Effects of cardiovascular medications on exercise responses.

[Peel C, Mossberg KA. Effects of cardiovascular medication on exercise responses. Phys Ther. 1995; 75:387-396.]

Key Words: Cardiovascular system, Exercise, general, Pharmacology, Phystology.

The role of the physical therapist includes monitoring physiological responses to activity and determining whether the responses are appropriate for the individual based on the individual's past and present medical history. Many cardiovascular medications have the potential to alter responses to both acute and chronic exercise in a predictable manner. Knowledge of how common drugs alter responses assists therapists in assessing the safety and appropriateness of exercise and in determining the effectiveness of exercise training. Although the incidence of heart disease has decreased in recent years, conditions that involve the cardiovascular system remain common in the adult population.[1] Hypertension, congestive heart failure, and coronary artery disease increase in incidence as persons become older.[2] Many patients who are referred to physical therapy for orthopedic, neurological, or general medical problems may have coexisting involvement of the cardiovascular system. Simple questioning of these individuals as to the medications that they are taking can provide valuable information about their current condition or medical history. Knowledge of how different classes of cardiovascular medications affect responses to activity may have an impact on the interpretation of evaluative findings and treatment planning.

Most medications that are prescribed for cardiovascular disease have either a direct or indirect effect on the heart or vascular system, including altering myocardial oxygen consumption, peripheral blood flow, and cardiac preload or afterload, Medications may either increase or decrease exercise capacity, or alter the expected changes in heart rate and blood pressure that normally occur with an increase in activity.[3-9] Medications can also be effective in controlling an abnormality (eg, a cardiac arrhythmia) at rest, but not during activity. By documenting patients' physiological responses while they are performing physical activities, therapists can provide valuable feedback back to patients' physicians to guide the medical management of the patients.

The first objective of this article is to present a general overview of ways in which cardiovascular medications can affect responses to physical activity or exercise, followed by a brief review of clinical measurements that are useful in assessing activity responses. The second objective is to review the effects of selected classes of cardiovascular medications on heart rate (HR), blood pressure (BP), and electrocardiographic (ECG) responses during exercise, exercise capacity, and training adaptations. Classes of medications that will be discussed include beta-adrenergic receptor antagonists, vasodilators, diuretics, digitalis, and antiarrhythmic agents.

Overview of Mechanisms by Which Medications Can Affect Exercise Responses

The physiological response to exercise is complex; involves integration of multiple systems;. and varies depending on the type, intensity, and duration of the activity. General changes include increases in cardiac output and myocardial oxygen consumption and an increase in blood flow to active skeletal muscle and the skin. In addition, energy-generating substrates are mobilized. Medications can be categorized according to their effects on factors that influence each of these responses. A summary of responses, with examples of medications that may affect each response, is presented in Table 1.

Cardiac output can be influenced by drugs that directly affect the heart by altering either myocardial contractility or the initiation and conduction of the cardiac action potential. For example, contractility is enhanced by inotropic agents such as digitalis and is depressed by beta-adrenergic receptor antagonists. Beta-receptor antagonists also decrease the rate of depolarization of the sinoatrial node, decreasing heart rate. A decrease in HR with no change in stroke volume (SV) results in a decrease in cardiac output.

Changes in preload and afterload will also influence cardiac output. Vasoconstriction in the venous circulation will increase preload and will increase cardiac output according to the Frank-Starling law of the heart.[10] Vasodilation on the arterial side of the circulation will decrease afterload, or the resistance to the ejection of blood from the left ventricle. With a decreased resistance, the heart can deliver a greater output for any given force of contraction.

Medications may also affect exercise responses by altering factors that determine myocardial oxygen demands or oxygen delivery. Primary factors that increase oxygen demand include an increase in HR, aortic pressure, and SV. To match the increased oxygen needs, an increase in blood flow and oxygen delivery occurs by vasodilation of coronary arteries. If a sufficient increase in blood flow is not possible because of coronary artery stenosis, then one strategy is to decrease oxygen demands by depressing HR, myocardial contractility, and/or total peripheral resistance. Some of the medications that are used to treat angina are effective because they decrease myocardial oxygen requirements via these mechanisms.

