Charles D. Ciccone
INTRODUCTION
Medications play an integral role in the treatment of patients with cardiovascular and pulmonary disorders. Drugs can be used to prevent or treat various pathologies and impairments in the heart, lungs, and circulation, and thereby reduce the functional limitations and disability associated with cardiopulmonary disease. Medications can likewise have a synergistic effect with physical therapy interventions. Drugs, for example, that improve cardiac pumping ability, may enable patients to participate more effectively in interventions that improve aerobic capacity and endurance. All medications likewise produce side effects that can have a direct impact on physical therapy interventions. For instance, drugs that lower blood pressure (antihypertensives) may produce dizziness and incoordination if they cause excessive hypotension. It, therefore, makes sense that physical therapists have a basic understanding of the common cardiovascular and pulmonary medications and how these medications can affect patients receiving physical therapy.
In this chapter, pharmacologic agents are grouped according to the preferred practice patterns listed in Chapter 6 of the Guide to Physical Therapist Practice, 2nd edition (revised).1 For each preferred practice pattern, medications that specifically address cardiovascular or pulmonary problems will be discussed as they relate to that practice pattern. It is, of course, not possible to describe all medications that might be related to each pattern. For example, medications used to control infection, treat cancer, and so forth, may help improve the patient’s overall health, thereby helping the patient participate in aerobic conditioning, respiratory exercises, and other activities that will ultimately lead to better cardiovascular and pulmonary function. This chapter, however, will focus only on the medications that directly affect the heart, circulation, or lungs and describe how these medications relate to the physical therapy interventions described in the preferred practice patterns. This chapter will likewise present an overview of these medications, their side effects, and the potential impact of these medications on patients receiving physical therapy. For more information about specific drugs, the reader is also encouraged to consult one of the resources listed at the end of this chapter.2–4
MEDICATIONS RELATED TO PREFERRED PRACTICE PATTERN A: PRIMARY PREVENTION/RISK REDUCTION FOR CARDIOVASCULAR/PULMONARY DISORDERS
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.
Antihypertensive Medications
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.
FIGURE 8-1 Sites of action of the major antihypertensive drug categories.
TABLE 8-1 Antihypertensive Medications
Diuretics
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.
Sympatholytic Agents
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—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.
Other sympatholytics—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.
Vasodilators
Certain sympatholytics (a-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.
FIGURE 8-2 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.
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 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
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
Statins
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.
FIGURE 8-3 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
Anticoagulants
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—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
Oral anticoagulants—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.
Other anticoagulants—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
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. Antithrom botic 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—Aspirin is well known for its analgesic, anti-inflammatory, 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
FIGURE 8-4 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.
Thrombolytics
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.
Smoking Cessation Drugs
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 non-pharmacological 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
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
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.
MEDICATIONS RELATED TO PREFERRED PRACTICE PATTERN B: IMPAIRED AEROBIC CAPACITY/ENDURANCE ASSOCIATED WITH DECONDITIONING
Many medications can help increase endurance and reduce deconditioning by treating systemic disorders. Pharmacologic treatment of conditions such as cancer, acquired immune deficiency syndrome (AIDS), and various musculoskeletal and neuromuscular disorders can enable patients to participate in endurance conditioning and other activities that help maintain and improve function and overall health. It is, however, beyond the scope of this chapter to discuss all of the medications that are directly used to treat these noncardiopulmonary conditions. There are likewise several groups of medications that are used to directly treat cardiopulmonary disorders, thereby helping improve endurance and aerobic capacity. These medications are described in other sections of this chapter that are related more closely to the preferred practice patterns used to treat specific cardiovascular and pulmonary problems (cardiovascular pump dysfunction, airway clearance dysfunction, and so forth). Hence, please refer to the other sections of this chapter for cardiopulmonary medications that have more direct effects on the cardiovascular and respiratory systems, and can, therefore, have a secondary effect on improving endurance and aerobic capacity in various systemic disorders.
There are, nonetheless, some systemic disorders that are associated closely with the cardiopulmonary systems and where the drug treatment of these disorders is directly implicated in maintaining proper cardiovascular and respiratory function. Two of these disorders, diabetes mellitus and obesity, are addressed here.
Diabetes Mellitus
Diabetes mellitus is a disease caused by inadequate insulin production (type 1 diabetes) or decreased tissue sensitivity to insulin (type 2 diabetes).66 Problems related to decreased production or effects of insulin include an impaired ability to store glucose in muscle and other tissues as well as alterations in the ability to store lipids and synthesize proteins. Defects in glucose storage can result in acute problems such as hypoglycemia because the body is not able to draw upon glucose reserves in muscle and other tissues. Likewise, blood glucose levels often increase dramatically following a meal (postprandial hyperglycemia), and prolonged, repeated exposure of blood vessels to elevated blood glucose levels can lead to pathological changes in the blood vessel wall (angiopathy) that ultimately causes narrowing and occlusion of the vessel. Angiopathy subsequently leads to many of the chronic sequelae associated with poorly controlled diabetes, including cardiovascular pathology (hypertension, myocardial infarction, cerebrovascular accident) and other problems such as poor wound healing, neuropathy, nephropathy, and retinopathy.
Fortunately, drug therapy used in combination with proper diet and exercise can help maintain normal blood glucose levels and therefore prevent the complications seen with uncontrolled diabetes mellitus. The drugs commonly used to control blood glucose levels in people with diabetes are summarized in Table 8-4, and these drugs are briefly discussed here.
TABLE 8-4 Drugs Used to Treat Diabetes Mellitus
Insulin
Insulin replacement is the cornerstone of drug treatment for type 1 diabetes, with the dosage and type of insulin determined according to the specific needs of each patient.67 Insulin is a polypeptide and is typically administered by parental methods such as subcutaneous injection. In addition to regular insulin (insulin that is identical to human insulin), biosynthetic techniques have been used to modify the insulin molecule to either increase or decrease the rate of insulin absorption. People can, therefore, use these insulin analogues to achieve optimal glycemic control as needed throughout the day or night.68 Some alternative ways to administer insulin have also been explored, including insulin pumps, transcutaneous insulin administration, or administration via other routes (nasal sprays, intrapulmonary inhalation, and so forth). It is beyond the scope of this chapter to describe these innovative methods for insulin delivery, and more information can be found in other sources.69,70
Oral Antidiabetic Agents
The primary form of drug treatment in type 2 diabetes consists of drugs that can be administered orally and help maintain normal blood glucose levels, that is, oral antidiabetic agents (see Table 8-4).71 These drugs work by various methods summarized in Table 8-4. In some patients, a single agent may be successful in managing blood glucose levels, but specific combinations may also be used to provide optimal glycemic control. For example, a drug that increases insulin release from the pancreas (eg, a sulfonylurea) might be combined with a drug that decreases hepatic glucose production and increases insulin sensitivity (metformin) and possibly a third agent that decreases glucose absorption from the gastrointestinal tract (acarbose). Insulin therapy can also be included in this drug regimen, especially in patients with severe or poorly controlled type 2 diabetes.72 Specific drug combinations must be selected based on the individual needs of each patient, but the use of several agents may ultimately provide the best treatment by controlling different aspects of glucose metabolism in people with type 2 diabetes.
The primary adverse effect associated with all antidiabetic medications (insulin, oral antidiabetics) is hypoglycemia.73 If these drugs are too effective in lowering blood glucose, patients may become irritable, confused, or diaphoretic, have increased heart rate, or exhibit other signs typical of hypoglycemia. Acute episodes of hypoglycemia can usually be resolved by administering some source of glucose, such as fruit juice or glucose tablets. Repeated episodes of hypoglycemia may require an adjustment in drug dosage or a change in the type of drug being administered.
Obesity
Obesity increases the risk for developing many pathological conditions including hypertension, diabetes mellitus, and myocardial infarction.74 Successful treatment of obesity typically requires a combination of several interventions including diet, exercise, counseling, and so forth.74 The use of drugs to manage obesity is often controversial because of the potential for drug abuse and adverse effects of these drugs. Nonetheless, judicious use of antiobesity drugs can be a valuable part of a comprehensive treatment plan for people who are obese but have been unable to lose weight through nonpharmacological interventions (diet and exercise).74 Drugs used to treat obesity are listed in Table 8-5, and the rationale for using these drugs is addressed here.
TABLE 8-5 Drugs Used to Treat Obesity
Sympathomimetic Appetite Suppressants
Many common appetite suppressants have amphetamine-like properties and generally increase sympathetic nervous system (sympathomimetic) effects in the body. When used as appetite suppressants, these agents are thought to increase the effects of norepinephrine and possibly dopamine at specific synapses located in the lateral hypothalamic feeding center.75,76 Although the details are not clear, increased release or effects of these neurotransmitters in the hypothalamus decrease hunger sensations and increase feelings of satiety. Consequently most, if not all, of the weight loss that occurs with these drugs is due to decreased food intake rather than other effects such as increased tissue metabolism or thermogenesis.
Common appetite suppressants are listed in Table 8-5. Although these agents can be used as part of a comprehensive weight loss program, their use as appetite suppressants is often questionable because of their strong potential for adverse effects and abuse. In particular, these drugs are notorious for producing CNS excitation and cardiovascular stimulation.77 That is, these agents increase sympathetic nervous activity via their influence on sympathetic transmitters such as norepinephrine. These sympathomimetic effects can be quite severe, and cardiovascular problems such as hypertension and cardiac arrhythmias may occur, especially in people with preexisting cardiovascular disease. Tolerance to these agents also develops within a few weeks after initiating treatment, and dosages often need to be increased to maintain their therapeutic effects.77 Considering these limitations, appetite suppressants may be helpful in short-term management to get the patient’s weight under control, but these drugs can hopefully be discontinued in favor of more long-term solutions such as diet and exercise.
