Download Titrating cardiovascular drugs

Clinical Chemistiy
42:8(B)
1312-1315
(1996)
Titrating cardiovascular drugs
I.
FRANK
MARCUS
Titrating
cardiovascular
drugs is important to ensure efficacy and to minimize
the risk of toxicity. A serum assay is
extremely
useful to guide digoxin therapy. Assessment
of
the effect of warfarin
on blood clotting should be used to
adjust dose. Serum cholesterol
and lipid measurements
guide therapy with antilipemic
agents. The antihypertensive drugs, beta blockers,
calcium
channel
blockers,
and
vasodilators
can be assessed by their clinical effects. There
is no strict relation between
serwn concentration
of antiarrhythmic
drugs and their effects, nor is it clear that the
long-term
efficacy of these drugs can be assessed by surrogate
A. Therapeutic drug measurement: useful/essential
Cardiac glycoside
Digoxin
B. Endpont or functional assays: useful/essential
Anticoagulants
Warfarin
Heparin
Antilipemics
HMG-C0A reduction inhibitors (Lovastatin)
Bile acid sequestrants (cholestyramine)
C. Serum assay not needed: effect is measurable clinically
Antihypertensives
Beta blockers
Calcium channel blockers
Coronary vasodilators
Diuretics
0. Therapeutic drug measurement: of limited clinical value
Antiarrhythmic drugs
Amiodarone
Procainamide
Quinidine
end points.
INDEXING
drugs.
Table 1. Methods to titrate cardiovasculardrugs.
masS:
digoxin . drug
anticoagulants
. warfarin
monitoring
#{149}
antiarrhythmic
blockers
#{149}
beta
Cardiovascular
drug categories include inotropic agents such as
digoxin; anticoagulants
such as warfarin and heparin;
antiarrhythmic drugs including amiodarone,
flecainide, and quinidine;
antihypertensive
agents with a variety of mechanisms;
beta
blockers;
and antilipemic
drugs. Titration
of cardiovascular
drugs is important
to ensure efficacy and to minimize the risk of
toxicity. The means used to accomplish these goals are shown in
Table 1. For certain cardiovascular
drugs, it is imperative to use
therapeutic
drug measurements
in serum or blood. For some,
end point effects or functional
assays are useful or imperative;
for others, serum assays are unnecessary
because the effects are
measurable clinically. The serum assay is of limited clinical value
to titrate some cardiovascular
drugs because of the wide range of
values associated with therapeutic
effect and because the serum
values may or may not predict the clinical response. In addition,
toxicity may not be related to the dose or the serum value.
The characteristics
of the ideal drug to be monitored
by
serum or blood concentration
are listed in Table 2. Digoxin, an
excellent example of such a drug, is a cardiac glycoside,
the
major action of which is to increase the force of contraction
of
the heart, and digitalis has been in use for >200 years for the
treatment
of congestive
heart failure, a use that William Withering astutely observed in 1775 [1]. The difficulty in relating the
University of Arizona Health Sciences Center, 1501 N. Campbell,
85724. Fax 520-626-4333;
e-mail [email protected].
Received February
15, 1996; accepted March 25, 1996.
Tucson,
HMG-C0A, 3-tydroxy-3-methylgIutaryI-coenzyme
A
appropriate
dose of digitalis to effect was illustrated by his initial
recommendations,
which were to “continue
the medicine until
the urine flows, or sickness or purging take place.” Withering
further observed that in some patients the “pulse would be
retarded
to an alarming degree, without any other preceding
effect.” Therefore,
he altered his recommendation
for the use of
digitalis to “let it be continued until it either acts on the kidneys,
the stomach, the pulse or the bowels; let it be stopped upon the
appearance
of any one of these effects” [1]. It was not until 1969
that Smith et al. [2] developed a serum assay for digoxin. The
results obtained by this assay confirmed
the clinical observation
that this drug has a narrow therapeutic
toxic ratio. Patients who
received 0.25 mg daily and who did not have symptoms
of
toxicity such as nausea or vomiting had digoxin serum concentrations
of 1-2 g/L,
whereas
patients
who had signs or
symptoms
of toxicity usually had serum digoxin concentrations
>2 ig/L. Smith et al. also observed that the major factor that
led to the higher digoxin concentrations
was not the dose but
appeared to be diminished
renal function. Data indicate that if
AZ
1312
Clinical Chemistry 42, No. 8(B), 1996
digoxin concentrations
are >2 .tg/L, the likelihood
of the
patient’s experiencing
toxic effects is almost 8 times greater than
for individuals with digoxin concentrations
of 1.0 .tg/L.
