Donatella Piovan

Effects of pinacidil on guinea-pig isolated perfused heart with particular reference to the proarrhythmic effect.

1 The effects of pinacidil (10, 30, 50 μm) on contractility (+ dP/dtmax), coronary perfusion pressure (cP), and ECG intervals (PR, QRS, QT) have been studied on constant‐flow perfused guinea‐pig hearts, driven at four frequencies (2.5, 3, 3.5, 4 Hz). 2 Pinacidil decreased +dP/dtmax, cP and the QT interval in a dose‐dependent manner, whereas the PR interval was increased. QRS duration was not modified. All these effects were independent of driving frequency. Pinacidil decreased the interval from Q‐wave to T‐wave peak (QTpeak) to a greater extent than the QT interval, thus decreasing the QTpeak/QT ratio. This effect, unlike that on QT interval, was more evident at the highest frequency of stimulation. 3 In 4 out of 20 hearts treated with pinacidil sustained ventricular fibrillation (VF) occurred following a short run of premature ventricular beats (R on T phenomenon). 4 In separate experiments, an attempt to induce VF electrically was made at drug concentrations ranging from 10 μm to 100 μm (8 experiments for each concentration). In control conditions and at the lowest concentration of pinacidil tested (10 μm) VF could never be induced; in the presence of 30 μm pinacidil VF was induced in 5 out of 8 experiments. Drug concentrations higher that 50 μm permitted the induction of VF in every case. 5 Although the concentrations of pinacidil producing ventricular fibrillation are 30–40 times higher than those found in patients under long term treatment with this agent, it is suggested that caution should be used in prescribing this drug, at least in patients suffering from myocardial ischaemia.

Pharmacokinetics and Electrophysiological Effects of Intravenous Ajmaline

SummaryThe pharmacokinetics of ajmaline were studied in 10 patients with suspected paroxysmal atrioventricular block who received a 1 mg/kg intravenous dose over 2 minutes for diagnostic purposes (ajmaline test). Plasma concentration decay followed a triexponential time course with a final half-life much longer (7.3 ±3.6 hours) than that previously found by other investigators (about 15 minutes). Mean total plasma clearance and renal clearance were 9.76 ml/min/kg and 0.028 ml/min/kg, respectively. Although most of the dose was eliminated through the extrarenal route (only 3.5% of the intravenous dose was recovered in urine), no fluorescent metabolites could be detected either in plasma or urine. The steady-state volume of distribution averaged 6.17 L/kg, and plasma protein binding ranged between 29 and 46%.Three patients developed a transient atrioventricular block after ajmaline administration. In the remainder, the drug prolonged atrio-His bundle (AH interval), His bundle-ventricular (HV interval) and intraventricular (QRS interval) conduction times. Corrected ventricular repolarisation time (QTc interval) showed less marked changes, which were biphasic at times. The mean maximum ajmaline-induced increase in HV interval was 98%, in QRS was 58%, in AH was 30%, and in QTc was 17%.In most cases the time course of electrocardiographic changes lagged behind that of plasma concentrations, suggesting a delayed equilibrium of plasma concentrations with the site of action (hysteresis). Despite that, the pharmacokinetic-pharmacodynamic model, which accounted for hysteresis, failed to fit the experimental data adequately. The duration of electrophysiological effects was short (about 30 minutes) in comparison with the slow decay of plasma concentrations, so that a threshold concentration exists under which no drug effect can be detected. Accordingly, if suprathreshold ajmaline plasma concentrations were steadily maintained (as can occur, for example, after repeated doses of lorajmine, an ajmaline prodrug), the duration of the electrophysiological effects would be unpredictably longer.

