Current trends in cardiovascular pharmacology.

[Ciccone CD. Current trends in cardiovascular pharmacology. Phys Ther. 1996;76:481-497.

Cardiovascular medications represent one of the largest and most frequently prescribed groups of drugs, and many patients receiving physical therapy also are taking medications for cardiovascular problems. Because cardiovascular disease is so common in industrialized societies, development of new cardiovascular drugs is an obvious priority in pharmacologic research. There has, however, also been an emphasis on examining how effective drugs are in actually improving morbidity and mortality associated with cardiovascular problems. Likewise, medications that are typically used for one form of cardiovascular disease are continually being studied to determine how effective they are in treating other cardiovascular problems.

The purpose of this article is to provide an update on the pharmacologic strategies currently used for three common types of cardiovascular disease: hypertension, congestive heart failure, and myocardial ischemia/infarction. Special emphasis will be placed on newer drugs and new applications of existing medications. This information will provide physical therapists with knowledge about the effects of these drugs and the rationale for why various medications are currently used.

Hypertension

Hypertension, a chronic sustained increase in blood pressure, is a common cardiovascular condition that can lead to other problems such as myocardial infarction (MI), renal failure, and cerebrovascular accident. Certain genetic or familial factors combined with lifestyle issues (poor diet, physical inactivity, levels of stress, and so forth) can contribute to a hypertensive state.1,2 The exact cause of hypertension, however, is unknown in most patients.

Although a definitive cause of hypertension is usually not apparent, it is known that the heart and peripheral vasculature typically undergo structural changes (remodeling) that help sustain the elevated blood pressure and potentiate further increases in hypertension.[3-5] In particular, vascular remodeling that causes thickening of arteriolar walls and a decrease in the internal diameter of arterioles and capillarics seems to be especially harmful in patients with hypertension.[4-6] Likewise, hypertension is associated with certain metabolic abnormalities such as glucose intolerance and insulin resistance.[7-11] That is, people with hypertension may have metabolic problems similar to those seen in the early stages of type 11 diabetes mellitus, where glucose metabolism is impaired because of reduced sensitivity of peripheral tissues to insulin.[12] Patients with hypertension also are more prone to lipid abnormalities such as increased serum triglycerides and cholesterol, and the atherosclerotic effects of increased blood lipids also may be exaggerated in hypertension.[13,14]

Drugs that traditionally have been used to reduce blood pressure are being reexamined to determine whether these agents have additional properties that favorably influence vascular remodeling and the metabolic abnormalities associated with hypertension.[15,16] Likewise, drugs that merely reduce blood pressure but do not favorably affect the other features of hypertension may not be the most advantageous agents. The primary antihypertensive drugs categories are listed in Table 1, and the pharmacology of each category is addressed here.

[TABULAR DATA 1 OMITTED]

Angiotensin-Converting Enzyme Inhibitors

Development of drugs that inhibit angiotensin-converting enzyme (ACE) is among the most important advancements in the treatment of cardiovascular disease. Angiotensin-converting enzyme inhibitors were developed during the 1980s to control activity of the systemic renin-angiotensin system in hypertension. This system is characterized by the interaction between renin, an enzyme released from the kidney, and angiotensinogen, a peptide circulating in the blood stream.[17] A fall in blood pressure causes renin to be released from the kidneys, which catalyzes the conversion of angiotensinogen to angiotensin I. Angiotensin I is then converted to angiotensin II by ACE, which is located in the lungs and many other tissues. Angiotensin II is a very powerful vasoconstrictor that helps elevate blood pressure. Angiotensin II (or its by-product, angiotensin 111) also promotes aldosterone release from the adrenal cortex, thus adding to the antihypotensive effect by increasing sodium and water retention.

Angiotensin-converting enzyme inhibitors decrease vascular resistance by limiting excessive production of angiotensin II in the bloodstream. Their actual role in hypertension, however, is probably much more complex. There is, for example, a fully functioning reninangiotensin system located in many tissues in the body, including the brain, heart, and peripheral vascular tissues.[17,18] Angiotensin-converting enzyme inhibitors, therefore, affect local production of angiotensin II in these tissues as well as in the general circulation. Likewise, angiotensin II produces effects other than just vasoconstriction and stimulation of aidosterone release. In particular, angiotensin II stimulates growth and proliferation of vascular smooth muscle.[4,19,20] Thus, ACE inhibitors can influence vascular resistance directly by limiting the production of a powerful vasoconstrictor, and these drugs also can prevent structural changes caused by hypertrophy and hyperplasia of peripheral vascular tissues.[19,21]

Angiotensin-converting enzyme inhibitors are gaining popularity as antihypertensive medications. There is considerable evidence that these agents prevent or reverse structural changes in large and small vessels throughout the vascular system, thus leading to improved vascular compliance and distensibility.[3,5,18,19,22] Likewise, these drugs do not produce any unfavorable effects on lipid or glucose metabolism, and they do not seem to potentiate any of the common metabolic abnormalities associated with hypertension. Finally, these drugs are tolerated fairly well, with the primary problems being an allergic-type reaction (skin rash) and a persistent dry cough in some individuals.

Beta- and Alpha-Adrenergic Antagonists

Hypertension is associated with increased sympathetic stimulation of the heart and vasculature,[23,24] and use of drugs that antagonize or block the effects of sympathetic stimulation of these tissues is a logical approach for decreasing blood pressure. Beta-blockers that bind to beta-1 adrenergic receptors located on the myocardium help block the cardioacceleratory effects of endogenous catecholamines (norepinephrine, epinephrine). Alpha-blockers that bind to alpha-1 adrenergic receptors located on the smooth muscle of the peripheral vasculature help reduce catecholamine-induced vasoconstriction. Both types of drugs have been used extensively for treating hypertension, and both groups have additional properties that potentially can affect the long-term control of blood pressure.

