Cardioactive Drugs Research Articles

Interactions with cardioactive drugs

International Journal of Clinical PracticeVolume 40, Issue 12 p. 537-538 Case Report Interactions with cardioactive drugs N G Kounis MD, N G Kounis MD Department of Medicine, Agios Andreas Hospital, University of Patras, Patras, GreeceSearch for more papers by this authorC Mallioris MD, C Mallioris MD Department of Medicine, Agios Andreas Hospital, University of Patras, Patras, GreeceSearch for more papers by this author N G Kounis MD, N G Kounis MD Department of Medicine, Agios Andreas Hospital, University of Patras, Patras, GreeceSearch for more papers by this authorC Mallioris MD, C Mallioris MD Department of Medicine, Agios Andreas Hospital, University of Patras, Patras, GreeceSearch for more papers by this author First published: 01 December 1986 https://doi.org/10.1111/j.1742-1241.1986.tb08051.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume40, Issue12December 1986Pages 537-538 RelatedInformation

The hemodynamic determinants of the isovolumic index

The isovolumic index is a recently described echocardiographic parameter of left ventricular function that is calculated as the ratio between the sum of the time of isovolumic contraction and relaxation divided by the ejection time. Although the individual components of this index may be altered by heart rate and loading conditions, an analysis of the net effect of such alterations on the isovolumic index has not been undertaken. Thus, dogs were instrumented with high-fidelity micromanometers in the left ventricle, ascending aorta, and left atrium to allow determination of the individual comoonents of the isovolumic index and calculation of the index itself. Four sets of experiments were undertaken in random order. Left atrial pacing was used to increase heart rate by approximately 10 bpm in five steps. Preload was elevated in five stages by saline infusions which caused successive increases of 1 to 2 mm Hg in the left ventricular end-diastolic pressure. Systolic blood pressure was lowered or raised by approximately 10 mm Hg per stage by three progressive, steady-state infusions of nitroprusside and phenylephrine, respectively. These experiments demonstrated little change in the isovolumic index over a broad range of heart rate. Increased left ventricular end-diastolic pressure and decreased systemic pressure caused shortening of the index. Multiple regression analysis of all experiments yielded the following: isovolumic index = 0.41 − 0.015 (left ventricular end-diastolic pressure) + 0.004 (systolic blood pressure); r = 0.57, standard error = 0.13, p < 0.0001. Therefore, this investigation establishes the hemodynamic determinants of the isovolumic index and provides the basis for interpretation of directional changes in response to cardiac diseases and cardioactive drugs that can alter loading conditions.

Drug hoarding in a Jerusalem community.

We carried out a drug hoarding survey of an Israeli urban neighbourhood. Large quantities of drugs were stored by most families, particularly families with children and the elderly. The commonest drugs held were analgesics-antipyretics, but cardioactive drugs, antibiotics and cough preparations were also held in large numbers. Two-thirds of drugs held were not in current use. Drug-labelling was illegible, although most patients knew the purpose of the drugs they kept. Expiration dates were absent from most drug packages. Drug packaging and storage in families with children was generally unsafe. Physicians and pharmacists have the responsibility to educate patients to store drugs correctly and to use stored drugs safely.

Characteristics of the time-dependent slow inward current in adult human atrial single myocytes

The slow inward current isi plays a prominent role in impulse formation and slow conduction in the human heart. For this reason, it may be involved in a great variety of arrhythmias that occur clinically, particularly at the supraventricular level. isi also appears to be the major target of numerous cardioactive drugs daily administered to many patients. Difficulties encountered in voltage clamping human tissues, inevitably dissected from restricted zones of myocardium with inadequate geometry, may explain why direct measurements of this current have never been performed on multicellular human preparations. The recent development of enzymatic techniques allowing the isolation of calcium-tolerant myocytes has provided a solution to these problems. To our knowledge only one abstract has presented until now records of isi in human ventricular myocytes. We describe here the result of experiments carried out to investigate the slow inward current in single cells isolated from adult human atria. The present work provides the first quantitative description of this current in human myocytes.

Drug analysis by Raman and micro-Raman spectroscopy

The technique of Raman spectroscopy, resonance Raman spectroscopy and micro-Raman spectroscopy is described for application to drug analysis and investigation. Possibilities and limits are mentioned for qualitative and quantitative analyses as well as for studies of structure and interactions. Some principal interaction modes, such as hydrogen bonding, proton transfer, charge transfer and ion-molecule attraction, are shown to explain drug reactivity. Illustrations are given based on several drug families, in particular vitamins, anti-depressants, cardio-active and anticancer drugs.

