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23
Arterial
hypertension, angina
pectoris, myocardial
infarction
SYNOPSIS
Hypertension
and
coronary heart
disease
(CHD)
are of
great importance. Hypertension
affects
above
20% of the
total
population
of the
USA
with
its
major impact
on
those over
age
50.
CHD is the
cause
of
death
in 30% of
males
and
22% of
females
in
England
and
Wales.
Management
requires
attention
to
detail, both
clinical
and
pharmacological.
The way
drugs
act in
these
diseases
is
outlined
and the
drugs
are
described
according
to
class.
•
Hypertension
and
angina
pectoris:
how
drugs
act
•
Drugs
used
in
both
hypertension
and
angina
Diuretics
Vasodilators
organic
nitrates,
calcium
channel
blockers.ACE
inhibitors,
angiotensin
II-
receptor antagonists
Adrenoceptor blocking drugs,
and (
Peripheral
sympathetic nerve terminal
Autonomic ganglion-blocking drugs
Central nervous
system
Treatment
of
angina
pectoris
•
Acute coronary syndromes
and
myocardial
infarction
•
Arterial
hypertension
•
Sexual
function
and
cardiovascular
drugs
•
Phaeochromocytoma
Hypertension:
how
drugs
act
Consider
the
following relationship:
Blood
pressure
=
cardiac
output
x
peripheral resistance
Therefore
drugs
can
lower blood pressure
by:
•
Dilatation
of
arteriolar
resistance
vessels.
Dilatation
can be
achieved through direct
relaxation
of
vascular smooth muscle cells,
by
stimulation
of
nitric oxide (NO) production,
or
by
blocking (suppressing) endogenous
vasconstrictors, noradrenaline (norepinephrine)
and
angiotensin.
•
Dilatation
of
venous
capacitance
vessels;
reduced
venous return
to the
heart (preload) leads
to
reduced
cardiac output, especially
in the
upright
position
•
Reduction
of
cardiac
contractility
and
heart
rate.
•
Depletion
of
body
sodium.
This reduces plasma
volume (transiently),
and
reduces arteriolar
response
to
noradrenaline (norepinephrine)
Modern
antihypertensive drugs lower blood
pressure with minimal interference with homeo-
static
control, i.e. change
in
posture, exercise.
461
23
ARTERIAL
H Y P E R T E N S I O N , A N G I N A P E C T O R I S, Ml
Angina pectoris:
how
drugs
act
Angina
can be
viewed
as a
problem
of
supply
and
demand. Drugs used
in
angina pectoris
are
those
that
either increase supply
of
oxygen
and
nutrients,
or
reduce
the
demand
for
these
— or
both.
Supply
can be
increased
by:
cardiac work
and
myocardial
oxygen need
by:
•
dilating coronary arteries
•
slowing
the
heart (coronary
flow,
uniquely,
occurs
in
diastole, which lengthens
as
heart rate
falls).
Demand
can be
reduced
by:
•
reducing
afterload,
(i.e. peripheral resistance),
so
reducing
the
work
of the
heart
in
perfusing
the
tissues
•
reducing preload, (i.e. venous
filling
pressure);
according
to
Starling's
Law of the
heart,
workload
and
therefore
oxygen demand varies
with stretch
of
cardiac muscle
fibres
•
slowing
the
heart.
Drugs
used
in
hypertension
and
angina
Two
groups
of
drugs, p-adrenergic blockers
and
calcium
channel blockers,
are
used
in
both hyper-
tension
and
angina. Several drugs
for
hypertension
are
used also
in the
treatment
of
heart
failure.
DiuretiCS
(see
also
Ch. 26)
Diuretics, particularly
the
thiazides,
are
useful
anti-
hypertensives. They cause
an
initial loss
of
sodium
with
a
parallel contraction
of the
blood
and
extra-
cellular
fluid
volume.
The
effect
may
reach
10% of
total
body sodium
but it is not
maintained.
After
several
months
of
treatment,
the
main blood press-
ure
lowering
effect
appears
to
reflect
a
reduced
responsiveness
of
resistance vessels
to
endogenous
vasoconstrictors, principally noradrenaline. While
this hyposensitivity
may be a
consequence
of the
sodium depletion, thiazides
are
generally more
effec-
tive
antihypertensive
agents than
loop
diuretics,
despite causing less salt loss,
and
evidence suggests
an
independent action
of
thiazides
on an
unidentified
ion-channel
on
vascular smooth muscle
cell
mem-
branes. Maximum
effect
on
blood pressure
is
delayed
for
several weeks
and
other drugs
are
best added
after
this time. Adverse metabolic
effects
of
thiazides
on
serum potassium, blood lipids, glucose tolerance,
and
uric acid metabolism
led to
suggestions that
they
should
be
replaced
by
newer agents
not
having
these
effects.
It is,
however,
now
recognised that
unnecessarily high
doses
of
thiazides
have been
used
in
the
past
and
that with
low
doses, e.g. bendro-
fluazide
(bendroflumethiazide)
1.25-2.5
mg/d
or
less
(or
hydrochlorothiazide
12.5-25
mg), thiazides
are
both
effective
and
well-tolerated. Moreover, they
are
not
only
by far the
cheapest antihypertensive
agents available worldwide
but
have proved
to be
the
most
effective
in
several outcome trials
in
preventing
the
major
complications
of
hypertension,
myocardial
infarction
and
stroke.
The
characteristic
reduction
in
renal calcium excretion induced
by
thiazides
may,
in
long-term therapy, also reduce
the
occurrence
of hip
fractures
in
older patients
and
benefit
women with postmenopausal osteoporosis.
Vasodilators
ORGANIC
NITRATES
Organic
nitrates (and nitrite) were introduced into
medicine
in the
19th century.
1
Denitration
in the
smooth muscle cell releases nitric oxide (NO), which
is
the
main physiological vasodilator, normally pro-
duced
by
endothelial cells.