Not only does digoxin have a narrow therapeutic-to-toxic
ratio, but also the manifestations
of toxicity can be serious or
fatal because this drug may enhance cardiac automaticity
and
cause ventricular
tachycardia
and (or) ventricular
fibrillation. As
previously
mentioned,
it is difficult
to assess clinically an increase in the inotropic effect. Because it is desirable to obtain the
maximum
inotropic
effect of digitalis
without
toxicity and
because the therapeutic-to-toxic
ratio is narrow, it has not been
clear what serum concentration
would be most appropriate
to
yield the desired inotropic effect. Young et al. [3] reported that
patients with congestive
heart failure who were treated with
digoxin and who had serum concentrations
of 0.9-1.2
j.tg/L
could exercise substantially
longer than patients who were given
placebo. However,
there was no increase in exercise duration in
patients who were treated with digoxin and who had concentrations >1.2 ig/L.
Other characteristics
that make digoxin an ideal drug to
monitor by serum drug concentration
are that it has few active
metabolites
and most of the drug is present in unchanged
form.
In addition, many drugs interact with digoxin; most raise serum
digoxin
concentrations,
frequently
to the toxic range with
potentially
dangerous
or fatal consequences
[4]. For example,
medications
such as quinidine that are usually prescribed
for the
treatment
of tachyarrhythmias
raise serum digoxin concentrations. The digoxinlquinidine
interaction
can be particularly
hazardous,
and fatalities have been reported with this combination, particularly
before this hazardous
drug interaction
was
known.
Finally,
common
alterations
in the pharmacokinetics
of
digoxin are not readily assessed. For example, renal function
decreases gradually with age. After age 65 years, there may be a
50% decrease in creatinine clearance; this is in turn reflected by
a decrease in digoxin clearance. Because muscle mass decreases
with aging and less creatinine is released from muscle, the serum
creatinine may not reflect the decrease in renal function [5].
Because digoxin concentrations
are used to titrate digoxin,
blood should be drawn for assay after an interval that allows
distribution
of the drug within the body. The best time to obtain
a serum concentration
is 6-12 h after the drug is given orally
and >4 h after the last intravenous
dose [6]. In interpreting
Table 2. CharacteristIcs of ideal drug to monitor by serum
drug concentration.
Narrow therapeutic-to-toxic dose ratio
Toxicity: serious or fatal
Good correlation between serum concentration and effect
Clinical effect not readily measurable
Few active metabolites
Myriad of drug interactions8
Factors that influence pharmacokinetics not easily assessed
Accurate, specific drug assay
Forexample,digoxinserum concentrations are increased by the antiarrhythmic drugs amiodarone, propafenone, quinidine, and verapamil.
1313
digoxin concentrations
one must be aware that cross-reactivity
with digoxin-like
materials and digoxin metabolites
may interfere with the accuracy of the serum digoxin assay. The most
common
error in interpreting
the digoxin concentration
is
failure to recognize that the concentrations
may be 2-3 times
that at equilibrium
if the blood is drawn 1-2 h after an oral dose
of digoxin.
ANTICOAGULANTS
A pharmacodynamic
assay of warfarin
is essential
for dosing.
The mechanism of action of warfarin is that it interferes with the
formation
of vitamin K-dependent
clotting factors, including
prothrombin.