Isosorbide-5-mononitrate in the treatment of acute left ventricular failure following acute myocardial infarction.

Eleven patients with acute left ventricular failure following acute myocardial infarction (mean pulmonary capillary wedge pressure [PCW] greater than 20 mmHg) were entered into an open, haemodynamic study of oral isosorbide-5-mononitrate (ISMN). Left ventricular failure was resistant to intravenous diuretic therapy. No patient received concurrent cardioactive drugs nor further diuretic therapy during the study period. Haemodynamic data were acquired via a flow-directed thermodilution catheter placed in the pulmonary artery. Baseline data were acquired prior to the intravenous administration of an ISMN challenge. Thereafter, oral ISMN (20 mg, 8 hourly) was administered over 48 h. Following intravenous ISMN challenge, mean PCW fell from 26.2 to 17.5 mmHg. Cardiac index fell from 2.4 to 2.3 l/min/m2 due to a fall in heart rate (103 to 96.8 beats/min) as stroke volume and blood pressure were unchanged. At 8 h following ISMN, two patients were withdrawn due to hypotension (systolic pressure less than 85 mmHg). In the remainder, PCW remained acceptable throughout 48 h (13.1 mmHg at 48 h), cardiac output, systemic blood pressure and heart rate showed no further significant change. These data suggest that ISMN is effective in the treatment of acute left ventricular failure following acute myocardial infarction.

Myocardial uptake of drugs and clinical effects.

The process of uptake of cardioactive drugs into the myocardium is a major determinant of the efficacy and potential toxicity of such agents. Evaluation of responses to anti-arrhythmic and positive inotropic agents is best performed with reference to their concentration in the myocardium, and the potential toxicity of drugs such as tricyclic antidepressants and anthracycline antineoplastics is likely to be related to peak myocardial drug concentrations. Although it has been appreciated for many years that even during long term drug administration the myocardial drug content may not be readily predictable on the basis of estimation of plasma drug concentrations, methodology for direct assessment of myocardial drug content has remained limited. The results of in vitro experiments, utilising tissue culture preparations of myocardial cells or isolated atria, have shed some light on the role of local factors as determinants of myocardial drug uptake. For many agents, attainment of maximal cardiac drug content in vitro is a very slow process (taking up to 3 hours), although maximal inotropic and electrophysiological effects may occur more rapidly. The prolonged time course of drug washout from these preparations also reflects their extensive and slow intracellular accumulation. Mechanical activity of the myocardium appears to accelerate drug uptake, particularly for otherwise slowly equilibrating agents, but the major determinant of the extent of drug uptake into isolated myocardial preparations is lipophilicity, perhaps reflecting the passage of drugs through the sarcolemma. In intact animals, assessment of myocardial drug content after acute drug administration has been performed utilising serial myocardial biopsy or sacrifice of animals. Studies in open-chested dogs suggest that acute accumulation of agents may be most closely predicted from the second compartment of a 3-compartment pharmacokinetic model, and that there is a variable correlation between changes in plasma and myocardial drug concentrations. For example, bretylium concentrations within the myocardium continue to increase for up to 6 hours after drug administration. Factors which may influence drug uptake into the myocardium in intact animals include ischaemia, which usually results in a delay in both drug uptake and subsequent clearance. This change can also be inferred from the time course of onset of antiarrhythmic drug effects in some models of myocardial ischaemia. Anoxia may also inhibit myocardial drug uptake.(ABSTRACT TRUNCATED AT 400 WORDS)

Analysis of the action of cardio-active drugs

AbstractEs wurde der Einfluß der N‐Methylquaternisierung auf die negativ inotrope Wirkung herzwirksamer Pharmaka untersucht und zu ihrer Wirkstoffanalyse herangezogen. Im Falle des Kalziumantagonisten Verapamil wurde ergänzend die zelluläre Lokalisation mit Hilfe der LAMMA‐Analyse ermittelt.

