Cardioselective beta-blocker treatment of hypertension in patients with asthma: when do benefits outweigh risks?

BACKGROUND: Benefits outweigh risks of cardioselective beta-blocker therapy in patients with nonsevere asthma and a history of heart failure or myocardial infarction (MI). This review summarizes the risks versus benefits of using cardioselective beta-blockers in the treatment of hypertension in patients with asthma. METHODS: We searched the English literature from 1976 to 2011 via PubMed, EMBASE, and SCOPUS using the following search terms: "beta-blocker treatment of hypertension" AND "asthma"; "cardioselective beta-blockers" AND "asthma." When pertinent articles were found, we assessed relevant articles cited in those papers. All studies related to cardioselective beta-blocker use in patients with asthma and hypertension were included. RESULTS: Seven studies with patient populations ranging from 10 to 17 patients evaluated cardioselective beta-blockers in patients with asthma and hypertension. Atenolol and/or immediate-release metoprolol were evaluated in these studies. The duration of beta-blocker therapy in four studies was 1-8 weeks; two studies were single dose and one investigation lasted 8 months. Metoprolol and atenolol were generally well tolerated except at higher doses such as metoprolol >100 mg daily. CONCLUSION: In the absence of concomitant cardiovascular disease, routine use of beta-blockers for the treatment of hypertension in patients with asthma should be avoided.

Effects of paroxetine on the pharmacokinetics and pharmacodynamics of immediate-release and extended-release metoprolol.

STUDY OBJECTIVE: To compare the effects of paroxetine on the pharmacokinetics and pharmacodynamics of the immediate-release (IR) and extended-release (ER) formulations of metoprolol. DESIGN: Prospective, randomized, open-label, 3-way crossover study. SETTING: General clinical research center. SUBJECTS: Fifteen healthy volunteers with at least one active cytochrome P450 (CYP) CYP2D6 allele (CYP2D6*1 or CYP2D6*2). INTERVENTION: In each of three phases conducted in random sequence, subjects received one of three metoprolol formulations administered on day 1: a single dose of metoprolol ER 100 mg, a single dose of metoprolol ER 200 mg, or two 100-mg doses of metoprolol IR administered 12 hours apart. Oral paroxetine 20 mg/day was then given alone on days 2-7 and coadministered with the same metoprolol formulation on day 8. Subjects received each of the other two formulations during the next two phases, with a 14-day washout period between each phase. MEASUREMENTS AND MAIN RESULTS: After receiving metoprolol on days 1 (before paroxetine) and 8 (after paroxetine), S- and R-metoprolol pharmacokinetic parameters and exercise heart rate and blood pressure responses were measured. The mean area under the plasma concentration-time curve values of both S- and R-metoprolol for each formulation were increased approximately 3- and 4-fold, respectively, by paroxetine. Paroxetine significantly increased the S- and R-metoprolol maximum concentration (C(max)) of each formulation and increased the elimination half-life of both isomers approximately 2-fold. When metoprolol IR was given with paroxetine, the S-metoprolol C(max) was significantly greater than that of either the 100-mg or 200-mg ER products. The maximum effect of metoprolol IR on heart rate was significantly greater than that of metoprolol ER 200 mg, independent of whether the agents were administered alone or with paroxetine. Both the heart rate and systolic blood pressure area under the effect-time curve values were significantly decreased by paroxetine. CONCLUSION: Paroxetine significantly inhibits the metabolism of both metoprolol IR and ER, resulting in an increase in the magnitude and duration of [H9252]-blockade. The potential risk of adverse effects from excessive ß-blockade may be greater with metoprolol IR than with metoprolol ER because of the significantly higher peak S-metoprolol plasma concentrations achieved with the IR formulation. Thus, if paroxetine treatment is indicated in patients receiving metoprolol, use of the ER formulation may reduce the risk of adverse effects.

Carvedilol therapy after cocaine-induced myocardial infarction in patients with asthma.

