Ebook Cardiovascular pharmacotherapeutics Part 2

(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 3

Special Topics

Cardiovascular Pharmacotherapeutics, 3rd ed © 2011 William H Frishman and Domenic A Sica, eds Cardiotext Publishing, ISBN:

978-0-9790164-3-1.

473

More 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

physi-cians, at an annual cost of over $30 billion; most of this

cost is out-of-pocket

As a health care discipline, alternative medicine is

de-fined 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,

conven-tional medical care In the 21st century, there is an

on-going 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

Complementa-ry 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

cardiovascu-lar disorders However, the use of CAM for treating

car-diovascular disease is a highly charged subject with both

critics and proponents.3 CAM therapies are a challenge

to the scientific training of many cardiovascular

physi-cians, 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

cardiovas-cular disease, especially in those who participate in

ran-domized 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 cause of the longer and better patient-practitioner inter-action.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 medi-cal 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

be-One study used the 2002 National Health Interview Survey and analyzed data on CAM use in 10,572 respon-dents with cardiovascular disease.6 Among those with cardiovascular disease, 36% had used CAM (exclud-ing prayer) in the previous 12 months The most com-monly used therapies were herbal products (18%) and

Alternative and Complementary

Medicine for Preventing and Treating

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

Pharmacotherapeu-tics 2nd ed New York: McGraw-Hill; 2003:15.

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

insuffi-ciency, < 1% for heart failure [HF] or stroke) Most,

how-ever, 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

medi-cine, megavitamin therapy, and some folk remedies)

that could complicate existing medical therapy or even

harm patients Although an increasing number of

phy-sicians 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

interac-tions, 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

collab-orative and more effective atmosphere of open

communi-cation Physicians’ knowledge of nutritional supplement

intake is also critical to avoid potentially dangerous

in-teractions with prescribed medication For example,

consider patients taking warfarin who are also ingesting

nonprescribed natural blood thinners such as garlic,

gin-ger, 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

pharma-cologically 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

phar-macologically active substances in a diluted form, and

4 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 in-adequate 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 micronu-trient supplements with beneficial, neutral, and harmful effects on the cardiovascular system (Table 30-2)

In 1994, the US Congress passed the Dietary ment 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, miner-als, botanicals, amino acids, enzymes) without the review

Supple-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 dis-claimer saying that the product is not intended to diag-nose, treat, cure, or prevent any disease

The Rationale for Targeted Nutritional Supplements for Cardiovascular HealthThe 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 phyto-nutrients, antioxidants, and nutraceuticals

The term nutraceutical includes a wide variety of

non-prescription 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, dos-age, and potential medication interactions Dietary phy-

Alternative and Complementary Medicine  475

tochemical products, antioxidant vitamins (A, C, E) and

bioactive food components (alpha- and beta-carotene)

have shown an antioxidant effect in reducing both

oxi-dative 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

Table 30-2: Clinical Effects of Nutraceutical Supplementation* to Prevent and Treat Cardiovascular Disease

Vitamin E No benefit, potential mortality risk with supplemental doses > 400 IU

Thiamine Useful in depletion state related to diuretics

Vitamin B12 Reduces homocysteine levels, but 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

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

Coenzyme Q10 No benefit proven

Omega 3 fatty acids No benefit proven in reducing the risk of CAD

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.

Vitamin E’s antioxidant and anticoagulant properties are

thought to protect against myocardial infarction (MI)

and thrombotic strokes.11 An extensive review article

as-sessed the preventive effects of vitamin E on the

devel-opment 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

ef-fects of vitamin E are stabilizing plaque, reducing

inflam-mation, decreasing thrombolytic aggregation, reducing

the expression of adhesion molecules on the arterial wall,

and enhancing vasodilation.12 However, prospective

con-trolled clinical trials have presented a confusing picture

Past major human trials on vitamin E

supplementa-tion have included the Alpha Tocopherol Beta Carotene

(ATBC), Cambridge Heart Antioxidant Study (CHAOS),

Gruppo Italiano per lo Studio della Sopravvivenza

nell-Infarto 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,

includ-ing 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

improve-ment in arterial compliance,20 and a recent report from

the Women’s Health Study demonstrated that women

re-ceiving vitamin E supplement had a lower risk of venous

thromboembolic disease.21 The Women’s Antioxidant

Cardiovascular Study (WACS) tested the effects of

ascor-bic acid (500 mg/d), vitamin E (600 IU every other day),

and beta carotene (50 mg every other day) on the

com-bined 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

pla-cebo 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 sicians older than 50 years.23 NCCAM is studying the effect of a tocopherol supplementation (1200 IU/day)

phy-on the progressiphy-on of carotid atherosclerosis in patients with CAD (stable angina pectoris or previous MI) in a placebo-controlled, randomized double-blind trial over 2 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.12There is also a suggestion that high doses of vitamin

E may confer an increased risk for developing calcific atherosclerosis.24

Vitamin CVitamin C is not only a scavenger antioxidant, but it also acts synergistically with vitamin E to reduce the perox-

yl 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 betes mellitus, patients with hypertension, and possibly women taking oral estrogen contraceptives Female users

dia-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 spe-cifically 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 1 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% Glu-tathione 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

ascor-bic 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)

deple-tion 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

re-fractory CHF that is unresponsive to high-dose diuretic

therapy.29 The nocturnal leg cramps associated with

di-uretic therapy are a hallmark symptom of B vitamin

de-pletion 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

hyperho-mocysteinemia In 1969, McCully31 first proposed the

ho-mocysteine hypothesis, identifying accelerated vascular

pathology as a sequela to homocystinurias, a rare

auto-somal recessive disease caused by a deficiency in

cystathi-one B-synthetase Several investigations have confirmed

his proposed connection between high plasma

homocys-teine levels and occlusive arterial disease, including

pe-ripheral vascular disease, CAD, and CHF.8,29

Hyperhomocysteinemia may be even more

detri-mental 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

re-lationship between higher homocysteine levels and lower

serum levels of B vitamins; therefore, much higher doses must be administered to those patients with severe hyper-homocysteinemia 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 do not provide clear evidence of any beneficial effects of B vitamin supplementation in cardiovascular disease risk reduction.35 Several trials including the Vi-tamins 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 re-cently, the Western Norway B-Vitamin Intervention Trial (WENBIT) have failed to demonstrate benefits with vi-tamin B supplementation.36-40a Moreover, treatment with folic acid plus vitamin B12 was associated with an in-creased 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 low-ering.41 Some limitations of this study may be the intro-duction 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 proathero-sclerotic effects of folic acid supplementation, which may have counteracted benefits associated with homocyste-ine 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 end-stage renal disease.42 A number of large trials are still in progress, including studies in populations with unforti-fied 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 homocyste-ine as a cardiovascular disease risk factor before it can be recommended routinely.35

Certainly, administration of B vitamins at the mended daily allowance levels (folic acid = 400 mg; B6 = 2 mg; B12 = 6 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 manifesta-tions 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 B12.34High-dose niacin (vitamin B3) is used in the treatment

recom-of hyperlipidemia and hypercholesterolemia and helps

478    Cardiovascular Pharmacotherapeutics

curb the development of atherosclerosis and its

compli-cations (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

cy-tokines 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,

pru-ritus, gastrointestinal disturbances, exacerbation of

asth-ma, 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

suf-fer from Raynaud’s phenomenon

In an attempt to find a safer form of niacin with fewer

adverse effects, investigators have developed

extended-release, 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

Ran-domized, double-blind, placebo-controlled investigations

showed that sustained-released niacin had an impact in

decreasing LDL-cholesterol, total cholesterol, and

triglyc-erides while raising high-density lipoprotein

(HDL)-cho-lesterol at the same time.45,46 A study by Ceali et al, which

compared the incidence, intensity, and duration of

flush-ing between the 1,000 mg reformulated niacin ER and the

1,000 mg commercially available formulation, when

ad-ministered as a single 2,000 mg dose to healthy male

vol-unteers, 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

pro-cess mediated primarily by prostaglandin D(2), which

leads to poor patient adherence and suboptimal dosing

Laropiprant is a selective antagonist of the

prostaglan-din D(2) receptor subtype 1 (DP1), which may mediate

niacin-induced vasodilation A study by Paolini et al48

showed that laropiprant does not interfere with the

ben-eficial lipid effects of niacin and can allow for the

admin-istration 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

monother-apy.49 The FDA has not approved the niacin-laropiprant

combination (Cordaptive) for clinical use, and the

com-mercial 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

cardiomyo-cytes.52 There are data to suggest that low levels of

25-hy-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 Framing-ham offspring study suggest a direct association of vi-tamin D deficiency and the incidence of cardiovascular disease.58 Low levels of vitamin D have also been asso-ciated with fatal strokes,59 HF,59 sudden cardiac death,60and 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 sun-light and vitamin D as the cause.61 Despite these findings, there is no suggested dose of vitamin D to prevent car-diovascular 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 athero-sclerosis.63 In various animal models, multiple forms of vitamin K have been shown to reverse the arterial calcifi-cation 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 carot-enoids found in nature, predominantly in fresh fruits and

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 cardiovascu-

lar disease and vitamin D deficiency into perspective Br J Nutri

2005;94:483.

Alternative and Complementary Medicine  479

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

associ-ated 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 1 study

re-porting that increased b carotene stores in subcutaneous

fat were correlated with a decreased risk of MI.66

How-ever, the results of the MRC/BHF Heart Protection Study

showed no benefit from b carotene 20 mg daily on

mor-bidity and mortality in high-risk individuals.19 In

addi-tion, 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

-caro-tene use in primary prevention of cardiovascular disease

Lycopene, an oxygenated carotenoid with great

antiox-idant properties, has shown a reduction in cardiovascular

risk both in epidemiological studies and supplementation

human trials A recent study in rats showed that

toma-toes, containing or not containing lycopene, have a higher

potential than lycopene to attenuate and/or to reverse

ox-idative stress-related parameters in a mild oxox-idative stress

context.67 However, more recent controlled clinical trials

and dietary intervention studies, using well-defined

sub-ject 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

con-sumption 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

dis-ease The richness of the polyphenolic contents of green

tea and red wine has made them popular choices for

as-sociated anticancer and cardiovascular health benefits.68

The serum antioxidant activity of red wine was

ad-dressed in a small study of volunteers, the results

indi-cating that 2 glasses of red wine consumed before a meal

offered considerable antioxidant protection for at least 4

hours.69 Red wine increased antioxidant activity through

a flavonoid-polyphenol effect In another small tion 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 con-sumption of black tea was shown to reverse endothelial vasomotor dysfunction in patients with CAD.71

investiga-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 mod-erate wine intake on ischemic cardiovascular disease.72Resveratrol, as an isolated substance, is now being inves-tigated as a potential drug for use in cardioprotection.Oligomeric proanthocyanidins, like carotenoids, are found predominantly in brightly colored fruits and veg-etables and represent a safe source of polyphenols and quercetin, which are believed to be the most active pro-tective ingredients in preventing the oxidation of LDL Oligomeric proanthocyanidins are significant free-radi-cal 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 in-vestigate the bioavailability of flavonoids and phenolic acids from cranberry juice cocktail and their breakdown products (in vivo metabolites) in healthy, older adults.73Nonetheless, many flavonoids are available as food sup-plements 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 1 hypertension.75

Until the benefits of flavonoids are resolved in spective controlled studies, patients may be encouraged

pro-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 addi-tional 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

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

cardioprotec-tive 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

evi-dence for any cardiovascular benefits of cocoa flavonols

(a type of flavonoid) has been gathered predominantly

from short-term and uncontrolled studies Therefore,

ad-ditional research with well-designed, long-term clinical

studies using cocoa would be most helpful in assessing

whether flavonol-rich cocoa could be a potential

candi-date for the treatment and/or prevention of

cardiovascu-lar 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

ben-efit, it will become a tasty addition to the clinical

arma-mentarium 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

Cal-cium 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 logical deficit.80 In anginal episodes due to coronary artery spasm, treatment with magnesium has been shown to be considerably efficacious.81 Magnesium deficiency, which

neuro-is better detected by mononuclear blood cell magnesium than the standard serum level performed at most hospi-tals, predisposes to excessive mortality and morbidity in patients with acute myocardial infarction Several studies have shown an association between intravenous magne-sium 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 chan-nel–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 sur-gery; in reducing the ventricular response in acute onset atrial fibrillation, including patients with Wolff-Parkin-son-White syndrome; and in the treatment of digoxin-induced supraventricular and ventricular arrhythmias, multifocal atrial tachycardia, and polymorphic ventricu-lar tachycardia or ventricular fibrillation from drug over-doses Intravenous magnesium is, however, not useful in monomorphic ventricular tachycardia and electroshock-resistant ventricular fibrillation.83

Magnesium has also shown considerable efficacy in relieving symptoms of mitral valve prolapse In a double-blind study of 181 participants, subjective results in the magnesium group were dramatic, with significant reduc-tions noted in weakness, chest pain, shortness of breath, palpitations, and even anxiety.84 Supplemental magne-sium and potassium should be avoided in patients with renal insufficiency

Ultimately, additional studies are needed to better derstand the association between magnesium intake, in-dicators of magnesium status, and heart disease

un-Trace MineralsCobaltous 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, polycy-themia, 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 athero-sclerosis 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-Table 30-3: Possible Benefits of Flavonol-Rich

Cocoa and Chocolate

8 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.

Alternative and Complementary Medicine  481

din) 100 mg of grape-seed extract twice daily resulted in

profound lowering of LDL-cholesterol and total

choles-terol However, there was no significant change in either

HDL-cholesterol or triglyceride level in either the

treat-ment or the placebo group Since insulin resistance may

be the major factor in disturbed lipid metabolism,

chro-mium’s favorable action on glucose/insulin metabolism

may be the key factor in cholesterol lowering.86 Although

no significant adverse reactions from chromium

polynic-otinate have been observed at the dose of 400 mg per day,

massive ingestion of chromium has been associated with

renal failure.87

Selenium is an antioxidant and an essential mineral

with immune-enhancing and cancer-fighting properties

Selenium is a cofactor of the enzyme glutathione

peroxi-dase, which serves as an antioxidant and is found in the

platelets and the arterial walls In contrast to vitamin E,

which prevents formation of lipid hydroperoxides in cell

membranes and LDL by acting as a biological free-radical

trap, selenium and glutathione peroxidase help destroy

lipid hydroperoxides already formed by peroxidation of

polyunsaturated fatty acids Selenium thereby defends

against the free-radical oxidative stress that escapes the

protection of vitamin E

In some areas of the world, soil deficiencies in

sele-nium have produced Keshan disease, a disorder of cardiac

muscle characterized by multifocal myocardial necrosis

that causes cardiomyopathy, CHF, and cardiac

arrhyth-mias Men with low levels of serum selenium (< 1.4

mmol/L) demonstrated increased thickness in the intima

and media of the common carotid arteries

A substudy report from the Physician’s Health Study

showed no relationship between selenium blood levels

and the risk of MI in well-nourished subjects.88

How-ever, these findings do not rule out the possibility of an

increased risk of MI in severe selenium deficiency Also,

questions have been raised about the reliability of plasma

selenium levels; other methods to obtain accurate body

measurements have been proposed.89

Several primary prevention trials and most of the

sec-ondary prevention trials that have evaluated the effects

of different antioxidant supplements on cardiovascular

disease have had the same result as that of The

Supple-mentation en Vitamines et Mineraux Antioxydants (SU

VI.MAX) study, a randomized, double-blind,

placebo-controlled primary prevention trial that studied the

ef-ficacy of several antioxidants including selenium.90 The

results demonstrated that a 7.5-year low-dose antioxidant

supplementation lowered total cancer incidence in men

but not in women A similar tendency was observed for

all-cause mortality Also the supplementation did not

re-sult in any major effect on ischemic cardiovascular

dis-ease incidence in men or women

Although selenium is quite safe at levels below 200

mg, excessive selenium can result in alopecia, abnormal

nails, emotional lability, lassitude, and a garlic odor to the breath Skin lesions and polyneuritis have been reported

in people taking selenium from health food stores.Copper is a pro-oxidant that oxidizes LDL and may contribute to the development of atherosclerosis Men with high serum copper (> 17.6 mmol/L) demonstrate increased thickening in the intima and media of the common carotid arteries.91 Excessive oral intake of cop-per may cause nausea, vomiting, diarrhea, and hemolytic anemia Even higher doses can result in renal and hepatic toxicity as well as central nervous system disturbances similar to those of Wilson’s disease Any multivitamin with a level of copper higher than the RDA level (2 mg) should be avoided Excessive levels of copper in drinking water, especially noted in homes with copper pipes, can also contribute to elevated serum copper levels

