Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 24) pdf

22
Adrenergic
mechanisms
and
drugs
SYNOPSIS
Anyone
who
administers drugs acting
on
cardiovascular adrenergic mechanisms requires
an
understanding
of how
they
act in
order
to
use
them
to the
best advantage
and
with
safety.
Adrenergic mechanisms
Classification
of
sympathomimetics:
by
mode

of
action
and
selectivity
for
adrenoceptors
Individual
sympathomimetics
Mucosal
decongestants
Shock
Chronic
orthostatic
hypotension
Adrenergic mechanisms
The
discovery
in
1895
of the
hypertensive
effect
of
adrenaline (epinephrine)
was
initiated
by Dr
Oliver,
a
physician

in
practice,
who
conducted
a
series
of
experiments
on his
young
son
into whom
he
injected
an
extract
of
bovine suprarenal.
The
effect
was
confirmed
in
animals
and led
eventually
to the
iso-
lation
and

synthesis
of
adrenaline
in the
early 1900s.
Many
related compounds were examined and,
in
1910, Barger
and
Dale invented
the
word sympatho-
mimetic
1
and
also pointed
out
that noradrenaline
(norepinephrine) mimicked
the
action
of the
sympathetic nervous system more closely than
did
adrenaline.
Adrenaline, noradrenaline
and
dopamine
are

formed
in the
body
and are
used
in
therapeutics.
The
natural synthetic path
is:
tyrosine
—>
dopa
—>
dopamine
—>
noradrenaline
—>
adrenaline.
Classification
of
sympathomimetics
BY
MODE
OF
ACTION
Noradrenaline
is
synthesised
and

stored
in
adrenergic
nerve terminals
and can be
released
from
these stores
by
stimulating
the
nerve
or by
drugs (ephedrine,
amfetamine).
These noradrenaline stores
may be
replenished
by
i.v. infusion
of
noradrenaline,
and
abolished
by
reserpine
or by
cutting
the
sympathetic

neuron.
Sympathomimetics
may be
classified
as
those
that act:
1.
directly:
adrenoceptor
agonists,
e.g. adrenaline,
1
'Compounds which

simulate
the
effects
of
sympathetic
nerves
not
only with varying intensity
but
with varying
precision
a
term

seems needed

to
indicate
the
types
of
action
common
to
these bases.
We
propose
to
call
it
"sympathomimetic".
A
term which indicates
the
relation
of
the
action
to
innervation
by the
sympathetic system, without
involving
any
theoretical preconception
as to the

meaning
of
that
relation
or the
precise mechanism
of the
action/
Barger
G,
Dale
H H
1910 Journal
of
Physiology
XLI:
19-50.
447
22
ADRENERGIC
MECHANISMSAND DRUGS
noradrenaline, isoprenaline (isoproterenol),
methoxamine, xylometazoline, oxymetazoline,
metaraminol (entirely);
and
dopamine
and
phenylephrine
(mainly)
2.

indirectly:
by
causing
a
release
of
noradrenaline
from
stores
at
nerve endings,
e.g.
amphetamines, tyramine;
and
ephedrine
(largely)
3.
by
both mechanisms
(1 and 2,
though
often
with
a
preponderance
of one or
other):
other
synthetic
agents.

Tachyphylaxis
(rapidly diminishing response
to
repeated administration)
is a
particular
feature
of
group
2
drugs.
It
reflects
depletion
of the
'releasable'
pool
of
noradrenaline
from
adrenergic nerve
ter-
minals that makes these agents less suitable
as, for
example,
pressor
agents
than
drugs
of

group
1.
Longer-term
tolerance
(see
p. 95) to the
effects
direct
sympathomimetics
is
much less
of a
clinical
problem
and
reflects
an
alteration
in
adrenergic
receptor density
or
coupling
to
second messenger
systems.
Interactions
of
sympathomimetics with other
vasoactive

drugs
are
complex. Some drugs block
the
reuptake mechanism
for
noradrenaline
in
adre-
nergic
nerve terminals
and
potentiate
the
pressor
effects
of
noradrenaline
e.g.
cocaine, tricyclic anti-
depressants
or
highly noradrenaline-selective
re-
uptake
inhibitors
such
as
roboxetine.
Others

de-
plete
or
destroy
the
intracellular stores within
adrenergic nerve terminals
(e.g.
reserpine
and
guanethidine)
and
thus block
the
action
of
indirect
sympathomimetics.
Sympathomimetics
are
also generally optically
active
drugs, with only
one
stereoisomer
conferring
most
of the
clinical
efficacy

of the
racemate:
for
instance laevo-noradrenaline
is at
least
50 times as
active
as the
dextro-
form.
Noradrenaline, adrenaline
and
phenylephrine
are all
used
clinically
as
their
laevo-isomers.
History.
Up to
1948
it was
known that
the
peripheral
motor (vasoconstriction)
effects
of

adrenaline were
preventable
and
that
the
peripheral inhibitory
(vasodilatation)
and the
cardiac stimulant actions
were
not
preventable
by the
then available antag-
onists (ergot alkaloids, phenoxybenzamine). That
same
year, Ahlquist hypothesised that
this
was due
to two
different
sorts
of
adrenoceptors
(a and
(3).
For
a
further
10

years, only antagonists
of
a-receptor
effects
(a-adrenoceptor
block) were known,
but in
1958
the
first
substance selectively
and
competitively
to
prevent p-receptor
effects
((3-adrenoceptor
block),
dichloroisoprenaline,
was
synthesised.
It
was, how-
ever,
unsuitable
for
clinical
use
because
it

behaved
as
a
partial agonist,
and it was not
until
1962
that
pronethalol
(an
isoprenaline analogue) became
the
first
(3-adrenoceptor blocker
to be
used clinically.
Unfortunately
it had a low
therapeutic index
and
was
carcinogenic
in
mice,
and was
soon replaced
by
propranolol
(Inderal).
It

is
evident that
the
site
of
action
has an
important
role
in
selectivity,
e.g.
drugs that
act on
end-organ
receptors
directly
and
stereospecifically
may be
highly selective, whereas drugs that
act
indirectly
by
discharging noradrenaline indiscriminately
from
nerve
endings,
e.g.
amfetamine, will have

a
wider
range
of
effects.
Subclassification
of
adrenoceptors
is
shown
in
Table
22.1.
Consequences
of
adrenoceptor
activation
All
adrenoceptors
are
members
of the
G-coupled
family
of
receptor proteins
i.e.
the
receptor
is

coupled
to
its
effector
protein through special transduction
proteins called G-proteins (themselves
a
large protein
family).
The
effector
protein
differs
amongst adreno-
ceptor
subtypes.
In the
case
of
[3-adrenoceptors,
the
effector
is
adenylyl
cyclase
and
hence cyclic
AMP is
the
second messenger molecule.

