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Biomedical subjects

M Packer

Publications and source records attributed to M Packer.

At least 55 records · Page 3Linked to original sources
PubMed1989

The clinical significance of nitrate tolerance in patients with chronic heart failure.

Tolerance develops during the prolonged use of organic nitrates in patients with chronic heart failure in a fashion similar to its development in patients with angina pectoris, the magnitude of tolerance development being directly proportional to the frequency of dosing. When nitroglycerin is given continuously or when isosorbide dinitrate is administered frequently throughout the day (e.g., every 4h), haemodynamic tolerance develops completely in most patients within 24-48h. Such tolerance can be avoided, however, when these drugs are given intermittently (e.g., every 8 or 12 h). Unfortunately, most clinical trials with isosorbide dinitrate have attempted to produce continuous haemodynamic effects by administering the drug at frequent intervals; this may explain why these trials have produced equivocal results. Two mechanisms have been proposed to explain the development of tolerance in patients with chronic heart failure. According to the first hypothesis, tolerance develops as a result of the depletion of intracellular sulfhydryl groups that are essential to the ability of nitroglycerin to activate guanylate cyclase--the key enzyme in the action of nitrates on blood vessels. According to the second hypothesis, tolerance develops as a result of the activation of endogenous neurohormonal systems; the resulting vasoconstriction limits the direct effects of the nitrovasodilators. A better understanding of both mechanisms may lead to interventions that will circumvent the development of tolerance and enhance the efficacy of long-term nitrate therapy.

Drug Tolerance↗
PubMed1989

Identification of risk factors predisposing to the development of functional renal insufficiency during treatment with converting-enzyme inhibitors in chronic heart failure.

Contrary to popular belief, the primary directive for the release of renin is not the preservation of circulatory homeostasis, since activation of this hormonal system in patients with chronic heart failure results in deleterious rather than beneficial effects on cardiac performance. Instead, renin appears to be released by the kidneys to maintain glomerular filtration rate when renal perfusion pressure is reduced. The renin-angiotensin system carries out this beneficial action by exerting a constrictor action on the efferent arteriole. In doing so, renal blood flow declines, but filtration fraction increases and thus, glomerular hydraulic filtration pressure (and renal function) is preserved, despite severe renal hypoperfusion. When the formation of angiotensin II is inhibited during converting-enzyme inhibition, the beneficial action of this hormone on the efferent arteriole is lost, and renal function may deteriorate. This sequence of events is most likely to be seen when four risk factors are present: hyponatremia; high-dose diuretic therapy; diabetes mellitus; and the use of long-acting converting-enzyme inhibitors. In randomized studies, renal insufficiency developed more frequently with enalapril and lisinopril than with captopril. This risk of worsening azotemia is particularly high in patients with the most severe (class IV) heart failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Is activation of the sympathetic nervous system beneficial or detrimental to the patient with chronic heart failure? Lessons learned from clinical trials with beta-adrenergic agonists and antagonists.

The sympathetic nervous system is markedly activated in most patients with congestive heart failure, but it is not clear whether such activity is clinically beneficial (and should be enhanced) or detrimental (and should be blocked). Some insights into this question can be gained by reviewing the results of clinical trials with beta-adrenergic agonists and antagonists. Long-term treatment with agents that stimulate the beta-receptor (prenalterol and pirbuterol) has not proved to be useful in the treatment of chronic heart failure; moreover, prolonged treatment with beta-agonists (dobutamine and pirbuterol) may adversely affect survival. Most of the studies with beta-agonists, however, have employed agents that interact nonselectively and with a high degree of intrinsic activity with both beta 1-and beta 2-receptors. It is possible that the problems that have been encountered with the use of beta-agonists could be minimized by agents that are more selective and have less intrinsic activity. Yet, such agents may actually function as beta-adrenergic antagonists (rather than agonists) in states of heightened sympathetic activity. Indeed, sustained therapy with drugs that attenuate the effects of the sympathetic nervous system (by blocking tyrosine hydroxylase or beta-adrenergic receptors) may produce hemodynamic and clinical improvement and may reduce long-term mortality in chronic heart failure. Although beta-adrenergic blockade carries important risks, these might be minimized by the use of drugs that spare myocardial and vascular beta 2-receptors or possess some intrinsic agonist activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1989

The current status of angiotensin converting enzyme inhibitors in the management of patients with chronic heart failure.

