Hemodynamic effects of newer antiarrhythmic drugs

The aim of antiarrhythmic drug therapy is to terminate or suppress specific arrhythmias and improve cardiovascular function. Short-term studies of the new Class I drugs encainide, mexilitine, and tocainide have demonstrated only minor falls in cardiac index with modest rises in mean aortic pressure. In contrast, disopyramide has been shown to depress myocardial function in both animals and patient studies. Heart failure may be precipitated by therapy with disopyramide and electromechanical dissociation has been reported. Class II agents with beta-adrenergic blocking actions all produce a degree of myocardial depression. Atenolol resembles propranolol in patients with coronary artery disease in its hemodynamic effects, whereas acebutolol is less of a depressant, resembling practolol. The Class III agent amiodarone has only a mild depressant effect associated with a reduction in afterload and an increase in coronary blood flow. The Class IV agent verapamil, which is a calcium channel blocker, has potent myocardial depressant actions and causes peripheral vasodilatation. Hypotension, heart failure, and shock have been precipitated particularly in patients receiving beta-blocking drugs concurrently. While all the new antiarrhythmic drugs currently studied will cause some degree of hemodynamic depression in an appropriately high concentration, present investigations suggest that particular caution needs to be taken when disopyramide, aprindine, atenolol, and verapamil are administered either acutely by the intravenous route or chronically by the oral route.     

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.     

Angiotensin receptor blockade in the challenging era of systolic hypertension

Systolic blood pressure is a major cardiovascular risk factor which is often associated with arterial stiffness. Markers of arterial stiffness, such as pulse pressure and carotid-femoral pulse wave velocity, have been proved independent predictors of cardiovascular risk. Recent evidence suggests that the renin-angiotensin system is involved in the pathogenesis of systolic hypertension and arterial stiffness. Outcome trials have shown impressive cardiovascular protection by reducing systolic blood pressure (BP) with drug treatment. However, in clinical practice systolic hypertension remains largely uncontrolled, first, because systolic BP goal is more difficult to be reached than diastolic and, second, because physicians are often reluctant to intensify treatment in patients with systolic BP close to 150 mmHg. Recent trials have focused on the effects of antihypertensive drugs not only on blood pressure, but also on pulse pressure and pulse-wave velocity. Blockade of the renin-angiotensin-aldosterone system, using angiotensin-converting enzyme inhibitors and more recently angiotensin receptor blockers, has been shown to provide beneficial effects on arterial stiffness that appear to be independent of their antihypertensive effects. Recent outcome trials have shown significant cardiovascular protection with angiotensin receptor blockers. These drugs have an excellent placebolike profile of adverse effects which is maintained when these drugs are combined with low-dose diuretics. Therefore, an angiotensin receptor blocker-based treatment strategy appears to be an attractive and evidence-based approach for the management of systolic hypertension, the reduction of arterial stiffness and the prevention of cardiovascular disease.     

Controlling cardiac arrhythmias by lengthening repolarization: Historical overview

An increasing confluence of experimental and clinical data on the gravity of proarrhythmic effects of class I agents has led to a shift to other electrophysiologic classes of agents for treating cardiac arrhythmias. The fact that β blockers reduce mortality in a variety of subsets of patients has suggested a wider role for this class of agents. Recent investigations have focused on the potential role of sotalol and amiodarone, 2 agents that not only block sympathetic antagonism, but also prolong cardiac repolarization. They have been test drugs in an increasing number of controlled and uncontrolled trials in patients at risk for arrhythmic deaths. Their properties have formed the basis for the hypothesis that arrhythmias may be effectively controlled independently of changes in conduction; they are prototypes of compounds that may favorably influence electrical instability in the myocardium. Amiodarone and sotalol are, however, complex molecules with attendant side effects; therefore, attention is also focusing on compounds that act simply by selective prolongation of cardiac repolarization. These agents have been termed “pure” class III agents. The properties of sotalol, the prototype of class III agents, are of particular interest because it is a racemic mixture wtth the levo-isomer having 50 times the β-blocking potency of the dextro-isomer; both have equipotent class III actions. Studies of the antiarrhythmic properties of β blockers, d- and d,l-sotatol, and amiodarone may provide insights into the nature of class III actions. There is clinical evidence indicating that class III drugs exert a varying spectrum of antifibrillatory and proarrhythmic (characterized by torsades de pointes) actions for a given degree of prolongation of repolarization. These differences currently are not explicable in terms of the specificity of their actions on ionic channels. There are differences between the socalled pure class III agents such as sematilide, dofetilide, and E-4031 and more complex compounds such as sotatel and amiodarone, which also exert antiadrenergic actions. In the development of newer drugs an appropriate balance needs to be struck between their proarrhythmic actions and their antifibrillatory properties. At present, it is unclear whether such antifibrillatory compounds should be relatively simple molecules with clearly defined electrophysiologic profiles in terms of actions on ion channels, currents, receptors, and pumps, or whether it may be more desirable to develop agents wtth complex electropharmacologic profiles with a multiplicity of actions. The available data suggest that sotalol and amiodarone are superior to class I agents and have the potential to reduce arrhythmia mortality.     