For
oc-adrenoceptors,
phospholipase
C is the
commonest
effector
protein
and the
second
messenger
here
is
IP
3
.
It is the
cascade
of
events initiated
by the
second messenger mole-
cules
that produces
the
variety
of
tissue
effects
as
shown

in
Table
22.1
It
should
be
clear that
specifi-
city
is
provided
by the
receptor subtype,
not the
messengers.
Complexity
of
adrenergic
mechanisms
Drugs
may
mimic
or
impair adrenergic mechanisms:
•
directly,
by
binding
on
adrenoceptors:

as
agonists
(adrenaline)
or
antagonists (propranolol)
448
CLASSIFICATION
OF S Y M PAT H O M I M E T I C S
22
449
TABLE
22. 1
Clinically
relevant
aspects
of
adrenoceptor
functions
and
actions
of
agonists
ctj-adrenoceptor
effects'
(
-adrenoceptor
effects
Eye:
2
mydriasis

Heart
(( ,
2
)
3
increased
rate
(SA
node)
increased
automaticity
(AV
node
and
muscle)
increased
velocity
in
conducting tissue
increased
contractility
of
myocardium
increased
O
2
consumption decreased refractory period
of all
tissues
Arterioles:

Arterioles:
constriction
(only slight
in
coronary
and
cerebral)
dilatation
(
2
)
Bronchi
(
2
):
relaxation
Anti-inflammatory
effect:
inhibition
of
release
of
autacoids (histamine, leukotrienses)
from
mast
cells,
e.g. asthma
in
type
1

allergy
Uterus:
contraction
(pregnant) Uterus
(
2
):
relaxation (pregnant)
Skeletal
muscle:
tremor
(
2
)
Skin:
sweat,
pilomotor
Male
ejaculation
Blood
platelet:
aggregation
Metabolic
effect:
hyperkalaemia
Metabolic
effects:
hypokalaemia
(
2

)
hepatic
glycogenolysis
(
2
)
lipolysis
, )
Bladder
sphincter:
Bladder
detrusor:
relaxation
contraction
Intestinal
smooth
muscle
relaxation
is
mediated
by a- and
-adrenoceptors.
2
-adrenoceptor
effects:
1
2
-receptors
on the
nerve ending i.e. presynaptic autoreceptors mediate negative feedback which inhibits

noradrenaline release.
1
For the
role
of
subtypes
( , and
2
) see
prazosin.
2
Effects
on
intraocular pressure involve
both
a- and
P-adrenoceptors
as
well
as
cholinoceptors.
3
Cardiac
-receptors
mediate
effects
of
sympathetic nerve stimulation. Cardiac
2
-receptors mediate

effects
of
circulating adrenaline,
when this
is
secreted
at a
sufficient rate, e.g. following
a
myocardial infarction
or in
heart failure. Both receptors
are
coupled
to the
same
'ntracellular signalling pathway (cyclic
AMP
production)
and
mediate
the
same
biological effects.
The use of the
term
cardioselective
to
mean
,

-receptor
selective
only,
especially
in the
case
of
-receptor blocking drugs,
is no
longer
appropriate.
Although
in
most
species
the
-receptor
is the
only
cardiac
-receptor, this
is not the
case
in
humans.
What
is not
generally
appreciated
is

that
the
endogenous sympathetic neurotransmitter, noradrenaline,
has
about
a
20-fold selectivity
for the
-receptor
—
similar
to
that
of the
antagonist, atenolol
—
with
the
consequence
that
under most
circumstances,
in
most
tissues,
there
is
little
or no
2

-
receptor stimulation
to be
affected
by a
nonselective -blocker.Why asthmatics should
be so
sensitive
to
-blockade
is
paradoxical:
all the
bronchial -receptors
are
2
, and the
bronchi themselves
are not
innervated
by
adrenergic fibres;
the
circulating adrenaline
levels
are,
if
anything,
low in
asthma.

•
indirectly,
by
discharging
noradrenaline
stored
in •
by
preventing
the
destruction
of
noradrenaline
(and
nerve
endings
2
(amfetamine)
dopamine)
in the
nerve
ending
(monoamine
•
by
preventing
reuptake
into
the
adrenergic

nerve
oxidase
inhibitors)
ending
of
released
noradrenaline
(and
•
by
depleting
the
stores
of
noradrenaline
in
nerve
dopamine)
(cocaine,
tricyclic
antidepressants
endings
(reserpine)
and
noradrenaline-selective
reuptake
inhibitors
•
by
preventing

the
release
of
noradrenaline
from
such
as
roboxetine)
nerve
endings
in
response
to a
nerve
impulse
(guanethidine)
2
Fatal
hypertension
can
occur
when
this
class
of
agent
is • fy
activation
of
adrenoceptors

on
adrenergic
taken
by a
patient
treated
with
monoamine
oxidase
inhibitor.
nerve endings
that
inhibit
release
of
22
ADRENERGIC
MECHANISMS
AND
DRUGS
noradrenaline
(
2
~autoreceptors)
(clonidine)
• by
blocking
sympathetic
autonomic
ganglia

(trimetaphan).
All
the
above mechanisms operate
in
both
the
central
and
peripheral nervous systems. This dis-
cussion
is
chiefly
concerned with agents that
influence
peripheral adrenergic mechanisms.
SELECTIVITY
FOR
ADRENOCEPTORS
The
following
classification
of
sympathomimetics
and
antagonists
is
based
on
selectivity

for
receptors
and
on
use.
But
selectivity
is
relative,
not
absolute;
some agonists
act on
both
a- and
-receptors, some
are
partial agonists and,
if
enough
is
administered,
many will extend their range.
The
same applies
to
selective antagonists (receptor blockers), e.g.
a
1
-

selective adrenoceptor blocker
can
cause severe
exacerbation
of
asthma
(a
2
effect)
even
at low
dose.
It is
important
to
remember this because
patients have died
in the
hands
of
doctors
who
have
forgotten
or
been ignorant
of
it.
3
Adrenoceptor

agonists
(Table
22.1)
+
effects,
nonselective:
adrenaline
is
used
as a
vasoconstrictor
(a)
with
local anaesthetics,
as a
mydriatic
and in the
emergency treatment
of
anaphylactic shock,
for
which condition
it has the
right
mix of
effects
(bronchodilator, positive cardiac
inotropic, vasoconstriction
at
high dose).