Beta-blockers were first used in the early 1960s as anti-hypertensive drugs. Propranolol was the first clinically important beta-blocker, and other beta-blockers (Tab. 2) were introduced as antihypertensive agents over the past three decades. These drugs were originally developed as antihypertensive agents because of their ability to slow heart rate and decrease the force of myocardial contraction.[25] Beta-blockers also have a general ability to decrease sympathetic activity throughout the body; that is, their antihypertensive effects are not mediated exclusively by an inhibitory effect on the heart.[25]

Table 2.
Beta-adrenergic Blockers

                                                   Intrinsic
Generic         Trade           Beta               Sympathomimetic
Name            Name            Sensitivity(a)     Activity (ISA)

Acebutolol      Sectral         Beta-1             Mild-moderate
Atenolol        Tenormin        Beta-1             None
Betaxolol       Kerlone         Beta-1             None
Bisoprolol      Zebeta          Beta-1             None
Carteolol       Cartrol         Nonselective       Moderate
Labetclol       Normodyne,      Nonselective(b)    None
Trandate
Metc>prolol     Lopressor       Beta-1             None
Nado.101        Corgard         Nonselective       None
Penbutblol      Levatol         Nonselective       Moderate
Pindolol        Visken          Nonselective       High
Propranolol     Inderal         Nonselective       None
Sotalol         Betapace        Nonselective       None
Timolol         Blocadren       Nonselective       None

(a) Beta-1 selectivity tends decrease in higher dosages.
(b) Also has alpha-1 blocking ability.

There are approximately 13 beta-blockers that are commonly used as antihypertensive agents (Tab. 2). These drug, are distinguished from one another by various additional properties such as how well they bind to beta-1 receptors versus other beta-receptors (beta sensitivity) and whether they can produce low background levels of sympathetic stimulation while blocking excessive catecholamine effects (intrinsic Sympathomimetic activity).[26,27] certain beta-blockers such as labetolol have received a great deal of attention because these drugs have beta-blocking and alpha-blocking properties.[28,29] These drugs will decrease heart rate and contractivity beta-1 effect) while simultaneously decreasing peripheral vascular resistance (alpha-1 effect). The combined cardiac and peripheral vascular effects should act synergistically to produce an optimal antihypertensive effect.

The primary problem associated with beta-blockers is that these agents may produce excessive slowing of heart rate and contractility, resulting in depressed cardiac function. Beta-blockers, however, are generally well-tolerated, and serious adverse effects are infrequent. As a result, beta-blocker therapy has been one of the most common forms of antihypertensive drug treatment. Nonetheless, there has been some criticism of beta-blockers because these drugs do not appreciable affect vascular remodeling in hypertension. That is, beta-blockers do not seem to decrease hypertrophy in large vessels such as the aorta, and specific beta-blockers have shown inconsistent effects in their ability to reduce small-vessel hypertrophy.[5]

Concern also has been raised because certain beta-blockers may perpetuate some of the metabolic problems associated with hypertension. Beta-blockers that lack intrinsic sympathomimetic activity can cause adverse changes in blood lipid profiles, including increased serum triglycerides and decreased high-density lipoproteins.[9,10] Patients with hypertension who receive beta-blockers also tend to have elevated plasma insulin and glucose levels following a glucose load, suggesting that these drugs promote glucose intolerance and insulin resistance.[30] The reasons for these effects are not fully understood but are probably related to blockade of beta-adrenergic receptors located on fat cells, liver cells, and other tissues, thus causing disruption of catecholamine-mediated control of lipid and carbohydrate metabolism in these tissues. Likewise, certain beta-blockers such as the relatively nonselective drugs (see Tab. 2) seem to have a greater tendency to produce adverse metabolic changes as compared with cardioselective agents and beta-blockers with intrinsic sympathomimetic activity.

Beta-blockers produce favorable hemodynamic changes in the heart and peripheral vasculature that mediate a decrease in blood pressure. The routine, long-term use of these medications in patients with hypertension has been questioned, however, because these drugs do not seem to produce distinct improvements in peripheral vascular structure and because some of these drugs may actually potentiate the metabolic problems associated with hypertension. The use of beta-blockers in hypertension continues to be debated, and additional research will be needed to determine whether the beneficial effects of these drugs are outweighed by potential limitations such as increased metabolic abnormalities in certain patients.

Alpha-blockers were first used as antihypertensive agents in the 1970s. The use of these agents in treating hypertension, however, has been somewhat limited over the years because they tend to produce a fairly dramatic decrease in blood pressure that can cause side effects such as hypotension, orthostatic hypotension, and reflex tachycardia (ie, heart rate increases to compensate for the hypotensive effect). Thus, alpha-blockers often were reserved for more severe, advanced cases of hypertension.

Alpha-blockers could be beneficial on a wider basis because these drugs lower blood pressure while producing positive effects on glucose and lipid metabolism. Alpha-blockers seem to decrease insulin resistance and improve glucose tolerance as well as decrease serum triglycerides and produce other beneficial effects on serum lipid profiles.[31-34] It follows that these drugs may be a useful addition to the antihypertensive regimen for many patients, and it will be interesting to see whether alpha-blockers will be used more often in the future.

Calcium Channel Blockers

Calcium channel blockers limit the entry of calcium into vascular tissues, thus limiting contraction of vascular smooth muscle.35 These drugs were originally developed during the 1960s to prevent coronary artery constriction during vasospastic angina, but they gained widespread use as antihypertensive agents during the 1980s.36,37 Calcium channel blockers exert their antihypertensive effects primarily by decreasing calcium entry into peripheral vascular tissues, thus decreasing peripheral vascular constriction and resistance.[35,36]

Calcium channel blockers may prevent or resolve some of the cardiovascular remodeling associated with hypertension. Long-term (6 months) administration of calcium channel blockers may help reduce structural changes in the left ventricle as well as small resistance vessels.[38,39] These drugs seem to inhibit structural changes in the vasculature primarily through inhibition of vascular smooth-muscle cell proliferation and secondarily through inhibition of atherosclerotic plaque formation in the vascular cell wall.[40]

Calcium channel blockers have been used in an expanded role in treating various stages of hypertension, including cases of early or borderline hypertension. These drugs are associated with several side effects, including swelling in the feet and ankles, orthostatic hypotension, headache, and nausea.[41] These agents also can influence heart rate, and certain calcium channel blockers (verapamil, diltiazem) are used routinely to manage certain cardiac arrhythmias. Recently, however, investigators reported that certain patients taking short-acting calcium channel blockers for treatment of hypertension had a 60% greater risk of MI compared with patients taking other antihypertensive medications.[42,43] This finding has obviously caused concern about the use of these medications, and additional research is needed to clarify whether these medications should continue to be used in the treatment of hypertension.

