Many medications are designed to control specific aspects of cardiovascular function so that the risk of cardiac and related diseases is reduced. Controlling blood pressure, for example, can reduce the risk of myocardial infarction, cerebrovascular accident, kidney disease, and so forth. In some cases, drug therapy can be initiated to prevent the first episode of a cardiovascular incident (primary prevention), or drug therapy can be used to prevent the reoccurrence of a specific problem (secondary prevention). Four primary pharmacological strategies that can be used to reduce cardiovascular risks include controlling high blood pressure (antihypertensives), decreasing plasma lipids (antihyperlipidemia drugs), treatment of overactive blood clotting (anticlotting agents), and cessation of cigarette smoking. These drug categories are described here.
Controlling high blood pressure (hypertension) is perhaps one of the most important ways to reduce the risk of cardiovascular disease. Hypertension, defined as a sustained and reproducible increase in blood pressure, typically leads to a number of problems including heart disease, stroke, and renal failure.5 The exact cause of hypertension is often unclear in the majority of people with high blood pressure. Many people become hypertensive because of the combined influence of several physiological and lifestyle factors such as increased body weight, poor diet, cigarette smoking, lack of stress management, physical inactivity, and so forth. Although resolution of these factors may successfully reduce blood pressure, drug therapy remains the most common way to control hypertension.
Antihypertensive drugs are organized into several major categories, and these categories are listed in Table 8-1. Each major category exerts an effect at a specific organ or tissue as indicated in Fig. 8-1. Details about the antihypertensive effects and potential problems of these drugs are presented here.
Table 8-1 Antihypertensive Medications ||Download (.pdf)
Table 8-1 Antihypertensive Medications
Presynaptic adrenergic inhibitors
Other direct-acting vasodilators
Drugs affecting the renin–angiotensin system
Angiotensin-converting enzyme (ACE) inhibitors
Angiotensin II receptor blockers
Calcium channel blockers
Adalat, Procardia, others
Cardizem, Dilacor, others
Calan, Verelan, others
Sites of action of the major antihypertensive drug categories.
Diuretics act on the kidneys to increase the excretion of sodium and water.6 The loss of sodium and water will reduce the total amount of fluid in the vascular system, thereby reducing blood pressure by decreasing excess fluid within the peripheral vasculature. Diuretics also reduce cardiac workload by decreasing the amount of fluid the heart must pump, and this effect is helpful in decreasing hypertensive heart disease and in treating certain forms of heart failure.
Many diuretics are currently available, and these drugs are classified according to their chemistry or mechanism and site of action (see Table 8-1). Specifically, thiazide diuretics are chemically similar to one another, loop diuretics are so named because they act on the loop of Henle in the nephron, and potassium-sparing diuretics increase the excretion of sodium and water without a concomitant increase in potassium excretion. Selection of a specific diuretic is based on the needs of each patient, with factors such as the patient's medical condition, age, and use of other medications influencing the choice of each diuretic.
Diuretics are remarkably safe when taken as directed. Problems may occur, however, if the patient overdoses and excretes too much water and electrolytes (sodium and potassium) from the body.7,8 Patients may become confused, dizzy, and unreasonably fatigued because the fluid and electrolyte balance in the body is disturbed. Potassium supplementation is frequently provided to patients on diuretic therapy in order to maintain potassium levels and thus prevent undue fatigue. Patients may likewise experience similar problems if they take the correct diuretic dosage but severely restrict their fluid intake. Consequently, physical therapists should watch for any change in the patient's behavior or physical ability that might indicate a problem in diuretic use.
As indicated earlier, hypertension typically results from the interaction of several physiological and lifestyle factors. These factors, however, seem to conspire and exert their effect on the cardiovascular system by activating the sympathetic nervous system.9 This idea makes sense when one considers that increased sympathetic activity will invariably increase blood pressure by stimulating cardiac output and increasing peripheral vascular resistance. Sympatholytic drugs are so named because they act at various sites in the sympathetic nervous system and attempt to break up or produce a “lytic” effect on sympathetic drive to the heart and vasculature. The primary sympatholytic drug strategies are described here.
β-Blockers decrease sympathetic stimulation of the heart and decrease cardiac output with a subsequent decrease in blood pressure.10 Specifically, these drugs occupy the type 1 beta-adrenergic (β1) receptor located on the heart and thereby prevent other chemicals such as the catecholamines (epinephrine and norepinephrine) from stimulating these receptors. Through their ability to occupy or “block” β1-receptors, β-blockers reduce cardiac stimulation and help normalize blood pressure. These drugs are useful under other conditions marked by excessive sympathetic cardiac stimulation, and β-blockers are also indicated in certain types of angina pectoris, cardiac arrhythmias, heart failure, and in helping the heart recover function after a myocardial infarction.11
Some commonly used β-blockers are listed in Table 8-1. Although all these drugs have the ability to block β1-receptors in the heart, specific β-blockers have additional properties that may make them more or less suitable for use in individual patients. Certain agents, for example, are known as cardioselective because they are fairly specific for β1-receptors located in the heart (see Table 8-1). Other β-blockers are nonselective because they affect cardiac β1-receptors as well as β2-receptors located on bronchiole smooth muscle and other tissues. Various other properties and side effects of each drug are also taken into account when selecting a specific drug for each patient.