otj
effects:
noradrenaline
(with slight
effect
on
heart)
is
selectively released physiologically where
it is
wanted;
as
therapeutic
agents
for
hypotensive
states (excepting septic shock) dopamine
and
dobutamine
are
preferred (for their cardiac
inotropic
effect).
Also having predominantly
1
effects
are
imidazolines (xylometazoline, oxymeta-
3
While

it is
simplest
to
regard
the
selectivity
of a
drug
as
relative,
being lost
at
higher doses, strictly speaking
it is the
benefits
of the
receptor selectivity
of an
agonist
or
antagonist,
which
are
dose-dependent.
A
10-fold
selectivity
of an
agonist
at

the
1
-receptor,
for
instance,
is a
property
of the
agonist
that
is
independent
of
dose,
and
means simply that
10
times
less
of the
agonist
is
required
to
activate this receptor
compared
to the
2
-subtype.
zoline),

metaraminol,
phenylephrine,
phen-
ylpropanolamine, ephedrine, pseudoephedrine: some
are
used solely
for
topical vasoconstriction (nasal
decongestants).
2
effects
in the
central nervous system:
clonidine.
effects,
nonselective (i.e.
1
+
1
):
isoprenaline
(isoproterenol).
Its
uses
as
bronchodilator
(
2
), for
positive cardiac inotropic

effect
and to
enhance
conduction
in
heart block
(
1
,
2
)
have been largely
superseded
by
agents with
a
more appropriately
selective
profile
of
effects.
Other agents with non-
selective
effects,
ephedrine, orciprenaline,
are
also
obsolete
for
asthma.

1
effects,
with some
a
effects:
dopamine,
used
in
cardiogenic
shock.
1
effects:
dobutamine,
used
for
cardiac inotropic
effect.
2
effects,
used
in
asthma,
or to
relax
the
uterus,
include: salbutamol, terbutaline, fenoterol, pirbuterol,
reproterol, rimiterol, isoxsuprine, orciprenaline, rit-
odrine.
Adrenoceptor

antagonists
(blockers)
See
page 474.
Effects
of a
sympathomimetic
The
overall
effect
of a
sympathomimetic depends
on
the
site
of
action (receptor agonist
or
indirect action),
on
receptor
specificity
and on
dose;
for
instance adre-
naline
ordinarily
dilates
muscle

blood
vessels
(
2
;
mainly arterioles,
but
veins also)
but in
very large
doses constricts them (a).
The end
results
are
often
complex
and
unpredictable, partly because
of the
variability
of
homeostatic
reflex
responses
and
partly because what
is
observed, e.g.
a
change

in
blood pressure,
is the
result
of
many
factors,
e.g.
vasodilatation
( ) in
some areas, vasoconstriction
(a) in
others,
and
cardiac stimulation
( ).
To
block
all the
effects
of
adrenaline
and
nor-
adrenaline, antagonists
for
both
a- and
-receptors
must

be
used. This
can be a
matter
of
practical
importance, e.g.
in
phaeochromocytoma (see
p.
495).
450
CLASSIFICATION
OF S Y M P AT H O M I M E T I C S
22
Physiological
note.
The
termination
of
action
of
noradrenaline released
at
nerve endings
is by:
•
reuptake into nerve endings where
it is
stored

and
also
subject
to MAO
degradation
•
diffusion
away
from
the
area
of the
nerve ending
and the
receptor
(junctional
cleft)
•
metabolism
(by
extraneuronal
MAO
and
COMT).
These processes
are
slower than
the
very
swift

destruction
of
acetylcholine
at the
neuromuscular
junction
by
extracellular acetylcholinesterase seated
alongside
the
receptors. This
difference
reflects
the
differing
signalling requirements: almost instan-
taneous (millisecond) responses
for
voluntary muscle
movement versus
the
much more leisurely
con-
traction
of
arteriolar muscle
to
control vascular
resistance.
Synthetic

noncatecholamines
in
clinical
use
have
t//
of
hours,
e.g.
salbutamol
4h,
because they
are
more
resistant
to
enzymatic degradation
and
conjugation.
They
may be
given orally although
much higher doses
are
required. They penetrate
the
central
nervous system
and may
have prominent

effects,
e.g.
amphetamine. Substantial amounts
appear
in the
urine.
Pharmacokinetics
Catecholamines
(adrenaline, noradrenaline, dopa-
mine,
dobutamine, isoprenaline) (plasma t
1
/
2
approx.
2
min)
are
metabolised
by two
enzymes, monoamine
oxidase
(MAO)
and
catechol-O-methyltransferase
(COMT).
These enzymes
are
present
in

large amounts
in the
liver
and
kidney
and
account
for
most
of the
metabolism
of
injected catecholamines.
MAO is
also
present
in the
intestinal mucosa (and
in
nerve
endings,
peripheral
and
central). Because
of
these
enzymes catecholamines
are
ineffective
when

swallowed,
but
noncatecholamines,
e.g.
salbutamol,
amphetamine,
are
effective
orally.
a
result
of
leakage
from
i.v. infusions.
The
effects
on
the
heart
(
1
)
include tachycardia, palpitations,
cardiac
arrhythmias
including
ventricular tachy-
cardia
and

fibrillation,
and
muscle tremor
((
2
).
Sym-
pathomimetic drugs should
be
used with great
caution
in
patients with heart disease.
The
effect
of the
sympathomimetic drugs
on the
pregnant
uterus
is
variable
and
difficult
to
predict,
but
serious
fetal
distress

can
occur,
due to
reduced
placental
blood
flow
as a
result both
of
contraction
of
the
uterine muscle
(a) and
arterial constriction
(a).
2
-agonists
are
used
to
relax
the
uterus
in
pre-
mature labour,
but
unwanted

cardiovascular actions
can
be
troublesome. Sympathomimetics were parti-
cularly
likely
to
cause cardiac arrhythmias
(
1
effect)
in
patients
who
received halothane anaesthesia
(now much less used).
Sympathomimetics
and
plasma potassium.
Adrenergic mechanisms have
a
role
in the
physio-
logical
control
of
plasma potassium concentration.
The
biochemical pump that

shifts
potassium into
cells
is
activated
by the (
2
-adrenoceptor
agonists
(adrenaline, salbutamol, isoprenaline)
and can
cause
hypokalaemia.
2
-adrenoceptor antagonists block
the
effect.
The
hypokalaemia
effects
of
administered
(
2
)
Sympathomimetics
may be
clinically
important,
particularly

in
patients having pre-existing hypo-
kalaemia,
e.g.
due to
intense adrenergic activity
such
as
occurs
in
myocardial
infarction,
4
in
fright
(admission
to
hospital
is
accompanied
by
transient
hypokalaemia),
or
with
previous diuretic therapy,
and
taking digoxin.
In
such

subjects
the use of a
sympathomimetic infusion
or of an
adrenaline-
containing local anaesthetic
may
precipitate
a
cardiac
arrhythmia. Hypokalaemia
may
occur
during
treatment
of
severe
asthma,
particularly
where
the
2
-receptor agonist
is
combined with
theophylline.
-adrenoceptor blockers,
as
expected, enhance
the

hyperkalaemia
of
muscular exercise;
and one of
their
benefits
in
preventing
cardiac arrhythmias
Adverse effects
These
may be
deduced
from
their actions
(Table
22.1,
Fig.
22.1). Tissue necrosis
due to
intense
vasoconstriction
(a)
around
injection
sites occurs
as
4
Normal
subjects,

infused
i.v. with
adrenaline
in
amounts
that
approximate
to
those
found
in the
plasma
after
severe
myocardial
infarction,
show
a
fall
in
plasma
K of
about
0.8
mmol/1
(Brown
M J
1983
New
England