Other NutraceuticalsCoenzyme Q10

Coenzyme Q 10, present in most foods, especially organ meats and fish, facilitates electron transport in oxidative metabolism Its reduced form, ubiquinol, protects mem-brane phospholipids and serum LDLs from lipid peroxi-dation as well as mitochondrial membrane proteins and DNA from free radical–induced oxidative damage Ubi-quinol’s antioxidant effects on membrane phospholipids and LDL directly antagonizes the atherogenesis process Vitamin E regeneration is significantly improved by the

addition of coenzyme Q 10 because of the ability of the ter ‘ to recycle the oxidized form of vitamin E back to its

lat-reduced form Coenzyme Q 10 also prevents the dant effect of a-tocopherols Supplemental coenzyme Q may also improve utilization of oxygen at the cellular lev-

pro-oxi-el, hence benefiting patients with coronary insufficiency.92

Coenzyme Q 10 deficiency has been implicated in several clinical disorders, including but not confined to heart failure, hypertension, Parkinson’s disease, and ma-

lignancy Although adverse effects of coenzyme Q 10 (such

as nausea and abdominal discomfort) are rare, it is not suggested for healthy pregnant or lactating women, as the unborn and the newborn both produce sufficient quanti-ties of the substance

3-hydroxy-3- methyl-glutaryl (HMG)-CoA reductase inhibitor therapy (statins) inhibits conversion of HMG-

CoA to mevalonate and lowers plasma Co Q 10

concen-trations In a small number of individuals, coenzyme Q 10

supplementation has been used successfully to act the adverse effect of myalgia associated with statin therapy.93 Several trials are currently being conducted on

counter-a lcounter-arge sccounter-ale to further study the effects of Co Q 10 on algias due to statin therapy

my-Additional work must be done in determining reliable

Q 10 levels for clinical purposes In addition to cholesterol and triglycerides, several other factors (including gender,

482    Cardiovascular Pharmacotherapeutics

alcohol consumption, age, and intensity of exercise) can

affect coenzyme Q levels Despite multiple claims of

ben-efit, additional studies with coenzyme Q need to be done

regarding dose (300 mg/d is the dose used in most

stud-ies) and clinical efficacy before a recommendation can be

made regarding its use in treating various cardiovascular

disorders as a primary or adjunctive treatment A

meta-analysis demonstrated a lack of mortality benefit in

pa-tients from the use of coenzyme Q 10 supplementation.94

At this time, the value of coenzyme Q 10 supplementation

in patients with cardiovascular disease is still an open

question, with neither convincing evidence supporting

nor refuting evidence of benefit or harm

L-Carnitine

Carnitine is a naturally occurring substance with several

physiologic roles It was approved by the FDA in 1986 in

both its intravenous and oral forms as an orphan drug

for the treatment of primary carnitine deficiency It is

also used for patients with conditions known to produce

secondary carnitine deficiency, such as renal failure and

various cardiovascular diseases One to two g/day given

orally in divided doses is adequate for most therapeutic

purposes Intravenous doses range from 40 to 100 mg/

kg For children, oral L-carnitine is given at 100 mg/kg/d

L-carnitine has a synergistic relationship with

coen-zyme Q 10, as it also penetrates the inner mitochondrial

membrane As a trimethylated amino acid, L-carnitine’s

primary function is in the oxidation of long-chain fatty

acids

Animal studies and clinical trials indicate that

car-nitine may be effective in treating patients with various

cardiovascular diseases, such as CAD, CHF, peripheral

vascular disease, arrhythmia, and hyperlipidemia

Carni-tine appears to boost fatty acid and carbohydrate oxidation

in the cell, while helping to remove harmful substances,

such as excessive acyl groups and free radicals, from the

cells The chronic administration of L-carnitine has been

shown to reduce blood pressure and attenuate the

inflam-matory process associated with arterial hypertension It

might produce a partial inactivation of the

renin-angio-tensin system resulting in a reduction in the production

and effects of angiotensin II.95 Additional clinical studies

with this substance are warranted before a firm clinical

recommendation for its use can be provided

Omega-3 Fatty Acids

Omega-3 fatty acids—such as eicosapentaenoic acid

(EPA) and docosahexaenoic acid (DHA)—are found in

fish oils (See Chapter 20, Lipid-Lowering Drugs)

Ome-ga-3 fatty acids are supposed to exert their beneficial

ef-fects by reducing sympathetic overactivity, enhancing

NO-mediated vasodilation, reducing monocyte adhesion,

and reducing levels of arachidonic acid-derived mediators

including thromboxane A2, thrombomodulin, and von Willebrand factor, and by also reducing insulin resistance probably through actions at the peroxisomal proliferator-activating receptor-gamma.96,96a In addition, consumption

of EPA stimulates the production of prostaglandin I3, an antithrombotic and antiplatelet-aggregating agent similar

to prostacyclin As an anticoagulant, omega-3 fatty acids can increase bleeding time, inhibit platelet adhesiveness, decrease platelet count, and reduce serum thromboxane levels Omega-3 fatty acids can also blunt the vasopres-sor effects of angiotensin II and norepinephrine and may reduce blood pressure and the risk of arrhythmia.16 The recent Study on Omega 3 Fatty Acids and Ventricular Ar-rhythmia (SOFA) did not find any evidence of a strong protective effect of intake of omega-3 polyunsaturated fatty acids from fish oil against ventricular arrhythmia in patients with implantable cardioverter-defibrillators.97

In a landmark decision in 2004, the FDA reported that

it would allow products containing omega-3 fatty acids

to claim that eating the product may reduce the risk of heart disease The FDA based its decision on the wealth

of scientific evidence that suggests a correlation between omega-3 fatty acids such as EPA and DHA and a reduced risk of CAD.97a The FDA subsequently approved omega-3 fatty acids as a treatment to reduce plasma triglycerides The triglyceride-lowering effect of these fish oil compo-nents may be one of many factors that might inhibit the progression of atherosclerosis In the GISSI-Prevenzione trial,16 Italian investigators reported overwhelming health benefits for participants who were placed on 1 g of ome-ga-3 essential fatty acids a day After the initial study had been re-evaluated, participants on the omega-3 program experienced a 20% reduction in all-cause mortality and a 45% decrease in sudden cardiac death.98 In another place-bo-controlled trial in patients with CHF (GISSI-HF), the use of 1 g of omega-3 essential fatty acids was associated with a statistically significant 9% reduction in all-cause mortality.99 In an accompanying editorial, Fonorow rec-ommended that omega-3 fatty acids be used as an adjunct

to other standard therapies in the treatment of patients with HF.100 In addition, 1 case-controlled study showed that those participants eating the equivalent of 1 fish meal

a week had a 50% less chance of sudden cardiac death compared to counterparts whose daily menus did not contain these vital fish oils.101

Recently, it was shown that EPA, at a dose of 1800 mg per day, could be a very promising regimen for preven-tion of major coronary events, especially since EPA seems

to act through several biological mechanisms However, the results of this study were from a population that was exclusively Japanese and therefore cannot be generalized

to other populations It is therefore necessary to tigate whether EPA is effective for prevention of major coronary events in hypercholesterolemic patients with or

inves-Alternative and Complementary Medicine    483

without CAD in other countries.102 A recent trial using

fish oil supplementation in patients who had a myocardial

infarction did not show benefit on subsequent

cardiovas-cular events,103 and a recent meta-analysis suggested a

possible pro-arrhythmic effect with fish oil in subsets of

cardiac patients.103a

L-Arginine

L-arginine is an essential amino acid that serves as the

substrate for the enzyme NO synthetase (eNOS), which

converts arginine to l-citrulline and produces NO

L-arginine is also known to be the substrate for other

pro-cesses, including arginine decarboxylase, which catalyzes

the synthesis of agmantine The latter is an endogenous

noncatecholamine a2 agonist that decreases peripheral

sympathetic outflow by an effect in the nucleus tractus

solitarius and therefore might be involved in the

antihy-pertensive effect of L-arginine.104

Thirteen weeks of oral administration of L-arginine

was shown to result in an increased generation of vascular

NO, a reduced endothelial release of superoxide anions,

and regression of intimal atherosclerotic lesions in rats on

a high-cholesterol diet.105

Previous studies have demonstrated that an

intracoro-nary infusion of L-arginine normalizes the defective

ace-tylcholine-induced vasodilation of coronary microvessels

in patients with hypercholesterolemia106 and in patients

with microvascular angina,107 as well in those with

athero-sclerosis.108 A study by Lerman et al in 1997109 examined

the effects of 6 months of oral L-arginine

supplementa-tion (3 g three times a day) They demonstrated that the

chronic oral L-arginine supplementation improved

coro-nary small vessel endothelial function in association with

a significant improvement in symptoms and a decrease in

plasma endothelin concentrations However, a study by

Blum et al110 concluded that chronic oral L-arginine

sup-plementation does not improve NO bioavailability in this

population of patients Possible explanations for the

dis-crepant study results in the Blum study include the

lim-ited cellular uptake of arginine, a competitive inhibition

of eNOS, or a limited cofactor availability for eNOS.111

Quyyumi examined the topic of stereospecificity and

concluded that parenteral arginine produces

nonste-reospecific peripheral vasodilation and improves

endo-thelium-dependent vasodilation in patients with stable

CAD.112

The doses of L-arginine employed in clinical trials was

8-21 g/d Adverse reactions associated with L-arginine

in-clude nausea, abdominal cramps, and diarrhea

Taurine

Taurine is an essential sulfonic amino acid that is

pres-ent in large quantities in the myocardium A deficiency of

taurine in the diet (animal food and seaweed) can cause

cardiomyopathy, and replacement will lead to recovery of myocardial function.113 Taurine in supplementary doses

of 500 mg to 3 g/d has been used in the treatment of CHF

in pilot studies, with apparent hemodynamic benefit ditional clinical study is needed Taurine has also been shown to have possible antiatherosclerotic effects.114 No adverse reactions have been reported with supplemental taurine treatment

Ad-Glutamic AcidGlutamic acid is the predominant dietary amino acid, es-pecially in vegetable protein In a cross-sectional epide-miologic study of 4680 participants, dietary glutamic acid may have independent blood pressure-lowering effects114awhich may contribute to the inverse relationship of veg-etable protein to blood pressure

Amino Acid MixturesRather than specific amino acids, the use of various ami-

no acid mixtures has been proposed as a treatment for patients with chronic HF, cardiac cachexia, systolic dys-function, and diabetes mellitus The proponents of this nutritional supplement believe that essential amino acids would shift the energy preference away from fatty acids, which would enhance adenosine diphosphate produc-tion, with favorable effects on cellular metabolism.115,116 A study showed that oral amino acid supplementation, in conjunction with standard pharmacologic therapy, ap-pears to increase exercise capacity by improving circula-tory function, muscle oxygen consumption, and aerobic production of energy in elderly outpatients with chronic

HF.117 Another study showed that long-term amino acid mixtures supplementation increased the number and volume of mitochondria and sarcomeres and decreased fibrosis in both skeletal and cardiac muscle in old rats Therefore, amino acids might improve the mechanical function of organs.118 Amino acid supplementation may also have benefits in enhancing myocycte survival and preserving mitochondrial function during ischemia-per-fusion injury.119

Herbal Remedies (Botanicals)

Since the beginning of human civilization, herbs have been an integral part of society, valued for their culi-nary and medicinal properties However, with the de-velopment of patent medicines in the early part of the twentieth century, herbal medicine lost ground to new synthetic medicines touted by scientists and physicians

to be more effective and reliable Nevertheless, about 3% of English-speaking adults in the United States still report having used herbal remedies in the preceding year This figure is probably higher among non–English-

484  Cardiovascular Pharmacotherapeutics

speaking Americans The term herbal medicine refers to

the use of plant structures known as phytomedicinals or

phytopharmaceuticals.120

Herbal medicine has made many contributions to

commercial drug preparations manufactured today,

in-cluding ephedrine from Ephedra sinica (ma-huang);

digitoxin from Digitalis purpurea (foxglove); salicin (the

source of aspirin) from Salix alba (willow bark); lovastatin

from Monascus purpureus (red yeast); and reserpine from

Rauwolfia serpentina (snakeroot), to name just a few.121,122

The discovery of the antineoplastic agent paclitaxel (Taxol)

from Taxus brevifolia (the Pacific yew tree) stresses the role

of plants as a continuing source for modern medicines

The use of herbal medicine has skyrocketed over the

last 10 years Out-of-pocket therapy is estimated at more

than $5 billion in the United States alone.120 The

follow-ing review of herbal medicinals affectfollow-ing the

cardiovas-cular system is based on information gleaned from the

scientific literature These herbs are roughly categorized

under the primary diseases that they are used to treat

(Table 30-4) Note that most herbal medicinals have

mul-tiple cardiovascular effects and that the purpose of this

organization is to simplify, not pigeonhole, herbs under

specific diseases In general, the dilution of active

compo-nents in herbal medicinals results in fewer adverse effects

and toxicities in comparison with the concentration of

active components in the allopathic medicines However,

cardiovascular disease is a serious health hazard and no

one should attempt to self-medicate with herbal remedies

without first consulting a physician.123

Congestive Heart Failure

Cardiac Glycosides

A number of herbs contain potent cardioactive

glyco-sides that have positive inotropic effects on the heart The

drugs digitoxin (derived from either Digitalis purpurea

[foxglove] or Digitalis lanata) and digoxin (derived from

D lanata alone) have been used in the treatment of CHF

for many decades Cardiac glycosides have a low

thera-peutic index, and the dose must be adjusted to the needs

of each patient The only way to control dosage is to use

standardized powdered digitalis, digitoxin, or digoxin

Treating CHF with nonstandardized herbal agents would

be dangerous and foolhardy Accidental poisonings due

to cardiac glycosides in herbal remedies are abundant in

the medical literature.124

Some common plant sources of cardiac glycosides

in-clude: D purpurea (foxglove, already mentioned); Adonis

microcarpa and Adonis vernalis (Adonis); Apocynum

can-nabinum (black Indian hemp); Asclepias curassavica

(red-headed cotton bush); Asclepias fruticosa (balloon cotton);

Calotropis precera (king’s crown); Carissa acokanthera

(bushman’s poison); Carissa spectabilis (wintersweet);

Cerbera manghas (sea mango); Cheiranthus cheiri

(wall-flower); Convallaria majalis (lily of the valley, laria); Cryptostegia grandiflora (rubber vine); Helleborus niger (black hellebore); Helleborus viridus; Nerium olean- der (oleander); Plumeria rubra (frangipani); Selenicereus grandiflorus (cactus grandiflorus); Strophanthus hispidus and Strophanthus kombè (strophanthus); Thevetia peru- viana (yellow oleander); and Urginea maritime (squill) Even the venom glands of the Bufo marinus (cane toad)

conval-contain cardiac glycosides.125Health providers should be aware of the cross-reac-tivity of cardiac glycosides from herbal sources with the digoxin radioimmunoassay A recent study found that measuring free digoxin does not eliminate the modest in-terferences caused by these herbal supplements in serum digoxin measurement by the digoxin immunoassay.126Treatment of intoxication with these herbal substances

is directed at controlling arrhythmias and hyperkalemia, which are the usual causes of fatalities

BerberineBerberine is an example of an alkaloid that is distributed widely in nature and used in the Orient for the treatment

Table 30-4 Some Conditions in Which Herbal Medicines Are Used as Cardiovascular Treatments

Conditions Examples of Herbs Used

Congestive heart failure Digitalis purpurea Digitalis lanata

Crataegus speciesBerberine

Systolic hypertension Rauwolfia serpentine

Stephania tetrandra Veratrum alkaloids

Angina pectoris Crataegus species

Panax notoginseng Salvia miltiorrhiza

Peter-DA, eds Cardiovascular Pharmacotherapeutics 2nd ed New York:

McGraw-Hill; 2003:865.