Angiotensin converting enzyme (ACE) inhibitors are the only therapeutic agents used in the treatment of chronic heart failure that have been shown to both improve symptoms and prolong life. These agents produce long-term haemodynamic and clinical benefits in about 60-65% of patients. The only reliable means of determining which patients are most likely to respond favourably to treatment is by a therapeutic trial; the response cannot be predicted by demographic factors, pretreatment left ventricular function or plasma renin activity. In addition to their symptomatic benefits, ACE inhibitors reduce the mortality of patients with chronic heart failure, possibly by decreasing ventricular wall stress and decreasing the frequency and complexity of ventricular arrhythmias. The most serious adverse effects of treatment, hypotension, functional renal insufficiency and potassium retention, occur most commonly in patients with the most advanced disease [New York Heart Association (NYHA) class III and IV heart failure] and when efforts are made to block the formation of angiotensin (Ang) II continuously (as with the use of long-acting ACE inhibitors). The unique characteristics of the ACE inhibitors support their use as first-line agents in patients with chronic heart failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Pathophysiological mechanisms underlying the adverse effects of calcium channel-blocking drugs in patients with chronic heart failure.

Although the vasodilator and anti-ischemic actions of calcium channel blocking drugs might be expected to produce hemodynamic benefits in chronic heart failure, none of these agents has been shown to exert favorable clinical effects in these patients. Furthermore, when left ventricular function is markedly impaired, short- and long-term therapy with calcium channel blockers can increase cardiovascular morbidity and mortality. Previous investigators have attributed these unfavorable results to the established negative inotropic effects of calcium channel blockers on the failing heart. Yet, this cardiodepressant action seems to account for only the deleterious responses seen during short-term therapy with these drugs, whereas the detrimental effects of long-term treatment can be more readily explained by the capacity of calcium channel blockers to activate endogenous neurohormonal systems, especially the renin-angiotensin system. According to this hypothesis, a number of cardioactive drugs (including calcium channel blockers, beta-blockers, and converting enzyme inhibitors) can depress myocardial contractility, but only calcium channel blockers, which activate neurohormonal systems, adversely affect patients with left ventricular dysfunction, whereas beta-blockers and converting enzyme inhibitors, which interfere with neurohormonal activity, can favorably modify the long-term outcome of these high-risk patients. If confirmed by future studies, these observations suggest that the effect of antianginal drugs on neurohormonal systems, as well as on cardiac contractility, should be an important consideration in the selection of a therapeutic agent in patients with coronary artery disease and chronic heart failure.

Calcium Channel Blockers↗
PubMed1988

Modulation of functional capacity and survival in congestive heart failure. Effects of activation of the sympathetic nervous system.

Although the sympathetic nervous system is markedly activated in most patients with congestive heart failure, it is not clear whether such activity is clinically beneficial (and should be reinforced) or detrimental (and should be pharmacologically blocked). Some insights pertinent to this important question can be gained by reviewing the results of clinical trials with beta agonists and antagonists. Neither beta 1-selective (prenalterol) nor beta 2-selective (pirbuterol) agonists have been shown to be effective in treating heart failure in double-blind, placebo-controlled studies; moreover, research has indicated that prolonged stimulation of beta receptors with oral or intravenous catecholamines may adversely affect survival. In contrast, sustained therapy with drugs that attenuate the effects of the sympathetic nervous system (by blocking either tyrosine hydroxylase or beta-adrenergic receptors) may produce hemodynamic and clinical improvement and may favorably affect long-term prognosis. These potential benefits of beta-adrenergic blockade contrast strikingly with the lack of efficacy (with respect to clinical status and survival) of agents that block alpha-adrenergic receptors. Beta-adrenergic blockade carries important risks in the patient with heart failure, however. The risk-to-benefit ratio cannot be delineated accurately until the outcome of additional randomized clinical trials is known.