Other Antiobesity Drugs
Several other drugs can be used to help treat obesity (Table 8-5). Orlistat (Xenical) is a lipase inhibitor that acts within the gastrointestinal tract to limit the breakdown and subsequent absorption of dietary fat.78 This effect helps reduce body weight because less dietary fat is absorbed and stored within the body. Orlistat may, however, cause a number of gastrointestinal problems including abdominal pain, flatulence, and fecal incontinence.79Sibutramine(Meridia) is another form of appetite suppressant, but this drug differs from the typical suppressants described earlier because sibutramine increases the effects of serotonin and norepinephrine in the CNS.79 The benefit of increased serotonin activity may be especially helpful in providing feelings of satiety and therefore reduced food intake. Side effects associated with sibutramine include increased blood pressure, insomnia, dizziness, dry mouth, and nausea.
In recognition of the benefits of increasing serotonin activity to help control appetite, several other strategies have been used to increase CNS serotonergic activity. One strategy combined fenfluramine, a serotonin-enhancing drug, with phentermine, an amphetamine-like appetite suppressant.80 This combination, known commonly as fen/phen, caused severe cardiopulmonary problems including pulmonary vasoconstriction and cardiac valve damage.80Consequently, fenfluramine and a related drug, dexfenfluramine, were removed from the market.
It is also recognized that certain endogenous neuropeptides are critical in regulating appetite and energy metabolism. Central neuropeptides such as neuropeptide Y, agouti-related peptide, orexins, and the melanocortins appear to regulate hypothalamic function, while peripheral neuropeptides such as cholecystokinin, leptin, and ghrelin may provide feedback control of CNS appetite mechanisms.81 Research is currently under way to develop drugs that might influence these neuropeptides, and thereby help control appetite. Although this research has not yet produced any commercially successful products, drugs that help suppress appetite by influencing these central and peripheral neuropeptides might soon be forthcoming.82
Drug treatment for obesity, therefore, remains somewhat questionable at the present time. There is little doubt that antiobesity interventions should center on a lifelong program of diet and exercise.83 The drugs addressed here may help complement such a program, but all the currently available antiobesity drugs produce side effects, and there is no guarantee that weight loss will be maintained if the drug is discontinued and poor eating habits are resumed. Perhaps new antiobesity drugs will be developed in the future that are safer and more effective, but the best way to prevent and treat obesity at the present time remains centered around nonpharmacological methods.
MEDICATIONS RELATED TO PREFERRED PRACTICE PATTERN C: IMPAIRED VENTILATION, RESPIRATION/GAS EXCHANGE, AND AEROBIC CAPACITY/ENDURANCE ASSOCIATED WITH AIRWAY CLEARANCE DYSFUNCTION
Airway clearance dysfunction can be treated pharmacologically in several different ways (Table 8-6). Certain medications can be used to decrease irritation and control excessive airway secretions in fairly minor and transient situations such as seasonal allergies and common upper respiratory tract infections. Some of these same medications can likewise be used to facilitate airway clearance in more chronic and potentially serious conditions such as asthma, chronic bronchitis, and emphysema. Specific medications that relax bronchiole smooth muscle (bronchodilators) or decrease airway inflammation are also essential in helping maintain airway function in many forms of pulmonary disease. These pharmacological strategies for treating problems related to airway clearance are addressed in this section.
TABLE 8-6 Respiratory Medications
Drugs Used to Control Respiratory Tract Irritation and Secretion
Antitussives and Antihistamines
Antitussives, known commonly as cough medicines, and antihistamines are among the most commonly used medications worldwide. Antitussives often consist of agents that are classified chemically and functionally as opioids. Although opioids are often used as analgesics, these drugs can also act as antitussives because they suppress the sensitivity of the cough reflex at the brainstem.84 Irritation of afferent pathways from the airways is normally integrated at the brainstem level, and the cough reflex is initiated from the brainstem through efferent pathways to the respiratory muscles. By suppressing this brainstem integration, airway irritants are less able to stimulate the cough reflex. Hence, certain opioids are typically used as antitussives (see Table 8-6), and these agents are found in many prescription and over-the-counter (OTC) preparations.
The primary problem associated with opioids is the chance for developing addiction. Fortunately, most of the opioids used to treat coughing have a relatively small chance for causing addiction compared with the more powerful opioids used to treat pain (eg, morphine, meperidine, and so forth). Still, excessive and prolonged use of opioid antitussives can produce some degree of tolerance (the need for more drug to achieve therapeutic effects) and dependence (the onset of withdrawal when the drug is stopped), and these drugs should, therefore, be used only for the occasional treatment of coughing.
Antihistamines are so named because these drugs occupy and block the type 1 histamine receptors (H1 receptor) located on respiratory and other tissues. Histamine is typically released from airway mast cells, following some allergic or infectious challenge, and histamine irritates the upper airway tissues leading to coughing and other symptoms (sneezing, itching in the eyes and nose). By blocking the H1 receptors, antihistamines prevent histamine from reaching the respiratory tissues, thus reducing the coughing and sneezing that is commonly associated with seasonal allergies, upper respiratory tract infections, and so forth. Antihistamines are, therefore, used alone or in combination with other medications (decongestants, antitussives, and so forth) to treat a wide variety of respiratory tract problems associated with increased histamine release.85
Antihistamines, unfortunately, are often associated with sedation, dizziness, and psychomotor slowing. These symptoms occur if the antihistamine crosses the blood–brain barrier and affects areas within the brain that control the level of alertness, including the reticular activating system. Several antihistamines, however, have been developed that do not cross the blood–brain barrier and thus do not cause significant sedation and other CNS-related side effects. These nonsedating antihistamines include loratadine (Claritin), desloratadine (Clarinex), and cetirizine (Zyrtec) (Table 8-6), and these agents are a useful option if sedation must be avoided during antihistamine administration.
As indicated, antitussive and antihistamine medications are often used for the treatment of transient or occasional coughing and other symptoms associated with relatively minor respiratory infections (common cold), seasonal allergies, and similar conditions.85 A vast array of antitussive products are available directly to consumers, and patients receiving physical therapy may take these OTC products to decrease coughing associated with colds, hay fever, and so forth. There is concern, however, that many of the OTC cough suppressants do not work and that use of these agents is no more effective than placebo in reducing coughing.85 Hence, some experts have questioned whether OTC cough preparations are justified, especially considering that these preparations might still pose risks to certain populations such as children.86,87
On the other hand, prescription agents may help control coughing in patients with more chronic and serious conditions, including asthma and COPD. Hence, physical therapists will often encounter patients who take antitussives for the treatment of coughing associated with more serious problems. There is concern, however, that indiscriminate use of antitussive medications may be counterproductive because these drugs may impair the ability of a “productive” cough to raise secretions and clear harmful substances from the airway. Coughing is the primary defense mechanism used by the lungs to maintain airway patency. To suppress this mechanism may, in some cases, do more harm than good because mucus and other harmful substances will accumulate in the airway. Consequently, antitussives still play an important role in treating patients with persistent and annoying coughs, but these drugs are being used more carefully, especially in people who have a productive cough that is helping to keep the airways open.
Decongestants
Nasal congestion typically occurs because the vasculature within the nasal mucosa dilates in response to some allergen or viral stimulus.88 Vasodilation within the mucosa causes feelings of congestion and “stuffy head” as well as an increase in discharge from dilated capillaries that creates the familiar “runny nose” associated with allergies, symptoms of the common cold, and so forth. To decrease these symptoms, decongestant medications cause vasoconstriction in the nasal vasculature, thus reducing the swollen nasal membranes and nasal discharge.
Decongestants are classified as α-receptor agonists because they mediate their vasoconstrictive effects by stimulating α1-receptors located on nasal arterioles and β2-receptors located on venous smooth muscle.89 Some α-receptor agonists that are commonly used as decongestants are listed in Table 8-6. Decongestant products can also be administered in several ways, including orally (as tablets, in syrups, and so forth), or by nasal sprays. The effects and side effects of these products are influenced largely by the method of administration and the dosing frequency. A decongestant, for example, will produce relatively specific effects on the nasal vasculature with few side effects if correct amounts of the drug are administered directly to the nasal mucosa via a nasal spray. Overuse and abuse of nasal sprays or oral forms of decongestant medications will produce more side effects because excessive amounts of the drug reach the systemic circulation and affect adrenergic receptors on other tissues, including the CNS, heart, and peripheral vasculature.
Side effects associated with decongestants include headache, nausea, and nervousness. More serious problems will occur if these drugs stimulate cardiac β1-receptors or cause widespread stimulation of α1-receptors in the systemic circulation. The effects on the heart and peripheral vasculature can lead to palpitations, arrhythmias, and increased blood pressure, especially if the patient has some preexisting cardiovascular problems. As indicated earlier, the likelihood of these problems is increased if large doses of the decongestant are administered indiscriminately. Patients may also become dependent on decongestants if high dosages are administered for prolonged periods. This dependence is probably caused by excessive stimulation of adrenergic receptors located in the CNS.