Circulating catecholamine and potassium concentrations early in acute myocardial infarction: Effect of intervention with timolol

In a prospective study, 20 patients with a first acute myocardial infarction and no current treatment with diuretics or cardioactive drugs were randomized to treatment with intravenous timolol (10 patients) or placebo (10 patients). Plasma adrenaline, noradrenaline, and serum potassium were estimated at baseline (mean ± SD 3.6 ± 0.8 hours after the onset of the infarction) and 4 hours after the start of treatment. The patient selection criteria embraced a low-risk study population. Before treatment, the serum potassium concentrations correlated inversely with plasma adrenaline but not with plasma noradrenaline concentrations. A rise of serum potassium (mean ± SD mmol/L) from 4.1 ± 0.3 to 4.4 ± 0.4 ( p < 0.05) in the placebo group and from 4.0 ± 0.4 to 4.5 ± 0.5 ( p < 0.05) in the timolol group was in multivariate analysis associated with infarct size, estimated as cumulative creatine kinase release, in the placebo group, and with the mean individual plasma adrenaline concentrations in the timolol group. By reversing the effect of adrenaline from a decrease to an increase in the serum potassium concentrations, timolol changes the relationships between circulating adrenaline, potassium, and infarct size.

Effects of buccal nitrate on left ventricular haemodynamics and volume at rest and during exercise-induced angina.

A novel approach has been employed to characterize the effects of a cardioactive drug on left ventricular haemodynamics and volume by simultaneously determining cardiac stroke volume (thermodilution) and left ventricular ejection fraction (nuclear probe). The effects of glyceryl trinitrate were evaluated in 12 patients with angiographically proven coronary artery disease at rest and 3, 7, 15 and 30 min following 10 mg buccal nitroglycerin (Suscard) administration. The impact of the drug on left ventricular haemodynamics and volume during exercise-induced angina was determined by repeating exercise 30 min following drug administration, at the workload that reliably induced angina during control exercise. At rest buccal nitroglycerin reduced systemic arterial pressure, cardiac and stroke volume indices, and increased heart rate. The left ventricular ejection fraction (E.F.) increased; its filling pressure together with end-diastolic and end-systolic volumes were significantly reduced. Compared with control supine-bicycle exercise, the drug reduced mean systemic arterial pressure and left ventricular filling pressure without change in cardiac and stroke volume indices. There was a smaller increase in left ventricular volume during exercise, and the fall in E.F. was attenuated. These data demonstrated differential actions of glyceryl trinitrate on left ventricular function related to the physiological state in obstructive coronary artery disease. These techniques appear to hold promise in the evaluation of the effects of other therapies on left ventricular volume in coronary artery disease.

Cardiac dynamics of the Langendorff perfused heart.

The Langendorff perfused heart is studied in a closed system with (i) automatic regulations to maintain constancy of the perfusion column (Krebs-Henseleit + 0.5% albumin or 25-30% washed erythrocyte suspension), (ii) continuous recording of rate, coronary flow, and supravalvular aortic pressure. A microcomputer with software interface is used for storage treatment and on-line analysis of the recorded variables. In 38 preparations perfused with Krebs-Henseleit, minimal diastolic (61.2 +/- 2.8 mm Hg) is significantly below and peak systolic (98.7 +/- 3.6 mm Hg) significantly above perfusion pressure (80 mm Hg). Pressure difference between minimal diastolic and peak systolic (delta P) is 37.5 +/- 1.8 mm Hg. Increases in perfusion pressure will be associated with increases of coronary flow and delta P, which is also increased by isoprenaline administration. Oxygen consumption decreased by 76% when perfusion pressure was lowered from 80 to 60 mm Hg in hearts perfused with a 30% erythrocyte suspension. All of these experimental results were interpreted as indicating that delta P measured in this system resulted from an ejected volume (x acceleration) from the heart. The ejected volume corresponds to a valvular leak caused by the rigid nature of the system which is devoid of aortic compliance. delta P may be considered an index of left ventricular performance, an indication that the Langendorff preparation studied under the present conditions is a working heart. A 100-microliter volume constant infusion syringe for time administration of cardioactive drugs may be inserted at the base of the perfusion column to obtain dose-response effects.