Nitrodilators
(a
generic
term
for
drugs that release
or
mimic
the
action
of NO)
activate
the
soluble guanylate cyclase
in
vascular
smooth muscle cells
and
cause
an
increase
in
intra-
cellular
cyclic
GMP
(guanosine monophosphate) con-
1
Murrell,
W
1879
Nitroglycerin
as a
remedy
for
angina
pectoris.
Lancet
1:
80-81.
Nitroglycerin
was
actually
first
synthesised
by
Sobrero
in
1847
who
noted when
he
applied
it
to
his
tongue
it
caused
a
severe headache.
462
VASO
OILATO
RS
23
centrations. This
is the
second messenger that alters
calcium
fluxes in the
cell, decreases stored calcium,
and
induces relaxation.
The
result
is a
generalised
dilatation
of
venules (capacitance vessels)
and to a
lesser extent
of
arterioles (resistance vessels), causing
a
fall
of
blood pressure that
is
postural
at
first;
the
larger
coronary arteries especially dilate. Whereas
some vasodilators
can
'steal'
blood away
from
atheromatous arteries, with their
fixed
stenoses,
to
other,
healthier arteries, nitrates probably have
the
reverse
effect
as a
result
of
their supplementing
the
endogenous
NO.
Atheroma
is
associated with
impaired
endothelial
function,
resulting
in
reduced
release
of NO
and, possibly,
its
accelerated
destruction
by the
oxidised
LDL in
atheroma (see
Ch.
25).
The
venous dilatation causes
a
reduction
in
venous return,
a
fall
in
left
ventricular
filling
pressure
with
reduced
stroke volume,
but
cardiac output
(per
min)
is
sustained
by the
reflex
tachycardia
induced
by the
fall
in
blood pressure.
Pharmacokinetics.
The
nitrates
are
generally well
absorbed across skin,
and the
mucosal
surface
of
the
mouth
or gut
wall. Nitrates absorbed
from
the
gut, however,
are
subject
to
extensive first-pass
metabolism
in the
liver,
as is
shown
by the
sub-
stantially larger doses required
by
that route over
sublingual application (this also explains
why
swallowing
a
sublingual tablet
of
glyceryl trinitrate
terminates
its
effect).
They
are
first
denitrated
and
then
conjugated
with glucuronic acid.
The
t1/2
periods vary (see below)
but for
glyceryl trinitrate
(GTN)
it is
1-4:
minutes.
Tolerance
to the
characteristic vasodilator headache
comes
and
goes quickly (hours).
2
Ensuring that
a
continuous steady-state plasma concentration
is
avoided prevents tolerance. This
is
easy with
occasional
use of
glyceryl trinitrate,
but
with nitrates
having longer
t
1
/2
(see below)
and
sustained release
formulations
it is
necessary
to
plan
the
dosing
to
allow
low
plasma concentration
for 4-8 h,
e.g. over-
2
Explosives
factory
workers exposed
to a
nitrate-
contaminated
environment lost
it
over
a
weekend
and
some
chose
to
maintain their intake
by
using nitrate impregnated
headbands
(transdermal absorption) rather than have
to
accept
the
headaches
and
reacquire tolerance
so
frequently.
night;
alternatively transdermal patches
may be
removed
for a few
hours
if
tolerance
is
suspected.
Uses. Nitrates
are
chiefly
used
to
relieve angina
pectoris
and
sometimes
left
ventricular
failure.
An
excessive
fall
in
blood pressure will reduce coronary
flow
as
well
as
cause fainting
due to
reduced cerebral
blood
flow, and so it is
important
to
avoid accidental
overdosing. Patients with angina should
be
instructed
on the
signs
of
overdose
—
palpitations, dizziness,
blurred vision, headache
and
flushing following
by
pallor
— and
what
to do
about
it
(below).
The
discovery that coronary artery occlusion
by
thrombosis
is
itself
'stuttering'
—
developing
gradually over hours
— and
associated with vaso-
spasm
in
other
parts
of the
coronary tree
has
made
the use of
isosorbide dinitrate
(Isoket)
by
continuous
i.v.
infusion adjusted
to the
degree
of
pain,
a
logical,
and
effective,
form
of
analgesia
for
unstable
angina.
Transient
relief
of
pain
due to
spasm
of
other
smooth muscle
(colic),
can
sometimes
be
obtained,
so
that
relief
of
chest pain
by
nitrates does
not
prove
the
diagnosis
of
angina pectoris.
Nitrates
are
contraindicated
in
angina
due to
anaemia.
Adverse effects. Collapse
due to
fall
in
blood
pressure resulting
from
overdose
is the
commonest
side
effect.
The
patient should remain supine,
and
the
legs
should
be
raised above
the
head
to
restore
venous return
to the
heart.
Nitrate
headache, which
may be
severe,
is
prob-
ably
due to the
stretching
of
pain-sensitive tissues
around
the
meningeal arteries resulting
from
the
increased pulsation that accompanies
the
local
vasodilatation.
If
headache
is
severe
the
dose should
be
halved. Methaemoglobinaemia occurs with heavy
dosage.
Interactions.
An
important footnote
to the use of
nitrates (and NO-dilators generally)
has
been
the
marked
potentiation
of
their vasodilator
effects
observed
in
patients taking
the
phosphodiesterase
(PDE)
inhibitor sildenafil
(Viagra).
This agent targets
an
isoform
of PDE
(PDE-5)
expressed
in the
blood
vessel wall. Other methylaxanthine
PDE
inhibitors,
such
as
theophylline,
do not
cause
a
similar
interaction because they
are
rather weak inhibitors
of
PDE-5, even
at the
doses
effective
in
asthma.
A
463
23
ARTERIAL
H Y P E R T E N S I O N , A N G I N A
PECTORIS,
Ml
number
of
pericoital
deaths
reported
in
patients
taking
sildenafil
have been attributed
to the
substantial
fall
in
blood
pressure
that
occurs when
used with
a
nitrate. This
is an
ironic twist
for an
agent
in
first-line
use in
erectile dysfunction
that
was
originally developed
as a
drug
to
treat angina.
