ArticlePDF AvailableLiterature Review

Cardiovascular Complications of Cocaine

Authors:
  • Heart Institute of the Caribbean
DOI 10.1378/chest.107.5.1426
1995;107;1426-1434Chest
Theodore D. Fraker, Jr
Assad H. Mouhaffel, Ernest C. Madu, Wendy A. Satmary and
Cardiovascular Complications of Cocaine
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Copyright1995by the American College of Chest Physicians, 3300
Physicians. It has been published monthly since 1935.
is the official journal of the American College of ChestChest
1995 by the American College of Chest Physicians
by guest on July 13, 2011chestjournal.chestpubs.orgDownloaded from
,~~~~~~~
11-
reviews
,1
i
-"
&,%A
r^-s,&
ascular
Complications
of
Cocaine*
Assad
H.
Mouhaffel,
MD;
Ernest
C.
Theodore
D.
Fraker,
Jr,
MD
(Chest
1995;
107:1426-34)
AMP=adenosine
monophosphate;
AV=atrioventricular;
CAD=coronary
artery
disease;
cAMP=cyclic
AMP;
EAD=early
after-depolarization;
IV=intravenous;
Ml=
myocardial
infarction
Key
words:
cocaine;
complications;
heart;
spasm;
myocar-
dial
infarction;
arrythmias;
myocarditis
Cocaine
use
and
abuse
continue
to
overwhelm
ur-
ban
economic,
social,
and
health-care
systems.
The
recreational
cocaine
use
has
increased
dramati-
cally
over
the
past
15
years
as
a
result
of
the
increased
availability
of
"crack,"
the
inexpensive
freebase
form.
It
is
estimated
that
30
million
Americans
(about
10%
of
the
population)
have
used
cocaine
at
least
once,
5
million
Americans
use
it
routinely,
while
an
additional
5,000
use
it
each
day.'
Approximately
5
to
10%
of
emergency
department
visits
in
the
United
States
are
thought
to
be
related
to
cocaine
use.2
Al-
though
neurologic,
obstetric,
gastrointestinal,
renal,
and
endocrine
complications
have
all
been
associated
with
cocaine
use,
the
most
common
complaints
from
patients
entering
emergency
departments
are
related
to
the
cardiovascular
system.3
The
effects
of
cocaine
use
place
a
substantial
economic
and
social
burden
on
the
health
care
system.
The
widespread
use
of
cocaine
and
the
potential
for
serious,
even
lethal,
medical
complications
has
led
to
increased
interest
in
all
facets
of
this
complex
drug.
The
large
body
of
information
has
added
to
the
present
understanding
of
the
actions
of
cocaine
and
the
relation
of
cocaine
use
to
serious
organ
dysfunction.
The
intent
of
this
communication
is
to
review
the
pharmacologic
ac-
tions
of
cocaine
and
recent
literature
describing
co-
caine-induced
cardiotoxicity.
PHARMACOLOGY
Cocaine
(benzoylmethyleegonine,
C17H21No4)
is
an
alkaloid
prepared
from
the
leaves
of
the
eryth-
*From
the
Division
of
Cardiology,
Department
of
Medicine,
Medical
College
of
Ohio,
Toledo
(Drs.
Mouhaffel
and
Fraker
and
Ms.
Satmary);
and
the
Division
of
Cardiovascular
Disease,
University
of
Tennessee,
Memphis
(Dr.
Madu).
Reprint
requests:
Dr.
Fraker,
Division
of
Cardiology,
Medical
College
of
Ohio,
3000
Arlington
Avenue,
Toledo,
OH
43699-
0008
Madu,
MD;
Wendy
A.
Satmary;
and
roxylon
coca
plant.4
The
crystalline
(powder)
form
of
cocaine
is
prepared
by
dissolving
the
alkaloid
in
hy-
drochloric acid
to
form
the
water
soluble
salt,
cocaine
hydrochloride.