Electrophysiologic effects of amrinone

Patients with congestive heart failure (CHF) have a high prevalence of complex ventricular arrhythmias. Accordingly, the electrophysiologic effects of new drugs for the treatment of CHF should be studied to determine whether they are safe in this population of patients. Fifteen patients with New York Heart Association functional classes II to IV CHF underwent hemodynamic and electrophysiologic testing during control conditions, and after 10 to 20 μg/kg/min of intravenous amrinone (dosages that increased cardiac output and decreased left ventricular filling pressures). All cardioactive drugs were stopped for at least 5 half-lives before entry into the study. Amrinone decreased the atrial effective refractory period from 256 to 240 ms (p = 0.015) and the AV nodal functional refractory period from 374 to 356 ms (p <0.05), and enhanced maximal 1:1 AV nodal conduction from 371 to 334 ms (p = 0.006). Prolonged HV intervals were present in 9 of 15 patients and were not affected by amrinone. Holter monitoring was performed in 10 patients during acute oral administration of amrinone. There were no significant changes in the frequency of ventricular extrasystoles or ventricular tachycardia, although the frequency of ventricular couplets tended to increase slightly. Amrinone therefore enhances AV conduction and does not appear to have significant arrhythmogenic potential during acute administration.

Chemical methods in association with physical methods in drug analysis

Physical methods, namely spectroscopy and separation techniques such as high-performance liquid chromatography, in which the analyte is not chemically changed during analysis, have gained increasing popularity in the field of pharmaceutical analysis. Nevertheless, chemical manipulation in combination with such methods will continue to play a vital role, as will be demonstrated with examples selected from methods developed for two new, cardioactive drugs, nadolol and captopril, and from other recent literature references.

Treatment of congestive heart failure by altering loading conditions of the heart

We have not emphasized the traditional approaches to the treatment of congestive heart failure, because there is abundant literature detailing the importance of rest and comfort for the patient, reduction of solute load, and administration of digitalis and diuretics. Instead, we have sought to emphasize the therapeutic interventions that are aimed at changing the mechanical loading conditions of the heart. Treatment expectations must be viewed within an age- or maturity-dependent framework. Thus, when a preterm or full-term newborn infant requires cardiocirculatory support, diminished cardiac reserve limits the benefits derived from diverse treatment methods. This unique fragility of the developing heart and circulation places a premium on the astute manipulation of all of the factors that determine optimum cardiovascular adaptation to stress. Beyond infancy, although cardiovascular reserve increases, it remains imperative to modify therapy by using cardioactive drugs that deal specifically with the separate mechanical and contractile variables to assure optimum survival.

Serum potassium concentration as a risk factor of ventricular arrhythmias early in acute myocardial infarction.

Sixty patients with a first acute myocardial infarction and no current treatment with cardioactive drugs were included in a prospective study of the relationship between serum potassium concentration and the early occurrence of ventricular tachycardia and premature ventricular contractions (PVCs). Serum potassium level (range 2.5 to 5 mmol/liter) was estimated 3.8 +/- 2.5 hr (mean +/- SD) after the onset of the infarction, and Holter monitoring was performed during the subsequent 12 hr. In multivariate analysis, serum potassium level was negatively and age positively related to ventricular tachycardia. Among the subclasses of PVCs (frequent unifocal, multifocal, couplets, bigeminy), serum potassium concentration was negatively related to the frequent unifocal subclass; hypertension was related to couplets and to the presence of any of the subclasses, and serum aspartate aminotransferase concentration was related to multifocal PVCs. Heart failure leading to death was related to all subclasses of PVC. Serum potassium concentration is an independent inverse predictor of the occurrence of ventricular tachycardia and frequent unifocal PVCs early in acute myocardial infarction.

Changes in oxygen consumption of the isolated heart muscle from animals treated with cardio-active drugs.

Changes in oxygen consumption of the isolated heart muscle from animals treated with cardio-active drugs.

