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Effects Cardiovascular Medications


Exercise Responses

Many patients who are refewed forphysical therapy take medications that af-
fect either their physiological responses to exercise or their ability to exercise.
Claire Peel
Kurt A Mossberg
m e purpose of this article is to discuss how medicationspotentially can affect
cardiovascular responses to exercise. m e effects of selected medications on
heart rate, blood pressure, and electrocardiographic responses during exercise;
on exercise performance; and on training adaptations are discussed. m e types
of medications included in this review are beta-adrenergic receptor antagonists,
vasodilators, diuretics, digitalis, and antiarrhythmic agents. m e mechanisms of
action and the clinical indications are described for each category of drugs.
Ways in which each of the categories of drugs interacts with exercise responses,
exercise performance, and training adaptations are described. Knowledge of a
person's medications can provide valuable information on current physical
condition and medical history and can alert therapists as to how exercise re-
sponses may be altered. Potential complications that are likely to occur during
exercise can be identijied, facilitating the design of safe and effective treatment
programs. [Peel C, Mossberg KA. Effects of cardiovascular medication on exer-
cise responses. Phys mer. 1995; 75387-396.1

Key Words: Cardiovascular gstem; &erc&e, general; Pharmacology; Physiology.

The role of the physical therapist in- Although the incidence of heart dis- how different classes of cardiovascular
cludes monitoring physiological re- ease has decreased in recent years, medications affect responses to activity
sponses to activity and determining conditions that involve the cardiovas- may have an impact on the interpreta-
whether the responses are appropriate cular system remain common in the tion of evaluative findings and treat-
for the individual based on the indi- adult popu1ation.l Hypertension, con- ment planning.
vidual's past and present medical gestive heart failure, and coronary
history. Many cardiovascular medica- artery disease increase in incidence as Most medications that are prescribed
tions have the potential to alter re- persons become older.2 Many patients for cardiovascular disease have either
sponses to both acute and chronic who are referred to physical therapy a direct or indirect effect on the heart
exercise in a predictable manner. for orthopedic, neurological, or gen- or vascular system, including altering
Knowledge of how common drugs eral medical problems may have coex- myocardial oxygen consumption,
alter responses assists therapists in isting involvement of the cardiovascu- peripheral blood flow, and cardiac
assessing the safety and appropriate- lar system. Simple questioning of these preload or afterload. Medications may
ness of exercise and in determining individuals as to the medications that either increase or decrease exercise
the effectiveness of exercise training. they are taking can provide valuable capacity, or alter the expected changes
information about their current condi- in heart rate and blood pressure that
tion or medical history. Knowledge of normally occur with an increase in
activity.39 Medications can also be
effective in controlling an abnormality
(eg, a cardiac arrhythmia) at rest, but
C Peel, PhD, PT, is Associate Professor and Chair, Department of Physical Therapy, The Univer-
sity of Texas Medical Branch, Galveston, TX,77555-1028 (USA). Address all correspondence to Dr not during activity. By documenting
Peel. patients' physiological responses while
they are performing physical activities,
KA Mossberg, PhD, PT, is Associate Professor, Department of Physical Therapy, The University of
Texas Medical Branch. therapists can provide valuable feed-

56 / 387 Physical Therapy / Volume 75, Number 5 / May 1995


back to patients' physicians to guide
the medical management of the
patients.
Table 1. Effects of Medications on the Cardiovascular and Metabolic
Responses to Exercise
The first objective of this article is to
present a general overview of ways in Medications That Could Alter
Physiological Response Response
which cardiovascular medications can
affect responses to physical activity or
exercise, followed by a brief review of Cardiac output
clinical measurements that are useful Direct effects on the heart
in assessing activity responses. The Contractility Increased by digitalis
second objective is to review the ef- Initiation/conduction of cardiac action potential Decreased by beta-blockers
fects of selected classes of cardiovas- Effects on the peripheral circulation
cular medications on heart rate (HR), Venodilation or constriction: preload Decreased by nitrates
blood pressure (BP), and electrocar-
Arterial vasoconstriction or dilation: afterload Decreased by alpha-1 antagonists
diographic (ECG) responses during
Blood volume Decreased by diuretics
exercise, exercise capacity, and train-
Myocardial oxygen consumption
ing adaptations. Classes of medications
that will be discussed include beta- Heart rate Decreased by beta-blockers
adrenergic receptor antagonists, vaso- Blood pressure
dilators, diuretics, digitalis, and antiar- Systolic wall tension Decreased by nitrates
rhythmic agents. Distribution of cardiac output
Blood flow to active skeletal muscle Decreased by alpha-1 antagonists
O v e ~ e wof Mechanisms by Blood flow to cutaneous vessels Decreased by alpha-1 antagonists
Which Medications Can Affect Metabolism
Exercise Responses Fatty acid mobilization and oxidation Decreased by beta-blockers
Glycogenolysis Decreased by beta-blockers
The physiological response to exercise
is complex; involves integration of
multiple systems; and varies depend-
Changes in preload and afterload will ripheral resistance. Some of the
ing on the type, intensity, and dura-
also influence cardiac output. Vaso- medications that are used to treat
tion of the activity. General changes
constriction in the venous circulation angina are effective because they de-
include increases in cardiac output
will increase preload and will increase crease myocardial oxygen require-
and myocardial oxygen consumption
cardiac output according to the Frank- ments via these mechanisms.
and an increase in blood flow to ac-
Starling law of the heart.10 Vasodila-
tive skeletal muscle and the skin. In
tion on the arterial side of the circula- Medications that affect peripheral
addition, energy-generating substrates
tion will decrease afterload, or the blood flow have the potential to influ-
are mobilized. Medications can be
resistance to the ejection of blood ence exercise responses. If the normal
categorized according to their effects
from the left ventricle. With a de- increase in skeletal muscle blood flow
on factors that influence each of these
creased resistance, the heart can de- is impaired, then exercise duration
responses. A summary of responses,
liver a greater output for any given may be decreased because of an accu-
with examples of medications that
force of contraction. mulation of metabolites of anaerobic
may affect each response, is presented
metabolism. For example, a nonspe-
in Table 1.
Medications may also affect exercise cific beta-receptor antagonist could
responses by altering factors that de- prevent relaxation of the vascular
Cardiac output can be influenced by
termine myocardial oxygen demands smooth muscle in the exercising mus-
drugs that directly affect the heart by
or oxygen delivery. Primary factors cle by blocking beta-2 receptors. The
altering either myocardial contractility
that increase oxygen demand include result of a decrease in beta-receptor
or the initiation and conduction of the
an increase in HR, aortic pressure, and mediated vasodilation could be a
cardiac action potential. For example,
SV. To match the increased oxygen decrease in oxygen delivery. This
contractility is enhanced by inotropic
needs, an increase in blood flow and effect, however, is most likely offset by
agents such as digitalis and is de-
oxygen delivery occurs by vasodilation the vasodilation that occurs in re-
pressed by beta-adrenergic receptor
of coronary arteries. If a sufficient sponse to the buildup of local
antagonists. Beta-receptor antagonists
increase in blood flow is not possible metabolites.
also decrease the rate of depolariza-
because of coronary artery stenosis,
tion of the sinoatrial node, decreasing
then one strategy is to decrease oxy- If there is an imbalance between heat
heart rate. A decrease in HR with no
gen demands by depressing HR, myo- production and heat dissipation, then
change in stroke volume (SV) results
cardial contractility, and/or total pe- endurance time also will be decreased
in a decrease in cardiac output.

