(BQ) Part 2 book Cardiovascular pharmacotherapeutics presentation of content: Cardiovascular Drug–Drug interactions, pediatric cardiovascular pharmacology, drug therapy of cerebrovascular disease, drug treatment of peripheral vascular disorders, cytokines and myocardial regeneration,...
Part Special Topics Alternative and Complementary Medicine for Preventing and Treating Cardiovascular Disease 30 William H Frishman, MD M ore and more individuals are looking outside the borders of conventional medicine for at least part of their health care needs.1 In the United States, more visits are being made to nonconventional healers than to physicians, at an annual cost of over $30 billion; most of this cost is out-of-pocket As a health care discipline, alternative medicine is defined as those medical approaches that in the past were not traditionally addressed in allopathic medical schools Complementary medicine is a term first used in Great Britain to describe the use of alternative medicine as an adjunct to, and not primarily a replacement for, conventional medical care In the 21st century, there is an ongoing effort to integrate complementary and alternative medicine (CAM) into conventional medicine practice (Integrative Medicine) In 1998, the National Institutes of Health, recognizing the need to vigorously evaluate CAM therapies, created the National Center for Complementary and Alternative Medicine (NCCAM), which supports ongoing scientific research and educational programs.2 In recent years, multiple hospitals have formed Centers of Integrative Medicine, and many allopathic medical schools are now offering course work in CAM CAM therapies have been used to treat cardiovascular disorders However, the use of CAM for treating cardiovascular disease is a highly charged subject with both critics and proponents.3 CAM therapies are a challenge to the scientific training of many cardiovascular physicians, with most positive observations being considered a placebo effect (see Chapter 2, The Placebo Effect in the Treatment of Cardiovascular Disease), which has been shown to be very powerful in patients with cardiovascular disease, especially in those who participate in randomized clinical trials (Table 30-1).4 A recent study with patient-based evaluations showed that cardiovascular patients treated by CAM doctors are more likely to be satisfied with the overall treatment outcome, possibly because of the longer and better patient-practitioner interaction.5 Therefore, physicians can no longer turn a deaf ear to the possibilities of CAM, and a growing number are already integrating CAM into their practices or are referring their patients to other CAM practitioners The American College of Cardiology has been sponsoring an annual course on CAM as part of their continuing medical education efforts In a recent workshop, the NCCAM emphasized the need for an exchange of ideas between CAM practitioners and scientists, and for collaborative research efforts One study used the 2002 National Health Interview Survey and analyzed data on CAM use in 10,572 respondents with cardiovascular disease.6 Among those with cardiovascular disease, 36% had used CAM (excluding prayer) in the previous 12 months The most commonly used therapies were herbal products (18%) and Table 30-1: Examples of Placebo Effects in Cardiovascular Disease from Clinical Trials Chronic stable angina pectoris improvement (symptomatic relief and enhanced exercise tolerance) 30-80% Heart failure improvement (symptomatic relief and improved exercise tolerance) 25-35% Adapted with permission from Frishman WH, Lee W-N, Glasser SP, et al The placebo effect in cardiovascular disease In: Frishman WH, Sonnenblick EH, Sica DA, eds Cardiovascular Pharmacotherapeutics 2nd ed New York: McGraw-Hill; 2003:15 Cardiovascular Pharmacotherapeutics, 3rd ed © 2011 William H Frishman and Domenic A Sica, eds Cardiotext Publishing, ISBN: 978-0-9790164-3-1 473 474 Cardiovascular Pharmacotherapeutics mind-body therapies (17%) Among herbs, echinacea, garlic, ginseng, ginkgo biloba, and glucosamine with or without chondroitin were most commonly used Overall, fewer respondents (10%) used CAM specifically for their cardiovascular conditions (5% for hypertension, 2% for coronary artery disease [CAD], 3% for vascular insufficiency, < 1% for heart failure [HF] or stroke) Most, however, who used CAM for their cardiovascular condition perceived the therapies to be helpful (80% for herbs) Clearly, the use of alternative medicine is far higher than previously reported Although most alternative therapies are relatively innocuous, some involve the use of pharmacologically active substances (eg, herbal medicine, megavitamin therapy, and some folk remedies) that could complicate existing medical therapy or even harm patients Although an increasing number of physicians are becoming more comfortable with alternative medicine, the widespread use of nutritional supplements with potential pharmacologic activities demands that all physicians not only inquire about their patient’s use of alternative medicine but also educate themselves and their patients as to the potential harms and benefits of these remedies The reluctance of patients to disclose their use of complementary medicines stems from fear of disapproval of these interventions by their physicians and from the belief that natural remedies are harmless Surveys also indicate that patients fail to discuss the use of dietary supplements with their health care providers because they believe that these practitioners know little or nothing about these products and may even be biased against them Rather than dismissing a patient’s highly motivated intentions toward health-conscious behaviors or refusing to prescribe for them out of fear of potential drug interactions, it behooves physicians to understand the range of complementary therapies available and when they can be safely integrated into conventional medicine Thus, they may more effectively counsel their patients in a collaborative and more effective atmosphere of open communication Physicians’ knowledge of nutritional supplement intake is also critical to avoid potentially dangerous interactions with prescribed medication For example, consider patients taking warfarin who are also ingesting nonprescribed natural blood thinners such as garlic, ginger, fish oil, ginkgo biloba, and even excessive amounts of vitamin E at the same time Such a combination clearly poses potential risks for both patient and the physician! This chapter limits its review to some of the pharmacologically active substances most commonly used or that have effects on the cardiovascular system based on the existing scientific literature This chapter pays attention to medicinal plants, which the author accepts to be pharmacologically active substances in a diluted form, and other alternative remedies (vitamins/minerals, other micronutrient supplements, homeopathic remedies, and chelation) Megavitamins and Other Micronutrient Substances Vitamins and minerals are required in trace amounts for normal bodily functioning A number of people have subscribed to the notion that “more is better.” Ingestion of micronutrient supplements (vitamins and minerals) beyond the “recommended daily allowances” (RDAs) is beneficial in certain deficiency states resulting from inadequate intake, disturbed absorption, or increased tissue requirements; however, routine dietary supplementation of micronutrients in the absence of deficiency states and beyond what one can usually obtain from consumption of a well-balanced diet has been shown to be of questionable benefit and in some cases may be harmful.7-9 Of course, there are exceptions This section reviews those micronutrient supplements with beneficial, neutral, and harmful effects on the cardiovascular system (Table 30-2) In 1994, the US Congress passed the Dietary Supplement Health and Education Act, which prevents the US Food and Drug Administration (FDA) from regulating vitamins, minerals, and herbal products as drugs The law permits the continued marketing of dietary supplements sold before October 15, 1994 (defined as vitamins, minerals, botanicals, amino acids, enzymes) without the review or approval of any government agency In June 2007, the FDA established the dietary supplement current Good Manufacturing Practice (cGMP) regulation that requires manufacturers to evaluate their products through testing identity, purity, strength, and composition Health claims can be made on the label with FDA approval and a disclaimer saying that the product is not intended to diagnose, treat, cure, or prevent any disease The Rationale for Targeted Nutritional Supplements for Cardiovascular Health The heart, which has approximately 5,000 mitochondria per cell and functions in a high-oxygen environment, is one of the most susceptible of all organs to free-radical oxidative stress Fortunately, it is also highly responsive to the benefits of targeted nutritional agents, such as phytonutrients, antioxidants, and nutraceuticals The term nutraceutical includes a wide variety of nonprescription nutritional supplements9a normally found in the body or in natural sources (such as vitamins, amino acids, and herbals).8 Strong scientific evidence from large and repeated clinical trials has confirmed their efficacy and safety as well as guidelines for patient selection, dosage, and potential medication interactions Dietary phy- Alternative and Complementary Medicine 475 Table 30-2: Clinical Effects of Nutraceutical Supplementation* to Prevent and Treat Cardiovascular Disease Nutraceutical Effect Vitamin E No benefit, potential mortality risk with supplemental doses > 400 IU Vitamin C No benefit proven Thiamine Useful in depletion state related to diuretics Vitamin B12 Reduces homocysteine levels, but no benefit proven Vitamin D No benefit proven Vitamin K May be effective in reducing vascular calcification Folic Acid Reduces homocysteine levels, but no benefit proven Pyridoxine (Vitamin B3) Reduces homocysteine levels, but no benefit proven Niacin (nicotinic acid) Reduces cholesterol, LDL-C, VLDL-triglycerides, raises HDL-C, mortality benefit in MI survivors Carotenoids No benefit proven, possible increased mortality risk Flavonoids No benefit proven Alcohol Small amounts (≤ 1oz/day in males, ≤ 0.5 oz/day females) may reduce risk of both cardiovascular and cerebrovascular diseases Magnesium May have benefits in reducing blood pressure, may be protective during acute MI Chromium Mild cholesterol-lowering effect Selenium No benefit proven Coenzyme Q10 No benefit proven L-Carnitine No benefit proven Omega fatty acids No benefit proven in reducing the risk of CAD L-arginine No benefit proven Taurine No benefit proven Amino acid mixtures No benefit proven * Supplementation is defined as prophylactic treatment beyond the normal daily requirements of substance Adapted with permission from Greenberg ER, Baron JA, Karagas MR, et al Mortality associated with low plasma concentration of beta carotene and the effect of oral supplementation JAMA 1996;275:699-703 Copyright © 1996 American Medical Association All rights reserved tochemical products, antioxidant vitamins (A, C, E) and bioactive food components (alpha- and beta-carotene) have shown an antioxidant effect in reducing both oxidative stress markers and low-density lipoprotein (LDL)oxidization process.10 Fat-soluble vitamins (K, E, D, and A) are stored to a variable extent in the body and are more likely to cause adverse reactions than water-soluble vitamins, which are readily excreted in the urine Excessive vitamin K can cause hemolysis in persons with glucose-6-phosphate dehydrogenase (G6PD) deficiency and anemia (with Heinz bodies), hyperbilirubinemia, and kernicterus in newborns; moreover, vitamin