3
GLYCERYLTRINITRATE
(see
also
above)
Glyceryl
trinitrate
(1879)
(trinitrin, nitroglycerin,
GTN)
(t
1
/2
3
min)
is an
oily, nonflammable
liquid
that explodes
on
concussion with
a
force
greater
than that
of
gunpowder. Physicians meet
it
mixed
with inert substances
and
made into
a
tablet,
in
which
form
it is
both innocuous
and
fairly
stable.
But
tablets more than
8
weeks
old or
exposed
to
heat
or air
will have lost potency
by
evaporation
and
should
be
discarded. Patients
should
also
be
warned
to
expect
the
tablet
to
cause
a
burning
sensation under
the
tongue
if it is
still contains
active
GTN.
An
alternative
is to use a
nitroglycerin
spray
(see below);
formulated
as a
pressurised
liquid
GTN has a
shelf
life
of at
least
3
years.
GTN
is the
drug
of
choice
in the
treatment
of an
attack
of
angina pectoris.
The
tablets should
be
chewed
and
dissolved under
the
tongue,
or
placed
in the
buccal sulcus, where absorption
is
rapid
and
reliable. Time spent ensuring that patients under-
stand
the way to
take
the
tablets
and
that
the
feeling
of
fullness
in the
head
is
harmless,
is
time well
spent.
The
action begins
in 2 min and
lasts
up to 30
min.
The
dose
in the
standard tablet
is 300
micro-
grams,
and 500 or 600
microgram strengths
are
also
available; patients
may use up to 6 mg
daily
in
total
but
those
who
require more than
2-3
tablets
per
week
should take
a
long-acting nitrate preparation.
GTN
is
taken
at the
onset
of
pain
and as a
pro-
phylactic immediately before
any
exertion likely
to
precipitate
the
pain. Sustained-release buccal
tablets
are
available (Suscard),
1-5 mg.
Absorption
from
the
gastrointestinal tract
is
good,
but
there
is
such extensive
hepatic
first-pass metabolism
that
3
It has
been argued that deaths
on
sildenafil largely
reflect
the
fact
that
it is
used
by
patients
at
high cardiovascular
risk.
But
recent postmarketing data shows that death
is 50
times
more likely
after
sildenafil taken
for
erectile
failure
than
alprostadil,
the
previous
first-line
agent.
Mitka
M
2000
Journal
of the
American Medical Association 283: 590.
the
sublingual
or
buccal route
is
preferred;
an
oral
metered aerosol that
is
sprayed under
the
tongue
(nitrolingual spray)
is an
alternative.
For
prophylaxis,
GTN can be
given
as an
oral
(buccal,
or to
swallow, Sustac) sustained-release
formulation
or via the
skin
as a
patch
(or
ointment);
these
formulations
can be
useful
for
victims
of
nocturnal
angina.
4
Venepuncture:
the
ointment
can
assist
difficult
venepuncture
and a
transdermal patch
adjacent
to
an
i.v. infusion site
can
prevent extravasation
and
phlebitis
and
prolong
infusion
survival.
Isosorbide dinitrate (Cedocard)
(t
1
/2
20
min)
is
used
for
prophylaxis
of
angina pectoris
and for
congestive heart
failure
(tabs sublingual,
and to
swallow).
An
i.v. formulation
500
micrograms/ml
(Isoket)
is
available
for use in
left
ventricular
failure
and
unstable
angina.
Isosorbide mononitrate
(Elantan)
(t
1
/2
4 h) is
used
for
prophylaxis
of
angina (tabs
to
swallow). Hepatic
first-pass
metabolism
is
much less than
for the
dinitrate
so
that systemic bioavailability
is
more
reliable.
Pentaerythritol tetranitrate (Peritrate) (t1/
2
8h) is
less
efficacious
than
its
metabolite pentaerythritol
trinitrate
(t1/211
h).
CALCIUM
CHANNEL
BLOCKERS
Calcium
is
involved
in the
initiation
of
smooth
muscle
and
cardiac cell contraction
and in the
pro-
pagation
of the
cardiac impulse. Actions
on
cardiac
pacemaker cells
and
conducting tissue
are
described
in
Chapter
24.
Vascular
smooth muscle cells. Contraction
of
these cells requires
an
influx
of
calcium across
the
cell
membrane. This occurs through
ion
channels
4
Useful,
but not
always
safe.
Defibrillator
paddles
and
nitrate
patches make
an
explosive combination,
and it is not
always
in the
patient's interest
to
have
the
patch
as
unobtrusive
as
possible
(Canadian Medical
Association
Journal
1993 148: 790).
464
VASODILATORS
23
that
are
largely
specific
for
calcium
and are
called
'slow
calcium channels'
to
distinguish them
from
'fast'
channels that allow
the
rapid
influx
and
efflux
of
sodium.
Activation
of
calcium
channels
by an
action
po-
tential
allows calcium
to
enter
the
cells. There
follows
a
sequence
of
events which results
in
activation
of
the
contractile proteins, myosin
and
actin, with
shortening
of the
myofibril
and
contraction
of
smooth
muscle. During relaxation calcium
is
released
from
the
myofibril
and,
as it
cannot
be
stored
in the
cell,
it
passes
out
again through
the
channel. Calcium
channel
(also
called calcium entry) blockers inhibit
the
passage
of
calcium through
the
voltage-
dependent
L-
(for 'long-opening') class membrane
channels
in
cardiac muscle
and
conducting tissue,
and
vascular smooth muscle, reduce available intra-
cellular
calcium
and
cause
the
muscle
to
relax.
5
There
are
three structurally distinct classes
of
calcium
channel blocker:
•
Dihydropyridines
(the
most numerous)
•
Phenylalkylamines (principally verapamil)
•
Benzothiazepine (diltiazem).
The
differences
between their clinical
effects
can
be
explained
in
part
by
their binding
to
different
parts
of the
L-type calcium channel.
All
members
of
the
group
are
vasodilators,
and
some have negative
cardiac
inotropic action
and
negative chronotropic
effect
via
pacemaker cells
and
depress conducting
tissue.
The
attributes
of
individual drugs
are de-
scribed
below.
