R.G. McAllister

Influence of severity of ventricular dysfunction on hemodynamic responses to intravenously administered verapamil in ischemic heart disease

The effects of verapamil, 0.145 mg/kg body weight, administered intravenously in a bolus injection followed by 0.005 mg/kg per min, on cardiovascular hemodynamics and on ventricular ejection fraction, determined with gated cardiac blood pool scanning, were studted in 25 patients, 8 with acute myocardial infarction and 17 with symptomatic coronary artery disease who were undergoing diagnostic cardiac catheterization. The mean (± standard deviation) plasma verapamil level, determined with a gas liquid chromatographic technique utilizing a nitrogen detector, was 161 ± 47 ng/ml (n = 8) during steady state conditions of drug infusion. In 15 patients with stable coronary artery disease having a normal or moderately reduced ejection fraction, verapamil reduced mean arterial pressure (−16 percent, probability [p] < 0.001), systemic vascular resistance (−23 percent, p < 0.001), stroke work index (−13 percent, p < 0.02), with no significant change in pulmonary vascular resistance, ejection fraction or heart rate; cardiac index was increased (+11 percent, p < 0.001) as was the stroke volume index (+7 percent, p < 0.01) and mean capillary wedge pressure (+10 percent, p < 0.01). In the seven patients with uncomplicated infarction, there was no effect on ejection fraction, heart rate or pulmonary vascular resistance. There was a decrease in systemic vascular resistance (−22 percent, p < 0.01) and mean arterial pressure (−16 percent, p < 0.01) with an increase in cardiac index (+27 percent, p < 0.05), stroke volume index (+4 percent, p < 0.05) and mean capillary wedge pressure (+17 percent, p < 0.02). In three patients, one wlth acute infarction and two with coronary artery disease, having a severely reduced ejection fraction and elevated mean capillary wedge pressure (20 mm Hg or greater), mean arterial pressure decreased markedly with a fall in stroke volume index and an abrupt increase in the mean pulmonary capillary wedge pressure. These findings were associated with clinical evidence of heart failure and dyspnea. It is concluded that (1) in patients with cardiac disease having a mild to moderate decrease in left ventricular ejection fraction accompanied by a normal or mildly elevated mean pulmonary capillary wedge pressure, the intrinsic depressant effect of verapamil is offset almost entirely by its potent vasodilator proporties, but (2) in patients with a severely reduced ejection fraction and a high pulmonary capillary wedge pressure, the depressant effects of the compound become clinically apparent with sudden further increases in pulmonary capillary wedge pressure and a decrease in stroke volume and mean arterial pressure.

The Pharmacology of verapamil. IV. Kinetic and dynamic effects after single intravenous and oral doses

Kinetics and plasma level–effect correlates for verapamil were studied in 20 normal young men (mean age, 25.2 ±3.6 yr). In a randomized four‐way crossover design, each subject received 10 mg verapamil intravenously and 80, 120, and 160 mg in single oral doses. Changes in heart rate, blood pressure, and PR interval were evaluated serially after each dose; plasma concentrations of verapamil were measured by high‐performance liquid chromatography. Levels of the active metabolite norverapamil were determined in five subjects. Verapamil kinetics were the same after intravenous and oral doses: elimination half‐life (t½β) ranged from 3.7 to 4.8 hr, apparent volume of distribution varied between 4.2 and 5.5 l/kg, and total clearance was 0.71 to 0.86 l/hr/kg. Verapamil bioavailability was not dose dependent and averaged 19.4%. Norverapamil, found only after oral doses, had a t½β and maximum concentration much the same as the parent drug. There were only minor effects on heart rate and blood pressure after single doses. Hysteresis analysis showed that plasma verapamil concentrations after intravenous doses correlated with PR interval prolongation only after a 30‐min lag time; there was no lag after oral doses. There was considerable interindividual variation in sensitivity to verapamils effect on atrioventricular conduction; subjects with longer control PR interval values tended to have greater prolongation of effect than those with shorter intervals. Verapamil was well tolerated in both dosage forms by all subjects.

The Pharmacology of Verapamil

The relative distribution of verapamil and its demethylated metabolite, norverapamil, was studied in rats at intervals after intraperitoneal injection of the parent drug (30 mg/kg). This route of drug

Pharmacokinetics of calcium-entry blockers

Effective use of drugs in therapy depends not only on clinical acumen but also on the availability of relevant pharmacokinetic and pharmacodynamic data. Such information assists in development of safe dosing regimens, prediction of abnormal handling of drugs in states of disease and disorder and anticipation of drug interactions. For the calcium-entry blocking agents now available in the United States (verapamil, nifedipine and diltiazem), these data appeared well after clinical patterns of use evolved. Nonetheless, their relevance continues to be demonstrated by the dependence of each agent on intact liver blood flow and function for normal rates of elimination; by the nonlinear kinetic characteristics for verapamil and diltiazem (and probably for nifedipine, as well) and the derivative implications for decreased dosing frequency requirements; and by observations now appearing on the relation between plasma drug levels and drug effects, both therapeutic and toxic. Such data are discussed herein, with emphasis on those aspects that impact on the clinical use of the calcium-entry antagonists.