Physical Therapy / Volume 75, Number 5 /May 1995 388 / 57


because of an excessive increase in detect arrhythmias and ischemic tionnaires can be used to determine
core temperature. Gordon and col- changes. An accurate assessment of the effects of interventions such as
leagues," for example, found an in- preexercise or baseline values is es- regular exercise and medications on
crease in core temperature during sential so that changes that occur with patients' lifestyles and perceptions of
exercise in patients with coronary activity can be identdied. For many their health status.16
artery disease when given propranolol patients performing continuous activi-
(a nonselective beta-receptor antago- ties at submaximal intensities, mea- Categories of Medications
nist) over that observed with a pla- surements made after 2 to 3 minutes
cebo. The exact mechanism is un- reflect steady-state responses. For Medications can be grouped into cate-
known, but may be related to some patients who are severely de- gories according to their mechanisms
increased sympathetic nervous system conditioned, or who have cardiopul- of action. By knowing the category
activity, including stimulation of monary disease, reaching a steady- in which a drug is included, clinicians
alpha-l receptors. Activation of state condition may not be possible. can determine the probable mecha-
alpha-1 receptors in the cutaneous Heart rate may continue to rise during nism of action and clinical indications.
circulation would produce vasocon- exercise rather than remaining steady The section that follows provides a
striction and consequently impair heat at a plateau level. Repeating measure- discussion of several categories of
dissipation. ments after 5 to 6 minutes and com- drugs. Examples of specific medica-
paring the measurements with those tions are included in Tables 2, 3, and
Medications can affect the metabolic made after 3 minutes is one way to 4.
response to exercise by interfering determine whether a steady-state level
with glycogenolysis or fatty acid mobi- is reached. Making measurements Beta-Adrenergic Receptor
lization and oxidation. Inadequate during the activity is ideal, although Antagonists
glycogen may limit endurance time values recorded during the initial 30
and the individual's ability to perform seconds after activity have been Mechanism of Action
moderate- to high-intensity activities. shown to accurately reflect the exer-
Inadequate mobilization and oxidation cise response in asymptomatic individ- The essential mechanism of action of
of fatty acids limits the ability to per- uals.lVn patients with cardiopulmo- the beta-adrenergic receptor antago-
form exercise for prolonged time nary disease who are at high risk of nists (beta-blockers) is to attenuate the
periods. The class of medications that experiencing a complication, continu- actions of the sympathetic nervous
has been most thoroughly studied in ous monitoring of HR and ECG re- system. Beta-receptors normally bind
terms of effects on the metabolic re- sponses is indicated. with norepinephrine and epinephrine,
sponse to exercise is the group of setting into motion subcellular events
beta-adrenergic receptor antagonists Assessing changes in the ability to that bring about increases in HR and
because of the important role played perform either submaximal or maxi- myocardial contractility (beta-l), bron-
by the sympathetic nervous system mal exercise as a result of either new chodilation (beta-21, and vasodilation
and catecholamines in maintaining medications or changes in dosage of in peripheral blood vessels (beta-2).17
metabolic homeostasis during strenu- current medications is also important. Stimulation of beta-2 receptors also
ous work. By blocking beta-2 recep- Because directly measuring maximal increases glycogenolysis, whereas fatty
tors in the liver, these medications can oxygen consumption (~o,max)is not acid mobilization may be increased by
impair glycogenolysis. Studies12J3 have practical in most clinical settings, maxi- beta-1 stimulation. Nonselective beta-
shown that there is less reliance on mal work rate can be used as an alter- adrenergic receptor antagonists pre-
fatty acid oxidation during exercise nate measurement. One method of vent stimulation of both beta-1 and
when taking beta-receptor antagonists. determining whether a change in beta-2 receptors. In an attempt to elicit
Additionally, there is no increase in medications affects general body en- more selective responses, beta-
the rate of muscle glycogen break- durance is to record the amount of blockers with varied properties have
down. The lack of a compensatory time that a submaximal work rate can been developed (Tab. 2). Selective
increase in glycogen breakdown prob- be performed. For an accurate com- beta-1 receptor antagonists exert pri-
ably contributes to the reduction in parison, the work rate and the testing mary effects on cardiac beta-receptors,
endurance time. conditions need to be the same for although their selectivity decreases at
tests conducted both before and after higher dosages. Beta-blockers that act
Clinical Measurements the change in medications. as partial agonists of beta-receptors
have been developed. These medica-
Responses to physical activity can be Recording ratings of perceived exer- tions are described as having intrinsic
monitored in most clinical environ- tion (RPE) during activity provides a sympathomirnetic activity (ISA) be-
ments by measuring HR and BP and measure of the patient's perception of cause they partially activate beta-
by observing for abnormal signs and the difficulty of the activity. Although receptors at rest when levels of cat-
symptoms. Electrocardiography, often this is a measurement of a subjective echolamines are low. The advantage is
available in hospital settings or cardiac phenomenon, both validity and reli- to minimize both bradycardia and
rehabilitation facilities, can be used to ability have been established.'5 Ques- depression of myocardial contractility