Cocaine
freebase
or
"crack"
is
the
cocaine
alkaloid
in
its
basic,
nonsalt
form
and
is
pre-
pared
from
cocaine
hydrochloride
by
organic
extrac-
tion
from
a
basic
solution
with
ether.5
Crack,
so-
called
because
of
the
popping
sound
made
when
it
is
heated,
is
not
water
soluble,
melts
but
does
not
decompose
when
heated,
and
vaporizes
at
higher
temperatures,
thus
allowing
it
to
be
smoked.
When
inhaled,
vapors
are
rapidly
absorbed
across
the
large
surface
area
of
the
alveolar
membrane.6
Cocaine
is
absorbed
from
all
body
mucous
membranes,
includ-
ing
nose,
lung,
and
gastrointestinal
tract.
It
can
be
administered
by
sublingual,
intravaginal,
rectal,
in-
tramuscular,
intravenous,
and
respiratory
routes.
Onset
of
cocaine
action
ranges
from
3
s
to
5
min
de-
pending
on
the
route
of
administration.
Peak
effect
varies
from
1
to
20
min
while
duration
of
action
ranges
from
5
to
90
min.
Peak
effect
and
duration
of
action
are
also
dependent
on
route
of
administration.
The
peak
cocaine
serum
level
occurs
within
sec-
onds
following
intravenous
administration,
and
co-
caine
has
an
elimination
half-life
of
30
to
60
min
in
man.7
It
is
metabolized
by
plasma
and
hepatic
cholinesterases
to
water-soluble
compounds,
ben-
zoylecgonine
and
ecgonine
methyl
ester,
which
are
excreted
in
the
urine.8
Cocaine
is
associated
with
le-
thal
cardiovascular
events,
including
myocardial
in-
farction
and
ventricular
fibrillation.
The
mechanisms
responsible
for
these
cardiotoxic
effects
of
cocaine
remain
largely
unresolved.
Cocaine
blocks
the
re-
uptake
of
norepinephrine
and
dopamine
at
the
preganglionic
sympathetic
nerve
endings.9
Because
this
is
the
major
mechanism
for
the
termination
of
action
of
locally
released
and
circulating
catechola-
mines,
cocaine
increases
the
synaptic
concentration
of
these
monoamines
available
for
binding
to
adren-
ergic
receptors,
thereby
enhancing
the
effect
of
ex-
ogenously
administered
norepinephrine.10-13
In
fact,
cocaine
potentially
increased
the
response
of
the
blood
pressure
to
injected
norepinephrine
in
experi-
mental
cats.10
Cocaine
has
also
been
shown
to
directly
release
dopamine
in
the
brain,
and
there
is
evidence
that
cocaine,
acting
via
a
central
nervous
system
Review
1426
%Ifiluuluvi
1995 by the American College of Chest Physicians
by guest on July 13, 2011chestjournal.chestpubs.orgDownloaded from
mechanism,
causes
the
release of
norepinephrine
and
epinephrine
from
the
adrenal
medulla.'14"5
The
net
result
of
this
combination
of
cocaine-induced
changes
on
neurotransmitter
release
and
reuptake
is
a
signif-
icant
elevation
of
catecholamine
concentration
in
adrenergic
synapses.
Several
studies
have
demon-
stra.ed
dose-related
increases
in
blood
pressure
and
heart
rate,
mydriasis,
and
other
physiologic
conse-
quences
of
enhanced
sympathetic
activity
following
cocaine
administration
in
man.16418
CELLULAR
EFFECTS
Cocaine
has
local
anesthetic
by
inhibiting
the
transient
inward
flux
of
sodium
across
the
cell
mem-
brane
during
depolarization.9
Neurotransmitters
re-
leased
from
cardiac
sympathetic
nerves
bind
to
both
a-
and
3-adrenergic
receptors
eliciting
a
cascade
of
intracellular
responses.
Stimulation
of
f-adrenergic
receptors
activates
adenylate
cyclase,
increasing
cy-
clic
adenosine
monophosphate
(AMP)
levels
leading
to
increased
Ca++
influx
into
the
myocardial
cells.