Diuretics

Diuretics increase renal sodium and water excretion.44 These drugs have been a mainstay in the treatment of hypertension since the 1950s because they reduce the amount of fluid in the vascular system, thus reducing intravascular pressure. Diuretics are often used as the first drug (monotherapy) in early or mild stages of hypertension, and these drugs also can be combined with other antihypertensive agents if blood pressure continues to increase.[45] The primary adverse effects associated with these drugs are, predictably, fluid and electrolyte imbalances that are caused by excessive sodium, potassium, and water excretion.[46,47] Severe adverse reactions are relatively rare, however, and diuretics are often advocated because they are generally safe and well-tolerated in most patients.[48,49]

Diuretics continue to be used extensively as antihypertensive agents.[45] These drugs do not, however, have any appreciable effect on vascular compliance or distensibility.[5,50] More importantly, there is evidence that certain diuretics such as the thiazide and thiazide-like diuretics (Tab. 1) are associated with glucose intolerance and insulin resistance, and these drugs may increase serum triglyceride and cholesterol levels.[9,10,51,52] These drugs, therefore, do not make any additional contribution to resolving the vascular consequences of hypertension, and certain types of diuretics may exaggerate the metabolic problems associated with high blood pressure. There has been a growing trend to use other drugs such as the ACE inhibitors or calcium channel blockers as initial therapy instead of the diuretic drugs.

Effects of Antihypertensive Agents on Morbidity and Mortality

Traditional antihypertensive therapy using beta-blockers and diuretics is predicted to reduce the incidence of stroke by 33% to 50% and the incidence of MI and other events related to coronary heart disease by 4% to 22% in patients with mild to moderate hypertension.[53] This effect seems true for middle-aged people with hypertension, and these benefits may be even greater in elderly individuals with hypertension.[54,55]

The major controversy currently surrounding antihypertensive drug therapy is whether or not the newer types of antihypertensive drugs (ACE inhibitors, calcium channel blockers) can provide even greater benefits than traditional medications, especially with regard to coronary heart disease. The classic antihypertensive drugs (beta-blockers, diuretics) are very successful in reducing the incidence of stroke and other problems, but these drugs are not as successful in preventing coronary heart disease and MI related to high blood pressure.[56,57] Diuretics and beta-blockers often produce unfavorable effects on serum lipids and glucose metabolism.[56] Drugs such as the ACE inhibitors, calcium channel blockers, and alpha-adrenergic blockers may be superior because they reduce blood pressure without causing undesirable metabolic effects.

Over the last 10 years, there has been a clear reduction in the use of beta-blockers and diuretics, with a concomitant increase in the use of alternative agents such as ACE inhibitors and calcium channel blockers.[58,59] These trends have occurred despite a paucity of evidence that these expensive newer drugs actually produce more favorable effects on morbidity and mortality than do the less expensive drugs traditionally used to lower blood pressure. Several large clinical trials are currently in progress to compare conventional regimens that primarily use beta-blockers and diuretics with newer regimens that use ACE inhibitors, calcium channel blockers, and alpha-adrenergic blockers.

Congestive Heart Failure

Congestive heart failure (CHF) is characterized by a decrease in cardiac pumping ability that leads to inadequate tissue perfusion and accumulation of fluid (congestion) in the lungs and other organs.[61,61] Although the causes of this condition may vary from patient to patient, it appears that some type of injury to the myocardium often initiates a progressive decline in myocardial function.[61] As the heart fails, several compensatory neurohumoral mechanisms occur, including increased sympathetic nervous system activation and increased activation of the renin-angiotensin system.[62,63] Rather than helping alleviate heart failure, these compensatory changes may actually exacerbate myocardial dysfunction by increasing cardiac work load. The prognosis for patients with heart failure often is rather poor, with 5-year mortality rates estimated at 60% and 45% for men and women, respectively.[63]

Drug therapy for heart failure traditionally has focused on two primary goals: increasing cardiac pumping ability (positive inotropic effect) and decreasing cardiac work load by reducing vascular resistance or the amount of fluid in the vascular system.[64] More recently, emphasis has been placed on selecting drugs that also help resolve the neurohumoral compensations that contribute to the progression of myocardial dysfunction in heart failure. Attempts also have been made to use drugs or drug combinations that not only decrease the symptoms of CHF but actually decrease the rather high mortality rate associated with this disease.