Physical The]apy / Volume 75, Number 5 /May 1995


is attributed to a decrease in myocar-
dial oxygen requirements by decreas-
Table 2. Common Beta-Adrenetgic Receptor Antagonists
ing HR, BP, and myocardial contractil-
ity both at rest and during exercise.
Medication The exact mechanism of a decrease in
Property Generic Trade BP is unknown, but may include a
lowering of plasma renin activity,
decreased cardiac output, or de-
Blocks beta-l and beta-2 Propranolol lnderal
receptors (nonselective) Nadolol Corgard
creased basal sympathetic outflow
Timolol Blocadren from the vasomotor centers in the
Pindolol Visken pons and medulla.lg Beta-blockers are
Selective for beta-l receptors Atenolol Tenormin used in the treatment of both atrial
Metoprolol Lopressor and ventricular arrhythmias because of
Nonselective with intrinsic Pindolol Visken their tendency to decrease automatic-
sympathomimetic activity Carteolol Cartrol ity of myocardial cells.20Common side
Penbutolol Levatol effects of persons taking beta-blockers
Antagonist for beta- and Labetolol Normodyne include fatigue and hypotension.
alpha-receptors Trandate

Alterations in Responses to
Acute Exercise
that can occur under resting condi- Clinical Indications
tions. In addition, agents that block Beta-blockers depress the increases in
both alpha-1 receptors and beta- Beta-blockers were originally devel- HR, BP, and myocardial contractility
receptors have been developed. These oped to treat angina, and now they that normally occur with exercise. The

-
medications are effective in decreasing are also used for hypertension and Figure summarizes the HR and BP
BP by preventing sympathetic stirnula- cardiac arrhythmias. Long-term use responses to activity in both persons
tion of the heart and by producing has been shown to decrease mortality who are asymptomatic and patients
arterial vasodilation. after myocardial infarctions.l8 Their with hypertension, coronary artery
effectiveness in the treatment of angina disease, rhythm disturbances, and
cardiomyopathy.+832l In patients with
myocardial ischemia and angina, beta-
blockers tend to increase exercise
tolerance because of the decreases in
Table 3. Common Examples of Direct-Acting and Indirect-Acting myocardial oxygen requirement.22
Vasodilators Typically, patients are able to exercise
for longer periods before the onset of
Medication angina. The decrease in myocardial
Action Generic Trade oxygen demand is primarily a result of
a decreased HR response, producing a
decrease in rate-pressure product
(RPP). End diastolic volume tends to
Nitrates Nitroglycerin Nitrostat
increase, resulting in an increase in SV
Nitro-bid
and ventricular wall tension. Unfortu-
lsosorbide dinitrate lsordil
nately, greater ventricular wall tension
Calcium antagonists Diltiazem Cardizem
during systole increases myocardial
Verapamil Calan
Nifedipine Procardia oxygen demand, partially offsetting the
Nicardipine Cardene beneficial effects of decreased HR and
Directly affects arterial Hydralazine Apresoline c0ntractility.~3
side of c~rculation Sodium nitroprusside Nipride
Facilitates opening of Minoxidil Loniten For people who are normotensive and
potassium channels for patients with hypertension, data on
Indirect-acting the effects of beta-blockers on exercise
ACEa inhibitors Captopril Capoten performance are unclear. Factors that
Enalapril Vasotec influence the response include the
Alpha-1 antagonists Prazosin Minipress individual's level of physical condition-
Centrally acting Methyldopa Aldomet ing, the specfic pharmacological agent
alpha-agonists Clonidine Catapres (selective versus nonselective), and the
dosage. In both asymptomatic subjects
"ACE=angrotensen-converting enzyme. and individuals with uncomplicated

Physical Therapy / Volume 75, Number 5 / May 1995


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Table 4. Common Examples of Diuretics

Category
Medication
Generic Trade
had hypertension. Other researchers2'
have reported maintenance of exercise
performance in well-conditioned sub-
jects taking carvedilol, a nonselective
beta-blocker with alpha-receptor
blocking properties. In general, with
beta-blocker administration, increases
in both SV and arteriovenous oxygen
Thiazides Hydrochlorothiazide Esidrix
Chlorothiazide Diuril
difference appear to compensate for
the decrease in HR. An increase in
Loop diuretics Furosemide Lasix
Furoside fatigue that is often reported with
Potassium-sparing agents Spironolactone Aldactone
initial use of beta-blockers tends to
Amiloride Midamor decrease with regular use.28

Alterations in Responses to
hypertension, nonselective beta- mal exercise capacity in asymptomatic Exercise Training
blockers tend to decrease maximal subjects.25 Cohen-Solal and col-
exercise performance in a dose- l e a g u e ~documented
~~ no effect on Because of the attenuated HR re-
dependent manner.24Beta-1 selective Vo,rnax or duration of exercise in sponse during exercise, the ability of
agents have less of an effect on maxi- individuals who were untrained and persons taking beta-blockers to benefit
from exercise training has been ques-
tioned. After a 4-month program that
involved 90-minute sessions three
times per week at an intensity of 85%
of symptom-limited maximal HR pro-
duced increases in ~o,maxand de-
A creases in submaximal HR in persons
200
with coronary artery disease who were
-WITHOUT BETA BLOCKADE taking beta-blockers.29
Ia0 -WITH BETA BLOCKADE

" 160 Adaptations also appear to occur in


EP
= 140
asymptomatic persons and in persons
with hypertension.30~31Because initia-
5
W
120 tion of beta-blocker therapy results in
& I00 impairment of cardiovascular fitness,
4I 8 0 the improvement with training has
been shown to be less than the irn-
60 provement that occurs with a place-
I I I 1 I b0.~5Additional studies are needed to
40
0 25 50 75 100 125 150 175 200 examine training adaptations that
6 occur when taking beta-blockers com-
pared with other antihypertensive
A
240 -
- WITHOUT BETA BLOCKADE
WITH BETA BLOCKADE
medications.
I" S
-E EG Exercise Prescriptions for
Patients Taking Beta-Blockers
W
g 160
Because of the decrease in maximal
8
a 120
HR, age-related equations used to
P
0
3 predict maximal HR and used to for-

3
m
60
I
0
mulate exercise prescriptions cannot
be used for patients taking beta-
I I I I I
blockers. Prescriptions need to be
40
0 25 50 75 100 125 150 175 200 based on an exercise stress test that is
FOWFR DLJTPLJT RNI performed whlle the patient is taking
the prescribed medication. Maximal
Flgure. Comparison of heart rate (A) and bloodpresst~re(B) wsponses in individ- HR cannot be predicted for patients
uals taking beta-receptor antagonists versus taking a placebo. Data are summarized taking beta-blockers because the ex-
from several source^.*^^^^ tent of the decrease is affected by the

