by adding sodium hydroxide
to phenytoin, an acid. Remember that sodium is positively
charged, so phenytoin must be negatively charged, like our
generic acid A
–
.
The mechanism, rate, and efficiency of drug absorption are highly
dependent on the route of drug administration. The various routes
of administration can generally be classified as Oral or Parenteral
(i.e., non- oral). (See below for additional details.)
Oral Administration. This is typically the most convenient for
patient compliance, but introduces specific requirements: unless
the drug is picked up by a carrier, it must be fairly lipid soluble
in order to pass through the membrane barriers of the intestinal
epithelium.
1. The patient is responsible for following the drug regimen;
therapy is dependent on patient compliance.
2. The compound must be tolerated; it cannot cause GI distress.
3. Compacted solids must break down before transit of the
gastrointestinal (GI) tract.
14 ESSENTIAL PHARMACOLOGY
4. The compound must be able to withstand “first pass metabo-
lism” in the liver (the drug must first pass through the liver
before being distributed throughout the circulation; the liver
actively metabolizes a wide range of drugs).
5. Sublingual administration avoids first- pass hepatic
metabolism.
6. Rectal administration avoids about 50% of oral first- pass hepatic
metabolism.
7. Influenced by motility of the GI tract – rate of absorption is
slowed by delay in gastric emptying or during sleep; extent of
absorption may be reduced by diarrhea.
8. Takes time– typically 30minutes to an hour before peak levels
in the blood may be reached.
Parenteral (Non- Oral) Administration
1. All forms of parenteral administration avoid hepatic first- pass
metabolism.
2. Intravenous administration circumvents barriers to absorp-
tion: administration can be by single injection, by infusion, or
through the use of a pump (e.g., in pain medication or hormone
administration).
3. Subcutaneous administration: often performed with depot forms
of the drug under the skin that are slowly absorbed because of
low solubility or time- release formulations.
4. Intramuscular, often also applying depot formulations.
5. Intrathecal injection in the brain to bypass the permeability
barrier protecting the central nervous system (CNS).
6. Topical (e.g., skin or mucous membranes): this includes the use
of transdermal patches for sustained delivery of potent, hydro-
phobic compounds.
7. Vaginal administration: mucous membranes provide less of a
barrier than skin.
8. Intranasal: may permit entry of small peptides such as insulin
through olfactory epithelia.
9. Inhalation (e.g., volatile anesthetics).
Movement ofDrugs toand fromSites ofAction 15
These are important considerations for the oral route of
administration.
Bioavailability is a measure of the fraction of the amount of
drug administered that is absorbed into the circulation. It can be
reduced by incomplete absorption from the GI tract or by hepatic
first- pass metabolism.
Two formulations of a given drug are said to be bioequivalent
if they have the same bioavailability. This should result in both for-
mulations of the drug providing the same plasma concentration of
the active compound over time when given in the same dosage.
Since drugs that are given orally pass through the liver, “first-
pass” hepatic metabolism is an important factor in determining bio-
availability. It can be substantially reduced with hepatic disease or
impaired hepatic blood flow in cardiac disease.
Bioavailability is often not 100%, but consistency and/or pre-
dictability is the most important issue.
Digoxin is a notorious example of a drug with bioavailability
that can vary markedly in different brands or lots– due mainly to
variation in dissolution of tablets.
Coatings (to prevent contact with gastric mucosa or to provide
sustained release) can cause incomplete and inconsistent absorp-
tion of a drug that otherwise is readily and reliably absorbed.
In addition to the effects of pH on drugs that are weak acids or
bases, the absorption and diffusion characteristics of a drug may
influence its distribution in the body over time.
1. The “blood- brain barrier (BBB)” may prevent drugs from enter-
ing the CNS or confine drugs to the CNS. The BBB is composed
of cellular structures in the capillary walls in the brain that are
resistant to drug permeation (see Figure3.5).