Cardioprotection with beta‐blockers: myths,facts and Pascal’s wager

Beta‐blockers were documented to reduce reinfarction rate more than 3 decades ago and subsequently touted as being cardioprotective for a broad spectrum of cardiovascular indications such as hypertension, diabetes, angina, atrial fibrillation as well as perioperatively in patients undergoing surgery. However, despite lowering blood pressure, beta‐blockers have never shown to reduce morbidity and mortality in uncomplicated hypertension. Also, beta‐blockers do not prevent heart failure in hypertension any better than any other antihypertensive drug class. Beta‐blockers have been shown to increase the risk on new onset diabetes. When compared with nondiuretic antihypertensive drugs, beta‐blockers increase all‐cause mortality by 8% and stroke by 30% in patients with new onset diabetes. Beta‐blockers are useful for rate control in patients with chronic atrial fibrillation but do not help restore sinus rhythm or have antifibrillatory effects in the atria. Beta‐blockers provide symptomatic relief in patients with chronic stable angina but do not reduce the risk of myocardial infarction. Adverse effects of beta‐blockers are common including fatigue, dizziness, depression and sexual dysfunction. However, beta‐blockers remain a cornerstone in the management of patients having suffered a myocardial infarction and for patients with heart failure. Thus, recent evidence argues against universal cardioprotective properties of beta‐blockers but attest to their usefulness for specific cardiovascular indications.     

Statins and blood pressure regulation

Hypertension and high serum cholesterol levels are two of the most relevant risk factors for cardiovascular diseases. A combined increase in both risk factors has been reported in a significant proportion of patients with coronary artery disease. Statins are the most widely used drugs to treat hypercholesterolemia, and they interact with blood pressure control in different populations of hypertensive patients. A significant reduction in blood pressure associated with the use of statins has been described in patients with untreated hypertension and in patients treated with antihypertensive drugs, particularly angiotensin converting enzyme inhibitors and calcium channel blockers. The effect of statins on blood pressure control has also been reported in diabetic patients. The mechanisms responsible for the hypotensive effect seem to be largely independent of the effect of statins on lipid profile, and are probably related to their interaction with endothelial function or angiotensin II receptors. The capacity of statins to improve blood pressure control could be a useful consideration for an integrated approach to better prevention of cardiovascular diseases.     

Eplerenone: A Selective Aldosterone Blocker

Recent studies suggest that aldosterone may play a larger role than once appreciated in normal physiologic function and cardiovascular disease. Some of the adverse cardiovascular effects that have been described include cardiac and vascular fibrosis, vascular necrosis and inflammation, impaired endothelial function, reduced fibrinolysis, hypertension, left ventricular hypertrophy (LVH), congestive heart failure, and cardiac arrhythmias. In light of these findings, the ability to block the actions of aldosterone has gained increased therapeutic importance. Eplerenone is a selective aldosterone receptor blocker that displays little interaction with androgen and progesterone receptors. Eplerenone has already been approved for the treatment of systemic hypertension and has been evaluated in numerous hypertension subgroups, including patients with low plasma renin activity; diabetes; LVH; uncontrolled blood pressure while receiving monotherapy with angiotensin‐converting enzyme inhibitors, angiotensin‐receptor blockers, calcium channel blockers, or beta‐blockers; and in black patients. Results of these trials indicate that eplerenone lowers blood pressure and reduces end‐organ damage. Further proof of the therapeutic importance of mineralocorticoid receptor blockade comes from the eplerenone post acute myocardial infarction survival and efficacy study (EPHESUS). In this large‐scale clinical outcome trial, eplerenone was shown to reduce total mortality by 15% as well as the combined endpoint of cardiovascular mortality/cardiovascular hospitalization by 13% when administered at a mean of 7.3 days post myocardial infarction to patients with evidence of systolic left ventricular dysfunction and symptoms of heart failure. Eplerenone is well tolerated, with an adverse effect profile comparable to placebo. The advent of selective aldosterone blockers, such as eplerenone, should prove to be of great therapeutic value in hypertension control and prevention of cardiovascular disease and associated end‐organ damage.     