K can counter the effects of oral anticoagulants by conferring biologic activity on prothrombin and factors VII, IX, and X In contrast, high doses of vitamin E may potentiate the effects of oral 476 Cardiovascular Pharmacotherapeutics anticoagulants by antagonizing vitamin K and prolonging prothrombin time Megavitamins and Minerals Vitamin E Vitamin E’s antioxidant and anticoagulant properties are thought to protect against myocardial infarction (MI) and thrombotic strokes.11 An extensive review article assessed the preventive effects of vitamin E on the development of atherosclerosis.12 a-Tocopherols are the key lipid-soluble, chain-breaking antioxidants found in the tissues and plasma Oxidation of unsaturated fatty acids in LDL particles, as a pivotal factor in atherogenesis, is widely recognized Vitamin E, a predominant antioxidant present in the LDL particle, blocks the chain reaction of lipid peroxidation by scavenging intermediate peroxyl radicals.12 Vitamin E supplementation can reduce lipid peroxidation by as much as 40% Key cardioprotective effects of vitamin E are stabilizing plaque, reducing inflammation, decreasing thrombolytic aggregation, reducing the expression of adhesion molecules on the arterial wall, and enhancing vasodilation.12 However, prospective controlled clinical trials have presented a confusing picture Past major human trials on vitamin E supplementation have included the Alpha Tocopherol Beta Carotene (ATBC), Cambridge Heart Antioxidant Study (CHAOS), Gruppo Italiano per lo Studio della Sopravvivenza nellInfarto Miocardico (GISSI), Secondary Prevention with Antioxidants of Cardiovascular Disease in End-Stage Renal Disease (SPACE), and Heart Outcomes Evaluation (HOPE) trials A statistical reanalysis of the data, including the totality of the evidence, suggests that a-tocopherol supplementation does not have a place in treating patients with preexisting cardiovascular disease.13-18 In addition, the results of the MRC/BHF Heart Protection Study19 in 20,536 high-risk individuals showed no benefit from Vitamin E supplementation (600 mg daily) on morbidity and mortality However, a recent study demonstrated that 100 and 200 mg of vitamin E caused a marked improvement in arterial compliance,20 and a recent report from the Women’s Health Study demonstrated that women receiving vitamin E supplement had a lower risk of venous thromboembolic disease.21 The Women’s Antioxidant Cardiovascular Study (WACS) tested the effects of ascorbic acid (500 mg/d), vitamin E (600 IU every other day), and beta carotene (50 mg every other day) on the combined outcome of MI, stroke, coronary revascularization, or cardiovascular disease death among 8171 female health professionals and found no significant overall benefits.22 To prevent pregnancy-associated hypertension, 10,154 pregnant women were randomized to received 1000 mg of vitamin C and 400 IU of vitamin E or matching placebo In the 9th to 16th week of gestation, vitamin therapy did not reduce the rate of adverse maternal or perinatal outcomes related to pregnancy-induced hypertension.22a In addition, the Physician’s Health Study II revealed no cardiovascular benefits from every other day supplements of 400 IU of vitamin E administered to 14,641 male physicians older than 50 years.23 NCCAM is studying the effect of a tocopherol supplementation (1200 IU/day) on the progression of carotid atherosclerosis in patients with CAD (stable angina pectoris or previous MI) in a placebo-controlled, randomized double-blind trial over years At this time, given the numerous studies and trials, the rationale for vitamin E use in healthy individuals and those with cardiovascular disease is still questionable.12 There is also a suggestion that high doses of vitamin E may confer an increased risk for developing calcific atherosclerosis.24 Vitamin C Vitamin C is not only a scavenger antioxidant, but it also acts synergistically with vitamin E to reduce the peroxyl radical In addition to blocking lipid peroxidation by trapping peroxyl radicals in the aqueous phase, vitamin C helps normalize endothelial vasodilative function in patients with heart failure by increasing the availability of nitric oxide.8 Although the evidence linking vitamin C to human cardiovascular disease is still being evaluated, one study did report that vitamin C slowed the progression of atherosclerosis in men and women older than 55 years.25 It is also well known that many groups known to be at an increased risk for CAD have lower blood levels of vitamin C, including men, the elderly, smokers, patients with diabetes mellitus, patients with hypertension, and possibly women taking oral estrogen contraceptives Female users of vitamin C supplement in the Nurse’s Health Study were shown to be at lower risk for CAD.26 British researchers found that higher blood levels of vitamin C were directly and inversely related to death from all causes and specifically death from ischemic heart disease in both men and women.27 The researchers strongly advocated modest consumption of fruits and vegetables, since their results suggested that the equivalent of extra serving of vitamin C–rich food reduced the risk of death by 20% However, the consumption of carotenoids, flavonoids, magnesium, and other health-promoting nutrients affected these data High doses of Vitamin C have also been associated with decreased levels of nitric oxide (NO) production by endothelial cells.28 Vitamin C at daily doses of 500 mg has been shown to increase red cell glutathione by 50% Glutathione is not only the major antioxidant responsible for inhibiting lipid peroxidation but also a key contributing agent in stabilizing immune function However, the results of the MRC/BHF Heart Protection Study showed no benefit from vitamin C supplementation (250 mg daily) on morbidity and mortality in high-risk Alternative and Complementary Medicine 477 patients with cardiovascular disease.19 The WACS also has recently showed that there were no overall effects of ascorbic acid on cardiovascular events among women at high risk for CVD.25 In addition, results from the Physician’s Health Study II did not show any benefit from 500 mg of vitamin C in prevention of cardiovascular disease.23 Megadose vitamin C (> 500 mg a day) in patients who are vulnerable to iron overload states should also be avoided Vitamin C supplements may exacerbate iron toxicity by mobilizing iron reserves Such patients may accumulate harmful excessive iron with higher doses of vitamin C, so caution must be employed for those with genetic diseases such as hereditary hemochromatosis, thalassemia major, or other diseases that promote iron overload B Vitamins Clinical cardiologists must be familiar with B vitamin support for their patients B vitamin (thiamine) depletion commonly occurs as a result of high-dose diuretic therapy used in the treatment of congestive heart failure (CHF) and should be considered in any patient with refractory CHF that is unresponsive to high-dose diuretic therapy.29 The nocturnal leg cramps associated with diuretic therapy are a hallmark symptom of B vitamin depletion The involuntary, painful contraction of the calf muscles and other areas of the leg can be alleviated with B vitamin support, resulting in an improved quality of life A randomized placebo-controlled double-blind study30 validated the efficacy of B complex supplementation in the treatment of nocturnal cramps Of 28 elderly patients, 86% taking vitamin B complex reported remission of prominent symptoms compared to the observation of no benefit in the placebo group Most cardiologists are now familiar with the idea of providing B vitamin supplementation to treat hyperhomocysteinemia In 1969, McCully31 first proposed the homocysteine hypothesis, identifying accelerated vascular pathology as a sequela to homocystinurias, a rare autosomal recessive disease caused by a deficiency in cystathione B-synthetase Several investigations have confirmed his proposed connection between high plasma homocysteine levels and occlusive arterial disease, including peripheral vascular disease, CAD, and CHF.8,29 Hyperhomocysteinemia may be even more detrimental in women than in men One study reported that women with CAD had higher homocysteine levels than matched control subjects.32 In another study involving postmenopausal women, high homocysteine levels in combination with hypertension resulted in an alarming 25 times higher incidence of stroke.33 It is well known that B vitamins reduce homocysteine levels significantly Research shows a dose-dependent relationship between higher homocysteine levels and lower serum levels of B vitamins; therefore, much higher doses must be administered to those patients with severe hyperhomocysteinemia and documented CAD.34 Although this may have been shown previously, it is now more apparent that this may no longer be the case The trials completed to date not provide clear evidence of any beneficial effects of B vitamin supplementation in cardiovascular disease risk reduction.35 Several trials including the Vitamins Intervention for Stroke Prevention (VISP) trial, Heart Outcomes Prevention Evaluation (HOPE-2) trial, the Cambridge Heart Antioxidant Study (CHAOS-2), the Norwegian Vitamin Trial (NORVIT), and more recently, the Western Norway B-Vitamin Intervention Trial (WENBIT) have failed to demonstrate benefits with vitamin B supplementation.36-40a Moreover, treatment with folic acid plus vitamin B12 was associated with an increased risk of cancer and all-cause mortality in patients with ischemic heart disease.40b In a recent study, Albert et al showed that after 7.3 years of treatment and follow-up, a combination pill of folic acid, vitamin B6, and vitamin B12 did not reduce a combined endpoint of total cardiovascular events among high-risk women, despite significant homocysteine lowering.41 Some limitations of this study may be the introduction of mandatory folate-food–fortification policies in the United States and Canada resulting in lesser effects of B vitamin supplements on homocysteine levels; the vitamin doses used; and potential unexpected proatherosclerotic effects of folic acid supplementation, which may have counteracted benefits associated with homocysteine lowering Recently it was shown that treatment with high doses of folic acid and B vitamins did not improve survival or reduce the incidence of vascular disease in patients with advanced chronic kidney disease and endstage renal disease.42 A number of large trials are still in progress, including studies in populations with unfortified food supplies in Western Europe, Australia, and Asia It is still necessary for ongoing clinical research to provide evidence on whether there may be any role for homocysteine-lowering B vitamin supplements in CVD prevention and for the overall importance of homocysteine as a cardiovascular disease risk factor before it can be recommended routinely.35 Certainly, administration of B vitamins at the recommended daily allowance levels (folic acid = 400 mg; B6 = mg; B12 = mg) appears to be safe A potential hazard of folic acid therapy is subacute degeneration of the spinal cord with a subclinical vitamin B12 deficiency; folic acid may mask the development of hematologic manifestations in these patients This situation can be avoided by either ruling out B12 deficiency before initiating folic acid therapy or by supplementing folic acid with vitamin B12.34 High-dose niacin (vitamin B3) is used in the treatment of hyperlipidemia and hypercholesterolemia and helps 478 Cardiovascular Pharmacotherapeutics curb the development of atherosclerosis and its complications (see Chapter 20, Lipid-Lowering Drugs) Recent studies indicate that niacin also increases the vascular endothelial cell redox