Pharmacodynamic variability of flecainide assessed by QRS changes

The effect of flecainide on the QRS interval was studied in 10 patients who were receiving long‐term oral treatment (50 to 150 mg twice daily) for arrhythmias that were refractory to other drugs. Total and free drug plasma levels and QRS durations were measured at intervals after the morning administration. Free drug plasma levels were linearly correlated with QRS duration in each patient and the slope of the line was widely variable in the population studied. Even after the data from one patient with an unusually high slope (0.454) was excluded from the analysis, the slope range was 0.0284 to 0.144. Pharmacodynamic variability could not be explained by heart rate changes, active metabolites, electrolyte disturbances, or free drug concentration. None of the pharmacokinetic parameters measured (average steady‐state concentration, fluctuation of maximum and minimum concentrations, time to peak concentration, final half‐life, and protein binding) showed an intersubject variability greater than 4.4 times. Our findings suggest that the determination of flecainide free plasma concentration may not be sufficient to forecast electrophysiologic effects in individual patients.

Amiodarone and amiodarone plus digitalis in the treatment of paroxismal supraventricular reciprocating tachyarrhythmias

Summary Therapeutic response, incidence of side effects and plasma levels of the drugs have been evaluated in patients with paroxysmal supraventricular reciprocating tachyarrhythmias treated with amiodarone (A) or amiodarone plus a glycoside (digoxin or medigoxin). 26 out 40 patients of group A (A.) and 15 out 23 of group AD (A. plus digitalis) remained free of tachyarrhythmic episodes during the follow-up period (12 month) and a significant overall decrease of paroxysms was recorded in the remaining patients. A. was withdrawn in 5 patients, for hyperthyroidism (3 cases), hypothyroidism (1 case) and photodermatosis mediate (1 case). Corneal deposits were frequent (68% of the patients) but scanty and not progressive. A significant correlation was found at steady state between A. plasma levels and digitalemia. However, unlike the results obtained by other AA during a short term A. treatment, digitalis plasma levels remained in the therapeutic range in all patients, without any evidence of toxicity.

Present and future trends in research and clinical applications of inodilators.

The rationale of combining vasodilatation with positive inotropic intervention in the treatment of chronic heart failure has found a new implementation in the “inodilator” drugs. Inodilators are characterized by the properties of exerting positive inotropic effect and inducing systemic vasodilatation. The cellular mechanisms involved in the regulation of contractility of cardiac and vascular muscle and the pathophysiological events occurring in heart failure are briefly discussed, and the pharmacological profile as well as the therapeutic use of these drugs are reviewed. On the basis of the mechanism of action, two groups of inodilators are distinguished, the phosphodiesterase inhibitors and the dopaminergic agents. The increase of [cAMP]1 induced by the phosphodiesterase inhibitors is responsible for their vasodilating effect and for the positive inotropic action, but many of them have in addition the ability to enhance the Ca2− sensitivity of cardiac contractile proteins. The complex organization and the cardinal role of the catecholaminergic receptor system in the control of cardiovascular function and its contribution to the pathophysiological events occurring in heart failure are the rational basis of the therapeutic use of dopaminergic agents. These drugs, acting on DA, β-, and α-receptors, exert not only positive inotropic and vasodilating effects, but also a diuretic action, and can reduce aldosterone and renin secretion, blunt an excessive sympathetic activity, and possibly promote the release of atrial natriuretic peptide. The multireceptor mechanism of dopamine-like drugs, which accounts for their favorable hemodynamic, neurohumoral, and diuretic effects, represents the most promising approach to inodilator therapy.

Electrocardiographic interactions between pinacidil, a potassium channel opener and class I antiarrhythmic agents in guinea-pig isolated perfused heart.