Alternative and Complementary Medicine    485

of CHF It is reported to also have antihypertensive and

antiarrhythmic actions

Hawthorn

Hawthorn (Crataegus oxyacantha) is a natural product

that is popular in European and American herbal

medi-cine practice Some of its cardiac uses include the

treat-ment of high and low blood pressure, rapid heartbeat, chest

pain, and blocked arteries.127 Hawthorn has been used as

an adjunct treatment with other cardiac drugs such as

di-goxin, warfarin, and amiodarone A placebo-controlled

study (Hawthorn Extract Randomized Blinded Chronic

HF Study [HERB CHF]) funded by the NCCAM was

car-ried out to determine the effect of hawthorn extract 450

mg twice a day versus the placebo in addition to standard

medical therapy in ambulatory patients with NYHA class

II to IV chronic HF on submaximal exercise as measured

by the 6-minute walk test The study reported no

appar-ent benefit from hawthorn-extract in patiappar-ents with class

II-IV CHF who were followed for 6 months Compared

to the placebo, there was also no benefit of hawthorn on

exercise tolerance or on quality of life.127 In addition, in a

recent study, hawthorn was found to have no effects on

HF progression in patients with known HF.128

Hypertension

Rauwolfia Serpentina

The root of Rauwolfia serpentina (snakeroot), the natural

source of the alkaloid reserpine, has been a Hindu

Ay-urvedic remedy since ancient times Extracts of

differ-ent parts and of plants resembling rauwolfia were used

in Hindu medicine for snakebite, insomnia, insanity, and

many other diseases and complaints.122 A 200 to 300 mg

dose of powdered whole root taken orally is equivalent to

0.5 mg of reserpine

Reserpine was the first potent drug widely used in the

long-term treatment of hypertension It acts by

irrevers-ibly blocking the uptake of biogenic amines

(norepineph-rine, dopamine, and serotonin) in the storage vesicles of

central and peripheral adrenergic neurons, thus leaving

the catecholamines to be destroyed by the intraneuronal

monoamine oxidase in the cytoplasm The depletion of

catecholamines accounts for reserpine’s sympatholytic

and antihypertensive actions

Rauwolfia alkaloids are contraindicated for use in

patients with a history of mental depression (especially

with suicidal tendencies), or an active peptic ulcer or

ul-cerative colitis and in those receiving electroconvulsive

therapy The most common adverse effects are sedation

and inability to concentrate and perform complex tasks

Reserpine may cause mental depression sometimes

re-sulting in suicide and must be discontinued at the first

sign of depression Reserpine’s sympatholytic effect and

its enhancement of parasympathetic actions account for

its other well-described adverse effects: nasal congestion, increased secretion of gastric acid, and mild diarrhea.Stephania Tetrandra

Stephania tetrandra is sometimes used in Traditional

Chinese Medicine (TCM) to treat hypertension

Tetran-drine, an alkaloid extract of S tetrandra, has been shown

to be a calcium-channel antagonist, paralleling the fects of verapamil Tetrandrine inhibits T and L calcium channels, interferes with the binding of diltiazem and methoxyverapamil at calcium-associated sites, and sup-presses aldosterone production.129 A parenteral dose (15 mg/kg) of tetrandrine in conscious rats decreased mean, systolic, and diastolic blood pressures for greater than 30 minutes; however, an intravenous dose of 40 mg/kg killed the rats by myocardial depression In stroke-prone hyper-tensive rats, an oral dose of 25 or 50 mg/kg produced a gradual and sustained hypotensive effect after 48 hours without affecting plasma renin activity.130

ef-Tetrandrine causes liver necrosis in dogs orally ministered 40 mg/kg of tetrandrine thrice weekly for 2 months, reversible swelling of liver cells at a 20 mg/kg dose, and no observable changes at a 10 mg/kg dose Given the evidence of hepatotoxicity, many more studies are necessary to establish a safe dosage of tetrandrine in humans

ad-Lingusticum Wallichii

The root of Lingusticum wallichii (xiong,

chuan-hsiung) is used in TCM as a circulatory stimulant, potensive agent, and sedative.131 Tetramethylpyrazine,

hy-the active constituent extracted from L wallichii, inhibits

platelet aggregation in vitro and lowers blood pressure

by vasodilation in dogs With its actions independent of the endothelium, tetramethylpyrazine’s vasodilatory ef-fect is mediated by calcium antagonism and nonselective antagonism of alpha adrenoceptors Some evidence sug-gests that tetramethylpyrazine can selectively act on the pulmonary vasculature.129 A recent study showed that a tetramethyl-pyrazine–eluting stent could inhibit the neo-intimal hyperplasia and did reduce in-stent restenosis in a porcine coronary artery restenosis model in comparison

to bare metal stents.132 Currently, there is insufficient formation to evaluate the safety and efficacy of this herbal medicinal for clinical use

in-Uncaria Rhynchophylla

Uncaria rhynchophylla (gou-teng) is sometimes used

in TCM to treat hypertension.129 Its indole alkaloids, rhynchophylline and hirsutine, are thought to be the ac-

tive principles of U rhynchophylla’s vasodilatory effect The mechanism of U rhynchophylla’s actions is unclear

Some studies point to an alteration in calcium flux in sponse to activation, whereas others point to hirsutine’s inhibition of nicotine-induced dopamine release One in

re-486  Cardiovascular Pharmacotherapeutics

vitro study has shown that U rhynchophylla extract

re-laxes norepinephrine-precontracted rat aorta through

endothelium-dependent and -independent mechanisms

For the endothelium-dependent component, U

rhyncho-phylla extract appears to stimulate endothelium-derived

relaxing factor/NO release without involving muscarinic

receptors.133 Also, in vitro and in vivo studies have shown

that rhynchophylline can inhibit platelet aggregation and

reduce platelet thromboses induced by collagen or

ad-enosine diphosphate plus epinephrine.129 The safety and

efficacy of this agent cannot be evaluated at present owing

to a lack of clinical data

Veratrum

Veratrum (hellebore) is a perennial herb growing in many

parts of the world All Veratrum plants contain poisonous

Veratrum alkaloids, which are known to cause vomiting,

bradycardia, and hypotension Most cases of Veratrum

poisonings are due to misidentification with other plants

A recent study showed that with Veratrum nigrum there

was a dose-dependent reduction in blood pressure and

heart rate after a single ingestion in rats.134 Once a

treat-ment for hypertension, however, the use of Veratrum

al-kaloids has lost favor owing to a low therapeutic index

and unacceptable toxicity, as well as the introduction of

safer antihypertensive drug alternatives

Angina Pectoris

Crataegus

Hawthorn, encompassing many Crataegus species such

as C oxyacantha and C monogina in the West and C

pinnatifida in China, has also acquired a reputation in

modern herbal literature as an important tonic for the

treatment of angina.135 Crataegus leaves, flowers, and

fruits contain a number of biologically active substances

such as oligomeric procyanidins, flavonoids, and

cate-chins From current studies, Crataegus extract appears to

have antioxidant properties and can inhibit the formation

of thromboxane A2.136 Also, Crataegus extract antagonizes

the increases in cholesterol, triglycerides, and

phospho-lipids in LDL and very low-density lipoprotein (VLDL)

in rats fed a hyperlipidemic diet; thus, it may inhibit the

progression of atherosclerosis.137

According to one study, Crataegus extract in high

concentrations has a cardioprotective effect on

ischemic-reperfused heart without causing an increase in coronary

blood flow.138 On the other hand, oral and parenteral

ad-ministration of oligomeric procyanins of Crataegus leads

to an increase in coronary blood flow in cats and dogs.139

Double-blind clinical trials have demonstrated

simulta-neous cardiotropic and vasodilatory actions of

Cratae-gus.140,141 Crataegus also lowers blood pressure due to its

action in lowering peripheral vascular resistance Animal

studies have also indicated that peripheral and coronary blood flow increases while arterial blood pressure de-creases.142 As mentioned previously, C oxyacantha was

shown to be of no clinical use in the treatment of HF Panax Notoginseng

Because of its resemblance to Panax ginseng (Asian seng), Panax notoginseng (san-qui) has acquired the com-

gin-mon name of pseudoginseng, especially since it is often

an adulterant of P ginseng preparations In TCM, the root

of P notoginseng is used for analgesia and hemostasis It

is also often used in the treatment of patients with angina and CAD.131

Although clinical trials are lacking, in vitro studies

us-ing P notoginseng do suggest possible cardiovascular

ef-fects One study that used purified notoginsenoside R1

extracted from P notoginseng on human umbilical vein

endothelial cells showed a dose- and time-dependent synthesis of tissue-type plasminogen activator without af-fecting the synthesis of plasminogen activating inhibitor, thus enhancing fibrinolytic parameters.143

Another study suggests that P notoginseng saponins

may inhibit atherogenesis by interfering with the eration of smooth muscle cells.144 According to a recent

prolif-study, it appears that P notoginseng exerts its therapeutic

effects on atherosclerosis through an anti-inflammatory action and regulation of the blood lipid profile.145 In vitro and in vivo studies using rats and rabbits have demon-

strated that P notoginseng may be useful as an antianginal

agent, since it dilates coronary arteries in all

concentra-tions The role of P notoginseng in the treatment of

hy-pertension is less certain, since it causes vasodilation or vasoconstriction depending on concentration and the tar-get vessel The results of these in vitro and in vivo studies are encouraging; however, clinical trials will be necessary

to enable more informed decisions regarding the use of P notoginseng The most common adverse effects reported

with ginseng were insomnia, diarrhea, and skin reactions.Salvia Miltiorrhiza

Salvia miltiorrhiza (dan-shen), a relative of the Western sage S officinalis, is native to China In TCM, the root of

S miltiorrhiza is used as a circulatory stimulant, sedative,

and cooling agent.131 One study showed that inhibition

of calcium ion influx in the vascular smooth muscle cells

is important for the vasorelaxant effect of shinone (an active component), and it is independent of pathways involving the endothelium, muscarinic recep-tors, beta-adrenoceptors, adenylyl cyclase, and guanylyl cyclase.146 In vitro, S miltiorrhiza, in a dose-dependent

dihydrotan-fashion, inhibits platelet aggregation and serotonin lease induced by either adenosine diphosphate (ADP)

re-or epinephrine, which is thought to be mediated by an increase in platelet cyclic adenosine monophosphate

Alternative and Complementary Medicine    487

(cAMP) caused by S miltiorrhiz’s inhibition of cAMP

phosphodiesterase S miltiorrhiza appears to have a

pro-tective effect on ischemic myocardium, enhancing the

re-covery of contractile force upon reoxygenation Clinical

trials will be necessary to further evaluate the safety and

efficacy of S miltiorrhiza.

Atherosclerosis and Hyperlipidemia

Allium Sativum

Garlic (Allium sativum) has played an important medical

as well as dietary role in human history.147 It has

preven-tive characteristics in cardiovascular diseases, regulating

blood pressure, and lowering blood sugar and cholesterol

levels It is also effective against bacterial, viral, fungal,

and parasitic infections, enhancing the immune system

and having antitumoral and antioxidant features Blood

pressure–reducing properties of garlic have been linked

to its hydrogen sulfide production and allicin content—

liberated from alliin and the enzyme alliinase—which

has angiotensin II inhibiting and vasodilating effects, as

shown in animal and human cell studies A recent

meta-analysis of randomized clinical trials studying the effect

of garlic on blood pressure suggests that garlic

prepara-tions may be superior to the placebo in reducing blood

pressure in individuals with hypertension.147

Another study suggests that suppressed LDL oxidation

may be one of the mechanisms that accounts for the

bene-ficial effects of garlic in cardiovascular health.148 However,

a trial by Gardner et al that used raw garlic, powdered

garlic supplement, and aged garlic extract supplement

given at an approximate dose of a 4-gram clove per day,

6 days a week for 6 months did not show any statistically

or clinically significant effects on LDL-C or other plasma

lipid concentrations in adults with moderate

hypercho-lesterolemia.149 Given the conflicting data, some

investi-gators have been hesitant to endorse the routine use of

garlic for cardiovascular disease despite some positive

findings because so many of the published studies had

methodologic shortcomings.150-152

The pharmacologic properties of garlic are extremely

complex, comprising a variety of sulfur-containing

com-pounds Many of the previous controlled trials of garlic

used different preparations containing all or some of

these active pharmacologic factors This may be the major

reason for the variability and confusion found in the

vari-ous research studies.150 The NCCAM is conducting a trial

to identify the compound(s) in garlic that are responsible

for its ability to prevent the formation of blood clots and

to determine the maximally effective dose and the

dura-tion of the benefits.153

Aside from a garlic odor on the breath and body,

moderate garlic consumption causes few adverse effects

Consumption in excess of 5 cloves daily may result in

heartburn, flatulence, and other gastrointestinal bances Case reports have also described bleeding in pa-tients ingesting large doses of garlic (average of 4 cloves per day) Because of its antithrombotic activity, garlic should also be used with caution in people taking oral an-ticoagulants Some individuals have also reported allergic reactions to garlic

distur-BerberineSimilar efficacies were observed in the reduction of total cholesterol as well as triglyceride in patients using both simvastatin and berberine The results showed the ratio-nale, effectiveness, and safety of the combination therapy

of both drugs for hyperlipidemia The combination can

be a possible new regimen for hypercholesterolemia.154Commiphora Mukul

Commiphora mukul (guggul) has been a mainstay of urveda medicine for thousands of years It has definite hypolipidemic actions and appears to work by blocking

Ay-an essential enzymatic step in cholesterol synthesis.155 The usual dose is 100 mg of guggulsterones daily However, one must be especially careful with Ayurveda medicines sold via the internet since it has been observed that one-fifth of both US- and Indian-manufactured medicines contain detectable lead, mercury, and arsenic.156

Monascus Purpureus

Monascus purpureus (red yeast) has been a mainstay of

TCM for thousands of years, and has been found to have hypolipidemic effects A product of the yeast, monaco-lin K, is lovastatin, the first statin drug The available red yeast formulations provide an equivalent lovastatin dose

of 2.5 to 10 mg Red yeast causes all the potential adverse effects seen with statin drugs, including rhabdomyolysis

It is also associated with drug–drug interactions similar

to those of lovastatin Some clinical trials are in progress

to study the effect of red yeast on hypercholesterolemia in patients with statin intolerance157 and also as a therapeutic supplement in combination with lifestyle changes versus simvastatin.158 Results of a preliminary study158a demon-strated that red yeast and a therapeutic lifestyle decreased LDL cholesterol without increasing creatinine phospho-kinase or pain levels, and suggested that red yeast may be

a treatment option for dyslipidemic patients who cannot tolerate statin therapy

Cerebral and Peripheral Arterial DiseasesGinkgo Biloba

Dating back well over 200 million years, Ginkgo biloba

(maidenhair tree) was apparently saved from extinction

by human intervention, surviving in Far Eastern temple gardens while disappearing for centuries in the West

488    Cardiovascular Pharmacotherapeutics

Although the root and kernels of G biloba have long been

used in TCM, Ginkgo gained attention in the West

dur-ing the twentieth century for its medicinal value after a

concentrated extract of G biloba leaves was developed in

the 1960s At least 2 groups of substances within G biloba

extract demonstrated beneficial pharmacologic actions

The flavonoids reduce capillary permeability and

fragil-ity and serve as free-radical scavengers The terpenes (ie,

ginkgolides) inhibit platelet-activating factor, decrease

vascular resistance, and improve circulatory flow

with-out appreciably affecting blood pressure Recently a study

that compared the effects of 300 mg/day of G biloba

versus the placebo in treadmill walking time and related

cardiovascular measures among patients with peripheral

artery disease showed no evidence for its therapeutic

us-age in patients.159

Continuing research appears to support the primary

use of G biloba extract for treating cerebral insufficiency

and its secondary effects on vertigo, tinnitus, memory,

and mood In a study evaluating 327 demented patients,160

120 mg of G biloba extract produced improvements in

dementia similar to other studies with donepezil and

tacrine However, a study by Solomon et al, showed no

benefit of G biloba on cognitive functioning.161 Although

approved as a drug in Europe, Ginkgo is not approved in

the United States and is instead marketed as a food

sup-plement, usually supplied as 40 mg tablets of extract The

recommended dose in Europe is one 40 mg tablet taken 3

times daily with meals (120 mg daily).161

Adverse effects of G biloba extract are rare but can

include gastrointestinal disturbances, headache, and skin

rash Several case reports of bleeding, including

subarach-noid hemorrhage, intracranial hemorrhage, and subdural

hematoma have been associated with G biloba.162 G

bi-loba should not be used in combination with analgesic

agents such as aspirin, ticlopidine, and clopidogrel or

an-ticoagulants such as warfarin and heparin, since it

under-mines the effect of the platelet inhibiting factor.163

Rosmarinus Officinalis

Known mostly as a culinary spice and flavoring agent,

Rosmarinus officinalis (rosemary) is listed in many herbal

sources as a tonic and all-around stimulant Traditionally,

rosemary leaves are said to enhance circulation, aid

di-gestion, elevate mood, and boost energy When applied

externally, the volatile oils are supposedly useful for

ar-thritic conditions and baldness

Although research on rosemary is scanty, some

stud-ies have focused on antioxidant effects of diterpenoids,

especially carnosic acid and carnosol, isolated from

rose-mary leaves In addition to having antineoplastic effects

(especially skin), the antioxidants in rosemary have been

credited with stabilizing erythrocyte membranes and

in-hibiting superoxide generation and lipid peroxidation.164

Essential oils of rosemary have demonstrated bial, hyperglycemic, and insulin-inhibiting properties.165Rosemary leaves contain high amounts of salicylates, and its flavonoid pigment diosmin is reported to decrease capillary permeability and fragility.166

antimicro-Due to a lack of studies, no conclusions can be reached regarding the use of the antioxidants of rosemary in in-hibiting atherosclerosis Although external application may cause cutaneous vasodilatation from the counterir-ritant properties of rosemary’s essential oils, there is no evidence to support any prolonged improvement in pe-ripheral circulation.166 While rosemary does have some carminative properties, it may also cause gastrointestinal and kidney disturbances in large doses