Physical Therapy / Volume 75, Number 5 /May 1995


specific agent and the d0sage.3~If and myocardial cells.l9 Normally, coronary, and renal vessels.*l Sodium
performing a graded exercise test is calcium enters the cell through "slow nitroprusside is a similar medication
not possible, then a training HR that is channels" and is responsible for the that releases nitric oxide after contact-
20 bpm greater than resting HR can be plateau phase of the cardiac action ing red blood cells." The result is
used, assuming that the patient is potential. The calcium influx then vasodilation of both arterioles and
symptorn-free at this intensity.33 causes a massive release of calcium venules. Another medication, rninoxi-
that is stored in the sarcoplasmic retic- dil, directly relaxes vascular smooth
If exercise stress test results are avail- ulum, resulting in the initiation of muscle, possibly by increasing the
able and maximal HR can be deter- crossbridge formation between actin permeability of the cell membrane to
mined, then the prescription can be and myosin. Therefore, blocking the potassium.*3
formulated using recommended guide- extracellular calcium influx results in a
lines. A recommended training inten- reduction of contractile activity of Clinical Indications
sity is 85% of the HR where symptoms cardiac muscle and vascular smooth
occur, or 60% to 90% of maximal muscle.l9 The clinical result is a de- Vasodilators are prescribed for angina,
HR.3"ven though maximal HR de- crease in myocardial afterload and hypertension, and heart failure, and
creases with beta blockade, the rela- systolic function, resulting in a de- the calcium antagonists occasionally
tionshp between the percentage of crease in myocardial oxygen demand. are used for cardiac a r r h y t h a s . The
maximal HR and the percentage of Because of the role of calcium in the major indication for nitrates is angina.
vo2max does not appear to be mean- cardiac action potential, these drugs Their effectiveness in patients with
ingfully altered.35 Therefore, an inten- also can affect HR and heart rhythm, coronary artery disease results primar-
sity of 6@/o to 90% of maximal HR and are sometimes used to treat car- ily from their effects on the peripheral
correlates with an intensity of 50% to diac arrhythmias. rather than the coronary circulation.
85% of vo2max. Decreases in both afterload and pre-
The angiotensin-converting enzyme load result in decreases in myocardial
(ACE) ~nhibitorsprevent the conver- oxygen requirements. Two common
sion of angiotensin I to angiotensin problems with nitrates are a reflex
Mechanisms of Action II.38 Angiotensin I1 not only is a pow- increase in HR, which increases myo-
erful vasoconstrictor, but also in- cardial oxygen demand, and dwelop-
Vasodilators act either directly or indi- creases serum aldosterone levels, ment of t0lerance.~3The reflex in-
rectly to relax the smooth muscle resulting in increased sodium reten- crease in HR occurs because blood
walls of blood vessels. Pharmacologi- tion. Preventing formation of angioten- tends to pool in the lower body and
cal agents may be relatively specitic as sin 11 results in inhibition of vasocon- sympathetic reflexes are activated. The
to their effects and act predominantly striction and a decrease in sodium development of tolerance is related to
on either the arterial or the venous retention. Both of these effects result the dosage and the frequency of tak-
sides of the circulation. Vasodilators in decreases in BP. ing the medication, and often occurs
are classified based on the mechanism when the drug is given in a sustained-
of their action (Tab. 3). Two categories of vasodilators that release transdermal preparation. Pa-
exert their effects through the sympa- tients who take high dosages, with
Nitrates promote smooth muscle relax- thetic nervous system are the centrally either oral or transdermal administra-
ation on both the arterial and the acting alpha-2 agonists and the tion, may experience a decrease in the
venous sides of the cir~ulation.3~ Arte- alpha-1 antagonists. Medications that effects of the drugs. Development of
riolar dilation reduces afterload, stimulate alpha-2 receptors in the tolerance can be prevented by not
whereas venodilation reduces venous central nervous system produce a taking the medication for a period of
return and thus decreases preload. decrease in sympathetic outflow from several hours during the course of a
Nitrates also dilate both epicardial and the brain stem.39 The result is a de- day.
collateral vessels in the heart in per- crease in arterial pressure because of
sons with normal coronary arteries. In decreases in both cardiac output and Calcium antagonists and ACE inhibi-
persons with atherosclerosis of the peripheral resistance. Alpha-1 antago- tors are often the first drugs used to
coronary arteries, nitrates d o not in- nists inhibit vasoconstriction in both treat mild to moderate hypertension.41
crease total blood flow to the heart.23 the arterial and venous sides of the Calcium channel antagonists also are
These medications appear to have a circulation.40 The result is a decrease prescribed for angina that is thought
beneficial effect on myocardial blood in peripheral vascular resistance and to result from coronary artery spasm.
flow by redistributing flow to suben- BP. In addition, this medication is used for
docardial areas, which tend to have the treatment of supraventricular ar-
poor perf~sion.3~ Other vasodilators act directly on rhythmias. Another common use of
vascular smooth muscle. One of these ACE inhibitors is for heart failure.
Calcium antagonists act to block medications, hydralazine, produces Their effectiveness is thought to be
voltage-dependent calcium channels relaxation of arterial smooth muscle related to a decrease in afterload,
on cell membranes of smooth muscle that is somewhat specific to cerebral, which allows for a greater cardiac