Journal
of
Medicine
309:1414).
451
22
ADRENERGIC
M E C H A N I S M S A N D
DRUGS
Fig. 22.1 Cardiovascular effects
of
noradrenaline
(norepinephrine),
adrenaline
(epinephrine)
and
isoprenaline
(isoproterenol):
pulse
rate/min,
blood
pressure
in
mmHg
(dotted
line
is
mean pressure),
peripheral
resistance

in
arbitrary
units.The
differences
are due to the
differential
a and
agonist selectivities
of
these agents
(see
text).
(By
permission,after
GinsburgJ,Cobbold
A F
I960
InrVane
J R et al
(eds)
Adrenergic
mechanism.
Churchill,
London)
after
myocardial
infarction
may be due to
block
of

2
-receptor-inducedhypokalaemia.
Overdose
of
sympathomimetics
is
treated according
to
rational consideration
of
mode
and
site
of
action
(see
Adrenaline, below).
Individual
sympathomimetics
The
actions
are
summarised
in
Table
22.1.
The
classic,
mainly endogenous substances will
be

described
first
despite
their limited role
in
therapeutics,
and
then
the
more selective analogues that have largely
replaced
them.
CATECHOLAMINES
5
For
pharmacokinetics,
see
above.
Adrenaline
(epinephrine)
Adrenaline
( - and
-adrenoceptor
effects)
is
used:
• as a
vasoconstrictor with local
anaesthetics
(1:80

000 or
weaker)
to
prolong their
effects
(about
2-fold)
• as a
topical mydriatic (sparing accommodation;
it
also lowers intraocular pressure)
•
for
severe allergic reactions, i.m., i.v.
(or
s.c.).
The
route must
be
chosen with care.
For
adults,
adrenaline
500
micrograms (i.e.
0.5 ml of the 1 in
1000
solution)
may be
given i.m.

and
repeated
5
Traditionally catecholamines have
had a
dual nomenclature
(as
a
consequence
of a
company patenting
the
name
Adrenalin),
broadly European
and N.
American.
The
latter
has
been chosen
by the
World Health Organization
as
International Nonproprietary Names (INN) (see
Ch. 6), and
the
European Union
has
directed member states

to use
INN.
Because
uniformity
has not yet
been achieved
and
because
of
the
scientific
literature,
we use
both.
For
pharmacokinetics,
see
above.
452
22
at
5-min intervals according
to the
response
(see
Ch. 8, p.
143).
If the
circulation
is

compromised
to a
degree
that
is
immediately
life-threatening, adrenaline
500
micrograms
may be
given
by
slow i.v. injection
at a
rate
of
100
micrograms/min (i.e.
1
ml/min
of the
dilute
1 in 10 000
solution) with continuous
monitoring
of the
ECG.
This
course
requires

extreme caution
and use of a
further
x 10
dilution (i.e.
a 1 in 100 000
solution)
may be
preferred
as
providing
finer
control
and
greater
safety.
The
s.c. route
is
generally
not
recommended
as
there
is
intense
vasoconstriction, which slows absorption.
Adrenaline
is
used

in
anaphylactic
shock because
its mix of
actions, cardiovascular
and
bronchial,
provide
the
best
compromise
for
speed
and
sim-
plicity
of use in an
emergency;
it may
also stabilise
mast
cell
membranes
and
reduce release
of
vaso-
active
autacoids (see
p.

280). Patients
who are
taking nonselective -blockers
may not
respond
to
adrenaline
(use salbutamol i.v.)
and
indeed
may
develop severe hypertension (see below).
Adrenaline
(topical)
decreases intraocular pressure
in
chronic open-angle glaucoma,
as
does dipivefrine,
an
adrenaline ester prodrug. They
are
contra-
indicated
in
closed-angle glaucoma because they
are
mydriatics. Hyperthyroid patients
are
intolerant

of
adrenaline.
Accidental
overdose with adrenaline occurs
occasionally.
It is
rationally treated
by
propranolol
to
block
the
cardiac
effects
(cardiac arrhythmia)
and
phentolamine
or
chlorpromazine
to
control
the
a
effects
on the
peripheral circulation that will
be
prominent when
the
(3

effects
are
abolished. Labetalol
(
+
block)
would
be an
alternative. p-adrenoceptor
block
alone
is
hazardous
as the
then unopposed
ot-
receptor vasoconstriction causes (severe) hyper-
tension (see Phaeochromocytoma,
p.
494).
Use of
antihypertensives
of
most other kinds
is
irrational
and
some
may
also potentiate

the
adrenaline.
Noradrenaline
(norepinephrine)
(chiefly
OL
and ,
effects)
The
main
effect
of
administered
noradrenaline
is to
raise
the
blood pressure
by
constricting
the
arterioles
INDIVIDUAL
SYM
PATHOM
I M ETI CS
and so
raising
the
total peripheral resistance, with

reduced blood
flow
(except
in
coronary arteries
which
have
few
1
-receptors).
Though
it
does
have
some cardiac stimulant
(
a
)
effect,
the
tachycardia
of
this
is
masked
by the
profound
reflex
bradycardia
caused

by the
hypertension. Noradrenaline
is
given
by
i.v. infusion
to
obtain
a
gradual sustained response;
the
effect
of a
single
i.v. injection
would
last only
a
minute
or so. It is
used where peripheral vaso-
constriction
is
specifically
desired, e.g. vasodilation
of
septic shock. Adverse
effects
include peripheral
gangrene

and
local necrosis; tachyphylaxis occurs
and
withdrawal
must
be
gradual.
Isoprenaline
(isoproterenol)
Isoprenaline (isopropylnoradrenaline)
is a
non-
selective
(3-receptor
agonist, i.e.
it
activates both
Pj-
and
P
2
-receptors.
It
relaxes smooth muscle, including
that
of the
blood vessels,
has
negligible metabolic
or

vasoconstrictor
effects,
but a
vigorous stimulant
effect
on the
heart. This latter
is its
main dis-
advantage
in the
treatment
of
bronchial asthma.
Its
principal uses
are in
complete heart block
and
occasionally
in
cardiogenic shock (hypotension).
Dopamine
Dopamine activates
different
receptors
depending
on the
dose used.
At the

lowest
effective
dose
it
stimulates
specific
dopamine (D
a
) receptors
in the
CNS
and the
renal
and
other vascular beds
(dilator);
it
also activates presynaptic autoreceptors (D
2
) which
suppress
release
of
noradrenaline.
As
dose
is
raised,
dopamine acts
as an

agonist
on
P^adrenoceptors
in
the
heart (increasing contractility
and
rate);
at
high
doses
it
activates a-adrenoceptors (vasoconstrictor).
It
is
given
by
continuous i.v.
infusion
because,
like
all
catecholamines,
its
i
l
/
2
is
short