1 Drugs that shorten action potential duration could decrease the Na‐channel blocking effect of class I antiarrhythmic agents by reducing the availability of Na channel in the inactivated state. 2 This hypothesis was tested in guinea‐pig perfused heart, measuring the surface ECG effects of three class I drugs endowed with different binding kinetics (15 μm mexiletine, 10 μm quinidine and 3 μm flecainide) in the presence of increasing concentrations of pinacidil (10 μm, 30 μm, 50 μm), a potassium channel opener that shortens action potential duration. 3 The ECG parameters measured were: the QRS interval, i.e. the intraventricular conduction time; the JT interval, which reflects the duration of ventricular repolarization; the ratio between JTpeak (the time from the end of QRS and the peak of T wave) and JT interval, which quantifies changes in the morphology of the T wave. 4 At the concentrations tested all the antiarrhythmic drugs widened the QRS complex by 55–60%. Flecainide did not significantly change JT interval, but quinidine prolonged and mexiletine shortened it. Mexiletine also decreased the JTpeak/JT ratio. Pinacidil by itself decreased the JT interval and the JT peak/JT ratio in a dose‐dependent way, but did not affect QRS duration. 5 In the presence of fixed antiarrhythmic drug concentrations, however, pinacidil decreased the QRS prolongation induced by mexiletine (−17%) and quinidine (− 8%), but not that induced by flecainide: this effect was already maximal at the lower concentration tested (10 μm) and there was no relationship between pinacidil‐induced JT shortening and QRS changes. To explain this unexpected result it has been supposed that, at the driving frequency used (4 Hz), myocardial cells were partially depolarized and that pinacidil could repolarize them, thus decreasing the number of inactivated Na channels and the effects of drugs that (mainly or partly) block the channels in the inactivated state. In agreement with this hypothesis, an additional series of experiments carried out with 15 μm mexiletine at a lower stimulation rate (2 Hz) showed only a negligible loss of QRS effect (−2.3%) at any pinacidil concentration. 6 Flecainide, but not quinidine and mexiletine, antagonized the JT shortening induced by pinacidil; furthermore, no drug modified the JTp/JT decrease induced by pinacidil. 7 These results indicate that: (a) an antagonism between class I antiarrhythmic drugs and pinacidil is possible; (b) mexiletine is the most involved among the drugs tested; (c) the interaction is not related to pinacidil‐induced repolarization shortening, but probably to changes in membrane resting potential. The possible clinical implications need to be defined.

The influence of acidosis on the myocardial uptake and electrocardiographic effects of disopyramide

The time course for the ECG effects and myocardial uptake of disopyramide was studied in isolated perfused guinea pig hearts under different pH conditions. At pH 7.46 the drug depressed the overall AV conduction time (PR) by 16.64%, the His-ventriculum conduction time (HV interval) by 30.46% and delayed the ventricular repolarization (QT interval) by 8.08%, on average. The maximum intraventricular pressure (Pmax) was also depressed by 35.6%. The maximum effect on the QT interval (constant rate: 0.609 min-1) was reached faster than the maximum effect on the PR and HV intervals (constant rates: 0.399 and 0.400 min-1, respectively), while the myocardium uptake process was complete before any ECG parameter reached a steady state (uptake constant: 1.58 min-1). Under conditions of extracellular acidosis (pH 6.92), the disopyramide disposition parameters (uptake rate constant and myocardial concentration) were not modified. However, the drug exerted significantly smaller effects on the HV and QT intervals and on myocardial contractility. These results are in contrast with those obtained previously with lidocaine and quinidine, and indicate that the influence of acidosis on class 1 antiarrhythmic agents may also depend on the characteristics of the individual drug.

AJMALINE TEST IN A PATIENT WITH CHRONIC-RENAL-FAILURE - A PHARMACOKINETIC AND PHARMACODYNAMIC STUDY

SummaryPharmacokinetic and pharmacodynamic properties were studied after intravenous administration of ajmaline 1 mg/kg in an anuric patient, who underwent the electrophysiological ajmaline test. The magnitude and rate of onset of the typical electrophysiological effects of ajmaline (prolongation in atrio-Hisian and His-ventriculum conduction times) were within the range of normal values. The plasma concentration curve showed a triexponential decay with half-lives as follows: initial phase (t½α) 1.34 min, fast elimination phase (t½β) 10.13 min and terminal (slow) phase (t½γ) 258.6 min. Other relevant pharmacokinetic parameters calculated were: total plasma clearance 45.91 L/h; volume of distribution 285.6L; protein binding 47%. Five hours after administration the patient underwent a 3.5h haemodialysis without any substantial increase in the slope of the final elimination phase of the curve. A major problem in interpreting the pharmacokinetic results is the lack of reliable reference data in healthy subjects. It is likely that the ajmaline t½ reported in the literature (13.4 min) does not reflect the true terminal t½ of the drug, because it was determined during an unduly short sampling period (30 min). Nevertheless, if we compare just the first 30 min of the concentration-time curves, our results are nearly superimposable on those found in healthy subjects.