Ibuprofen, Pharmacokinetics and Pharmacodynamics in the Isolated Rabbit Heart

Myocardial pharmacokinetics and dynamic effects of the non-steroidal antiinflammatory drug ibuprofen were studied in isolated, spontaneously beating and retrogradely perfused rabbit hearts. Both myocardial uptake and disposition of ibuprofen showed two-compartment characteristics, which possibly reflects extracellular and intracellular binding sites. Initial and terminal kinetic half-lives were about 0.6 and 13.4 min., respectively. Vd beta was about 82 ml/g myocardial tissue. Stepwise increased ibuprofen concentrations from 30 to 160 micrograms/ml in the Krebs-Henseleit perfusion liquid produced a progressive increase in coronary flowrate up to 178%, which then decreased somewhat at higher concentrations. Preliminary observations showed a direct relaxing effect on PGF-2 alpha produced contractions in coronary vasculature. Oxygen consumption increased simultaneously to 143% at 160 micrograms/ml and then decreased. Myocardial contractility (measured by amplitude and rate of contraction) decreased progressively to about 55% at concentrations from 60-160 micrograms/ml and further to 20% at 580 micrograms/ml. Myocardial efficiency expressed as the ratio of contraction rate to oxygen consumption decreased to about 0.2. Heart beat frequency decreased simultaneously to 73%. The electrocardiographic PQ and QRS intervals increased to 143 and 139%, respectively, whereas the QT interval did not increase significantly. Asystolia occurred in some cases at ibuprofen concentrations of 580 micrograms/ml. The findings suggest that ibuprofen at therapeutic concentrations may possibly produce some coronary vasodilation accompanied by a slight negative inotropic effect. Interactions with other cardioactive drugs seem possible. The drug may cause direct cardiotoxic effects at supratherapeutic concentrations.

Comparative hemodynamic effects of intravenous dobutamine and MDL-17,043, a new cardioactive drug, in severe congestive heart failure

In 14 patients with severe congestive heart failure (CHF) due to ischemic heart disease or idiopathic dilated cardiomyopathy, the hemodynamic response to intravenous infusion of dobutamine (D) was compared to that of a new non-catechol, non-glycoside, inotropic and vasodilator agent, MDL-17,043 (MDL) administered in incremental intravenous doses. D and MDL produced coraparable increases in cardiac index (L/min/m 2) (1.8 ± 0.4 to 2.9 ± 0.8 and 1.7 ± 0.3 to 3.3 ± 0.6, respectively; both p = 0.001) and stroke volume index (ml/beat/m 2) (24 ± 8 to 35 ± 9 and 22 ± 7 to 39 ± 11, respectively; both p = 0.001). Both D and MDL reduced left ventricular filling pressure (29 ± 5 to 24 ± 5 and 29 ± 6 to 17 ± 6 mm Hg, respectively; both p < 0.05), and mean right atrial pressure (11 ± 4 to 8 ± 4 and 13 ± 5 to 6 ± 4 mm Hg, respectively; both p = 0.001). The overall changes in heart rate and mean arterial pressure were small with both D and MDL. However, MDL in comparison to D resulted in a significantly lower left ventricular filling pressure ( p = 0.001), mean pulmonary arterial pressure ( p = 0.001), and mean arterial pressure ( p < 0.05). The salutary hemodynamic effects of MDL on cardiac index and left ventricular filling pressure were sustained for an average of 9.6 hours, whereas the effects of D dissipated within 30 minutes of stopping the infusion. No serious adverse effects were noted during acute administration with either drug. Therefore, intravenous MDL may be a useful substitute for D in the acute therapy of severe CHF.

Continuous Monitoring of Mixed Venous Oxygen Saturation in Hemodynamically Unstable Patients

A balloon-tipped catheter has recently become available which, when placed in the pulmonary artery, in addition to enabling the usual measurements of pulmonary arterial pressure, pulmonary capillary wedge pressure, and cardiac output by thermodilution, measures mixed venous oxygen saturation (SvO2) by spectrophotometry. Unlike the measurement of cardiac output by thermodilution, which is done intermittently, the continuous measurement of SvO2 is an effective method of monitoring hemodynamically unstable patients, since changes in cardiac output will immediately become apparent via a corresponding change in SvO2. This is of particular benefit in patients in whom knowledge of the immediate effects of therapy is important. It is also of value in assessing the time of onset of action and duration of action when a cardioactive drug is given to increase cardiac output. We suggest that monitoring SvO2 will provide an earlier indication of the effect of both diagnostic and therapeutic interventions and, therefore, will improve our management in such patients.

Arrhythmias in Patients with Drug Toxicity, Electrolyte, and Endocrine Disturbances

The common rhythm disturbances related to electrolyte imbalance are due predominantly to abnormalities of potassium. An understanding of the mechanism underlying these abnormalities is facilitated by a brief review of normal electrical activity during impulse propagation in cardiac tissue. Also discussed are the actions of all cardioactive and antiarrhythmic drugs on membrane permeability to ions. Lastly, the nonspecific arrhythmias associated with endocrine disturbances are outlined.