Basic and clinical pharmacology 15th katzung

, AccessProvidedby:




Basic
&
Clinical
Pharmacology,
15e




Bertram
G.
Katzung




A
78-year-old
woman
is
brought
to
the
hospital
because
of
suspected
aspirin
overdose*.
She
has
taken
aspirin
for
joint
pain
for
many
years
without
incident,
but
during
the
past
year,
she
has
exhibited
signs
of
cognitive
decline.
Her
caregiver
finds
her
confused,
hyperventilating,
and
vomiting.
The
caregiver
finds
an
empty
bottle
of
aspirin
tablets
and
calls
9-1-1.
In
the
emergency
department,
samples
of
venous
and
arterial
blood
are
obtained
while
the
airway,
breathing,
and
circulation
are
evaluated.
An
intravenous
(IV)
drip
is
started,
and
gastrointestinal
decontamination
is
begun.
After
blood
gas
results
are
reported,
sodium
bicarbonate
is
administered
via
the
IV.
What
is
the
purpose
of
the
sodium
bicarbonate?




can
be
defined
as
the
study
of
substances
that
interact
with
living
systems
through
chemical
processes.
These
interactions
usually
occur
by
binding
of
the
substance
to
regulatory
molecules
and
activating
or
inhibiting
normal
body
processes.
These
substances
may
be
chemicals
administered
to
achieve
a
beneficial
therapeutic
effect
on
some
process
within
the
patient
or
for
their
toxic
effects
on
regulatory
processes
in
parasites
infecting
the
patient.
Such
deliberate
therapeutic
applications
may
be
considered
the
proper
role
of

which
is
often
defined
as
the
science
of
substances
used
to
prevent,
diagnose,
and
treat
disease.

is
the
branch
of
pharmacology
that
deals
with
the
undesirable
effects
of
chemicals
on
living
systems,
from
individual
cells
to
humans
to
complex
ecosystems
(Figure
1–1).
The
nature
of
drugs—their
physical
properties
and
their
interactions
with
biological
systems—is
discussed
in
part
I
of
this
chapter.




Major
areas
of
study
in
pharmacology.
The
actions
of
chemicals
can
be
divided
into
two
large
domains.
The
first
(left
side)
is
that
of
medical
pharmacology
and
toxicology,
which
is
aimed
at
understanding
the
actions
of
drugs
as
chemicals
on
individual
organisms,
especially
humans
and
domestic
animals.
Both
beneficial
and
toxic
effects
are
included.
Pharmacokinetics
deals
with
the
absorption,
distribution,
and
elimination
of
drugs.
Pharmacodynamics
concerns
the
actions
of
the
chemical
on
the
organism.
The
second
domain
(right
side)
is
that
of
environmental
toxicology,
which
is
concerned
with
the
effects
of
chemicals
on
all
organisms
and
their
survival
in
groups
and
as
species.




Downloaded2021­7­287:13PYourIPis178.238.11.245
Chapter1:Introduction:TheNatureofDrugs&DrugDevelopment&Regulation,BertramG.Katzung Page
©2021McGrawHill.AllRightsReserved.TermsofUse•PrivacyPolicy•Notice•Accessibility

, AccessProvidedby:




New
drugs
are
added
every
year;
they
are
needed
for
several
reasons
including:
(1)
increasing
resistance
by
bacteria
and
other
parasites;
(2)
discovery
of
new
target
processes
in
diseases
that
have
not
been
adequately
treated;
and
(3)
recognition
of
new
diseases.
Furthermore,
a
dramatic
increase
has
occurred
in
the
number
of
large
molecule
drugs
(especially
antibodies)
approved
during
the
last
two
decades.
The
development
of
new
drugs
and
their
regulation
by
government
agencies
are
discussed
in
part
II.

*The
author
thanks
Barry
Berkowitz,
PhD,
for
contributions
to
the
second
part
of
this
chapter
in
previous
editions.




Prehistoric
people
undoubtedly
recognized
the
beneficial
or
toxic
effects
of
many
plant
and
animal
materials.
Early
written
records
list
remedies
of
many
types,
including
a
few
that
are
still
recognized
as
useful
drugs
today.
Most,
however,
were
worthless
or
actually
harmful.
Beginning
about
1500
years
ago,
sporadic
attempts
were
made
to
introduce
rational
methods
into
medicine,
but
none
was
successful
owing
to
the
dominance
of
systems
of
thought
(“schools”)
that
purported
to
explain
all
of
biology
and
disease
without
the
need
for
experimentation
and
observation.
These
schools
promulgated
bizarre
notions
such
as
the
idea
that
disease
was
caused
by
excesses
of
bile
or
blood
in
the
body,
that
wounds
could
be
healed
by
applying
a
salve
to
the
weapon
that
caused
the
wound,
and
so
on.

Around
the
end
of
the
17th
century,
concepts
based
on
observation
and
experimentation
began
to
replace
theorizing
in
physiology
and
clinical
medicine.
As
the
value
of
these
methods
in
the
study
of
disease
became
clear,
physicians
in
Great
Britain
and
on
the
Continent
began
to
apply
them
systematically
to
the
effects
of
traditional
drugs
used
in
their
own
practices.
Thus,
—the
science
of
drug
preparation
and
the
medical
uses
of
drugs—began
to
develop
as
the
precursor
to
pharmacology.
However,
any
real
understanding
of
the
mechanisms
of
action
of
drugs
was
prevented
by
the
absence
of
methods
for
purifying
active
agents
from
the
crude
materials
that
were
available
and—even
more—by
the
lack
of
methods
for
testing
hypotheses
about
the
nature
of
drug
actions.

