Pharmacotherapy in congestive heart failure: Cardiopulmonary effects of ophthalmically administered beta-blockers

Early clinical studies reported that timolol and other topical beta-blockers were effective in reducing intraocular pressure, without the side effects associated with other antiglaucoma agents. However, because people with cardiovascular or respiratory diseases were generally excluded from many of these early studies, the risk of serious cardiovascular and respiratory side effects was seriously underestimated. Once these drugs were made available to the general population, reports of systemic side effects began to proliferate. Very quickly adverse effects from topical beta-blockade became "old news." Despite this new found recognition, many treating physicians still remained unaware of the potential for systemic beta-blockade from topical applied beta-blockers. A significant portion of a topically administered dose of a beta-blocker can be absorbed and thereby effect systemic beta-blockade. Sensitivity to systemic beta-blockade can be quite dramatic in certain highly susceptible patients, particularly those with either cardiac or pulmonary abnormalities. Careful review of patients' medications will generally lessen, but not completely eliminate, the risk of undesired complications attributable to topical beta-blockade.     

Management of Global Risk Across the Continuum of Hypertensive Heart Disease

Identification and management of cardiovascular (CV) risk factors are essential to help prevent CV disease and slow its progression. Long-term epidemiologic data show that hypertension is associated with a two- to four-fold increase in CV morbidity and mortality; moreover, antihypertensive therapy has been proven to significantly reduce the risk of CV events. Clinical trial data also suggest that different antihypertensive agents generally provide similar reductions in CV risks and outcomes. Beta blockers have historically played an integral role in hypertension treatment, particularly among patients at high CV risk; however, a recent meta-analysis, based primarily on the use of atenolol, found that β blockers may provide less clinical benefit as initial therapy than other classes of antihypertensive agents. Beta blockers are heterogeneous, and atenolol data may not be representative of other β blockers. Newer β blockers, which provide both cardioselective β₂-adrenergic receptor blockade and endothelium-dependent vasodilation, may prove to be more effective in reducing CV morbidity and mortality. Intensive strategies to control global CV risk have been shown to significantly reduce CV events. The challenge remains to develop effective risk assessment tools to identify at-risk patients who often go undetected.     

Do the Metabolic Effects of β Blockers Make Them Leading or Supporting Antihypertensive Agents in the Treatment of Hypertension?

Reduction of blood pressure to guideline goals (i.e., <130/80 mm Hg) in persons with diabetes is crucial to optimally reduce cardiovascular events and kidney disease progression. Since many patients will be >20/10 mm Hg above this goal, most guidelines recommend using agents that block the renin–angiotensin system in concert with a thiazide-like diuretic to achieve goal blood pressure. Meta-analyses of clinical trials indicate that while all classes of antihypertensive agents reduce cardiovascular risk, they exert different effects on glucose utilization and lipids and, hence, may affect morbidity. Specifically, β blockers, in general, worsen insulin resistance and increase triglycerides in a dose-dependent fashion. Moreover, they are not recommended as initial therapy for hypertension treatment in the absence of heart failure or recent myocardial infarction, especially in the elderly. Recent studies support the notion that newer β blockers with vasodilating effects have a better metabolic profile when compared with those that purely affect β receptors. Thus, vasodilating β blockers, by being neutral on glycemic and metabolic factors, are associated with less use of additional medication for lipid or glucose control and may provide a potentially greater cardiovascular risk reduction by virtue of these effects.     

Metabolic Properties of Vasodilating β Blockers: Management Considerations for Hypertensive Diabetic Patients and Patients With the Metabolic Syndrome

Type 2 diabetes and hypertension are both insulin-resistant states that impose an excessive risk burden for future major cardiovascular events, including coronary heart disease, stroke, and heart failure. β-adrenergic receptor antagonists are effective for the treatment of hypertension, but they are underused in diabetic patients because of possible adverse effects on carbohydrate and lipid metabolism, including insulin resistance, glucose intolerance, and dyslipidemia. Traditional β blockers, both nonselective and selective, are vasoconstrictive due to unopposed α₁ activity; however, vasodilating β blockers are not associated with these negative metabolic effects. This review discusses the background of insulin resistance and its link to diabetes and hypertension, emphasizing the role of vascular control by the renin-angiotensin and sympathetic nervous systems on insulin sensitivity and glucose utilization. Clinical evidence is reviewed for the use of vasodilating β blockers in the treatment of hypertension and in reducing cardiovascular risk in the diabetic population.     