Drugs Used to Improve Cardiac Pumping Ability in CHF

Digitalis glycosides. Digitalis glycosides such as digoxin (Lanoxin) and digitoxin (Crystodigin) have been used to treat heart failure for over 200 years, and these agents continue to be one of the most commonly prescribed medications in the United States.[65,66] These drugs increase cardiac pumping ability through a complex mechanism that ultimately results in increased intracellular calcium in myocardial cells.[67,68] Increased intracellular calcium improves the mechanical pumping ability of myocardial cells by facilitating increased interaction of contractile filaments. Digitalis drugs also exert electrophysiologic effects that slow heart rate and normalize autonomic influence on the heart by decreasing sympathetic influence and increasing parasympathetic activity.[69] This combination of digitalis' mechanical and electrophysiologic effects improves myocardial contractility and function, thus helping to improve the symptoms of heart failure.[70]

Despite their common use, these drugs have a relatively small margin of safety, and accumulation of digitalis in the body can lead to serious problems with digitalis toxicity.[71] Digitalis toxicity is characterized by symptoms such as fatigue, confusion, gastrointestinal problems, and cardiac arrhythmias.[71] Questions about the efficacy of digitalis also have been raised because the prognosis of patients with heart failure often remains poor even when these patients are treated with digitalis. Digitalis can decrease symptoms of heart failure and provide short-term improvements in cardiac function but does not seem to stop the progression of heart failure or decrease the high mortality rate.[65,70,72] As a result, considerable effort has been made to find other agents that are safer and more effective than digitalis. Alternatively, the combination of digitalis with other agents such as ACE inhibitors has been investigated as a means of providing optimal survival in patients with CHF.[70]

Other positive inotropic agents. Agents such as phosphodiesterase (PDE) inhibitors and dobutamine have been used on a limited basis in certain cases of CHF because these drugs produce an increase in cardiac pumping ability (positive inotropic effect).[73] Phosphodiesterase inhibitors such as amrinone (Inocor) and milrinone (Primacor) have been developed over the last 10 years.[74-76] These agents inhibit the PDE enzyme located in cardiac cells, thus allowing cyclic adenosine monophosphate (cAMP) to increase.[76] Increased cAMP facilitates calcium influx into the myocardial cells, and increased intracellular calcium facilitates myocardial contractility because of increased interaction of contractile filaments.[76] These medications also produce moderate levels of peripheral vasodilation, which enhances their beneficial effects by decreasing the amount of blood returning to the heart (cardiac preload) and by decreasing the pressure the heart must pump against (cardiac afterload).[75,76]

Phosphodiesterase inhibitors were developed as a possible alternative to digitalis drugs. There is no conclusive evidence, however, that these agents are more effective than digitalis drugs in the long-term management of CHF. More importantly, evidence exists that PDE inhibitors may actually have a greater risk of adverse effects, including an increased mortality rate, as compared with digitalis.[73,75] Currently, PDE inhibitors are administered intravenously for the short-term (<5 days) treatment of severe CHF,[74] but these drugs do not seem to play an important role in the long-term management of heart failure.

Dobutamine (Dobutrex) has traditionally been used for the short-term management of acute heart failure.[77,78] This drug increases myocardial contractility by directly stimulating beta-1 receptors on the heart.[79] Dobutamine also reduces cardiac afterload by blocking the effects of catecholamines on vascular alpha-1 receptors.[77] The combined effects of increased cardiac contractility and decreased cardiac afterload make this drug especially valuable in the short-term treatment of cardiac decompensation following heart surgery and MI.[77]

Use of dobutamine in the long-term management of CHF has been somewhat limited, however, because of side effects such as cardiac arrhythmias[80-81] and because patients often become tolerant to dobutamine during continuous administration of this agent.[77] Likewise, dobutamine must be administered by intravenous infusion, thus making routine use of this drug somewhat impractical for community-dwelling patients.[82] Portable infusion pumps, however, may enable certain patients to receive continuous dobutamine infusion at home for prolonged periods.[83,84] Problems with drug tolerance can be minimized by instituting dobutamine-free intervals on a periodic basis.[85] It does not appear that dobutamine therapy increases survival, but this drug may temporarily improve symptoms in some patients with advanced CHF who are refractory to more conventional forms of treatment.[86,87]

Beta-blockers. Beta-adrenergic blockers decrease catecholamine-induced stimulation of the myocardium, thereby decreasing heart rate and myocardial contraction. It may seem odd, therefore, that these drugs would be helpful in heart failure, a condition in which pumping ability is already compromised. Heart failure is characterized, however, by an increase in sympathetic stimulation of the myocardium through the local release of norepinepbrine from sympathetic nerve terminals and from circulating catecholamines from the adrenal medulla.[88,89] Excessive sympathetic stimulation results in a rapid but ineffective heart rate (tachycardia), which further compromises the pumping ability of the heart. Beta-blockers inhibit sympathetic stimulation of the myocardium, which improves ventricular function by prolonging diastolic filling time and promoting more complete emptying during systole.[88-90]

Beta-blockers are currently being considered a way of enhancing cardiac function in certain types of, heart failure. In particular, drugs that have combined beta-blocking and alpha-blocking effects (eg, labetolol; see Tab. 2) may be especially advantageous because these agents will help normalize cardiac sympathetic effects through beta-1 blockade and decrease cardiac preload and afterload through alpha-1 blockade.[88] Investigations currently in progress will help determine the optimal way that beta-blockers can be used with other medications and whether the addition of beta-blocker therapy will help decrease the morbidity and mortality commonly seen in patients with CHF.[89.90]

Drugs Used to Reduce Vascular Resistance or Fluid Volume in CHF

Diuretics. Diuretics increase sodium and water excretion, thus reducing the amount of fluid in the vascular system. This effect is beneficial in patients with heart failure because diuretics help reduce excess fluid that has accumulated in the lungs and other organs.[91] Diuretics seem especially helpful when combined with other agents such as digitalis or ACE inhibitors.[63] As a result, these agents have been used on a widespread basis for several decades to treat patients with heart failure, and these drugs will probably continue to play a principal role in the management of heart failure in the future.

ACE inhibitors. Angiotensin-converting enzyme inhibitors have been used increasingly to treat patients who have heart failure because the renin-angiotensin system is activated in heart failure, resulting in increased vascular resistance through the vasoconstrictive effects of angiotensin II and through the structural/remodeling effects induced by angiotensin II on vascular tissues. Increased vascular resistance increases the pressure that the heart must pump against (afterload), and this increase in cardiac afterload is extremely detrimental to the failing heart. Angiotensin-converting enzyme inhibitors block the synthesis of circulating levels of angiotensin II, thus decreasing vascular resistance and cardiac afterload. Some of the beneficial effects also are mediated through local inhibition of the renin-angiotensin system located directly within the myocardium and vascular walls.[92]

Angiotensin-converting enzyme inhibitors improve cardiac function and decrease the symptoms associated with CHF, especially poor exercise tolerance.[93,94] These drugs also may produce more long-term improvement in cardiac function than traditional CHF medications (diuretics, digitalis), and there is considerable evidence that ACE inhibitors substantially reduce the morbidity and mortality associated with this disease.[95] The effects of ACE inhibitors on morbidity and mortality in people with CHF is addressed later in this article.