Medications that affect peripheral blood flow have the potential to influence exercise responses. If the normal increase in skeletal muscle blood flow is impaired, then exercise duration may be decreased because of an accumulation of metabolites of anaerobic metabolism. For example, a nonspecific beta-receptor antagonist could prevent relaxation of the vascular smooth muscle in the exercising muscle by blocking beta-2 receptors. The result of a decrease in beta-receptor mediated vasodilation could be a decrease in oxygen delivery. This effect, however, is most likely offset by the vasodilation that occurs in response to the buildup of local metabolites.

If there is an imbalance between heat production and heat dissipation, then endurance time also will be decreased because of an excessive increase in core temperature. Gordon and colleagues,[11] for example, found an increase in core temperature during exercise in patients with coronary artery disease when given propranolol (a nonselective beta-receptor antagonist) over that observed with a placebo. The exact mechanism is unknown, but may be related to increased sympathetic nervous system activity, including stimulation of alpha-1 receptors. Activation of alpha-1 receptors in the cutaneous circulation would produce vasoconstriction and consequently impair heat dissipation.

Medications can affect the metabolic response to exercise by interfering with glycogenolysis or fatty acid mobilization and oxidation. Inadequate glycogen may limit endurance time and the individual's ability to perform moderate- to high-intensity activities. Inadequate mobilization and oxidation of fatty acids limits the ability to perform exercise for prolonged time periods. The class of medications that has been most thoroughly studied in terms of effects on the metabolic response to exercise is the group of beta-adrenergic receptor antagonists because of the important role played by the sympathetic nervous system and catecholamines in maintaining metabolic homeostasis during strenuous work. By blocking beta-2 receptors in the liver, these medications can impair glycogenolysis. Studies[12,13] have shown that there is less reliance on fatty acid oxidation during exercise when taking beta-receptor antagonists. Additionally, there is no increase in the rate of muscle glycogen breakdown. The lack of a compensatory increase in glycogen breakdown probably contributes to the reduction in endurance time.

Clinical Measurements

Responses to physical activity can be monitored in most clinical environments by measuring HR and BP and by observing for abnormal signs and symptoms. Electrocardiography, often available in hospital settings or cardiac rehabilitation facilities, can be used to detect arrhythmias and ischemic changes. An accurate assessment of preexercise or baseline values is essential so that changes that occur with activity can be identified. For many patients performing continuous activities at submaximal intensities, measurements made after 2 to 3 minutes reflect steady-state responses. For some patients who are severely deconditioned, or who have cardiopulimonaty disease, reaching a steadystate condition may not be possible. Heart rate may continue to rise during exercise rather than remaining steady at a plateau level. Repeating measurements after 5 to 6 minutes and comparing the measurements with those made after 3 minutes is one way to determine whether a steady-state level is reached. Making measurements during the activity is ideal, although values recorded during the initial 30 seconds after activity have been shown to accurately reflect the exercise response in asymptomatic individuals.[14] In patients with cardiopulmonary disease who are at high risk of experiencing a complication, continuous monitoring of HR and ECG responses is indicated.

Assessing changes in the ability to perform either submaximal or maximal exercise as a result of either new medications or changes in dosage of current medications is also important. Because directly measuring maximal oxygen consumption ([Vo.sub.2]max) is not practical in most clinical settings, maximal work rate can be used as an alternate measurement. One method of determining whether a change in medications affects general body endurance is to record the amount of time that a submaximal work rate can be performed. For an accurate comparison, the work rate and the testing conditions need to be the same for tests conducted both before and after the change in medications.

Recording ratings of perceived exertion (RPE) during activity provides a measure of the patient's perception of the difficulty of the activity. Although this is a measurement of a subjective phenomenon, both validity and reliability have been established.15 Questionnaires can be used to determine the effects of interventions such as regular exercise and medications on patients' lifestyles and perceptions of their health status.[16]

Categories of Medications

Medications can be grouped into categories according to their mechanisms of action. By knowing the category in which a drug is included, clinicians can determine the probable mechanism of action and clinical indications. The section that follows provides a discussion of several categories of drugs. Examples of specific medications are included in Tables 2, 3, and 4.