Although β-blockers are generally tolerated well by most patients, these drugs can cause certain side effects that impact physical therapy interventions. By virtue of their ability to reduce cardiac stimulation, these drugs may reduce heart rate during exercise. β-Blockers, for example, should reduce maximal heart rate by approximately 20 to 30 beats per minute (bpm). This effect could potentially limit maximal exercise capacity, but this effect is probably not substantial at the submaximal exercise workloads that are typically used in physical therapy interventions. Certain patients may, in fact, be able to exercise more effectively at submaximal workloads because β-blockers help control other symptoms (angina, arrhythmias) that limit exercise in these patients.
Bronchoconstriction may also occur in certain patients if they have some type of bronchoconstrictive lung disease (asthma, chronic obstructive pulmonary disease [COPD]) and they are also taking a nonselective β-blocker that affects the lungs as well as the heart. This situation is typically resolved by switching the patient to a β1-specific (cardioselective) drug that also does not affect β2-receptors on the lungs. As with many antihypertensives, β-blockers may cause orthostatic hypotension, which is characterized as an excessive fall in blood pressure when the patient sits or stands up too rapidly. Older individuals may not tolerate β-blockers as well as younger individuals because these drugs tend to cause confusion, depression, and other behavioral changes in the elderly.
Finally, there is some controversy about how β-blockers can be used most effectively in treating hypertension.12 Although these drugs have often been used in the initial stages of treatment, recent studies suggest that these drugs might not be the best method for treating early, uncomplicated hypertension. It likewise appears that other agents such as diuretics (as already discussed) and ACE inhibitors (see later) might be a better first choice for treating hypertension because these drugs might prevent cardiac events (stroke, coronary artery disease) more effectively than β-blockers.11,13 Future research should help clarify how β-blockers and other drugs can be used most effectively in the treatment of high blood pressure.
In addition to β-blockers, several other drug strategies are available that decrease sympathetic activity at other locations within the sympathetic nervous system (see Table 8-1). α-Blockers, for example, bind to the α1-adrenergic receptor located on vascular smooth muscle and prevent catecholamines from reaching these α1-receptors and causing vasoconstriction.14 Decreased vasoconstriction will reduce peripheral vascular resistance with a concomitant decrease in blood pressure. Another strategy for reducing peripheral vascular resistance is to decrease the release of norepinephrine from the presynaptic sympathetic nerve terminals that normally supply vascular smooth muscle. These drugs, known as presynaptic adrenergic inhibitors, will lower vascular resistance and decrease blood pressure because the sympathetic neurons cannot release as much neurotransmitter on the vascular smooth muscle. Finally, a small group of drugs is classified as centrally acting sympatholytics because they directly affect sympathetic nervous system activity in the brain stem. Specifically, these drugs either stimulate α2-adrenergic receptors or stimulate specific imidazoline receptors located in the vasomotor area located in the pons and medulla.15 By acting on these brainstem receptors, these drugs reduce sympathetic discharge to the heart and peripheral vasculature, and this effect should reduce blood pressure and produce an antihypertensive effect.
Sympatholytics, which were described previously, are listed in Table 8-1. These drugs share some side effects including a tendency for hypotension and orthostatic hypotension. That is, these drugs may be too effective in reducing sympathetic activity, and patients may have abnormally low blood pressure at rest or when moving suddenly to a sitting or standing position. Another problem commonly associated with these sympatholytics is reflex tachycardia. Drugs such as the α-blockers and presynaptic adrenergic inhibitors typically cause a substantial decrease in peripheral vascular resistance thereby producing a beneficial antihypertensive effect. The body, however, will sense this reduction in blood pressure and use various mechanisms including the baroreceptor reflex to increase heart rate (reflex tachycardia) to bring blood pressure back to the original hypertensive levels. Hence, reflex tachycardia is a misguided attempt on the part of the body to maintain blood pressure at high levels, even though this increased blood pressure is not normal. Clearly, reflex tachycardia is an indication that the normal control of blood pressure has been disrupted and the mechanisms that regulate blood pressure have been reset to maintain blood pressure at higher levels in people who are hypertensive.
Nonetheless, reflex tachycardia can often be controlled nicely by combining a β-blocker with the sympatholytic agent that caused this problem. In addition to controlling reflex tachycardia, the combination of a β-blocker and α-blocker or presynaptic adrenergic inhibitor often provides synergistic antihypertensive effects by reducing sympathetic drive to the heart and peripheral vasculature, respectively.
Certain sympatholytics (α-blockers, presynaptic adrenergic inhibitors) and other drugs (ACE inhibitors, calcium channel blockers; see later) cause vasodilation. There is, however, a select group of drugs classified specifically as vasodilators because these drugs have a direct effect on the vascular endothelium or vascular smooth muscle. Organic nitrates such as nitroglycerin, for example, are converted to nitric oxide within the vascular wall, where they inhibit smooth muscle contraction and allow the vessel to dilate. Other agents such as hydralazine and minoxidil increase the intracellular production of cyclic adenosine monophosphate (cAMP), which serves as a chemical messenger that causes vascular relaxation and vasodilation. Vasodilators are quite effective in reducing peripheral vascular resistance, and they are often called on to help control more severe or resistant forms of hypertension.16,17
Vasodilators can cause several side effects that are related to their ability to decrease peripheral vascular resistance. Reflex tachycardia can occur for the same reasons stated earlier; that is, a sudden or profound fall in peripheral vascular resistance will activate the baroreflex and cause an increase in heart rate in an attempt to return blood pressure to the original, albeit hypertensive, levels. Orthostatic hypotension and dizziness may also occur, because the peripheral vasculature is maintained in a relaxed and dilated state and is less able to cope with changes in posture. Patients may complain of headaches because of vasodilation in meningeal vessels, and peripheral edema (swollen ankles and so forth) may occur because vasodilation increases the pressure gradient that forces fluid out of the capillaries and into the extravascular (interstitial) space.