(2
min).
An
i.v.
in-
fusion
(2-5 micrograms/kg/min) increases renal
blood
flow
(partly through
an
effect
on
cardiac out-
put).
As the
dose rises
the
heart
is
stimulated,
resulting
in
tachycardia
and
increased cardiac out-
put.
At
these
higher

doses,
dopamine
is
referred
to
as
an
'inoconstrictor'.
Dopamine
is
stable
for
about
24 h in
sodium
chloride
or
dextrose. Subcutaneous leakage causes
vasoconstriction
and
necrosis
and
should
be
treated
by
local injection
of an
a-adrenoceptor
blocking

agent (phentolamine
5 mg,
diluted).
453
22
ADRENERGIC
MECHANISMSAND DRUGS
It
may be
mixed with dobutamine.
For
CNS
aspects
of
dopamine, agonists
and
antagonists:
see
Neuroleptics, Parkinsonism.
Dobutamine
Dobutamine
is a
racernic mixture
of d- and 1-
dobutamine.
The
racemate behaves primarily
a
1
adrenoceptor

agonist
with greater inotropic
than
chronotropic
effects
on the
heart;
it has
some
-
agonist
effect,
but
less than dopamine.
It is
useful
in
shock (with dopamine)
and in low
output heart
failure
(in the
absence
of
severe hypertension).
Dopexamine
Dopexamine
is a
synthetic catecholamine whose
principal action

is as an
agonist
for the
cardiac
2
-
adrenoceptors
(positive
inotropic
effect).
It is
also
a
weak
dopamine agonist (thus causing renal
vasodilatation)
and
inhibitor
of
noradrenaline
uptake thereby enhancing stimulation
of
cardiac
1
-
receptors
by
noradrenaline.
It is
used occasionally

to
optimise
the
cardiac
output,
particularly
perioperatively.
NONCATECHOLAMINES
Salbutamol, fenoterol, rimiterol, reproterol,
pir-
buterol, salmeterol, ritodrine
and
terbutaline
are fi-
adrenoceptor agonists that
are
relatively selective
for
2
-receptors,
so
that cardiac
(chiefly
1
-receptor)
effects
are
less prominent. Tachycardia still occurs
because
of

atrial (sinus node)
2
-receptor
stimulation;
the
2
-adrenoceptors
are
less numerous
in the
ventricle
and
there
is
probably less risk
of
serious
ventricular
arrhythmias than with
the use of
nonselective catecholamines.
The
synthetic agonists
are
also longer-acting than isoprenaline because they
are
not
substrates
for
catechol-O-methyltransferase,

which methylates catecholamines
in the
liver. They
are
used principally
in
asthma,
and to
reduce
uterine contractions
in
premature labour.
Salbutamol
(see also Asthma)
Salbutamol
(Ventolin)
(t
1/2
4h) is
taken orally,
2-4 mg up to 4
times/day;
it
also acts quickly
by
inhalation
and the
effect
can
last

as
long
as 4h,
which makes
it
suitable
for
both prevention
and
treatment
of
asthma.
Of an
inhaled dose
< 20% is
absorbed
and can
cause cardiovascular
effects.
It
can
also
be
given
by
injection,
e.g.
in
asthma,
premature labour

2
-receptor)
and for
cardiac
inotropic
(
1
)
effect
in
heart
failure
(where
the (
2
vasodilator action
is
also
useful).
Clinically
imp-
ortant hypokalaemia
can
also occur
(the
shift
of
potassium
into cells).
The

other
drugs
above
are
similar.
Salmeterol (Serevent)
is a
variant
of
salbutamol
that
has
additional binding property
to a
site
adjacent
to the
2
-adrenoceptor, which results
in
slow
onset
and
long duration
of
action (about
12 h)
(see
p.
560).

Ephedrine
Ephedrine
(t
l
/
2
approx.
4 h) is a
plant alkaloid with
indirect sympathomimetic actions that resemble
adrenaline peripherally. Centrally
(in
adults)
it
pro-
duces increased alertness, anxiety, insomnia, tremor
and
nausea;
children
may be
sleepy
when
taking
it.
In
practice central
effects
limit
its use as a
sym-

pathomimetic
in
asthma.
Ephedrine
is
well absorbed when given orally
and, unlike most other sympathomimetics, under-
goes relatively
little
first-pass metabolism
in the
liver;
it is
largely excreted unchanged
by the
kidney.
It
is
usually given
by
mouth
but can be
injected.
It
differs
from
adrenaline principally
in
that
its

effects
come
on
more slowly
and
last longer. Tachyphylaxis
occurs
on
repeated
dosing.
Ephedrine
can be
used
as a
bronchodilator,
in
heart block,
as a
mydriatic
and as a
mucosal vasoconstrictor,
but
newer drugs,
which
are
often
better
for
these purposes,
are

dis-
placing
it. It is
sometimes
useful
in
myasthenia
gravis (adrenergic agents enhance cholinergic
neuro-
muscular transmission).
Pseudoephedrine
is
similar.
Phenylpropanolamine
(norephedrine)
is
similar
but
with less
CNS
effect.
Prolonged administration
of
phenylpropanolamine
to
women
as an
anorectic
has
been

associated with pulmonary valve abnor-
malities
and led to its
withdrawal
in
some
countries.
Amfetamine
(Benzedrine)
and
dexamphetamine
(Dexedrine)
act
indirectly. They
are
seldom used
for
their
peripheral
effects,
which
are
similar
to
those
of
454
SHOCK
22
ephedrine,

but
usually
for
their
effects
on the
central
nervous system (narcolepsy, attention
deficit
in
children). (For
a
general account
of
amphetamine,
see p.
193)
Phenylephrine
has
actions qualitatively similar
to
noradrenaline
but a
longer duration
of
action,
up to
an
hour
or so. It can be