Physical Therapy / Volume 75, Number 5 / May 1995


output without increasing the force of Exercise Responses in Persons Long-term therapy, over several
contraction. With Angina months, has been shown to increase
exercise performance in persons with
Exercise Responses in Persons In persons with angina, exercise per- mild to moderate heart failure.55 Ef-
With Hypertension formance is improved with vasodila- fects include increased exercise dura-
tors. Studies9*51-53have documented tion, increased peak oxygen consump-
Calcium antagonists, ACE inhibitors, increased peak work rate, increased tion, and increased peripheral
alpha-1 antagonists, and centrally exercise time before the onset of 1 arteriovenous oxygen ddference. The
acting alpha-agonists are commonly mm of ST-segment depression, and effects are similar to those resulting
used for hypertensi~n.~l In general, increased exercise time before the from exercise training. These re-
these melcations produce decreases onset of angina. Possible explanations sponses may be explained by an in-
in both systolic and dastolic BP dur- for these effects include a decrease in creased ability of skeletal muscle
ing e x e r ~ i s e . ~Calcium
~ > ~ 5 antagonists myocardial oxygen consumption and blood vessels to dilate during exercise,
also have the potential to produce an increase in coronary blood flow to possibly because of a decrease in
negative inotropic effects, similar to ischemic areas. These two mecha- sodium retenti0n.55.5~ Another possible
the beta-blockers. Depression of myo- nisms can be Merentiated by analyz- mechanism is that patients improve in
cardial contractility with these agents ing changes in the relationship be- clinical symptoms when on long-term
appears to be minimal; verapamil is a tween the onset of ST-segment therapy and become more active.56
possible exception45Calcium antago- depression and the value of the RPP
nists and centrally acting alpha-2 ago- during a graded exercise test. If there
nists may affect HR during exercise, is a decrease in myocardial oxygen
with increases associated with nifedi- consumption, then ST-segment de- Mechanism of Action
pine and decreases associated with pression will occur at a similar RPP. If
verapamil, diltiazem, and methyldo- there is an increase in coronary blood Digitalis-like medications, which in-
pa.&-& Veraparnil can also decrease flow, then ST-segment depression will clude digoxin and digitoxin, are com-
maximal HR in a dose-dependent occur at a higher value of RPP. The monly prescribed for heart failure.
mant1er.~9 precise mechanism most likely is de- These compounds increase myocardial
termined by the severity of coronary contractility by inhibiting the sodium
Calcium antagonists and ACE mhibi- artery disease and by the specific potassium adenosine triphosphatase
tors do not appear to significantly agent. A higher RPP at the onset of (ATPase) enzyme in cell membranes
affect ~o,maxor maximal work rate in ST-segment depression, indicating an of cardiac muscle cells. The result is
relatively asymptomatic persons. In- increase in coronary blood flow to an accumulation of intracellular so-
creases in RPE during submaximal ischemic areas, has been reported dium, which is exchanged for calcium.
exercise with ACE inhibitors, but not with the calcium antagonist nisolo- The increase in intracellular calcium
with calcium antagonists, have been pine, which is a relatively new agent increases contractility. The effect is
described.44In another report,5O no that is currently used in Eur0pe.5~ somewhat opposite to that seen with
effect on either submaximal or maxi- the calcium channel blockers.
mal RPE in asymptomatic persons Exercise Responses in Persons
taking ACE Inhibitors was reported. With Heart Failure Clinical Indications
Differences in the results of these two
studies may be due to the fact that the Angiotensin-converting enzyme inhibi- Because of their positive inotropic
subjects dlffered in age and activity tors and selected direct-acting vasodi- effects, the digitalis-like drugs are used
level. Persons who exercise regularly lators are used to treat patients with to treat heart failure. These drugs also
may be more sensitive to small differ- heart failure because of these medica- have electrophysiological effects. A
ences in sensations of perceived exer- tions' action of decreasing peripheral common effect is a decrease in con-
tion. The lack of an effect on exercise resistance and indirectly allowing an duction velocity through the atrioven-
performance of these two groups of increase in cardiac output.54 Stud- tricular node, which can result in heart
medications is important because ies5515~have documented effects of block.57 This action is used therapeuti-
hypertension often occurs in people both short-term and long-term therapy cally to treat atrial fibrillation. Another
who are physically active. Prescribing with these medications. Short-term important feature of these medications
a drug that will not affect exercise changes involve improvements in is their low therapeutic index, inlcat-
performance is important for these hemodynamics, and include a de- ing that there is a narrow margin be-
individuals and tends to maximize crease in mean systemic arterial and tween therapeutic dosages and toxic
compliance with endurance exercise. pulmonary wedge pressures and in- dosages. Common problems include
Moreover, appropriate training also creases in cardiac output during exer- bradycardia, various arrhythmias, and
has a beneficial effect on the treatment cise. Most studies of short-term effects fatigue.
of hypertension. have not documented increases in
either exercise time or peak oxygen
consumption.