Drugs Affecting the Renin–Angiotensin System
The renin–angiotensin system (see Fig. 8-2) helps maintain blood pressure and regulate vascular perfusion throughout the body.18,19 If, for example, blood pressure suddenly decreases and remains at hypotensive levels for more than a few seconds, the kidneys sense this change and release an enzyme called renin. Renin converts angiotensinogen (a small protein) into angiotensin I. Angiotensin I is inactive until it contacts an enzyme known as ACE. The ACE is located in the lungs and other tissues, and this enzyme converts angiotensin I into a very powerful vasoconstrictor, angiotensin II. By increasing vascular resistance, angiotensin II elevates blood pressure back to reasonable levels, thus averting hypotensive problems including shock. Angiotensin II also stimulates the release of aldosterone, and aldosterone helps maintain vascular fluid volume by increasing renal sodium and water reabsorption.
The renin–angiotensin system and effects of angiotensin II. Angiotensin-converting enzyme inhibitors interrupt this system by blocking the conversion of angiotensin I to angiotensin II, and angiotensin II receptor blockers prevent angiotensin II from stimulating vascular tissues.
The renin–angiotensin system is, therefore, a normal physiologic process that helps maintain blood pressure. Many people with hypertension, however, have elevated renin levels, even though blood pressure is already too high. The normal function of the renin–angiotensin system has obviously been disturbed in these individuals, resulting in production of a powerful vasoconstrictor (angiotensin II) that leads to additional increases in blood pressure that perpetuate hypertension in these people. In addition to producing vasoconstriction, prolonged increases in angiotensin II also stimulate hypertrophy and remodeling of the vasculature (see Fig. 8-2) so that the vascular wall becomes less compliant and begins to encroach on the lumen and reduce blood flow through the vessel. These changes, both the acute vasoconstriction and the more chronic and permanent effects on vascular wall hypertrophy, are devastating to cardiovascular function because they produce dramatic increases in blood pressure and workload on the heart. Drugs that help reduce activity in the renin–angiotensin system are therefore critical in decreasing the risks associated with elevated renin activity.
A primary strategy for reducing activity in the renin–angiotensin system is to administer drugs known as ACE inhibitors.20 By inhibiting the enzyme that converts angiotensin I to angiotensin II, these drugs reduce the vasoconstriction and vascular hypertrophy associated with angiotensin II. ACE inhibitors are, therefore, helpful in controlling high blood pressure, especially in individuals who have increased activity in the renin–angiotensin system. These drugs are also beneficial in certain forms of heart failure because they reduce the stress and workload on the myocardium that is caused by increased production of angiotensin II.
Table 8-1 lists some common ACE inhibitors. As indicated in the table, ACE inhibitors are usually identified by generic names that end with a “-pril” suffix (captopril, enalapril, and so forth). Regarding side effects, these drugs are relatively safe and well tolerated in most individuals. Some people may experience an allergic reaction, but this reaction is usually not severe. Other people may develop some annoying side effects, including nausea, dizziness, and a dry, persistent cough.
ACE inhibitors were the first drug strategy developed for reducing activity in the renin–angiotensin system. More recently, a second option has become available, where drugs can be administered that bind to and occupy the angiotensin II receptor located on cardiovascular tissues, thereby preventing angiotensin II from reaching these tissues and causing vasoconstriction and other detrimental effects. These newer drugs, known as angiotensin II receptor blockers, can also be used to control cardiovascular damage associated with increased production of angiotensin II. Angiotensin II receptor blockers appear to be at least as effective as ACE inhibitors, but the angiotensin II receptor blockers tend to have fewer side effects and they do not produce the dry cough commonly associated with ACE inhibitors. Hence, several angiotensin II receptor blockers, such as losartan and eprosartan, are currently available (see Table 8-1), and these drugs offer an alternative for people who cannot tolerate the more traditional ACE inhibitors. Likewise, recent studies suggest that some patients with kidney disease might benefit from a combination of an angiotensin II receptor blocker and an ACE inhibitor.21 Methods for controlling the renin–angiotensin system in hypertension and other forms of cardiovascular disease continue to be investigated, and future research will clarify how ACE inhibitors and angiotensin II receptor blockers can be used most effectively in clinical situations.
Calcium channel blockers decrease the entry of calcium into cardiovascular tissues.22 As is the case with all contractile tissues, calcium ions are the key intracellular mediators that influence the interaction between thick (myosin) and thin (actin) contractile filaments within these tissues. In vascular smooth muscle, an increase in intracellular calcium typically results in a stronger interaction between these contractile filaments, thereby increasing the strength of smooth muscle contraction and the amount of vasoconstriction in the vessel. Calcium channel blockers restrict the entry of calcium ions into vascular tissues by inhibiting the opening of specific protein channels located on the smooth muscle cell membrane. These drugs, therefore, reduce the strength of vascular smooth muscle contraction and help reduce high blood pressure by promoting vasodilation in the peripheral vasculature.22 Calcium is also important in regulating cardiac rhythm, and some calcium channel blockers can be used to control certain types of arrhythmias that are caused by abnormal calcium stimulation within the heart (see later).