INTRODUCTION: Cocaine-induced myocardial infarction (MI) is well documented. Current literature recommends avoiding beta-blockers in the acute care setting, but after discharge from the hospital, benefits of beta-blocker use may outweigh risks in patients with recent MI resulting from cocaine use. Cardioselective beta-blocker therapy has been demonstrated to be beneficial in post-MI patients with nonsevere asthma. This review article is to compare the risks and benefits of using carvedilol in patients with asthma who have had cocaine-induced MI. METHODS: The authors searched the English literature from 1984 to July 2010 via PubMed, EMBASE and SCOPUS using the following search terms: "cocaine-induced myocardial infarction AND treatment," "cocaine AND carvedilol," "beta blockers AND asthma," and "carvedilol AND asthma." All studies and case reports related to carvedilol use associated with bronchospasm in patients with asthma and carvedilol use after cocaine-induced MI were included. RESULTS: Carvedilol has theoretical advantages in patients who use cocaine, but there are no controlled studies confirming the superior efficacy of this agent. Reports of carvedilol use in patients with asthma are rare, but findings include increased asthma symptoms and hospitalization in some patients. Fatal asthma has also been reported because of this noncardioselective beta-blocker. CONCLUSIONS: Based on a lack of evidence supporting the theoretical advantages but documented risks associated with its use in patients with asthma, carvedilol should be avoided in asthma patients who have a history of cocaine-induced MI. Cardioselective beta-blockers should be used in post-MI patients with nonsevere asthma.

A dyshomeostasis of electrolytes and trace elements in acute stressor states: impact on the heart.

Acute stressor states are associated with a homeostatic activation of the hypothalamic-pituitary-adrenal axis. A hyperadrenergic state follows and leads to a dyshomeostasis of several intra- and extracellular cations, including K, Mg, and Ca. Prolongation of myocardial repolarization and corrected QT interval (QTc) of the ECG are useful biomarkers of hypokalemia and/or hypomagnesemia and should be monitored to address the adequacy of cation replacement. A dyshomeostasis of several trace elements, including Zn and Se, are also found in critically-ill patients to compromise metalloenzyme-based antioxidant defenses. Collectively, dyshomeostasis of these electrolytes and trace elements have deleterious consequences on the myocardium: atrial and ventricular arrhythmias; induction of oxidative stress with reduced antioxidant defenses; and adverse myocardial remodeling, including cardiomyocytes lost to necrosis and replaced by fibrous tissue. To minimize such consequences during hyperadrenergic states, systematic surveillance of electrolytes and trace elements, together with QTc, are warranted. Plasma K and Mg should be maintained at > or =4.0 mEq/L and > or =2.0 mg/dL, respectively (the 4 and 2 rule).

Prevalence and predictors of abnormal cardiovascular responses to exercise testing among individuals with type 2 diabetes: the Look AHEAD (Action for Health in Diabetes) study.

OBJECTIVE: We examined maximal graded exercise test (GXT) results in 5,783 overweight/obese men and women, aged 45-76 years, with type 2 diabetes, who were entering the Look AHEAD (Action for Health in Diabetes) study, to determine the prevalence and correlates of exercise-induced cardiac abnormalities. RESEARCH DESIGN AND METHODS: Participants underwent symptom-limited maximal GXTs. Questionnaires and physical examinations were used to determine demographic, anthropometric, metabolic, and health status predictors of abnormal GXT results, which were defined as an ST segment depression > or =1.0 mm, ventricular arrhythmia, angina pectoris, poor postexercise heart rate recovery (<22 bpm reduction 2 min after exercise), or maximal exercise capacity less than 5.0 METs. Systolic blood pressure response to exercise was examined as a continuous variable, without a threshold to define abnormality. RESULTS: Exercise-induced abnormalities were present in 1,303 (22.5%) participants, of which 693 (12.0%) consisted of impaired exercise capacity. ST segment depression occurred in 440 (7.6%), abnormal heart rate recovery in 206 (5.0%), angina in 63 (1.1%), and arrhythmia in 41 (0.7%). Of potential predictors, only greater age was associated with increased prevalence of all abnormalities. Other predictors were associated with some, but not all, abnormalities. Systolic blood pressure response decreased with greater age, duration of diabetes, and history of cardiovascular disease. CONCLUSIONS: We found a high rate of abnormal GXT results despite careful screening for cardiovascular disease symptoms. In this cohort of overweight and obese individuals with type 2 diabetes, greater age most consistently predicted abnormal GXT. Long-term follow-up of these participants will show whether these abnormalities are clinically significant.