Venous InsufficiencyAesculus Hippocastanum

The seeds of Aesculus hippocastanum (horse chestnut)

have long been used in Europe to treat venous disorders such as varicose veins The medicinal qualities of horse chestnut reside mostly in its large seeds, which resemble edible chestnuts The seeds contain a complex mixture of saponins, glycosides, and several other active ingredients

In addition to a high level of flavonoids, horse chestnuts contain several minerals including magnesium, manga-nese, cobalt, and iodine

The saponin glycoside aescin from horse chestnut tract (HCE) inhibits the activity of lysosomal enzymes, which are thought to contribute to varicose veins by weak-ening vessel walls and increasing permeability, result-ing in dilated veins and edema In animal studies, HCE increases venous tone, venous flow, and lymphatic flow

ex-in a dose-dependent fashion HCE also antagonizes lary hyperpermeability induced by histamine, serotonin,

capil-or chlcapil-orofcapil-orm HCE decreases edema fcapil-ormation of phatic and inflammatory origin HCE’s dose-dependent antioxidant properties can inhibit in vitro lipid peroxida-tion Randomized double-blind, placebo-controlled trials using HCE show a statistically significant reduction in edema, as measured by plethysmography.167 Standardized HCE is prepared as an aqueous-alcohol extract of 16%

lym-to 21% of triterpene glycosides, calculated as aescin The usual initial dose is 90 to 150 mg of aescin daily, which may be reduced to 35 to 70 mg daily after improvement.166Standardized HCE preparations are not available in the United States, but nonstandardized products may be available Some manufacturers promote the use of topi-cal preparations of HCE for treatment of varicose veins as well as hemorrhoids; however, at least 1 study has dem-onstrated very poor aescin distribution at sites other than the skin and muscle tissues underlying the application site.168 For now, research studies have yet to confirm any clinical effectiveness of topical HCE preparations

Alternative and Complementary Medicine    489

Although adverse effects are uncommon, HCE may

cause gastrointestinal irritation and facial rash Parenteral

aescin has produced isolated cases of anaphylactic

reac-tions as well as hepatic and renal toxicity.166 In the event of

toxicity, aescin is completely dialyzable, with elimination

dependent on protein binding

Ruscus Aculeatus

Like A hippocastanum, Ruscus aculeatus (butcher’s

broom) is known for its use in treating venous

insuf-ficiency R aculeatus is a short evergreen shrub found

commonly in the Mediterranean region Two steroidal

saponins extracted from the rhizomes of R aculeatus

(ruscogenin and neurogenin) are thought to be its active

components.168 Topical Ruscus extract’s vascular effects

are also temperature-dependent and appear to counter

the sympathetic nervous system’s temperature-sensitive

vascular regulation Based on the influence of prazosin,

diltiazem, and rauwolscine, the peripheral vascular

ef-fects of Ruscus extract appear to be selectively mediated

by effects on calcium channels and alpha-adrenergic

receptors

Several small clinical trials using topical Ruscus extract

support its role in treating venous insufficiency One

ran-domized double-blind, placebo-controlled trial involving

18 volunteers169 showed a statistically significant decrease

in femoral vein diameter (median decrease of 1.25 mm)

using duplex B-scan ultrasonography 2.5 hours after

applying 4 to 6 g of a cream containing 64 to 96 mg of

Ruscus extract Another small trial (n = 18) showed that

topical Ruscus extract may be helpful in reducing venous

dilatation during pregnancy.170 Oral agents may be as

use-ful as topical agents for venous insufficiency, although the

evidence is less convincing

Although capsule, tablet, ointment, and suppository

(for hemorrhoids) preparations of Ruscus extract are

available in Europe, only capsules are available in the

Unit-ed States These capsules contain 75 mg of Ruscus extract

and 2 mg of rosemary oil.166 Aside from occasional nausea

and gastritis, adverse effects from using R aculeatus have

rarely been reported, even at high doses Although there

is ample evidence to support the pharmacologic activity

of R aculeatus, there is still a relative deficiency of clinical

data to establish its actual safety and efficacy

Other Herbs with Adverse Cardiovascular

Effects

For the following noncardiovascular herbal remedies,

only cardiovascular actions are emphasized (Table 30-5)

Tussilago Farfara

Tussilago farfara (coltsfoot, kuan dong-hua) is a perennial

herb that is grown in many parts of northern China,

Eu-rope, Africa, Siberia, and North America Over the years,

T farfara has been used as a demulcent antitussive agent

due to a throat-soothing mucilage within the herb

Re-cently, the use of T farfara has lost favor due to several

studies that found senkirkine, a pyrrolizidine alkaloid known to cause hepatotoxicity, in all parts of the herb In

addition, rats fed a diet containing T farfara had a high

risk of developing hemangioendothelial sarcoma of the liver.166 A diterpene isolated from T farfara, named tus-

silagone, is shown to be a potent respiratory and vascular stimulant.171

cardio-Ephedra Sinica

Ephedra sinica (joint fir, ma-huang), the natural source of

the alkaloid ephedrine, has been used in TCM for over 5,000 years as an antiasthmatic and decongestant Ephe-dra, also known as Ma Huang, was commonly used to en-hance athletic performance, “fat burning,” and weight loss before its removal from the United States in April 2004 due to acute adverse health reactions including lethal arrhythmias, stroke, vasoconstriction, and MI A recent case report of MI in a 29-year-old patient exemplifies the long-term danger of ephedrine products and is the first report of coronary artery aneurysm associated with its use.172

diterpenoid ester alkaloids, including aconitine, which

Table 30-5 Adverse Cardiovascular Reactions Observed with Herbal Medicines Used for Other Indications

Examples Herbal Medicines

Hypertension Tussilago farfara

Ephedra sinica

Hypotension Aconitum species

Digitalis toxicity Over 20 herbal substances

with activity to digitalis radioimmunoassay

Bradycardia Aconitum species

Jin bu huanReproduced with permission from Sinatra ST, Frishman WH, Peter- son SJ, Lin G Use of alternative/complementary medicine in treat- ing cardiovascular disease In: Frishman WH, Sonnenblick EH, Sica

DA, eds Cardiovascular Pharmacotherapeutics 2nd ed New York:

McGraw-Hill; 2003:869.

490    Cardiovascular Pharmacotherapeutics

have been linked to several deaths in Hong Kong and

Australia Death usually results from cardiovascular

col-lapse and ventricular tachyarrhythmias induced by

aco-nite alkaloids These alkaloids activate sodium channels

and cause widespread membrane excitation in cardiac,

neural, and muscular tissues Characteristic

manifesta-tions of aconite intoxication include nausea, vomiting,

diarrhea, hypersalivation, and generalized paresthesias

(especially circumoral numbness) Muscarinic activation

may cause hypotension and bradyarrhythmias

Aconite-induced cardiac arrhythmias can also lead to cardiac

fail-ure in as little as 5 minutes to as long as 4 days

Management of aconite intoxication consists of

symp-tomatic relief, since no specific antidote exists

Amioda-rone and flecainide may be used as antiarrhythmic agents

Intragastric charcoal can decrease alkaloid absorption A

fatal dose can be as little as 5 mL of aconite tincture, 2

mg of pure aconite, or 1 g of plant Considering their low

therapeutic index and unacceptable toxicity, Aconitum

and its products are not recommended even in

therapeu-tic doses, since an erroneous dose can be fatal

Jin Bu Huan

Often misidentified as a derivative of Polygala chinensis,

jin bu huan is most likely derived from the Stephania

genus This herbal remedy contains an active alkaloid

known as levotetrahydropalmatine, which is a potent

neuroactive substance Jin bu huan is used as an analgesic,

sedative, hypnotic, and antispasmodic agent as well as a

dietary supplement It is associated with significant

car-diorespiratory toxicity, including respiratory failure and

bradycardia requiring endotracheal intubation There is

no specific antidote for the treatment of acute Jin bu huan

overdose Several cases of hepatitis have also been

associ-ated with long-term ingestion of Jin bu huan Although

it is now banned in the United States, Jin bu huan is still

being imported illegally as jin bu huan anodyne tablets.174

Drug–Herbal Interactions

The increased use of alternative medicine in the United

States have made information about potential drug–

herb interactions very important, especially for

medica-tions with a narrow therapeutic index, such as warfarin

and digoxin.175 Commonly used herbs that can interact

with warfarin are listed in Table 30-6 There is also

evi-dence to suggest that the herb St John’s Wort

(Hyperi-cum perforatum) acts as an inducer of the cytochrome

p450 3A4 enzyme.176 St John’s wort can reduce digoxin

blood levels.177 Cardiovascular drugs such as

amioda-rone, amlodipine, diltiazem, felodipine, lidocaine,

losar-tan, lovastatin, nifedipine, propafenone, simvastatin, and

verapamil are substrates of the enzyme Patients receiving

any of these medications along with St John’s Wort would

be at risk for exacerbation of an arrhythmia, angina, or

hypertension.178

There are herbal remedies (eg, cola, ginger, licorice) that have pharmacodynamic interactions with antihyper-tensive drugs that will counteract their hypotensive ef-fects Ginseng has been shown to increase digoxin levels and to reduce the effects of warfarin.179

Suspected drug–herbal interactions should be ported by clinicians to the FDA’s Med Watch Program The FDA has established the Special Nutritionals Adverse Event Monitoring System, a computer database that in-cludes information about suspected adverse effects re-lated to dietary supplements as nutritional products A recent study showed that the majority of St John’s Wort products fail to adequately address clinically relevant safety issues on their labeling Health care providers and consumers may benefit if the FDA re-examined labeling requirements for dietary supplements.180,180a

re-Homeopathic Remedies

Homeopathy has been used widely to treat various

cardi-ac disorders It is a healing system dating bcardi-ack to the 18th century created by Samuel Christian Hahnemann, a Ger-man physician who lost faith in conventional allopathic medicine.181 Hahnemann based homeopathy on 3 laws: (1) the law of similars, (2) the law of infinitesimals, and (3) the law of chronic suppressions or law of chronic dis-

ease The basic premise is that like is cured by like (similia similibus curentur)—diseases can be treated by substances

that produce the same signs and symptoms in a healthy individual.194 The preparation of remedies involves se-rial dilution, commonly to the extent that no molecules

of the original substance remain, and vigorous shaking between dilutions (potentisation) During this process, information is thought to be transferred from the diluted substance to the solvent, which in the light of current

Table 30-6 Potential and Documented Interactions of Herbs with Warfarin

Potential Increase in Risk of Bleeding

Chamomile GinkgoFeverfew Horse chestnutGarlic Licorice rootGinger

Documented Reports of Possible Decrease in Warfarin’s Effects

Ginseng Green teaReproduced with permission from Frishman WH, Sinatra ST, Moi- zuddin M Herbal approach to cardiac disease In: Frishman WH,

Weintraub MI, Micozzi M, eds Complementary & Integrative

Thera-pies for Cardiovascular Disease St Louis: Elsevier; 2005:101.

Alternative and Complementary Medicine  491

knowledge seems implausible Many people therefore

as-sume that any effects of homoeopathy must be from

non-specific placebo effects

Recently, homeopathy as a healing art has been under

great scrutiny, especially in the United Kingdom, because

of major meta-analyses showing no significant

ben-efit with homeopathy that is greater than the placebo.182

There have been several reports of undertreatment for

serious medical conditions by homeopathic physicians

and advice given not to vaccinate for certain illnesses like

mumps, measles, and rubella.183 However, homeopathy

continues to show great popularity, especially in

third-world communities that cannot afford more expensive,

allopathic medicines.184

Chelation

In general terms, chelation therapy is a process of using

specific molecules (chelating agents) to form complexes

that inactivate heavy metals (metal ions), which can then

be excreted safely in the urine The most popular

applica-tion of this therapy has been in heavy metal toxicity

(in-cluding hemachromatosis) when the binding of chelating

agents to these metals forms soluble, inactive complexes

that are eliminated in the urine.185 This aforementioned

use of chelation therapy is well established and accepted

However, a more intriguing and controversial aspect

of chelation therapy is its use for treating atherosclerotic

disease Managing cardiovascular disease with this

ther-apy involves the repeated administration of intravenous

ethylenediaminetetraacetic acid (EDTA) supplemented

with some “nutrients” (such as vitamins C, B complex and

B6, heparin, and magnesium sulfate) This use of

chela-tion began in the 1950s when a group from Michigan

reported on its use in treating atherosclerotic

cardiovas-cular disease.186 This led to great controversy about the

benefits of chelation therapy that has continued to this

day (Table 30-7) The focus of the arguments are related

to efficacy, safety, and the possible mechanism of benefit

Despite the ongoing controversy, it is estimated that

che-lation therapy accounts for more than 800,000 patient

vis-its in the United States each year.187

The major questions surrounding EDTA chelation for

clinical use have continued to revolve around its efficacy

and safety The perception is that there is no generally

ac-cepted scientific evidence from well-conducted studies to

justify its use One meta-analysis, however, did conclude

that there was evidence to support the use of EDTA in

treating cardiovascular disease.188 However, most of the

studies included in the analysis were not controlled, and

by 2001 not a single reputable cardiovascular society had

endorsed chelation therapy for treating cardiovascular

disease, including the American College of Cardiology/

American Heart Association guidelines for managing

pa-tients with stable angina.189

At the same time, how safe is chelation therapy? The concerns regarding the safety of EDTA treatment have been addressed by the proponents of this therapy, includ-ing the publication of guidelines for its safe use.190 How-ever, it is well known that EDTA is not a benign drug when high doses are administered over a short time Some of the adverse effects of high doses of EDTA include neph-rotoxicity, bone marrow depression, hypocalcemic tetany, allergic reactions, insulin shock, hypotension, thrombo-emboli, electrocardiographic changes including cardiac arrhythmias, and prolongation of the prothrombin time.191The National Institutes of Health funded the Trial to Assess Chelation Therapy (TACT) at more than 100 cen-ters in the United States and Canada This randomized, controlled trial is designed to determine whether patients treated with EDTA chelation therapy in addition to stan-dard medications and who have had a previous MI will have fewer cardiac events and deaths than others treated with standard medications alone The trial began in 2003 and was terminated in 2008 for procedural reasons with

no benefit from chelation demonstrated.192

Conclusion

Alternative medicine represents those healing traditions that in the recent past were not part of standard allopathic medical training However, more and more individuals are seeking CAM practitioners and remedies for part of their health care needs Although most CAM therapies are relatively innocuous and often improve patient well-being most likely through a placebo effect, 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 cause harm

Physicians must be aware of CAM practices so that they can best counsel their patients in an atmosphere of

Table 30-7 Theoretical Benefits of Using EDTA Chelation Therapy in CAD

1 Decalcification of complex atheroscleroticplaques

2 Decreased platelet aggregability

3 Reduction in oxygen-derived free radicals

4 Lowering of serum iron

5 Lowering of serum cholesterol

Reproduced with permission from Frishman WH, Wolff AI lation therapy In: Frishman WH, Weintraub MI, Micozzi M, eds

Che-Complementary & Integrative Therapies for Cardiovascular Disease

St Louis: Elsevier; 2005:289.

492  Cardiovascular Pharmacotherapeutics

open communication Rather than dismissing a patient’s

highly motivated intentions towards health-conscious

behaviors, it behooves the physician to understand the

range of CAM treatments and when they might be safely

integrated with conventional medicine

Despite the lack of scientific rigor in previous studies

of CAM therapies, the NCCAM, a part of the National

Institute of Health is now actively coordinating clinical

trials, advancing scientific research and training

research-ers to study CAM Ultimately it will be the fusion of the

best medical practices from those which are rigorously

studied in clinical trials that will provide the most

favor-able clinical outcomes in medicine

In addition, physicians must remember that many of our current drugs came out of herbal medicine practice (eg, digitalis, aspirin, lovastatin, reserpine), and home-opathy (nitroglycerin) Much of our bedside approach

to sick patients was adopted and modified from ancient and deeply rooted cultures (eg, Ayurveda) We have the responsibility as medical professionals to preserve and protect the physical, psychological, and spiritual “heart”

of our patients Achieving a “placebo effect” while doing

“no harm” is a benefit clinicians should not ignore

Note: References for this chapter can be found here:

www.cvpct3.com

Cardiovascular Pharmacotherapeutics, 3rd ed © 2011 William H Frishman and Domenic A Sica, eds Cardiotext Publishing, ISBN:

978-0-9790164-3-1.