The
therapeutic
benefit
of the
calcium blockers
in
hypertension
and
angina
is due
mainly
to
their
action
as
vasodilators. Their action
on the
heart
gives non-dihydropyridines
an
additional role
as
Class
4
antiarrhythmics.
Pharmacokinetics. Calcium channel blockers
in
general
are
well absorbed
from
the
gastrointestinal
tract
and
their systemic bioavailability
depends
on
the
extent
of
first-pass metabolism
in the gut
wall
and
liver,
which varies between
the
drugs.
All
5
Several calcium-selective channels have been described
in
different
tisues,
e.g.
the N
(present
in
neuronal tissue)
and T
(transient, found
in
brain, neuronal
and
cardiovascular
tissue);
the
drugs discussed here selectively target
the L
channel
for its
cardiovascular importance.
undergo metabolism
to
less active products,
pre-
dominantly
by
cytochrome P-450
CYP3A,
which
is
the
source
of
interactions with other drugs
by
enzyme
induction
and
inhibition.
As
their action
is
ter-
minated
by
metabolism,
dose
adjustments
for
patients
with impaired renal function
are
therefore
either
minor
or
unnecessary.
Indications
for use
•
Hypertension:
amlodipine,
isradipine,
nicardipine, nifedipine, verapamil
•
Angina:
amlodipine, diltiazem, nicardipine,
nifedipine,
verapamil
•
Cardiac
arrhythmia:
verapamil
•
Raynaud's
disease:
nifedipine
•
Prevention
of
ischaemic neurological damage
following
subarachnoid haemorrhage:
nimodipine.
Adverse
effects.
Headache, flushing, dizziness,
palpitations
and
hypotension
may
occur during
the
first
few
hours
after
dosing,
as the
plasma concen-
tration
is
increasing, particularly
if the
initial dose
is
too
high
or
increased
too
rapidly. Ankle oedema
may
also develop. This
is
probably
due to a
rise
in
intracapillary
pressure
as a
result
of the
selective
dilatation
by
calcium blockers
of the
precapillary
arterioles.
Thus
the
oedema
is not a
sign
of
sodium
retention.
It is not
relieved
by a
diuretic
but
dis-
appears
after
lying
flat,
e.g.
overnight.
In
theory
the
oedema
should also
be
attenuated
by
combining
the
calcium blocker with another vasodilator which
is
more
effective
(than calcium blockers)
at
relaxing
the
postcapillary
venules,
e.g.
a
nitrate
or an
ACE
inhibitor. Bradycardia
and
arrhythmia
may
occur.
Gastrointestinal
effects
include constipation,
nausea
and
vomiting; palpitation
and
lethargy
may
be
felt.
There
has
been some concern that
the
shorter-
acting calcium
channel
blockers
may
adversely
affect
the
risk
of
myocardial
infarction
and
cardiac
death.
The
evidence
is
based
on
case-control studies
which cannot escape
the
possibility that sicker
patients,
i.e.
with worse hypertension
or
angina,
received
calcium channel blockade.
The
safety
and
efficacy
of the
class
has
been
strengthened
by the
recent
findings
of two
prospective comparisons
with other antihypertensives.
6
465
23
ARTERIAL
H Y P E R T E N S I O N , A N G I N A P E C T O R I S, M
Interactions
are
quite numerous.
The
drugs
in
this
group
in
general
are
extensively metabolised,
and
there
is
risk
of
decreased
effect
with enzyme inducers,
e.g.
rifampicin,
and
increased
effect
with enzyme
inhibitors, e.g. cimetidine. Conversely, calcium
channel blockers decrease
the
plasma clearance
of
several
other drugs
by
mechanisms that include
delaying their metabolic breakdown.
The
conse-
quence,
for
example,
is
that diltiazem
and
verapamil
cause
increased exposure
to
carbamazepine, quinidine,
statins, ciclosporin, metoprolol, theophylline
and
(HIV)
protease
inhibitors.
Verapamil increases
plasma concentration
of
digoxin, possibly
by
interfering
with
its
biliary excretion. Beta-adreno-
ceptor blockers
may
exacerbate atrioventricular
block
and
cardiac
failure.
Grapefruit
juice
raises
the
plasma concentration
of
dihydropyridines
(except
amlodipine)
and
verapamil.
Individual
calcium blockers
Nifedipine
(t
l
/
2
2h) is the
prototype dihydro-
pyridine.
It
selectively dilates arteries with little
effect
on
veins;
its
negative myocardial inotropic
and
chronotropic
effects
are
much less than those
of
verapamil. There
are
sustained-release formulations
of
nifedipine that permit once daily dosing with
minimal peaks
and
troughs
in
plasma concentration
so
that adverse
effects
due to
rapid fluctuation
of
concentrations
are
also lessened. Various methods
have been used
to
prolong,
and
smooth, drug
delivery,
and
bioequivalence between
these
formu-
lations cannot
be
assumed; prescribers
should
specify
the
brand
to be
dispensed.
The
adverse
effects
of
calcium blockers
with
a
short
duration
of
action
may
include
the
hazards
of
activating
the
sympathetic system each time
a
dose
is
taken.
The
dose
range
for
nifedipine
is
30-90
mg
daily.
In
addition
to the
adverse
effects
listed above,
gum
hypertrophy
may
occur.
Nifedipine
can be
taken
'sublingually',
by
biting
a
capsule
and
squeezing
the
contents under
the
tongue.
In
point
of
fact,
absorption
is
still largely
from
the
stomach
after
this
6
Both
the
NORDIL
and
INSIGHT trials (Lancet
2000
356:
359-365,
366-372) confirmed that
a
calcium channel blocker
(diltiazem
and
nifedipine respectively)
had the
same
efficacy
as
older therapies (diuretics
and/or
-blockers)
in
hypertension with
no
evidence
of
increased
sudden
death.
manoeuvre;
it
should
not be
used
in a
hypertensive
emergency
because
the
blood pressure reduction
is
unpredictable
and
sometimes large enough
to
cause
cerebral
ischaemia (see
p.
492).
Amlodipine
has a
t
1
/2
(40 h)
sufficient
to
permit
the
same
benefits
as the
longest-acting
formulations
of
nifedipine
without requiring
a
special
formulation.