Table 2. Common Beta-Adrenergic Receptor Antagonists
                                  Medication
Property                          Generic               Trade
Blocks beta-1 and beta-2          Propranolol           Inderal
receptors (nonselective)          Nadolol               Corgard
Timolol                           Blocadren             Blocadren
Pindolol                          Visken                Visken
Selective for beta-1 receptors    Atenolol              Tenormin
Metoprolol                        Lopressor             Tenormin
Nonselective with intrinsic       Pindolol              Visken
sympathomimetic activity          Carteolol             Cartrol
Penbutolol                        Levatol               Levatol
Antagonist for beta- and          Labetolol             Normodyne
  alpha-receptors                                       Trandate

Table 3. Common Examples of Direct-Acting and Indirect-Acting
Vasodilators
                                  Medication
Action                            Generic                 Trade
Direct-acting
Nitrates                          Nitroglycerin           Nitrostat
Nitro-bid
                                  Isosorbide dinitrate    Isordil
Calcium antagonists               Diltiazem               Cardizem
                                  Verapamil               Calan
                                  Nifedipine              Procardia
                                  Nicardipine             Cardene
Directly affects arterial         Hydralazine             Apresoline
side of circulation               Sodium nitroprusside    Nipride
Facilitates opening of            Minoxidil               Loniten
  potassium channels
Indirect-acting
ACE(a) inhibitors                 Captopril               Capoten
                                  Enalapril               Vasotec
Alpha-1 antagonists               Prazosin                Minipress
Centrally acting                  Methyldopa              Aldomet
alpha-agonists                    Clonidine               Catapres
(a) ACE=angiotensen-converting enzyme.

Table 4. Common Examples of Diuretics
                            Medication
Category                    Generic                Trade
Thiazides                   Hydrochlorothiazide    Esidrix
                            Chlorothiazide         Diuril
Loop diuretics              Furosemide             Lasix
                                                   Furoside
Potassium-sparing agents    Spironolactone         Aldactone
                            Amiloride              Midamor

Beta-Adrenergic Receptor Antagonists

Mechanism of Action

The essential mechanism of action of the beta-adrenergic receptor antagonists beta-blockers) is to attenuate the actions of the sympathetic nervous system. Beta-receptors normally bind with norepinephrine and epinephrine, setting into motion subcellular events that bring about increases in HR and myocardial contractility (beta-1), bronchodilation (beta-2), and vasodilation in peripheral blood vessels (beta-2).17 Stimulation of beta-2 receptors also increases glycogenolysis, whereas fatty acid mobilization may be increased by beta-1 stimulation. Nonselective beta-adrenergic receptor antagonists prevent stimulation of both beta-1 and beta-2 receptors. In an attempt to elicit more selective responses, beta-blockers with varied properties have been developed (Tab. 2). Selective beta-1 receptor antagonists exert primary effects on cardiac beta-receptors, although their selectivity decreases at higher dosages. Beta-blockers that act as partial agonists of beta-receptors have been developed. These medications are described as having intrinsic sympathomimetic activity (ISA) because they partially activate beta-receptors at rest when levels of catecholamines are low. The advantage is to minimize both bradycardia and depression of myocardial contractility that can occur under resting conditions. In addition, agents that block both alpha-1 receptors and beta-receptors have been developed. These medications are effective in decreasing BP by preventing sympathetic stimulation of the heart and by producing arterial vasodilation.