Early Initiation of β Blockade in Heart Failure: Issues and Evidence

Despite clinical trials demonstrating that inhibitors of the renin-angiotensin and sympathetic nervous systems can reduce the mortality and morbidity risk associated with heart failure, these drugs have remained underutilized in general clinical practice. In particular, many patients with heart failure due to left ventricular systolic dysfunction fail to receive β blockers, although this class of drugs, as well as other antihypertensive agents such as angiotensinconverting enzyme inhibitors or angiotensin receptor blockers, are recommended as part of routine heart failure therapy by national expert consensus guidelines. In-hospital initiation of β-blocker therapy may improve long-term utilization by physicians and compliance by patients through obviating many of the misperceived dangers associated with β blockade. The following review of the clinical trial data from the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial, the Metoprolol Controlled-Release Randomized Intervention Trial in Heart Failure (MERIT-HF), the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial, and the Initiation Management Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) trial on the efficacy, safety, and tolerability of β blockers indicates that early initiation can be safely achieved and can improve patient outcomes.     

The Place of Alpha Blockers in the Treatment of Hypertension

Alpha₁ adrenoceptor antagonists are safe, effective, well tolerated drugs which can be used alone or in combination with other drug groups in a wide range of hypertensive patients. Alpha₁ blockers not only lower blood pressure but may improve insulin sensitivity and the adverse lipid profile in many hypertensive patients. In addition to causing few side effects, alpha₁ blockers are not contra-indicated in patients with associated cardiovascular or respiratory disease. Alpha₁ blockers offer the potential to improve the risk factor profile more than conventional antihypertensive drugs.     

Should β Blockers Be Used in the Treatment of Hypertension in the Elderly?

The lack of benefit and the potential negative side effects of β blockers are overstated, especially in the elderly. This emphasis has led to recommendations by some investigators that these agents not be used in the management of hypertension in this age group. There are numerous reasons why these recommendations should not be followed. The use of β blockers in the elderly hypertensive has resulted in a reduction in strokes and congestive heart failure. In addition, it should be emphasized that elderly patients are more likely to have silent coronary artery disease or sustain myocardial infarctions. There is abundant evidence that β blockers are effective therapy in reducing mortality once a myocardial infarction has occurred. In fact, there is a clear reduction in sudden cardiac death. Furthermore, national statistics document that elderly patients have a prevalence of congestive heart failure that varies from 6%–10%. Multiple studies have now documented that β blockers are additive to angiotensin-converting enzyme inhibitors in reducing mortality for congestive heart failure. Thus, elderly hypertensive patients may benefit from the use of β blockers, especially if there is evidence of ischemic heart disease, cardiac arrhythmias, or congestive heart failure.     

Medikamentöse Therapie von Herz- und Lungenerkrankungen

Many patients suffer from both heart and lung diseases. The choice of medical drugs should not only be driven by the clinical and prognostic effects on the target organ but should also be selected based on the effects on the respective other organ. Beta blockers and statins have both beneficial and harmful effects on the respiratory system. Angiotensin-converting enzyme (ACE) inhibitors and amiodarone can cause severe lung damage. Low-dose thiazides and calcium antagonists are first-line medications in hypertensive asthma patients but beta blockers should be avoided. Theophyline should be used with caution in patients with known cardiac disease. Glucocorticosteroids can cause cardiovascular symptoms while the phosphodiesterase inhibitor roflumilast appears to have no relevant cardiovascular side effects. Anticholinergic drugs have both favorable and unfavorable cardiovascular (side) effects. Short-acting beta-2 sympathomimetic drugs (SABA) and macrolides in particular can trigger arrhythmia and some SABAs are associated with a higher incidence of myocardial infarction. Detailed knowledge of the effects of drugs used for the treatment of lung and heart diseases on the respective other organ and the associated complications and long-term effects are essential in providing optimal medical care to the many patients who present with both respiratory and cardiovascular diseases.     