Calcium channel blockers are listed in Table 8-1. These agents can be subclassified according to their chemical structure, with several drugs being grouped together as dihydropyridine agents because they share a common chemical background. Because of their vasodilating properties, these drugs may cause dizziness, orthostatic hypotension, and peripheral edema (swollen ankles), and so forth. Because of their effects on calcium entry in the heart, these drugs may also affect cardiac rhythm and may increase the risk of arrhythmia in certain patients. There was likewise concern that some calcium channel blockers such as the short-acting form of nifedipine may actually increase the risk of heart attack in older individuals, and that these drugs might exacerbate certain problems such as kidney disease and diabetes mellitus.23,24 Nonetheless, calcium channel blockers are a mainstay in the treatment of hypertension and other cardiovascular diseases, and careful use of these drugs can produce beneficial effects with minimal risk in many patients.
Control of Hyperlipidemia
A significant risk factor in cardiovascular disease is the unfavorable accumulation of cholesterol and other lipids in the bloodstream.25 Elevated plasma lipids (hyperlipidemia) and certain lipid–protein complexes such as the low-density lipoproteins (LDL) are associated with an increased risk of cardiovascular disease. Hyperlipidemia causes accumulation of fatty deposits within the arterial walls, thus leading to atherosclerosis and various other cardiovascular pathologies (thrombosis, infarction, and so forth). Proper diet and exercise are critical in improving the plasma lipid profile in people with lipid disorders. In addition, several drug strategies are available that can help control the quantity and type of lipids present in the bloodstream. These strategies are listed in Table 8-2, and they are discussed briefly here.
Table 8-2 Drugs Used to Control Hyperlipidemia ||Download (.pdf)
Table 8-2 Drugs Used to Control Hyperlipidemia
Primary Effect(s) on Plasma Lipids
Lovastatin (Mevacor, others)
Reduce total cholesterol and LDL cholesterol levels; may also produce a modest decrease in triglycerides and a slight increase in HDL levels
Fenofibrate (TriCor, Triglide, others)
Decrease triglyceride levels; gemfibrozil may also decrease VLDL levels and increase HDL concentrations
Bile acid sequestrants
Cholestyramine (Questran, others)
Reduce total cholesterol and LDL concentrations by adhering to bile acids in GI tract (liver uses excess cholesterol to synthesize more bile)
Niacin (Niacor, Niaspan, others)
Decreases total cholesterol and triglyceride concentrations
Reduces total cholesterol by inhibiting cholesterol absorption from GI tract
The term statin describes a group of drugs that inhibit a key enzyme responsible for cholesterol biosynthesis.26,27 Specifically, these drugs inhibit the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase that catalyzes one of the early steps in cholesterol synthesis in the liver and other cells. Statins are, therefore, also known as HMG-CoA reductase inhibitors, and these drugs can directly inhibit hepatic cholesterol production and reduce total cholesterol levels in the bloodstream. Statins also decrease plasma LDL cholesterol levels by increasing the production of receptors on liver cells that degrade LDLs, and they inhibit the production of LDL precursors such as very low-density lipoproteins (VLDLs), thus further decreasing plasma LDL cholesterol levels. These drugs may produce other favorable changes in the plasma lipid profile including decreased triglyceride levels and increased high-density lipoprotein (HDL) levels, although the exact reasons for these effects are not clear.27 Statins may likewise have direct beneficial effects on the vascular endothelium, and they can help reduce atherosclerotic plaque formation, presumably by inhibiting specific enzymes and metabolic pathways that lead to atherosclerosis within the vascular wall.28 These drugs, therefore, produce multiple beneficial effects on lipid and vascular function, and statins have become one of the primary methods for controlling hyperlipidemia in patients at risk for cardiovascular disease.
Statins consist of atorvastatin (Lipitor), rosuvastatin (Crestor), simvastatin (Zocor), and several similar drugs (see Table 8-2). These drugs are typically used in people who have not been successful in controlling plasma lipid levels by using just diet and exercise interventions, or in any individuals who are at high risk for developing coronary artery disease.26,29 Administration of statins may substantially decrease the risk of heart attack, and the magnitude of this benefit seems to be related directly to the extent that cholesterol and other lipid abnormalities can be reduced.26 The most common side effects associated with these drugs are gastrointestinal problems, such as stomach pain, nausea, diarrhea, gas, and heartburn.
Although less common, some patients may also experience muscle pain, cramps, and severe weakness and fatigue.30,31 These symptoms may indicate myositis that can lead to severe breakdown and destruction of skeletal muscle (rhabdomyolysis). Statin-induced rhabdomyolysis is a serious problem that can cause renal failure as the kidneys try to excrete myoglobin and other muscle constituents that have been released into the bloodstream during muscle breakdown. In addition to statin-induced myopathy, peripheral neuropathies may occur in some patients.30 Physical therapists should therefore be alert for any unexplained increase in muscle pain and weakness or neuropathic symptoms (numbness, tingling) in patients receiving statin drugs. Therapists should alert the medical staff so that drug therapy can be changed before these neuromuscular problems become severe or life-threatening.