Physical Th.erapy / Volume 75, Number 5 /May 1995


Effects of Digitalis on Exercise Clinical Indications Antiarrhythmic Agerrts
Responses
Diuretics are used in the management Mechanism of Action
In many patients, digitalis improves of congestive heart failure and hyper-
left ventricular performance during tension. For the management of heart Abnormalities of cardiac rhythm are
exercise, as indicated by higher ejec- failure, diuretics are beneficial because thought to result from three factors:
tion fractions and systolic BP.s8 Studies of their effects on fluid volume and on reentrant circuits, delayed afterpoten-
of measurements of peak oxygen venous capacitance. The decrease in tials, and enhanced automaticity of
consumption and work rate led to fluid volume tends to improve dys- ectopic The incidence of dys-
differing results, with increases59 and pnea and alleviate swelling. The veno- rhythmias is directly related to the
no change reported.58 There appears dilation decreases peripheral resis- severity of heart disease and to the
to be an inverse relationship between tance, facilitating a decrease in age of the patient.65 Persons who are
pretreatment aerobic capacity and the preload. Of the three categories, loop at high risk for having dysrhythrmas
degree o f improvement in physical diuretics are commonly used for heart include those with coronary artery
work capa~ity.5~ Persons with low failure.61 disease that involves multiple vessels,
aerobic capacities and moderate to left ventricular dysfunction, and
severe heart failure tend to show the In the treatment of hypertension, di- exercise-induced ST-segment depres-
greatest improvements when taking uretics produce a decrease in BP ini- s i ~ nAntiarrhythmic
. ~ ~ agents are effec-
digitalis-like compounds. tially because of a decrease in blood tive in suppressing dysrhythrnias be-
volume. With continued use, blood cause of their actions of decreasing
The accuracy of stress testing to sup- volume tends to increase toward pre- membrane automaticity, slowing im-
port a diagnosis of coronary artery medication levels as peripheral resis- pulse conduction through the myo-
disease is diminished in persons tak- tance decreases.62 The long-term effec- cardium, and prolonging refractory
ing digitalis.@Exercise-induced ST- tiveness of diuretics most likely is periods.67
segment depression usually is used as attributed to a decrease in peripheral
the major criterion for a positive stress resistance. Thiazide diuretics are com- Effects of Exercise on
test. Digitalis produces ST-segment monly used for hypertension, either Dyshythmias
depression in 25% to 100% of persons alone or in combination with
with normal coronary arteries.60There- potassium-sparing diuretics. The addi- Exercise often increases dysrhythrnias
fore, ST-segment changes that occur tion of a potassium-sparing diuretic to because of the increase in activity of
with exercise testing in patients taking a thiazide diuretic prevents the loss of the sympathetic nervous system and
digitalis could result in a false-positive potassium that would occur when the increase in circulating cat-
stress test result, supporting an inaccu- using a thiazide diuretic alone. Potas- echo1amines.a Catecholamines
rate diagnosis of cardiac ischemia. sium supplements also are commonly shorten membrane refractory periods,
used in combination with thiazide increase myocardial conduction veloc-
Diuretics diuretics. ity, increase the movement of calcium
into cardiac cells, and increase auto-
Mechanism of Action Effects of Diuretics on Exercise maticity. These effects have the poten-
Responses tial to enhance reentrant circuits, to
Diuretics increase the excretion of increase the amplitude of afterpoten-
sodium and water by the kidneys, Diuretics produce decreases in BP at tials, and to increase activity of ectopic
producirig a decrease in blood vol- rest and during exercise, with minimal foci. Consequently, catecholamines
ume. Three general categories of di- changes in HR during e~ercise.~5 Most tend to increase the probability of
uretics are thiazides, loop diuretics, diuretics have the potential to produce dysrhythas. In addition, myocardial
and potassium-sparing agents (Tab. 4). hypokalemia, which may lead to car- ischemia can produce changes in pH
Thiazides and potassium-sparing di- diac dysrhythmias. An increased inci- and potassium that alter electrophysi-
uretics exert their actions primarily at dence of premature ventricular con- ologic properties of myocardial cells.
the dlstal tubule. Loop diuretics act at tractions has been reported for
the thick ascending limb of the loop patients taking hydro~hlorothiazide.~3 Given the inherent changes with exer-
of Henle. Thiazides and loop diuretics Prolonged exercise in the heat is not cise, medications that are effective in
increase the excretion of sodium, recommended for patients taking controlling dysrhythmias when pa-
potassium, chloride, and bicarbonate. diuretics because of the cumulative tients are at rest may not be effective
Potassiuin-sparing diuretics decrease effects of heat, exercise, and diuretics during exertion or stress. In addition,
the excretion of potassium and in- on blood volume and electrolytes. The side effects of antiarrhythmic agents
crease the excretion of sodium, chlo- length of time that an individual who may be more apparent during exer-
ride, and bicarbonate. is taking a diuretic can safely exercise cise. For example, many of these
in the heat is variable, and depends medications have negative inotropic
on the heat index and the physical effects, which manifest themselves as
condition of the individual. decreases in either exercise perfor-