493

It has been estimated that 3.8 billion prescriptions were

filled in 2007, representing a 72% increase from 1997 to

2007 It has also been estimated that the average number

of prescriptions filled by each person in the United States

increased from 8.9 a year in 1997 to 12.6 in 2007.1 In terms

of prescription volume, cholesterol-lowering

medica-tions, angiotensin-converting enzyme (ACE) inhibitors,

and beta-blockers were among the top 5 therapeutic

cat-egories of drugs dispensed (antidepressants and codeine

and combination pain medications were the other two).2

Given the increase in prescription drug utilization,

espe-cially among the elderly, drug–drug interactions are to be

expected in many individuals In addition, the volume of

prescriptions written for cardiovascular medications

in-creases the likelihood that a medication given for a

car-diovascular indication will be involved in the interaction

In the majority of instances, drug–drug interactions

are deemed to be undesirable Certainly, many untoward

effects can be attributed to drug interactions, but the

neg-ative connotation associated with drug–drug interactions

is sometimes unjustified There are times when drug

inter-actions are beneficial (for example, when a loop diuretic

and a thiazide diuretic are given concomitantly to produce

synergistic diuresis or when lisinopril and chlorthalidone

are co-administered for synergistic antihypertensive

ef-fects) In addition, there are instances when 2 drugs

are known to interact with each other, but the benefit is

deemed to outweigh the risks; for example, giving

amiod-arone along with warfarin for a patient with chronic atrial

fibrillation In this case, the dosage of warfarin is reduced

to compensate for the increased plasma concentrations

induced by amiodarone and the patient is educated and

monitored for signs and symptoms of digoxin toxicity

Many reported drug–drug interactions are also of

questionable clinical significance For example,

atorvas-tatin can increase the steady-state plasma concentrations

of digoxin by 20%, but this interaction is unlikely to be of any clinical significance in the vast majority of patients.3 It

is therefore important that patients are educated ing any significant drug interactions with the medica-tions they are taking With the abundance of information available to the lay public on medications, resourceful but medically uneducated patients may rather easily find information on the medicines that they are taking and become falsely alarmed should they read about a drug interaction regarding some of their medicines that they were not made aware of, whether it be of clinical conse-quence or not

regard-Drug interactions of most concern are those with a low therapeutic index and serious adverse effects, such that even minor disruptions in plasma concentrations can result in toxicity (see Chapter 1, Basic Principles of Clinical Pharmacology Relevant to Cardiology) Also

of concern are patients being treated for serious or tentially fatal diseases, in that maintenance of thera-peutic drug concentrations is of critical importance for

po-a fpo-avorpo-able outcome Drug–drug interpo-actions cpo-an result

as a consequence of pharmacokinetic (ie, alterations in drug absorption, distribution, metabolism, and/or excre-tion) and/or pharmacodynamic (ie, alterations in phar-macologic effect) interactions It should be noted that drug–drug interactions will often involve multiple mech-anisms, sometimes involving both pharmacokinetics and pharmacodynamics

Pharmacokinetic Drug Interactions

AbsorptionThere are various ways that drug–drug interactions may occur as a consequence of altered drug absorption from

Cardiovascular Drug–Drug Interactions

Angela Cheng-Lai, PharmD

James J Nawarskas, PharmD

William H Frishman, MD

31

494    Cardiovascular Pharmacotherapeutics

the gastrointestinal (GI) tract These predominantly

in-volve binding interactions, alterations in GI motility,

al-terations in gastric pH, and reductions in intestinal flora

(Table 31-1) Binding interactions involve drug chelation

or adsorption to form nonabsorbable drug complexes

This may be seen through cation binding (eg, aluminum

or magnesium-containing antacids; iron) to medicinal

resins such as tetracycline, fluoroquinolones, digoxin, or

quinapril, resulting in a nonabsorbable drug complex

Cholestyramine and colestipol may adsorb and thereby

inhibit the absorption of several drugs such as

hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase

in-hibitors, furosemide, digoxin, and warfarin

Drugs that affect gastric transit time can also elicit

drug–drug interactions Metoclopramide and various

laxatives can accelerate gastric motility, thereby reducing

the bioavailability of medications in controlled-release

formulations, and the reduction in gastric motility due

to anticholinergic agents may result in delayed

absorp-tion of medicaabsorp-tions from the small intestine Drugs with

pH-dependent dissolution (eg, rosuvastatin) may display

reduced absorption when given with antacids or other

drugs that increase stomach pH such as H2-receptor

an-tagonists or proton-pump inhibitors Aspirin is a weak

acid that prefers an acidic environment for absorption, as

seen when the drug exists in its lipid-soluble, nonionized

form In addition, many enteric-coated medications rely

on the relatively alkaline environment of the small

intes-tine for dissolution and as such may display altered

ab-sorption should the gastric pH increase Antibiotics may

enhance the efficacy of warfarin by altering intestinal

flo-ra and reducing the bacterial synthesis of vitamin K The

absorption of digoxin, which is partially metabolized by

GI microorganisms, may be increased due to a reduction

in bacterial metabolism caused by erythromycin therapy

Distribution

Drug–drug interactions involving drug distribution

cen-ter on alcen-terations in plasma protein binding Albumin

binds acidic drugs, and a1-acid glycoprotein binds basic

drugs Displacement of a drug from its protein-binding

site by another drug forms the basis for certain drug–

drug interactions, as it is the free (unbound) drug that

elicits pharmacologic actions This is most commonly

seen when 2 highly protein-bound (> 90%) drugs are

co-administered However, the clinical relevance of such

in-teractions is frequently low since the newly displaced free

drug is then susceptible to metabolism and elimination,

which ultimately reduces the free drug concentration to

that which was present before the interaction

MetabolismWith regards to pharmacokinetic drug–drug interactions, alterations in drug metabolism may be most frequently cited as the cause of the interaction Drug metabolism oc-curs at many different sites throughout the body, but the majority of drug metabolism involves enzymatic reactions

in the liver and intestine, where drugs are metabolized to inactive or less active metabolites These enzymes may be inhibited or induced, resulting in a variety of drug–drug interactions (Tables 31-1 and 31-2) Enzyme inhibition typically leads to an increase in drug plasma concentra-tions secondary to a reduction in drug metabolism This

is one of the most common mechanisms of drug–drug interactions

Enzyme inhibition may also, however, lessen drug fect if the object drug is a prodrug in need of metabo-lism to form the active moiety In this instance, enzyme inhibition would lessen the therapeutic effect by reduc-ing the formation of active drug An example of this type

ef-of interaction involves the reduced conversion ef-of dogrel to its active metabolite due to inhibition of the CYP2C19 isozyme by proton-pump inhibitors (PPIs) Enzyme induction typically leads to diminished drug ef-fect secondary to accelerated metabolism The CYP3A4 and 2C9 isozymes are especially susceptible to induction.4However, if a drug has toxic metabolites, enzyme induc-tion may actually increase drug toxicity, as may be seen with acetaminophen and its metabolism to hepatotoxic metabolites.4

clopi-The enzymes of the cytochrome P450 (CYP450) tem constitute the primary drug-metabolizing enzymes, and as such play a large role in drug–drug interactions (see Chapter 1, Basic Principles of Clinical Pharmacology Relevant to Cardiology) These enzymes facilitate drug elimination by converting them from a hydrophobic to

sys-a hydrophilic stsys-ate.5 Drug–drug interactions are typically the result of a competitive binding interaction between

a substrate drug and an inhibitor drug, in which both drugs compete for the enzyme’s binding site The degree

of inhibition is dependent on many factors, such as ity of the substrate for the enzyme, the concentration of the substrate required for inhibition, and the half-life and time to steady-state concentrations of the inhibitor drug.6

affin-Of the more than 30 human CYP450 isozymes that have been identified, those most frequently involved with drug–drug interactions are CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4, with the latter being responsible for the metabolism of about half of the drugs currently available on the market.6,7 Table 30-2 lists substrates, in-hibitors, and inducers of each of these isozymes.7-12

Absorption Chelation Aluminum or magnesium-containing antacids or iron

chelat-ing to digoxin or quinaprilAdsorption Cholestyramine adsorption to HMG-CoA reductase inhibi-

tors, furosemide, digoxin, and warfarinAltered gastrointestinal

motility Metoclopramide may increase gastric motility and thereby decrease digoxin absorption; the reduction in gastric motility

due to anticholinergic agents may result in delayed absorption

of many medications from the small intestine

Altered gastrointestinal pH Reduced rosuvastatin absorption (pH-dependent drug

dis-solution) with antacids or other drugs that increase stomach pH; aspirin absorption may also be decreased in a less acidic environment

Reduction in intestinal flora Increased efficacy of warfarin by antibiotics due to less

bacterial synthesis of vitamin K; digoxin absorption may be increased by erythromycin due to a reduction in bacterial digoxin metabolism

Distribution Altered plasma protein

binding Valproic acid may displace warfarin from protein binding sites, resulting in a transient increase in warfarin effect

Metabolism Enzyme inhibition increasing

drug effect/toxicity Amiodarone may interfere with the metabolism of warfarin through CYP2C9 inhibition, thereby potentiating the effects of

drug effect Reduction in the hemodynamic effects of felodipine by carba-mazepine induction of CYP 3A4

Elimination Decreased renal clearance Reduction in digoxin clearance by amiodarone or quinidine,

resulting in elevated serum digoxin concentrations

Antacids may decrease the urinary excretion of quinidine by alkalinizing the urine

Increased renal clearance Antacids may reduce serum salicylate concentrations by

alka-linizing the urine and reducing renal tubular reabsorption of salicylate, thereby increasing renal clearance

496    Cardiovascular Pharmacotherapeutics

Table 31-2 Substrates, Inhibitors, and Inducers of the Main Drug-Metabolizing Cytochrome P450 isozymes

Artemisinin Atazanavir Cimetidine Ciprofloxacin Enoxacin Ethinyl Estradiol Fluvoxamine Mexiletine

Tacrine Thiabenda- zole Zileuton

Barbiturates Cruciferous vegetables Grilled meat

Carbamazepine Primidone Rifampin Smoking

Chloramphenicol Cimetidine Clopidogrel Delavirdine Efavirenz Esomeprazole Felbamate Fluconazole Fluoxetine Fluvoxamine Isoniazid Moclobemide Modafinil Omeprazole

pine Ticlopidine Voriconazole

Oxcarbaze-Aminoglutethimide Artemisinin Barbiturates Carbamazepine Phenytoin Primidone Rifampin Rifapentine

Amiodarone Clopidogrel Delavirdine Disulfiram Doxifluridine Efavirenz Fluconazole Fluorouracil Imatinib Leflunomide Metronidazole Miconazole Phenytoin Sulfamethoxazole Sulfaphenazone

azone Valproic acid Voriconazole

Sulfinpyr-Aminoglutethimide Barbiturates Bosentan Carbamazepine Griseofulvin Phenytoin Primidone Rifabutin Rifampin Rifapentine

Amiodarone Bupropion Chloroquine Cinacalcet Diphenhydramine Fluoxetine Haloperidol Imatinib Paroxetine Propafenone Propoxyphene Quinidine Terbinafine Thioridazine

Carbamazepine Phenobarbital Phenytoin Rifampin Ritonavir

Cardiovascular Drug–Drug Interactions 497

CYP3A4 (abbreviated list)

Pioglitazone Prednisolone Prednisone Propoxy- phene Quazepam Quetiapine Quinidine Quinine Ranolazine Repaglinide Rifabutin Ritonavir Saquinavir Sibutramine Sildenafil Simvastatin Sirolimus Tacrolimus Tadalafil Tamoxifen Tamsulosin Testosterone Tiagabine Tipranavir Topiramate Triazolam Vardenafil Verapamil Ziprasidone Zolpidem Zonisamide

Amiodarone Amprenavir Aprepitant Atazanavir Chloramphenicol Clarithromycin Conivaptan Cyclosporine Darunavir Dasatinib Delavirdine Diltiazem Erythromycin Fluconazole Fluoxetine Fluvoxamine Fosamprenavir Grapefruit juice Imatinib Indinavir

Isoniazid Itraconazole Ketoconazole Lapatinib Miconazole Nefazodone Nelfinavir Posaconazole Ritonavir Quinupristin Saquinavir Tamoxifen Telithromycin Troleandomycin Verapamil Voriconazole

Aminoglutethimide Bexarotene Bosentan Carbamazepine Dexamethasone Efavirenz Fosphenytoin Griseofulvin Modafinil Nafcillin Nevirapine Oxcarbazepine Phenobarbital Phenytoin Primidone Rifabutin Rifampin Rifapentine

St John’s wort

Data from Horn et al;7-11 Anderson et al.12

Table 31-2 Substrates, Inhibitors, and Inducers of the Main Drug-Metabolizing Cytochrome P450 isozymes

(continued)

Elimination

The elimination of drugs from the body typically

oc-curs through the kidney This may take place through

1 of 3 mechanisms: (1) glomerular filtration, which

depends on the protein binding of the drug as well as

the glomerular filtration rate; (2) active tubular

secre-tion, which occurs in the proximal renal tubule; and (3)

passive tubular reabsorption of nonionized weak acids

and bases in the proximal and distal renal tubules.12,13

Drug interactions involving glomerular filtration

typi-cally involve a nephrotoxic drug increasing the serum

concentration of a drug dependent on glomerular

filtra-tion for eliminafiltra-tion This, however, is not considered a

true drug–drug interaction as the interaction is due to

a drug adverse effect as opposed to a pharmacokinetic

or pharmacodynamic interaction.12 Alternatively, the

methylxanthines (eg, caffeine) may increase renal blood flow and glomerular filtration, thereby accelerating drug clearance

Interactions involving active tubular secretion are most commonly seen when 2 acidic or 2 basic drugs compete for the same transport system For example, the basic drug quinidine may reduce the renal clearance of the basic drug digoxin by 30% to 50%.14,15 The reabsorp-tion of drugs in the kidney is affected by pH, and drugs that either acidify or alkalinize the urine may elicit drug–drug interactions For example, the urinary excretion of the basic drug quinidine may be decreased by antacids, which alkalinize the urine, resulting in increased quini-dine tubular reabsorption due to reduced ionization in the alkaline urine Alternatively, reabsorption of salicy-lates is reduced by antacids, resulting in increased renal salicylate clearance

498    Cardiovascular Pharmacotherapeutics

Drug Transporters

A relatively new development in our understanding of

drug–drug interactions involves drug transporter

pro-teins Transporter proteins actively move drugs in

(up-take) or out (efflux) of cells, and certain transporters

may have their activity enhanced or reduced by various

drugs These proteins can affect various

pharmacokinet-ic properties of medpharmacokinet-ications P-glycoprotein is an efflux

transporter found on enterocytes that transports drugs

from the cell cytoplasm back into the intestinal lumen,

where they are then excreted This ultimately results in a

lower bioavailability for orally administered medications

The uptake transporters can transport either organic

an-ions (organic anion transporters [OATs]) or organic

cat-ions (organic cation transporters [OCTs]) and are found

on enterocytes, renal tubular cells, and bile canaliculi.16

These transporters actively pump drugs into cells such as

hepatocytes and renal tubular cells, where they may then

be secreted into the bile, metabolized (liver), or secreted

into the urine (kidney).17

Digoxin is a P-glycoprotein substrate and is

suscep-tible to interactions with P-glycoprotein inhibitors such

as amiodarone, erythromycin, or clarithromycin (Table

31-3) In these instances, the inhibitor will increase the

bioavailability of the substrate, and elevated serum

di-goxin concentrations may be the consequence This is

widely known to occur when amiodarone and digoxin are

given together but can also explain the elevations in

se-rum digoxin concentrations that have been reported with

concomitant clarithromycin and erythromycin

adminis-tration.18,19 Quinidine is also a P-glycoprotein inhibitor,

which may also contribute to its interaction with

digox-in.16 Conversely, digoxin plasma concentrations may be

reduced by inducers of P-glycoprotein.16,20

The elimination of several HMG-CoA reductase

in-hibitors is partially dependent on OATs In fact, over

5-fold increases in plasma concentrations of pravastatin has been demonstrated when this drug was given con-comitantly with the OAT inhibitor cyclosporine.21 Re-garding cation transporters, procainamide is an OCT substrate and can compete with other OCT substrates for transport from the plasma into hepatocytes or renal tubu-lar cells Metformin, triamterene, and cimetidine are also OCT substrates, the latter of which has been shown to reduce the renal clearance of procainamide.17,22