Antihypertensive medications and their effects on lipid metabolism

Hypertension and hyperlipidemia are interrelated and share common pathophysiologic mechanisms, such as insulin resistance and endothelial dysfunction. Accumulating evidence shows that it is important to regulate hypertension and hyperlipidemia to reduce cardiovascular risk. However, medications such as β-blockers and thiazide diuretics, which are widely used for blood pressure regulation, are known to have several metabolic side effects. Despite deleterious effects on glucose metabolism and lipid metabolism, these medications have been proven to reduce cardiovascular risk. On the other hand, calcium channel blockers, angiotensin-converting enzyme inhibitors, and α-blockers have either no effect or favorable effects on the lipid profile. This review outlines the need to control hypertension, options for several antihypertensive medications, their differing effects on lipid metabolism, and the clinical implications of their effects on lipid parameters.     

Topical diltiazem and bethanechol decrease anal sphincter pressure without side effects

BACKGROUND: Topical nitrates lower anal sphincter pressure and heal anal fissures, but a majority of patients experience headache. The internal anal sphincter has a calcium dependent mechanism to maintain tone, and also receives an inhibitory extrinsic cholinergic innervation. It may therefore be possible to lower anal sphincter pressure using calcium channel blockers and cholinergic agonists without side effects. AIMS: To investigate the effect of oral and topical calcium channel blockade and a topical cholinomimetic on anal sphincter pressure. METHODS: Three studies were conducted, each involving 10 healthy volunteers. In the first study subjects were given oral 60 mg diltiazem or placebo on separate occasions. They were then given diltiazem once or twice daily for four days. In the second and third studies diltiazem and bethanechol gels of increasing concentration were applied topically to lower anal pressure. RESULTS: A single dose of 60 mg diltiazem lowered the maximum resting anal sphincter pressure (MRP) by a mean of 21%. Once daily diltiazem produced a clinically insignificant effect but a twice daily regimen reduced anal pressure by a mean of 17%. Diltiazem and bethanechol gel produced a dose dependent reduction of the anal pressure; 2% diltiazem produced a maximal 28% reduction, and 0.1% bethanechol a maximal 24% reduction, the effect lasting three to five hours. CONCLUSIONS: Topical diltiazem and bethanechol substantially reduce anal sphincter pressure for a prolonged period, and represent potential low side effect alternatives to topical nitrates for the treatment of anal fissures.     

Beta-blocker-induced psoriasis: a rare side effect--a case report

Beta blockers are one of the oral agents shown to decrease cardiovascular morbidity and mortality rates in randomized, controlled trials, and hence, they are widely used for the management of many cardiovascular situations. In terms of side effects there are 3 major modes of action: (1) contraction of smooth muscles, particularly of bronchi with nonselective agents; (2) exaggerated cardiac effects; and (3) central nervous system effects. There are also some rare side effects of beta blockers, some of which are unpredictable, but the others are related to mode of action at the cellular level. Beta-blocking agents may cause psoriaform eruptions and worsen existing psoriasis. Psoriasis may be an inconvenient side effect of beta blockade. Herein, we report a case of beta-blocker-induced psoriasis.     

Should β Blockers No Longer Be Considered First-line Therapy for the Treatment of Essential Hypertension Without Comorbidities?

Although most guidelines committees historically recommended initial diuretics and/or β blockers for uncomplicated hypertension, clinical trial outcomes analyzed in the last 5 to 7 years have been suboptimal with atenolol, the world’s most popular β blocker. Several meta-analyses have suggested that despite lowering blood pressure, any and all β blockers inadequately protect hypertensive patients from cardiovascular events. These phenomena have been attributed to ineffective lowering of central aortic or inter-visit blood pressures, or adverse metabolic effects (particularly when combined with diuretics). Although there has never been a head-to-head comparison of atenolol with any other β blocker in hypertensive patients, indirect comparisons can be done with network and Bayesian meta-analyses, which suggest that heterogeneity of β-blockers’ pharmacology also extends to outcomes. Although once-daily atenolol as initial antihypertensive therapy may be unwise, whether initial β blockers newer than atenolol reduce cardiovascular risk to the same extent as other antihypertensive drugs should be answered with more clinical trials.     