Physical Therapy /Volume 75, Number


mance or BP during exercise. Because A patient's medications and the rea- 11 Gordon NF, Myburgh DP, Schwellnus MP,
Van Rensburg JP. Effect of B-blockade o n ex-
of their effects on the electrophysi- sons for taking each medcation can ercise core temperature in coronary artery dis-
ologic characteristics of cells, these provide valuable information about ease patients. Med Sci Sports here. 1987;19:
medications have the potential to medical history and current condition. 591-596.
cause abnormal rhythms. The effect of Because of the vast number of medi- 12 Frisk-Holmberg M, Jorfeldt L, Juhlin-
Dannfelt A. Metabolic effects in muscle during
slowing of the impulse through the cations, and the multiple names for antihypertensive therapy with Pl- and Pl/P2-
myocardium may become apparent similar compounds, being able to adrenoceptor blockers. CIin Phannacol Ther.
during exercise as a bundle branch locate information about a medication 1981;30:611-618.
block or a complete heart block. is imperative for optimal clinical prac- 13 Cleroux J, Van Nguyen P, Taylor AW,
Leenen FHH Effects of B1- vs B1 + B2-
tice. Reference texts that index medi- blockade on exercise endurance and muscle
Because of the potential increase in cations using several categories are metabolism in humans. J Appl Physiol. 1989;
dysrhythmias during exercise, knowl- available in most clinical settings.'O 66548-554.
This information can be invaluable in 14 McArdle WD, Zwiren L, Magel JR. Validity
edge of the patient's physical condi- of the post exercise heart rate as a means of
tion and medical history is important. the development of safe and effective estimating heart rate during work of varying
Patients at high risk for having dys- treatment programs. Furthermore, by intensities. Res Q. 1969;40:523-528.
rhythmias during exercise can be monitoring HR and BP and observing 15 Skinner JS, Hutsler R, Bergsteinova V, Bus-
kirk ER. The validity and reliability of a rating
identified by determining the severity signs and symptoms, therapists are scale of perceived exertion. Med Sci Sports.
of their disease, including any history able to determine whether drugs are 1973;5:94-96.
of complex or sustained dysrhythrmas. effective during activity. By being 16 Lohr KN, Ware JE. Advances in health as-
Patients who are taking antiarrhythc cognizant of changes induced by sessment. J Chronic Disease. 1987;40:15-65.
medications may need to be evaluated cardiovascular medications, therapists 17 Shand DG. Propranolol. N Engl J Med.
1975;293:280-285.
under conditions of graded exercise to can assist patients to increase the 18 Yusuf S, Wittes J, Friedman L. Overview of
ensure that their arrhythrmas are under quality and quantity of their physical results of randomized cllnical trials in heart
control during activity. Monitoring HR activity. disease. J M . 1988;260:2088-2093.
and BP during activity may provide 19 Rutherford JD, Braunwald E, Cohn PF.
Chronic ischemic heart disease. In: Braunwald
clues as to the effectiveness of medica- E, ed. Heart Disease. 3rd ed. Philadelphia, Pa:
tion. In the absence of ECG, palpation References WB Saunders Co; 1988:1314-1378.
of peripheral pulses can be used to 1 Healthy People 2000. Washington, DC: US
20 Bigger JT, Ho5man BF. Antiarrhythmic
detect irregular rhythms. Continued drugs. In: Gilman AG, Rall TW, Nies AS, Tay-
Department of Health and Human Services, lor P, eds. Goodman and Gilman's The Phar-
monitoring and observation during the Public Health Service; 1991. macological Basis of Therapeutics. 8th ed.
recovery period is also important 2 O'Rourke RA, Chatterjee K, Wei JY. Coro- New York, NY: Pergamon Press; 1990:840-
nary heart disease 18th Bethesda conference 873.
because dysrhythmias often occur report: cardiovascular disease In the elderly. 21 Deegan R, Wood AJJ. P-Receptor antago-
during recovery rather than during J A m CON Cardiol. 1987;10:52A-56A. nism does not fully explain esmolol-induced
peak exercise.69 If exercise is stopped 3 Epstein SE, Robinson BF, Kahler RL, Braun- hypotension. CIin Phannacol Ther. 1994;56:
abruptly and the individual remains in wald E. Effects of beta-adrenergic blockade on 223-228.
the cardiac response to maximal and submaxi- 22 Thadani V, Davidson C, Singleton W, Tay-
an upright position, pooling of blood ma1 exercise in man. J Clin Invest. 1965;44: lor SH. Comparison of the immediate effects
in the lower body occurs. A decrease 1745-1753. of five beta-adrenoreceptor-blocking drugs
in venous return results, which can 4 Astrom H. Haemodynamic effects of beta- with different ancillary properties in angina
adrenergic blockade. Br Heart J. 1968;30:44- pectoris. N Engl J Med. 1979;300:750-755.
decrease blood flow to the heart and 49.
facilitate an irregular rhythm. By con- 23 Murad F. Drugs used for the treatment of
5 Reybrouck T, Amery A, Billiet L. Hemody- angina: organic nitrates, calcium-channel
tinuing to exercise at a low intensity namic response to graded exercise after blockers, and beta-adrenergic antagonists. In:
during recovery, a sudden decrease in chronic beta-adrenergic blockade. J Appl Gilman AG, Rall TW, Nies AS, Taylor P, eds.
Physiol. 1977;42:133-138. Goodman and Gilman's The Phannacological
venous return is avoided. 6 Bruce RA, Hossack KF, Kusumi F, Clarke LJ. Basis of Therapeutics.8th ed. New York, NY:
Acute effects of oral propranolol on hemody- Pergamon Press; 1990:764-783.
namic responses to upright exercise. Am J 24 Kaiser P, Hylander B, Eliasson K, Kaijser L.
Cardiol. 1979;44:132-140. Effect of beta-sensitive and nonselective beta
7 Sklar J, Johnston GD, Overlie P, et al. The blockade o n blood pressure relative to physi-
To be able to perform sustained activ- erects of cardioselective (Metoprolol) and a cal performance in men with systemic hyper-
ity, changes in HR, myocardial con- nonselective (Propranolol) beta-adrenergic tension. Am J Cardiol. 1985;55:79&84D.
tractility, and peripheral blood flow blocker on the response to dynamic exercise 25 Gordon NF, Duncan JJ. Effect of beta
in normal men. Circulation. 1982;65:894-8%. blockers on exercise physiology: implications
are required. Medications that are
8 Wilmore JH, Freund BJ, Joyner MJ, et al. for exercise training. Med Sci Sports here.
prescribed for cardiovascular condi- Acute response to submaximal and maximal 1991;23:668-676,
tions have the potential to either posi- exercise consequent to beta-adrenergic 26 Cohen-Solal A, Baleynaud S, Laperche T,
tively or negatively affect exercise blockade: implications for the prescription of et al. Cardiopulmonary response during exer-
exercise. Am J Cardiol. 1985;55:135B141D, cise of a B1 selective P-blocker (atenolol) and
performance or training adaptations. 9 Zusman RM, Higgins J, Christensen D, a calcium channel blocker (diltiazem) in un-
These agents may also alter the ex- Boucher CA. Bepridil improves left ventricular trained subjects with hypertension.
pected changes in HR and BP that performance in patients with angina pectoris. J Cardiouasc Phannacol. 1993;22:33-38.
occur with activity, or they may in- J Cardiovasc Phannacol. 1993;22:474-480. 27 Loefsjoegaard-Nilsson E, Atmer B, Gunolf
10 Katz AM. Physiology of the Heart. New M, Krug-Gourley S. Effects of carvedilol during
crease the potential for rhythm York, NY: Raven Press; 1977:197-227.
dsturbances.