This
results
in
further
calcium
entry,
release
from
cytosolic
stores,
and
increased
intracellular
free
cal-
cium
levels,
the
end
result
being
an
increased
force
of
contraction.
Whereas
a-adrenergic
receptor
stim-
ulation
activates
phospholipase
C,
increasing
inositol
triphosphate,
stimulation
of
a-1-adrenergic
receptors
activates
phospholipase
C,
which
hydrolyzes
phos-
phatidylinositol
into
two
second
messengers:
inositol
triphosphate
and
diacylglycerol.
Diacylglycerol,
in
turn,
activates
protein
kinase
C,
which
phosphory-
lates
and
regulates
the
calcium
channels.
These
sec-
ond
messengers,
in
turn,
elicit
increases
in
cytosolic
calcium.
Elevations
in
cytosolic
calcium
can
provoke
oscillatory
depolarizations
of
the
cardiac
membrane,
triggering
sustained
action
potential
generation
and
extra
systoles.19
Few
studies
have
analyzed
the
effect
of
cocaine
on
calcium
flux
at
the
molecular
level.
Wide
variations
in
experimental
design,
including
the
choice
of
an
animal
model
vs
an
in
vitro
study
or
the
administra-
tion
of
a
high
vs
a
low
dose
of
cocaine,
may
confound
this
attempt.
Studies
with
skinned
ferret
myocardial
fibers,20
denervated
tissues,
and
human
umbilical
arteries
in
vitro,21
which
are
devoid
of
sympathetic
innervation,
all
support
the
concept
that
cocaine
may
directly
alter
calcium
flux
across
the
cell
membrane
and
contradict
the
traditional
concept
of
cocaine
as
exclusively
potentiating
the
response
to
endogenous
catecholamines.
21
Cocaine-induced
alterations
in
cal-
cium
ion
flux
were
demonstrated
by
fluorescence
using
45Ca++
in
experiments
using
the
rat
aorta.22
In
these
studies,
low
doses
of
cocaine
(10[-5]M)
caused
enhanced
norepinephrine-
and
serotonin-induced
Ca++
influx,
while
high
doses
(10[03]M)
caused
decreased
Ca++
influx.
Although
cocaine
potentiated
NE-
and
5-HT-induced
contractions,
it
had
no
effect
on
high-K+-induced
contractions.
Consequently,
the
authors
concluded
that
cocaine
most
likely
causes
increased
receptor-mediated
Ca++
entry,
but
not
voltage-dependent
Ca++
entry.22
Other
investigators
agree
that
cocaine
probably
does
not
increase
Ca++
entry
through
voltage-dependent
channels,
since
it
is
unlikely
that
it
causes
depolarization
of
the
myo-
cyte.21
By
inference,
therefore,
it
appears
that
co-
caine
increases
calcium
influx
through
receptor-
operated
membrane
channels.21
In
vitro
studies
examining
cocaine's
effect
on
the
working
ferret
myocardium
indicate
that
low
con-
centrations
of
cocaine
(<10[-5]
M)
produce
positive
inotropic
responses
associated
with
an
increased
am-
plitude
and
shortened
duration
of
the
tricellular
Ca++
transient
recorded
with
aequorin.20
Conversely,
high
cocaine
concentrations
(>
10[-4]
M)
not
only
decreased
the
amplitude
of
the
aequorin
response,
but
also
prolonged
the
time
course
of
the
Ca++
transient.
The
higher
concentrations
were
associated
with
a
negative
inotropic
effect.
The
mechanisms
by
which
high
concentrations
of
cocaine
decrease
intra-
cellular
calcium
is
unclear.
It
has
been
proposed
that
it
is
related
to
blockade
of
the
sodium
channels
in
the
sarcolemma
via
cocaine's
local
anesthetic
proper-
ties.23
Blockade
of
these
channels
decreases
the
amount
of
sodium
entering
the
cell
during
each
de-
polarization,
which
in
turn
would
decrease
the
amount
of
sodium
available
for
sodium-calcium
ex-
change.