It is completely absorbed, highly bound to plasma
albumin, and metabolized
by hepatic microsomes
with a t112 of
37 h. Approximately
80 drugs reportedly
interact with warfarin;
most of them cause an enhanced effect of warfarin. These drugs
include antibiotics
such as metronidazole
(Flagyl#{174})
and tnmethoprim/sulfamethoxazole
(Bactrim#{174})
as well as antiarrhythmics such as amiodarone
and propafenone.
Prothrombin
time,
used to titrate the drug, is obtained by observing the time to clot
formation
when calcium
and thromboplastin
are added to
citrated plasma. The patient’s prothrombin
time is compared
with a mean/normal
prothrombin
time obtained
from plasma
from 20 healthy individuals. The potency of thromboplastin
can
vary widely. It is now standardized
and is expressed
as the
international
sensitivity index, or ISI. When the prothrombin
ratio is raised to the power of the ISI, one obtains an international normalized
ratio, or 1NR: INR = (Patient’s prothrombin
time/Control
prothrombin
time)ISI. Warfarin
is prescribed
for
the treatment
of deep venous thrombosis,
to prevent emboli
from forming on mechanical
heart valves and in the atria of
patients with atrial fibrillation.
These clots can become dislodged and cause strokes.
Before treatment
with warfann of patients with atrial fibrillation, this arrhythmia
was a major cause of stroke. Several trials
involving thousands of patients with atrial fibrillation have been
conducted to answer the question of the optimal dose and effect
of warfarin measured by the prothrombin
time. The aim is to
provide the greatest protection
against stroke with the lowest
rate of severe bleeding
complications,
which are defined as
bleeding that requires hospitalization
or causes a cerebral hemorrhage. This dose has now been established
as an INIR of 2-3
/7]. However,
the question of whether all patients with atrial
fibrillation
should be treated with warfarin is still unresolved.
The annual risk of bleeding
is 1.7% in patients with atnial
fibrillation
who are treated with warfarin; in atrial fibrillation
patients who are at low risk, the annual stroke rate is 1% (A
low-risk patient is defined as younger than 65, with no diabetes,
high blood pressure, or a history of embolic stroke. Therefore,
the use of warfarin in this low-risk group may not be warranted.
In patients age 75 years who have at least one of the abovementioned
risk factors, the annual stroke rate is 8.1%; however,
the risk of severe bleeding also is increased. Therefore,
studies
to determine
the optimal 1NR and (or) combination
of antithrombotic
agents are continuing.
An 1NR of 2-3 is recommended for the treatment
of patients with deep venous throm-
1314
Marcus:
bosis [8], and 2.5-3.5
is the
mechanical
heart valves [9].
optimal
INR
Titrating
for patients
with
cardiovascular
drugs
diameter of the extramural coronary vessels and can decrease
myocardial
oxygen demand by lowering systemic pressure.
ANTILIPEMICS
CARDIOVASCULAR
Serum lipids, particularly
high concentrations
of total cholesterol and HDL cholesterol,
are a major risk factor for myocardial infarction and cardiovascular
mortality [10]. Coronary heart
disease can be prevented by lowering the total serum cholesterol
with lipid-lowering
drugs such as the 3-hydroxy-3-methylglutaryl-CoA
reductase
inhibitors.
In a recent study there was a
31 % relative risk reduction of nonfatal myocardial
infarction or
death from coronary
heart disease in the treated group compared with those who received placebos [Ii]. Reductions
were
similar for the risks of nonfatal myocardial
infarction as well as
death from all cardiovascular
causes. Plasma cholesterol
was
20% lower in the treated group than in patients who received
placebos, and LDL concentrations
were reduced 26%.
The goal of antilipemic
therapy in patients with coronary
LIMITED
CLINICAL
DRUGS
VALUE
FOR
WHICH
SERUM
ASSAY
the
IS OF
IN TITRATION
pressure (<140/90
mmHg is usually a goal of therapy). Some
antihypertensive
drugs have multiple actions. This is particularly
true of beta blockers, which can cause bradycardia;
this may
require discontinuation
of the drug or a decrease in dose. If a
drug lowers blood pressure but causes adverse side effects, it may
be necessary
to decrease
the dose. The desired effect may
persist, but the adverse effects can diminish or become tolerable.