Other Antihyperlipidemia Drugs
Other drugs used to treat hyperlipidemia include fibric acids such as clofibrate and gemfibrozil (Lopid) (Table 8-2). These drugs can decrease total plasma triglyceride and VLDL levels, probably by increasing the activity of the lipoprotein lipase enzyme that metabolizes triglycerides in the liver and other tissues.32 Several agents including cholestyramine (Questran) act as bile acid sequestrants, meaning that these drugs gather up and retain bile acids in the GI tract. This action increases the elimination of bile acids from the body, thereby forcing the liver to divert cholesterol to form more bile acids and decreasing the amount of cholesterol available for causing lipid disorders.33 Niacin (nicotinic acid, Niacor, Niaspan, others) can also be used to reduce plasma LDL levels because this drug inhibits VLDL synthesis, thus decreasing the production of the primary LDL precursor.34 Finally, agents such as ezetimibe (Zetia) inhibit the absorption of cholesterol from the GI tract, thereby limiting the total amount of cholesterol available from dietary sources.35
These antihyperlipidemia drugs are associated with various side effects. In particular, many of these drugs cause gastrointestinal problems including nausea, stomach pain, gas, and diarrhea. Other side effects may occur depending on the particular agent, therapeutic dosage, and length of time the drugs are administered. Nonetheless, these agents can be used alone or combined with one another or statin drugs to improve the plasma lipid profile of people with hyperlipidemia. Proper drug management used in conjunction with diet and exercise will hopefully reduce the risk of cardiovascular disease in people with lipid disorders.
Treatment of Overactive Blood Clotting
Adequate blood clotting or hemostasis is essential for maintaining normal cardiovascular function. If the blood clots too rapidly, a thrombus can form in the arterial or venous system and disrupt or block blood flow through the occluded vessel.36 This occlusion can be especially harmful if it occurs in the coronary artery or carotid artery because it leads to myocardial or cerebral infarction, respectively. There is likewise the risk that a piece of the thrombus can break off and form an embolism that subsequently lodges elsewhere in the vascular system. For example, a thrombus that forms in the large veins in the legs can dislodge and travel to the lungs where it creates a pulmonary embolism.
Consequently, drugs are often administered to reduce the risk of various clotting problems in people with evidence of excessive blood clotting.36 These drugs typically work by affecting one or more of the clotting factors illustrated in Fig. 8-3. These drugs are likewise categorized as anticoagulant, antithrombotic, and thrombolytic agents depending on how they affect the clotting activity. The three drug categories are summarized in Table 8-3, and they are addressed here.
Mechanism of blood coagulation. Factors involved in clot formation are shown above the dashed line; factors involved in clot breakdown are shown below the dashed line. See text for details about how specific drugs can modify these clotting mechanisms. (Ciccone CD. Pharmacology in Rehabilitation. 4th ed. Philadelphia, PA: FA Davis; 2007:348, with permission.)
Table 8-3 Drugs Used to Treat Overactive Clotting ||Download (.pdf)
Table 8-3 Drugs Used to Treat Overactive Clotting
Primary Effect and Indication
Inhibit synthesis and function of clotting factors; used primarily to prevent and treat venous thromboembolism
Unfractionated heparin (generic)
Warfarin (Coumadin, Jantoven)
Direct thrombin inhibitors
Factor Xa inhibitor
Inhibit platelet aggregation and platelet-induced clotting; used primarily to prevent arterial thrombus formation
Other platelet aggregation inhibitors
Facilitate clot dissolution; used to reopen occluded vessels in arterial and venous thrombosis
Anticoagulants are used primarily to reduce excessive clot formation in the large veins in the legs (venous thrombosis). These drugs act on specific clotting factors to normalize hemostasis and prevent venous thrombosis or reduce the risk of further thrombosis in people who have already had an episode of thromboembolic disease. Anticoagulants consist of two primary types of drugs: heparin and oral anticoagulants.
Heparin enters the bloodstream and inhibits the activity of several key clotting factors, including thrombin (Fig. 8-3). This inhibition actually occurs because heparin accelerates the reaction between thrombin and another circulating protein known as antithrombin III.37 As its name implies, antithrombin III binds to thrombin and decreases the ability of thrombin to convert fibrinogen to fibrin. Fibrin normally forms the sticky protein strands that comprise the basic structure of the clot (see Fig. 8-3). Heparin, therefore, acts indirectly via an effect on thrombin to ultimately reduce the formation of one of the components that creates a clot (fibrin), thereby reducing the risk of thrombosis.