Pharmacodynamic Drug Interactions

Pharmacodynamic drug–drug interactions involve an alteration in pharmacologic drug response that may be either additive or antagonistic between the substrate drug and the interacting drug Multiple examples of these types

of interactions may be found involving cardiovascular medications In terms of additive effects, some classic ex-amples involve the use of thiazide diuretics to augment the antihypertensive efficacy of various medications such

as ACE inhibitors or beta blockers Thiazide diuretics are also routinely used to produce synergistic diuresis when added to a loop diuretic

While these examples demonstrate therapeutic benefits, harm may also occur, for example, when ad-ministering spironolactone and potassium (producing hyperkalemia) or quinidine and erythromycin (addi-tive QT prolongation) Antagonistic interactions may be seen when nonsteroidal anti-inflammatory medications (NSAIDs) are given with antihypertensives (reduced anti-hypertensive efficacy) or loop diuretics (reduced sodium and water excretion)

As mentioned above, for any given drug–drug action there may be multiple mechanisms contributing

inter-to the interaction Also, not all drug interactions are of clinical relevance It is the responsibility of the health care provider to recognize the significance of any given inter-action and determine the applicability of this interaction

to the patient

This chapter will focus on cardiovascular drug–drug interactions, primarily those of clinical consequence Drug interactions from major cardiovascular drug classes are described in terms of proposed mechanisms, clinical consequences, and suggested courses of action Due to a high degree of interpatient variability in drug disposition and drug effects, significant interactions do not always occur in every patient given a drug interaction listed Therefore, this chapter is intended to serve as a guide to important interactions that are likely to occur in clinical situations Because information on drug interactions are constantly evolving due to new drugs that are released and new information being published in the literature, interested readers are encouraged to consult frequent-

Table 31-3 P-glycoprotein Substrates, Inhibitors,

CarbamazepineRifampin

St John’s wortTipranavir

Data from Horn et al.16

Cardiovascular Drug–Drug Interactions    499

ly updated references for a comprehensive list of drug

interactions.13,23

Angiotensin Converting Enzyme Inhibitors

ACE inhibitors are used extensively for the management

of hypertension and heart failure A number of drug

in-teractions have been cited with this class of agents, and

a few clinically relevant ones are described here.24,25

Be-cause ACE inhibitors lower blood pressure, they can

work synergistically with other blood pressure lowering

agents such as diuretics to further reduce blood

pres-sure In many cases, the combined used of ACE inhibitors

and diuretics can provide better blood pressure control

However, the concurrent use of these 2 agents can also

cause excessive hypotension Thus, in patients who are

al-ready receiving diuretics, it may be preferable to initiate

the ACE inhibitor at a lower dose or to temporarily

dis-continue the diuretic for 2 to 3 days before starting ACE

inhibitor therapy.25 In addition, blood pressure and fluid

status should be monitored in these patients

Due to their ability to lower aldosterone levels and

cause potassium retention, ACE inhibitors may cause

an excessive rise in serum potassium levels when given

concurrently with other agents that increase serum

potas-sium, such as potassium-sparing diuretics, eplerenone, or

potassium supplements Thus, it is important to monitor

serum potassium in patients using these combinations,

especially in patients with renal impairment.25 Because

ACE inhibitors and NSAIDs exert opposing effects on

prostaglandin release, the concurrent use of both agents

may theoretically lead to less vasodilation and diminished

efficacy from ACE inhibitors.25 For example,

indometha-cin has been shown to diminish the antihypertensive

ef-fects of enalapril and perindopril in patients who were

maintained on these ACE inhibitors for blood pressure

control.26-27 Although uncommon, clinically significant

nephrotoxicity has also occurred when ACE inhibitors

were given concurrently with NSAIDs.25,28 Therefore, one

must monitor renal function carefully, especially in

pa-tients with renal impairment, when ACE inhibitors and

NSAIDs are given together

Concerns have been raised regarding the

counteract-ing effect of aspirin on the augmentation of prostacyclin

synthesis by ACE inhibitors, thus diminishing the

ben-eficial effects of ACE inhibitors in heart failure patients.29

Results from clinical trials investigating the interaction

between ACE inhibitors and aspirin have been

inconsis-tent.29-32 At this point, the evidence for benefit or harm

from aspirin therapy in heart failure patients using ACE

inhibitors remains inconclusive pending further study.29

Some evidence suggest that low doses of aspirin (40 to

80 mg) are sufficient to inhibit thromboxane synthesis,

whereas higher doses of aspirin (> 325 mg) may be quired to completely inhibit the synthesis of vasodilating prostaglandins.33 For this reason, it may be helpful to use

re-a lower dose of re-aspirin (ie, 81 mg) in pre-atients with here-art failure who are treated with ACE inhibitors concurrent-

ly.29 Of note, ACE inhibitors increase insulin sensitivity and may therefore increase the hypoglycemic effect of antidiabetic agents.25,34-35 In patients using ACE inhibi-tors and antidiabetic therapy concurrently, blood glucose should be monitored regularly, and dosages of antihyper-glycemic agents should be adjusted as needed.25,34 Other medications that interact with ACE inhibitors include allopurinol, azathioprine, cyclosporine, and lithium.36-45These interactions are described in Table 31-4.23-45

Angiotensin Receptor Blockers (ARBS)

Compared to other classes of antihypertensive agents, ARBs are well tolerated and appear to have a low potential for drug interactions.46,47 Similar to ACE inhibitors, ARBs have a synergistic pharmacodynamic effect on blood pressure control by reacting with diuretics such as hydro-chlorothiazide.46 Drugs that are likely to interact with all ARBs include lithium, NSAIDs, potassium-sparing di-uretics, eplerenone, and potassium supplements Other drug interactions involving ARBs are more specific to individual agents Among the agents in this class, losar-tan and irbesartan have greater affinities for cytochrome P450 isoenzymes and thus are more likely to interact with other drugs.46

Losartan has affinity for CYP2C9, which facilitates the conversion of losartan to the carboxylic acid derivative E-3174 (a metabolite that has 10 to 14 times more antihy-pertensive activity than the parent compound, losartan)

In addition, it has modest affinity for the CYP1A2 and CYP3A4 isoenzymes, both of which are also involved in the formation of E-3174.47 Fluconazole (an antifungal agent) is an effective CYP2C9 inhibitor that suppresses the conversion of losartan to E-3174 In healthy volun-teers who received both losartan and fluconazole, an in-crease in the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of losar-tan, as well as reductions in the plasma levels of E-3174, were observed.48 Alterations of these pharmacokinetic parameters could potentially lead to a decreased antihy-pertensive efficacy of losartan However, the clinical sig-nificance of this interaction is unknown.47

Rifampin (an antibacterial agent frequently used for the treatment of tuberculosis and potent inducer of the CYP3A4 system) is another agent that has the poten-tial to interact with losartan The AUC of losartan was reduced by 35% and that of E-3174 by 40% when losar-tan and rifampin were concurrently administered to

ment) and renal function

NSAIDs NSAIDs interfere with the

pro-duction of vasodilator and uretic prostaglandins

natri-Diminished antihyperten-sive and natri-uretic effects

Monitor blood pressure and adjust therapy as needed

NSAIDs Reduced production of

angio-tensin II (which maintains GFR

by efferent arteriolar tion when kidneys are under-perfused) by ACE inhibitors and reduced renal vasodilatory prostaglandins (which support adequate renal blood flow by afferent arteriolar vasodilation)

constric-by NSAIDs may cause a loss of synergistic action to sustain glo-merular filtration

Acute renal insufficiency Monitor renal function, especially in patients with renal impairment

Antihypergly-cemic Agents ACE inhibitors increase insulin sensitivity and may increase the

hypoglycemic effect of betic agents

antidia-Hypoglycemia Monitor blood glucose closely and

adjust dosages of antihyperglycemic agents as needed Patients should also

be warned about the possibility of hypoglycemia when ACE inhibitors are given currently with antidiabetic agents

Azathioprine Unknown Anemia may

pos-sibly be due to the etin-lowering effects of ACE inhibitors

erythropoi-sion (anemia

Myelosuppres-or leukopenia)

Avoid concurrent administration of azathioprine and ACE inhibitors If these drugs must be given together, monitor hemoglobin, hematocrit, platelets, and white cell counts every 2

to 3 weeks

Cyclosporine Long term cyclosporine therapy

may cause renal hypoperfusion, which may activate the rennin-angiotensin system for mainte-nance of glomerular filtration

Under these circumstances, the co-administration of an ACE inhibitor (which decreases the production of angiotensin II) could trigger acute renal failure

Acute renal failure Monitor renal function closely

Lithium Because lithium is mostly

ex-creted by the kidneys and is dependent on both glomerular filtration and sodium concentra-tion in the proximal tubule, the possible reduction of glomerular filtration and sodium concentra-tion by ACE inhibitors may lead

to increased lithium retention

Lithium ity (weakness, tremor, exces-sive thirst, confusion)

toxic-If lithium and ACE inhibitors are used concurrently, monitor serum lithium concentrations frequently, especially

in patients with impaired renal tion, congestive heart failure or vol-ume depletion Lower lithium doses may be required

func-Cardiovascular Drug–Drug Interactions    501

healthy volunteers.49 In addition, the half-lives of

losar-tan and E-3174 were reduced by 50% Due to the extent

of this pharmacokinetic effect, the interaction is likely to

be clinically significant and may necessitate an increase

in losartan dosage when it is given concurrently with

rifampin.46,49

In common with losartan, irbesartan has a marked

af-finity for CYP2C9, CYP3A4, and CYP1A2.47 Drug

inter-actions could occur with tolbutamide or warfarin since

both of these agents competitively inhibit the oxidation

of irbesartan However, a pharmacokinetic interaction

between irbesartan and tolbutamide or irbesartan and

warfarin (along with other drugs such as nifedipine,

magnesium and aluminium hydroxides, simvastatin, or

digoxin) was not observed.50 Furthermore, a study in

healthy volunteers showed that irbesartan did not affect

the steady-state pharmacodynamics and

pharmacokinet-ics of warfarin.51 Therefore, dosage adjustment of

irbesar-tan or warfarin, or additional anticoagulation monitoring,

is probably not necessary when irbesartan and warfarin

are used concurrently.51

Telmisartan has no CYP-dependent metabolites and

is mainly excreted via the bile.46 Thus, there is a low

po-tential for interaction with this agent Although the Cmax

of digoxin was increased by 50% when telmisartan was

given concurrently with digoxin, it was suggested that

this elevation is transient and is unlikely to be of clinical

significance.46-47 Clinically relevant drug interactions with

ARBs are summarized in Table 31-5.23,46-51

Antiarrhythmic Agents

Due to their narrow therapeutic index, small alterations

in the serum concentrations of antiarrhythmics can lead

to decreased therapeutic effectiveness or increased verse effects As most antiarrhythmics are metabolized via the CYP450 enzymes, pharmacokinetic interactions comprise the majority of clinically significant interac-tions seen with this class of agents.52 Using the Vaughn-Williams classification, more frequently used class I agents include quinidine, procainamide, disopyramide, lidocaine, mexiletine, flecainide, and propafenone All of these agents except procainamide are metabolized via the CYP450 enzymes and are implicated in numerous drug–drug interactions.52

ad-For example, quinidine alone has been involved in more than 30 different drug interactions, many of which can lead to major clinical consequences Notable interac-tions include that of quinidine and digoxin, where quini-dine was shown to decrease the clearance of digoxin and caused an increase in digoxin concentrations and possible digoxin toxicity.14 Another interaction is between quini-dine and erythromycin, where erythromycin increased quinidine concentrations through inhibition of quinidine metabolism via CYP3A4 and induced possible quinidine toxicity.53

Class II and IV antiarrhythmics consist of ers and calcium antagonists; interactions involving these agents are discussed under their respective classifications

beta-block-in this section Class III antiarrhythmic agents beta-block-include amiodarone, dofetilide, dronedarone, ibutilide, and so-talol Of these agents, amiodarone is commonly used and

is involved in large numbers of drug interactions since it

is metabolized by CYP3A4 and it is a potent inhibitor of several CYP450 enzymes (CYP1A2, 2C9, 2D6, and 3A4)

A well-known interaction involving the itory effect of amiodarone is its reaction with warfarin, where amiodarone decreases warfarin metabolism via inhibition of CYP3A4 and causes an elevation in plasma

reac-If these agents are used concurrently, monitor carefully for hypersensitivity reaction

ACE = angiotensin converting enzyme; NSAIDs = nonsteroidal anti-inflammatory drugs; GFR = glomerular filtration rate

Table 31-4 Selected Drug–Drug Interactions with ACE Inhibitors

(continued)

502    Cardiovascular Pharmacotherapeutics

warfarin concentration.54 Another well-known

interac-tion with amiodarone that involves a different mechanism

is the interaction with digoxin, where the oral

bioavail-ability of digoxin is increased due to the inhibition of

P-glycoprotein by amiodarone Thus, dosages of warfarin

and digoxin should empirically be reduced by one-half

when amiodarone is added.52

Grapefruit juice has been reported to interact with

many drugs by inhibiting CYP3A4 and the

P-glycopro-Table 31-5 Selected Drug–Drug Interactions with Angiotensin Receptor Blockers

NSAIDs NSAIDs interfere with

the production of dilator and natriuretic prostaglandins

vaso-Diminished pertensive and natri-uretic effects

antihy-Increased risk of renal impairment, especially

in volume-depleted patients

Monitor blood pressure, fluid status, and renal function Therapy should be adjusted as needed

Lithium Increased renal lithium

reabsorption at the mal tubular site

proxi-Lithium toxicity (weakness, tremor, excessive thirst, confusion)

If lithium and ARBs are used concurrently, monitor serum lithium concentrations fre-quently, especially in patients with impaired renal function, congestive heart failure, or vol-ume depletion Lower lithium doses may be requiredARBs

(losartan) Fluconazole Fluconazole decreases the conversion of

losar-tan to its active lite, E-3174

metabo-Diminished pertensive effects from losartan

antihy-Monitor blood pressure and adjust dosage of losartan as needed

Rifampin Rifampin significantly

induces the metabolism

of losartan and E-3174, resulting in a decrease in the AUC and half-life of both compounds

Diminished pertensive effects from losartan

antihy-Monitor blood pressure and adjust dosage of losartan as needed

ARBs = Angiotensin receptor blockers; NSAIDs = nonsteroidal anti-inflammatory drugs; AUC = area under the tration-time curve

concen-tein transport system.54 Because a number of mic agents are metabolized through CYP3A4, grapefruit juice should be avoided in patients taking antiarrhythmic drugs such as amiodarone and dronedarone that under-

antiarrhyth-go extensive hepatic metabolism with this enzyme.23,55Besides pharmacokinetic interactions, antiarrhythmic agents are involved in many pharmacodynamic interac-tions For example, additive negative inotropic effects may be observed when beta-blockers are added to fle-