state, resulting in the inhibition of oxidative stress and vascular inflammatory genes, key cytokines involved in atherosclerosis.43 Over-the-counter niacin preparations are marketed under different names; some have no free nicotinic acid, which is the cholesterol-lowering component of niacin.44 Adverse effects of niacin include cutaneous flushing, pruritus, gastrointestinal disturbances, exacerbation of asthma, and even acanthosis nigricans Very high doses can cause liver toxicity Vasodilation and flushing, the most common side effects of niacin, may help patients who suffer from Raynaud’s phenomenon In an attempt to find a safer form of niacin with fewer adverse effects, investigators have developed extendedrelease, once-daily formulations of niacin (Niaspan) This slowly metabolized form of niacin does not reach maximum serum levels for several hours after ingestion, resulting in fewer and less severe adverse effects.45,46 Randomized, double-blind, placebo-controlled investigations showed that sustained-released niacin had an impact in decreasing LDL-cholesterol, total cholesterol, and triglycerides while raising high-density lipoprotein (HDL)-cholesterol at the same time.45,46 A study by Ceali et al, which compared the incidence, intensity, and duration of flushing between the 1,000 mg reformulated niacin ER and the 1,000 mg commercially available formulation, when administered as a single 2,000 mg dose to healthy male volunteers, found it to be an improved therapeutic option.47 Studies have also resulted in a new combination drug (extended release niacin [ERN] and laropiprant) Niacin is not optimally used, mainly because of flushing, a process mediated primarily by prostaglandin D(2), which leads to poor patient adherence and suboptimal dosing Laropiprant is a selective antagonist of the prostaglandin D(2) receptor subtype (DP1), which may mediate niacin-induced vasodilation A study by Paolini et al48 showed that laropiprant does not interfere with the beneficial lipid effects of niacin and can allow for the administration of a 2g dose of ERN in dyslipidemic patients In another trial of 1,613 patients, 10.2% patients stopped taking the medication in the ERN and laropiprant group because of flushing versus 22.2% with niacin monotherapy.49 The FDA has not approved the niacin-laropiprant combination (Cordaptive) for clinical use, and the commercial sponsor has withdrawn the combination agent from further study Vitamin D Vitamin D receptors have been found in the vascular smooth muscle,50 the endothelium,51 and in cardiomyocytes.52 There are data to suggest that low levels of 25-hy- Figure 30-1 Hypothetical associations between vitamin D insufficiency and cardiovascular disease MG, matrix GIa protein; RAS, renin-angiotensin system Adapted with permission from Cambridge University Press from Zitterman A, Schleithoff SS, Koerfer R Putting cardiovascular disease and vitamin D deficiency into perspective Br J Nutri 2005;94:483 doxyvitamin-D may be associated with the development of cardiovascular disease (Figure 30-1).53-55 Studies have shown an inverse relationship between vitamin D levels and plasma renin activity,56 hypertension,56 and coronary artery calcification.57 Recently, results from the Framingham offspring study suggest a direct association of vitamin D deficiency and the incidence of cardiovascular disease.58 Low levels of vitamin D have also been associated with fatal strokes,59 HF,59 sudden cardiac death,60 and calcific aortic stenosis It has also been observed that the prevalence of heart disease increases the further the distance from the equator, suggesting a deficiency of sunlight and vitamin D as the cause.61 Despite these findings, there is no suggested dose of vitamin D to prevent cardiovascular disease,62,62a and prospective studies need to be done to see if vitamin D supplementation can actually prevent cardiovascular disease.62b Vitamin K Insufficient vitamin K in the diet has been thought to increase the risk of soft tissue calcification and atherosclerosis.63 In various animal models, multiple forms of vitamin K have been shown to reverse the arterial calcification caused by vitamin K antagonists In humans, these findings have not been confirmed, and vitamin K is not recommended as an antiatherosclerotic treatment Carotenoids Serum carotenoids have been extensively studied in the prevention of CAD There are approximately 600 carotenoids found in nature, predominantly in fresh fruits and Alternative and Complementary Medicine vegetables, with carrots being the primary source of b carotene and tomatoes being the best source of lycopene Although lycopene has twice the antioxidant activity of b carotene, the latter has been the primary focus of study because of its activity as a precursor to vitamin A Elevated levels of serum b carotene have been associated with a lower risk of cancer and overall mortality.64 Research studies have shown an association between a high dietary intake of b carotene and a reduction in the incidence of cardiovascular disease,65 with study reporting that increased b carotene stores in subcutaneous fat were correlated with a decreased risk of MI.66 However, the results of the MRC/BHF Heart Protection Study showed no benefit from b carotene 20 mg daily on morbidity and mortality in high-risk individuals.19 In addition, the WACS recently showed that b carotene did not reduce cardiovascular risk in women with a high risk of cardiovascular disease,41 and results from the Physician’s Health Study II23 did not reveal any benefit from b-carotene use in primary prevention of cardiovascular disease Lycopene, an oxygenated carotenoid with great antioxidant properties, has shown a reduction in cardiovascular risk both in epidemiological studies and supplementation human trials A recent study in rats showed that tomatoes, containing or not containing lycopene, have a higher potential than lycopene to attenuate and/or to reverse oxidative stress-related parameters in a mild oxidative stress context.67 However, more recent controlled clinical trials and dietary intervention studies, using well-defined subject populations, have not provided any clear evidence for the use of lycopene in the prevention of cardiovascular diseases.10 Flavonoids Residents of France, whose diet is steeped in high-fat cheeses, rich sauces, gravies, pâtés, and other highly saturated fats, have a lower incidence of CAD than their American counterparts The typical French diet is the routine consumption of fresh fruits and vegetables that contain vital phytonutrients that may effectively reduce peroxidative tendencies and retard the varied interactions involved in atherogenesis and thrombosis Red wine consumption could be another factor Recent research has shown that plant-derived polyphenolic compounds are promising nutraceuticals for control of various disorders such as cardiovascular, neurological, and neoplastic disease The richness of the polyphenolic contents of green tea and red wine has made them popular choices for associated anticancer and cardiovascular health benefits.68 The serum antioxidant activity of red wine was addressed in a small study of volunteers, the results indicating that glasses of red wine consumed before a meal offered considerable antioxidant protection for at least hours.69 Red wine increased antioxidant activity through 479 a flavonoid-polyphenol effect In another small investigation performed in the Netherlands,70 the use of dietary bioflavonoids, phenolic acids, and quercetin showed a reduction in the incidence of heart attack and sudden death Quercetin-rich black tea, apples, and onions were the best foods evaluated, as they contain polyphenols in amounts similar to those found in the red grapes used in making wine and grape juice Short- and long-term consumption of black tea was shown to reverse endothelial vasomotor dysfunction in patients with CAD.71 Resveratrol, a component of wine, has been shown to activate platelet NO synthase and inhibit reactive oxygen species production and ultimately platelet function This activity may contribute to the beneficial effects of moderate wine intake on ischemic cardiovascular disease.72 Resveratrol, as an isolated substance, is now being investigated as a potential drug for use in cardioprotection Oligomeric proanthocyanidins, like carotenoids, are found predominantly in brightly colored fruits and vegetables and represent a safe source of polyphenols and quercetin, which are believed to be the most active protective ingredients in preventing the oxidation of LDL Oligomeric proanthocyanidins are significant free-radical scavengers that inhibit lipid peroxidation and contain anti-inflammatory and antiallergenic properties as well As this point, the optimal amount of flavonoids in the diet, the form or method of supplementation, and the dose are uncertain A trial is being conducted to investigate the bioavailability of flavonoids and phenolic acids from cranberry juice cocktail and their breakdown products (in vivo metabolites) in healthy, older adults.73 Nonetheless, many flavonoids are available as food supplements in doses as high as 500 and 1000 mg, an amount that may be 10 to 20 times the daily intake in a typical vegetarian diet An epidemiologic report from the Physician’s Health Study did not show a strong inverse association between intake of flavonoids and total CAD.74 A study at Boston University is currently recruiting subjects to compare the effect of drinking concord purple grape juice (7 ml/kg or about 16 oz/day for a 70 kg person) and the effect of a calorie-matched placebo on 24-hour ambulatory blood pressure, blood pressure reactivity, and vascular function in men and women in the category of prehypertension and Stage hypertension.75 Until the benefits of flavonoids are resolved in prospective controlled studies, patients may be encouraged to consume a diet that includes tea, apples, and onions in generous amounts Current research does not support the benefits of supplemental flavonoid intake, but additional research in this area is needed and is ongoing It does appear that ethyl alcohol in small amounts, without regard to beverage type, might provide protection against cardiovascular or cerebrovascular disease.76 480 Cardiovascular Pharmacotherapeutics Table 30-3: Possible Benefits of Flavonol-Rich Cocoa and Chocolate Antioxidant effect Antiatherosclerotic effect (prevention of LDL oxidation) Increase in HDL Improved insulin sensitivity Antiplatelet effect Increases nitric oxide production and vascular relaxation Anti-inflammatory effect Blood pressure lowering action (interference with actions of angiotensin converting enzyme inhibition) Reproduced with permission from Mehrinfar R, Frishman WH Flavanol-rich coca: A cardioprotective nutriceutical Cardiol in Rev 2008;16:109-115 Flavonol-Rich Cocoa Can chocolate be considered a health food? There is a growing body of medical literature that describes the possible short-term in vitro and in vivo cardioprotective effects of cocoa and chocolate (Table 30-3).77,78 They may exert antioxidant, anti-inflammatory, antiplatelet, and antihypertensive effects77 and may improve vascular function However, it should also be noted that the evidence for any cardiovascular benefits of cocoa flavonols (a type of flavonoid) has been gathered predominantly from short-term and uncontrolled studies Therefore, additional research with well-designed, long-term clinical studies using cocoa would be most helpful in assessing whether flavonol-rich cocoa could be a potential candidate for the treatment and/or prevention of cardiovascular disease The beneficial effects of chocolate also need to be balanced against its high caloric and high fat content Ultimately, if flavonol-rich cocoa is shown to be