Other vasodilators. Various vasodilating drugs have been used to decrease vascular resistance and cardiac preload and afterload in patients with CHF. These agents typically cause relaxation of vascular tissues by directly inhibiting smooth-muscle contraction (eg, hydralazine, minoxidil, organic nitrates) or by decreasing sympathetic stimulation of the peripheral vasculature (eg, prazosin).[96,97] Regardless of the drug mechanism, reduction in vascular resistance helps decrease the work load on the failing heart.

Various vasodilators have been introduced over the past 30 years that have been helpful for patients with CHF. These vasodilators typically have been used in combination with other drugs such as digoxin and diuretics.[96,97] Continued use of these vasodilators may diminish somewhat in the future, however, because ACE inhibitors seem to provide more effective and longer-lasting control of peripheral resistance in patients with CHF.[98]

Effects of Pharmacotherapy on Morbidity and Mortality in CHF

Conventional treatment of CHF with drugs such as digitalis, diuretics, and vasodilators may produce short-term benefits that help decrease the symptoms of this disease, but there is little evidence that these drugs delay the progression of heart failure and reduce the risk of death from CHF.[99] In contrast, ACE inhibitors apparently provide more long-term improvement in cardiac function and help decrease morbidity and mortality of patients with CHF.[100-102] Meta-analysis of recent clinical trials of patients with CHF indicated that total mortality was reduced by 28% and that the combined incidence of death and hospitalization was reduced by 31% when ACE inhibitors were administered instead of a placebo.[95]

As a result, there is an indication that pharmacologic treatment may help improve the prognosis of patients with CHF. Current treatment of many patients consists of ACE inhibitors used alone or in combination with other more conventional drugs (diuretics, digitalis, other vasodilators). Nonetheless, the mortality rate continues to be rather high for people with CHF, and additional research is needed to determine the optimal use of ACE inhibitors and other drugs in treating specific types of CHF.[103]

Myocardial Ischemia and infarction

Problems related to myocardial ischemia and infarction remain the leading cause of death in the United States and other industrialized nations.[60] Factors contributing to myocardial ischemia are complex, but ischemia is caused primarily by coronary artery atherosclerosis that decreases the ability of the coronary arteries to supply adequate oxygen to meet the demands of the myocardium.[60] An imbalance between myocardial oxygen supply and demand causes the characteristic symptoms of pain associated with angina pectoris. Progressive atherosclerosis also leads to the development of coronary artery thrombosis, resulting in vessel occlusion and MI.[60,104] Drug therapy for ischemic heart disease has focused on resolving an acute imbalance between myocardial oxygen supply and myocardial oxygen demand; that is, drugs are often used to treat the symptoms of ischemic heart disease (angina pectoris) and restore myocardial oxygen balance before additional damage occurs to the heart. More recently, however, attention also has been directed toward preventing ischemia and infarction by controlling the factors that lead to coronary occlusion or by resolving thrombus formation in the coronary arteries.

Drugs Used to Treat Symptoms of Ischemia: Antianginal Medicotions

Nitrates. Organic nitrates such as nitroglycerin have been used since the mid-1800s to prevent or decrease symptoms of angina pectoris. Nitrates are potent vasodilators because they are metabolized in vascular tissues to form nitrous oxide, a powerful inhibitor of vascular smooth-muscle contraction.[105-107] It was originally held that nitrates decrease anginal symptoms by increasing coronary artery dilation, thus increasing myocardial blood flow and oxygen supply. It is now understood, however, that these agents decrease angina primarily by increasing peripheral venous dilation, thus reducing cardiac preload, and, to a lesser extent, by increasing arterial dilation, thus decreasing cardiac afterload.[105] Nitrates, therefore, act primarily as peripheral vasodilators, decreasing myocardial oxygen demand and reducing or relieving anginal symptoms.[105]

Nitrate tablets are traditionally administered sublingually at the onset of an anginal episode to resolve symptoms. Sublingual administration allows the drug to be absorbed rapidly into the systemic circulation without first being metabolized and destroyed in the liver, as would occur if these drugs were taken orally and absorbed from the gastrointestinal tract (a phenomenon known as the first-pass effect).[108] An alternative method of nitrate administration is through transdermal patches. Patch administration provides a slow, steady infusion of the drug into the systemic circulation, and this type of drug delivery seems to prevent the onset of angina better than conventional sublingual tablets.

Many anginal episodes are asymptomatic or "silent" and can only be detected through electrocardiographic monitoring. [109-111] Patch administration may help control episodes of silent ischemia that would not be treated through sublingual administration because the person would be unaware that an anginal episode was occurring.

The primary side effects of nitrates are due to the drugs' vasodilating properties. Headache, dizziness, and orthostatic hypotension are fairly common, especially immediately after administration of a sublingual dose.[41] Tolerance, or a decrease in drug effectiveness, also may develop during continuous nitrate use, especially when transdermal patches are used to deliver these drugs on a daily basis.106 Nitrate tolerance can be prevented, however, by instituting daily nitrate-free periods when the patch is not worn. A person can wear the patch, for example, for 12 hours and take the patch off for 12 hours.[106,112,113] The daily period when the patch is worn should correspond to the part of the day when each person experiences the majority of anginal episodes, thus providing optimal benefits while still instituting nitrate-free intervals to prevent tolerance.