Hence, decongestant medications are used to control discharge associated with fairly minor and transient irritation in the nasal mucosa.90 These drugs are available in many OTC medications and can be easily obtained by consumers. Decongestants are, however, relatively powerful drugs that can produce serious side effects if they are misused. Physical therapists should be aware that inappropriate use can lead to cardiovascular problems, and therapists should monitor heart rate and blood pressure in patients who may be developing cardiovascular problems from the misuse or abuse of these medications.
Mucolytics and Expectorants
Mucolytic medications break up mucus in the airways, thereby enabling the patient to cough up respiratory secretions more easily.91 Mucolytics such as acetylcysteine (Mucomyst) degrade disulfide bonds within mucus secretions, thus making the mucus less viscous and more fluid. Another type of mucolytic is dornase alfa (Pulmozyme), which is a deoxyribonuclease enzyme that breaks up DNA in respiratory secretions. Under conditions such as cystic fibrosis, DNA is released from various inflammatory cells as these cells degenerate in the airway lumen. The accumulation of this DNA contributes to the viscosity of respiratory secretions and increases the likelihood that these secretions will clog the airway and cause infection and atelectasis. Dornase alfa catalyzes the breakdown of this DNA, thereby making the respiratory secretions less viscous and more amenable to being coughed up and cleared from the airway.
Mucolytics can, therefore, be helpful in various conditions where there is a chance that respiratory secretions may accumulate in the airways. These conditions range from fairly minor respiratory tract secretions to chronic conditions such as cystic fibrosis and COPD. These medications are also tolerated fairly well, although excessive use can cause nausea and vomiting, and irritation of the mouth and throat may occur when these drugs are administered by inhalation in high doses for prolonged periods. These drugs are nonetheless helpful during physical therapy interventions that increase discharge and clearance of sputum. Airway clearance techniques will be more productive and easier to perform if the mucus in the respiratory tract is less viscous and easier to cough up.
Expectorant medications are also used to facilitate mucus secretion and clearance. Expectorants increase the secretion of a thin, watery sputum in the upper respiratory tract. By increasing the volume while also decreasing the viscosity of respiratory secretions, these drugs may enable the patient to cough up these secretions more easily. The most common expectorant currently used is guaifenesin, which is typically indicated in treating relatively acute and transient upper respiratory tract problems (infections, bronchitis, and so forth). This drug is available in several prescription forms, and it is also included in many OTC products. Guaifenesin is tolerated fairly well, with no major side effects that would jeopardize the therapeutic use of this medication or have a direct impact on the patient’s response to physical therapy. There is some concern, however, about whether or not this medication is actually effective in treating respiratory disorders. Despite the widespread use of guaifenesin, there is a little evidence that this drug actually improves airway clearance and increases pulmonary function. Nonetheless, guaifenesin continues to be administered, often in combination with other agents (mucolytics, antitussives), to treat various pulmonary disorders that cause congestion and accumulation of sputum in the airways.
Bronchodilators
Bronchodilators relax airway smooth muscle and increase or maintain the size of the airway lumen. These drugs can be helpful in diseases associated with bronchospasm, including asthma and COPD. The most common bronchodilators are classified as β-adrenergic agonists, xanthine derivatives, or anticholinergic agents (Table 8-6), and these agents are described here.
β-Adrenergic Agonists
β-Adrenergic agonists cause bronchodilation via the mechanism illustrated in Fig. 8-5. These drugs bind to and activate the β2-receptors located on airway smooth muscle cells. Stimulation of these receptors inhibits respiratory smooth muscle contraction, thus causing relaxation and bronchodilation. This effect is actually mediated by the production of an intracellular chemical known as cAMP (see Fig. 8-5). By activating the β2-receptor located on the smooth muscle cell membrane, these drugs increase activity of the adenyl cyclase enzyme located on the inner surface of the cell membrane. This enzyme catalyzes the conversion of adenosine triphosphate (ATP) to cAMP within the cell. Increased intracellular cAMP causes activation of other enzymes within the cell (protein kinases) that ultimately cause inhibition of airway smooth muscle contraction. The action of cAMP in this situation is a classic example of an intracellular second messenger system. The drug acts as an extracellular “first messenger” that binds to a surface receptor, then initiates the production of an intracellular “second messenger” (cAMP) that relays the message within the cell, and ultimately changes cell function in some way.
FIGURE 8-5 Mechanism of action of β-agonists on respiratory smooth muscle. β-Agonists facilitate bronchodilation by stimulating adenyl cyclase activity, which in turn increases intracellular cAMP production. cAMP activates protein kinase, which appears to add an inhibitory phosphate group to contractile proteins, thus causing muscle relaxation and bronchodilation. (Ciccone CD. Pharmacology in Rehabilitation. 4th ed. Philadelphia, PA: FA Davis; 2007:374, with permission.)
β-Adrenergic agonists that are used clinically as bronchodilators can be classified according to their selectivity for β-receptors. Certain agents such as albuterol and terbutaline (see Table 8-6) are fairly selective for β2-receptors located on respiratory tissues, whereas other agents such as isoproterenol and metaproterenol are not as selective and also stimulate β1-receptors located on the heart and other tissues. Some agents such as epinephrine may even stimulate α-receptors located on the peripheral vasculature (a1-receptors) or in the central nervous system (a2-receptors). A drug that is more selective for β2-receptors will have the obvious advantage of causing relatively fewer side effects because this drug predominately affects respiratory tissues with minimal effects on the heart, peripheral vasculature, and so forth.
β-Adrenergic bronchodilators can also be classified as either short acting or long acting depending on how long they can sustain their bronchodilating effects with each dose.92 Long-acting agents are typically more convenient because they do not have to be administered as often, and they may produce a somewhat more stable and predictable response. Finally, β-adrenergic drugs are typically administered orally or by inhalation. By inhaling these drugs through a nebulizer or metered-dose inhaler, the drug is applied more directly to the respiratory tissues, thus minimizing absorption into the systemic circulation and reducing the chance of side effects on other tissues. Inhalation, however, may not be effective in distributing the drug to the more distal parts of the airway, especially, if the airway is already constricted to some degree. In this case, oral administration may be advantageous because the drug will be absorbed into the bloodstream where it can then be distributed to all aspects of the airway via the pulmonary circulation.
Side effects associated with β-adrenergic agonists are related to drug selectivity and the dose and route of administration. A β2-selective drug that is administered in limited amounts by inhalation will be relatively free from serious side effects. Overuse of this type of drug, however, can cause irritation of the mouth and upper respiratory tract, which can actually increase the risk of a bronchoconstrictive attack.93 If high doses of a nonselective β-agonist reach the systemic circulation, this drug may cause stimulation of the heart that leads to cardiac palpitations and arrhythmias. High levels of a nonselective agent in the bloodstream can also cause stimulation of adrenergic receptors in the CNS, resulting in nervousness, irritability, and insomnia.
β-Adrenergic agonists can, therefore, be used safely and effectively as bronchodilators, but overuse should be avoided because of potential toxicity to the lungs and other organs. Proper use of these drugs can allow physical therapists to capitalize on their bronchodilating properties during airway clearance techniques and respiratory exercises. That is, it will be easier for patients to raise secretions and participate in respiratory muscle training if the airways are fairly open and dilated. Therapists should, however, also be alert for any signs of overuse, including cardiac abnormalities (increased pulse rate, arrhythmias) or signs of agitation, anxiety, and so forth.
Xanthine Derivatives
Theophylline and similar drugs (see Table 8-6) are classified chemically as xanthine derivatives because these drugs are structurally similar to other xanthines such as caffeine. For simplicity, theophylline will be used to represent this drug category and illustrate the therapeutic and adverse effects associated with the xanthines. Theophylline is a powerful bronchodilator that appears to relax airway smooth muscle through a combination of several effects.94This drug may, for example, inhibit the breakdown of cAMP, thus allowing intracellular cAMP to remain at higher levels and mediate smooth muscle relaxation for longer periods. Theophylline may also cause bronchodilation by inhibiting calcium release within airway smooth muscle cells and by blocking the ability of adenosine to stimulate airway smooth muscle contraction. This drug also appears to have anti-inflammatory effects, and theophylline may mediate some of its bronchodilating effects by controlling airway inflammation (inflammation as a causative factor in bronchospasm is discussed in the next section). Theophylline is, therefore, a fairly complex drug that often helps control bronchoconstriction in asthma, COPD, and other conditions that cause airway constriction.
Theophylline is typically administered orally, although this drug can also be injected intravenously in acute or severe bronchoconstrictive episodes. As indicated earlier, theophylline is structurally and chemically similar to caffeine, and the major problems associated with theophylline are the caffeine-like effects of this drug. Symptoms such as nervousness, trembling, insomnia, nausea, and tachycardia can occur even when plasma drug levels are in the therapeutic range. As plasma levels approach toxic levels, excessive CNS and cardiac stimulation can cause seizures and potentially severe cardiac arrhythmias. Theophylline toxicity is, therefore, a serious concern when this drug is used in fairly high doses.94 Physical therapists should acknowledge that this drug can produce beneficial effects by helping to maintain airway patency, but therapists should also be alert for any behavioral or cardiac signs (severe nervousness, tremors, arrhythmias, and so forth) that may indicate theophylline toxicity.