of benefit, it will become a tasty addition to the clinical armamentarium of nutraceuticals being used to prevent and treat heart disease.8,77 Magnesium A high intake of magnesium, potassium, and calcium through increased consumption of fruits and vegetables may improve blood pressure levels and reduce CAD and stroke (see Chapter 12, Magnesium, Potassium, and Calcium as Cardiovascular Disease Therapies).79 Magnesium deficiency has been shown to trigger vasoconstriction and enhance vascular endothelial injury, thus promoting the development and progression of atherosclerosis One study showed that there is a relationship between a low magnesium concentration in serum at 48 hours after onset of ischemic stroke and the intensity of the resulting neurological deficit.80 In anginal episodes due to coronary artery spasm, treatment with magnesium has been shown to be considerably efficacious.81 Magnesium deficiency, which is better detected by mononuclear blood cell magnesium than the standard serum level performed at most hospitals, predisposes to excessive mortality and morbidity in patients with acute myocardial infarction Several studies have shown an association between intravenous magnesium supplementation during the first hour of admission for MI and reductions in both morbidity and mortality Multiple cardioprotective and physiologic activities of magnesium include antiarrhythmic effects, calcium channel–blocking effects, improvement in NO release from coronary endothelium, and the ability to help prevent serum coagulation.82 Intravenous magnesium has been reported to be useful in preventing atrial fibrillation and ventricular arrhythmias after cardiac and thoracic surgery; in reducing the ventricular response in acute onset atrial fibrillation, including patients with Wolff-Parkinson-White syndrome; and in the treatment of digoxininduced supraventricular and ventricular arrhythmias, multifocal atrial tachycardia, and polymorphic ventricular tachycardia or ventricular fibrillation from drug overdoses Intravenous magnesium is, however, not useful in monomorphic ventricular tachycardia and electroshockresistant ventricular fibrillation.83 Magnesium has also shown considerable efficacy in relieving symptoms of mitral valve prolapse In a doubleblind study of 181 participants, subjective results in the magnesium group were dramatic, with significant reductions noted in weakness, chest pain, shortness of breath, palpitations, and even anxiety.84 Supplemental magnesium and potassium should be avoided in patients with renal insufficiency Ultimately, additional studies are needed to better understand the association between magnesium intake, indicators of magnesium status, and heart disease Trace Minerals Cobaltous chloride is sometimes used in the treatment of iron deficiency and chronic renal failure Excessive cobalt intake may cause cardiomyopathy and CHF, with pericardial effusions due to deposition of cobalt-lipoic acid complexes in the heart High cobalt consumption has also been implicated in thyroid enlargement, polycythemia, neurologic abnormalities, and interference with pyruvate and fatty acid metabolism Rarely, excessive iron ingestion may cause cardiomyopathy, CHF, and cardiac arrhythmias from hemochromatosis Chromium assists in glucose and lipid metabolism It may bring about regression of cholesterol-induced atherosclerosis In a study of 40 hypercholesterolemic patients (total cholesterol 210 to 300 mg/dL),85 a combination of 200 mg of chromium polynicotinate and (proanthocyani- 762 Index enoxaparin sodium (Lovenox), 315, 671–72 enoximone, 199 enterococcal endocarditis, 596–97, 597–600t enterococci resistant to vancomycin (VRE), 597, 600t Ephedra sinica (joint fir), 489 epileptic seizures, 560 epinephrine (Adrenalin) in children, 525–26 therapeutic use, 700–701 eplerenone (Inspra), 159t, 161, 696 epoprostenol (Flolan) adverse effects, 427 pulmonary hypertension, 426–30, 428f, 429t Raynaud’s syndrome, 578 therapeutic use, 713–14 eprosartan (Teveten) bioavailability, 127, 128t stroke prevention, 138 therapeutic use, 660–61 eptifibatide (Integrilin), 277, 676 ergot alkaloids, 562–63 erythropoietin about, 614–15 animal studies, 615 clinical trials, 615–16 esmolol (Brevibloc) adverse effects and drug interactions, 243 antiarrhythmic effects, 243 pediatric use, 534, 541 pharmacokinetics and metabolism, 243 pharmacology, 242–43 therapeutic use, 24, 682 esomeprazole, 504 estrogen conjugated, gender issues, 744 ineffectiveness as lipid-lowering agent, 361–62 etanercept, 591 ETC-216, 369–70 ethacrynic acid (Edecrin), 528, 691 ethical issues in clinical trials, 26–29 ethnicity and cardiovascular drug response, 751–52 ethylenediaminetetraacetic acid (EDTA) chelation therapy, 491, 491t exenatide (Byetta) cardiovascular outcomes, 415t, 422 off-label use for obesity, 407 exercise tolerance and placebo effect, 22, 23 expert opinion, 50 ezetimibe (Zetia) adverse effects, 360 clinical trials, 359–60 elderly patients, 748 pediatric use, 537 pharmacology, 359 therapeutic use, 360, 704 dosing in liver disease or congestive heart failure, 732–33 dosing in renal insufficiency, 739 F factor IXa inhibitors, 302–3 factor VII inhibitor, 303 factor Xa inhibition, 289–90 See also fondaparinux deep venous thrombosis, 586–88 idraparinux, 290, 303 orally administered, 301–2 FADs See fibric acid derivatives (FADs) fatty acid synthase inhibitors, 411, 411f felodipine (Plendil), 687 fenofibrate (Lofibra; Tricor) adverse effects and drug interactions, 342, 506 clinical trials, 341 mechanisms of action, 338–40 pharmacokinetics, 338 therapeutic use, 341, 705 fenofibric acid (Trilipix), 341, 705 fenoldopam (Corlopam) adverse effects, 443 hypertensive emergencies, 442–43 pharmacology, 442, 442t therapeutic use, 443–44, 714 fetal arrhythmias, 542–43 fibric acid derivatives (FADs) about, 337 adverse effects and drug interactions, 341–42 chemical structure, 337f clinical trials, 340–41 elderly patients, 748 mechanisms of action, 338–40 pharmacokinetics, 337–38 in pregnancy and lactation, 725 therapeutic use, 341, 705–6 dosage in liver disease or congestive heart failure, 733 dosage in renal insufficiency, 739 fibrinogen, 271–72 Fick’s law, 6–7 first-dose hypotension, 130 fish oil supplements, 361 flavonoids, 479 flecainide (Tambocor), 238–39, 540, 665 fluoxetine (Prozac) binge eating disorder, 399 off-label use for obesity, 410 Raynaud’s syndrome, 579 fluvastatin (Lescol), 343f, 350–51, 707 fluvoxamine (Luvox), 399 fondaparinux sodium (Arixtra) clinical trials, 289–90 deep venous thrombosis, 586–87 mechanisms of action, 289, 303, 303f therapeutic use, 672 fosinopril (Monopril), 657–58 functional renal insufficiency, 145 furosemide (Lasix) braking phenomenon, 161 congestive heart failure, pediatric, 528 pharmacodynamics, 158–59, 159t therapeutic use, 691–92 future costs, health economics, 43 G G proteins, 3, 4f galantamine hydrobromide, 96 garlic (Allium sativum), 487 gated channel receptors, 3, 4f gemfibrozil (Lopid) adverse effects, 341–42 atrial fibrillation prevention, 256 clinical trials, 340 drug-drug interactions, 341–42, 506 mechanisms of action, 338–40 pharmacokinetics, 337–38 therapeutic use, 341, 705–6 gender See also under specific drug names and classes health economics analysis and, 50–51, 52t medication-related issues, 743–44 gene therapy adenoviruses and gene transfer, 373–74 atherosclerosis, 373–75 chimeraplasty, 374 gene expression inhibition, 374 inotropic agents, 202 genetics and drug metabolism, 12, 13f gentamicin, 596, 597t, 599t, 601t, 606t ghrelin, 411 giant-cell arteritis, 590 Ginkgo biloba, 487–88, 575 gliclazide, 414t, 416 glimepiride, 414t, 416 glipizide, 414t, 416 glitazones, 372 glucocorticoids, 590 glucose intolerance, diuretic-associated, 173 glucose tablets, 393 a-glucosidase inhibitors, 414t, 417 glutamic acid supplementation, 483 Index glyburide, 414t, 416 glycoprotein Ib receptor antagonists, 296–87 glycoprotein IIb/IIIa receptor antagonists about, 271–72, 272f adverse effects, 277 antiplatelet agents disintegrins, 272–73 monoclonal antibodies, 273–77, 275t orally active, 277–78 synthetic, 277 combination use with thrombolytic agents, 313–114 gender issues, 743 platelet binding, 272, 273f granulocyte colony stimulating factor about, 610 animal studies, 611–12, 612f clinical trials, 612–14 grapefruit juice, 502–3 growth factors, 573 GT16-239 (bile acid sequestrant), 371 guanabenz (Wytensin), 88t, 89, 655 guanadrel (Hylorel), 710 guanethidine (Ismelin), 710–11, 743 guanfacine (Tenex), 88t, 89, 655 guggul (Commiphora mukul), 487 GW501516 (PPAR agonist), 372 H half-life, 9–10, 10f hawthorn (Crataegus oxyacantha), 485 HDL cholesterol, low, 327–28, 328t HDL infusion therapy, 369–70 health economics and drug utilization, 39–54 about, 39–40 cost-effectiveness analysis, 40, 41t cost-utility analysis and quality of life, 44–45, 54 data sources, 48–50 efficacy vs effectiveness, 43–44, 44t evaluation methods decision-analytic models, 45–47, 45f, 46f mathematical spreadsheets, 47– 48, 49t health care costs and medication adherence, 33 incremental benefits of new therapies, 39 patient subgroups, evaluation targeting age, gender, and pretreatment lipid levels, 50–51, 52t comorbid conditions, 52 pretreatment blood pressure, 50–51, 52t perspective of analysis, 41–42 resource and cost components, 42–43 sensitivity analysis (robustness) of results, 52–53, 53f, 54 time frame (discounting and time horizon), 43 types of analyses, 40–41, 42t ultimate use of evaluations, 50 heart failure See also congestive heart failure (CHF) ACE inhibitors, 139, 142–43 angiotensin II receptor blockers, 143 digitalis glycosides, 193 diuretics, 167–71 drug metabolism and, 13 medication adherence impact on, 33 nesiritide, 446–48 new drugs in development, 624t pathophysiology, 167–68 prevalence, 31 heart transplantation, 189, 331–32 heme-oxygenase-1, 375 hemodialysis low-molecular-weight heparin, 286 occluded access and thrombolytic agents, 321 hemodilution, 575 hemorrhage, 316–17 hemorrhagic stroke intracerebral hemorrhage, 563–64, 563t new drugs in development, 629t pathophysiology, 548t, 549 subarachnoid hemorrhage, 563t, 564 heparin See also low-molecular-weight heparin (LMWH) adverse effects, 280–81 cardioembolic stroke, 559 dosing, 280 mechanisms of action, 278, 279f oral administration, 302 pharmacodynamics, 279 pharmacokinetics, 279 shortfalls for usage, 281 therapeutic use, 672–73 adjunctive, with thrombolytic agents, 314–15 myocardial infarction and unstable angina, 279–80, 314–15 orthopedic and general surgery, 279 venous thrombosis, 279 unfractionated, 581–82 hepatocyte growth factor (HGF), 573 763 herbal remedies about, 483–84, 484t angina pectoris, 486–87 atherosclerosis, 487 cerebral and peripheral artery diseases, 487–88 congestive heart failure, 484–85 drug-herbal interactions, 490, 490t herbs with adverse cardiovascular effects, 489t Aconitum spp., 489–90 Ephedra sinica (joint fir), 489 jin bu huan, 490 Tussilago farfara (coltsfoot), 489 hyperlipidemia, 487 hypertension, 485–86 venous insufficiency, 488–89 HIF1a (hypoxia-inducible factor1-a), 573 hirudin adverse effects, 288 deep venous thrombosis, 588 mechanisms of action, 287 monitoring therapy and dosage, 288 myocardial infarction, 287–88 percutaneous transluminal coronary angioplasty, 288 HMG-CoA reductase inhibitors atorvastatin (See atorvastatin (Lipitor) in children, 537 drug-drug interactions, 505, 506 effectiveness, 354–55 elderly patients, 748 ethnicity and efficacy, 752 fluvastatin (Lescol), 343f, 350–51, 707 gender issues, 744 with implantable cardioverterdefibrillators, 354 innovative uses, 354 intermittent claudication, 353–54 lovastatin (See lovastatin) noncardiac vascular surgery, 354 peripheral arterial disease, 570–71 pitavastatin, 353 pravastatin (See pravastatin (Pravachol) in pregnancy and lactation, 725 rosuvastatin (Crestor), 353, 709 simvastatin (See simvastatin (Zocor) therapeutic use, 706–10 dosage in liver disease or congestive heart failure, 733 dosage in renal insufficiency, 740 homeopathic remedies, 490–91 human recombinant growth hormone (hrGH), 410 764 Index hydralazine (Apresoline) adverse effects, 224 gender issues, 743 pharmacology, 223–24 therapeutic use, 714 hydrochlorothiazide (HydroDIURIL) congestive heart failure, pediatric, 528–29 pharmacodynamics, 159t, 160 therapeutic use, 694 hydroflumethiazide (Diucardin; Saluron), 694 hyperaldosteronism, 144 hypercalcemia, 186 hypercholesterolemia cost-effectiveness of treatments, 50–51, 52t treatment criteria, 325–26, 326t, 327t hyperglycemia, 173, 413 See also diabetes mellitus hyperglycemic agents cardiovascular outcomes, 414t– 415t, 416–22 clinical trials, 422–24 DPP-IV inhibitors, 415t, 421–22 glucagon-like peptide-1 agonists, 415t, 422 a-glucosidase inhibitors, 414t, 417 insulin, 415t, 422 insulin secretagogues, 414t, 416–17 metformin, 415t, 417–18 sulfonylureas, 414t, 416 thiazolidinediones, 415t, 418–21 hyperkalemia, 145, 172 hyperlipidemia See also lipid-lowering drugs beta-blockers causing, 82 diuretic-induced, 173 herbal remedies, 487 screening criteria, 325 treatment rationale for coronary artery disease prevention, 324–25 hypertension See also antihypertensive drugs in children (See also pediatric pharmacology, antihypertensive drugs) about, 532 chronic, management of, 535–36 hypertensive emergencies, 532 combination drug therapy, 377–84 (See also antihypertensive drugs, combination therapy) defined, 162 diuretic therapy, 162–67 herbal remedies, 485–86 medication adherence impact on, 32 nonspecific vasodilators, 223–25 peripheral neuron depleters, 90–91 placebo effect on, 23–24 pulmonary (See pulmonary hypertension) systemic (See systemic hypertension) hypertensive emergencies calcium channel blockers, 113 in children, 535 fenoldopam, 442–43 nitrates, 209 hypertriglyceridemia, 326–27 hypertrophic cardiomyopathy beta-adrenergic blocking drugs, 78 calcium channel blockers, 114 placebo effect in, 25 hyperuricemia, diuretic-related, 173–74 hypoglycemia, 82 hypokalemia, 171–72, 171f, 184–85 hypomagnesemia causes of, 172, 181t in congestive heart failure, 179 in diabetes, 179 diagnosis and treatment, 180–82 hyponatremia, 171, 460 hypoxia-inducible factor1-a (HIF1a), 573 I ibutilide (Corvert) adverse effects and drug interactions, 247 antiarrhythmic effects, 247 pediatric use, 542 pharmacokinetics and metabolism, 246–47 pharmacology, 246 therapeutic use, 247, 667–68 idrabiotaparinux, 303 idraparinux, 290, 303 ileal Na+/bile acid cotransporter (IBAT) inhibitors, 370–71 iloprost (Ventavis) peripheral vascular disorders, 572 pulmonary hypertension, 430–31 Raynaud’s syndrome, 578 therapeutic use, 714–15 imidazole receptor agonists, 90 imipenem/cilastatin combination, 596, 600t implanted cardiac assist devices, infection, 605, 607 impotence and diuretics, 174 inamrinone (Inocor), 526–28, 699 incremental cost-effectiveness ratio (ICER), 40 indapamide (Lozol), 137, 694 indomethacin, 544, 544t idraparinux, 587 infective endocarditis See endocarditis, infective infliximab, 591 informed consent, 28 inhaled drug administration, injected drug administration, inotropic agents, 189–203 about, 189–90 calcium channel sensitizers, 199– 201 catecholamines, 195–97, 195f, 196t digitalis glycosides (See also digoxin) clinical use, 192–94 pharmacology, 190–92 structure, pharmacokinetics, and metabolism, 192, 192f toxicity, 194–95 elderly patients, 748 gene therapy, 202 hemodynamic effects, 202, 203t parenteral, indications for, 189, 190t PDE inhibitors (See phosphodiesterase (PDE) inhibitors) pediatric, 519–26 in pregnancy and lactation, 725 SERCA agonists, 201–2, 202f therapeutic use, 699–703 dosage in liver disease or congestive heart failure, 732 dosage in renal insufficiency, 739 insulin, 415t, 422 insulin secretagogues, 414t, 416–17 insurmountable antagonism, 129 integrins, 271 intermittent claudication aspirin, 568 chelation therapy, 575 cilostazol, 567–68 ketanserin, 574 low-molecular-weight heparin, 285 NM-702, 568 pentoxifylline, 566–67 statins, 353 a-tocopherol, 574 treatment, 565, 566t intestinal microorganisms, 14 intracellular receptors, 3–4, 4f intracerebral hemorrhage pathophysiology, 548t, 549 as thrombolytic therapy complication, 316–17 treatment, 563–64, 563t intrinsic sympathomimetic activity, 66–67, 67f ipratropium bromide, 97 irbesartan (Avapro), 501, 661 ischemic heart disease See myocardial ischemia Index 765 ischemic stroke calcium channel blockers, 116 complications, 559–60 low-molecular-weight heparin, 282 neuroprotective agents, 560–62, 561f, 561t, 562f new drugs in development, 629t pathophysiology, 548–49, 548f, 549f prevention about, 549, 550t angiotensin II receptor blockers, 551 anticoagulants, 555–56, 556t antihypertensive drugs, 549–51 antiplatelet and antithrombotic drugs, 551t, 552–55 aspirin, 553 clopidogrel, 554 dietary therapy, 552 dipyridamole, 554–55 HMG-CoA inhibitors, 552 risk reduction, 549–52 sarpogrelate, 555 tidopidine, 553–54 triflusal, 555 warfarin, 555–56 treatment about, 556–57 cardioembolic stroke, 559 thrombolytic therapy, 320, 557–59 vascular occlusive stroke, 557 ISIS 301012 (mipomersen), 374 isoproterenol (Isuprel), 524–25, 700 isosorbide dinitrate (Isordil; Sorbitrate), 210–11, 211t, 715 isosorbide mononitrate (ISMO; Imdur; Monoket), 206t, 211, 715–16 isradipine (DynaCirc), 533, 687 istaroxime (PST-2744), 202, 202f itraconazole, 506 J jin bu huan, 490 junctional ectopic tachycardia, 538 K ketanserin, 574, 579 kidney and drug excretion, 14–15 kidney disease dose adjustment in renal insufficiency, 735–41 drug metabolism and, 12–13 functional renal insufficiency, 145 renal cell carcinoma, 175 kinetics, steady-state, 10–11, 11f kistrin, 273 L L-4F (Apo A-I mimetic peptide), 370 labetalol (Normodyne; Trandate) alpha-adrenergic activity of, 67 for dissecting aneurysms, 79 hypertension in children, 534 therapeutic use, 685 lactation and cardiovascular drug use, 721–27 large vessel vasculitis See vasculitis, large vessel LDL cholesterol, 325–26, 326t, 327t left bundle branch block, 312 left ventricular assist device (LVAD), 605 left ventricular function, 23 left ventricular hypertrophy ACE inhibitors and ARBs, 135 regression, 79, 164 lepirudin (Refludan), 287, 673 leptin, 404–5, 404f levosimendan, 199–200, 199f lidocaine (Xylocaine) adverse effects, 236 in children, 540 drug interactions, 236–37 pharmacokinetics and metabolism, 236 pharmacology, 236 therapeutic use, 237, 664–65 life expectancy, as effectiveness criterion, 43–44 lifibrol, 364–65 linezolid, 597, 598–99, 600t Lingusticum wallichii, 485 lipid-lowering drugs, 323–75 about, 323–24 bile acid sequestrants (See bile acid sequestrants) in children, 536–37 combination therapy, 360–61 coronary artery disease prevention, 324–25 dietary fiber (psyllium), 362–63 drug-drug interactions, 506, 517– 18t elderly patients, 330, 748 estrogen as, 361–62 ezetimibe, 359–60 fibric acid derivatives (See fibric acid derivatives) fish oil supplements, 361 HMG-CoA reductase inhibitors (See HMG-CoA reductase inhibitors) investigational therapies, 626t acyl-coenzyme A transferase inhibitors, 366 Apo A-I mimetic peptides, 370 bile acid sequestrants, 371 cholesterol vaccines, 373 cholesteryl ester transfer protein inhibition, 366–68 HDL infusions, 369–70 ileal Na+/bile acid cotransporter inhibitors, 370–71 lifibrol, 364–65 lipoprotein lipase activators, 371 lipoprotein-associated phospholipase A2, 368–69 liver X receptors, 373 peroxisome proliferator-activated receptor modulators, 372–73 7a-hydroxylase enhancers, 371– 72 somatic gene therapy, 373–75 squalene synthase inhibitors, 365–66 toll-like receptor modulators, 370 low serum HDL cholesterol, 327– 28, 328t nicotinic acid (See nicotinic acid) policosanol, 364 risk assessment, 325–27, 326t, 327t special problems, 328–32 age, 328–30, 329f calcific aortic stenosis, 332 cerebrovascular disease, 332 cognitive function, 332 coronary angioplasty, 331 coronary artery bypass graft surgery, 331 diabetes mellitus, 328 gender, 328, 744 heart transplantation, 331–32 myocardial infarction, 330–31 nephrotic syndrome, 332 pregnancy and lactation, 725 systemic hypertension, 330 therapeutic use, 703–10 dosage in liver disease or congestive heart failure, 732–33 dosage in renal insufficiency, 739–40 thyroxine analogues, 362 lipoprotein lipase activators, 371 lipoprotein-associated phospholipase A2 (Lp-PLA2), 368–69 liraglutide (Victoza), 407, 415t, 422 lisinopril (Prinivil; Zestril) congestive heart failure, pediatric, 531 post-myocardial infarction, 143 for stroke prevention, 136 therapeutic use, 658 lithium, 175 liver disease cardiovascular drug dosing recommendations, 729–34 drug metabolism and, 12 766 Index liver X receptors (LXRs), 373 lixivaptan, 459–60 LMWH See low-molecular-weight heparin (LMWH) loop diuretics adverse effects hyponatremia, 171 metabolic abnormalities, 173, 174 ototoxicity, 174–75 elderly patients, 747 pediatric use, 528 pharmacodynamics, 158–60, 160f pharmacokinetics, 159t, 160f in pregnancy and lactation, 724 therapeutic use, 690–92 dosage in liver disease or congestive heart failure, 732–33 dosage in renal insufficiency, 738 lorazepam, 560 lorcaserin, 406 losartan (Cozaar) bioavailability, 127, 128t drug-drug interactions, 499, 501 heart failure, 143–44 metabolism, 128 myocardial infarction, 143 therapeutic use, 661 lotrafiban, 278 lovastatin (Altocor; Mevacor) adverse effects, 344–45 chemistry and pharmacology, 342, 343f clinical trials, 343 effects on clinical endpoints, 343–44 pharmacokinetics, 342–43 therapeutic use, 344, 707–8 low-molecular-weight heparin (LMWH) about, 281, 282t acute ischemic stroke, 282 adverse effects, 286–87 angina pectoris, 286 atrial fibrillation, thromboembolic prophylaxis, 285–86 cancer-associated thrombosis, 304 clinical trials, 281–82 cost-effectiveness, 287 deep venous thrombosis, 582–83 dosages, 286 hemodialysis thromboprophylaxis, 286 intermittent claudication, 285 myocardial infarction, 282 percutaneous transluminal coronary angioplasty restenosis, 285 proximal deep vein thrombosis, 284–85 Raynaud’s syndrome, 581 unstable angina, 282–83 venous thromboembolism prevention, 283–84, 284t Lp-PLA2 (lipoprotein-associated phospholipase A2), 368–69 LU 135252 (darusentan), 435, 435t lubeluzole, 561 lung, drug excretion, 15 lupus erythematosus, systemic, 264 LVAD (left ventricular assist device), 605 LY517717 (oral antithrombin agent), 302 lycopene, 479 M magnesium about, 177 adverse effects, 256 antiarrhythmic effects, 256 cardiovascular effects, 178f arrhythmias, 179–80 congestive heart failure, 179 hypertension, 180 ischemic heart disease, 177–78 myocardial infarction, 178–79 stroke, 180 clinical use, 180–82, 181t, 182t deficiency (See hypomagnesemia) electrophysiology, 255–56 hemodynamic effects, 256 indications and dosage, 256 pharmacokinetics and metabolism, 256 pharmacology, 255 supplements and cardiovascular health, 480 malonyl-coenzyme A, 411 mannitol about, 158 cerebral edema, 560 congestive heart failure, pediatric, 529 MAO (monoamine oxidase) inhibitors, 393 MCC-135 (Caldaret), 201–2 mecamylamine (Inversine), 711 medication adherence, 31–38 assessment, 32 barriers adverse effects, 34–35 asymptomatic disease, 33–34 pill burden and dosing complexity, 35, 35f, 36t characteristics influencing, 33–34, 34t cost impact of, 33 health outcomes heart failure, 33 hypertension, 32 post-myocardial infarction, 32–33 once-daily dosing options, 35–37, 36t strategies for improving, 37t survival and placebo vs medical therapy, 25–26 megavitamins and micronutrients about, 474 carotenoids, 478–79 clinical effects, 474t cocoa flavonol, 480, 480t flavonoids, 479 