Stressor states and the cation crossroads.

Neurohormonal activation involving the hypothalamic-pituitary-adrenal axis and adrenergic nervous and renin-angiotensin-aldosterone systems is integral to stressor state-mediated homeostatic responses. The levels of effector hormones, depending upon the degree of stress, orchestrate the concordant appearance of hypokalemia, ionized hypocalcemia and hypomagnesemia, hypozincemia, and hyposelenemia. Seemingly contradictory to homeostatic responses wherein the constancy of extracellular fluid would be preserved, upregulation of cognate-binding proteins promotes coordinated translocation of cations to injured tissues, where they participate in wound healing. Associated catecholamine-mediated intracellular cation shifts regulate the equilibrium between pro-oxidants and antioxidant defenses, a critical determinant of cell survival. These acute and chronic stressor-induced iterations in extracellular and intracellular cations are collectively referred to as the cation crossroads. Intracellular cation shifts, particularly excessive accumulation of Ca2+, converge on mitochondria to induce oxidative stress and raise the opening potential of their inner membrane permeability transition pores (mPTPs). The ensuing loss of cationic homeostasis and adenosine triphosphate (ATP) production, together with osmotic swelling, leads to organellar degeneration and cellular necrosis. The overall impact of iterations in extracellular and intracellular cations and their influence on cardiac redox state, cardiomyocyte survival, and myocardial structure and function are addressed herein.

Adenosine deaminase in the diagnosis of tuberculous pericardial effusion.

Not long ago, primary tuberculosis was considered a rare disease; now with an increasing incidence worldwide, physicians should relearn many of its basic aspects and manifestations. Pericarditis is a rare finding seen with tuberculosis, but its prognosis is excellent with treatment, so early diagnosis is crucial. Pathogenesis is particularly important, and it must be taken in consideration when interpreting diagnostic tools. Herein we report on a healthy 32-year-old woman who presents with a 1-month history of febrile illness, malaise, and weakness; more recently, she also had resting dyspnea, which was progressively worsening. A positive PPD and an abnormal chest radiograph prompted hospitalization, where she was found to have pulsus paradoxus of 20 mm Hg. The echocardiogram showed diastolic right chamber collapse along with respiratory variation of the mitral inflow, consistent with pericardial tamponade. A pericardiocentesis was performed with resolution of her resting dyspnea; more than 1000 mL of serous fluid drained from the pericardial space over the following 24 hours. Although sputum and pericardial fluid cultures and smear for AFB and other organisms were negative, as well as a negative pericardial fluid PCR for Mycobacterium tuberculosis DNA; an elevated (44.4 U/L [normal, 0 to 18]) adenosine deaminase level in the pericardial fluid was consistent with the probable diagnosis of tuberculous pericardial effusion. The patient was treated with resolution of the clinical syndrome and no recurrence of the effusion thereafter. Adenosine deaminase, an enzyme marker of cell-mediated immune response activity to M tuberculosis that includes activated T-lymphocytes and macrophages, appears in pericardial fluid. The diagnosis of probable tuberculous effusion can be made without demonstration of mycobacterium.

Macro- and micronutrients in patients with congestive heart failure, particularly African-Americans.