The anticoagulant effects of heparin occur rapidly; that is, this drug begins to affect thrombin, fibrin, and so forth, as soon as it enters the bloodstream. Unfortunately, heparin is absorbed poorly from the upper gastrointestinal tract, and this drug must, therefore, be administered by parenteral (nonoral) routes. The traditional form of heparin, known as unfractionated heparin, is typically administered by repeated intravenous infusion. More recently, a subtype of heparin has been extracted from the unfractionated form of this drug. These newer forms are known as low-molecular-weight heparins (LMWHs) to distinguish them chemically from the more general or unfractionated forms of heparin.38 Some common LMWHs include enoxaparin (Lovenox), dalteparin (Fragmin), and similar drugs with generic names that end with the “-parin” suffix. LMWHs also offer some distinct advantages over the unfractionated forms, including the ability to administer the LMWHs by subcutaneous injection, much in the same way that insulin is administered to treat diabetes mellitus. Other advantages of LMWHs over unfractionated heparin include a more predictable response, fewer side effects, and less need to perform laboratory monitoring of clotting time.38,39
Heparin treatment is, therefore, helpful in the initial treatment of venous thrombosis because of its rapid effects. The emergence of the LMWHs has also substantially improved the convenience and safety of these drugs in helping control venous thromboembolic disease. The development of LMWHs has also expanded the use of this form of anticoagulant therapy, and LMWHs are now being considered for the treatment of other forms of thrombosis including acute myocardial infarction and ischemic stroke.40,41 Still, heparin therapy, including use of LMWHs, is associated with some potentially serious side effects including an increased risk of bleeding in various tissues throughout the body. In certain patients, heparin and LMWHs can also activate the immune system to form antibodies that cause increased platelet aggregation (thrombocytopenia) that results in a paradoxical increase in blood coagulation. This condition, known commonly as heparin-induced thrombocytopenia (HIT), can be severe and life-threatening because of widespread platelet-induced clotting in various blood vessels.42
This group of anticoagulants consists of warfarin (Coumadin), dicumarol, and similar agents (Table 8-3). These drugs act on the liver to inhibit the production of certain clotting factors. Specifically, these drugs inhibit the regeneration of vitamin K in the liver.43,44 Vitamin K normally helps to catalyze the hepatic production of certain clotting factors (eg, clotting factors VII, IX, and X; see Fig. 8-3). By limiting the amount of vitamin K that is available in the liver, oral anticoagulants (also known as vitamin K antagonists) delay the production of these clotting factors, thereby decreasing the ability of the blood to clot.
As their name implies, these drugs can be administered orally. There is, however, a time lag of 3 to 5 days before these drugs exert their therapeutic effects and reduce hemostasis to normal levels.43 This time lag occurs because these drugs gradually reduce the hepatic production of clotting factors while the body metabolizes the clotting factors that are already in the bloodstream. Several days are needed to reach a balance between reduced clotting factor production in the liver and the appearance of lower and more reasonable amounts of these clotting factors in the circulation.
Hence, oral anticoagulants are often used sequentially with heparin. At the onset of a thrombosis, heparin therapy is initiated to cause a rapid effect and normalization of clotting time. Traditional treatment protocols then called for a change from heparin to oral anticoagulants within 2 to 3 days, with heparin being discontinued after 4 to 5 days.45 This sequence allowed the rapid effects of heparin to overlap with the more gradual effects of the oral anticoagulants. With the advent of LMWHs, however, some patients are now remaining on the LMWH heparin for much longer periods (12 days or more) before being switched to oral anticoagulants such as warfarin. Regardless of when the patient is switched to the oral anticoagulant, many patients must remain on the oral anticoagulant for several weeks to several months depending on the specific needs of each patient.45
As is the case with all anticlotting drugs, the primary problem associated with oral anticoagulants is the increased risk of bleeding and hemorrhage in various tissues and organs.43 This risk is obviously increased if patients are taking these drugs in high doses for extended periods of time. Overdose can likewise cause serious or even fatal bleeding. Physical therapists should, therefore, be aware of any symptoms or discomfort that might indicate hemorrhage in patients taking these drugs. A patient, for example, with sudden or unexplained joint pain may be experiencing intrajoint hemorrhage. Therapists should alert the medical staff about any increase in symptoms that might be associated with increased hemorrhage in patients taking oral anticoagulants or any anticlotting drug.
Several other strategies have been developed to prevent excessive clotting that leads to venous thrombosis (see Table 8-3).46 These strategies include drugs that directly inhibit thrombin activity, such as lepirudin (Refludan), bivalirudin (Angiomax), and argatroban. Drugs have also been developed that inhibit other specific clotting factors, including fondaparinux (Arixtra), which inhibits the active form of clotting factor 10 (factor Xa). Efforts continue to develop other agents that can serve as alternatives to traditional anticoagulants such as heparin and warfarin.
Antithrombotics are characterized by their ability to decrease platelet activity and reduce clots formed by platelet aggregation.36,47 These platelet-induced clots often occur in arteries including the coronary arteries and carotid arteries. Antithrombotic drugs are, therefore, useful in preventing myocardial infarction, ischemic stroke, and other problems associated with arterial thrombus formation. These drugs essentially work by inhibiting the ability of specific endogenous chemicals to stimulate platelets (see Fig. 8-3), thereby preventing abnormal platelet activation. The primary antithrombotic strategies are described here.
Aspirin is well known for its analgesic, antiinflammatory, and antifever effects. Over the past several years, the realization that aspirin can also produce therapeutic antithrombotic effects has led to some exciting and innovative treatment for myocardial infarction.48 Aspirin exerts all of its therapeutic effects by inhibiting the production of prostaglandins. Specifically, aspirin inhibits the cyclooxygenase enzyme that is responsible for producing prostaglandins in various cells throughout the body. Prostaglandins are small lipid compounds that help regulate cell activity during normal function and when cells are injured or diseased. Certain prostaglandins, known as thromboxanes, are particularly important in regulating platelet activity. Thromboxanes that are produced by the cyclooxygenase enzyme cause platelets to change their shape and begin to stick together (aggregate) at the site where a clot is forming. By inhibiting the production of thromboxanes, aspirin can reduce this platelet activity and prevent excessive or abnormal platelet-induced clotting (Fig. 8-4).49
Effects of antithrombotic agents on platelet activation. Platelets are normally activated by endogenous chemicals such as the thromboxanes, adenosine diphosphate (ADP), and fibrinogen. Specific drugs (indicated in brackets) limit the production or block the effects of these chemicals on the platelet, thereby reducing platelet-induced clotting.