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.     

Heart failure and diabetes: Clinical significance and epidemiology of this two-way association

People with type 2 diabetes (T2DM) and those with prediabetes have an increased risk of heart failure (HF). Longer duration of T2DM correlates with a greater risk of HF, but HF is also seen in patients with recent-onset diabetes. Insulin resistance is more likely to be present in patients with HF. The risk of HF persists even in the face of standard-of-care preventive treatments for atherosclerotic cardiovascular (CV) disease. HF is commonly the presenting symptom of CV disease in people with diabetes and is the most expensive complication of diabetes because of the high cost of hospitalizations. Recently hospitalization for HF has been included in CV outcome trials (CVOTs), including for medications that are used to treat T2DM, which has led to new therapies for all HF patients. In addition, these CVOTs have shown that many drugs used in the therapy of diabetes are either neutral or detrimental in the HF patient and should be used with caution in patients with existing HF or those at high risk of HF. Most recently, sodium-glucose cotransporter-2 receptor blockers have shown efficacy in both HF with reduced ejection fraction (EF) and HF with preserved EF. The only other oral or injectable diabetes agent shown to improve outcomes in both is metformin.     

Emerging options in the management of myocardial ischemia

Improved understanding of the pathogenesis of symptomatic and silent myocardial ischemia has led to important advances in the prevention and treatment of these syndromes. For example, recognition of the role of platelets in the atherogenic process and of thrombosis in acute myocardial ischemia has led to extensive use of aspirin and thrombolytic therapy, with resultant decreases in mortality. Both nitrates and β-adrenergic blockers effectively alleviate myocardial ischemia. However, long-term nitrate use is limited by the occurrence of tolerance β blockers have been shown to decrease subsequent cardiovascular events in patients with acute myocardial infarction; however, adverse effects are often associated with their use. Calcium antagonists have been shown to be effective in the treatment of stable and vasospastic angina. In patients with coronary artery disease and symptoms resulting from either fixed obstruction or vasospasm, these agents decrease the frequency of angina episodes. The 3 types of calcium antagonists currently available—phenylalkylamine, benzothiazepine, and dihydropyridine derivatives—while chemically a heterogeneous group, share the common property of decreasing depolarization of smooth muscle, albeit to varying degrees. Nonetheless, other characteristics, including varying electrophysiologic effects, distinguish these groups. The novel calcium antagonist amlodipine is effective and well tolerated as an antianginal agent, and offers the advantage of once-daily dosing. Calcium antagonists appear to be well tolerated in patients with concomitant conditions such as diabetes and are effective in commonly coexistent cardiovascular disorders such as hypertension.     

Multiorgan-protective actions of blockers of the renin-angiotensin system, statins and erythropoietin: common pleiotropic effects in reno-, cardio- and neuroprotection

Renal diseases induce nephroprotective measures that may affect the heart, brain and other organs. In addition, many cardiovascular and neurological diseases are accompanied by renal lesions. For these reasons, multiorgan-protective measures, including cardio-, reno- and neuro-protective measures, are necessary to treat these diseases. The drugs used in nephrology are often pleiotropic. Although they usually address a single organ or tissue, many of them have complex actions that may provide multiorgan-protection. The present paper aims to review 3 classes of drugs that are commonly prescribed in nephrological practice: statins, RAS blockers (such as ACEIs and ARBs) and erythropoietin (EPO). This paper highlights the renoprotective actions, as well as those that are protective of the heart, brain and other organs, of these drugs at the cellular and molecular level. Their protective actions are attributable to their main effects and pleiotropic effects. The protective pleiotropic actions of these drugs may be exerted on multiple organs, making them multiorgan-protective. Another objective is to analyse the shared multiorgan-protective pleiotropic effects of RAS blockers (ACEIs and ARBs), statins and erythropoietin. This will allow for the practical association of the main renoprotective drugs with multiorgan protection.     