This
exchanger
consists
of
an
outward
so-
dium
current
coupled
with
calcium
influx
across
the
sarcolemma
during
depolarization
in
a
ratio
of
three
sodium
ions
to
one
calcium
ion.
Therefore,
cocaine's
local
anesthetic
properties
may
lead
to
decreased
in-
tracellular
calcium
levels
and
diminished
Ca++
re-
lease
during
each
depolarization.23
Another
study
suggests
that
cocaine's
negative
in-
otropic
effect
at
high
doses
may
be
related
to
a
de-
crease
in
myofilament
responsiveness.23
In
this
in
vitro
study
using
human
cardiac
ventricular
trabec-
ulae
and
coronary
artery
segments
obtained
at
heart
transplantation,
cocaine
(10[-6]
-
10[-3]
M)
pro-
duced
negative
inotropic
and
relaxant
effects
in
both
vascular
smooth
muscle
and
myocardium.
In
contrast
to
other
studies,
low
doses
of
cocaine
did
not
cause
a
vasoconstrictor
response
or
positive
inotropy.
In
car-
diac
muscle,
the
negative
inotropic
response
was
as-
sociated
with
a
simultaneous
decrease
in
peak
intra-
cellular
Ca++.
However,
this
decrease
was
not
re-
produced
in
vascular
smooth
muscle.
It
was
concluded
that
the
depressant
effects
of
cocaine
on
cardiac
vs
vascular
smooth
muscle
occur
by
different
mecha-
nisms
and
that
the
negative
inotropy
in
smooth
muscle
is
related
to
a
decrease
in
myofilament
responsiveness.
Other
investigators
have
also
pro-
CHEST
/107/5/
MAY,
1995
1427
1995 by the American College of Chest Physicians
by guest on July 13, 2011chestjournal.chestpubs.orgDownloaded from
posed
that
negative
inotropy
is
associated
with
de-
creased
Ca++
sensitivity
of
the
contractile
proteins
or
myofilaments
after
cocaine
administration.20'24'25
Thus,
the
vascular
response
to
cocaine
at
high
doses
may
be
related
to
changes
in
myofilament
calcium
responsiveness,
and
this
response
may
be
mediated
through
intracellular
changes
in
cyclic
AMP
(cAMP)25
or
the
protein
kinase-C
system.26
Cocaine
may
act
directly
on
a
second
messenger
system,
such
as
inositol
triphosphate
associated
with
a-adrenergic
receptors
or
the
G
protein
associated
with
3-adren-
ergic
receptors,
to
effect
a
change
in
phosphorylation
and
activation
of
the
calcium
channels,
resulting
in
altered
calcium
flux.
Previous
studies
with
vasodila-
tors
have
demonstrated
that
agents
associated
with
increased
cytoplasmic
cAMP
levels
can
cause
uncou-
pling
of
calcium-force
relations.27
Perhaps
cocaine
works
in
a
similar
manner
to
produce
its
negative
inotropic
effect
at
high
concentrations.
This
concept
that
cocaine
may
directly
interact
with
second
mes-
senger
systems
rather
than
the
membrane
receptors
themselves
is
quite
alluring,
and
future
studies
are
needed
to
further
investigate
this
theory.
Cocaine's
exact
site
of
action,
in
terms
of
altering
calcium
ion
flux,
remains
unclear.
It
has
been
sug-
gested
by
Isner
and
Chokshi21
that
cocaine
may
in-
teract
with
either
angiotensin
II
or
histamine
H2
re-
ceptors. Kalsner28
speculated
that
cocaine
may
alter
channel
gating
characteristics
by
fitting
into
a
portion
of
the
actual
calcium
L-channel
receptor
or
its
envi-
ronment.
The
cardiac
effects
of
cocaine
are
extremely
com-
plex,
with
increased
adrenergic
activity
enhancing
myocardial
contractility,
pacemaker
activity,