Aspirin can, therefore, be considered an “antiplatelet” drug that is useful in preventing heart attacks. Aspirin can also be used to help prevent other platelet-induced thrombi, including certain forms of ischemic stroke.47 Use of aspirin in stroke remains somewhat controversial, however, and aspirin must be used very cautiously in treating stroke because of the risk of increased intracranial bleeding. Aspirin can likewise be used to help prevent deep vein thrombosis, to prevent occlusion of arterial grafts (including coronary bypass surgery), and to decrease the risk of thrombogenesis following valve replacement and similar cardiac procedures.
What is also remarkable is that substantial antithrombotic effects can be achieved using very low doses of aspirin. Many antithrombotic regimens use aspirin doses of 1 adult aspirin tablet (325 mg) or even 1 pediatric tablet (81 mg) per day.50,51 At these doses, the side effects commonly associated with aspirin, including gastric irritation and liver/kidney toxicity, are minimal. As indicated earlier, all drugs that reduce clotting may increase the risk of hemorrhage, and the risk of intracranial hemorrhage and other types of bleeding must be considered in each patient receiving aspirin therapy. Nonetheless, aspirin therapy has become a well-accepted method for preventing an initial episode of myocardial infarction, and aspirin is often an essential part of the treatment of secondary prevention in people who have already had a heart attack or certain people with ischemic stroke.
Other Antithrombotic Agents
Although aspirin is commonly used to decrease platelet-induced clotting, this drug is only a weak inhibitor of platelet activity. Hence, other strategies have been explored to provide more powerful antiplatelet effects. One alternative is to use drugs that block the effects of adenosine diphosphate (ADP) on the platelet52 (Fig. 8-4). Like thromboxanes, ADP also stimulates platelet activity and causes the platelet to aggregate and form a thrombus. Certain drugs such as clopidogrel (Plavix) and ticlopidine (Ticlid) occupy and block the ADP receptor located on the platelet, thereby preventing ADP from activating the platelet and causing aggregation and thrombogenesis. Another option is to use drugs known as glycoprotein (GP) IIb/IIIa inhibitors.53 These drugs inhibit the effects of other platelet-stimulating substances such as fibrinogen (Fig. 8-4). Fibrinogen normally activates the platelet by binding to the GP IIb/IIIa receptor, but drugs such as abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat) block this receptor and prevent fibrinogen from increasing platelet aggregation.
These newer antiplatelet drugs, therefore, offer some alternatives to aspirin therapy. Once again, the primary problem associated with these drugs is the increased risk of hemorrhage, especially with the GP IIb/IIIa inhibitors. The ADP inhibitors seem to be safer in terms of less chance of bleeding, but clopidogrel can cause pain in the chest and elsewhere throughout the body, and ticlopidine may cause skin rashes and gastrointestinal disturbances.
Drugs such as the anticoagulants (heparin, Coumadin) and antithrombotics (aspirin, others) can help normalize blood clotting and prevent further thrombogenesis. These drugs, however, do not appreciably affect clots that have already formed. A third category of drugs known as thrombolytics is so named because they activate clot breakdown (thrombolysis) and reestablish blood flow through the occluded vessel.54 If administered in a timely manner, thrombolytics can reopen the vessel, restore blood flow to the tissue supplied by that vessel, and prevent tissue death.
Commonly used thrombolytics include streptokinase (Streptase), urokinase (Kinlytic), and several similar agents (Table 8-3). Although these drugs differ from one another in their exact mechanism of action, they all increase the conversion of plasminogen to plasmin in the bloodstream.55 Plasmin (also known as fibrinolysin) is the activated form of the enzyme that initiates fibrin degradation and clot breakdown (Fig. 8-3). Thrombolytic drugs, therefore, stimulate the body's endogenous mechanism for destroying clots and help maintain blood flow through any vessels that have become occluded by a thrombus.
Thrombolytic drugs have been used primarily to reopen occluded coronary vessels in people who are in the process of developing a myocardial infarction.56 When administered intravenously, these drugs activate plasmin throughout the systemic circulation. Plasmin travels throughout the systemic circulation until it arrives at the occluded coronary vessel and lyses the thrombus, thereby restoring blood flow to the myocardium and salvaging the function of the cardiac tissue. Although thrombolytic drugs can provide benefits if administered up to 12 hours after the onset of symptoms, optimal effects are realized if these drugs are administered as soon as possible after coronary thrombosis.57
Thrombolytic agents, therefore, represent one of the most important advances in the treatment of acute myocardial infarction, and proper use of these drugs has helped to increase the survival and outcome of many people who would have otherwise succumbed to a heart attack. These drugs may also provide benefits in other types of acute infarction including severe deep venous thrombosis and pulmonary embolism. Thrombolytics may likewise be considered as an option in treating ischemic stroke.58 By lysing cerebral thrombi, these drugs have the potential to restore blood flow to the brain and attenuate the damage that occurs in ischemic stroke. Thrombolytics must, however, be used very cautiously in treating stroke because of the increased risk of intracranial bleeding, and these drugs should be administered only after diagnostic tests (eg, computerd tomography) have conclusively ruled out the possibility of cerebral hemorrhage. There is likewise a much smaller window of opportunity for administering these drugs during ischemic stroke, and they must typically be administered within 3 hours to decrease neurological deficits and improve outcomes in people with ischemic stroke.58
The primary drawback of thrombolytic therapy is the increased risk of bleeding and hemorrhage.59 These drugs activate clot breakdown throughout the systemic circulation in a rather nonselective manner. As a result, the ability to generate and sustain beneficial clots in the vasculature can also be impaired leading to hemorrhage in the brain, abdominal cavity, joints, and so forth. This chance of hemorrhage is increased in certain high-risk patients, including older individuals, people with severe or untreated hypertension, and people with a history of hemorrhagic stroke or other bleeding disorders. Thrombolytic drugs should, therefore, be used cautiously in situations where the benefit of restoring blood flow through an occluded vessel far outweighs the risk of hemorrhage elsewhere in the vascular system.