Cardiovascular Drug–Drug Interactions    503

cainide or intravenous disopyramide.12 Additive effects

on the reduction of atrioventricular nodal conduction

and myocardial contractility may also be observed when

amiodarone is added to other agents such as diltiazem,

verapamil, digoxin, and beta-blockers.12

A number of drugs such as erythromycin,

cotrimoxa-zole, clarithromycin, azithromycin, gatifloxacin,

ketocon-azole, moxifloxacin, pentamidine, chloroquine, quinine,

cisapride, tricyclic antidepressants, haloperidol,

pheno-thiazines, and risperidone have been implicated in the

prolongation of QT interval, resulting in an increased

risk of proarrhythmia.52,54 Concurrent use of drugs that

prolong QT interval with Class Ia or Class III

antiarrhyth-mics (which may also prolong QT interval) could increase

the risk of drug-induced arrhythmia due to the combined

pharmacodynamic effects.52 Therefore, clinicians should

be aware of this possible interaction and monitor patients

accordingly when concurrent use of more than one QT

prolongation drug is necessary.52 Overall, antiarrhythmic

agents have been implicated to interact with a number of

drugs that include other antiarrhythmic agents,

antibac-terials, antidepressants, antifungals, antiretrovirals, beta

blockers, calcium antagonists, digoxin, enzyme inducers,

H2 blockers, neuromuscular blockers, theophylline, and

warfarin.23,52,54,56-92 Selected interactions involving

antiar-rhythmic agents are listed on Tables 31-6 and 31-7.23-24,52-92

Anticoagulant Agents

Anticoagulants play an important role in various

thera-pies including the prophylaxis and/or treatment of

venous thrombosis, pulmonary embolism and atrial

fi-brillation with thromboembolism Because these agents

inhibit or diminish the synthesis of clotting factors,

bleeding is a worrisome adverse effect Concomitant use

of an anticoagulant with other anticoagulants,

antiplate-let drugs, fibrinolytics, and/or NSAIDs may cause

phar-macodynamic interactions that further increase the risk

of bleeding Therefore, patients who are required to use

more than one of these drugs must be monitored closely

for signs and symptoms of bleeding; laboratory tests such

as international normalized ration (INR) and activated

partial thromboplastin time (aPTT) should be performed

when appropriate

In the United States, warfarin is used almost

exclu-sively when oral anticoagulation is needed Warfarin has

a relatively narrow therapeutic index, requiring regular

monitoring for safety and efficacy Because warfarin is

al-most entirely metabolized in the liver, impaired hepatic

function may increase sensitivity to this drug Drug

inter-actions with warfarin are plentiful and may be attributed

to several mechanisms, such as a reduction in warfarin

metabolism or clearance (increases warfarin effect);

dis-placement of warfarin from plasma protein binding sites (increases warfarin effect); or an increase in warfarin me-tabolism (decreases warfarin effect).93 Due to the com-plex response of warfarin to concurrent drug therapy, it

is difficult to predict the occurrence and degree of ence from other drugs on anticoagulation in individual patients.94 For clinical practice, one should monitor for changes in INR when adding or discontinuing any drugs suspected to cause an interaction in patients receiv-ing warfarin.94 In many cases, the onset of the adverse prothrombin time response from warfarin might begin between 1 to 2 days after starting the concurrent drug regimen.94 However, the potentiation of warfarin effects may occur within 2 weeks and even up to 2 months in some cases after initiating amiodarone.88,94 Selected drug interactions with warfarin are listed on Table 31-8.23-24,94-106

influ-Antiplatelet Agents

Antiplatelet agents are frequently used drugs; they are employed in various therapies including the reduction of cardiac events in patients with acute coronary syndrome Similar to anticoagulants, bleeding is a concerning ad-verse effect Concurrent use of an antiplatelet agent with other antiplatelet drugs, anticoagulants, fibrinolytics, and/or NSAIDs may further increase the risk of bleeding

In addition to pharmacodynamic interactions with other drugs that could potentiate the risk of bleeding, pharmacokinetic interactions involving antiplatelet agents have been reported For example, ticlopidine has shown to decrease the metabolism of phenytoin and the-ophylline.12 Thus, ticlopidine may increase the plasma concentrations of phenytoin and theophylline and cause

an increased risk of toxicity of the latter agents It is portant to monitor patients closely for signs and symp-toms of phenytoin or theophylline toxicity and adjust dosages accordingly when either of these agents is used concomitantly with ticlopidine

im-The pharmacokinetic interaction between clopidogrel and PPIs has caused much research and debate Clopido-grel, a thienopyridine, is a prodrug that is transformed

in vivo to an active metabolite, which irreversibly binds

to the platelet P2Y12 receptor and subsequently blocks platelet activation and aggregation.107 The active metabo-lite of clopidogrel is formed through the CYP450 enzyme system after 2 sequential reactions involving CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, with CY-P2C19 playing a major role.107 PPIs inhibit the CYP2C19 pathway and may interfere with the conversion of clopi-dogrel to its active form, which may subsequently lead to

a diminished clinical efficacy from clopidogrel

A number of studies have examined the effects of PPIs

on clopidogrel’s clinical efficacy However, results of these

504    Cardiovascular Pharmacotherapeutics

studies have been conflicting and inconsistent While

some large observational studies found an increase in

car-diovascular events in participants prescribed clopidogrel

who also took PPIs, others did not find a significant

dif-ference in clinical outcomes based on PPI exposure.108-112

It is interesting that more reports finding a drug

in-teraction between clopidogrel and PPIs were associated

with omeprazole.107 This may be due to a higher degree

of CYP2C19 inhibition by omeprazole compared to other

PPIs such as rabeprazole and pantoprazole.107 In

Novem-ber 2009, the US Food and Drug Administration (FDA)

recommended that the concomitant use of omeprazole

and clopidogrel should be avoided.113 Because

esomepra-zole is a component of omepraesomepra-zole, this PPI should also

be avoided in combination with clopidogrel.113 Further,

other drugs that are potent inhibitors of the CYP2C19

enzyme, such as cimetidine, fluconazole, ketoconazole,

voriconazole, etravirine, felbamate, fluoxetine,

fluvox-amine, and ticlopidine, should be avoided in patients

tak-ing clopidogrel.113

In addition to the FDA recommendations, several

suggestions have been made to address the uncertainties

of the clopidogrel-PPI interaction One suggestion is for

clinicians to consider using pantoprazole when a PPI is

indicated.107,114 Because pantoprazole is a weak inhibitor

of CYP2C19, a significant interaction with clopidogrel

will probably occur Another suggestion is to stagger the

dosing of clopidogrel and PPIs.114-115 Because most PPIs

are eliminated within 10 hours, inhibition of CYP2C19

is likely to be short lived, and separation of clopidogrel

and PPI by 12 to 20 hours should in theory prevent an

interaction.115

In contrast to the above recommendation by some

au-thors, the FDA stated that separating the dose of

clopi-dogrel and omeprazole in time would not reduce the

possibility of a drug interaction.113 Perhaps the most

im-portant suggestion of all is that clinicians must evaluate

the necessity of PPI therapy.107,114 In patients whom PPIs

are not absolutely indicated, switching PPI therapy to H2

antagonists (ie, ranitidine, famotidine, nizatidine) or

ant-acids would help to avoid a clopidogrel-PPI interaction.113

Beta-Adrenergic Blockers

Beta blockers are generally well tolerated and are widely

used for various cardiovascular and other clinical

condi-tions (see Chapter 5, Alpha- and Beta-Adrenergic

Block-ing Drugs) Heart rate, myocardial contractility, and

blood pressure are all reduced with beta-blockade; some

of these effects may be additive with those of digoxin or

nondihydropyridine calcium channel blockers

Specifi-cally, digoxin and beta-blockers can have additive

inhibit-ing effects on AV nodal activity.116 The concurrent use of

verapamil and beta-blockers can lead to hypotension, modynamically significant bradycardia, and heart failure,

he-as well he-as hemodynamic collapse.116-119Rebound hypertension may occur following the abrupt withdrawal of clonidine in patients who received concurrent treatment with clonidine and beta-blocker.120This phenomenon may be due to an unopposed alpha ef-fect following clonidine withdrawal.23 This exaggerated clonidine withdrawal response may be minimized with the use of cardioselective beta-blockers (eg, atenolol, metoprolol) or by the use of a combined alpha- and beta-adrenergic blocker such as labetalol.12,116 Alternatively, the beta-blocker may be discontinued first before clonidine is

to be withdrawn from concomitant therapy with a blocker.23 Use of alpha blockers (eg, prazosin and doxa-zosin) may also help to prevent rebound hypertension associated with clonidine withdrawal.23

beta-Several beta-blockers (bisoprolol, carvedilol, lol, propranolol, and timolol) are substrates of CYP2D6; carvedilol is also a substrate of CYP2C9 and propranolol

metopro-a substrmetopro-ate of CYP2C19.12,93 Some beta blockers may also inhibit the metabolism of other drugs.121 Therefore, many beta blockers are susceptible to pharmacokinetic inter-actions that would affect either the metabolism of the beta-blocker itself or the metabolism of other drugs The concurrent use of amiodarone and metoprolol or pro-pranolol has been associated with bradycardia, cardiac arrest, and ventricular arrhythmias.12 This adverse effect may be attributed to the additive cardiac effects from both amiodarone and beta blockers In addition, amiodarone may inhibit beta-blocker metabolism leading to increased beta-blocker effects and possibly beta-blocker toxicity.23Another important interaction is that between pro-pranolol and thioridazine Propranolol may inhibit the metabolism of thioridazine, thus increasing thioridazine plasma levels and increasing the risk of cardiac arrhyth-mias and tardive dyskinesia.122 For this reason, the con-current administration of thioridazine and propranolol is contraindicated Other interactions involving beta block-ers are described in Table 31-9.12,23-24,116-127 Note that pro-pranolol is involved in more drug interactions compared

to other beta-blockers This may be due to the propensity

of propranolol’s metabolism to be affected by other drugs

or its ability to inhibit the metabolism of some drugs thermore, propranolol is the oldest beta-blocker, thus it is the most comprehensively studied

Fur-Calcium Antagonists

Calcium antagonists are a diverse class of drugs

common-ly used in the management of cardiac conditions such as hypertension, supraventricular arrhythmias and angina pectoris (see Chapter 8, Calcium Channel Blockers) Due

Cardiovascular Drug–Drug Interactions    505

to their high frequency in usage, there is an increased

potential for calcium antagonists to be administered

con-currently with other agents and cause drug interactions.128

Diltiazem and verapamil may produce additive

depres-sion on AV nodal conduction and myocardial

contrac-tility when they are used concurrently with amiodarone,

beta-blockers, or digoxin.12 Because calcium antagonists

are metabolized by CYP3A4, they are also susceptible to

pharmacokinetic interactions with drugs that either

in-hibit or induce CYP3A4.12 Carbamazepine, phenytoin

and phenobarbital are inducers of CYP3A4 and have led

to decreases in the hemodynamic effects of calcium

chan-nel blockers, particularly felodipine.12,23,129-130 Inhibitors of

the CYP3A4, such as itraconazole and grapefruit juice,

have been demonstrated or would be expected to cause

increased serum concentrations of calcium antagonists,

particularly the dihydropyridines.12,131-132

In addition to being a substrate of CYP3A4, verapamil

and diltiazem are inhibitors of CYP3A4 and can interact

with drugs that are metabolized by this isoenzyme.12 For

example, verapamil and diltiazem may inhibit the

CY-P3A4-mediated metabolism of certain HMG-CoA

reduc-tase inhibitors (atorvastatin, lovastatin, and simvastatin)

and increase the risk of myopathy and

rhabdomyoly-sis.133-134 Because pravastatin is not extensively hepatically

metabolized and both fluvastatin and rosuvastatin are

metabolized via CYP2C9, these statins may serve as safer

alternatives in patients who are on concurrent diltiazem

or verapamil therapy.12,93 Another noteworthy interaction

is between that of calcium antagonists and cyclosporine

Diltiazem, verapamil, amlodipine, felodipine, and

nica-rdipine all have shown to increase cyclosporine serum

concentrations to various degrees.135-139 Therefore, one

must monitor cyclosporine levels closely and reduce the

dose of cyclosporine accordingly when this agent is given

concomitantly with interacting calcium antagonists.36

This interaction may be a desirable one since it could

result in decreased cost as a result of lower cyclosporine

dosage requirements.12

A particularly important interaction is that of calcium

antagonists and digoxin Diltiazem and verapamil reduce

the clearance of digoxin and may increase serum digoxin

concentrations by as much as 50% and 70%,

respective-ly.12,140-141 Therefore, one must monitor digoxin levels

care-fully and adjust the dosage of this drug accordingly when

it is given concurrently with interacting calcium

antago-nists Selected interactions involving calcium antagonists

are summarized on Table 31-10.12,23,128-147

Digoxin

Digoxin is the most commonly used digitalis glycoside

(see Chapter 13, Inotropic Agents) This drug has been

used frequently for the management of atrial fibrillation and heart failure Because digoxin has a narrow thera-peutic index, a change in drug concentration due to drug interactions may lead to clinical adverse effects Interac-tions with digoxin have been discussed under other ther-apeutic classes in this section; a few important ones are highlighted here

Due to its negative chronotropic effect, the concurrent use of digoxin with diltiazem, verapamil, amiodarone,

or beta-blockers may cause additive effects on AV nodal conduction and lead to bradycardia or heart block.148-149Serum electrolyte disturbances, such as hypokalemia and hypomagnesemia may predispose patients to digoxin tox-icity Thus, serum electrolytes should be monitored rou-tinely in patients on chronic digoxin therapy, especially in those who are also on diuretic therapy, which can cause

a decrease in serum electrolytes.150-151 Antibiotic therapy with erythromycin or tetracycline can reduce digoxin bioinactivation by destroying specific bacteria flora in the colon, thus increasing its availability for absorption and can lead to increased digoxin concentration and pos-sible digoxin toxicity.152-153 Amiodarone, propafenone and quinidine have all shown to decrease digoxin clearance and increase digoxin serum concentrations.14,154-155 There-fore, one must monitor digoxin concentrations carefully and adjust the dosage of digoxin accordingly when it is given concurrently with interacting agents Selected inter-actions involving digoxin are listed on Table 31-11.23,148-160

Diuretics and Nitrates

Diuretics, especially thiazide diuretics, are commonly used in combination with ACE inhibitors, ARBs, and beta-blockers for additive antihypertensive effects How-ever, combinations of diuretics and ACE inhibitors may also cause postural hypotension in some patients due to vasodilation and relative intravascular volume depletion

A good way to prevent first-dose hypotension is to start

an ACE inhibitor on a lower dose for patients who are using diuretics concurrently.93 Blood pressure, fluid sta-tus, and body weight should be monitored regularly upon initiation of both diuretic and ACE inhibitor therapy Thiazide and loop diuretics may cause potassium loss and should be used carefully with other drugs that can decrease potassium levels, such as corticosteroids, am-photericin, or itraconazole.46 The hypokalemic effect of diuretics can usually be overcome by concurrent use of drugs that increase serum potassium Concomitant use

of agents such as ACE inhibitors, ARBs, and sparing diuretics not only prevent potassium loss from thiazide diuretics; they also provide enhanced effects on blood pressure control.46 On the contrary, use of agents that increases serum potassium such as ACE inhibitors

potassium-506    Cardiovascular Pharmacotherapeutics

and potassium supplements, along with

potassium-spar-ing diuretics (ie, triamterene, spironolactone, amiloride),

may cause hyperkalemia Therefore, it is important to

perform periodic determination of serum electrolytes in

all patients receiving diuretic therapy.46

NSAIDs can reduce the diuretic and antihypertensive

efficacy of diuretics by inhibiting renal sodium excretion

and decreasing renal prostaglandin production.161

An-other notable interaction is between thiazide diuretics

and lithium.162 Hydrochlorothiazide may decrease

lithi-um clearance and increase serlithi-um lithilithi-um concentration

and cause lithium toxicity Therefore, it is important to

monitor serum lithium concentrations and adjust lithium

doses accordingly during concomitant therapy with

thia-zide diuretics

Nitrates have been the mainstay in the management of

angina for many years Due to their vasodilating effects,

nitrates may cause hypotension when they are used with

other agents that lower blood pressure The interaction

between nitrates and sildenafil has caught much media

attention due to a number of deaths associated with this

interaction.163 Co-administration of nitrates and

sildena-fil significantly increases the risk of potentially

life-threat-ening hypotension Thus, the administration of nitrates

should be avoided in patients who have taken sildenafil

within the past 24 hours.163 Similarly, the concurrent use

of nitrates with other phosphodiesterase 5 inhibitors such

as tadalafil and vardenafil is contraindicated In patients

who are using tadalafil for erectile dysfunction, at least 48

hours should elapse after the last dose of this agent before

nitrate administration is considered.164 A suitable time

in-terval following vardenafil dosing for the safe

administra-tion of nitrates has not been determined.165

Lipid-Lowering Drugs

The bile acid sequestrants (cholestyramine, colestipol,

and colesevelam) are safe and effective agents for the

treatment of hyperlipidemia Because they are not

ab-sorbed into the circulation, they have the advantage of

avoiding systemic drug–drug interactions.93 In spite of

this, bile acid sequestrants may bind to many medications

and cause decreased plasma concentrations and reduced

effectiveness of other medications.96,166 Therefore, it is

rec-ommended that other drugs be administered at least 2

hours before or 4 to 6 hours after bile acid sequestrants.12

Gemfibrozil and fenofibrate are very effective at

re-ducing triglycerides, and they are sometimes used in

con-junction with HMG-CoA reductase inhibitors (statins)

for patients who also need reductions in low-density

lipo-protein cholesterol However, the concurrent use of fibric

acid derivatives and statins may cause an increased risk of

myopathy or rhabdomyolysis.167-168 Thus, it is important

to monitor patients closely for symptoms of myopathy by

checking creatine phosphokinase levels periodically, and limiting the dose of statins while the patient is on this combination therapy