Clinical Indications

Beta-blockers were originally developed to treat angina, and now they are also used for hypertension and cardiac arrhythmias. Long-term use has been shown to decrease mortality after myocardial infarctions.[18] Their effectiveness in the treatment of angina is attributed to a decrease in myocardial oxygen requirements by decreasing HR, BP, and myocardial contractility both at rest and during exercise. The exact mechanism of a decrease in BP is unknown, but may include a lowering of plasma renin activity, decreased cardiac output, or decreased basal sympathetic outflow from the vasomotor centers in the pons and medulla.[19] Beta-blockers are used in the treatment of both atrial and ventricular arrhythmias because of their tendency to decrease automaticity of myocardial cells.[20] Common side effects of persons taking beta-blockers include fatigue and hypotension.

Alterations in Responses to Acute Exercise

Beta-blockers depress the increases in HR, BP, and myocardial contractility that normally occur with exercise. The Figure summarizes the HR and BP responses to activity in both persons who are asymptomatic and patients with hypertension, coronary artery disease, rhythm disturbances, and cardiomyopathy.[3-8,21] In patients with myocardial ischemia and angina, beta-blockers tend to increase exercise tolerance because of the decreases in myocardial oxygen requirement.22 Typically, patients are able to exercise for longer periods before the onset of angina. The decrease in myocardial oxygen demand is primarily a result of a decreased HR response, producing a decrease in rate-pressure product (RPP). End diastolic volume tends to increase, resulting in an increase in SV and ventricular wall tension. Unfortunately, greater ventricular wall tension during systole increases myocardial oxygen demand, partially offsetting the beneficial effects of decreased HR and contractility.[23]

For people who are nonnotensive and for patients with hypertension, data on the effects of beta-blockers on exercise performance are unclear. Factors that influence the response include the individual's level of physical conditioning, the specific pharmacological agent (selective versus nonselective), and the dosage. In both asymptomatic subjects and individuals with uncomplicated hypertension, nonselective beta-blockers tend to decrease maximal exercise performance in a dose-dependent manner.[24] Beta-1 selective agents have less of an effect on maximal exercise capacity in asymptomatic subjects.[25] Cohen-Solal and colleagues[26] documented no effect on [Vo.sub.2]max or duration of exercise in individuals who were untrained and had hypertension. Other researchers[27] have reported maintenance of exercise performance in well-conditioned subjects taking carvedilol, a nonselective beta-blocker with alpha-receptor blocking properties. In general, with beta-blocker administration, increases in both SV and artetiovenous oxygen difference appear to compensate for the decrease in HR. An increase in fatigue that is often reported with initial use of beta-blockers tends to decrease with regular use.[28]

Alterations in Responses to Exercise Training

Because of the attenuated HR response during exercise, the ability of persons taking beta-blockers to benefit from exercise training has been questioned. After a 4-month program that involved 90-minute sessions three times per week at an intensity of 85% of symptom-limited maximal HR produced increases in [Vo.sub.2]max and decreases in submaximal HR in persons with coronary artery disease who were taking beta-blockers.[29]

Adaptations also appear to occur in asymptomatic persons and in persons with hypertension.[30,31] Because initiation of beta-blocker therapy results in impairment of cardiovascular fitness, the improvement with training has been shown to be less than the improvement that occurs with a placebo.25 Additional studies are needed to examine training adaptations that occur when taking beta-blockers compared with other antihypertensive medications.

Exercise Prescriptions for Patients Taking Beta-Blockers

Because of the decrease in maximal HR, age-related equations used to predict maximal HR and used to formulate exercise prescriptions cannot be used for patients taking beta-blockers. Prescriptions need to be based on an exercise stress test that is performed while the patient is taking the prescribed medication. Maximal HR cannot be predicted for patients taking beta-blockers because the extent of the decrease is affected by the specific agent and the dosage.[32] If performing a graded exercise test is not possible, then a training HR that is 20 bpm greater than resting HR can be used, assuming that the patient is symptom-free at this intensity.[33]

If exercise stress test results are available and maximal HR can be determined, then the prescription can be formulated using recommended guidelines. A recommended training intensity is 85% of the HR where symptoms occur, or 60% to 90% of maximal HR.[34] Even though maximal HR decreases with beta blockade, the relationship between the percentage of maximal HR and the percentage of [Vo.sub.2]max does not appear to be meaningfully altered.[35] Therefore, an intensity of 60% to 90% of maximal HR correlates with an intensity of 50% to 85% of [Vo.sub.2]max.

