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Biomedical subjects

M Packer

Publications and source records attributed to M Packer.

At least 127 records · Page 7Linked to original sources
PubMed1983

Hemodynamic responses to combined therapy with captopril and hydralazine in patients with severe heart failure.

The hemodynamic benefits and safety of combined therapy with captopril and hydralazine were studied during invasive hemodynamic monitoring in 14 patients with severe heart failure. In eight patients, the individual effects of both drugs were evaluated before the administration of combined therapy, whereas hydralazine was added to maintenance captopril therapy in the other six patients. In the first group, captopril alone produced a marked decrease in pulmonary wedge pressure (28 +/- 4 to 18 +/- 5 mm Hg) and mean arterial pressure (85 +/- 20 to 69 +/- 13 mm Hg) (both p less than 0.001) without a significant increase in cardiac index. Hydralazine alone produced a marked increase in cardiac index (1.6 +/- 0.4 to 2.7 +/- 0.5 liters/min per m2) (p less than 0.001), but with a minimal decrease in pulmonary wedge pressure (28 +/- 4 to 23 +/- 4 mm Hg) (p less than 0.05) and without a significant change in mean arterial pressure. The combination of captopril and hydralazine produced an increase in cardiac index similar to that of hydralazine alone and decreases in pulmonary wedge pressure and mean arterial pressure similar to those with captopril alone. Most important, when hydralazine was added to captopril in the entire group of 14 patients, cardiac index increased markedly with little additional decrease in mean arterial pressure and no significant increase in heart rate. The one patient who experienced symptomatic hypotension with combination therapy also had dizziness with captopril alone. Seven of the nine patients maintained on long-term treatment experienced symptomatic improvement. Thus, in patients with severe chronic heart failure, the combined use of captopril and hydralazine is feasible and produces acute hemodynamic improvement superior to that from either drug alone.

Aged↗
PubMed1983

Vasodilator and inotropic therapy for severe chronic heart failure: passion and skepticism.

Although substantial progress has been made in the last 5 years in the development of vasodilator and inotropic drugs for the management of patients with severe chronic heart failure, much of the enthusiasm that surrounded the introduction of many of these agents has subsequently been tempered by reports of drug failure or adverse reactions. In this review and analysis, currently available vasodilator and inotropic agents are critically and comparatively evaluated to assess their respective advantages and limitations. It is apparent that the ability of most of these drugs to produce substantial clinical benefits in patients with severe heart failure has probably been overstated. Therapy fails to achieve the desired clinical results all too frequently, possibly as the result of: the choice of an ineffective drug; the administration of an effective drug in subtherapeutic doses; the administration of an effective drug to improperly selected patients; the failure of initial hemodynamic benefits to be sustained; the occurrence of severe or serious adverse reactions; and the failure to alter concomitant therapy appropriately. The present analysis indicates that there is no uniformly effective or safe vasodilator or inotropic drug for patients with severe heart failure; all agents have important limitations. Of the available therapeutic choices, however, long-term converting enzyme inhibition appears to produce more consistent hemodynamic and clinical benefits with an acceptable degree of adverse reactions than other pharmacologic approaches for the management of these severely ill patients.

Administration, Oral↗
PubMed1983

Hemodynamic patterns of response during long-term captopril therapy for severe chronic heart failure.

To determine the relationship between the early and late hemodynamic effects of captopril in patients with severe heart failure, we performed serial right heart catheterizations in 51 such patients who were treated with the drug for 2 to 8 weeks. Four hemodynamic patterns of response were observed. Nine patients had minimal responses initially (type I); six failed to improve during long-term treatment, but three showed delayed hemodynamic benefits. Twenty-eight patients had initial beneficial drug effects that were sustained after 48 hr and after 2 to 8 weeks (type II). In seven patients, first doses of captopril produced marked beneficial responses, but these became rapidly attenuated after 48 hr; nevertheless, continued therapy for 2 to 8 weeks was accompanied by spontaneous restoration of the hemodynamic effects of first doses of the drug, i.e., triphasic response (type III). In the remaining seven patients, attenuation of initial response was not reversed by prolonged captopril therapy; hemodynamic variables after 2 to 8 weeks had returned to their pretreatment values, i.e., drug tolerance (type IV). Plasma renin activity was lower in patients with minimal responses (0.6 +/- 0.2 ng/ml/hr) and was higher in patients with triphasic responses (9.4 +/- 2.5 ng/ml/hr) than in patients with types II and IV response patterns (4.4 +/- 0.7 and 2.8 +/- 0.5 ng/ml/hr, respectively; both p less than .05). Although first-dose effects of captopril are frequently sustained, the occurrence of delayed, attenuated, and triphasic responses indicates that a complex and variable relationship may exist between the early and late hemodynamic effects of vasodilator drugs in patients with severe heart failure.