Anticholinergic Agents
Anticholinergic drugs are so named because they decrease acetylcholine (cholinergic) activity at various sites in the body. One such site is the lungs, where acetylcholine normally stimulates bronchiole smooth muscle contraction and causes constriction of the airway. By inhibiting this effect, anticholinergic agents help facilitate bronchodilation.95 Use of these drugs, however, is limited because they tend to inhibit acetylcholine activity on many tissues throughout the body rather than exert anticholinergic effects on only the lungs. By inhibiting acetylcholine activity in other tissues, these drugs cause an array of side effects including dry mouth, constipation, tachycardia, confusion, and blurred vision. Nonetheless, the anticholinergic drugs ipratropium (Atrovent) and tiotropium (Spiriva) can produce fairly localized effects on the lungs, especially when these drugs are administered by inhalation. Consequently, these anticholinergic agents may be used alone or in combination with other bronchodilators such as the β2 agonists (addressed earlier) to prevent bronchospasm in patients with COPD or asthma.96
Treatment of Airway Inflammation
Inflammation within the airway may be the underlying factor that initiates the airway constriction associated with asthma, bronchitis, and other forms of bronchospastic disease.97 Although the cause of this inflammation may not be clear, the presence of chronic inflammation appears to sensitize the airway and bring about a hyperreactive bronchoconstrictive response. If this inflammation is reduced, many of the problems related to increased airway reactivity (bronchospasm, coughing, and accumulation of secretions) can likewise be controlled or eliminated. Three primary strategies for treating airway inflammation are glucocorticoids, leukotriene modifiers, and cromones (see Table 8-6), and these strategies are described here.
Glucocorticoids
Glucocorticoids are anti-inflammatory steroids that include drugs such as prednisone, cortisone, and agents with similar chemical structures and pharmacological effects. These agents, known also as corticosteroids, are effective in treating inflammation in various tissues because they affect specific regulatory genes within key inflammatory cells such as lymphocytes, eosinophils, neutrophils, and mast cells.98 Within these cells, glucocorticoids increase the expression of genes that ultimately produce anti-inflammatory proteins (eg, lipocortins), and they decrease the expression of genes that code for inflammatory mediators such as tumor necrosis factor a, interferon-γ, and certain interleukins. Because of their effect at the genomic level, glucocorticoids can inhibit virtually all steps of the inflammatory response.
Glucocorticoids can, therefore, be used to treat inflammation in respiratory and other tissues, but these drugs can also produce several serious side effects. When high doses are administered systemically for prolonged periods, glucocorticoids can cause breakdown (catabolism) of muscle, tendon, bone, skin, and other tissues. Glucocorticoids can potentially cause many other side effects including hypertension, gastric ulcers, exacerbation of diabetes mellitus, glaucoma, and suppression of normal production of cortisol (the body’s endogenous glucocorticoid) from the cortex of the adrenal gland (adrenocortical suppression).99,100 Hence, the benefit of using these drugs to control inflammation must always be balanced against the potential risk of side effects.
With regard to treating bronchoconstrictive diseases, glucocorticoids have long been successful in reducing the inflammation that underlies these diseases and thereby reducing the incidence of bronchospasm. In the past, however, these drugs needed to be administered systemically, usually as oral preparations or by injection during severe attacks. Systemic administration increased the risk of catabolic and other side effects because the drug reached virtually all tissues in the body, rather than just the respiratory tissues.100 A major breakthrough occurred when glucocorticoids were synthesized in an aerosol format and thus could be administered by inhalation. That is, the chemistry of certain compounds was modified so that these drugs retained their anti-inflammatory effects but were soluble enough to be packaged in aerosol forms, including metered-dose inhalers.
Several glucocorticoids are now available in forms that can be administered by inhalation (see Table 8-6). This type of administration offers the obvious advantage of applying the drug more directly to the inflamed respiratory tissues, with minimal absorption into the systemic circulation. There is, of course, the danger that some of the drug will be absorbed into the pulmonary circulation and eventually be distributed systemically, thus increasing the risk of systemic side effects. This danger seems minimal, however, if the total amount of glucocorticoid inhaled each day is kept below a certain level. Beclomethasone, for example, seems to produce relatively few systemic side effects if less than 1,000 μg is administered by inhalation each day.
Consequently, the development of inhaled forms of glucocorticoids has revolutionized the treatment of asthma and other bronchoconstrictive diseases.101 These drugs are now incorporated into the treatment regimen much sooner because they do not pose as great a risk as the oral (systemic) forms of treatment. Use of glucocorticoids earlier in the course of the disease may also help delay disease progression and reduce the need for subsequent medications and medical treatment. Physical therapists should realize that the inhaled forms of these drugs can now serve as the cornerstone for treating asthma and other conditions. Therapists should, however, also be aware that these drugs can still cause substantial problems if they are overused or if the patient must revert to systemic administration in severe cases of asthma or COPD.
Leukotriene Modifiers
Leukotrienes are lipid compounds that are produced within cells lining the respiratory mucosa. These compounds are similar in structure and function to prostaglandins. Like the prostaglandins, leukotrienes tend to augment the inflammatory response, and leukotrienes seem to be especially prevalent in mediating inflammation and other effects (edema, increased mucus secretion) in asthma and in similar conditions associated with airway hyperreactivity.102It follows that drugs that help control the biosynthesis and effects of leukotrienes will be useful in reducing airway inflammation and preventing bronchospastic attacks.
One way to modify leukotriene effects is to inhibit the enzyme that synthesizes these compounds.103 Leukotrienes are produced from arachidonic acid by the lipoxygenase enzyme, and several drugs have been developed that selectively inhibit this enzyme. An agent that is currently available is zileuton (Zyflo), with the likelihood that other lipoxygenase inhibitors will be in the market soon. A second option for controlling leukotriene effects is to administer drugs that occupy and block the leukotriene receptor located on respiratory cells.104 These leukotriene receptor blockers prevent leukotrienes from activating these receptors, thus reducing their ability to inflame the airways and cause bronchoconstriction. Leukotriene receptor blockers that are currently available include montelukast (Singulair) and zafirlukast (Accolate) (Table 8-6).
Agents that modify leukotriene production or effects are tolerated fairly well. Some fairly minor problems such as headache and nausea may occur, and some patients may need to be monitored periodically to guard against more serious problems such as liver toxicity. Nonetheless, the emergence of leukotriene modifiers has been a significant advancement in treating airway inflammation because these drugs may help reduce the need for anti-inflammatory steroids in conditions such as asthma. Development of additional drugs that affect leukotrienes should provide more options for nonsteroidal management of respiratory diseases that have an inflammatory and bronchospastic component.
Cromones
Cromolyn (Intal, Nasalcrom, other trade names) and nedocromil (Alocril, Tilade) help prevent inflammation in the airway by inhibiting the release of inflammatory mediators from cells in the respiratory mucosa. Although the exact cellular mechanism is not known, these drugs stabilize mast cells and possibly other cells (eosinophils, macrophages, neutrophils, and so forth) and thereby decrease the release of histamine, leukotrienes, and other inflammatory chemicals from these cells. These cells, therefore, cannot fully participate in the chemical response that is needed to provoke irritation and inflammation in the airway.
Cromolyn and nedocromil can be administered by inhalation or nasal spray to treat relatively transient conditions such as seasonal allergies. These drugs can likewise be used alone or in combination with other agents (anti-inflammatory steroids, bronchodilators) to decrease inflammation and prevent bronchospasm in more chronic conditions including asthma.105 When administered in the appropriate inhaled dose, these drugs are remarkably free of serious side effects. One important limitation, however, is that these drugs must be administered prior to exposure to the allergen or irritant that causes inflammation in the airway. That is, cromolyn and nedocromil must be present to stabilize mast cells and other inflammatory cells before these cells become stimulated and release histamine, leukotrienes, and so forth. These drugs can prevent an allergic or bronchospastic attack, but they cannot stop an attack that is already in progress. When used to control chronic conditions, these drugs must, therefore, be taken continuously to provide a prophylactic effect and control airway inflammation. Still, these agents afford one more option in the treatment of airway inflammation and bronchospasm, and physical therapists may see these drugs used as part of the comprehensive treatment of asthma, COPD, and similar respiratory conditions.
MEDICATIONS RELATED TO PREFERRED PRACTICE PATTERN D: IMPAIRED AEROBIC CAPACITY/ENDURANCE ASSOCIATED WITH CARDIOVASCULAR PUMP DYSFUNCTION OR FAILURE
Discussed in this section are drugs that help to treat cardiovascular pump dysfunction associated with myocardial ischemia (antianginal medications) and altered cardiac rhythm (antiarrhythmic medications) and cardiovascular pump failure. Other medications can, of course, help improve myocardial function indirectly by treating other cardiovascular problems such as high blood pressure, increased plasma lipids. These medications are addressed in other sections of this chapter.
Drugs Used to Treat Cardiovascular Pump Dysfunction
Angina Pectoris
Angina pectoris is chest pain that typically occurs when the supply of oxygen to the heart is inadequate to meet myocardial oxygen demands. An imbalance between myocardial oxygen supply and demand can occur for several reasons, and angina pectoris is subclassified according to the factors that precipitate an anginal attack. Drug therapy is likewise focused on resolving the precipitating factors and on helping to restore the normal balance between myocardial oxygen supply and utilization. The primary drug therapies used to relieve symptoms of angina pectoris are described here.