Further, fenofibrate may be the preferred fibric acid derivative for combination therapy since fenofibrate has been associated with fewer reports of myopathy or rhab-domyolysis compared to gemfibrozil during concurrent use with statins.169-170 In fact, a new formulation of feno-fibrate (Trilipix) was FDA-approved in 2008 for use in conjunction with statins and, as such, represents the only fibric acid derivative officially approved for this indica-tion That is not to say that other formulations of fenofi-brate would not be as safe; they just have not sought FDA approval for this indication

Statins are highly effective in reducing low-density poprotein cholesterol and are generally well tolerated Be-cause many statins are metabolized by CYP-450 enzymes (atorvastatin, lovastatin and simvastatin by CYP3A4; fluvastatin and rosuvastatin by CYP2C9), they are sus-ceptible to interactions with other drugs that are induc-ers or inhibitors of these enzymes Enzyme (CYP3A4) inhibitors such as cyclosporine, erythromycin, diltiazem, and itraconazole have been associated with possible cases

li-of rhabdomyolysis when used concurrently with tatin.12 Similarly, cases of rhabdomyolysis have been re-ported with concurrent use of cyclosporine, itraconazole,

lovas-or nefazodone with simvastatin.12,171-172 To minimize the occurrence and extent of these drug–drug interactions, pravastatin may be used with CYP3A4 inhibitors instead since it does not undergo extensive hepatic metabolism

In some cases, fluvastatin or rosuvastatin may be used since neither agent is a substrate of CYP3A4 Selected interactions involving lipid-lowering agents are listed on Table 31-12.12,23,93,166-173

Conclusion

With the vast and growing number of cardiovascular drugs in our armamentarium, the task of tracking every drug interaction can be overwhelming if not impossible Many drug–drug interactions, however, may be detect-

ed and resolved through knowledge and sound clinical judgments based on pharmacokinetic and pharmacody-namic data Major drug–drug interactions that lead to significant clinical consequences should be committed

to memory, especially if the drugs involved are used quently in one’s area of practice Furthermore, prevention

fre-of polypharmacy through periodic medication regimen review is a good way to avoid unfavorable drug–drug interactions

Note: References for this chapter can be found here:

www.cvpct3.com

Cardiovascular Drug–Drug Interactions  507

Table 31-6 Selected Drug-Drug Interactions with Class I Antiarrhythmic Agents

Primary Drugs Interacting Drugs Proposed Mechanism of 

Monitor blood pressure and ECG; concurrent use of two or more Class IA antiarrhythmic agents is generally not recommended.

pointes, cardiac arrest)

If concurrent use of quinidine and a class III antiarrhythmic is absolutely necessary, monitor ECG carefully.

Amiodarone Additive cardiac

toxic-ity; additive effects on QT prolongation

May increase serum quinidine concentration

Increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)

The concurrent use of a Class Ia and a Class III antiarrhythmic agent is generally not recom- mended If concurrent use is deemed necessary, quinidine dose should be reduced by one-third, and the patient should be monitored for signs of arrhythmias.

Disopyramide Additive cardiac effects Slight increase in disopyramide

concentrations Monitor for disopyramide toxicity (dosage ad-justment for both drugs may be needed) Flecainide

Propafenone

Methadone

Additive effects on QT prolongation Increased risk of cardiotoxicity (QT prolongation, torsades de

pointes, cardiac arrest)

Concurrent use of two or more drugs that long QT interval is generally not recommended Mexiletine Inhibition of CYP2D6 hepatic

pro-enzymes by quinidine results

in decreased metabolism of mexiletine

Increased serum mexiletine concentration Monitor for mexiletine toxicity.

Procainamide Additive cardiac effects;

in-terference with renal amide clearance

procain-Increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)

Monitor ECG and procainamide concentrations and adjust dosage as needed.

Propafenone Hepatic metabolism of

propafenone may decrease Increased plasma propafenone concentrations Monitor for propafenone toxicity and adjust dos-age of propafenone as needed Antibacterials

pro-Increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest); increased quinidine plasma concentration by clarithromycin and erythromycin

Concurrent use of two or more drugs that long QT interval is generally not recommended; monitor for quinidine toxicity

pro-Antifungals

(fluconazole) Additive effects on QT prolongation Increased risk of cardiotoxicity (QT prolongation, torsades de

pointes, cardiac arrest)

Concurrent use of two or more drugs that long QT interval is generally not recommended Antifungals (Itraconazole,

pro-ketoconazole) Decreased quinidine metabolism Increased plasma quinidine concentration Monitor for quinidine toxicity; concurrent use of itraconazole and quinidine is contraindicated Antifungals

(Posaconazole,

voriconazole)

Inhibition of quinidine metabolism Increase risk of QT prolongation and torsades de pointes; increased

quinidine plasma concentration

Concurrent use of posaconazole or voriconazole and quinidine is contraindicated.

Antipsychotics

(Thiorida-zine, ziprasidone) Additive cardiac effects Increased risk of cardiotoxicity (QT prolongation, torsades de

pointes, cardiac arrest)

Concurrent use of quinidine and thioridazine or ziprasidone is contraindicated.

Possible decreased

beta-block-er metabolism and clearance

Augmentation of beta-blocker fects (bradycardia, hypotension) Monitor blood pressure, heart rate, and adjust dosages as needed.

ef-Calcium antagonists

(vera-pamil, diltiazem) Inhibition of quinidine metabolism Increased plasma quinidine concentrations Monitor for quinidine toxicity.

Digoxin Decreased renal and

non-renal clearance of digoxin Increased plasma digoxin con-centrations and increased risk of

succi-Increased toxicity of interacting drugs (respiratory depression, apnea, prolonged neuromuscular blockade)

Monitor for respiratory depression and longed neuromuscular blockade; respiratory support should be provided as needed Tricyclic Antidepres-

pro-sants (amitriptyline,

desipramine, imipramine,

nortriptyline)

Decreased antidepressant metabolism; additive cardiac effects

Increased adverse effects from tidepressants (dry mouth, urinary retention, sedation) and increased risk of cardiotoxicity (QT prolon- gation, torsades de pointes, cardiac arrest)

an-Monitor for increased antidepressant adverse fects and signs and symptoms of additive cardiac effects (changes in ECG) Concurrent use of a Class Ia antiarrhythmic and a tricyclic antide- pressant is generally not recommended Urinary alkalinizers (acet-

ef-azolamide, antacids) Increase in urinary pH may result in a significant decrease

in quinidine renal elimination

Possible increased serum dine concentrations and quinidine toxicity

quini-Monitor for quinidine toxicity and adjust dosage

of quinidine as needed.

Warfarin Decreased clotting factor

synthesis Increased bleeding risk from warfarin Monitor INR; adjust warfarin dose as needed.

Procainamide Antiarrhythmics

(disopyramide, quinidine) Additive cardiac effects; quinidine also decreases

procainamide clearance via competition for renal tubular secretion.

Increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)

Monitor blood pressure and ECG; concurrent use of two or more class IA antiarrhythmic agents is generally not recommended.

pointes, cardiac arrest)

If concurrent use of procainamide and a class III antiarrhythmic is absolutely necessary, monitor ECG carefully.

Amiodarone Decreased procainamide

clearance May increase serum procainamide concentration and lead to

procain-amide toxicity.

Monitor for signs of procainamide toxicity (QT prolongation, torsades de points), assess pro- cainamide levels, and reduce procainamide dose accordingly.

Flecainide

Propafenone Additive effects on QT prolongation Increased risk of cardiotoxicity (QT prolongation, torsades de

pointes, cardiac arrest)

Concurrent use of two or more drugs that long QT interval is generally not recommended Antibacterials

pro-Increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest) Increased procainamide plasma concentration by ofloxacin

Concurrent use of two or more drugs that long QT interval is generally not recommended; monitor ECG and procainamide serum concen- tration and adjust procainamide dose as needed.

pro-Antifungals

(fluconazole) Additive effects on QT prolongation Increased risk of cardiotoxicity (QT prolongation, torsades de

pointes, cardiac arrest)

Concurrent use of two or more drugs that long QT interval is generally not recommended Antipsychotics (Halo-

Concurrent use of a Class IA antiarrhythmic and

an antipsychotic is generally not recommended Concurrent use of procainamide and thiorida- zine or ziprasidone is contraindicated.

H2 Antagonists

(Cimetidine, ranitidine) Decreased procainamide renal clearance due to competition

for active tubular secretion

Increase risk of procainamide toxicity (cardiac arrhythmias, hypotension, CNS depression)

Monitor for signs and symptoms of amide toxicity Monitor procainamide plasma concentration Decrease dose of procainamide

Monitor for signs and symptoms of additive cardiac effects (changes in ECG) Concurrent use of a Class IA antiarrhythmic and a tricyclic antidepressant is generally not recommended.

Disopyra-mide Antiarrhythmics(Procainamide, quinidine) Additive cardiac effects Increased risk of cardiotoxicity (QT prolongation, torsades de

pointes, cardiac arrest)

Monitor blood pressure and ECG, concurrent use of two or more Class Ia antiarrhythmic agents is generally not recommended Antiarrhythmics

pointes, cardiac arrest)

If concurrent use of disopyramide and a class III antiarrhythmic is absolutely necessary, monitor ECG carefully.

Table 31-6 Selected Drug-Drug Interactions with Class I Antiarrhythmic Agents

(continued)

Propafenone Additive effects on QT prolongation Increased risk of cardiotoxicity (QT prolongation, torsades de

pointes, cardiac arrest)

Concurrent use of two or more drugs that long QT interval is generally not recommended Antibacterials

pro-Increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest) Increased disopyramide plasma concentration by azithromycin, clarithromycin, and erythromycin

Concurrent use of two or more drugs that long QT interval is generally not recommended; monitor for signs and symptoms of disopyra- mide toxicity (anticholinergic effects, hypoten- sion, heart failure, cardiac arrhythmias).

pro-Antifungals (fluconazole) Additive effects on QT

prolongation Increased risk of cardiotoxicity (QT prolongation, torsades de

pointes, cardiac arrest)

Concurrent use of two or more drugs that long QT interval is generally not recommended Antifungals

pro-(itraconazole) Decreased disopyramide metabolism Increased plasma disopyramide concentration and risk of

disopyra-mide toxicity.

Monitor for signs and symptoms of mide toxicity Adjust dose of disopyramide as needed.

Concurrent use of a Class IA antiarrhythmic and

an antipsychotic is generally not recommended Concurrent use of disopyramide and thiorida- zine is contraindicated.

Antiretrovirals

(atazanavir, ritonavir,

saquinavir)

Inhibition of disopyramide metabolism Increased disopyramide plasma concentration and increased risk

Additive cardiovascular effects Bradycardia, hypotension,

de-creased cardiac output Monitor blood pressure, heart rate, and cardiac function and adjust dosages as needed Digoxin Unknown Increased plasma digoxin con-

centrations and increased risk of digoxin toxicity

Monitor for signs and symptoms of digoxin toxicity, check digoxin level, and decrease dose

Monitor for signs and symptoms of additive cardiac effects (changes in ECG) Concurrent use

of a Class Ia antiarrhythmic and a tricyclic depressant is generally not recommended.

metabolism Increased serum lidocaine concen-tration; increased lidocaine toxicity Monitor for signs and symptoms of lidocaine toxicity (neurotoxicity, cardiac arrhythmias,

hypotension, seizures) and reduce lidocaine dose

caine toxicity

Monitor for signs and symptoms of caine toxicity and adjust dosage of lidocaine accordingly.

lido-Beta blockers

(Metoprolol, nadolol,

propranolol)

Decreased lidocaine metabolism Increased lidocaine plasma con-centration; increased risk of lido-

caine toxicity

Monitor for signs and symptoms of caine toxicity and adjust dosage of lidocaine accordingly.

lido-Cimetidine Decreased lidocaine

metabo-lism possibly due to decreased hepatic blood flow

Increased lidocaine plasma centration; increased risk of lido- caine toxicity

con-Monitor for signs and symptoms of caine toxicity and adjust dosage of lidocaine accordingly.

lido-Phenytoin Increased lidocaine

metabo-lism and elimination Phenytoin also has additive cardiac depressive effects with lidocaine.

Decreased plasma lidocaine centration and decreased lidocaine effectiveness

con-Assess the therapeutic efficacy of lidocaine and adjust dosage as needed.

Succinylcholine Unknown Increased toxicity of

neuro-muscular blockers (respiratory depression, apnea, prolonged neuromuscular blockade)

Monitor for respiratory depression and longed neuromuscular blockade; respiratory support should be provided as needed.

(amiodarone, quinidine) Decreased metabolism of mexiletine Increased mexiletine plasma con-centration; increased risk of

mexi-letine toxicity (nausea, dizziness, cardiac arrhythmias)

Monitor for signs and symptoms of letine toxicity and adjust dosage of mexiletine accordingly.

mexi-Table 31-6 Selected Drug-Drug Interactions with Class I Antiarrhythmic Agents

(continued)

(Table 31-6 continued on p 509)

Ritonavir Inhibition of mexiletine

metabolism Increased mexiletine plasma concentration; increased risk of

mexiletine toxicity

Monitor for signs and symptoms of letine toxicity and adjust dosage of mexiletine accordingly.

mexi-Theophylline Mexiletine inhibits the

CYP1A2 metabolism of theophylline

Increased theophylline plasma concentration; increased risk of theophylline toxicity (nausea, vomiting, palpitation, seizures)

Monitor for signs and symptoms of theophylline toxicity, check theophylline serum concentra- tion, and adjust dose of theophylline as needed.

and decreases metabolism of flecainide; additive effects on

QT prolongation

Increased flecainide plasma concentration; increased risk of flecainide toxicity (cardiac ar- rhythmias, neurologic effects, exacerbation of heart failure).

Monitor ECG and monitor for signs and toms of flecainide toxicity and reduce dosage of flecainide accordingly.

pointes, cardiac arrest)

Concurrent use of two or more drugs that long QT interval is generally not recommended.

pro-Antifungals

(fluconazole) Additive effects on QT prolongation Increased risk of cardiotoxicity (QT prolongation, torsades de

pointes, cardiac arrest)

Concurrent use of two or more drugs that long QT interval is generally not recommended Antipsychotics (Thiorida-

pro-zine, ziprasidone) Additive cardiac effects Increased risk of cardiotoxicity (QT prolongation, torsades de

pointes, cardiac arrest)

Concurrent use of flecainide and thioridazine or ziprasidone is contraindicated.

flecainide toxicity.

Monitor for signs and symptoms of flecainide toxicity and reduce dosage of flecainide accord- ingly Concurrent use of flecainide and ritonavir

or saquinavir or tipranavir is contraindicated Cimetidine Decreased flecainide renal

clearance Increased flecainide plasma concentration; increased risk of

flecainide toxicity

Monitor for signs and symptoms of flecainide toxicity and reduce dosage of flecainide accordingly.

Selective serotonin

inhibitors

(fluoxetine, sertraline)

Decreased metabolism of flecainide Increased flecainide plasma concentration; increased risk of

flecainide toxicity

Monitor for signs and symptoms of flecainide toxicity and reduce dosage of flecainide accordingly.

propafenone; additive effects

on QT prolongation

Increased propafenone plasma concentration; increased risk of propafenone toxicity (blurred vi- sion, CNS depression, tachycardia)

Monitor ECG and monitor for signs and toms of propafenone toxicity and reduce dosage

pointes, cardiac arrest)

Concurrent use of two or more drugs that long QT interval is generally not recommended.

pro-Antifungals

(fluconazole) Additive effects on QT prolongation Increased risk of cardiotoxicity (QT prolongation, torsades de

pointes, cardiac arrest)

Concurrent use of two or more drugs that long QT interval is generally not recommended Antipsychotics (ris-

pro-peridone, thioridazine,

ziprasidone)

Additive cardiac effects Increased risk of cardiotoxicity

(QT prolongation, torsades de pointes, cardiac arrest)

Concurrent use of propafenone and thioridazine

propafenone toxicity

Monitor for signs and symptoms of propafenone toxicity and reduce dosage of propafenone accordingly Concurrent use of propafenone and ritonavir or saquinavir or tipranavir is contraindicated.

Increased risk of cyclosporine toxicity (renal dysfunction, cho- lestasis, paresthesias)

Monitor cyclosporine concentration and adjust dosage of cyclosporine as needed.

Table 31-6 Selected Drug-Drug Interactions with Class I Antiarrhythmic Agents

(continued)