For example, decreasing the dose of beta blockers may ameliorate or eliminate fatigue, lethargy, and impotence.
Cardiovascular
drugs such as verapamil, diltiazem, and beta
blockers may be used to decrease the rate response
of the
ventricle to the rapid rate of the atrium in patients who have
atrial fibrillation.
Again, one can assess this effect clinically by
measuring the pulse. Although the major goal of therapy may be
to decrease the rate, the therapeutic
end point may not be
achieved because of the other actions of the drug, such as
bradycardia
and hypotension.
The response to diuretics in patients with congestive
heart
failure is readily assessed by the increase in urine output, or it
may be determined
by a rapid decrease in weight over hours or
days that reflects diuretic-produced
fluid loss. These findings
For some cardiovascular
drugs, a broad range of serum concentrations is associated
with therapeutic
or adverse effects. In
addition, active metabolites
may not be routinely measured,
or,
if assayed, their therapeutic
roles may be unclear.
An example of the wide range of therapeutic
serum concentrations associated with a therapeutic
effect was given in a study
by Giardina et al. [13]. Thirty-three
patients with heart disease
who had >10 premature
ventricular
beats per hour were treated
with 3 g of procainamide
per day. The dose was increased daily
by 1.5 g until the daily dose was 7.5 g. Twenty-two
patients had
arrhythmia
suppression
(defined as >75% decrease in premature ventricular
beat frequency).
Serum procainamide
concentrations associated
with the therapeutic
effect were 1.8-17.0
mg/L. In the patients who were effectively treated, the serum
concentration
of the major metabolite,
N-acetylprocainamide,
had a similar wide range of 1.8-25.2 mgfL.
The attainment
of “therapeutic”
serum procainamide
concentrations
does not ensure clinically effective arrhythmia
suppression. In another study, Waxman et al. administered
procainamide to 126 patients who had sustained ventricular
arrhythmias
induced by inserting
a catheter
into the right ventricle
and
stimulating
the heart. Most patients received the drug intravenously at a dose of 1-2.5 g followed by a constant infusion. The
efficacy of the drug was assessed by the inability to stimulate the
abnormal
rhythm electrically
in these patients after procainamide was administered.
The serum concentrations
of procainamide were 13.8 ± 6 mg/L in the patients
who were still
inducible
and 12.2 ± 5 mg/L in the patients who were not
inducible,
not significantly
different [14]. Why then measure
serum concentration
of antiarrhythmic
drugs such as procainamide? When treating
patients with such drugs, the serum
concentration
provides information
that the dose administered
results in serum concentrations
below, within, or above the
range usually associated with a therapeutic
effect. The reasons
for the poor correlation
between measured values in serum with
clinical effects of antiarrhythmic
drugs are probably related to
variations in the arrhythmia
circuits for reentrant
arrhythmias,
the changing myocardial
substrate over time, and the effects of
alterations
of autonomic
tone on the arrhythmia.
For example,
an increase in sympathetic
tone can alter the conduction
time
and refractoriness
of the arrhythmia
reentrant
circuit so that a
drug that may be effective in preventing
an arrhythmia
during
dominant
vagal tone may be completely
ineffective
during
exercise or excitement.
A related
issue in titrating
antiarrhythmic
drugs is the
are usually reflected by a decrease in the signs and symptoms of
heart failure.
Coronary
vasodilators
such as nitroglycerin
immediately
relieve angina pectonis, which is due to a discrepancy
between
myocardial oxygen demand caused by excitement or exercise and
the inability of the coronary circulation
to satisfy that demand.