magnesium, 480 rationale for cardiovascular health, 473–75 trace minerals, 480 vitamin B supplements, 477–78 vitamin C, 476–77 vitamin D, 478, 478f vitamin E, 476 vitamin K, 478 meglitinide analogues, 414t, 416–17 melagatran, 300–301 menopause and stroke risk, 552 metabolic acidosis, 173 metabolic alkalosis, 172–73 metabolic syndrome, 327, 327t metaraminol (Aramine), 701 metformin (Glucophage) cardiovascular outcomes, 418 contraindications, 417–18 off-label use for obesity, 407, 408t therapeutic use, 415t, 417–18 methacholine, 95 methotrexate, 590 methoxamine (Vasoxyl), 701 methyclothiazide (Enduron), 694–95 methyldopa (Aldomet) adverse effects, 88–89 gender issues, 744 pharmacology, 88–89, 88t therapeutic use, 655–56 use in pregnancy, 91 methylprednisolone, intravenous pulse, 590 methysergide, 563 metoclopramide, 494 metolazone (Mykrox; Zaroxolyn) congestive heart failure, pediatric, 529 pharmacodynamics, 160 therapeutic use, 695 metoprolol (Lopressor; Toprol XL) congestive heart failure, 78 ethnicity and efficacy, 751 therapeutic use, 682–83 mexiletine (Mexitil), 237–38, 665 miglitol (Glyset), 414t, 417 migraine, 116, 562–63 Index milrinone lactate (Primacor) acute heart failure, 193 congestive heart failure, 189, 198– 99, 198f pediatric use, 526–28 therapeutic use, 699 minerals See megavitamins and micronutrients minoxidil (Loniten), 224–25, 716 mipomersen (ISIS 301012), 374 mitral valve prolapse, 78 moclobemide, 393 moexipril (Univasc), 658 monascus purpureus (red yeast), 487 monoamine oxidase (MAO) inhibitors, 393 monoclonal antibodies, 273–77 moricizine (Ethmozine), 665–66 morphine, 545 moxonidine, 90 muscarinic effects, 93 muscarinic receptors antagonists, 96–97 types of, 93–95, 94t muscle contraction, 100 mycophenolate mofetil, 591 myocardial contractility calcium and, 187 calcium channel blockers, 101–2, 101t gene therapy and stem cell therapy interventions, 202 inotropic agents, 189 myocardial infarction ACE inhibitors, 143 angiotensin II receptor blockers, 143 aspirin, 41, 41f, 43t, 261–63 bivalirudin, 289 calcium channel blockers, 113–14 cytokines and myocardial regeneration, 609–17 cardiac remodeling, 609 darbepoetin, 615–16 erythropoietin, 614–16 granulocyte colony stimulating factor, 610–14, 612f stem cell factor, 616 stem-cell mediated repair, 609–10, 610f digoxin precautions, 193 heparin, 279–80 hirudin, 287–88 lipid-lowering drugs, 330–31 low-molecular-weight heparin, 282 magnesium, 177–78 medication adherence impact, 32–33 new drugs in development, 627t thiazolidinediones and, 419–20 thrombolytic agents, 306–18 (See also under thrombolytic agents) warfarin, 292–93 myocardial ischemia beta-adrenergic blocking drugs, 75–76, 76t magnesium, 177–78 new drugs in development, 627t nitrates, 208–9 placebo effect, 20, 20t, 21t, 22 platelet role atherosclerosis, 258–59 thrombosis, 259–60, 259f silent episodes, 76, 113 myocardial protection, 80 myocardial remodeling, 167–68 myocardial rupture, 317–18 N nadolol (Corgard), 541, 679 nafcillin, 598, 601t, 606t naltrexone, 395, 410 NAPc2 (recombinant nematode anticoagulant peptide), 586 nateglinide (Starlix), 414t, 416–17 natriuretic peptides, 445–50 about, 445 BNP, 445–46 (See also nesiritide) in children, 532 C-type, 433, 445 effects in humans, 447t therapeutic use, 449–50, 698 NCX-4016 (prostacyclin analogue), 298–99 nebivolol (Bystolic) congestive cardiomyopathy, 78 direct vasodilatory activity, 67 therapeutic use, 683 nefazodone, 506 nematode anticoagulation protein (NAPc2), 303 neonates, drug disposition, 12 neostigmine, 96 nephrotic syndrome, 332 nesiritide adverse effects, 448–49 in children, 532 clinical trials, 446–48 elderly patients, 748 pharmacokinetics, 446 pharmacology, 445–46, 446f, 447t in pregnancy and lactation, 725 therapeutic use, 449–50, 698 dosage in liver disease or congestive heart failure, 732 dosage in renal insufficiency, 739 neuronal and ganglionic blockers elderly patients, 749 767 in pregnancy and lactation, 725 therapeutic use, 710–12 dosage in liver disease or congestive heart failure, 733 dosage in renal insufficiency, 740 neurovascular disease See cerebrovascular disease new drugs in development See also under specific drug classes and disorders update on, 619 angina pectoris, 621t antiplatelet and anticoagulant drugs, 620t antithrombotics, 621t arrhythmias, 622t atherosclerosis, 623t drug-eluting stents, 630t heart failure, 624t hypertension, 625t lipid disorders, 626t myocardial infarction, 627t myocardial ischemia, 627t peripheral vascular disorders, 627– 28t pulmonary hypertension, 628t stroke, 629t vascular restenosis, 629t niacin See nicotinic acid Nic VAX (nicotine vaccine), 394 nicardipine (Cardene), 533, 688 nicotine addiction, 385–86, 386t nicotine replacement therapy, 387–90 gender issues, 744 nicotine gums, 388t, 389 nicotine inhaler, 389–90 nicotine lozenges, 389 nicotine nasal spray, 389 nicotine patches, 387–89, 388t pharmacokinetics, 386 smokeless tobacco, 387 nicotine vaccines, 393–95 nicotinic acid (niacin; Niacor; Niaspan) adverse effects, 358–59 chemical structure, 355f in children, 537 clinical trials, 356–57 as lipid-lowering agent, 355 pharmacokinetics, 355 pharmacology, 355–56 therapeutic use, 357–58, 706 nicotinic effects, defined, 93 nifedipine (Adalat; Nifedical XL; Procardia) angina, 107 congestive cardiomyopathy, 114–15 hypertension in children, 533 Raynaud’s syndrome, 576 therapeutic use, 688–89 nimodipine (Nimotop), 689 768 Index nisoldipine (Sular), 689 nitrate tolerance, 206, 212–13, 212t nitrates adverse effects, 211–12 clinical indications, 207t hypertensive emergencies, 209 ischemic heart disease, 208–9 combination therapy, 73–74, 209– 10, 209f congestive heart failure, 209–10 dosing, 211 drug-drug interactions, 506 effects on regional circulation, 206–7 ethnicity and efficacy, 752 as exogenous endothelium-derived relaxing factors, 208 formulations and pharmacokinetics, 205, 206t, 210–11, 210f gender issues, 744 hemodynamics and clinical efficacy, 207–8, 207t mechanisms of action, 205–6, 207t nitrate tolerance, 206, 212–13, 212t Raynaud’s syndrome, 580 nitrendipine for stroke prevention, 138 nitric oxide, 205, 530 nitroglycerin cerebral vasospasm, 209 congestive heart failure, pediatric, 530 as exogenous endothelium-derived relaxing factor, 208 formulations and pharmacokinetics, 206t, 210 intravenous, for acute hypertension, 209 Raynaud’s syndrome, 580 therapeutic use, 206, 716–17 nitroprusside (Nitropress) about, 213 in children congestive heart failure, 529–30 hypertension, 535 dosage, 214–15 indications, 213–14, 214t microcirculation effects, 207 precautions, 214, 214t therapeutic use, 718 nitrovasodilators, 205–15 See also nitrates; nitroprusside about, 205 pediatric use, 529–30, 535 NM-702, 567–68 NO-1886 (lipoprotein lipase activator), 371 noncompetitive antagonism, 129 noncompetitive inhibition, nonsteroidal anti-inflammatory drugs (NSAIDs), 175 norepinephrine (Levophed) inotropic activity, 196, 196t pediatric use, 526 therapeutic use, 701 nortriptyline, 392 nutraceuticals, 473–75, 474t nutritional deficiencies, 12 O OATS (organic anion transporters), 498 obesity about, 397–98 approved drug therapies, 399–403 in children, 537 drug categories, 399 orlistat (Xenical), 400t, 401t, 402–3, 537 sibutramine (Meridia), 399, 400t, 401t, 402 sympathomimetics, 399 treatment recommendations, 399 body mass index, 398 cardiovascular disease and, 398 dietary interventions, 398–99 drugs in development, 403t b3-adrenergic receptor agonists, 403–4 leptin, 404–5, 404f lorcaserin, 406 rimonabant (Acomplia), 405–6, 405f new targets for pharmacotherapies fatty acid synthase inhibitors, 411, 411f neuropeptide Y mediators, 411– 12 regulatory gut peptides, 412 uncoupled proteins, 410–11 off-label use of medications, 406– 10 bupropion (Wellbutrin), 409t, 410 exenatide (Byetta), 407 fluoxetine with phentermine, 410 growth hormone, 410 liraglutide, 407 metformin (Glucophage), 407, 408t naltrexone plus bupropion (Contrave), 410 pramlintide (Symlin), 407, 410 topiramate (Topamax), 408t, 410 zonisamide (Zonegran), 409t, 410 OCTs (organic cation transporters), 498 odiparcil, 301 olmesartan (Benicar), 661 olprinone, 199 omega-3 fatty acids (Lovaza; Omacor) elderly patients, 749 in pregnancy and lactation, 725 supplementation, 482–83 therapeutic use, 710 dosage in liver disease or congestive heart failure, 733 dosage in renal insufficiency, 740 omeprazole, 504 oral drug administration, orbofiban, 278 organic anion transporters (OATs), 498 organic cation transporters (OCTs), 498 organic nitrates See nitrates orlistat (Xenical), 400t, 401t, 402–3, 537 osmotic diuretics, 158, 529 osteoporosis, 174 otamaxiban, 303 ototoxicity, loop diuretics, 174–75 oxacillin, 598, 601t, 606t oxytocin, 451, 451f P pacemaker endocarditis, 607 paclitaxel, 463f, 463t, 464 PAD See peripheral arterial disease (PAD) Panax notoginseng, 486 papaverine (Para-Time SR), 717 parasympathetic nervous system, 93–97 patent ductus arteriosus, 543–45 PD 72953 (PPAR agonist), 372 PDE inhibitors See phosphodiesterase (PDE) inhibitors pediatric pharmacology, 519–46 antiarrhythmic drugs, 537–43 about, 537–38 adenosine, 542 amiodarone, 541–42 arrhythmia diagnoses, overview, 538 beta-adrenergic blocking drugs, 541 bretylium, 542 digoxin, 542 disopyramide, 540 fetal arrhythmias, 542–43 flecainide, 540 ibutilide, 542 lidocaine, 540 procainamide, 539–40 prolonged QT syndrome, 538–39 propafenone, 540–41 sotalol, 542 verapamil, 542 Index 769 antihypertensive drugs beta-adrenergic blocking drugs, 533–34 calcium channel blockers, 532–33 chronic hypertension, 535 diazoxide, 534–35 esmolol, 534 hydralazine, 534 hypertensive emergencies, 535 isradipine, 533 labetalol, 534 nicardipine, 533 nifedipine, 533 nitroprusside, 535 propranolol, 533–34 vasodilators, 534–35 congestive heart failure, 520t a1-adrenergic receptor blockers, 530–31 ACE inhibitors, 531 beta-adrenergic blocking drugs, 531–32 captopril, 531 digoxin, 519–21, 521t diuretics, 528–29 dobutamine, 523–24 dopamine, 521–23 enalapril, 531 epinephrine, 525–26 inamrinone, 526–28 inotropes and vasopressors, 519– 26 isoproterenol, 524–25 lisinopril, 531 milrinone, 526–28 natriuretic therapy, 532 nesiritide, 532 nitric oxide, 530 nitroglycerin, 529–30 nitroprusside, 529–30 nitrovasodilators, 529–30 norepinephrine, 526 phentolamine, 530–31 phosphodiesterase inhibitors, 526–28 prazosin, 530 cyanotic spells, 545–46 lipid disorders about, 536 bile-acid binding resins, 536–37 cholesterol absorption inhibition, 537 HMG-CoA reductase inhibitors, 537 hyperlipidemia management, 328–30, 329f niacin, 537 obesity treatment, 537 patent ductus arteriosus, 543–45 psychotropic drugs and arrhythmia, 543 pulmonary hypertension, 545 penbutolol (Levatol), 684 penicillin, 596, 597t, 598 pentoxifylline (Pentoxil; Trental) intermittent claudication, 566–67, 591 therapeutic use, 717–18 pepstatin, 149 peptides See also natriuretic peptides mimetic, 370 regulatory gut, 412 percutaneous transluminal coronary angioplasty aspirin and, 263 hirudin, 287–88 restenosis and low-molecularweight heparin, 285 warfarin, 293 perindopril (Aceon), 137, 658–59 peripheral arterial disease (PAD), 565– 75 See also intermittent claudication about, 565 ACE inhibitors, 135 antiplatelet drugs, 568–70, 569t aspirin, 265, 568–69 buflomedil, 575 carnitine, 571 chelation therapy, 575 defibrotide, 574–75 ginkgo biloba, 575 growth factors, 573 hemodilution, 575 herbal remedies, 487–88 ketanserin, 574 L-arginine, 572 naftidrofuryl, 574 phosphodiesterase inhibitors, 566– 68 prostaglandins, 571–72 statins, 570–71 thrombolytics, 573–74 a-tocopherol, 574 vasodilators, 572 peripheral arteries and calcium channel blockers, 100–101, 101t peripheral neuron depleters, 90–91 peripheral vascular disorders (PVD), 565–92 deep vein thrombosis (See deep venous thrombosis (DVT)) iloprost, 