16 ESSENTIAL PHARMACOLOGY
The barrier is composed of endothelial tight junctions and
glial (astrocyte) pericapillary “end feet.”
The BBB constitutes a cellular barrier similar to that of the
GI epithelium. Drugs and endogenous metabolites exit the cere-
brospinal fluid (CSF) by bulk flow via arachnoid villi + secretion
of organic acids by the choroid plexus. Similar to drug excretion
by transport proteins in kidney tubules.
The BBB is neither absolute nor invariable (e.g., it is reduced
in the neonate and by inflammation).
As a consequence, most drugs designed to enter the CNS
are hydrophobic (so they can permeate cell membranes),
can be taken orally (because they can cross the barriers in
the GI tract), and may need to be metabolized by the liver
into more hydrophilic forms before they can be excreted by
the kidney.
Interneuron
Perivascular macrophage
Microglia
Basal lamina
Tight junction
Pericyt
e
Astrocyte
Capillary
Endothelial cell
structures that comprise the “blood- brain barrier” (BBB) and retard the movement
SOURCE:
Movement ofDrugs toand fromSites ofAction 17
2. Antiparasitic drugs can be confined to the GI tract to act specifi-
cally on intralumenal parasites if the drugs are given orally and
are charged or hydrophilic.
3. Binding to plasma proteins (mainly serum albumin or acid gly-
coprotein) may limit the access of a drug to its target and create
a reservoir of drug. Binding is greater with hydrophobic drugs
and is rather nonselective in that agents with similar physico-
chemical properties but different structures may compete with
one another. Fractional binding is usually relatively independent
of concentration. This is because the large numbers of binding
sites are usually not saturated by the small concentration of drug
needed for a therapeutic effect. However, statements about “%
protein bound” imply “in the therapeutic range,” as illustrated
in Figure3.6.
4. Protein binding can reduce free drug concentration at the locus
of action, at sites of metabolism (e.g., in the liver), and at sites
of excretion (e.g., filtration in the kidney). The bound drug also
2.0
1.8
1.6
1.4
1.2
1.0
0.8
Protein bound drug ug/ml
0.6
0.4
0.2
0.0
0.0 0.5 1.0 1.5 2.0 2.5
Total drug ug/ml
Therapeutic range
Low affinity binding
High affinity binding
3.0 3.5 4.0 4.5
5.0
18 ESSENTIAL PHARMACOLOGY
represents a large reservoir of drug that may take a long time
to be eliminated. Normally these factors are taken into account
in establishing dosing regimens. However, problems can arise if
something unexpected happens:
A decrease in concentration of plasma proteins (e.g., liver
disease or blood loss), or a decrease in fractional binding (e.g.,
displacement by another drug) can lead to an increased concen-
tration of free drug at sites of action. However, this also leads to
increased rates of metabolism and/or urinary excretion. These
effects might be significant, or they might counteract one another
so that the therapeutic effects of the drug are not greatly altered.
There may be serious consequences, however, if a change in
blood pH causes a sudden release of a large reservoir of bound
drug. A notorious example of this is the dumping of the very
hydrophobic local anesthetic bupivacaine (a weak base BH
+
)
from plasma proteins during cardiac arrest due to a drop in pH
caused by applying too much of the drug during epidural anes-
thesia. The binding of the drug is reduced when it is charged
(BH
+
) at low pH. This can occur if the drug is injected directly
into a vein in error. The increased concentration of free anes-
thetic can complicate management of the cardiac arrest.
5. Placental transfer of drugs. Rule of thumb: If the drug can
be absorbed by the mother’s GI tract, it can get to the fetus. The
intestinal tract and the placenta present similar permeability
barriers. To some extent, the fetus can be protected by using a
charged drug that is administered to the mother intravenously
and cannot cross membrane barriers readily.
6. The distribution of local anesthetics or other drugs can be
conveniently confined to specific regions by local coadministra-
tion of vasoconstrictors.