Adult↗
PubMed1982

Deleterious effects of hydralazine in patients with pulmonary hypertension.

Thirteen consecutive patients with primary and secondary pulmonary hypertension who had normal left ventricular function were treated with hydralazine in an effort to reduce pulmonary vascular resistance and clinical symptoms. Despite marked decreases in systemic vascular resistance (40 per cent; P less than 0.001), hydralazine produced only moderate decreases in pulmonary arteriolar resistance (21 per cent), without improving stroke volume or pulmonary-artery pressure. Instead, mean arterial pressure fell markedly (17.5 mm Hg, P less than 0.01) in association with a reflex increase in heart rate (11 beats per minute, P less than 0.01). Four patients became symptomatically hypotensive within 24 hours of the initiation of treatment; two of these four required pressors for circulatory support, and one died. Progressive renal insufficiency developed in one patient, and a symptomatic decrease in systemic arterial oxygen saturation occurred in another; both changes were reversed upon discontinuation of the drug. In conclusion, hydralazine fails to produce consistent hemodynamic and clinical benefits in patients with primary and secondary pulmonary hypertension, and it frequently causes serious adverse reactions.

Adult↗
PubMed1982

Hemodynamic characterization of tolerance to long-term hydralazine therapy in severe chronic heart failure.

We performed hemodynamic studies in 11 patients with severe chronic heart failure whose symptoms had returned to their pretreatment status after 37 +/- 15 weeks (mean +/- S.E.M.) of therapy with the vasodilator hydralazine. The cardiac index increased from 1.85 to 3.47 liters per minute per square meter of body-surface area, and systemic vascular resistance decreased from 1748 to 754 dyn . sec. cm-5 (both p less than 0.01) during initial hydralazine administration but returned to pretreatment values on repeat evaluation; withdrawal of the drug produced no hemodynamic deterioration. Responsiveness to hydralazine could not be restored by doubling the oral dose or by intravenous administration; tolerance was associated with fluid retention in five patients but was not reversed by intensive diuresis. In contrast, the responses to nitroprusside evaluated before and after the development of hydralazine tolerance were unaltered; other oral vasodilators were still effective. We conclude that drug-specific tolerance may account for the lack of clinical improvement in some patients with severe heart failure who receive long-term treatment with hydralazine.

Adult↗
PubMed1982

Contrasting hemodynamic responses in severe heart failure: comparison of captopril and other vasodilator drugs.

Four studies were conducted in 36 patients with severe chronic heart failure to compare the central hemodynamic effects of captopril (CPT) to other vasodilator agents. While CPT produced less marked increases in cardiac output than did hydralazine (n = 14), nitroprusside (n = 15), or prazosin (n = 7), it produced decreases in left ventricular filling pressures similar to nitroprusside and prazosin but more than hydralazine. CPT and isosorbide dinitrate (n = 11) produced similar decreases in systemic vascular resistance and left ventricular filling pressure. However, cardiac output increased less with CPT than with nitrates, because heart rate slowed during CPT therapy. In addition, mean right atrial pressure decreased less with CPT than with nitrates, because CPT had minimal effects on limb venous capacitance and pulmonary arteriolar resistance. Alterations in left ventricular pressure-volume relationships likely contributed to the marked decreases in left ventricular filling pressures seen with CPT. In conclusion, the central hemodynamic effects of CPT differ significantly from other vasodilator drugs used in the treatment of heart failure patients. These effects cannot be characterized simply in terms of "balanced" peripheral arterial and venous vasodilation; CPT exerts highly complex effects on peripheral vessels as well as having actions independent of its peripheral vasodilator effects.

Adult↗
PubMed1982

Clinical relevance of verapamil plasma levels in stable angina pectoris.