Calcium channel blockers. Calcium channel blockers were developed in the 1960s to treat angina pectoris, and the number of calcium channel blockers and their use for angina as well as for other conditions (hypertension, arrhythmias) has grown over the past 30 years. The primary role of calcium channel blockers in ischemic heart disease is to increase coronary artery dilation and provide increased perfusion and oxygen delivery,114 which reduces symptoms of effort (classic angina) as well as angina caused by coronary artery vasospasm (Prinzmetal's ischemia).[114,115] Calcium channel blocker drugs cause coronary vasodilation by limiting calcium entry into coronary artery smooth-muscle cells and by limiting calcium release from intracellular storage sites.[114,116] Decreased cytosolic calcium in the vascular smooth-muscle cells results in less interaction of contractile filaments, thus promoting vascular relaxation and dilation.

Selection of a particular agent for treatment of angina depends on each patient's symptoms and concomitant problems (common calcium channel blockers are listed in Tab. 1). Agents such as diltiazem and verapamil, for example, also have antiarrhythmic effects, and some of their beneficial effects in preventing ischemia and infarction are undoubtedly related to their ability to stabilize heart rate in certain individuals.116 Calcium channel blockers may cause side effects such as peripheral edema (ankle swelling), and there may be serious concerns about the fact that these drugs may actually increase the risk of infarction in some patients. In particular, moderate to high doses of the short-acting form of nifedipine have been associated with a significant increase in the risk of mortality in patients with coronary heart disease.[42] Research is under way to determine the reason for this increased risk and to determine whether other calcium channel blockers pose similar risks to patients who have coronary heart disease.

Beta-blockers. The effectiveness of beta-blockers in treating patients who have ischemic heart disease was realized soon after these drugs were introduced as antihypertensive agents.[117] These drugs have been used for more than 20 years to decrease cardiac work load and oxygen demand, thus preventing symptoms of angina pectoris in certain individuals. Likewise, beta-blockers have antiarrhythmogenic effects, and some of their benefits in myocardial ischemia are related to their ability to stabilize heart rate and prevent some of the more serious types of rhythm disturbances.[118]

Perhaps one of the most important effects of betablockers is their ability to help prevent reinfarction following MI. These drugs apparently reduce cardiac work load and prevent postinfarction arrhythmias, thus allowing the damaged heart to recover more completely.[119-122] Use of beta-blockers and other agents (thrombolytic drugs, aspirin) should enable patients to survive infarction as well as limit cardiac damage, thus allowing them to begin earlier and more aggressive cardiac rehabilitation programs.

Drugs Used to Prevent or Resolve Coronary Thrombosis and Infarction

Thrombolytic agents. Perhaps the most exciting pharmacologic advancement for treating acute MI has been the development of thrombolytic drugs. These agents are relatively new, having appeared on the market only within the last 5 to 10 years. Thrombolytic drugs facilitate the breakdown of clots that have already formed in the coronary arteries, thus reestablishing myocardial perfusion and oxygenation.[123] This effect can limit infarct size and help restore function'to the myocardium, thus reducing mortality and improving recovery in patients who have sustained an acute infarction.[124-126] Thrombolytic agents originally were thought to be effective only if administered directly into the blocked coronary artery via cardiac catheterization.[127] These drugs can be administered intravenously into the systemic circulation, where they will activate specific clotdissolution factors that eventually act at the site of thrombosis (ie, the coronary artery).[124] There also seems to be a fairly large window of opportunity (3-6 hours) for administering these agents following the onset of infarction.[125,128] It is undoubtedly best, however, to begin thrombolytic treatment as soon as possible following the onset of symptoms.[129-131]

Thrombolytic agents that are currently used to treat acute MI are listed in Table 3. These agents initiate clot breakdown by directly or indirectly converting plasminogen (profibrinolysin) to plasmin (fibrinolysin).[123] There has been considerable debate about which type of thrombolytic agent is safest and most effective.[132] Tissue plasminogen activator (T-PA), a substance that is identical to the body's endogenous thrombolytic activating agent, is said by some to be more effective in reopening occluded vessels and may produce less systemic inhibition of the clotting mechanism.[123,133,134] Other studies[135,136] have not shown a clear advantage of T-PA over less expensive agents such as streptokinase. Additional research is needed to clarify whether one type of thrombolytic agent is superior in terms of safety and cost-effectiveness in acute MI.

Table 3.
Thrombolytic Agents

Generic            Trade
Name               Name       Mechanism of Action

Anistreplase(a)   Eminase    Consists of a streptokinase-plasminogen
                             complex that
                             binds to fibrin, where it is
                            activated, allowing
                            streptokinase to convert
                            plasminogen to plasmin and
                            begin fibrinolysis
Streptokinase  Kabikinase,  Binds to plasminogen and
                Streptase   facilitates ability of
                            endogenous factors to
                            convert plasminogen to
                            plasmin
Tissue-type    Activase    Identical to endogenous T-PA;
  plasminogen              directly converts
  activator                plasminogen to plasmin to
  (t-PA)(b)                initiate clot breakdown
Urokinase    Abbokinase   Directly converts plasminogen
                          to plasmin

(a) Also known as anisoylated plasminogen-streptokinase activator
complex
(APSAC).
(b) Also known as Alteplase or recombinant T-PA (rt-PA).

The primary drawback of using thrombolytic drugs to reopen occluded coronary arteries is that hemorrhage may occur elsewhere in the vascular system. Problems such as hemorrhagic stroke have been noted following thrombolytic treatment.[137,138] To reduce the incidence of adverse effects, criteria have been developed to limit the use of thrombolytic agents.[139] These drugs are contraindicated, for example, in patients with a history of hemorrhagic stroke, active internal bleeding, or similar cardiovascular risks.[139-141] Emphasis also has been placed on using additional drugs (aspirin, anticoagulants, beta-blockers) to prevent reinfarction and to facilitate recovery of the myocardium after thrombolytic treatment.[142-143] Nonetheless, thrombolytic therapy continues to gain acceptance, and these drugs will certainly continue to play a valuable role in decreasing, morbidity and mortality following infarction.[144]

Aspirin. Several large clinical trials published between 1988 and 1991 indicated that low doses of aspirin may be effective in reducing the incidence of a first MI or reducing the incidence of a second infarction following a nonfatal MI.[145-147] This information resulted in the widespread use of aspirin in many patients with ischemic heart disease. Aspirin inhibits platelet-induced coronary thrombosis by inhibiting the biosynthesis of prostaglandins. Certain prostaglandins known as the thromboxanes are potent stimulators of platelet activity,[148] and platelet aggregation is often responsible for causing thrombosis in the coronary arteries, especially if these arteries have already been partially obstructed by atherosclerotic lesions.[104] Aspirin inhibits thromboxane-induced platelet aggregation, thus decreasing the risk of coronary thrombosis and MI.