Adrenergic alpha-Antagonists↗
PubMed1988

Vasodilator and inotropic drugs for the treatment of chronic heart failure: distinguishing hype from hope.

During the past 10 years, more than 80 orally active vasodilator and inotropic agents have been tested in the clinical setting to evaluate their potential utility in the treatment of chronic heart failure. Although the initial reports of all of these drugs suggested that each represented a major therapeutic advance, only three agents--digoxin, captopril and enalapril--have produced consistent long-term hemodynamic and clinical benefits in these severely ill patients. Most of the other drugs that have been tested have not (to date) distinguished themselves from placebo therapy in large-scale, controlled trials, even though these agents produce hemodynamic effects that closely resemble those seen with digitalis and the converting-enzyme inhibitors. These observations suggest that the hemodynamic derangements that characteristically accompany the development of left ventricular dysfunction cannot be considered to be the most important pathophysiologic abnormality in chronic heart failure. Although cardiac contractility is usually depressed in this disease, positive inotropic agents do not consistently improve the clinical status of these patients. Similarly, although the systemic vessels are usually markedly constricted, drugs that ameliorate this vasoconstriction do not consistently relieve symptoms, enhance exercise capacity or prolong life. Hence, correction of the central hemodynamic abnormalities seen in heart failure may not necessarily provide a rational basis for drug development, and future advances in therapy are likely to evolve only by attempting to understand and modify the basic physiologic derangements in this disorder.

Calcium Channel Blockers↗
PubMed1988

Effect of vasodilator and inotropic drugs on clinical symptoms and long-term survival in chronic congestive heart failure.

The major therapeutic goals in the treatment of congestive heart failure are the relief of symptoms and the prolongation of life, but it remains unclear whether there is a relation between changes in exercise tolerance and alterations in the risk of death. Although all vasodilator and inotropic agents produce short-term haemodynamic benefits, these acute effects do not predict the long-term clinical responses to these drugs. Converting-enzyme inhibitors appear to improve symptoms and survival. A combination of hydralazine and isosorbide dinitrate produces variable effects on exercise tolerance but appears to prolong life. Catecholamines and phosphodiesterase inhibitors may reduce dyspnea and fatigue but adversely affect mortality. Calcium channel blocking drugs may exert deleterious effects on both symptoms and prognosis. alpha-Adrenergic blocking drugs produce no beneficial or adverse effects on clinical status or mortality. Hence, there is no consistent relation between the symptomatic and prognostic effects of drug therapy in patients with chronic heart failure. This variability makes it impossible to predict the effects of any drug on exercise tolerance or survival based on an evaluation of the agent's short-term haemodynamic effects.

Adrenergic alpha-Antagonists↗
PubMed1988

Cumulative hemodynamic response to short-term treatment with flosequinan (BTS 49465), a new direct-acting vasodilator drug, in severe chronic congestive heart failure.

Pharmacologic tolerance develops rapidly to the hemodynamic effects of many vasodilator drugs used in the treatment of congestive heart failure. We evaluated the responses to 3 days of therapy with a new long-acting vasodilator drug, flosequinan (BTS 49465), in 16 patients with severe chronic heart failure. On each of the 3 days, flosequinan (100 or 150 mg orally) produced marked increases in cardiac index and decreases in left ventricular filling pressure, mean right atrial pressure, and systemic vascular resistance (all p less than 0.01) without significant changes in heart rate. Whereas the effects of flosequinan on right and left ventricular filling pressures on the first and third days were similar, cardiac index was higher and systemic vascular resistance was lower after the third dose than after the first dose of the drug, indicating the occurrence of a cumulative vasodilator effect on arterial resistance vessels. Since all hemodynamic changes persisted for longer than 24 h after each dose of the drug, the daily administration of flosequinan also produced a progressive improvement in the hemodynamic state recorded before each dose of the drug. These data indicate that pharmacologic tolerance does not develop to the effects of flosequinan during short-term therapy with the drug in patients with severe chronic heart failure. Instead, further hemodynamic improvement may occur because of a cumulative vasodilator effect that results from the drug's prolonged duration of action.