Its
slow
association with L-channels
and
long
duration
of
action render
it
unsuitable
for
emergency
reduction
of
blood pressure where
frequent
dose
adjustment
is
needed.
On the
other
hand
an
occasional
missed dose
is of
little consequence.
Amlodipine
differs
from
all
other dihydropyridines
listed
in
this chapter
in
being
safe
to use in
patients
with cardiac
failure
(the
PRAISE
7
Study).
Verapamil
(t
l
/
2
4 h) is an
arterial vasodilator
with
some venodilator
effect;
it
also
has
marked negative
myocardial
inotropic
and
chronotropic actions.
It is
given thrice daily
as a
conventional tablet
or
daily
as a
sustained-release formulation. Because
of its
negative
effects
on
myocardial conducting
and
contracting cells
it
should
not be
given
to
patients
with bradycardia, second
or
third degree heart
block,
or
patients with Wolff-Parkinson-White
syndrome
to
relieve atrial
flutter
or
fibrillation.
Amiodarone
and
digoxin increase
the AV
block.
Verapamil
increases plasma quinidine concen-
tration
and
this interaction
may
cause dangerous
hypotension.
Diltiazem
(t
l
/
2
5 h) is
given thrice daily,
or
once
or
twice
daily
if a
slow-release formulation
is
pre-
scribed.
It
causes less myocardial depression
and
prolongation
of AV
conduction than does verapamil
but
should
not be
used where there
is
bradycardia,
second
or
third degree heart block
or
sick
sinus
syndrome.
Isradipine
(t
1
/2
8 h) is
given once
or
twice daily
(it is
similar
to
nifedipine).
Nicardipine
(t
1
/2
4 h) is
given
x
3/d.
7
PRAISE
=
Prospective Randomised Amlodipine Survival
Evaluation (see Packer
M et al
1996
The
effect
of
amlodipine
on
morbidity
and
mortality
in
severe chronic heart
failure.
New
England Journal
of
Medicine 335:
1107-1114).
466
23
Nimodipine
has a
moderate
cerebral
vasodilating
action.
Cerebral ischaemia
after
subarachnoid
haemorrhage
may be
partly
due to
vasospasm;
clinical
trial evidence indicates that nimodipine
given
after
subarachnoid haemorrhage reduces
cerebral
infarction
(incidence
and
extent).
8
Although
the
benefit
is
small,
the
absence
of any
more
effec-
tive
alternatives
has led to the
routine administration
of
nimodipine
(60 mg
every
4
hours)
to all
patients
for
the
first
few
days following subarachnoid
haemorrhage.
No
benefit
has
been
found
in
similar
trials following other
forms
of
stroke.
Other
members
include
felodipine,
isradipine,
laci-
dipine,
lercanidipine,
nisoldipine.
ANGIOTENSIN
CONVERTING
ENZYME
(ACE)
INHIBITORS
AND
ANGIOTENSIN
(AT)
II
RECEPTOR
ANTAGONISTS
Renin
is an
enzyme produced
by the
kidney
in
response
to a
number
of
factors
including adrenergic
activity
(
1
-receptor)
and
sodium depletion. Renin
converts
a
circulating glycoprotein (angiotensinogen)
into
the
biologically inert angiotensin
I,
which
is
then changed
by
angiotensin converting enzyme
(ACE
or
kininase
II)
into
the
highly potent vaso-
constrictor
angiotensin
II. ACE is
located
on the
luminal
surface
of
capillary endothelial cells, parti-
cularly
in the
lungs;
and
there
are
also
renin-
angiotensin systems
in
many organs, e.g. brain,
heart,
the
relevance
of
which
is
uncertain.
Angiotensin
II
acts
on two
G-protein coupled
receptors,
of
which
the
angiotensin 'AT
1
subtype
accounts
for all the
classic actions
of
angiotensin.
As
well
as
vasoconstriction these include stimulation
of
aldosterone (the sodium-retaining hormone)
production
by the
adrenal
cortex.
It is
evident that
angiotensin
II can
have
an
important
effect
on
blood pressure.
In
addition,
it
stimulates cardiac
and
vascular smooth muscle cell growth, contributing
probably
to the
progressive
amplification
in
hyper-
tension
once
the
process
is
initiated.
The AT
2
receptor
subtype
is
coupled
to
inhibition
of
muscle
growth
or
proliferation,
but
appears
of
minor
importance
in the
adult cardiovascular system.
The
8
Packard
J D et al
1989
British
Medical Journal 289: 636.
VASODILATORS
recognition
that
the
AT
1
-receptor
subtype
is the
important target
for
drugs antagonising angiotensin
II
has
led,
a
little
confusingly,
to two
alternative
nomenclatures
for
these drugs: either AT
1
-receptor
blockers,
or
angiotensin
II
receptor antagonists
(AURA).
Bradykinin
(an
endogenous vasodilator occurring
in
blood vessel walls)
is
also
a
substrate
for
ACE.
Potentiation
of
bradykinin contributes
to the
blood
pressure lowering action
of ACE
inhibitors
in
patients with low-renin causes
of
hypertension.
Either
bradykinin
or one of the
neurokinin substrates
of
ACE
(such
as
substance
P) may
stimulate cough
(below).
The AT
1
blockers
differ
from
the ACE
inhibitors
in
having
no
effect
on
bradykinin
and do
not
cause cough. Those that achieve complete
blockade
of the
receptor
are
slightly more
effective
than
ACE
inhibitors
at
preventing angiotensin
II
vasoconstriction.
ACE
inhibitors
are
more
effective
at
suppressing aldosterone production
in
patients
with normal
or low
plasma renin.
Uses
Hypertension.
The
antihypertensive
effect
of ACE
inhibitors
and AT
1
receptor blockers results primarily
from
vasodilatation (reduction
of
peripheral resist-
ance)
with little change
in
cardiac output
or
rate;
renal
blood
flow
may
increase
(desirable).
A
fall
in
aldosterone production
may
also contribute
to the
blood
pressure
lowering action
of ACE
inhibitors.