Aspirin also is helpful in preventing reinfarction during and after administration of thrombolytic drugs.[149] In particular, aspirin combined with anticoagulant drugs (eg, heparin, warfarin) can prevent coronary artery reocclusion following thrombolysis by T-PA, streptokinase, and similar drugs,[150,151] thus further reducing mortality following MI.[149] Use of aspirin often is continued for prolonged periods (several months) or even indefinitely to help ensure coronary artery patency after infarction and thrombolysis.

Perhaps the most remarkable fact about aspirin is that very low dosages, typically 75 to 100 mg each day, are needed to obtain an antithrombotic effect.[152] Thus, rather substantial benefits can be obtained using this inexpensive drug at dosages that do not typically cause the side effects (gastrointestinal irritation and ulceration) that are commonly noted when higher dosages of aspirin are used to treat pain and inflammation. There is some concern, however, that long-term aspirin use, even at these low dosages, may eventually cause toxicity and may increase the risk of hemorrhage, especially hemorrhagic stroke.[128] As a result, chronic aspirin administration continues to be studied to determine the long-term effects of this intervention in preventing primary infarction or reinfarction.

Anticoagulants. The primary anticoagulant drugs are heparin and warfarin. Heparin must be given parenterally (intravenously or subcutaneously) to inhibit the effects of thrombin-induced clot formation.[153] Warfarin (Coumadin, Panwarfin) can be administered orally to inhibit the liver's ability to synthesize certain clotting factors, thus slowing down the rate at which clots can be formed.[154] These two drugs have been used routinely for more than 40 years in a variety of clinical situations where excessive clot formation can lead to thromboembolic disease (eg, after surgery or during prolonged bed rest).

The primary roles of anticoagulants in patients with MI is to help prevent initial infarction in high-risk patients and to prevent reinfarction following an initial MI.[155,156] Warfarin and heparin often are combined with aspirin to provide maximal protection against coronary occlusion or reocclusion.[150] There is consensus that use of an anticoagulant (heparin or warfarin) combined with an antiplatelet drug (aspirin) provides greater benefit than either type of drug given separately.[123] This fact makes sense considering that each type of drug affects different aspects of the clotting mechanism, thus providing a synergistic and additive effect.

Predictably, the primary concern with anticoagulant use is the risk of hemorrhage.[153,157] This risk can be minimized; however, by using fairly low dosages of each type of agent and by routinely monitoring blood coagulation levels to ensure that hemostasis is not excessively inhibited.[151]

Lipid-lowering drug therapy. Lipid-lowering agents have been used for more than 30 years to help improve serum lipid profiles and decrease coronary atherosclerosis, the primary underlying factor in coronary artery disease (CAD).[104,158] Various forms of hyperlipidemias and dyslipidemias contribute to atherosclerotic plaque formation in the coronary arteries, thus causing narrowing of the coronary artery lumen and subsequent thrombosis.[159] Some serum lipid abnormalities that are associated with CAD include high triglyceride levels, high total cholesterol levels, increased low-density lipoprotein (LDL)-cholesterol levels, reduced high-density lipoprotein (HDL)-cholesterol levels, or various combinations of these and other abnormalities.[159-161] Lipid-lowering drug therapy may be helpful in many patients to help provide optimal control over abnormal lipid profiles, especially when nonpharmacologic interventions (diet, exercise) are unsuccessful.[162]

Five primary types of lipid-lowering agents are commonly used to control CAD (Tab. 4).[163] These drugs work by somewhat different mechanisms to decrease the formation of cholesterol, triglycerides, or the lipoproteins associated with atherosclerosis (Tab. 4). Selection of a drug, therefore, is based on the lipid disorder, and combinations of several different lipid-lowering agents may be helpful in some patients.[159,162]

Table 4.
Lipid-lowering Agents

                                    Mechanism and Primary
Categary     Examples               Effects
HMG-CoA       Lovastatin (Mevacor)  Inhibit cholesterol
  reductase   Pravastatin           biosynthesis; decrease
  inhibitors   (Provachol)          serum low-density
              Simvastotin (Zocor)  lipoprotein (LDL)-cholesterol
                                   levels; may also decrease
                                   triglycerides and increase
                                   high-density lipoprotein
                                   levels
Fibric acid   Clofibrate (Abitrate,  Mechanism not completely
  derivatives   Atromid-S)           understood; may increase
              Gemfibrozil (Lopid)   LDL breakdown; may help
                                   decrease serum LDL-cholesterol
                                   and triglyceride
                                  levels
Bile acid       Cholestraymine   Increases fecal excretion of
  sequestrants   (Cholybor,      bile acid, thus increasing
                   Questran)     the use of serum
                                 cholesterol to replace bile
                                acids; decreases serum
                                LDL-cholesterol levels
Nicotinic acid                  Inhibits synthesis of
  (Niacin,                       precursors for LDL;
  Niacor,                        decreases serum
  Nicobid,                       cholesterol and triglyceride
  others)                        levels
Probucol                         Increases LDL breakdown;
  (Lorelco)                      decreases serum
                                 cholesterol and may also
                                 decrease deposition of
                                 lipid onto arterial wall

Despite their widespread use, there has been some conflicting evidence about whether lipid-lowering drugs actually decrease CAD-related morbidity and mortality in all patients with lipid abnormalities. These drugs are beneficial in men who have abnormal lipid-profiles and a history of CAD as well as in men with abnormal lipids who have not yet developed overt CAD.[158,164] The benefits of these agents seem less apparent in other groups (women, elderly individuals), especially if there are lipid abnormalities but CAD is not clinically evident.[158] Thus, lipid-lowering drugs play a critical role in helping to decrease the incidence of CAD-related problems, but these drugs may not be equally effective in all types of patients.