The use of mifepristone in the treatment of neuropsychiatric disorders.

Mifepristone is a potent glucocorticoid and progesterone receptor antagonist. The pathophysiology of a number of neuropsychiatric disorders implicates abnormalities in glucocorticoid function. These include mood disorders such as psychotic major depression and bipolar depression. In addition, cognitive disorders such as Alzheimer's disease might also be partially mediated by abnormalities in the hypothalamic-pituitary-adrenal axis. Preliminary studies suggest that mifepristone might have a role in the treatment of a number of neuropsychiatric disorders.     

COVID‐19 and renin‐angiotensin system inhibition: role of angiotensin converting enzyme 2 (ACE2) ‐ Is there any scientific evidence for controversy?

Renin–angiotensin system (RAS) blockers are extensively used worldwide to treat many cardiovascular disorders, where they are effective in reducing both mortality and morbidity. These drugs are known to induce an increased expression of angiotensin‐converting enzyme 2 (ACE2). ACE2 acts as receptor for the novel SARS coronavirus‐2 (SARS‐CoV‐2) which raising the important issue of possible detrimental effects that RAS blockers could exert on the natural history and pathogenesis of the coronavirus disease‐19 (COVID‐19) and associated excessive inflammation, myocarditis and cardiac arrhythmias. We review the current knowledge on the interaction between SARS‐CoV‐2 infection and RAS blockers and suggest a scientific rationale for continuing RAS blockers therapy in patients with COVID‐19 infection.     

Large vessel coronary vasospasm: diagnosis, natural history and treatment

The diagnosis of coronary artery spasm is confirmed by angiography, for example, change in caliber of the coronary arteries plus evidence of ischemia. The prevalence and contribution of coronary artery spasm in the individual patient with symptoms of ischemic heart disease is not known and depends on how the condition is defined. The prognosis of patients with coronary artery spasm appears to depend on the presence or absence of severe coronary atherosclerosis, that is, those with severe disease have a worse prognosis. Nitrates should be used to initiate therapy in all patients with this problem. Intravenous nitrates have proven useful in patients whose symptoms are difficult to control and who require hospitalization. beta blockers used alone may be detrimental in patients with coronary artery spasm, but studies supporting the detrimental effects are few. The combination of nitrates, beta blockers and nifedipine has proved effective therapy for many patients with recurrent angina at rest, possibly related to coronary artery spasm. Several open-label and double-blind placebo control trials have shown that all of the calcium antagonists are effective short-term agents for patients with proven coronary artery spasm. When nifedipine was compared with isosorbide dinitrate in a randomized crossover, double-blind trial in patients with coronary artery spasm, both drugs were shown to be efficacious and neither was superior. The traditional alpha-blocking agents have not been shown to be an effective therapy, but a recent study of prazosin, a selective alpha blocker, revealed excellent results in patients whose conditions were resistant to therapy with traditional calcium blockers, beta blockers and, in 1 case, phenoxybenzamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Calcium channel blockers in myocardial and cerebral ischemia: a clinician's review from bench to bedside

Calcium channel blockers constitute a very important group of drugs that are commonly used in the treatment of cardiovascular and cerebrovascular disorders. Current indications for these medications include hypertension, angina, supraventricular arrhythmias, and prevention of coronary and cerebral vasospasm. Although calcium channel blockers originally held great promise in the treatment of myocardial and cerebral ischemia, clinical results have been discouraging. An understanding of the basic physiological mechanisms of actions for these drugs is important for the practising clinician and may explain the disappointing results for the treatment of ischemia to date. This paper is a narrative review, from a clinician's viewpoint, of the structure and role of calcium channels in cardiac and cerebrovascular tissues, as well as a review of the in vitro and clinical results of calcium channel blockade in myocardial and cerebral ischemia.     