19
Chapter 4
Biotransformation
of Drugs
A
nimals and plants have evolved in environments enriched
in an unimaginably diverse array of small molecules that
can enter the organisms and influence processes dependent
upon endogenous small molecules. Over billions of years diverse
mechanisms have evolved to protect organisms involving modi-
fication of such xenobiotics through destruction, modification,
or excretion. The processes that have evolved are so diverse that
organisms appear to have the ability to defend themselves not only
against this onslaught by chemicals now present, but also against
new molecules that have not existed before but arise through indus-
try and pharmacology. Some generalizations apply to these complex
systems of drug biotransformation as follows.
20 ESSENTIAL PHARMACOLOGY
4.1 Consequences ofDrug Metabolism
1. Drug metabolism often results in compounds that are more
polar, and are therefore more readily excreted by the kidney and
not subject to passive reabsorption in the tubules. This is impor-
tant for clearance of both drugs and environmental toxins.
2. Metabolism usually causes inactivation or reduced activity of
drugs, limiting their effective lifetime in the body.
3. However, sometimes fortuitously, or by deliberate design, drug
metabolism transforms inactive agents to active compounds.
Inactive “prodrugs” are sometimes designed to enhance absorp-
tion and/or bioavailability of the active drug.
4. Although detoxification is usually the end result of biotrans-
formation, intermediates formed during metabolism can cause
serious (and sometimes unforeseen) toxicity, especially when
something distorts the normal metabolic pathway (this is where
drug- drug interactions can become very important).
4.2 Enzymatic Biotransformation Reactions
Many distinct enzyme systems have evolved that can metabolize
foreign compounds. Most drugs are acted on not by a single enzyme,
but by multiple enzymes and multiple pathways involving a series
of reactions that can result in the generation of a complex array of
drug metabolites. The liver is the major site of drug metabolism, but
significant drug metabolism can also occur in the plasma, kidneys,
and lungs.
Often the metabolism of a given drug may proceed through at
least two major steps classified as Phase I and Phase II reactions.
1. Non- synthetic, or Phase I reactions may initially modify a drug
so that subsequent reactions can take place
(a) Oxidation (N- or O- dealkylation; hydroxylation of N,
aliphatic, or aromatic moieties; removal of amino functions;
desulfuration or formation of sulfoxides).
Biotransformation of Drugs 21
(b) Hydrolysis of esters and amides.
(c) Reduction of nitro or azo moieties.
2. Synthetic, or Phase II reactions may provide a “handle” on the
molecule that can be recognized by transport proteins to enhance
secretion or further metabolism.
(a) Conjugation of carboxyl or hydroxyl functions with glucu-
ronic acid, glycine, sulfate, or glucose.
(b) Acetylation of amino functions (alkyl or aromatic amines,
sulfonamides).
(c) Methylation (O– , S– , and N– ).
3. Sequential reactions are common– e.g., insertion of a hydroxyl
function followed by conjugation at the hydroxyl with glucuro-
nate (Phase I followed by Phase II reactions). But this is not
always the case– a phase II enzyme may be able to attack a drug
molecule without prior phase I modification.
4.3 Metabolizing Systems inthe Smooth
Endoplasmic Reticulum (“Microsomal” Fraction
ofCell Homogenates)
A large number of drug- metabolizing enzymes are present on the
smooth endoplasmic reticulum of hepatocytes and intestinal epithe-
lial cells. These are sites where drugs that are given orally may first
interact with metabolic enzymes. It is important to remember that
these systems are subject to induction, that is, increased expression
of the genes encoding the metabolizing enzymes in response to the
presence of the enzyme substrates. It is also important to note that
some reactions may lead to the formation of toxic intermediates
during drug metabolism.
Important examples of drug metabolism are the following:
1. Glucuronide synthesis from UDP- glucuronate– several distinct
enzymes (glucuronyltransferases) on the endoplasmic reticu-
lum are involved with different genetic and environmental
( “induction”) regulation.