Plasma levels of verapamil and norverapamil were evaluated in 77 patients who received oral verapamiL for treatment of angina pectoris. There was a sixfold interpatient variation in verapamil plasma concentrations, but plasma concentrations were linearly related to doses of the drug (240 to 480 mg/day) in the same patient (r = 0.81). Plasma concentrations of norverapamil, the major active metabolite of verapamil, were similar to those of verapamil. Although verapamil produced a significant improvement in exercise tolerance in most patients, the increase in exercise time was not related to plasma levels of the drug; however, most patients with improvement had plasma levels exceeding 100 ng/ml. An increase in the dose of verapamil from 320 to 480 mg daily produced a substantial (71%) increase in plasma levels of the drug but no significant increase in exercise tolerance (4%). The average increase in the P-R interval with 480 mg of verapamil in these 77 patients was small (8%) (161 +/- 18 to 174 +/- 22 ms); on.y six patients had first-degree heart block. These minor effects on atrioventricular conduction were noted despite plasma verapamil concentrations in 76 patients that exceeded 100 ng/ml, a level that successfully converts supraventricular tachycardias after intravenous drug administration. We differences between the effects of oral and intravenous verapamil on atrioventricular conduction may be the result of stereoselective hepatic inactivation of verapamil's I-isomer. Determination of plasma levels of verapamil is of limited value in the management of patients with angina pectoris, but may be useful in the identification of nonresponders with plasma levels less than 100 ng/ml who may benefit from a further increment in drug dose.

Administration, Oral↗
PubMed1982

Long-term effectiveness of verapamil in stable and unstable angina pectoris. One-year follow-up of patients treated in placebo-controlled double-blind randomized clinical trials.

The clinical responses to 12 months' treatment with verapamil were evaluated in 63 patients with stable and unstable angina pectoris in whom the effectiveness of verapamil had been established in short-term double-blind placebo-controlled randomized clinical trials. In 41 patients with effort-related angina, long-term responses were sustained for periods exceeding 1 year. Twenty patients were evaluated by clinical history and showed a sustained reduction in frequency of anginal attacks and consumption of nitroglycerin with verapamil compared with the initial placebo control periods; the magnitude of this benefit was similar to that observed during double-blind treatment with the drug. Twenty-one patients were evaluated by serial treadmill exercise testing and showed a sustained improvement in exercise duration after 4, 8, 16, 24, and 52 weeks of verapamil treatment; withdrawal of the drug resulted in a deterioration of exercise performance to levels similar to those seen before initiation of therapy. In 22 patients with unstable angina at rest, verapamil produced an amelioration of anginal symptoms that was sustained in most patients for longer than 1 year. However, these patients continued to have a high incidence of death and myocardial infarction in a frequency similar to that previously reported in large clinical studies using either combinations of verapamil and nitrates, nifedipine and propranolol, or propranolol and nitrates. Calcium-channel antagonists may decrease the number of patients requiring coronary artery bypass surgery for relief of refractory angina, but they do not appear to alter the natural history of the disease.

Adult↗
PubMed1982

Central hemodynamic effects of dipyridamole in severe heart failure: comparison with hydralazine.

The effects of dipyridamole, a coronary and peripheral vasodilator drug, on cardiac performance were investigated in nine patients with severe chronic heart failure. Dipyridamole (30 to 80 mg IV) increased cardiac index (1.63 to 2.65 l/min/m2) and decreased systemic vascular resistance (2097 to 1124 dyn/sec/cm-5). Left ventricular filling pressure decreased (23.7 to 20.7 mm Hg) without significant changes in mean right atrial pressure or heart rate. These effects were similar to the hemodynamic responses after 100 mg hydralazine in the same patients, but they were of shorter duration (less than 90 min). In contrast, oral dipyridamole induced only modest responses in three of eight patients despite large single doses of the drug (150 to 300 mg). Dipyridamole is a rapid-acting short-lived vasodilator, which exerts predominantly arterial vasodilator actions similar to those of hydralazine. Due to inconsistent response after oral doses, however, the therapeutic application of dipyridamole in long-term management of chronic heart failure appears to be limited.

Administration, Oral↗
PubMed1982

Hemodynamic consequences of combined beta-adrenergic and slow calcium channel blockade in man.