Vasodilators

Mechanisms of Action

Vasodilators act either directly or indirectly to relax the smooth muscle walls of blood vessels. Pharmacological agents may be relatively specific as to their effects and act predominantly on either the arterial or the venous sides of the circulation. Vasodilators are classified based on the mechanism of their action (Tab. 3).

Nitrates promote smooth muscle relaxation on both the arterial and the venous sides of the circulation.[36] Arteriolar dilation reduces afterload, whereas venodilation reduces venous return and thus decreases preload. Nitrates also dilate both epicardial and collateral vessels in the heart in persons with normal coronary arteries. In persons with atherosclerosis of the coronary arteries, nitrates do not increase total blood flow to the heart.[23] These medications appear to have a beneficial effect on myocardial blood flow by redistributing flow to subendocardial areas, which tend to have poor perfusion.[37]

Calcium antagonists act to block voltage-dependent calcium channels on cell membranes of smooth muscle and myocardial cells.[19] Normally, calcium enters the cell through "slow channels" and is responsible for the plateau phase of the cardiac action potential. The calcium influx then causes a massive release of calcium that is stored in the sarcoplasmic reticulum, resulting in the initiation of crossbridge formation between actin and myosin. Therefore, blocking the extracellular calcium influx results in a reduction of contractile activity of cardiac muscle and vascular smooth muscle.[19] The clinical result is a decrease in myocardial afterload and systolic function, resulting in a decrease in myocardial oxygen demand. Because of the role of calcium in the cardiac action potential, these drugs also can affect HR and heart rhythm, and are sometimes used to treat cardiac arrhythmias.

The angiotensin-converting enzyme (ACE) inhibitors prevent the conversion of angiotensin I to angiotensin II.[38] Angiotensin II not only is a powerful vasoconstrictor, but also increases serum aldosterone levels, resulting in increased sodium retention. Preventing formation of angiotensin II results in inhibition of vasoconstriction and a decrease in sodium retention. Both of these affects result in decreases in BP.

Two categories of vasodilators that exert their effects through the sympathetic nervous system are the centrally acting alpha-2 agonists and the alpha-1 antagonists. Medications that stimulate alpha-2 receptors in the central nervous system produce a decrease in sympathetic outflow from the brain stem.[39] The result is a decrease in arterial pressure because of decreases in both cardiac output and peripheral resistance. Alpha-1 antagonists inhibit vasoconstriction in both the arterial and venous sides of the circulation.40 The result is a decrease in peripheral vascular resistance and BP.

Other vasodilators act directly on vascular smooth muscle. One of these medications, hydralazine, produces relaxation of arterial smooth muscle that is somewhat specific to cerebral, coronary, and renal vessels.[41] Sodium nitroprusside is a similar medication that releases nitric oxide after contacting red blood cells.[42] The result is vasodilation of both arterioles and venules. Another medication, minoxidil, directly relaxes vascular smooth muscle, possibly by increasing the permeability of the cell membrane to potassium.[43]

Clinical Indications

Vasodilators are prescribed for angina, hypertension, and heart failure, and the calcium antagonists occasionally are used for cardiac arrhythmias. The major indication for nitrates is angina. Their effectiveness in patients with coronary artery disease results primarily from their effects on the peripheral rather than the coronary circulation. Decreases in both afterload and preload result in decreases in myocardial oxygen requirements. Two common problems with nitrates are a reflex increase in HR, which increases myocardial oxygen demand, and development of tolerance.[23] The reflex increase in HR occurs because blood tends to pool in the lower body and sympathetic reflexes are activated. The development of tolerance is related to the dosage and the frequency of taking the medication, and often occurs when the drug is given in a sustained-release transdermal preparation. Patients who take high dosages, with either oral or transdermal administration, may experience a decrease in the effects of the drugs. Development of tolerance can be prevented by not taking the medication for a period of several hours during the course of a day.