used
as a
nasal decongestant
(0.25-0.5%
solution),
but
sometimes irritates.
In the
doses
usually
given,
the
central
nervous
effects
are
minimal,
as are the
direct
effects
on the
heart.
It is
also used
as a
mydriatic
and
briefly
lowers
intraocular

pressure.
Mucosal
decongestants
Nasal
and
bronchial decongestants (vasoconstrictors)
are
widely used
in
allergic rhinitis, colds, coughs
and
sinusitis,
and to
prevent otitic barotrauma,
as
nasal drops
or
nasal sprays.
All the
sympathomimetic
vasoconstrictors, i.e.
with
a
effects,
have been used
for
the
purpose, with
or
without

an
antihistamine
(Hj-receptor),
and
there
is
little
to
choose between
them. Ischaemic damage
to the
mucosa
is
possible
if
they
are
used excessively (more
often
than 3-hourly)
or
for
prolonged periods
(> 3
weeks).
The
occurrence
of
rebound congestion
is

also liable
to
lead
to
over-
use.
The
least objectionable drugs
are
ephedrine
0.5%
and
phenylephrine 0.5%. Xylometazoline 0.1%
(Otrivine)
should
be
used,
if at
all,
for
only
a few
days since longer application reduces
the
ciliary
activity
and
will lead
to
rebound congestion.

Naphazoline
and
adrenaline should
not be
used,
and nor
should blunderbuss mixtures
of
vaso-
constrictor
antihistamine, adrenal steroid
and
anti-
biotics.
Oily drops
and
sprays, used
frequently
and
long-term,
may
enter
the
lungs
and
eventually
cause
lipoid pneumonia.
It
may

sometimes
be
better
to
give
the
drugs
orally
rather than
up the
nose. They interact with
antihypertensives
and can be a
cause
of
unexplained
failure
of
therapy
unless
enquiry into patient
self-
medication
is
made. Fatal hypertensive crises have
occurred
when
patients treated
for
depression with

a
monoamine oxidase inhibitor have taken these
preparations.
Shock
Definition.
Shock
is a
state
of
inadequate capillary
perfusion
(oxygen
deficiency)
of
vital tissues
to an
extent
that adversely
affects
cellular metabolism
(capillary
endothelium
and
organs) causing mal-
function,
including release
of
enzymes
and
vasoactive

substances,
6
i.e.
it is a low
flow
or
hypo-
perfusion
state.
The
cardiac
output
and
blood pressure
are low in
fully
developed cases.
But a
maldistribution
of
blood
(due
to
constriction, dilatation, shunting)
can be
sufficient
to
produce tissue
injury
even

in the
presence
of
high
cardiac output
and
arterial blood
pressure (warm shock), e.g. some cases
of
septic
shock.
The
essential element, hypoperfusion
of
vital
organs,
is
present whatever
the
cause, whether
pump
failure
(myocardial
infarction),
maldistribution
of
blood (septic shock)
or
loss
of

total intravascular
volume (bleeding
or
increased permeability
of
vessels
damaged
by
bacterial
cell
products, burns
or
anoxia).
Function
of
vital organs, brain (consciousness,
respiration)
and
kidney (urine
formation)
are
clinical
indicators
of
adequacy
of
perfusion
of
these organs.
Treatment

may be
summarised:
•
Treatment
of
the
cause:
bleeding, infection,
adrenocortical
deficiency
•
Replacement
of
any
fluid
lost
from
the
circulation
•
Perfusion
of
vital
organs
(brain, heart, kidneys)
and
maintenance
of the
mean blood pressure.
Blood

flow
(oxygen delivery) rather than blood
pressure
is of the
greatest immediate importance
for
the
function
of
vital organs.
A
reasonable blood
pressure
is
needed
to
ensure organ perfusion
but
peripheral vasoconstriction
may
maintain
a
normal
mean arterial pressure
despite
a
very
low
cardiac
output.

Under these circumstances, blood
flow
to
vital organs will
be
inadequate
and
multiple organ
6
In
fact,
a
medley
of
substances (autacoids), kinins,
prostaglandins, leukotrienes, histamine,
endorphins,
serotonin,
vasopressin,
has
been implicated.
In
endotoxic
shock,
the
toxin also induces synthesis
of
nitric oxide,
the
endogenous

vasodilator,
in
several types
of
cells other than
the
endothelial cells which
are
normally
its
main source.
455
22
ADRENERGIC
M E C H A N I S M S A N D
DRUGS
failure
will ensue unless
the
patient
is
resuscitated
adequately.
The
decision
how to
treat shock
depends
on
assessment

of the
pathophysiology:
•
whether cardiac
output,
and so
peripheral blood
flow,
is
inadequate (low
pulse
volume, cold-
constricted periphery)
•
whether cardiac output
is
normal
or
high
and
peripheral blood
flow
is
adequate (good pulse
volume
and
warm dilated periphery),
but
there
is

maldistribution
of
blood
•
whether
the
patient
is
hypovolaemic
or
not,
or
needs
a
cardiac inotropic agent,
a
vasoconstrictor
or
a
vasodilator.
Types
of
shock
In
poisoning
by a
cerebral depressant
or
after
spinal cord trauma,

the
principal cause
of
hypo-
tension
is low
peripheral resistance
due to
reduced
vascular
tone.
The
cardiac output
can be
restored
by
simply tilting
the
patient head-down
and by
increasing
the
venous
filling
pressure
by
infusing
fluid.
Vasoactive
drugs (noradrenaline, dobutamine)

may be
beneficial.
In
central circulatory failure (cardiogenic shock,
e.g.
after
myocardial
infarction)
the
cardiac output
and
blood pressure
are low due to
pump
failure;
myocardial
perfusion
is
dependent
on
aortic pressure.
Venous
return
(central
venous pressure)
is
normal
or
high.
The low

blood pressure
may
trigger
the
sympathoadrenal mechanisms
of
peripheral circu-
latory
failure
summarised below.
Not
surprisingly,
the use of
drugs
in low
output
failure
due to
acute myocardial damage
is
dis-
appointing. Vasoconstriction
(by an
-adreno-
ceptor agonist),
by
increasing peripheral resistance,
may
raise
the

blood pressure
by
increasing
afterload,
but
this additional burden
on the
damaged heart
can
further
reduce
the
cardiac out-
put. Cardiac stimulation with
a
1
-adrenoceptor
agonist
may
fail;
it
increases myocardial oxygen
consumption
and may
cause
an
arrhythmia.
Dobutamine, dopexamine
or
dopamine

offer
a
reasonable choice
if a
drug
is
judged necessary;
dobutamine
is
preferred
as it
tends
to
vasodilate, i.e.
it
is an
'inodilator'.
A
selective phosphodiesterase
inhibitor such
as
enoximone
may
also
be
effective,
unless
its use is
limited
by

hypotension.
If
there
is
bradycardia
(as
sometimes complicates
myocardial
infarction),
cardiac output
can be
increased
by
vagal block with atropine, which acceler-
ates
the
heart rate.
Septic shock
is
severe sepsis with hypotension that
is
not
corrected
by
adequate intravascular volume
replacement.
It is
caused
by
lipopolysaccharide