In
the
late
18th
and
early
19th
centuries,
François
Magendie
and
his
student
Claude
Bernard
began
to
develop
the
methods
of


and

Advances
in
chemistry
and
the
further
development
of
physiology
in
the
18th,
19th,
and
early
20th
centuries
laid
the
foundation
needed
for
understanding
how
drugs
work
at
the
organ
and
cellular
levels.
Paradoxically,
real
advances
in
basic
pharmacology
during
this

Downloaded2021­7­287:13PYourIPis178.238.11.245
Chapter1:Introduction:TheNatureofDrugs&DrugDevelopment&Regulation,BertramG.Katzung Page
©2021McGrawHill.AllRightsReserved.TermsofUse•PrivacyPolicy•Notice•Accessibility

, AccessProvidedby:




time
were
accompanied
by
an
outburst
of
unscientific
claims
by
manufacturers
and
marketers
of
worthless
“patent
medicines.”
Not
until
the
concepts
of
rational
therapeutics,
especially
that
of
the

were
reintroduced
into
medicine—only
about
60
years
ago—did
it
become
possible
to
adequately
evaluate
therapeutic
claims.

Around
the
1940s
and
1950s,
a
major
expansion
of
research
efforts
in
all
areas
of
biology
began.
As
new
concepts
and
new
techniques
were
introduced,
information
accumulated
about
drug
action
and
the
biologic
substrate
of
that
action,
the

During
the
last
60
years,
many
fundamentally
new
drug
groups
and
new
members
of
old
groups
have
been
introduced.
The
last
three
decades
have
seen
an
even
more
rapid
growth
of
information
and
understanding
of
the
molecular
basis
for
drug
action.
The
molecular
mechanisms
of
action
of
many
drugs
have
now
been
identified,
and
numerous
receptors
have
been
isolated,
structurally
characterized,
and
cloned.
In
fact,
the
use
of
receptor
identification
methods
(described
in
Chapter
2)
has
led
to
the
discovery
of
many
orphan
receptors—receptors
for
which
no
ligand
has
been
discovered
and
whose
function
can
only
be
guessed.
Studies
of
the
local
molecular
environment
of
receptors
have
shown
that
receptors
and
effectors
do
not
function
in
isolation;
they
are
strongly
influenced
by
other
receptors
and
by
companion
regulatory
proteins.
Most
recently,
it
has
become
clear
that
gravitational
change,
radiation,
and
other
aspects
of
space
outside
the
Earth’s
environment
require
the
development
of
space
medicine.
This
has
opened
another
important
area
for
the
future
of
pharmacology.
One
result
of
these
discoveries
is
the
confirmation
that
pharmacology
represents
an
area
where
anatomy,
biochemistry,
genetics,
physiology,
pathology,
clinical
medicine,
and
the
environment
meet.
Many
problems
that
the
health
practitioner
confronts
can
now
be
corrected
or
mitigated
using
pharmacologic
tools.

—the
relation
of
the
individual’s
genetic
makeup
to
his
or
her
response
to
specific
drugs—is
becoming
an
important
part
of
therapeutics
(see
Chapter
5).
Decoding
of
the
genomes
of
many
species—from
bacteria
to
humans—has
led
to
the
recognition
of
unsuspected
relationships
between
receptor
families
and
the
ways
that
receptor
proteins
have
evolved.
Furthermore,
discovery
of
regulatory
functions
exerted
by
the
neighbors
of
chromosomes
and
the
noncoding
regions
of
DNA
on
the
expression
of
exons
has
opened
a
new
area
of
possible
manipulation
of
the
genes—epigenetics—that
control
pharmacologic
responses.

The
discovery
that
small
segments
of
RNA
can
interfere
with
protein
synthesis
with
extreme
selectivity
has
led
to
investigation
of


and

as
therapeutic
agents.
Similarly,
short
nucleotide
chains
called

synthesized
to
be
complementary
to
natural
RNA
or
DNA,
can
interfere
with
the
readout
of
genes
and
the
transcription
of
RNA.
Finally,
new,
efficient
methods
of
DNA
editing
have
made
possible
the
modification
of
genes
that
encode
proteins
that
are
critical
to
immunologic
functions,
including
anticancer
receptors
on
T-cells.
These
developments
have
led
to
a
dramatic
increase
in
large
molecule
therapeutics
in
the
last
20
years
(Table
1–1).

TABLE
1–1




2000 63 3
(5%) 1
(2%)


2008 34 5
(15%) 1
(3%)


2010 49 8
(16%) 4
(8%)


2015 69 13
(19%) 9
(13%)


2017 63 10
(16%) 9
(14%)



MABs,
monoclonal
antibodies.

Unfortunately,
the
medication-consuming
public
is
still
exposed
to
vast
amounts
of
inaccurate
or
unscientific
information
regarding
the
pharmacologic
effects
of
chemicals.
This
results
in
the
irrational
use
of
innumerable
expensive,
ineffective,
and
sometimes
harmful
remedies
and
the
growth
of
a
huge
“alternative
health
care”
industry.
Furthermore,
manipulation
of
the
legislative
process
in
the
United
States
has
allowed
many
substances
promoted
for
health—but
not
promoted
specifically
as
“drugs”—to
avoid
meeting
the
Food
and
Drug
Administration
(FDA)
standards

Downloaded2021­7­287:13PYourIPis178.238.11.245
Chapter1:Introduction:TheNatureofDrugs&DrugDevelopment&Regulation,BertramG.Katzung Page
©2021McGrawHill.AllRightsReserved.TermsofUse•PrivacyPolicy•Notice•Accessibility