Adult↗
PubMed1988

Interaction of prostaglandins and angiotensin II in the modulation of renal function in congestive heart failure.

Despite a dramatic fall in renal blood flow, glomerular filtration rate is usually preserved in patients with congestive heart failure until the terminal stages of the disease. This maintenance of renal function appears to be achieved in part by the synthesis of two vasoactive factors within the kidney--angiotensin II and prostaglandins--which are rapidly released whenever renal perfusion is compromised or sympathetic nerve traffic to the kidneys is increased. Although these two hormonal systems exert opposite effects on systemic and renal blood flow and sodium and water excretion, both act to preserve glomerular filtration rate: prostaglandins by a vasodilator action exerted primarily on the afferent arteriole and angiotensin II by a vasoconstrictor effect on the efferent arteriole. Consequently, when the synthesis of these hormones is experimentally blocked, renal function deteriorates, especially in subjects with marked renal hypoperfusion and sodium depletion; these two factors interact to determine the importance of intrarenal hormonal release in the modulation of renal function. Clinically, four specific factors have been identified that predispose patients with heart failure to the development of functional renal insufficiency after treatment with converting-enzyme or cyclo-oxygenase inhibitors: (1) marked renal hypoperfusion, (2) vigorous diuretic therapy, (3) diabetes mellitus, and (4) intensity of hormonal inhibition within the kidney. This last risk factor may provide the basis for differentiating among enzyme-inhibitory drugs and suggests that renal insufficiency in low-output states may be minimized by the development of therapeutic agents that block hormonal synthesis selectively at sites that are critical to the disease process but spare the homeostatic tissue-based enzyme systems that exist within the kidney.

Angiotensin II↗
PubMed1987

Prevention and reversal of nitrate tolerance in patients with congestive heart failure.

To evaluate possible mechanisms underlying the development of nitrate tolerance, we treated 35 patients who had severe chronic heart failure with a prolonged (48-hour) intravenous infusion of nitroglycerin (6.4 micrograms per kilogram of body weight per minute) given either continuously or intermittently (12-hour infusions separated by intervals of 12 hours). Intravenous nitroglycerin produced immediate hemodynamic benefits in all patients, but the magnitude of this improvement was greatly diminished after 48 hours of continuous therapy with the drug. This attenuation was accompanied by cross-tolerance to oral isosorbide dinitrate and by an increase in heart rate, plasma renin activity, and body weight. In contrast, intermittent therapy with intravenous nitroglycerin was not associated with a loss of hemodynamic efficacy or cross-tolerance to oral nitrates and was not accompanied by changes in neurohormonal activity or body weight. In eight patients in whom nitrate tolerance developed during continuous intravenous therapy, the administration of the sulfhydryl-containing compound N-acetylcysteine (200 mg per kilogram orally) restored the hemodynamic state toward that observed at the start of the infusion of nitroglycerin (partial reversal of tolerance). In contrast, N-acetylcysteine had little hemodynamic effect in patients who were not receiving nitroglycerin. These data support the hypothesis that neurohormonal activation and depletion of sulfhydryl groups may interact to cause the loss of hemodynamic efficacy that occurs during prolonged treatment with intravenous nitroglycerin in patients with heart failure. Evaluation of the suggested role of sulfhydryl depletion in the development of tolerance will, however, require direct studies of vascular tissue.

Acetylcysteine↗