(LPS)
endotoxins
from
Gram-negative organisms
and
other cell products
from
Gram-positive organ-
isms; these initiate
host
inflammatory
and
pro-
coagulant responses through
the
release
of
cytokines,
e.g. interleukins,
and the
resulting
diffuse
endo-
thelial
damage
is
responsible
for
many
of the

adverse manifestations
of
shock, including multi-
organ
failure.
First, there
is a
peripheral vaso-
dilatation
from
activation
of
nitric oxide
by LPS and
cytokines, with eventual
fall
in
arterial pressure.
This
initiates
a
vigorous sympathetic discharge that
causes constriction
of
arterioles
and
venules;
the
cardiac
output

may be
high
or low
according
to the
balance
of
these influences. There
is a
progressive
peripheral anoxia
of
vital organs
and
acidosis.
The
veins (venules) dilate
and
venous pooling occurs
so
that blood
is
sequestered
in the
periphery
and
effective
circulatory volume
falls
because

of
this,
and of
fluid
loss into
the
extravascular space
from
endothelial damage caused
by
bacterial products.
When septic shock
is
recognised, appropriate
antimicrobials should
be
given
in
high dose
immediately
after
the
taking
of
blood cultures (see
p.
237). Beyond that,
the
prime
aim of

treatment
is
to
restore
cardiac
output
and
vital organ perfusion
by
accelerating venous return
to the
heart
and to
reverse
the
maldistribution
of
blood. Increasing
intravascular
volume will achieve this, guided
by
the
central venous pressure
to
avoid overloading
the
heart. Oxygen
is
essential
as

there
is
often
uneven
pulmonary
perfusion.
After
adequate
fluid
resuscitation
has
been
established, inotropic support
is
usually required.
Noradrenaline
is the
inotrope
of
choice
for
septic
shock:
its
potent -adrenergic
effect
increases
the
mean arterial pressure
and its

modest
1
effect
may
raise
cardiac
output,
or at
least maintain
it as the
peripheral vascular resistance increases.
Dobutamine
may be
added
further
to
augment cardiac output.
456
CHRONIC ORTHOSTATIC HYPOTENSION
22
Some clinicians
use
adrenaline,
in
preference
to
noradrenaline plus dobutamine,
on the
basis that
its

powerful
a and (3
effects
are
appropriate
in the
setting
of
septic shock;
it may
exacerbate splanchnic
ischaemia
and
lactic
acidosis.
Hypotension
in
(atherosclerotic) occlusive vascular
disease
is
particularly serious,
for
these
patients
are
dependent
on
pressure
to
provide

the
necessary
blood
flow
in
vital organs whose
supplying
vessels
are
less able
to
dilate.
It is
important
to
maintain
an
adequate mean arterial pressure, whichever inotrope
is
selected.
CHOICE
OF
DRUG
IN
SHOCK
On
present knowledge
the
best drug would
be one

that both stimulates
the
myocardium
and
selectively
modifies
peripheral resistance
to
increase
flow
to
vital organs.
•
Dobutamine
is
used when cardiac inotropic
effect
is the
primary requirement.
•
Adrenaline
is
used when
a
more
potent
inotrope
than dobutamine
is
required, e.g. when

the
vasodilating action
of
dobutamine compromises
mean arterial pressure.
•
Noradrenaline
is
used when vasoconstriction
is
the
first
priority, plus some slight cardiac
inotropic
effect,
e.g.
septic
shock.
Monitoring
drug
use
Modern monitoring
by
both invasive
and
non-
invasive techniques
is
complex
and is

undertaken
in
units dedicated
to
and, equipped for, this
activity.
The
present comment
is an
overview. Monitoring
will normally require close attention
to
heart rate
and
rhythm, blood pressure,
fluid
balance
and
urine
flow,
pulmonary
gas
exchange
and
central
venous pressure.
The use of
drugs
in
shock

is
secondary
to
accurate assessment
of
cardiovascular
state (especially
of
peripheral
flow)
and to
other
essential management, treatment
of
infection
and
maintenance
of
intravascular volume.
Restoration
of
intravascular
volume
7
In
an
emergency, speed
of
replacement
is

more
important than
its
nature.
Crystalloid
solutions,
e.g.
isotonic saline, Hartmann's, Plasma-Lyte,
are im-
mediately
effective,
but
they leave
the
circulation
quickly.
(Note that dextrose solutions
are
completely
ineffective
because they distribute across both
the
extracellular
and
intracellular compartments.) Macro-
molecules
(colloids)
remain
in the
circulation longer.

The
two
classes (crystalloids
and
colloids)
may be
used together.
The
choice
of
crystalloid
or
colloid
for
fluid
resuscitation remains controversial. There have been
no
prospective, randomised trials
of
sufficient
power
in
either sepsis
or
trauma,
to
detect
a
significant
difference

in
mortality. Albumin
is
relatively expen-
sive
and
offers
no
advantage over cheaper, synthetic
colloids such
as
etherified starch.
Colloidal isotonic solutions
of
macromolecules
include: dextrans (glucose polymer), gelatin (hydro-
lysed collagen)
and
hydroxyethyl starch.
Dextran
70
(mol.
wt. 70
000)
has a
plasma restoring
effect
lasting
5-6 h.
Dextran

40 is
used
to
decrease
blood
sludging
and so to
improve peripheral blood
flow.
Gelatin
products (Haemaccel,
Gelofusine)
have
a
plasma restoring
effect
of 2-3 h (at
best).
Etherified
starch.
Several hydroxyethyl starch
solutions
are
available, with widely
differing
effects
on
plasma volume.
The
high molecular weight

(450000)
solutions have
a
volume restoring
effect
for
6-12
h,
while that
of
medium molecular weight
(200
000) starches last
4-6 h.
Adverse
effects
include anaphylactoid reactions;
dextran
and
hetastarch
can
impair haemostatic
mechanisms.
Chronic orthostatic
hypotension
Chronic orthostatic hypotension occurs most com-
monly with increasing age,
in
primary progressive
7