Calcium antagonists and ACE inhibitors are often the first drugs used to treat mild to moderate hypertension.41 Calcium channel antagonists also are prescribed for angina that is thought to result from coronary artery spasm. In addition, this medication is used for the treatment of supraventricular arrhythmias. Another common use of ACE inhibitors is for heart failure. Their effectiveness is thought to be related to a decrease in afterload, which allows for a greater cardiac output without increasing the force of contraction.

Exercise Responses in Persons With Hypertension

Calcium antagonists, ACE inhibitors, alpha-1 antagonists, and centrally acting alpha-agonists are commonly used for hypertension.[41] In general, these medications produce decreases in both systolic and diastolic BP during exercise.[44.45] Calcium antagonists also have the potential to produce negative inotropic effects, similar to the beta-blockers. Depression of myocardial contractility with these agents appears to be minimal; verapamil is a possible exception.[45] Calcium antagonists and centrally acting alpha-2 agonists may affect HR during exercise, with increases associated with nifedipine and decreases associated with verapamil, diltiazem, and methyldopa.[46-48] Verapamil can also decrease maximal HR in a dose-dependent manner.[49]

Calcium antagonists and ACE imibitors do not appear to significantly affect [Vo.sub.2]max or maximal work rate in relatively asymptomatic persons. Increases in RPE during submaximal exercise with ACE inhibitors, but not with calcium antagonists, have been described.[44] in another report,[50] no effect on either submaximal or maximal RPE in asymptomatic persons taking ACE inhibitors was reported. Differences in the results of these two studies may be due to the fact that the subjects differed in age and activity level. Persons who exercise regularly may be more sensitive to small differences in sensations of perceived exertion. The lack of an effect on exercise performance of these two groups of medications is important because hypertension often occurs in people who are physically active. Prescribing a drug that will not affect exercise performance is important for these individuals and tends to maximize compliance with endurance exercise. Moreover, appropriate training also has a beneficial effect on the treatment of hypertension.

Exercise Responses in Persons With Angina

In persons with angina, exercise performance is improved with vasodilators. Studies[9,51-53] have documented increased peak work rate, increased exercise time before the onset of 1 mm of ST-segment depression, and increased exercise time before the onset of angina. Possible explanations for these effects include a decrease in myocardial oxygen consumption and an increase in coronary blood flow to ischemic areas. These two mechanisms can be differentiated by analyzing changes in the relationship between the onset of ST-segment depression and the value of the RPP during a graded exercise test. If there is a decrease in myocardial oxygen consumption, then ST-segment depression will occur at a similar RPP. If there is an increase in coronary blood flow, then ST-segment depression will occur at a higher value of RPP. The precise mechanism most likely is determined by the severity of coronary artery disease and by the specific agent. A higher RPP at the onset of ST-segment depression, indicating an increase in coronary blood flow to ischemic areas, has been reported with the calcium antagonist nisolopine, which is a relatively new agent that is currently used in Europe.[51]

Exercise Responses in Persons With Heart Failure

Angiotensin-converting enzyme inhibitors and selected direct-acting vasodilators are used to treat patients with heart failure because of these medications' action of decreasing peripheral resistance and indirectly allowing an increase in cardiac output.[54] Studies[55.56] have documented effects of both short-term and long-term therapy with these medications. Short-term changes involve improvements in hemodynamics, and include a decrease in mean systemic arterial and pulmonary wedge pressures and increases in cardiac output during exercise. Most studies of short-term effects have not documented increases in either exercise time or peak oxygen consumption.

Long-term therapy, over several months, has been shown to increase exercise performance in persons with mild to moderate heart failure.55 Effects include increased exercise duration, increased peak oxygen consumption, and increased peripheral arteriovenous oxygen difference. The effects are similar to those resulting from exercise training. These responses may be explained by an increased ability of skeletal muscle blood vessels to dilate during exercise, possibly because of a decrease in sodium retention.[55,56] Another possible mechanism is that patients improve in clinical symptoms when on long-term therapy and become more active.[56]

Digitalis

Mechanism of Action

Digitalis-like medications, which include digoxin and digitoxin, are commonly prescribed for heart failure. These compounds increase myocardial contractility by inhibiting the sodium potassium adenosine triphosphatase (ATPase) enzyme in cell membranes of cardiac muscle cells. The result is an accumulation of intracellular sodium, which is exchanged for calcium. The increase in intracellular calcium increases contractility. The effect is somewhat opposite to that seen with the calcium channel blockers.