Cardiovascular considerations in using topical, oral, and intravenous drugs for the treatment of glaucoma and ocular hypertension: focus on beta-adrenergic blockade

Glaucoma and ocular hypertension are highly prevalent conditions in individuals over the age of 40 and are commonly seen together in patients with cardiovascular disease. Many of the antiglaucoma medications, when systemically absorbed, affect the sympathetic and parasympathetic nervous systems of patients and can cause cardiovascular toxicity. Such adverse effects are frequently associated with the long-term use of potentially toxic agents in elderly people, who are most prone to chronic eye disease. Moreover, patients may not associate their symptoms with the topical eye medications, and consequently may not report adverse drug effects. Drug-drug interactions can also occur when patients are taking medications for both cardiovascular disease and glaucoma. This review focuses on beta-adrenergic blockers as topical antiglaucoma medications and other topical antiglaucoma drugs. The systemic toxicity of these agents is reviewed, along with the possible drug interactions. Brief mention is also made of other antiglaucoma medications used alone and in combination with topical beta-blockers.     

New insights and new approaches for the treatment of essential hypertension: selection of therapy based on coronary heart disease risk factor analysis, hemodynamic profiles, quality of life, and subsets of hypertension

The pharmacologic therapy of mild primary hypertension (diastolic blood pressure less than 105 mm Hg) has effectively reduced hypertensive arteriolar end organ disease such as cerebrovascular accidents, congestive heart failure, and nephropathy, but there has been no convincing evidence that coronary heart disease (CHD) or its complications, acute myocardial infarction or angina, have been reduced. The risks of therapy with certain antihypertensive drugs may outweigh their treatment benefits as it relates to CHD. The optimal treatment strategy should be to reduce all CHD risk factors, reverse the hemodynamic abnormalities present by lowering the systemic vascular resistance (SVR), preserving cardiac output (CO) and perfusion, and to select the best antihypertensive drug for concomitant medical diseases or problems while maintaining a good quality of life. Antihypertensive drugs that have favorable or neutral effects on CHD risk factors include alpha blockers, calcium channel blockers, central alpha agonists, and angiotensin-converting enzyme inhibitors. On the other hand, diuretics and beta blockers without intrinsic sympathomimetic activity have unfavorable effects on many CHD risk factors. Baseline and serial evaluation of the effects of these drugs on serum lipids, lipid subfractions, glucose, uric acid, electrolytes, exercise tolerance, left ventricular hypertrophy, blood pressure, SVR, CO, perfusion, concomitant diseases, and side effects is necessary to evaluate overall cardiovascular risk.     

Beta-blockers in hypertension

Beta blockers have been used in the treatment of cardiovascular conditions for decades. Despite a long history and status as a guideline-recommended treatment option for hypertension, recent meta-analyses have brought into question whether β blockers are still an appropriate therapy given outcomes data from other antihypertensive drug classes. However, β blockers are a heterogenous class of agents with diverse pharmacologic and physiologic properties. Much of the unfavorable data revealed in the recent meta-analyses were gleaned from studies involving nonvasodilating, traditional β blockers, such as atenolol. However, findings with traditional β blockers may not be extrapolated to other members of the class, particularly those agents with vasodilatory activity. Vasodilatory β blockers (i.e., carvedilol and nebivolol) reduce blood pressure in large part through reducing systemic vascular resistance rather than by decreasing cardiac output, as is observed with traditional β blockers. Vasodilating ability may also ameliorate some of the concerns associated with traditional β blockade, such as the adverse effects on metabolic and lipid parameters, including an increased risk for new-onset diabetes. Furthermore, vasodilating ability is physiologically relevant and important in treating a condition with common co-morbidities involving metabolic and lipid abnormalities such as hypertension. In patients with hypertension and diabetes or coronary artery disease, vasodilating β blockers provide effective blood pressure control with neutral or beneficial effects on important parameters for the co-morbid disease. In conclusion, it is time for a reexamination of the clinical evidence for the use of β blockers in hypertension, recognizing that there are patients for whom β blockers, particularly those with vasodilatory actions, are an appropriate treatment option.     