Cigarette smoking is one of the primary risk factors for developing cardiovascular disease and pulmonary problems such as emphysema and lung cancer. Strategies to quit smoking are, therefore, an essential component in the prevention and risk reduction for cardiopulmonary disorders. Three primary drug strategies addressed here are nicotine replacement therapy, bupropion, and varenicline.
Nicotine Replacement Therapy
The primary pharmacological intervention used to help people quit smoking is nicotine replacement.60 Cigarettes are essentially a method for delivering nicotine, and smokers typically become hooked on cigarettes because of nicotine's strong addictive potential. Alternative methods for delivering nicotine have therefore been developed. Nicotine can be administered via patches, gum, tablets/lozenges, inhalers, or nasal sprays.60 Nicotine patches have received a great deal of publicity, because this method of administration is convenient and provides a slow, steady influx of nicotine to help diminish the craving for this drug. A series of patches can also be used as part of a plan to wean the person from nicotine, with the dose of nicotine in these patches being progressively diminished over the course of several weeks.
Nicotine replacement therapies can increase the likelihood that a person can successfully quit smoking by approximately 50% to 75%.60 The success of nicotine replacement therapy can also be enhanced when combined with other nonpharmacological interventions including social support and counseling that provides strategies to resist or avoid the cues that initiate the desire for a cigarette.60
Problems associated with nicotine patches or gum include nausea and mild headache. Because nicotine stimulates catecholamine release, nicotine replacement may be contraindicated in people with certain types of cardiovascular disease including severe angina pectoris, life-threatening arrhythmias, recent myocardial infarction, or recent cerebrovascular accident. Nicotine patches may likewise cause skin irritation and may be contraindicated in people with sensitive skin or dermatological disease.
Bupropion (Zyban) is another pharmacological strategy used to help people quit smoking.61 This drug was developed originally as an antidepressant but is also marketed as a method for smoking cessation. Exactly how bupropion helps people quit smoking is not clear, but this drug may decrease nicotine cravings by potentiating the effects of dopamine and norepinephrine in the brain.62 Bupropion acts on specific CNS synapses in the limbic system that release dopamine and norepinephrine. This drug inhibits the reuptake of these neurotransmitters after they are released from the presynaptic terminal, thus potentiating their effects on the postsynaptic neuron. Nicotine and other addictive substances may mediate some of their effects through increased dopamine release in the limbic system, and bupropion may, therefore, help substitute for the nicotine effects by increasing dopamine influence in the brain. By also increasing norepinephrine influence in the brain, bupropion may help diminish the severity of nicotine withdrawal.62
When used as an antismoking agent, bupropion is typically administered at a dose of 300 mg/d for 7 to 12 weeks. This dosage regimen is generally well tolerated, with the most common side effects being insomnia and dry mouth, although seizures can occur in rare cases.61 As is the case with nicotine replacement therapy, the success of bupropion is enhanced when this drug is combined with nonpharmacological interventions such as counseling and social support. Still, bupropion is only partially successful in long-term smoking cessation, with only 23% of people using this drug remaining cigarette-free 1 year after quitting smoking.63 The success rate of people who took bupropion, however, was approximately twice that of people who took a placebo.63 The rather poor success rates of bupropion and other interventions such as nicotine replacement therapy underscore a basic fact: Nicotine is highly addictive, and it is often very difficult to quit smoking after developing a habit for cigarettes.
Varenicline (Chantix) is a relatively new non-nicotine drug developed to help people quit smoking. This drug binds to nicotine receptors in the brain, thereby preventing nicotine from stimulating these receptors.64 This drug, however, is classified as a nicotine receptor partial agonist, which means that it blocks the receptor from nicotine supplied by cigarettes while still providing some stimulation of the receptor. Low-level stimulation of the nicotine receptor will hopefully reduce nicotine cravings and prevent the smoker from going into withdrawal.64 This drug can, therefore, be substituted for cigarettes and then slowly withdrawn as other interventions (counseling and support) are implemented.
Varenicline can increase the success rate of quitting cigarettes when compared to a placebo or other pharmacological interventions such as bupropion.65 Some possible side effects include headache, drowsiness, GI problems (nausea, gas, constipation), and disturbed sleeping. This drug, however, is generally tolerated well by most people at the dosages used to quit smoking.65 Varenicline is, therefore, an alternative treatment for patients who cannot tolerate other pharmacological treatments (nicotine replacement, bupropion), or when other interventions have not been successful in maintaining abstinence from cigarettes.