Organic nitrates—Organic nitrates include nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, and amyl nitrate (see Table 8-7). These drugs act primarily as vasodilators in the peripheral vasculature.106 That is, nitroglycerin and other nitrates are converted to nitric oxide within the vasculature, thereby relaxing vascular smooth muscle, which leads to vasodilation. These drugs also cause some degree of vasodilation in the coronary arteries and can increase blood flow to the myocardium. Their primary benefits in treating angina pectoris, however, are related to their ability to cause vasodilation in the systemic circulation, including the peripheral venous and arterial systems. This systemic vasodilation decreases the amount of blood returning to the heart (cardiac preload) and decreases the pressure that the heart must pump against (cardiac afterload). By decreasing cardiac preload and afterload, nitrates reduce the workload on the myocardium, which helps reduce angina by decreasing myocardial oxygen demand. By normalizing cardiac workload and oxygen demand, nitrates may also produce other beneficial effects including improved myocardial contractility and decreased risk of cardiac arrhythmias.
TABLE 8-7 Organic Nitrates
Although several different types of organic nitrates can be used to treat angina, nitroglycerin is the most common. Nitroglycerin can be administered by placing a tablet under the patient’s tongue (sublingually) at the onset of an angina attack. Sublingual administration allows rapid absorption into the circulation via the venous drainage from the oral mucosa. More importantly, sublingual administration allows the drug to be introduced into the systemic circulation before passing through the liver. If a nitroglycerin tablet is swallowed, it will be absorbed from the upper gastrointestinal tract where it then passes directly to the liver via the hepatic portal vein. This so-called “first-pass effect” results in more than 99% of the active form of nitroglycerin being metabolized and inactivated before the drug reaches the systemic circulation. Hence, sublingual administration avoids this first-pass inactivation and allows more active nitroglycerin to reach the peripheral circulation where it can exert beneficial effects.
Another option for administering nitrates is to use a nitroglycerin patch. Small adhesive patches that are impregnated with this drug can be adhered to various sites on the surface of the skin. The drug is then slowly absorbed through the skin and into the systemic circulation. Transdermal nitroglycerin patches offer several advantages including a convenient method for administering the drug and a better chance for preventing the onset of an angina attack compared to sublingual pills that are typically taken after an attack has already started. Nitroglycerin patches also avoid the first-pass effect because they can be applied to any site on the skin, and the drug will be absorbed into the subcutaneous venous drainage at that site and reach the systemic circulation before reaching the liver.
The side effects most commonly associated with nitroglycerin and other nitrates are related to their vasodilating effects.107 Problems with dizziness, hypotension, and orthostatic hypotension may occur because these drugs cause blood to pool in the peripheral circulation. These problems may be especially common when a patient takes a sublingual tablet and gets a sudden absorption of nitroglycerin into the systemic circulation. Patients may complain of headaches because nitrates dilate the meningeal vessels. Finally, nitrates may lose their effectiveness because the body becomes tolerant to the drug when it is administered continuously via patches.107 Fortunately, this form of drug tolerance is rapidly reversed when the drug is discontinued for even a few hours. Consequently, patches are often applied in a 24-hour cycle where the patch is applied for 12 to 14 hours and then removed for the other 10 to 12 hours. This cycle avoids the development of drug tolerance while still allowing adequate control of angina symptoms.
Other drugs used to treat angina—Other strategies for decreasing angina symptoms include β-blockers and calcium channel blockers.108 As discussed earlier, β-blockers decrease heart rate and myocardial contraction force because they block the effects of catecholamines (epinephrine and norepinephrine) on the heart. These drugs are, therefore, helpful in reducing angina symptoms because they reduce myocardial oxygen demand. In contrast, calcium channel blockers are effective in reducing angina symptoms primarily because they increase myocardial oxygen supply. By limiting the entry of calcium into coronary vascular smooth muscle, these drugs maintain coronary artery vasodilation and prevent coronary vasospasm. Calcium channel blockers are, therefore, especially useful in the type of angina known as Prinzmetal ischemia, which occurs because of increased reactivity and vasospasm in the coronary arteries.109
Side effects and other details about β-blockers and calcium channel blockers have been discussed earlier in this chapter. These drugs are often used in various combinations with organic nitrates to provide optimal management of angina symptoms in each patient.108 A patient, for example, with classic or stable angina might take a β-blocker orally every day, with sublingual nitroglycerin being used at the onset of an angina attack. Patients with more severe or unstable forms of angina may require a more aggressive regimen that also incorporates calcium channel blockers along with oral β-blockers and oral or transdermal nitroglycerin.
Cardiac Arrhythmias
Cardiac arrhythmias can be characterized as any disturbance in cardiac excitability that results in a heart rate that is too fast, too slow, or simply irregular.110 The causes and classification of specific arrhythmias are fairly complex and well beyond the scope of this chapter.110 Drug treatment of arrhythmias is likewise a detailed and difficult topic that involves a number of potentially useful agents. Nonetheless, this topic can be simplified somewhat by classifying the commonly used antiarrhythmic agents into four categories.110 These categories are listed in Table 8-8 and they are described briefly here.
TABLE 8-8 Classification of Antiarrhythmic Drugs
Sodium channel blockers— Drugs in this category control myocardial excitability by stabilizing the opening and closing of sodium channels located on heart cell membranes. These drugs are helpful in treating a variety of arrhythmias because they tend to normalize the function of cardiac sodium channels; that is, these drugs can decrease the activity of sodium channels that are firing too rapidly or increase the activity of channels that are firing too slowly. This category of antiarrhythmics is further subdivided according to exactly how these drugs influence cardiac excitability (see Table 8-8).
β-Blockers— As discussed earlier in this chapter, β-blockers bind to β1-receptors on the heart and prevent excessive stimulation by sympathetic catecholamines (epinephrine, norepinephrine). This effect helps normalize cardiac sympathetic activity and is helpful in controlling arrhythmias associated with increased sympathetic excitation of the myocardium.
Drugs that prolong repolarization— These drugs stabilize heart rate by delaying repolarization and prolonging the refractory period of cardiac action potentials. This effect lengthens the time between successive heart beats (diastole) and is especially helpful in treating certain types of tachycardia.
Calcium channel blockers— By inhibiting calcium entry into cardiac pacemaker cells, these drugs stabilize myocardial excitability and help reestablish the normal generation of cardiac rhythm in the sinoatrial node. Calcium channel blockers also decrease the conduction of electrical impulses throughout the heart by limiting the entry of calcium into cardiac muscle cells.
Consequently, a large number of drugs are available that can be used to treat cardiac arrhythmias, and selection of a specific agent obviously depends on the type of arrhythmia and other medical and physiological factors in each patient. There are likewise variable side effects associated with individual antiarrhythmic drugs depending on the category and chemical features of each drug. The primary problem, however, is that these agents may be “proarrhythmic,” meaning that they can increase the chance of cardiac arrhythmias.111 In an attempt to resolve one type of arrhythmia, these drugs may inadvertently alter cardiac excitability so that a different type of arrhythmia emerges. Consequently, physical therapists should occasionally monitor a patient’s pulse or look for other symptoms (severe fatigue, diaphoresis, and so forth) that may indicate the presence of these proarrhythmic effects, especially when patients are exercising.
Drugs Used to Treat Cardiovascular Pump Failure
Cardiovascular pump failure occurs when the heart is unable to adequately supply oxygen to the tissues throughout the body.112 This problem, described more simply as heart failure, is often a progressive decline in myocardial function that produces several characteristic symptoms including shortness of breath, poor exercise tolerance, tachycardia, and edema in the lungs and peripheral tissues. Drug treatment of heart failure consists of two primary strategies: to increase myocardial pumping ability and to decrease the workload on the failing heart (Table 8-9). Drugs used to achieve these strategies are described here.
TABLE 8-9 Drugs Used to Treat Heart Failure
Drugs That Increase Myocardial Pumping Ability
Digitalis— Digitalis is the term commonly used to represent a group of drugs known as the cardiac glycosides. This group includes agents such as digoxin and digitoxin, and these drugs have been used extensively in the treatment of heart failure.113 Digitalis exerts a positive inotropic effect on the heart, meaning that this drug increases myocardial contraction force.114 Digitalis exerts some of its positive inotropic effect by increasing the amount of calcium inside heart muscle cells. This increase in intracellular calcium results in a greater interaction between actin and myosin filaments, which results in increased contractile force. Digitalis also exerts beneficial electrophysiological effects on the heart, including an increase in cardiac parasympathetic activity (by stimulating the vagus nerve) and a decrease in cardiac sympathetic activity.114 These electrophysiological effects contribute to digitalis’s positive inotropic properties because they prevent tachycardia and allow the heart to fill more completely during diastole and pump more effectively during systole.
Digitalis can, therefore, be helpful in increasing myocardial contraction force and improving the symptoms of heart failure. There is concern, however, that digitalis does not produce any long-term benefits and that the use of this drug does not really improve the survival of people with heart failure. More importantly, digitalis is notorious for having a small margin of error between the amount of drug that causes therapeutic effects and the amount that causes toxicity.115 A relatively small increase in blood levels beyond the therapeutic range can result in digitalis toxicity. Digitalis toxicity is characterized by several symptoms including loss of appetite, fatigue, confusion, depression, and blurred vision. By altering calcium concentration in certain areas of the heart, digitalis can also disturb cardiac rhythm and cause severe arrhythmias such as ventricular tachycardia and ventricular fibrillation. Digitalis must, therefore, be used carefully, and patients experiencing any untoward effects should be quickly evaluated for possible digitalis toxicity.