Cardiac effects of quinidine on guinea‐pig isolated perfused hearts after in vivo quinidine pretreatment

1 Experimental and clinical studies suggest that class I and class III antiarrhythmic drugs may be subject to pharmacological tolerance during long term treatment, leading to loss of therapeutic effectiveness. 2 The aim of this study was to ascertain whether prolonged in vivo treatment with the Class Ia agent quinidine can modify cardiac (electrical and mechanical) responses to the drug. 3 A group of guinea‐pigs (n=7) were treated intraperitoneally (q.d.) for 6 days with 75 mg kg−1 quinidine sulphate. Preliminary pharmacokinetic experiments indicated that this dose could attain plasma concentrations similar to those that are therapeutic in man (2–5 mg l−1). A control group (n=7) received a saline solution for the same period. 4 Twenty‐four hours after the last administration hearts were removed and retrogradely perfused at constant flow (stimulation frequency: 2.5 Hz). The following parameters were measured: maximal derivative of intraventricular pressure (dP/dtmax); coronary perfusion pressure (Cp); PR, QRS and JT intervals, on surface ECG. The effects of quinidine on these parameters were measured at different concentrations (2, 4, 8, 12, 16, 20 μM) and compared in the two experimental groups. 5 In the control group quinidine decreased in a dose‐dependent manner dP/dt and increased PR and QRS intervals. JT interval was increased at the lowest concentrations and decreased at the highest (biphasic effect). Cp did not change significantly. 6 In the pretreated group quinidine qualitatively produced the same effects on dP/dt and ECG intervals as in control group. Also the magnitude of these effects was not significantly different between the two groups. In contrast with findings in control experiments, Cp was significantly decreased by increasing quinidine concentration. Mean baseline Cp was higher in pretreated than in the control group (though not significantly, P=0.072) and quinidine addition abolished this difference. Thus, it is suggested that quinidine withdrawal induced a rebound increase in coronary tone, due to the unmasking of vasoconstrictor homeostatic mechanisms elicited by the in vivo vasodilating effect of the drug. 7 In conclusion, our data do not support the possibility that tolerance ensues during long term quinidine treatment, at least as far as electrophysiological and contractility effects are concerned. Further experimental work is needed to explain the appearance of a coronary vasodilating effect in pretreated hearts.

Determination of lorajmine and its metabolite ajmaline in plasma and urine by a new high-performance liquid chromatographic method

Lorajmine is a monochloroacetyl derivative of ajmaline with electrophysiological properties somewhat different from those of the compound of origin. Since lorajmine is rapidly hydrolyzed to ajmaline by plasma and tissue esterases, it is crucial to measure plasma levels of both drugs separately. A major problem in assaying lorajmine is its chemical instability in plasma both after blood sampling and during the extraction procedure. Furthermore, lorajmine (unlike ajmaline) is not fluorescent and has a very low UV absorbance, so the standard detectors for high-performance liquid chromatography cannot be used. We describe a new method that solves the problems of instability and sensitivity. Plasma esterases are first blocked pharmacologically (neostigmine); ajmaline is then measured by direct on-column injection of samples. Last, lorajmine is completely converted to ajmaline, extracted, and measured with a fluorescence detector. The molar concentration of ajmaline obtained in the last step, minus that found by direct injection, gives the concentration of lorajmine. Some examples of pharmacokinetic applications are also given.