Another type of agent that may help prevent lipid-related problems in women is estrogen. Studies performed in the 1980s indicated that estrogen replacement can reduce the risk of cardiovascular incidents in women following menopause, including a reduced incidence of MI.[165-167] The benefits of estrogen seem limited to women who are postmenopausal because estrogen may actually increase the incidence of cardiovascular problems in men and in women before menopause.[168,169] Estrogen appears to improve serum lipid profiles in women after menopause by decreasing LDL levels and increasing HDL levels.[170] In addition, transdermal estrogen patches have been developed to provide a convenient method for continuous, prolonged estrogen delivery.[171] As a result, estrogen replacement has gained acceptance over the last 5 years as a method for preventing, lipid disorders and reducing CAD in women following menopause.

Effects of Pharmacotherapy on Morbidity and Mortality in Myocardial Ischemia and Infarction

In contrast to drugs that merely decrease symptoms of angina (nitrates), agents that prevent or resolve coronary thrombosis may help reduce illness and death associated with coronary heart disease. In particular, early administration of thrombolytic agents following acute MI is associated with reduced mortality.[172] Two large clinical trials that compared thrombolytic treatment using streptokinase with no thrombolytic treatment demonstrated that in-hospital mortality was reduced by 15%173 and 23%.[174] Results of subsequent studies suggested that these benefits were even greater when acute thrombolytic treatment (streptokinase, T-PA) was combined with other agents such as aspirin and heparin.[126,135,136,174]

Mortality and morbidity also are substantially reduced when certain drugs are administered for prolonged periods to prevent reinfarction following MI. Angiotensin-converting enzyme inhibitors, for example, may be helpful in patients who survive MI but have decreased left ventricular function.[175,176] The risk of developing a recurrent MI was reduced by 25% and the risk of death from recurrent MI was reduced by 32% when the ACE inhibitor captopril was administered instead of a placebo. 175 Similarly, administration of ramipril (another ACE inhibitor) versus a placebo resulted in a 27% reduction in the risk of death in a population of high-risk patients who had sustained an infarction.[176]

Drugs such as aspirin, beta-blockers, anticoagulants, and lipid-lowering agents also can be administered to reduce morbidity and mortality postinfarction or to prevent infarction in specific high-risk patients. As a result, in studies that are currently in progress, attempts are being made to compare various combinations of these agents to determine which drugs are most effective in preventing infarction or reinfarction.

Clinical implications

Cardiovascular medications affect cardiovascular adaptations to an acute bout of exercise and to exercise training.[177] For example, cardiovascular responses to exercise are attenuated somewhat in patients who are taking beta-blockers because these drugs limit the increase in heart rate and myocardial contractility that typically occurs as exercise work load increases. Some patients, however, may actually have an improved ability to exercise because cardiovascular medications help control symptoms that limit an exercised about. The patient who is limited by symptoms of angina pectoris or CHF, for example, may actually have an improved ability to exercise if these symptoms are controlled by the appropriate medications. In this article, it is not possible to review all the potential ways that cardiovascular drugs can influence exercise responses, and this topic has been addressed elsewhere.[177,178] Therapists should be aware, however, that these drugs often have profound effects that can affect both short-term and long-term responses to exercise.

Many of the side effects of cardiovascular drugs also can have an effect on physical therapy. Medications that cause peripheral vasodilation often can produce hypotension, dizziness, and syncope, especially if these medications are combined with physical therapy interventions that also produce extensive peripheral vasodilation. For example, systemic heat (large whirlpool, Hubbard tank, therapeutic pool) or aerobic exercise can produce vasodilation that exaggerates the effect of the vasodilating drugs, thus producing a profound decrease in vascular resistance and blood pressure. Procedures that increase systemic vasodilation should be used very cautiously in patients who are taking any antihypertensive medication or any other medication that produces systemic vasodilation.

Clinicians should recognize that they can play a critical role in implementing various nonpharmacologic interventions that act synergistically with pharmacotherapy to provide optimal management of cardiovascular disease.[179,180] Exercise, proper diet, weight loss, and other lifestyle modifications are essential in decreasing the risk of almost all types of cardiovascular disease.[181-183] These nonpharmacologic interventions also can decrease the need for specific medications, thus decreasing the risk of drug-related side effects.[184] Physical therapists can implement exercise programs as well as educate patients for the need to adjust their lifestyle to obtain the best results and possibly even decrease the need for long-term administration of cardiovascular medications.

Summary

Cardiovascular drugs continue to be a mainstay in the treatment of cardiovascular disease. There is no question that these drugs are critical in improving cardiac function and decreasing the effects of conditions such as hypertension, CHF, and myocardial ischemia/infarction. Increased emphasis, however, has been placed on determining the most effective use of traditional medications in these cardiovascular problems. In many cases, standard drug therapy has been challenged somewhat by newer drugs or new uses of existing medications that seem to provide better outcomes in terms of disease progression and survival.

Physical therapists should be aware that many patients will be taking cardiovascular medications and that these drugs can have a favorable impact on the patients' ability to participate in virtually all aspects of the rehabilitation program. Likewise, these drugs have side effects that may adversely affect a patient's response to specific physical therapy interventions. Finally, therapists should be aware that the use of cardiovascular drugs is constantly being reexamined to assess optimal drug use and effectiveness. Strategies for preventing and treating cardiovascular disease will undoubtedly continue to be an area of interest and research for some time.

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