Nolan
J
2001 Fluid resuscitation
for the
trauma patient.
Resuscitation
48:
57-69.
457
22
ADRENERGIC
MECHANISMSAND
DRUGS
autonomic
failure
and
secondary
to
parkinsonism
and
diabetes.
The
clinical features
can be
mimicked
by
saline depletion.
The two
conditions
are

clearly
separated
by
measurement
of
plasma levels
of
noradrenaline (supine
and
erect)
and
renin. These
are
elevated
in
saline depletion,
but
depressed
in
most causes
of
hypotension
due to
autonomic
failure.
Since
blood pressure
can be
considered
a

product
of
Volume'
and
'vasoconstriction',
the
logical initial
treatment
of
orthostatic hypotension
is to
expand
blood volume using
a
sodium-retaining adrenocortical
steroid (fludrocortisone
8
)
or
desmopressin
(p.
716)
—
plus elastic support stocking
to
reduce venous
pooling
of
blood when erect.
It

is
more
difficult
to
reproduce
the
actions
of the
endogenous vasoconstrictors,
and
especially their
selective release
on
standing,
in
order
to
achieve
erect
normotension without supine hypertension.
Because
of the
risk
of
hypertension when
the
patient
is
supine, only
a

modest increase
in
erect blood
pressure should
be
sought; fortunately
a
systolic
blood pressure
of
85-90
mmHg
is
usually adequate
to
maintain cerebral perfusion
in
these patients.
Few
drugs have been
formally
tested
or can be
recommended with confidence. Clonidine
and
pindolol
are
partial agonists
at,
respectively,

a and
receptors,
and may
therefore
be
more
effective
agonists
in the
absence
of the
endogenous agonist,
noradrenaline, than
in
normal subjects. Midodrine,
an
a-adrenoceptor agonist,
is the
only vasoconstrictor
drug
to
receive
UK
regulatory approval
for the
treatment
of
postural hypotension.
It
should

be
given
at
doses
of
5-15
mg
t.i.d.
Postprandial
fall
in
blood pressure (probably
due to
redistribution
of
blood
to the
splanchnic
area)
is
characteristic
of
this condition;
it
especially
occurs
after
breakfast
(blood volume
is

lower
in the
morning). Substantial doses
of
caffeine
(two large
cups
of
coffee)
can
mitigate this,
but
they need
to be
taken
before
or
early
in the
meal.
The
action
may be
due to
block
of
splanchnic vasodilator adenosine
receptors.
Administration
of the

somatostatin ana-
logue, octreotide, prevents postprandial hypotension,
but the
requirement
for
twice daily subcutaneous
injections
makes
the
drug
an
unlikely candidate
for
regular
use in
this group
of
patients.
8
Effective
doses
may not
affect
blood volume
and may
work
by
sensitising
vascular adrenoceptors.
Some

of the
variation
in
reported results
of
drug
therapy
may be due to
differences
in
adrenergic
function
dependent
on
whether
the
degeneration
is
central,
peripheral, preganglionic, postganglionic
or
due to
age-related changes
in the
adrenoceptors
on
end-organs.
In
central autonomic degeneration,
'multisystem atrophy', noradrenaline

is
still present
in
peripheral sympathetic nerve endings.
In
these
patients,
an
indirect-acting amine
may be
success-
ful,
and one
patient titrated
the
amount
of
Bovril
(a
tyramine-rich
meat extract drink)
she
required
in
order
to
stand up.
9
Erythropoietin
has

been used with success
(it
increases haematocrit
and
blood viscosity).
• The
adrenergic
arm of the
autonomic
system
uses
noradrenaline
(norepinephrine)
as its
neurotransmitter.
•
Adrenaline
(epinephrine),
unlike
noradrenaline,
is a
circulating
hormone.
•
These
two
catecholamines
act on the
same
adrenoceptors:

1
and
2
which
are
blocked
by
phenoxybenzamine
but not by
propranolol,
and (
1
and
2
which
are
blocked
by
propranolol
but not
phenoxybenzamine.
Noradrenaline
is a
20-fold weaker
agonist
at
2
-receptors
than
is

adrenaline.
•
Distinction
between
receptor
classes
is
made
initially
by
defining
the
differing
ability
of two
agonists
(or
antagonists)
to
mimic
(or
block)
the
effects
of
catecholamines.
•
Often
these differences
correlate

with
a
difference
in
receptor
type
on two
different tissues: e.g.
stimulation
of
cardiac
contractility
by
1
-receptors
and
bronchodilatation
by
2
-receptors.
• The
distinction
between
1
- and
2
-receptors
corresponds
to
their

principal
location
on
blood
vessels
(causing
vasoconstriction)
and
neurons.
•
Catecholamines themselves
can be
used
in
therapy
when rapid onset
and
offset
are
desired. Selective
mimetics
at
each
of the
four
main
receptor
subtypes
are
used

for
individual
locations,
e.g:
1
for
nasal
decongestion,
2
for
systemic hypotension,
for
heart
failure
or
shock,
2
for
bronchoconstriction.
•
Both
a-
and
-blockade
are
used
in
hypertension;
selective
-blockade

is
used
in
angina
and
heart
failure.
9
Karet
F E et al
1994 Bovril
and
moclobemide:
a
novel
therapeutic strategy
for
central autonomic failure. Lancet
344:1263-1265.
458
CHRONIC
ORTHOSTATIC
HYPOTENSION
22
GUIDETO
FURTHER
READING
Ahlquist
R P
1948

A
study
of
adrenotropic receptors.
American
Journal
of
Physiology 153: 586-600
Astiz
M E,
Rackow
E C
1998 Septic shock. Lancet 351:
1501-1505
Bernard
G D et al
2001
Efficacy
and
safety
of
recombinant human activated protein
C for
severe
sepsis.
New
England Journal
of
Medicine 344:
699-709

Brown
M J
1995
To
-block
or
better block? British
Medical
Journal 311:
701-702
Califf
R M,
Bengtson
J R
1994 Cardiogenic shock.
New
England Journal
of
Medicine
330:1724-1730
Evans
T W,
Smithies
M
1999
ABC of
intensive care.
Organ dysfunction. British Medical Journal 318:
1606-1609
Ewan

P W
1998 Anaphylaxis. British Medical Journal
316:1442-1445
Insel
P
A1996 Adrenergic receptors
—
evolving
concepts
and
clinical implications.
New
England
Journal
of
Medicine 334:
580-585.
Lynn
W
A1999 Severe
sepsis.
In:
Pusey
C
(ed)
Horizons
in
medicine. Royal College
of
Physicians

of
London, London,
p
55-68
Wheeler
A P,
Bernard
G D
1999 Treating patients with
severe sepsis.
New
England Journal
of
Medicine
340:
207-214
459