Both
classes slow progression
of
glomerulopathy.
Whether
the
long-term
benefit
of
these drugs
in
hypertension exceeds that
to be
expected
from
blood
pressure reduction alone remains controversial.
ACE
inhibitors
and
AT
1
-receptor blockers
are
most
useful
in
hypertension when
the
raised blood
pressure results
from
excess renin production (e.g.
renovascular
hypertension),
or
where concurrent
use of
another drug (diuretic
or
calcium blocker)
renders
the
blood pressure renin-dependent.
The
fall
in
blood pressure
can be
rapid,
especially
with
short-acting
ACE
inhibitors,
and low
initial doses
of
these
should
be
used
in
patients
at
risk:
those
with
impaired renal
function,
or
suspected cerebrovascular
disease.
These
patients
may be
advised
to
omit
any
concurrent
diuretic treatment
for a few
days
before
the
first
dose.
The
antihypertensive
effect
increases
progressively over weeks with continued adminis-
467
23
ARTERIAL
H Y P E RT E N S I O N , A N G I N A
PECTORIS,
Ml
tration
(as
with other antihypertensives)
and the
dose
may be
increased
at
intervals
of 2
weeks.
Cardiac
failure
(see
p.
517).
ACE
inhibitors have
a
useful
vasodilator
and
diuretic-sparing
(but
not
diuretic-substitute) action
in all
grades
of
heart
failure.
Their reduction
of
mortality
in
this condition,
due
possibly
to
their being
the
only vasodilator
which does
not
reflexly
activate
the
sympathetic
system,
has
made
the ACE
inhibitors more critical
to the
treatment
of
heart
failure
than
of
hyper-
tension, where they
are not
usually
an
essential part
of
management.
The AT
1
blockers have
not yet
been
introduced
for the
treatment
of
cardiac
failure.
This
may
only
be a
matter
of
time,
but the
establishment
of
new
drugs
for
cardiac
failure
encounters
the
problem
of
demonstrating
efficacy
against
a
back-
ground
of
existing
ACE
inhibitor therapy, where
a
placebo
control
is no
longer ethically acceptable.
Diabetic nephropathy.
In
patients with type
I
(insulin
dependent) diabetes, hypertension
often
accompanies
the
diagnosis
of
frank
nephropathy
and
aggressive blood pressure control
is
essential
to
slow
the
otherwise inexorable decline
in
renal
func-
tion that
follows.
ACE
inhibitors appear
to
have
a
specific
renoprotective
effect,
possibly because
of
the
role
of
angiotensin
II in
driving
the
underlying
glomerular hyperfiltration
in
these patients.
9
These
drugs
are now
considered first-line treatment
for
hypertensive type
I
diabetics, although most patients
will need
a
second
or
third agent
to
reach
the new
BP
targets
for
these patients
(see
below). There
is
also
evidence that
ACE
inhibitors have
a
proteinuria-
sparing
effect
in
type
I
diabetics with
'normal'
BP,
but
here
it is
less
clear
whether this
effect
extends
beyond just
a
BP-lowering
effect.
10
For
hypertensive
type
2
diabetics with nephropathy, there
are
better
data
to
support
use of
AT
1
-receptor blockers than
ACE
inhibitors
for a
renoprotective
effect
indepen-
dent
of the
blood pressure lowering
effect.
9
For a
review,
see:
Cooper
M E
1998 Pathogenesis,
prevention
and
treatment
of
diabetic nephropathy.
Lancet
352:213-219.
10
The
EUCLID
study group 1997
The
EUCLID
study.
Randomised, placebo-controlled trial
of
lisinopril
in
normotensive patients with insulin-dependent diabetes
and
normoalbuminuria
or
microalbiminuria. Lancet 349:
1787-1792.
Myocardial
infarction (MI). Following
a
myocardial
infarction,
the
left
ventricle
may
fail
acutely
from
the
loss
of
functional
tissue
or in the
long-term
from
a
process
of
'remodelling'
due to
thinning
and
enlargement
of the
scarred ventricular wall. Angio-
tensin
II
plays
a key
role
in
both
of
these processes
and an ACE
inhibitor given
after
an MI
markedly
reduces
the
incidence
of
heart
failure.
The
effect
is
seen even
in
patients without overt signs
of
failure,
but who
have
low
left
ventricular ejection
fractions
during
the
convalescent phase
(3-10
days)
follow-
ing
their
MI.
Patients such
as
this receiving
captopril
in the
SAVE
trial,
11
had a 37%
reduction
in
progressive heart
failure
over
the
60-month
follow-
up
period
compared
to
placebo.
The
benefits
of
ACE
inhibition
after
MI are
additional
to
those
conferred
by
thrombolysis, aspirin
and
-blockers.
Cautions. Certain constraints apply
to the use of
ACE.
•
Heart
failure:
severe
hypotension
may
result
in
patients taking diuretics,
or who are
hypovolaemic, hyponatraemic, elderly, have
renal
impairment
or
with systolic blood
pressure
< 100
mmHg.
A
test dose
of
captopril
6.25
mg by
mouth
may be
given because
its
effect
lasts only
4-6 h. If
tolerated,
the
preferred
long-acting
ACE
inhibitor
may
then
be
initiated
in
low
dose.
•
Renal
artery
stenosis
(whether unilateral, bilateral
renal
or
suspected
from
the
presence
of
generalised atherosclerosis):
an ACE
inhibitor
may
cause renal
failure
and is
contraindicated.
•
Aortic
stenosis/left
ventricular
outflow
tract
obstruction:
an ACE
inhibitor
may
cause severe,
sudden hypotension
and,
depending
on
severity,
is
relatively
or
absolutely
contraindicated.
•
Pregnancy
represents
a
contraindication
(see
below).
•
Angioedema
may
result (see below).
Adverse
effects
ACE
inhibitors cause persistent
dry
cough
in
10-15%
of
patients. Urticaria
and
angioedema
(< 1
11
Swedberg
K P et al
1992
New
England Journal
of
Medicine
327:
669-677.