The foundation role of beta blockers across the cardiovascular disease spectrum: a year 2009 update

Hypertension is a risk factor for myocardial infarction (MI), stroke, and heart failure and precedes heart failure in 91% of cases. This becomes even more important considering that the number of Americans with hypertension increased from 65 million in 2005 to 72 million in 2007. If blood pressure is effectively controlled this risk can be minimized-blood pressure reductions as small as 2 mm Hg have been shown to reduce the risk of cardiovascular events by up to 10%. There is also strong evidence that blood pressure targets for populations at high risk of cardiovascular disease, including those with diabetes, coronary artery disease, and chronic kidney disease, should be lower than 140/90 mm Hg. The number and type of antihypertensive drugs have increased dramatically from 28 diuretics in 1972 to over 125 agents today, including fixed dose combination dosage forms. Beta blockers have been available for the treatment of hypertension since the 1960s. However, there has been resistance to using these agents in patients with diabetes and renal failure because of metabolic side effects, and in other patients because of tolerability concerns such as depression, weight gain, and impotence. Two newer beta blockers with vasodilatory effects (carvedilol and nebivolol) have proven efficacy and tolerability in patients with hypertension and appear to lack the adverse effects associated with older beta blockers. Carvedilol causes vasodilation by alpha blockade, and nebivolol via nitric oxide mechanisms. Both of these agents reduce peripheral vascular resistance and maintain cardiac output. Clinical trial evidence to date leads to the conclusion that beta blockers are strongly indicated post-MI and in all patients with left ventricular dysfunction regardless of symptoms. Their beneficial abilities include improvement of oxygen supply and demand (which can reduce myocardial ischemia), anti-arrhythmic properties, and beneficial effects on cardiac remodeling.     

Regression of Small Resistance Artery Structural Alterations in Hypertension by Appropriate Antihypertensive Treatment

Regardless of the mechanisms that initiate the rise of blood pressure, the development of structural changes in the systemic vasculature is the end result of established hypertension. Indices of small resistance artery structure, such as the ratio of tunica media to internal lumen, may have a strong prognostic significance in hypertensive patients, over and above all other known cardiovascular risk factors. Hence, the regression of vascular alterations seems to be an appealing goal for antihypertensive treatment. Different antihypertensive drugs may have different effects on vascular structure. Complete normalization of small resistance artery structure was demonstrated in hypertensive patients after long-term and effective antihypertensive therapy with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium antagonists. Little or no improvement was observed with β-blockers or diuretics. Evidence from several studies suggests that some antihypertensive drugs are more effective than others in reversing microvascular structural alterations in hypertension.     

Pathophysiology of Target-Organ Disease: Does Angiotensin II Remain the Key?

Basic research provides an increasingly compelling rationale for renin-angiotensin system (RAS) blockade in hypertension treatment and cardiovascular risk reduction. Clinical trials addressing blood pressure-independent effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, however, have yielded mixed results, in part because of incomplete RAS blockade. Animal studies have shed new light on the complexity of RAS pathways involved in the induction of target-organ damage. New outcomes trials are under way to explore the full potential of more complete RAS blockade with regard to cardiovascular target-organ protection.     

Penetration and effect of topically applied dimethylsulfoxide or indomethacin on adjuvant arthritis in the rat

The present study, using ¹⁴C-DMSO, established the systemic and local load and distribution of topically applied DMSO in adjuvant arthritic rats. Under equivalent conditions, the antiinflammatory effects (systemic and local) of topical DMSO treatments were compared with a topical treatment of a control vehicle or of indomethacin, a known effective antiinflammatory agent. No significant systemic or local antiinflammatory effect of topical DMSO was seen in the adjuvant arthritic rats. Indomethacin, applied topically, had a significant systemic antiinflammatory effect; however, no significant local antiinflammatory effect of indomethacin was observed.