572 large vessel vasculitis about, 589–90 cytotoxic drugs, 590–91 glucocorticoids, 590 immunomodulatory drugs, 591 new drugs in development, 627–28t peripheral arterial disease (See peripheral arterial disease (PAD)) Raynaud’s phenomenon (See Raynaud’s syndrome) risk factor modification, 591 thromboangiitis obliterans, 591 treprostinil, 572 peroxisome proliferator-activated receptor (PPAR) modulators, 372–73 P-glycoproteins, 498, 498t pharmacokinetic properties of approved cardiovascular drugs, 633–51 See also pharmacokinetics under specific drug name or class pharmacology, basic principles, 3–15 drug disposition and pharmacokinetics absorption, administration routes and, 7–8 binding to plasma proteins, bioavailability, 8, 8f, 8t clearance, 10 distribution to tissues, 8–9 half-life, 9–10, 10f passage of drugs across cell membranes, 6–7 steady-state kinetics, 10–11, 11f volume of distribution, drug metabolism disease effects on, 12–13 enterohepatic circulation and, 14 excretion, 14–15 extracorporeal circulation, 12 genetic factors, 12, 13f induction, 13, 14t, 15f inhibition, 13–14, 14t by intestinal microorganisms, 14 mechanisms and pathways, 11–12 nutritional deficiency, 12 species and age, 12 receptors, 3–6 description of, 3–4, 4f kinetics of drug-receptor interactions, 4–5 quantitative considerations, 5–6, 5f, 6f pharyngitis, streptococcal, 607, 608t phenobarbital, 505, 560 phenoxybenzamine (Dibenzyline), 62–63, 654 phentermine (Fastin; Ionamin), 399 phentolamine (Regitine), 530–31, 654 phenylephrine (Neo-Synephrine), 701 phenytoin, 505, 560 pheochromocytoma, 62 phosphodiesterase (PDE) inhibitors, 197–99, 198f congestive heart failure, 198–99, 526–28 770 Index elderly patients, 749 pediatric use, 526–28 peripheral arterial disease, 566–68 in pregnancy and lactation, 726 pulmonary hypertension, 436 Raynaud’s syndrome, 580 therapeutic use, 699, 712 dosage in liver disease or congestive heart failure, 733 dosage in renal insufficiency, 740 physiostigmine, 96 pimobendan, 200–202 pindolol (Visken), 684 pioglitazone (Actos), 415t, 418–21, 551 pitavastatin (Livalo), 353 placebo effect, 17–29 adverse reactions, 19, 19t alternative and complementary medicine, 473, 473t characteristics in arrhythmia, 24–25 in chronic stable exertional angina, 20–22 in congestive heart failure, 22–23 in hypertension, 23–24 in hypertrophic cardiomyopathy, 25 in ischemic heart disease, 20, 20t, 21t treatment adherence and survival, vs medical therapy, 25–26 clinical trials ethics of placebo controls, 26–29 history of, 18 informed consent, 28 definition, 17–18 diagnostic procedures, 17 gender differences, 20–21 regression to the mean mimicking, 19, 20f as treatment component, 17, 18f validation, 19 plant sterols, 363–64 plasma concentration, in drug tissue distribution, 8–9 plasma proteins, plasma renin, 71 platelets atherosclerosis, 258–59 physiology, 257–58, 258f thrombosis, 259–60, 259f policosanol, 364 polythiazide (Renese), 695 potassium See also hypokalemia about, 182 cardiovascular effects atherosclerosis prevention, 184, 184f stroke, 183–84 systemic hypertension, 182–83, 183t electrophysiologic effects, 184–85 supplementation general considerations, 185 intravenous, 186 oral, 183, 185–86, 185t potassium-sparing diuretics adverse effects, 172 congestive heart failure, pediatric, 529 elderly patients, 748 pharmacodynamics, 159t, 160–61 in pregnancy and lactation, 724 therapeutic use, 696–97 dosage in liver disease or congestive heart failure, 732 dosage in renal insufficiency, 739 potency, defined, PPAR (peroxisome proliferator-activated receptor) modulators, 372–73 practolol toxicity, 66 pramlintide (Symlin), 407, 410 prasugrel (Effient) about, 269 clinical trials, 269–71, 270f peripheral arterial disease, 570 therapeutic use, 676 pravastatin (Pravachol) about, 347–48 adverse effects, 350 chemical structure, 343f clinical use, 349–50 drug-drug interactions, 506 effects on clinical endpoints, 348– 49, 349f ischemic stroke prevention, 552 therapeutic use, 708–9 prazosin (Minipress) adverse effects, 63 congestive heart failure, 61, 530 hypertension, 60–61 pediatric use, 530 Raynaud’s syndrome, 578 therapeutic use, 63, 653 pregnancy guide to drug use in, 721–27 a-methyldopa safety, 91 Probabilistic Sensitivity Analysis, 53, 53f procainamide (Pronestyl; Procanbid) adverse effects, 234 antiarrhythmic effects, 234 arrhythmias in children, 539–40 drug-drug interactions, 234, 498 electrophysiology, 233 gender issues, 744 hemodynamic effects, 234 pharmacokinetics and metabolism, 234 pharmacology, 233 therapeutic use, 234, 663–64 prolonged QT syndrome, 538–39 propafenone (Rythmol) adverse effects and drug interactions, 240 antiarrhythmic effects, 240, 540–41 electrophysiology, 239 pediatric use, 540–41 pharmacokinetics and metabolism, 239–40 pharmacology, 239 therapeutic use, 240, 666 propionic acid derivative (compound 8), 372 propranolol (Inderal) adverse effects, 241 alpha-adrenergic receptors, 241 angina, 107 dissecting aneurysms, 79 drug-drug interactions, 241, 504 electrophysiology, 240–41 ethnicity and efficacy, 751 hemodynamic effects, 241 hypertrophic cardiomyopathy, 114 migraine, 563 pediatric use arrhythmias, 541 hypertension, 533–34 pharmacokinetics and metabolism, 241 pharmacology, 240 therapeutic use, 241–42, 679–80 prospective data sources, 48–50 prostacyclins See also epoprostenol (Flolan); iloprost (Ventavis) about, 426 analogues beraprost, 431 cicaprost, 431 NCX-4016, 298–99 pulmonary hypertension, 426–32 treprostinil, 431 prostaglandin E1, 544–45 prostaglandins intermittent claudication, 572 peripheral arterial disease, 571–72 Raynaud’s syndrome, 578–79 prostatic hypertrophy, benign, 62 prosthetic valve endocarditis, 604–5, 606t prosthetic valve obstruction, 293, 318–19 protein C activators, 303–4 protein YY, 411 proteins drug transporter, 498, 498t uncoupled, 410–11 prothrombin time, 291 Index 771 pro-urokinase, 558–59 psychotropic drugs, 543 psyllium (dietary fiber), 362–63 pulmonary drug administration, pulmonary edema, high-altitude, 117 pulmonary embolism, 319–20 pulmonary hypertension, 425–38 about, 425–26 alpha-adrenergic blocking drugs, 62 combination therapies, 437 drug therapy in children, 545 emerging therapies, 437 endothelin inhibitors, 432–36 new drugs in development, 628t pathophysiology, 425, 426f phosphodiesterase inhibitors, 436–37 primary, calcium channel blockers for, 115–16 prostacyclins, 426–32 treatment guidelines, 437f PVD See peripheral vascular disorders (PVD) pyridostigmine, 96 Q QT-interval prolongation syndrome, 79 quality of life (QOL), 44–45, 54 quality-adjusted life years (QALYs), 40, 41t quinapril (Accupril), 659 quinethazone (Hydromax), 695–96 quinidine (Quinaglute; Dura-Tabs) adverse effects, 233 drug-drug interactions, 233, 498, 501 electrophysiology, 232 gender issues, 744 hemodynamic effects, 233 pharmacokinetics and metabolism, 232–33 pharmacology, 232 therapeutic use, 233, 664 quinupristin-dalfopristin combination, 596, 600t R RAAS See renin-angiotensin-aldosterone system (RAAS) race and cardiovascular drug response, 751–52 ramipril (Altace) cancer risk and, 145 for stroke prevention, 136 therapeutic use, 659–60 ranolazine (Ranexa), 217–22 about, 217 adverse effects, 222 clinical trials, 219–22 combination therapy with beta blockers, 74 elderly patients, 745 hemodynamic effects, 218t pharmacodynamics, 217–19 pharmacokinetics, 219 in pregnancy and lactation, 722 therapeutic use, 222, 662 dosage in liver disease or congestive heart failure, 730 dosage in renal insufficiency, 736 Rauwolfia serpentina (snakeroot), 485 Raynaud’s syndrome about, 575–76 ACE inhibitors and ARBs, 579 aspirin, 581 beta-blockers, adverse effects, 81–82 calcitonin gene-related peptide, 581 calcium channel blockers, 117, 576, 578 drug therapy, 577t endothelin blocking agents, 579–80 low-molecular-weight heparin, 581 nitric oxide donors, 580 prostaglandins, 578–79 serotonin blocking agents, 579 sympathetic blocking agents, 578 thromboxane synthase inhibitors, 581 triiodothyronine, 580 razaxaban, 587 reboxetine, 395 receptors affinity, 129–30 basic principles, 3–6 description, 3–4, 4f drug-receptor kinetics, 4–5 rectal drug administration, red wine, cardiovascular benefits, 479 remodeling, cardiac, 609 renal cell carcinoma, 175 renal insufficiency dose adjustment in, 735–41 functional, 145 renin, biosynthesis and actions, 147– 49, 148f renin-angiotensin-aldosterone system (RAAS) See also angiotensin II receptor blockers (ARBs); angiotensinconverting enzyme (ACE) inhibitors about, 121 direct renin inhibition, 147–56 (See also aliskiren (Tekturna) future development, 155–56 renin inhibitors, 149–50, 149f feedback loops, 121, 123 in heart failure, 167–68 inhibition ACE inhibitors and ARBs, combination therapy, 133–35 adverse effects, 145–46 blood pressure-lowering effects, 131–33 cancer and ACE inhibitors, 144– 45 cardiac effects, 139, 142–44 development of, 149–50, 149t drug interactions, 146 hemodynamic effects, 130–31 hypertension in other disorders, 135–36 miscellaneous clinical effects, 144 renal effects, 138–39, 140t–141t stroke and, 136–38 mechanism of action, 121, 123–24 pharmacology ACE inhibitors, 124–27 angiotensin-receptor blockers, 127–30 repaglinide (Prandin), 414t, 416–17 reserpine adverse effects, 87–88 hypertension, 87–88, 88t plant sources, 485 therapeutic use, 711 restenosis, vascular, 629t resveratrol, 479 reteplase (Retavase) about, 306 combination use with abciximab, 313–114 therapeutic use, 678 retrospective data sources, 50 rheumatic fever, 607, 608t rifampin, 598, 601–2, 606t rilmenidine, 90 rimonabant (Acomplia), 395, 405–6, 405f rivaroxaban (Xarelto), 588 rivastigmine, 96 robustness, in data analysis, 52–53, 53f ropinirole, 444 rosiglitazone (Avandia), 415t, 418–20 Rosmarinus officinalis (rosemary), 488 rosuvastatin (Crestor), 353, 709 Ruscus aculeatus (butcher’s broom), 489 S S-8921 (IBAT inhibitor), 370–71 saliva, drug excretion in, 15 Salvi miltiorrhiza, 486–87 sarcoplasmic reticulum calcium ATPase (SERCA) agonists, 201–2, 202f sarpogrelate, 555, 579 saxagliptin (Onglyza), 415t, 421 772 Index SCH-530348, 570 scopolamine, 97 second messenger systems, selective serotonin reuptake inhibitors (SSRIs), 392–93, 399 selegiline, 393 selenium supplements, 481 sensitivity analysis, 52–53, 53f, 54 serotonin receptor antagonists, 579 serotonergic agents, 399 7a-hydroxylase enhancers, 371–72 7E3 Fab See abciximab sexual dysfunction, 174 sham therapy, 22 shock alpha-adrenergic blocking drugs, 62 cardiogenic, 312 vasodilatory, 456 sibrafiban, 278 sibutramine (Meridia), 399, 400t, 401t, 402 signal transduction, transmembrane, sildenafil (Revatio) pulmonary hypertension, 436 Raynaud’s syndrome, 580 therapeutic use, 712 simvastatin (Zocor) about, 345–46 adverse effects, 347 chemical structure, 343f drug-drug interactions, 506 effects on clinical endpoints, 346– 47, 346f, 347f therapeutic use, 709–10 sinus node dysfunction, 81 sinus tachycardia, 108 sirolimus (rapamycin), 462, 463f, 463t sitagliptin (Januvia), 415t, 421 sitaxsentan, 436 sitostanol, 363–64 b-sitosterol, 363–64 SK&F 97426 (bile acid sequestrant), 371 smokeless tobacco, 387 smoking cardiovascular risk factors, 385 nicotine addiction, 385–86 plasma drug levels and, 13, 15f smoking cessation, 385–96 about, 385 anxiolytics, 393 bromocriptine, 393 bupropion, 391–92, 396t cessation rates, 390, 390t clonidine, 392, 396t drug dosage adjustments during, 387t glucose tablets, 393 investigational therapies cytochrome P-450 inhibition, 393 naltrexone, 395 nicotine vaccines, 393–95 reboxetine, 395 rimonabant (Acomplia), 395 monoamine oxidase inhibitors, 393 nicotine replacement therapy, 387–90, 396t gender issues, 744 nicotine gums, 388t, 389 nicotine inhaler, 389–90 nicotine lozenges, 389 nicotine nasal spray, 389 nicotine patches, 387–89, 388t smokeless