The administration of verapamil to patients receiving beta-adrenergic blocking drugs is reported to produce adverse circulatory reactions, but a systematic investigation of this potential drug interaction has not been performed in man. We administered 40-, 80- and 120-mg doses of verapamil orally to 15 patients with angina pectoris who were receiving high doses of propranolol or metoprolol. Verapamil produced dose-dependent decreases in cardiac performance: with 120 mg, cardiac index decreased by 0.38 l/min/m2, stroke volume index decreased by 2.8 ml/beat/m2 and heart rate decreased by 6 beats/min, associated with increases in pulmonary capillary wedge (2.2 mm Hg) and mean right atrial pressures (1.7 mm Hg) (all p less than 0.01); two patients had marked, but asymptomatic, hypotensive reactions. In contrast, repeat administration of 120-mg doses of verapamil 24--30 hours after withdrawal of beta blockade produced no significant cardiodepressant effects despite significantly higher plasma levels of verapamil than during propranolol therapy (383.1 vs 205.1 ng/ml, p less than 0.01). In conclusion, verapamil produces significant negative inotropic and chronotropic effects in patients treated with beta-adrenergic antagonists; combination therapy should therefore be used with caution in patients with angina pectoris.

Adult↗
PubMed1982

Selection of vasodilator drugs for patients with severe chronic heart failure: an approach based on a new classification.

Although vasodilator drugs are of proven worth in the management of patients with severe heart failure, a useful system of classification of vasodilator drugs has not yet been devised. The traditional system of classification based on the dominant arterial and/or venous sites of action as determined by limb plethysmography has major conceptual and practical limitations. This article discusses the merits of a new classification format based on pharmacological mechanisms of action. According to this new system, vasodilator drugs can be divided into two groups: (1) direct-acting agonists (hydralazine, minoxidil, nitrates and nitroprusside) which demonstrate dose-dependent responses and generalised vasodilator effects, and thus require invasive monitoring for dose titration; and (2) neurohumoral antagonists (prazosin, trimazosin, phentolamine, captopril and teprotide), whose effects are qualitatively and quantitatively independent of the dose administered, show marked regional heterogeneity and have characteristic temporal patterns of response. This new classification system permits the rational formulation of clinical recommendations concerning the choice of a vasodilator drug for patients with severe chronic heart failure. However, widespread application of this new classification system awaits the development of reliable means of identifying patients with neurohumoral-dependent vasoconstriction without the necessity of a therapeutic trial.

Heart Failure↗
PubMed1981

Provocation of myocardial ischemic events during initiation of vasodilator therapy for severe chronic heart failure. Clinical and hemodynamic evaluation of 52 consecutive patients with ischemic cardiomyopathy.

Although hydralazine provokes myocardial ischemic events in hypertensive patients not in heart failure by producing reflex tachycardia, the frequency of and mechanisms underlying ischemic events when this drug is administered as a vasodilator agent to patients with heart failure is unknown. The responses to hydralazine in 52 consecutive patients with severe chronic heart failure secondary to coronary artery disease were reviewed. Twelve patients (23 percent) had 16 ischemic events during the initial administration of hydralazine (angina at rest in 12 and myocardial infarction in 4); these generally occurred in the absence of significant tachycardia and hypotension. Thirty-five of the 52 patients received nitroprusside (8 of whom had ischemic events with hydralazine), but this drug provoked ischemia in only 1 of the 35 although it resulted in greater decreases in systemic arterial pressure than occurred with hydralazine. In patients with ischemic event only with hydralazine, left ventricular filling pressure decreased 14.6 mm Hg with nitroprusside but only 3.9 mm Hg with hydralazine (probability [p] less than 0.01). Provocation of ischemia with hydralazine may therefore be due to the relative preservation of elevated left ventricular preload with this drug, since ischemic events are not in common with nitroprusside despite greater decreases in systemic pressures.

Adult↗
PubMed1981

Sustained effectiveness of minoxidil in heart failure after development of tolerance to other vasodilator drugs.

Although a variety of vasodilator drugs produce acute hemodynamic improvement in patients with severe chronic heart failure, long-term treatment with these agents may be associated with the development of drug tolerance and loss of initial beneficial effects. Five serial right heart catheterizations in a 78 year old man with severe chronic heart failure due to idiopathic cardiomyopathy documented the development of hemodynamic and clinical tolerance to oral hydralazine and oral captopril after initial responses were observed to both agents. However, sustained hemodynamic and clinical improvement by invasive testing was noted with minoxidil (20 mg orally twice daily) after 4 and 9 weeks of continuous therapy. These observations indicate that pharmacologic tolerance may occur with a variety of vasodilator drugs and may account for the failure of some patients to improve clinically with long-term therapy despite initial favorable hemodynamic effects. However, such tolerance seems to be drug-specific and, hence, its recognition in an individual patient does not prelude responsiveness to other vasodilator agents.

Administration, Oral↗