Other positive inotropic agents— Because of the limitations and potential problems associated with digitalis, other drugs that selectively increase myocardial contraction force have been developed (Table 8-9).116 These drugs, however, have not proven to be substantially better than digitalis in improving outcomes in people with heart failure. Many of these other positive inotropes must also be given by parenteral (nonoral) routes and are typically administered by continuous intravenous infusion to treat acute or severe heart failure.
Other positive inotropic agents include inamrinone and milrinone (Primacor).117 These drugs are classified as phosphodiesterase inhibitors because they inhibit the phosphodiesterase enzyme that degrades cAMP in cardiac cells. By inhibiting cAMP degradation, these drugs increase intracellular cAMP levels, which leads to increased intracellular calcium and a stronger muscle contraction. Another option for increasing myocardial contraction force is to use dobutamine (Dobutrex).117 This drug selectively stimulates cardiac β1-receptors, which results in a stronger cardiac contraction. Finally, dopamine can be used to increase myocardial contraction force because this drug stimulates β1-receptors on the heart.117 At the appropriate dosage, dopamine also stimulates vascular dopamine receptors, which causes vasodilation in the peripheral vasculature and kidneys. Dopamine’s vasodilating effects contribute to this drug’s benefits in severe, acute heart failure because peripheral vasodilation helps decrease the workload on the failing heart, and dilation of the kidneys helps preserve renal function and allows the excretion of excess sodium and water.
Drugs That Decrease Cardiac Workload
Heart failure tends to become progressively worse because changes occur in the cardiovascular system, which increase myocardial workload. These changes, mediated primarily by increased sympathetic nervous system activity and increased activity in the renin–angiotensin systems, create a vicious cycle where increased cardiac workload causes additional damage to the heart, which further diminishes cardiac pumping ability, perpetuates increased sympathetic and renin–angiotensin activity, adds to the stress and workload on the myocardium, and so forth.118 It is, therefore, essential to try to stop this vicious cycle by administering drugs that decrease cardiac workload and spare the heart from additional damage.
Several drugs already discussed in this chapter can be used to decrease cardiac workload in people with heart failure (Table 8-9). These drugs include the diuretics, vasodilators, renin–angiotensin system inhibitors, and β-blockers.118Diuretics help excrete excess fluid and electrolytes in the vascular system, thereby reducing the volume of fluid that needs to be pumped by the failing heart. Vasodilators decrease cardiac workload by reducing the pressure in the arterial system (cardiac afterload) and by allowing more blood to pool in the peripheral venous system, thereby reducing the volume of blood returning to the heart (cardiac preload). By reducing the acute and chronic vasoconstriction produced by angiotensin II, drugs that inhibit the renin–angiotensin system (ACE inhibitors, angiotensin II blockers) can substantially reduce detrimental effects on the heart and vascular systems. Finally, β-blockers reduce the excitatory effects of the sympathetic nervous system on the heart, and these drugs help prevent further damage caused by excessive sympathetic stimulation.
Side effects and other details about these drugs were discussed earlier in this chapter. Drugs that decrease cardiac workload can be combined with digitalis and other positive inotropic drugs to provide optimal treatment for people with various forms of heart failure. In fact, drugs such as the renin–angiotensin inhibitors and β-blockers are now considered essential for the treatment of heart failure because these drugs may actually decrease morbidity and increase life expectancy in people with heart failure.119 Hence, drug treatment of heart failure has improved substantially over the past few years, and we may see additional benefits as more is learned about how various drugs can be combined to effectively treat this disease.
MEDICATIONS RELATED TO PREFERRED PRACTICE PATTERN E: IMPAIRED VENTILATION AND RESPIRATION/GAS EXCHANGE ASSOCIATED WITH VENTILATORY PUMP DYSFUNCTION OR FAILURE
Drugs Used to Treat Ventilatory Pump Dysfunction
Several pharmacological strategies already discussed in this chapter can be used to indirectly treat ventilatory pump dysfunction. For example, bronchodilators, mucolytics, and other drugs that facilitate airway clearance can help improve airway patency, thereby reducing the workload on the ventilatory musculature. There are likewise many pharmacological strategies that can improve the patient’s general health in various musculoskeletal, neuromuscular, and other disorders, thereby enabling the patient to perform general aerobic conditioning exercises and specific exercises that improve the strength and endurance in the respiratory muscles. There are not, however, any medications that specifically increase respiratory muscle strength or endurance. Hence, pharmacological treatment of ventilatory pump dysfunction typically focuses on resolving other pathologies and impairments that will ultimately help the patient increase ventilation and improve gas exchange.
Nonetheless, administration of supplemental oxygen is a strategy that is commonly used to help alleviate the sequelae of ventilatory pump dysfunction.120 A brief overview of the therapeutic use of oxygen follows.
Oxygen
Oxygen is typically administered to correct the hypoxia that often accompanies poor ventilation and impaired gas exchange that is secondary to a number of respiratory problems. By inhaling supplemental oxygen, arterial oxygen levels can be sustained so that oxygen delivery to peripheral tissues remains adequate to meet the metabolic demands of these tissues. This strategy, of course, will not provide a permanent solution to respiratory dysfunction. Oxygen can, nonetheless, help alleviate the hypoxia that often accompanies ventilatory pump dysfunction in acute situations. Long-term oxygen therapy is likewise generally felt to improve exercise tolerance, decrease morbidity, and improve quality of life in people with chronic conditions such as COPD.121
Supplemental oxygen can be administered via nasal cannulae, oxygen mask, oxygen tent/hood, or directly into an endotracheal tube.120 Other parameters such as the oxygen dose (liters per minute), hours per day of oxygen administration, supply system (canister of compressed gas, liquid oxygen reservoir), and the dosage required during exercise must all be considered on the basis of the needs of each patient. Despite the obvious benefit of preventing hypoxia, great care must be taken to avoid administering too much oxygen and subjecting the patient to oxygen toxicity. Oxygen toxicity occurs because of the increased production of various reactive oxygen species or oxygen “free radicals.”120 These highly reactive oxygen species cause damage to many cellular components including membrane lipids, cellular proteins, and DNA. As a result, cell death often occurs with subsequent loss of tissue and organ function. In particular, the respiratory tissues may be especially prone to excessive doses of supplemental oxygen, which can lead to airway inflammation, increased alveolar permeability, and pulmonary edema that can lead to death.120 Hence, oxygen administration is a two-edged sword; therapeutic doses can be helpful in preventing hypoxia, but excessive administration may ultimately cause severe damage to many tissues, including the pulmonary system.
Drugs Used to Treat Ventilatory Pump Failure
Medications related to this condition are designed to treat the problem that is potentiating respiratory failure. For pulmonary conditions such as asthma and COPD, medications already described in this chapter can be used in higher doses and in greater numbers (combining several synergistic drugs) to thwart respiratory failure. An aggressive drug regimen can hopefully prevent respiratory failure so that the patient can resume treatment of the underlying condition at lower (maintenance) drug doses, whereas other interventions including physical therapy are used to prevent subsequent episodes of respiratory failure. However, even pharmacological therapy can fail, in which case the patient must be placed in mechanical ventilation.
MEDICATIONS RELATED TO PREFERRED PRACTICE PATTERN F: IMPAIRED VENTILATION AND RESPIRATION/GAS EXCHANGE ASSOCIATED WITH RESPIRATORY FAILURE
The following medications are not designed to directly improve ventilation, but rather to improve patients’ tolerance to mechanical ventilation. Although the Guide does not associate assistive ventilatory support with Practice Pattern 6F, many patients with respiratory failure may ultimately require this intervention. Three primary pharmacological interventions include antianxiety/sedative drugs, analgesics, and neuromuscular blockers. Examples of these drugs are listed in Box 8-1, and the use of these agents in patients receiving mechanical ventilation is addressed here.
Antianxiety and Sedative Agents
Antianxiety agents are often administered to patients receiving mechanical ventilation, especially when these patients are being treated in the intensive care unit (ICU).122 Patients in the ICU are subjected to a bright, noisy, and potentially intimidating environment. Use of an antianxiety agent can help keep the person calm and relaxed and also decrease the apprehension that typically occurs when the patient is intubated and mechanically ventilated.122
BOX 8-1
Medications Commonly Used As Adjuncts to Mechanical Ventilation
Antianxiety agents and sedatives
Benzodiazepines*
Lorazepam (Ativan)
Midazolam (generic)
Others
Propofol (Diprivan)
Haloperidol (Haldol)
Analgesics
Morphine (Kadian, Duramorph, others)
Neuromuscular blockers
Atracurium (Tacrium)
Pancuronium (generic)
Rocuronium (Zemuron)
Succinylcholine (Anectine, Quelicin)
Vecuronium (generic)
*All benzodiazepines have antianxiety effects; selection of a specific agent in patients with mechanical ventilation is based on the individual needs of each patient.