Not all patients with heart failure, defined as a reduced ejection fraction, will have an activation of the RAAS, salt and water retention, or the congestive heart failure (CHF) syndrome. Beyond this cardiorenal perspective, CHF is accompanied by a systemic illness that includes oxidative stress, a proinflammatory phenotype, and a wasting of soft tissues and bone. A dyshomeostasis of calcium, magnesium, zinc, selenium, and vitamin D contribute to the appearance of oxidative stress and to compromised endogenous defenses that combat it. A propensity for hypovitaminosis D, given that melanin is a natural sunscreen, and for secondary hyperparathyroidism in African-Americans make them more susceptible to these systemic manifestations of CHF-a situation which is further threatened by the calcium and magnesium wasting that accompanies the secondary aldosteronism of CHF and the use of loop diuretics.

Exercise capacity and cardiovascular/metabolic characteristics of overweight and obese individuals with type 2 diabetes: the Look AHEAD clinical trial.

OBJECTIVE: We examined associations of cardiovascular, metabolic, and body composition measures with exercise capacity using baseline data from 5,145 overweight and/or obese (BMI > or = 25.0 kg/m2) men and women with type 2 diabetes who were randomized participants for the Look AHEAD (Action for Health in Diabetes) clinical trial. RESEARCH DESIGN AND METHODS: Peak exercise capacity expressed as METs and estimated from treadmill speed and grade was measured during a graded exercise test designed to elicit a maximal effort. Other measures included waist circumference, BMI, type 2 diabetes duration, types of medication used, A1C, history of cardiovascular disease, metabolic syndrome, beta-blocker use, and race/ethnicity. RESULTS: Peak exercise capacity was higher for men (8.0 +/- 2.1 METs) than for women (6.7 +/- 1.7 METs) (P < 0.001). Exercise capacity also decreased across each decade of age (P < 0.001) and with increasing BMI and waist circumference levels in both sexes. Older age, increased waist circumference and BMI, a longer duration of diabetes, increased A1C, a history of cardiovascular disease, having metabolic syndrome, beta-blocker use, and being African American compared with being Caucasian were associated with a lower peak exercise capacity for both sexes. Hypertension and use of diabetes medications were associated with lower peak exercise capacity in women. CONCLUSIONS: Individuals with diabetes who are overweight or obese have impaired exercise capacity, which is primarily related to age, female sex, and race, as well as poor metabolic control, BMI, and central obesity.

Esophageal electric fields are correlated to atrial defibrillation thresholds: towards patient-specific optimization of external atrial defibrillation.

Studies have investigated the effect of defibrillator paddle position on the efficacy of external electrocardioversion of atrial fibrillation, without agreeing upon an optimal placement. We wish to investigate using esophageal electric fields (EEFs) to predict atrial defibrillation thresholds (ADFTs) on a patient-specific basis. We propose to (1) investigate the relationship between EEFs and ADFTs using computer simulations, (2) develop an esophageal probe that can accurately measure three-dimensional electric fields and (3) investigate the relationship between EEFs and ADFTs values in-vivo. Sixteen anterior-anterior and eleven anterior-posterior placements were simulated yielding a negative relationship between EEFs and ADFTs (R2=0.91 and 0.93, respectively). An esophageal probe was developed that accurately measures EEFs. Animal studies showed a negative relationship between EEFs and ADFTs. This data suggests using EEFs to predict ADFTs on a patient-specific basis is plausible.

Pharmacokinetic factors in the adverse cardiovascular effects of antipsychotic drugs.