Clinical Indications

Because of their positive inotropic effects, the digitalis-like drugs are used to treat heart failure. These drugs also have electrophysiological effects. A common effect is a decrease in conduction velocity through the atrioventricular node, which can result in heart block.[57] This action is used therapeutically to treat atrial fibrillation. Another important feature of these medications is their low therapeutic index, indicating that there is a narrow margin between therapeutic dosages and toxic dosages. Common problems include bradycardia, various arrhythmias, and fatigue.

Effects of Digitalis on Exercise Responses

In many patients, digitalis improves left ventricular performance during exercise, as indicated by higher ejection fractions and systolic BP.[58] Studies of measurements of peak oxygen consumption and work rate led to differing results, with increases[59] and no change reported.[58] There appears to be an inverse relationship between pretreatment aerobic capacity and the degree of improvement in physical work capacity.[58] Persons with low aerobic capacities and moderate to severe heart failure tend to show the greatest improvements when taking digitalis-like compounds.

The accuracy of stress testing to support a diagnosis of coronary artery disease is diminished in persons taking digitalis.[60] Exercise-induced ST-segment depression usually is used as the major criterion for a positive stress test. Digitalis produces ST-segment depression in 25% to 100% of persons with normal coronary arteries.[60] Therefore. ST-segment changes that occur with exercise testing in patients taking digitalis could result in a false-positive stress test result, supporting an inaccurate diagnosis of cardiac ischemia.

Diuretics

Mechanism of Action

Diuretics increase the excretion of sodium and water by the kidneys, producing a decrease in blood volume. Three general categories of diuretics are thiazides, loop diuretics, and potassium-sparing agents (Tab. 4). Thiazides and potassium-sparing diuretics exert their actions primarily at the distal tubule. Loop diuretics act at the thick ascending limb of the loop of Henle. Thiazides and loop diuretics increase the excretion of sodium, potassium, chloride, and bicarbonate. Potassium-sparing diuretics decrease the excretion of potassium and increase the excretion of sodium, chloride. and bicarbonate.

Clinical Indications

Diuretics are used in the management of congestive heart failure and hypertension. For the management of heart failure, diuretics are beneficial because of their effects on fluid volume and on venous capacitance. The decrease in fluid volume tends to improve dyspnea and alleviate swelling. The venodilation decreases peripheral resistance, facilitating a decrease in preload. of the three categories, loop diuretics are commonly used for heart failure.[61]

In the treatment of hypertension, diuretics produce a decrease in BP initially because of a decrease in blood volume. With continued use, blood volume tends to increase toward premedication levels as peripheral resistance decreases.[62] The long-term effectiveness of diuretics most likely is attributed to a decrease in peripheral resistance. Thiazide diuretics are commonly used for hypertension, either alone or in combination with potassium-sparing diuretics. The addition of a potassium-sparing diuretic to a thiazide diuretic prevents the loss of potassium that would occur when using a thiazide diuretic alone. Potassium supplements also are commonly used in combination with thiazide diuretics.

Effects of Diuretics on Exercise Responses

Diuretics produce decreases in BP at rest and during exercise, with minimal changes in HR during exercise.[45] Most diuretics have the potential to produce hypokalemia, which may lead to cardiac dysrhythmias. An increased incidence of premature ventricular contractions has been reported for patients taking hydrochlorothiazide.[63] Prolonged exercise in the heat is not recommended for patients taking diuretics because of the cumulative effects of heat, exercise, and diuretics on blood volume and electrolytes. The length of time that an individual who is taking a diuretic can safely exercise in the heat is variable, and depends on the heat index and the physical condition of the individual.