The most common antianxiety agents are the benzodiazepines (see Box 8-1). These drugs increase the effects of γ-aminobutyric acid (GABA), which is an inhibitory neurotransmitter found throughout the CNS. Increased CNS inhibition produces an antianxiety effect and may likewise cause some degree of sedation and muscle relaxation, which can also be beneficial in helping the patient tolerate mechanical ventilation in the ICU. Hence, benzodiazepines such as lorazepam (Ativan) and midazolam are commonly used to provide a calming effect and maintain adequate relaxation in patients who are being mechanically ventilated.123 Sedation is the most common side effect associated with benzodiazepine agents. This effect is not usually a problem, however, and as indicated, sedation may be somewhat beneficial when these drugs are administered for relatively short periods of time to patients who are acutely ill and receiving mechanical ventilation in the ICU.
In addition to the benzodiazepines, other drugs can be used to induce sedative effects (Box 8-1). In particular, propofol (Diprivan) is a sedative–hypnotic that is often used as an adjunct during general anesthesia, but can also be used to help provide sedation to people who are being ventilated in the ICU.122 Certain antipsychotics such as haloperidol (Haldol) may also provide sedation, especially in patients who are agitated.124 The exact choice of an antianxiety or sedative agent depends on the particular needs of the patient undergoing mechanical ventilation.
Analgesics
Analgesics are also administered frequently to patients who are being mechanically ventilated.124 These drugs help alleviate pain that accompanies trauma, surgery, and so forth, and may also help the patient tolerate the discomfort and apprehension associated with intubation and ventilation. Opioids such as morphine are the most common type of analgesics used in these situations (see Box 8-1).124 These drugs inhibit CNS synapses that mediate painful sensations and reduce the patient’s awareness and perception of all painful stimuli.125 Opioid analgesics also cause sedation, but this side effect often complements their analgesic effects during short-term use in patients who are mechanically ventilated.
Neuromuscular Blockers
Drugs that eliminate skeletal muscle contraction may need to be administered to some patients undergoing mechanical ventilation.126 These drugs, known as neuromuscular blockers (see Box 8-1), bind to the postsynaptic receptor at the skeletal neuromuscular junction and negate the excitatory effects of acetylcholine on skeletal muscle. This effect causes skeletal muscle paralysis throughout the body so that the patient remains immobile and does not thrash about. The thoracic wall likewise remains relaxed and compliant, thus allowing the ventilator to control chest inflation and deflation without resistance from the patient’s respiratory and thoracoabdominal musculature.
The use of neuromuscular blockers in patients receiving mechanical ventilation is understandably a rather extreme and potentially dangerous intervention. These drugs are, therefore, used as a last resort when other drugs (antianxiety agents, analgesics) are not able to adequately control agitation. The primary problem associated with neuromuscular blockers is that prolonged muscular weakness sometimes occurs after these drugs are discontinued. Neuromuscular blockers, or possibly the combination of neuromuscular blockers with anti-inflammatory steroids (prednisone, cortisone, other glucocorticoids), may precipitate a syndrome of severe muscle weakness in certain patients who receive mechanical ventilation during an acute illness. This syndrome is identified by several different names, including acute steroid myopathy, critical illness polyneuromyopathy, prolonged neurogenic weakness, and the floppy person syndrome. Muscle weakness associated with this syndrome occurs because of direct muscle pathology (myopathy), abnormalities at the neuromuscular junction, nerve pathology (neuropathy), or a combination of muscle and nerve pathology (polyneuromyopathies).127 The type and extent of this muscle weakness vary from patient to patient, but weakness can often be quite severe and last for several months after these drugs are discontinued and the patient is removed from ventilation.
Hence, a syndrome of acute, severe muscle weakness may emerge in certain patients who receive mechanical ventilation during an acute illness, especially if drugs such as the neuromuscular blockers and glucocorticoids are administered. Neuromuscular blockers, either used alone or in combination with glucocorticoids, are often considered a risk factor in the development of neuromuscular pathology in people who are acutely ill and receiving mechanical ventilation.128 There are, however, cases where severe muscle weakness developed in patients who were mechanically ventilated but were not exposed to either neuromuscular blockers or glucocorticoids. Consequently, the exact cause of these neuromuscular problems is not known, and the development of severe muscle weakness following mechanical ventilation remains a serious and poorly understood phenomenon. Future research into the exact factors that increase the risk of this problem will hopefully lend insight into how these neuromuscular pathologies can be avoided.
Drugs Used to Treat Acute Respiratory Failure and Acute Respiratory Distress Syndrome
There are several supportive measures that can be used in cases of acute respiratory failure in adults or acute respiratory distress syndrome (ARDS). ARDS typically occurs following some recent insult such as trauma, pneumonia, sepsis, or drug overdose.129 Patients typically exhibit bilateral infiltrates on chest radiograph, high ventilatory inflation pressures, and a high requirement for supplemental oxygen.129 Interventions used during ARDS are targeted at providing cardiopulmonary support and preventing organ failure or infection secondary to poor oxygenation and perfusion.
With regard to pulmonary medications, three primary strategies are typically used to maintain adequate gas exchange and tissue oxygenation. These strategies are surfactant therapy, nitric oxide, and anti-inflammatory steroids. Surfactant is an oily substance produced by cells within the alveoli that helps reduce surface tension and prevent alveolar collapse. Nitric oxide relaxes vascular smooth muscle with subsequent vasodilation of the pulmonary vasculature, and this effect helps improve gas exchange, especially in areas of the lung that are underperfused. Anti-inflammatory steroids (glucocorticoids, see Table 8-6) help prevent airway inflammation and bronchoconstriction, thus maintaining airway patency and ventilation. Additional details about the use of these strategies and side effects of these drugs can be found in the next section of this chapter.
MEDICATIONS RELATED TO PREFERRED PRACTICE PATTERN G: IMPAIRED VENTILATION, RESPIRATION/GAS EXCHANGE, AND AEROBIC CAPACITY/ENDURANCE ASSOCIATED WITH RESPIRATORY FAILURE IN THE NEONATE
Respiratory failure in neonates can be caused by myriad problems including prematurity, infection (pneumonia), postsurgical complications, congenital anomalies, and so forth. There have likewise been many advances in pharmacological and nonpharmacological treatment of neonatal respiratory problems, including innovative ways to control acid–base balance, fluid–electrolyte levels, and mechanical ventilation. Although it is not possible to review all of these treatment approaches, there are a few pharmacological strategies that have emerged as being especially important in the treatment of neonatal respiratory distress syndrome. Addressed here are three such strategies: surfactant replacement therapy, nitric oxide administration, and glucocorticoid therapy.
Surfactant Replacement Therapy
Respiratory problems often arise in neonates because of inadequate production of surfactant. Surfactant is a mixture of phospholipids, neutral lipids, and proteins that is normally synthesized by alveolar pneumocytes. Surfactant decreases surface tension within the alveolus, thus allowing the alveolus to expand during inspiration. Without sufficient surfactant, the alveoli will collapse rendering gas exchange impossible. Neonates may not produce enough surfactant because they are born prematurely, or because surfactant is inactivated by other problems (pneumonia, meconium aspiration, and so forth).130 Insufficient surfactant production, known also as hyaline membrane disease, can lead to respiratory distress syndrome and acute respiratory failure simply because the neonate cannot inflate his or her lungs.
Hence, the development of methods to supplement inadequate surfactant production is arguably the most important advancement in treating neonatal respiratory distress syndrome. Various types of surfactant that can be used therapeutically are listed in Table 8-10. Administration of surfactant has proven to reduce the morbidity and mortality associated with acute respiratory distress in the newborn, and early surfactant replacement may reduce the risk of the child developing subsequent chronic lung disease.130 Surfactant can be obtained from one of the three sources: human surfactant (extracted from human amniotic fluid), animal surfactant (harvested from cow or pig lungs), or artificial surfactant (synthetic mixtures of lipids and phospholipids) (see Table 8-10).131 Although the natural forms (human or animal) were originally thought to be safer and more effective than synthetic agents, recent studies suggest that the newer synthetic surfactants may provide equivalent results in terms of improved lung function and lower mortality.132 Efforts continue to produce a safe, effective, and relatively inexpensive method for providing surfactant replacement to neonates with ARDS.
TABLE 8-10 Source and Composition of Surfactants
Surfactant is typically administered to neonates via an endotracheal tube by using repeated bolus doses of the drug in aerosol form. The optimal dose and number of treatments will vary depending on the type of surfactant and the needs of each infant.129 Surfactant replacement may cause some side effects as the drug is being administered, including airway obstruction, bradycardia, and oxygen desaturation.129 There is likewise a slight risk of more serious complications including pulmonary hemorrhage, intracranial hemorrhage, and an increased chance of maintaining a patent ductus arteriosus.129 Nonetheless, surfactant replacement therapy is the most common and effective pharmacological method for resolving neonatal respiratory distress syndrome, and this intervention is typically the cornerstone of treatment for preventing respiratory failure in infants.
Nitric Oxide
Nitric oxide causes vascular smooth muscle relaxation with subsequent vasodilation of vascular beds. Vascular endothelial cells, including the cells that line the pulmonary vessels, normally produce this substance. With regard to neonates, nitric oxide may play a critical role in dilating the pulmonary vessels and supplying blood to areas of the lungs that are beginning to be ventilated as the infant begins to breathe.133 Endogenous production of nitric oxide, therefore, helps facilitate gas exchange by promoting a match between vascular perfusion and alveolar ventilation (the so-called ventilation–perfusion ratio).134 In neonatal respiratory distress syndrome, certain areas of the pulmonary vascular bed may not adequately dilate because the infant is premature or because of other problems (infection, meconium aspiration, hypothermia, and so forth). Inadequate vasodilation increases pulmonary arterial pressure, leading to a syndrome of persistent pulmonary hypertension in the newborn (PPHN).133 Inhalation of nitric oxide will dilate the pulmonary vasculature and supply blood to areas of the lung that are being ventilated. This effect will help reduce pulmonary hypertension and improve gas exchange by normalizing the ventilation–perfusion ratio.