Physical Th.erapy/ Volume 75, Number 5 / May 1995


exercise. J Cardiovasc Pbarmacol. 1992;19: hemoglobin. J Pbarmacol Exp Ther. 1974;191: isosorbide dinitrate on exercise capacity in
S108-S113. 557-563. congestive heart failure. Am J Med. 1980;69:
28 Fellenius E. Muscle fatigue and beta 43 Meisheri KD, Cipkus LA, Taylor CJ. Mecha- 559 -566.
blockers: a review. Int J Sport Med. 1983;4: nism of action of minoxidil sulfate-induced 57 Hoffman BF, Bigger JT. Digitalis and allied
1-8. vasodilation: a role for increased Kt perme- cardiac glycosides. In: Gilman AG, Rall TW,
29 Gordon NF, Kruger PE, Hons BA, Cilliers ability. J Pbarmacol &D Tber. 1988;245:751- Nies AS, Taylor P, eds. Goodman and Gil-
JF. Improvcd exercise ventilatory responses 760. man 's The Pbannacological Basis of Thera-
after training in coronary heart disease during 44 Derman WE, Sims R, Noakes TD. The ef- peutics. 8th ed. New York, NY: Pergamon
long-term beta-adrenergic blockade. Am J fects of antihypertensive medications on phys- Press; 1990:814-839.
Cardiol. 1983;51:755-758. iological response to maximal exercise testing. 58 Fleg JL, Rothfeld B, Gottlieb SH, Wright J.
30 Ewy G I ~Wilmore
, JH, Morton AR, et al. J Cardiovasc Pbarmacol. 1992;19:S122-S127. Effect of maintenance digoxin therapy on aer-
The effect (of beta-adrenergic blockade on ob- 45 Chick TW,Halperin AK, Gacek EM. The obic performance and exercise left ventricular
taining a trained state. J Cardiopulmonary Re- effect of antihypertensive medications on ex- function in mild to moderate heart failure due
babil. 1989;9:110-114. ercise performance: a review. Med Sci Sports to coronary artery disease: a randomized,
31 Savin WM, Gordon EP, Kaplan SM, et al. Ererc. 1988;20:447- 454, placebo-controlled, crossover trial. J A m CON
Exercise training during long-term beta- 46 Agre JC, Leon AS, Hunninghake DB, et al. Cardiol. 1991;17:743751.
blockade treatment in healthy subjects. Am ] The effects of methyl dopa and propranolol 59 Sullivan M, Atwood JE, Myer J, et a]. In-
Cardiol. 1985;55:101D-109D. on the response to dynamic and static exer- creased exercise capacity after digoxin admin-
32 Gordon NF, Van Rensburg JP, Vander cise during treatment of mild hypertension in istration in patients with heart failure. J A m
Hewer DP, et al. Effect of dual B-blockade men. J Cardiopulmonary Rebabil. 1986;6:214- CON Cardiol. 1989;13:1138-1143.
and calcium antagonism on endurance perfor- 230. 60 Meyers DG, Bendon KA, Hankins JH,
mance. Med Sci Sports Exerc. 1987;19:1-6. 47 Chick TW,Halperin AK, Jackson JE, VanAs Stratbucker RA. The effect of baseline electro-
33 Pollock ML, Wilmore JH. Exercise in A. The effect of nifedipine on cardiopulmo- cardiographic abnormalities on the diagnostic
Health and Disease. 2nd ed. Philadelphia, Pa: nary responses during exercise in normal sub- accuracy of exercise induced ST segment
WB Saunders Co; 1990. jects. Chest. 1986;89:641-646. changes. Am Heart J. 1990;119:272-276.
34 American College of Sports Medicine: Po- 48 Stein D, Lowentrial DT, Porter S, et al. Ef- 61 Weiner IM. Diuretics and other agents em-
sition statement on the recommended quantity fects on nifedipine and verapamil on isometric ployed in the mobilization of edema fluid. In:
and quality of exercise for developing and and dynamic exercise in normal subjects. Am Gilman AG, Rall TW,Nies AS, Taylor P, eds.
maintaining cardiorespiratory and muscular J Cardiol. 1984;54:386-389. Goodman and Gilman 's The Pbannacological
fitness in healthy adults. Med Sci Sports Ererc. 49 Petri H, Arends BG, Van Baak MA. The Basis of Therapeutics. 8th ed. New York, NY:
1990;22:265-274. e5ect of verapamil on cardiovascular and met- Pergamon Press; 1990:713-731.
35 Gordon NF, Van Rensburg JP, Russell abolic responses to exercise. Eur/ Appl 62 Conway J, Lauwers P. Hemodynamic and
HMS. Effect of beta selective adrenoceptor Pbysiol. 1986;55:499-502. hypotensive effects of long-term therapy with
blockage on physiological response to exer- 50 Leon AS, McNally C, Casal D, et al. Anala- chlorothiazide. Circulation. 1960;21:21.
cise. Br Heart J. 1985;54:96-33. pril alone and in combination with hydrochlo- 63 Hollifield JW. Potassium and magnesium
36 DeCosler PM, Chierchia S, Davies GJ, et al. rothiazide in the treatment of hypertension: abnormalities: diuretics and arrhythmias in
Combined effects of nitrates on the coronary effect on treadmill exercise performance. hypertension. Am J Med. 1984;77:28-32.
and peripherial circulation in exercise induced J Cardiopulmonary Rebabil. 1986;6:251-256. 64 Gilman AG, Rall TW,Nies AS, Taylor P.
ischemia. Circulation. 1990;81:1881-1886. 51 Lai C, Cherchi A, Onnis E, et al. Effect of Goodman .and Gilman's The Pbannacological
37 Horwitz LD, Gorlin R, Taylor WJ, Kemp calcium antagonists on exercise tests. Basis of Therapeutics. 8th ed. New York, W :
HG. Effects of nitroglycerin on regional myo- J Cardiovasc Pbannacol. 1992;20:S55.-S64. Pergamon Press; 1990.
cardial blood flow in coronary artery disease. 52 Steinbeck G, Reuschel-Janetschek E. Slow- 65 Ryan M, Lown B, Horn H. Comparison of
J Clin Invcst. 1971;50:1578-1584. release gallopamil evaluated by exercise test ventricular ectopic activity during 24-hour
38 Cody KJ. Pharmacology of angiotensin: and long-term electrocardiography. monitoring and exercise testing in patients
converting enzyme inhibitors as a guide to J Cardiovasc Pbarmacol. 1992;20:S83-S87. with coronary heart disease. N Engl JMed.
their use in congestive heart failure. Am J Car- 53 Delonca J, Kipfer P, Righetti A. Effects of 1975;292:224-229.
diol. 1990;66:7D-13D. oral isradipine on left ventricular function at 66 Lillis DL, Hanson P. Ventricular ectopy in
39 Hoffman BF, Lefkowitz RJ. Catecholamines rest and during exercise in patients with stable cardiac rehabilitation patients on exercise
and sympathomimetic drugs. In: Gilman AG, chronic angina: a double-blind, placebo- training and nonexercising days. Clin Cardiol.
Rall TW, Nies AS, Taylor P, eds. Goodman controlled crossover study. J Cardiovasc Pbar- 1989;12:569-574.
and Gilmtzn 's The Pbannacological Basis of macol. 1992;19:126-133, 67 Podrid PJ, Venditti FJ, Levine PA, Klein
Therapeutics. 8th ed. New York, NY: Perga- 54 Garrison JC, Peach MJ. Renin and angio- MD. The role of exercise testing in evaluation
mon Press; 1990:187-220. tensin. In: Gilman AG, Rall TW,Nies AS, Tay- of arrhythmias. Am J Cardiol. <988;62:24~-
40 Hoffman BF, Lefkowitz RJ. Adrenergic re- lor P, eds. Goodman and Gilman's The Phar- 33H.
ceptor antagonists. In: Gilman AG, Roll TW, macological Basis of Therapeutics. 8th ed. 68 Podrid PJ, Bumio F, Fogel RI. Evaluating
Nies AS, Taylor P, ed. Goodman and Gil- New York, NY: Pergamon Press; 1990:749- patients with ventricular arrhythmia: role of
man's The Pharmacological Basis of Thera- 763. the signal-averaged electrocardiogram, exer-
peutics. 8th ed. New York: Pergamon Press; 55 Drexler H, Banhardt U, Meinertz T, et al. cise test, ambulatory electrocardiogram, and
1990:221-243. Contrasting peripheral short-term and long- electrophysiologic studies. Cardiol Clin. 1992;
41 Gerber JG, Nies AS. Antihypertensive term effects of converting enzyme inhibition 10:371-395.
agents and the drug therapy of hypertension. in patients with congestive heart failure: a 69 Jelinek MV, Lown B. Exercise stress testing
In: Gilman AG, Rall TW, Nies AS, Taylor P, double-blind, placebo-controlled trial. Circu- for exposure of cardiac arrhythmia. Pmg Car-
eds. Goodman and GilmanS The Pbannaco- lation. 1989;79:491-502. diovasc Dis. 1974;16:497-522.
logical Basis of Therapeutics. 8th ed. New 56 Franciosa JA, Goldsmith SR, Cohn JN. Con- 70 Physicians' Desk Reference. 49th ed.
York, NY: Pergamon Press; 1990:784-813. trasting immediate and long-term effects of Montvale, NJ: Medical Economics Data Pro-
42 Smith PR, Kmszyna H. Nitroprusside pro duction Co: 1995.
duces cyanide poisoning via a reaction with

Physical Therapy / Volume 75, Number 5 /May 1995

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