Angiotensin receptor blockade in diabetic renal disease--focus on candesartan

Prevention and regression of diabetic renal disease can be obtained through the combination of strict blood pressure control, which frequently requires the combination of different antihypertensive drugs, with tight glycaemic control. Recent evidence obtained with the angiotensin receptor blockers has allowed the recognition by most guidelines that this class of agents constitutes the first choice to treat hypertension in type 2 diabetic patients presenting with diabetic renal disease at any stage of evolution, from microalbuminuria to advanced renal failure. Of course this must be accompanied by an integral coverture of the increased global cardiovascular risk that always accompanies this situation. This short review contains the most relevant evidence in favour of angiotensin receptor blockers, with particular emphasis on the capacities of candesartan for controlling blood pressure and protecting the kidney. In patients with type 2 diabetes and varying degrees of albuminuria, treatment with candesartan 8-32mg daily was shown to reduce urinary albumin excretion (UAE) by up to 60%. When given in addition to an ACE inhibitor (dual blockade), reductions in UAE of 25-35% relative to ACE inhibitor monotherapy have been found.     

Perioperative use of esmolol

Stressful surgical stimuli, such as endotracheal intubation, surgical incision, organ manipulation and emergence from anesthesia, elicit adrenergic responses that precipitate transient but intense increases in heart rate and blood pressure. Although this response is well tolerated in healthy patients, patients with ischemic heart disease are at significant risk of myocardial ischemia and infarction owing to the sudden increase in myocardial oxygen demand. Parenteral beta blockers are effective in blunting this adrenergic response, but the duration of action of these agents is long-lasting and the degree of beta blockade is often difficult to predict. Further, long-acting parenteral beta blockers may cause adverse effects, the reversal of which presents a difficult clinical problem in patients with ischemic heart disease. The availability of esmolol, an ultrashort-acting parenteral beta-adrenergic antagonist with a half-life of 9 minutes, brings obvious advantages to the perioperative management of hypertension and tachycardia. With esmolol treatment, the difficulties of therapy with long-lasting beta blockers are avoided. Also, to blunt the adrenergic response, the anesthesiologist will have an alternative to increasing the depth of anesthesia, which can accentuate cardiovascular depression and prolong awakening and postoperative respiratory depression. Clinical studies performed during the perioperative period reveal that esmolol is safe and effective in this setting. Esmolol has been shown to be safe and efficacious in patients in ASA classifications I through IV and patients undergoing carotid endarterectomy and coronary artery bypass surgery. The pharmacokinetic profile, rapid onset and elimination half-life make this agent particularly well suited to treat the very intense but transient adrenergic responses to surgical stress in patients undergoing cardiac and noncardiac surgery.     

Nicardipine for systemic hypertension: Effects on blood pressure and target organ function

Nicardipine has been shown to lower blood pressure in patients with uncomplicated hypertension as well as in patients with concomitant renal impairment, coronary artery disease or congestive heart failure. The decrease in blood pressure induced by nicardipine is related to a concurrent decrease in total peripheral vascular resistance.

The antihypertensive actions of nicardipine are maintained during long-term administration without the development of tachyphylaxis. In patients receiving diuretics or β blockers, the addition of nicardipine has been shown to produce an additional decrease in blood pressure. The combined use of nicardipine and β blockers may be beneficial in the treatment of hypertension: the increase in peripheral vascular resistance during β blockade may be prevented by nicardipine-induced vasodilation; conversely, β blockers may prevent reflex tachycardia and other consequences of peripheral vasodilatation. Although nicardipine may increase the heart rate acutely, tachycardia does not occur during long-term therapy.

Preliminary data suggest that nicardipine exerts potent antihypertensive effects in patients with renal insufficiency without altering renal parameters. In patients with normal renal function, nicardipine has been shown to cause acute natriuresis and an increase in renal blood flow and glomerular filtration rate. Nicardipine also has a favorable effect on peripheral and cerebral blood flow. Like other dihydropyridines, nicardipine appears to have an antiatherogenetic effect in the experimental model. Short-term therapy with nicardipine does not affect serum lipid levels.

Results from several studies suggest that nicardipine is an effective antihypertensive agent that can be used as monotherapy or in combination with other drugs such as β blockers or diuretics. Nicardipine may also have a favorable effect on target organ function and on various circulatory parameters without causing adverse metabolic or biochemical consequences.