Nitric oxide is typically administered to neonates by inhalation in doses ranging from 5 to 80 parts per million.129 This treatment generally decreases the symptoms of neonatal respiratory distress syndrome and improves arterial oxygenation because of better ventilation–perfusion ratios throughout the lung.135 Nitric oxide may also produce optimal benefits if combined with other pharmacologic interventions such as surfactant replacement therapy.
Short-term inhalation of nitric oxide is tolerated fairly well, although this substance can irritate the respiratory tissues, inhibit platelet aggregation, inactivate surfactant, and cause severe acute pulmonary edema in some infants.136When administered to term or near-term infants, or preterm infants who are not severely ill, nitric oxide may improve the chance of survival and decrease the chance that the child will develop chronic lung disease.137,138On the other hand, nitric oxide inhalation may not be effective in severely ill, premature babies and may increase the risk of other problems such as intraventricular hemorrhage in this population.137 Nitric oxide therapy, therefore, continues to be an option for treating certain cases of neonatal respiratory distress syndrome, and future studies should help clarify how this intervention can be used most effectively with minimal risk to the infant.
Glucocorticoids
As indicated earlier in this chapter, glucocorticoids are anti-inflammatory steroids that play a key role in controlling airway inflammation in diseases such as asthma and COPD (see Table 8-6). These drugs may also help prevent and treat respiratory distress syndrome in neonates. When administered to the mother before the infant is born (antenatally), glucocorticoids cross the placenta and facilitate lung maturation in the infant. This treatment can, therefore, be used when premature birth is imminent and help improve respiratory function after the baby is born.139 Glucocorticoids can likewise be administered directly to the neonate (postnatally) to treat inflammation and reduce the risk of the infant developing chronic respiratory problems.140
The use of glucocorticoids is always associated with some potentially severe side effects. Administration to neonates can increase the risk of gastrointestinal bleeding, hyperglycemia, and hypertension.141 There is also a concern that antenatal and postnatal glucocorticoid administration could impair growth and development of the lungs, brain, and other tissues in the neonate.139,142 One study investigated the chance of developmental problems and failed to see any detrimental effects of a single antenatal glucocorticoid dose on individuals who ultimately reached adulthood (mean age 31 years).143 Another study found that premature infants receiving a specific postnatal glucocorticoid regimen (4.75 mg/kg dexamethasone over 2 weeks) did not experience any adverse effects on growth or neurodevelopment when the children reached 3 years of age.144 These findings, however, cannot rule out the possibility that problems may occur if multiple or higher doses are given antenatally or postnatally. Despite these concerns, glucocorticoids remain, along with surfactant therapy and other pharmacological and nonpharmacological interventions, an important option for reducing the incidence of neonatal respiratory distress syndrome and preventing chronic respiratory problems as the child matures.
MEDICATIONS RELATED TO PREFERRED PRACTICE PATTERN H: IMPAIRED CIRCULATION AND ANTHROPOMETRIC DIMENSIONS ASSOCIATED WITH LYMPHATIC SYSTEM DISORDERS
General Treatment Strategies for Lymphedema
The lymphatic system drains excess fluid and macromolecules (proteins, other cells) from the interstitial spaces throughout the body and returns these substances to the vascular system via the thoracic duct. Any disruption in this drainage system results in accumulation of excess fluid in the affected region, a condition known commonly as lymphedema. Because the affected body part is often the patient’s arm or leg, physical therapists play a critical role in helping to reduce the swelling and improving function in the affected extremity.
Lymphedema is typically classified as either primary or secondary depending on the causative factors.145 Primary lymphedema occurs because of some inherent defect in the development or function of the lymphatic vessels, such as congenital malformation of the lymphatics or fibrosis of lymph nodes. Secondary lymphedema is associated with a specific insult to the lymphatics such as surgical removal of lymph nodes, infection, trauma. Regardless of the initiating factor, lymphedema often results in substantial disability because of pain, decreased movement, impaired circulation, and increased risk of infection in the affected limb(s).
Treatment of lymphatic system disorders typically focuses on physical methods (massage, exercise, compressive dressings or garments) to reduce the accumulation of fluid in the affected arm or leg.146 This fact is especially true in chronic lymphedema associated with removal or damage to the lymph nodes following treatment for breast cancer and other malignancies. Operative treatment for lymphedema is also an option in selected cases where a specific blockage of the lymphatics can be removed surgically.
Drug therapy may also play a role in resolving specific lymphatic disorders. Infection in the lymphatic system, for example, can impair lymph drainage, and the use of appropriate anti-infectious agents is often useful in treating this form of lymphedema. This fact is especially true for filarial infections, where small parasitic worms (filariae) invade the lymphatics and restrict lymph flow resulting in severe lymphedema known commonly as elephantiasis.147Specific anti-infectious agents such as ivermectin, diethylcarbazine, and albendazole destroy these parasitic worms, and these drugs can often be very effective in resolving this type of lymphedema.
Other anti-infectious agents can be used to treat infection in limbs with chronic lymphedema.145 The accumulation of lymph, a fluid rich in proteins, in a limb with poor circulation creates a milieu for the growth of bacteria and other microorganisms. Hence, an appropriate anti-infectious drug can help resolve these infections and reduce the pain and swelling in the affected limb.
In addition, anti-inflammatory agents such as glucocorticoids (prednisone, others) can be used to treat cellulitis and other inflammatory responses associated with lymphedema. Pain medications may also be useful for the short-term management of pain and tenderness in affected extremities. These medications do not directly resolve edema, but can help reduce pain and inflammation so that the patient can participate in exercises and other interventions that help reduce swelling.
Hence, several drug strategies are available to treat the causative factor in certain lymphatic disorders (eg, infection), and to help treat other problems associated with lymphedema. There is, however, considerable controversy about whether any drugs can reduce the accumulation of lymph in either primary or secondary lymphedema. Several drug strategies have been proposed to actually reduce the swelling associated with lymphatic system disorders, and these strategies are addressed briefly in the next section.
Specific Drugs That May Decrease Lymphedema
Diuretics
As discussed earlier in this chapter, diuretics increase the renal excretion of sodium and water and thereby, remove excess fluid from the body. These drugs would seem like a logical choice to reduce the accumulation of fluid in a lymphedematous arm or leg. Diuretics, however, are often not effective in the long-term management of lymphedema because they can reduce the fluid content in the affected limb, but do not remove the proteins and other cells that create an osmotic force to draw fluid into the interstitial space.148,149 In other words, any loss of fluid from the interstitial space will quickly be replaced because the proteins and other osmotically active substances are still present to pull fluid out of the capillaries and cells and maintain the lymphedema.
Hence, diuretics fail to resolve the underlying factors that cause lymph to accumulate in the tissues, and the affected limb does not really undergo a substantial reduction in size or volume. Long-term use of diuretics is, therefore, not typically helpful in chronic lymphedema, and their use is often discouraged because of the risk of disturbing the body’s fluid and electrolyte balance.149
Benzopyrone Derivatives
Benzopyrones are a group of compounds that include coumarin and flavonoid drugs.150,151 These compounds are believed to stimulate macrophage function and thereby increase the breakdown and removal of proteins and other waste products in lymphedema. By helping remove these osmotically active substances, these drugs would reduce the tendency for fluid to accumulate in the interstitial space and thereby reduce lymphedema.
There is, however, conflicting evidence about the effectiveness of coumarin and other benzopyrones in treating lymphedema.152,153 Although some studies suggest beneficial effects, other studies have failed to determine conclusively that these drugs are useful in reducing limb volume and improving function in people with lymphedema.152 Hence, coumarin is used in certain countries (eg, parts of Europe), but this drug is not approved for treating lymphedema in the United States. It is not clear if additional research will establish a more definitive role for this drug in treating lymphedema.
Selenium
Selenium is a trace element in the body that can also act as an antioxidant and free-radical scavenger. This effect purportedly helps reduce free-radical damage thereby decreasing the inflammation and tissue damage that can increase lymphedema after surgery or following radiation treatments.154 The actual effects of this treatment remain unclear, and additional studies are needed to verify that selenium can actually reduce the severity and improve outcomes in people with lymphedema.155
Several drug strategies have, therefore, been advocated for reducing lymphedema. None of these strategies have been overwhelmingly successful, however. At the present time, drug therapy plays a secondary role in the treatment of lymphedema, with physical interventions (massage, exercise, and compression) being a much more accepted method for reducing chronic lymphedema.
SUMMARY
This chapter described medications that are commonly used to help prevent or treat cardiopulmonary disease. These medications were grouped according to how they relate to the preferred cardiopulmonary practice patterns listed in the Guide to Physical Therapist Practice. Medications often promote improvements in function that are synergistic with the interventions and anticipated goals listed in the practice patterns. These medications, however, also produce side effects that can have a negative impact on the patient and on the patient’s response to physical therapy. By understanding the therapeutic and adverse effects of these medications, physical therapists will hopefully be able to capitalize on the beneficial effects while being aware of the potential side effects of these drugs.
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