468
23
in 100
patients)
are
much rarer, occurring usually
in
the
first
weeks
of
treatment.
The
angioedema varies
from
mild swelling
of the
tongue
to
life-threatening
tracheal
obstruction, when
s.c.
adrenaline (epine-
phrine) should
be
given.
The
basis
of the
reaction
is
probably
pharmacological rather than allergic,
due
to
reduced breakdown
of
bradykinin.
Impaired
renal
function
may
result
from
reduced
glomerular
filling
pressure, systemic hypotension
or
glomerulonephritis,
and
plasma crearinine should
be
checked
before
and
during treatment. Hypo-
natraemia
may
develop, especially where
a
diuretic
is
also
given;
clinically significant hyperkalaemia
(see
effect
on
aldosterone above)
is
confined
to
patients with impaired renal
function.
ACE
inhi-
bitors
are
fetotoxic
in the
second trimester, causing
reduced renal perfusion, hypotension, oligohy-
dramnios
and
fetal
death.
Neutropenia
and
other
blood dyscrasias
occur.
Other reported reactions
include rashes, taste disturbance (dysguesia),
musculoskeletal
pain, proteinuria, liver
injury
and
pancreatitis.
AT
1
receptor blockers
are
contraindicated
in
pregnancy,
but
avoid most other complications
—
particularly
the
cough
and
angioedema. They
are
the
only antihypertensive drugs
for
which there
is
no
'typical' side
effect.
Interactions. Hyperkalaemia
can
result
from
use
with potassium-sparing diuretics. Renal clearance
of
lithium
is
reduced
and
toxic concentrations
of
plasma lithium
may
follow.
Severe hypotension
can
occur
with diuretics (above),
and
with
chlorpro-
mazine,
and
possibly other phenothiazines.
Individual drugs
Captopril
(Capoten)
has a
t
l
/
2
of 2 h and is
partly
metabolised
and
partly excreted unchanged; adverse
effects
are
more common
if
renal
function
is
impaired;
it is
given twice
or
thrice daily. Captopril
is the
shortest-acting
of the ACE
inhibitors,
one of
the few
where
the
oral drug
is
itself
active,
not
requiring de-esterification
after
absorption.
Enalapril
(Innovace)
is a
prodrug
(t
l
/
2
35 h)
that
is
converted
to the
active enalaprilat
(t
l
/
2
10 h).
Effec-
tive
24-h
control
of
blood
pressure
may
require
twice daily administration.
VASODILATORS
Other members include
cilazapril,
fosinopril,
imidapril,
lisinopril,
moexipril,
perindopril,
quinapril,
mmipril,
and
trandolapril.
Of
these,
lisinopril
has a
marginally
longer
t
1
/
2
than enalapril, probably
justifying
its
popularity
as a
once-daily
ACE
inhibitor. Some
of
the
others
are
longer-acting, with quinapril
and
ramipril having also
a
higher degree
of
binding
to
ACE
in
vascular tissue.
The
clinical significance
of
these
differences
is
disputed.
In the
Heart
Out-
comes
Prevention Evaluation
(HOPE)
Study
of
9297
patients, ramipril reduced,
by
20-30%,
the
rates
of
death, myocardial infarction,
and
stroke
in a
broad
range
of
high-risk
patients
who
were
not
known
to
have
a low
ejection
fraction
or
heart
failure.
12
The
authors considered that
the
results could
not be
explained entirely
by
blood pressure reduction.
Losartan
was the
first
AT
1
receptor antagonist
licensed
in the UK. It is a
competitive blocker with
a
noncompetitive active metabolite.
The
drug
has a
short
t// (2 h) but the
metabolite
is
much longer
lived
(t
1
/2
10 h)
permitting once daily dosing. Other
AT
1
receptor antagonists
in
clinical
use
include
candesartan,
eprosartan,
irbesartan,
telmisartan
and
valsartan.
Some
of
these appear more
effective
than
losartan, which
is
generally used
in
combination
with hydrochlorothiazide.
In a
landmark study this
combination
was 25%
more
effective
than atenolol
plus hydrochlorothiazide
in
preventing stroke.
13
This
class
of
drug
is
very well tolerated;
in
clinical
trials their side
effect
profiles
are
indistinguishable
or
even better than placebo. Unlike
the ACE
inhibitors
they
do not
produce cough,
and are a
valuable
alternative
for the
10-15%
of
patients
who
dis-
continue their
ACE
inhibitor
for
this reason.
AT
1
receptor
antagonists
are
used
to
treat hypertension
but any
role
in
cardiac
failure
or
after
myocardial
infarction
(as
have
ACE
inhibitors) remains
to be
established.
The
cautions listed
for the use of ACE
inhibitors
(above)
apply also
to AT
1
receptor blockers.
12
Yusuf
S,
Sleight
P,
Pogue
J et al
2000
Effects
of an
angiotensin-converting-enzyme
inhibitor, ramipril,
on
cardiovascular
events
in
high-risk patients.
The
Heart
Outcomes
Prevention Evaluation Study Investigators.
New
England
Journal
of
Medicine
342:145-53.
13
Dahlof
B et al
2002
Cardiovascular morbidity
and
mortality
in the
Losartan Intervention
for
Endpoint
reduction
in
hypertension
study
(LIFE):
a
randomised
trial
against
atenolol.
Lancet
359:
995-1010.
469
23
ARTERIAL
H Y P E R T E N S I O N , A N G I N A P E C T O R I S, Ml
Other vasodilators
Several
older drugs
are
powerfully
vasodilating,
but
precluded
from
routine
use in
hypertension
by
their adverse
effects.
Minoxidil
and
nitroprusside
still have special indications.
Minoxidil
is a
vasodilator selective
for
arterioles
rather
than
for
veins, similar
to
diazoxide
and
hydralazine. Like
the
former,
it
acts through
its
sulphate metabolite
as an
ATP-dependent potassium
channel
opener.
It is
highly
effective
in
severe
hypertension,
but
causes increased cardiac output,
tachycardia,
fluid
retention
and
hypertrichosis.