tobacco, 387 withdrawal symptoms, 386, 386t nortriptyline, 392, 396t selective serotonin reuptake inhibitors, 392–93 thromboangiitis obliterans, 591 upper airway stimulants, 393 varenicline (Chantix), 390–91, 396t snuff, 387 sodium channel modulators BDF 9198, 201 ranolazine, 217–22 sotalol (Betapace; Sorine) adverse effects and drug interactions, 246 antiarrhythmic effects, 74–75, 246, 542 pediatric use, 542 pharmacokinetics and metabolism, 246 pharmacology, 245–46 therapeutic use, 246, 668 spare-receptor theory, spironolactone (Aldactone) adverse effects, 174 congestive heart failure, pediatric, 529 pharmacokinetics, 159t, 160–61 therapeutic use, 696–97 spreadsheets, health economics analysis, 47–48, 49t squalene synthase inhibitors, 365–66 SSRIs (selective serotonin reuptake inhibitors), 392–93, 399 St John’s wort, 490 Staphylococcus aureus antibiotic therapy, 597–603, 601t methicillin-sensitive, 598–99, 601t statins See HMG-CoA reductase inhibitors steady-state kinetics, 10–11, 11f stem cell factor, 616 stem cell therapy cardiac repair, cytokine-mediated about, 609–10, 610f darbepoetin, 615–16 erythropoietin, 614–16 granulocyte colony stimulating factor, 610–14, 612f stem cell factor, 616 congestive heart failure, 202 stents, drug-eluting See drug-eluting stents Stephania tetranda, 485 Streptococcus viridans, 596 streptokinase (Kabikinase; Streptase) about, 305 cardiogenic shock, 313 ischemic stroke, 557–58 myocardial infarction, 307, 308 therapeutic use, 678 streptomycin, 598t stroke See also hemorrhagic stroke; ischemic stroke ACE inhibitors preventing, 136–37 angiotensin receptor blockers preventing, 137–38 aspirin, 264 cardioembolic, 559 magnesium, 180 new drugs in development, 629t potassium, 183–84 vascular occlusive, 557 subarachnoid hemorrhage pathophysiology, 548t, 549 treatment, 563t, 564 sublingual drug administration, sudden cardiac death, smoking and, 385 sulfonylureas, 414t, 416 sumatriptan, 562 supraventricular arrhythmias, in children, 538 supraventricular tachycardia antiarrhythmic agents in children, 540–42 calcium channel blockers, 109–10, 109t fetal, 542–43 surgery alpha2-adrenergic agonists in, 91 heparin preventing venous thromboembolism, 279 myocardial protection with betaadrenergic blocking drugs, 80 surmountable antagonism, 129 sympathetic nervous system, 87 sympatholytic blocking agents centrally acting, 87–90, 88t peripheral neuron depleters, 90–91 Raynaud’s syndrome, 578 sympathomimetic activity, intrinsic, 66–67, 67f sympathomimetic agents, 399 Index 773 syncope, 80 systemic hypertension beta-adrenergic blocking drugs, 70–72, 71t, 72t calcium channel blockers in combination therapy, 111 in elderly patients, 110–11 hypertension with diabetes, 112 hypertension with heart disease, 112–13 calcium pathophysiology, 186–87 ischemic stroke risk and, 549–51 lipid-lowering drugs, 330 nitrates, 209 potassium, 182–83, 183t selective alpha-adrenergic blockers, 60–61 systemic lupus erythematosus, 264 T tachycardia See also supraventricular tachycardia atrial, 230–31 AV-nodal reentrant, 230 junctional ectopic, 538 sinus, 108 ventricular, 231–32, 538 tadalafil (Adcirca), 436–37, 712 TAK-422 (oral antithrombin agent), 302 Takayasu arteritis, 590 TA-NIC (nicotine vaccine), 394 taurine supplementation, 483 Taxus drug-eluting stent paclitaxel-eluting, 461f, 462, 463t platform, 464 polymer, 465 telcagepant, 562 telmisartan (Micardis) bioavailability, 127, 128t drug-drug interactions, 501 stroke prevention, 137, 138 therapeutic use, 662 tenecteplase (TNK-tPA; TNKase), 306, 679 terazosin (Hytrin) hypertension, 60–61 therapeutic use, 63, 653–54 terlipressin, 452, 452f tetralogy of Fallot, 79 thiazide diuretics adverse effects hyponatremia, 171 impotence, 174 metabolic abnormalities, 173–74 elderly patients, 747–48 gender issues, 743 pediatric use, 528–29 pharmacodynamics, 159t, 160 in pregnancy and lactation, 724 therapeutic use, 692–96 thiazolidinediones adverse effects, 418–19 cardiovascular outcomes, 415t, 418–21 thienopyridines, 266–71 See also clopidogrel; prasugrel; ticlopidine thioridazine, 504 thrombin, 287 thrombin inhibitors, 588–89 thromboangiitis obliterans, 591 thrombocytopenia, heparin-induced, 280–81 thrombolysis, prehospital, 309 thrombolytic agents, 305–21 See also reteplase; streptokinase; tissue plasminogen activator (tPA) about, 305, 307t acute myocardial infarction about, 306 adjunctive therapy, 314–15 anterior wall, 311 cardiogenic shock, 312 comparison of agents, 307–8, 308t completeness of reperfusion, 311 effect on mortality, 306–7, 308t elderly patients, 312–13 with GP IIb/IIIa receptor inhibitors, 313–114 indications and contraindications, 318, 318t inferior wall, 311–12 left bundle branch block, 312 non-Q-wave myocardial infarction, 312 patency with different agents, 309–10, 310f, 310t prehospital thrombolysis, 309 reocclusion and reinfarction, 309–10 timing and efficacy, 308–9, 309f complications, 316–18 coronary angioplasty, 315–16, 316f deep venous thrombosis, 320, 589 fibrin specificity, 306 ischemic stroke, 320, 557–59 obstructive mechanical prosthetic valve, 318–19 peripheral arterial disease, 573–74 pharmacology, 305, 306f pulmonary embolism, 319–20 specific agents, 305–6 therapeutic use, 677–79 dosage in liver disease or congestive heart failure, 731 dosage in renal insufficiency, 738 thrombotic arterial occlusion, 320 thrombomodulin, 304 thrombosis and platelets, 259–60, 259f thromboxane synthase inhibitors, 581 thymoxamine, 578 thyroxine analogues, 362 Ticagrelor (AZD6140), 297–98, 297f, 570 ticlopidine (Ticlid) about, 267–68 adverse effects, 267 drug-drug interactions, 503 ischemic stroke prevention, 553–54 peripheral arterial disease, 568 therapeutic use, 676 time factors, in thrombolytic agent efficacy, 308–9, 309f time horizon, health economics analysis, 43 timolol (Blocadren), 563, 680–81 tiotropium, 97 tirofiban (Aggrastat), 277, 677 tissue binding, ACE inhibitors, 124–26, 126t tissue distribution of drugs, 8–9 tissue factor pathway inhibitors, 303 tissue plasminogen activator (tPA) about, 305–6 elderly patients, 313 ischemic stroke, 558 myocardial infarction double bolus vs continuous infusion, 307–8 reteplase vs streptokinase and, 308 streptokinase vs., 307 TNK-tPA vs., 308 TNF (tumor necrosis factor) inhibitors, 591 TNK-tPA (tenecteplase), 306, 679 tobacco, smokeless, 387 tobacco withdrawal, 91 toborinone, 199 tocainide (Tonocard), 665 a-tocopherol, 574 tolazamide, 416 tolbutamide, 414t, 416 tolvaptan (Samsca), 457–59, 719 topiramate (Topamax) contraindications, 157–58 migraine, 563 off-label use for obesity, 408t, 410 torcetrapib, 367 torsemide (Demadex), 159–60, 159t, 692 total body clearance, 10 tPA See tissue plasminogen activator (tPA) trandolapril (Mavik), 143, 660 transdermal drug administration, 7–8 transient ischemic attack, 264 774 Index transition-state mimetics, 150 transmembrane enzyme receptors, 3, 4f trapidil, 299 treatment adherence See medication adherence treprostinil (Remodulin) peripheral vascular disorders, 572 pulmonary hypertension, 431 therapeutic use, 718 triamterene (Dyrenium), 159t, 161, 697 triflusal, 299, 555 triiodothyronine, 580 trimethaphan (Arfonad), 711–12 troglitazone (Rezulin), 415t, 418 tryptamine, 97 tumor necrosis factor (TNF) inhibitors, 591 Tussilago farfara (coltsfoot), 489 TXA2/PGH2 receptor antagonists, 295–96 U Uncaria rhynchophylla, 485–86 uncoupled proteins, 410–11 urokinase, 305 V valproic acid, 563 valsartan (Diovan) atrial fibrillation prevention, 256 combination with aliskiren, 135 heart failure, 143–44 myocardial infarction, 143 stroke prevention, 137 therapeutic use, 662 vancomycin, 596, 597–99t, 598, 601t, 606t varenicline (Chantix), 390–91 vascular dementia, 560 vascular endothelial growth factor (VEGF), 453, 573 vascular occlusive stroke, 557 vascular resistance, peripheral, 71 vascular restenosis, 629t vascular surgery, noncardiac, 354 vascularity, vasculitis, large vessel about, 589–90 cytotoxic drugs, 590–91 glucocorticoids, 590 immunomodulatory drugs, 591 vasodilators elderly patients, 749 hypertension in children, 534–35 nonspecific, 223–25 peripheral arterial disease, 572 in pregnancy and lactation, 726 therapeutic use, 712–18 dosage in liver disease or congestive heart failure, 733–34 dosage in renal insufficiency, 740–41 vasodilatory shock, 456 vasopressin (Pitressin) about, 451–52, 451f, 452t adverse effect, 456–57 analogues, 452, 452f cardiac arrest, 455–56 congestive heart failure, 457, 734 elderly patients, 749 physiologic effects, 454–55 in pregnancy and lactation, 726 therapeutic use, 719 dosage in liver disease or congestive heart failure, 734 dosage in renal insufficiency, 741 monitoring, 456 vasodilatory shock, 456 vasopressin receptors about, 452–54, 453f antagonists, 457–60 dose adjustments in renal insufficiency, 741 dosing recommendations in liver disease or congestive heart failure, 734 elderly patients, 749 in pregnancy and lactation, 726 therapeutic use, 719 location and effects of stimulation, 453t V2, gene therapy, 202 vasospasm, cerebral, 116, 209 vasospastic angina, 74 VEGF (vascular endothelial growth factor), 453, 573 veins, calcium channel blocker effects, 101 venous insufficiency, herbal remedies, 488–89 venous thromboembolism See also deep venous thrombosis aspirin, 264 heparin, 279 low-molecular-weight heparin, 283–84, 284t prophylaxis recommendations, 581, 582t warfarin, 585–86 ventilatory function, 81 ventricular arrhythmias, 110 ventricular fibrillation (VF), 232 ventricular tachycardia (VT), 231–32, 538 verapamil (Calan; Isoptin; Verelan) adverse effects, 118, 251 angina pectoris, 107 arrhythmias, 108–10, 109t, 251 drug-drug interactions, 251, 505 electrophysiology, 250 hemodynamic effects, 251 hypertrophic cardiomyopathy, 114 migraine, 563 pharmacokinetics and metabolism, 250–51 pharmacology, 250 supraventricular tachycardia in children, 542 therapeutic use, 251, 689–90 Veratrum (hellebore), 486 vernakalant, 250 vesnarinone, 199 vildagliptin (Galvus), 415t, 421 vitamin B supplements, 477–78 vitamin C supplements, 476–77 vitamin D supplements, 478, 478f vitamin E supplements, 476 vitamin K antagonists, 583, 585–86 supplements, 478 vitamins and minerals See megavitamins and micronutrients voglibose, 414t, 417 volume of distribution (Vd), VRE (enterococci resistant to vancomycin), 597, 600t W warfarin (Coumadin) adverse effects, 293–94 cardioembolic stroke, 559 clinical recommendations angioplasty and thrombolysis, 293 atrial fibrillation, 293 myocardial infarction, 292–93 prosthetic valves, 293 unstable angina, 293 deep venous thrombosis, 583, 585– 86 dosing, 291–92, 292f drug-drug interactions, 503 513–14t ethnicity and efficacy, 752 interactions with herbs, 490, 490t ischemic stroke prevention, 555–56 laboratory monitoring, 290t, 291 mechanism of action, 290 pharmacokinetics, 290–91 therapeutic use, 673–74 Wolff-Parkinson-White syndrome, 230 X xemilofiban (SC-54684A), 278 Xience V drug-eluting stent everolimus-eluting, 462, 463, 463t Index platform, 464 polymer, 465 ximelagatran about, 289 deep venous thrombosis, 589 hepatotoxicity, 556 Y YM-150 (oral antithrombin agent), 302 yohimbine, 63 Z zonisamide (Zonegran), 409t, 410 zotarolimus, 462–63, 463f, 463t 775 ... 2nd ed New York: McGraw-Hill; 20 03:15 Cardiovascular Pharmacotherapeutics, 3rd ed © 20 11 William H Frishman and Domenic A Sica, eds Cardiotext Publishing, ISBN: 978-0-9790164-3-1 473 474 Cardiovascular. .. efforts One study used the 20 02 National Health Interview Survey and analyzed data on CAM use in 10,5 72 respondents with cardiovascular disease.6 Among those with cardiovascular disease, 36%... of a 2g dose of ERN in dyslipidemic patients In another trial of 1,613 patients, 10 .2% patients stopped taking the medication in the ERN and laropiprant group because of flushing versus 22 .2% with