Antipsychotics may cause serious adverse cardiovascular effects, including prolonged QT interval and sudden death. This review considers antipsychotic-induced cardiovascular events from three perspectives: high-risk drugs, high-risk individuals and high-risk drug interactions. Pharmacokinetic drug interactions involving the cytochrome P450 (CYP) enzymatic pathway and pharmacodynamic interactions leading to direct cardiotoxic effects are discussed. Original reports on antipsychotic-induced drug interactions are reviewed, with consideration of management guidelines. The literature was reviewed from 1 January 1966 to 1 February 2002. The literature search revealed only 12 original articles published on antipsychotic drug interactions leading to cardiovascular adverse events. Only 4 of the 12 reports were prospective studies; the remainder were either retrospective or anecdotal.Although poor study designs preclude a definitive statement, it appears that pharmacokinetic interactions primarily involved the CYP2D6 and CYP3A4 enzymatic pathways. Those involving the CYP2D6 isozyme included interactions with tricyclic antidepressants, selective serotonergic reuptake inhibitors and beta-blockers. Among these drug interactions, tricyclic antidepressants were most likely to reach clinical significance because of their limited therapeutic index. Drug interactions related to the CYP3A4 pathway were generally less severe, and involved high-potency antipsychotics coadministered with inhibitors such as clarithromycin. Strategies are discussed for the management of adverse cardiovascular events related to antipsychotic drug interactions, including the use of an algorithm. Large, randomised, placebo-controlled studies with strict inclusion criteria are needed to determine the role that antipsychotics play in QT prolongation and sudden death.

Effects of grapefruit juice on intestinal P-glycoprotein: evaluation using digoxin in humans.

STUDY OBJECTIVES: To determine the effects of grapefruit juice on the pharmacokinetics of oral digoxin, a P-glycoprotein substrate not metabolized by cytochrome P450 3A4, in healthy volunteers, and to assess whether polymorphic multidrug-resistance-1 (MDR1) expression contributes to interindividual variability in digoxin disposition. DESIGN: Prospective, open-label, unblinded, crossover study. SETTING: University research center. SUBJECTS: Seven healthy adult volunteers (four men, three women). INTERVENTION: Each subject received a single oral dose of digoxin 1.0 mg with water or grapefruit juice with at least a 2-week washout between treatments. During the grapefruit juice phase, juice was administered 3 times/day for 5 days before digoxin administration to maximize any effect on P-glycoprotein. MEASUREMENTS AND MAIN RESULTS: Digoxin pharmacokinetics in the presence and absence of grapefruit juice were compared. The MDR1 exon 26 C3435T genotype was determined by real-time polymerase chain reaction. Compared with water, grapefruit juice significantly reduced the digoxin absorption rate constant (3.0 +/- 2.4 to 1.2 +/- 1.0 hr(-1), p<0.05) and increased absorption lag time (0.32 +/- 0.12 to 0.53 +/- 0.34 hr, p<0.05). Grapefruit juice did not affect digoxin maximum concentration (Cmax), area under the curve (AUC), elimination half-life, or renal clearance. The effect of grapefruit juice on digoxin Cmax (-45% to +41%) and AUC(0-4) (-29% to +25%) varied substantially among subjects and was inversely correlated with the values during the water phase. Trends toward higher digoxin Cmax AUC, and absorption rate constant during the water phase were found in CC homozygotes compared with subjects carrying a T allele. CONCLUSION: Inhibition of intestinal P-glycoprotein does not appear to play an important role in drug interactions involving grapefruit juice. Interindividual variability in response to grapefruit juice may be related to the balance of intestinal drug uptake and efflux transport.

Lower serum digoxin concentrations in heart failure and reassessment of laboratory report forms.

Serum digoxin concentrations (SDC) have been used clinically since the early 1970s. Whereas the therapeutic range for SDC is frequently cited as either 0.8 to 2.0 ng/mL or 0.5 to 2.0 ng/mL, studies over the past decade suggest an upper limit of 1.0 ng/mL for treating heart failure. The same upper limit for SDC is suggested for patients with heart failure and atrial fibrillation with rapid ventricular response. Reducing the upper limit of the therapeutic range to 1.0 ng/mL on computerized and paper laboratory report forms may guide clinicians to avoid unnecessarily high SDC, thus minimizing risk of digoxin toxicity without sacrificing therapeutic benefit for heart failure.