The
hair growth
is
generalised
and
although
a
cosmetic
problem
in
women,
it has
been exploited
as a
topical
solution
for the
treatment
of
baldness
in
men.
Sodium nitroprusside
is a
highly
effective
anti-
hypertensive agent when given i.v.
Its
effect
is
almost immediate
and
lasts
for 1-5
min. Therefore
it
must
be
given
by a
precisely controllable
infusion.
It
dilates both
arterioles
and
veins,
which would
cause
collapse
if the
patient stands
up,
e.g.
for
toilet
purposes. There
is a
compensatory sympathetic
discharge
with
tachycardia
and
tachyphylaxis
to
the
drug.
The
action
of
nitroprusside
is
terminated
by
metabolism within erythrocytes.
Specifically,
electron
transfer
from
haemoglobin iron
to
nitro-
prusside yields
methaemoglobin
and an
unstable
nitroprusside radical. This breaks
down,
liberating
cyanide
radicals capable
of
inhibiting cytochrome
oxidase
(and thus cellular respiration). Fortunately
most
of the
cyanide remains bound within erythro-
cytes
but a
small
fraction
does
diffuse
out
into
the
plasma
and is
converted
to
thiocyanate. Hence,
monitoring plasma
thiocyanate
concentrations during
prolonged (days) nitroprusside
infusion
is a
useful
marker
of
impending systemic cyanide
toxicity.
Poisoning
may be
obvious
as a
progressive metabolic
acidosis
or
manifest
as
delirium
or
psychotic symp-
toms.
Toxic
subjects
are
also reputed
to
emit
the
characteristic
bitter almond smell
of
hydrogen
cyanide. Clearly nitroprusside
infusion
should
not
be
undertaken without meticulous regard
for the
manufacturer's recommendations
and
precautions;
outside specialist units
it may be
safer
overall
to
choose
another more
familiar
drug.
Sodium
nitroprusside
is
used
in
hypertensive
emergencies,
refractory
heart failure
and for
con-
trolled
hypotension
in
surgery.
An
infusion
14
may
begin
at
0.3-1.0
micrograms/kg/min
and
control
of
blood
pressure
is
likely
to be
established
at
0.5-6.0
micrograms/kg/min; close monitoring
of
blood
pressure
is
mandatory usually with direct arterial
monitoring
of
blood pressure; rate changes
of
infu-
sion
may be
made every 5-10 min.
Diazoxide
is
chemically
a
thiazide
but has no
appreciable diuretic
effect;
indeed,
like other
potent
arterial
vasodilators
it
causes
salt
and
water retention.
It
reduces peripheral arteriolar resistance through
activation
of the
ATP-dependent potassium channel
(c.f.
nicorandil
and
minoxidil), with little
effect
on
veins.
The
t1/2
is 36 h.
The
principal
use of
diazoxide
has
been
in the
emergency
treatment
of
severe hypertension.
The
maximum
effect
after
an
i.v. bolus occurs within
5 min and
lasts
for at
least
4 h. The
dangers
from
excessive
hypotension
are now
recognised
to
out-
weigh
the
benefit,
and
emergency
use of
diazoxide
is
almost obsolete.
Because
it
stimulates
the
same potassium
channel
in the
pancreatic islet cells
as is
blocked
by
sulphonylureas, diazoxide causes hyperglycaemia.
This
effect
renders diazoxide unsuitable
for
chronic
use in
hypertension,
but a
useful
drug
to
treat
insulinoma. Long-term oral administration causes
the
same problem
of
hair growth seen with
minoxidil (see below
and
'alopecia').
Hydralazine
now has
little
use
long-term
for
hyper-
tension,
but it may
have
a
role
as a
vasodilator (plus
nitrates)
in
heart
failure.
It
reduces peripheral
resistance
by
directly relaxing
arterioles,
with negli-
gible
effect
on
veins.
In
common with
all
potent
arterial
vasodilators,
its
hypotensive action
is
accompanied
by a
compensatory baroreceptor-
mediated
sympathetic discharge, causing tachycardia
and
increased cardiac
output.
There
is
also
renin
release
with secondary salt
and
water retention,
14
Light causes
sodium
nitroprusside
in
solution
to
decompose; hence solutions should
be
made
fresh
and
immediately protected
by an
opaque
cover, e.g. metal
foil.
The
fresh
solution
has a
faint
brown
colour;
if the
colour
is
strong
it
should
be
discarded.
470
[...]... intermediate Classification of -adrenoceptor blocking drugs • Pharmacokinetic: lipid-soluble, water-soluble, see above • Pharmacodynamic (Table 23.1) The associated properties (partial agonist action and membrane stabilising action) have only minor clinical importance with current drugs at doses ordinarily used and may be insignificant in most cases But it is desirable that they be known, for they can sometimes... the drug (See the note to Table 22.1, p 449, regarding use of the terms 2 selective and cardioselective.) The question is whether the differences between selective and nonselective -blockers constitute clinical advantages In theory 1-blockers are less likely to cause bronchoconstriction, but in practice few available TABLE 23 1 are sufficiently selective to be safely 1blockers recommended in asthma Bisoprolol... since there may be less up-regulation of receptors, such as occurs with prolonged receptor block Some -blockers have membrane stabilising (quinidine-like or local anaesthetic) effect This property is clinically insignificant except that agents having this effect will anaesthetise the eye (undesirable) if applied topically for glaucoma (timolol is used in the eye and does not have this action), and... obscures the vasodilatation that is characteristic of a-adrenoceptor blocking drugs Chlorpromazine has many actions of which aadrenoceptor block is a minor one, but sufficient to cause hypotension, and to be clinically useful in amphetamine overdose P-ADRENOCEPTOR BLOCKING DRUGS Actions These drugs selectively block the -adrenoceptor effects of noradrenaline (norepinephrine) and adrenaline (epinephrine) They . (Table
23.1).
The
associated
properties (partial agonist action
and
membrane
stabilising action) have only minor clinical
importance with current drugs
. verapamil)
•
Benzothiazepine (diltiazem).
The
differences
between their clinical
effects
can
be
explained
in
part
by
their binding
to
different
parts