Antiarrhythmic Agents

Mechanism of Action

Abnormalities of cardiac rhythm are thought to result from three factors: reentrant circuits, delayed afterpotentials, and enhanced automaticity of ectopic foci.[64] The incidence of dysrhythmias is directly related to the severity of heart disease and to the age of the patient.[65] Persons who are at high risk for having dysrhythmias include those with coronary artery disease that involves multiple vessels, left ventricular dysfunction, and exercise-induced ST-segment depression. Antiarrhythmic agents are effective in suppressing dysrhythmias because of their actions of decreasing membrane automaticity, slowing impulse conduction through the myocardium, and prolonging refractory periods.[67]

Effects of Exercise on Dysrhythmias

Exercise often increases dysrhythmias because of the increase in activity of the sympathetic nervous system and the increase in circulating catecholamines.[68] Catecholamines shorten membrane refractory periods, increase myocardial conduction velocity, increase the movement of calcium into cardiac cells, and increase automaticity. These effects have the potential to enhance reentrant circuits, to increase the amplitude of afterpotentials, and to increase activity of ectopic foci. Consequently, catecholamines tend to increase the probability of dysrhythmias. In addition, myocardial ischemia can produce changes in pH and potassium that alter electrophysiologic properties of myocardial cells.

Given the inherent changes with exercise, medications that are effective in controlling dysrhythmias when patients are at rest may not be effective during exertion or stress. In addition, side effects of antiarrhythmic agents may be more apparent during exercise. For example, many of these medications have negative inotropic effects, which manifest themselves as decreases in either exercise performance or BP during exercise. Because of their effects on the electrophysiologic characteristics of cells, these medications have the potential to cause abnormal rhythms. The effect of slowing of the impulse through the myocardium may become apparent during exercise as a bundle branch block or a complete heart block.

Because of the potential increase in dysrhythmias during exercise, knowledge of the patient's physical condition and medical history is important. Patients at high risk for having dysrhythmias. during exercise can be identified by determining the severity of their disease, including any history of complex or sustained dysrhythmias. Patients who are taking antiarrhythmic medications may need to be evaluated under conditions of graded exercise to ensure that their arrthythmias are under control during activity. Monitoring HR and BP during activity may provide clues as to the effectiveness of medication. In the absence of ECG, palpation of peripheral pulses can be used to detect irregular rhythms. Continued monitoring and observation during the recovery period is also important because dysrhythmias often occur during recovery rather than during peak exercise.69 If exercise is stopped abruptly. and the individual remains in an upright position, pooling of blood in the lower body occurs. A decrease in venous return results, which can decrease blood flow to the heart and facilitate an irregular rhythm. By continuing to exercise at a low intensity during recovery, a sudden decrease in venous return is avoided.

Summary

To be able to perform sustained activity. changes in HR, myocardial contractility, and peripheral blood flow are required. Medications that are prescribed for cardiovascular conditions have the potential to either positively or negatively affect exercise performance or training adaptations. These agents may also alter the expected changes in HR and BP that occur with activity, or they may increase the potential for rhythm disturbances.

A patient's medications and the reasons for taking each medication can provide valuable information about medical history and current condition. Because of the vast number of medications, and the multiple names for similar compounds, being able to locate information about a medication is imperative for optimal clinical practice. Reference texts that index medications using several categories are available in most clinical settings.[70] This information can be invaluable in the development of safe and effective treatment programs. Furthermore, by monitoring HR and BP and observing signs and symptoms, therapists are able to determine whether drugs are effective during activity. By being cognizant of changes induced by cardiovascular medications, therapists can assist patients to increase the quality and quantity of their physical activity.

References

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C Peet, PhD, PT, is Associate Professor and Chair, Department of Physical Therapy, The University of Texas Medical Branch, Galveston, TX, 77555-1028 (USA). Address all correspondence to Dr Peel.

KA Mossberg, Phd, PT, is Associate Professor, Department of Physical Therapy, The University of Texas Medical Branch.