Coronary
vasodilators
increase blood flow by increasing
the
convential wisdom that one could assess efficacy of antiarrhythmic drugs for treatment
of serious arrhythmias
by surrogate end
points. For example, it has been the practice to give antiarrhythmic drugs in sufficient doses to suppress the premature
ventricular beats, as recorded by 24-h ambulatory
electrocardiographic
monitor. This was thought to predict the efficacy of the drugs in
preventing
recurrent
sustained serious ventricular
arrhythmias
disease is to decrease the serum cholesterol
to <5.17 mmolJL
(<200 mg/dL) and to decrease the LDL concentration
to <2.86
mmollL
(<100
mg/dL)
[12]. Because the response
of the
individual
patient to therapy with antilipemic
agents varies,
measuring
serum lipids is essential to titrating these drugs.
CARDIOVASCULAR
DRUGS
TITRATED
BY CLINICAL
EFFECT
Many cardiovascular
drugs can be measured
simply by their
responses
to the primary actions of the drugs. For example,
antihypertensive
agents are easily titrated by measuring
blood
Clinical Chemistrj
such as ventricular
tachycardia
and ventricular
fibrillation.
Other clinicians
have used the technique
described
above of
inducing
the sustained
arrhythmia
in the electrophysiological
laboratory
and testing antiarrhythmic
drugs serially until one is
found that prevents the induction of the arrhythmia.
Although a
recently published study (Electrophysiological
Study vs Electrocardiographic
Monitoring
trial) found that these two methods
have equal predictive value, the efficacy of both methods is not
impressive
because 60% of patients who were predicted
to be
effectively
treated
by either method
had recurrence
of the
arrhythmias
within 4 years [15]. Another clinical trial showed
that patients who had frequent premature
ventricular
beats after
a myocardial
infarction and who were randomized
to treatment
with one of several antiarrhythmic
drugs to suppress
their
premature
ventricular
beats during 24-h ambulatory
electrocardiographic
monitoring
actually had a higher mortality rate than
the placebo-treated
patients [16]. These studies have resulted in
an awareness
that surrogate
end points for evaluating
the
efficacy of antiarrhythmic
drugs are not valid [17]. Consequently, there is an appropriate
reluctance
to prescribe antiarrhythmic drugs. For these reasons nonpharmacological
methods
of treatment
such as automatic
implanted
cardioverter
defibrillators are being used more frequently to treat serious ventricular
arrhythmias.
In summary, some cardiovascular
drugs can be titrated best by
assay of serum concentration,
some by laboratory
assessment of
effect, and others by clinical efficacy. Large-scale
multicenter
therapeutic
trials have greatly
enhanced
knowledge
of the
indications,
benefits, and risks as well as appropriate
dose or
serum
concentration
of specific
42, No. 8(B), 1996
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
drugs or therapy.
14.
I am grateful
manuscript
preparation
to Paul Nolan
and to Pam Abrams
of the manuscript.
for his critical review of the
and Risa O’Connor
for help in
15.
accepted guidelines for a therapeutic serum level of the drug. JAm
CoIl Cardiol 1993;21:378A.
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York: Churchill-Livingston, 1994:343-51.
Ewy GA, Yau L, Lullian M, Marcus Fl. Digoxin metabolism in the
elderly. Circulation 1969;39:449-53.
Howanitz PJ, Steindel SJ. Digoxin therapeutic drug monitoring
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Clagett GP, Anderson FA Jr, Heit J, Levine M, Wheeler HB.
Prevention
of venous
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Chest
1995;
108(Suppl)4:312S-345.
Stein PD, Alpert JS, Copeland JG, Dalen JE, Goldman S, Turpie
AGG. Antithrombotic therapy in patients with mechanical
and
biological prosthetic heart valves. Chest 1995;108(Suppl)4:
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Stamler J, Wentworth 0, Neaton J. Is the relation between serum
cholesterol and risk of death from CHD continuous and graded?
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Shepherd J, Cobb SM, Ford I, Isles CG, LorimerAR, Macfarline PW,
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Adult Treatment Panel II, expert panel on detection, evaluation,
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