The Pharmacology of Verapamil. III. Pharmacokinetics in Normal Subjects After Intravenous Drug Administration

Summary: The pharmacokinetics of verapamil were determined in 8 normal male subjects (age range. 24–28 years) after administration of 0.2 mg/kg over a 3–4 min period. Plasma drug concentrations were measured by a gaschromatographic method using a nitrogen-specific detector with a sensitivity of 5 ng/ml. Verapamil levels fell in a biexponential pattern, and the data were fitted to a two-compartment model with the NONLIN computer program. The distribution phase half-life was 3.51 min and that of the elimination phase, 110.5 min: the volume of distribution was 178 ±.26 liters, and the plasma clearance was 1.06 ± 0.27 liters/min. The P-R interval of the surface electrocardiogram was increased in each subject in direct proportion to the verapamil plasma level, but with considerable between-subject variability. One subject developed transient Mobitz I block at a plasma drug concentration of 162 ng/ml. At peak verapamil concentrations, mean T-wave amplitude decreased 35 ± 11% from control height. The results of this study suggest that P-R interval prolon gation can be used as an indication of verapamil effect in patients with sinus phythm.

Measurement of verapamil concentrations in plasma by gas chromatography and high pressure liquid chromatography.

: This study was carried out to compare gas chromatography (GC) and high-pressure liquid chromatography (HPLC) procedures in the measurement of plasma levels of verapamil. Other analytic methods previously reported are not widely available (mass fragmentography) or are subject to interference from drug metabolites (spectrophotofluorometry). A single extraction and derivatization procedure was developed to prepare samples for either GC or HPLC analysis. The GC procedure used a nitrogen-specific detector; the HPLC, a fluorescence detector. In a 1--500 ng/ml range of verapamil concentrations, both methods resulted in good separation of verapamil from a major metabolite, norverapamil, and from compound D517, used as an internal standard. Intraassay variation was similar for both procedures, with only slightly higher interassay variability found for the GC technique. Excellent correlation was found during analysis of the same unknown samples by both methods (r = 0.97; p less than 0.001). Either assay procedure appears satisfactory for use in measurement of verapamil levels in plasma.This study was carried out to compare gas chromatography (GC) and high-pressure liquid chromatography (HPLC) procedures in the measurement of plasma levels of verapamil. Other analytic methods previously reported are not widely available (mass fragmentography) or are subject to interference from drug metabolites (spectrophotofluorometry). A single extraction and derivatization procedure was developed to prepare samples for either GC or HPLC analysis. The GC procedure used a nitrogen-specific detector; the HPLC, a fluorescence detector. In a 1--500 ng/ml range of verapamil concentrations, both methods resulted in good separation of verapamil from a major metabolite, norverapamil, and from compound D517, used as an internal standard. Intraassay variation was similar for both procedures, with only slightly higher interassay variability found for the GC technique. Excellent correlation was found during analysis of the same unknown samples by both methods (r = 0.97; p less than 0.001). Either assay procedure appears satisfactory for use in measurement of verapamil levels in plasma.

Nifedipine-propranolol interaction: dependence of cardiovascular effects on plasma drug concentrations

The relationships between plasma drug concentrations and cardiovascular effects during combined administration of nifedipine and propranolol were evaluated in dogs anesthetized with thiopental. Three received small intravenous (i.v.) doses of nifedipine followed by propranolol, and 6 were given higher doses of nifedipine followed by propranolol; in 5, the order of drug doses was reversed, with propranolol administration followed by nifedipine. When dosing regimens that produced stable plasma levels of both drugs were used, the observed effects were closely related to the plasma concentrations of the individual agents. When small doses of nifedipine were combined with propranolol, at plasma levels associated with a significant degree of β-adrenoceptor blockade, moderate decreases in spontaneous heart rate and cardiac output as well as increases in atrioventricular conduction time were produced. With higher doses of nifedipine, combined infusion with propranolol resulted in more pronounced depression in cardiac function, characterized by decreases in cardiac output, heart rate, and mean pulmonary arterial pressure, as well as increases in atrioventricular conduction time. When propranolol administration was followed by nifedipine, similar dose-dependent cardiovascular effects resulted, with profound toxicity apparent when large doses of nifedipine were used. These studies in an acute anesthetized dog model suggest that the magnitude of cardiovascular depression resulting from nifedipine and propranolol in combination is dependent on the plasma concentrations of both agents. Furthermore, in the presence of β-adrenoceptor blockade, the direct effects of nifedipine on myocardial conducting tissue, which are usually absent when this calcium antagonist is given alone, may become apparent and result in depression of atrioventricular and sinoatrial nodal functions.

Pharmacodynamic comparison of verapamil and nifedipine in anesthetized dogs

The relationships between steady-state plasma concentrations of verapamil or nifedipine and the resultant hemodynamic and electrophysiologic effects were evaluated in anesthetized, instrumented dogs. In different groups of animals, the drugs were given intravenously by loading-maintenance infusions designed to rapidly achieve and sustain stable plasma drug concentrations, over four different target ranges which span those found in clinical use of these agents. Plasma levels of nifedipine varied from 5 to 125 ng/ml, and those of verapamil, from 40 to 500 ng/ml. Nifedipine produced no apparent effects on the surface electrocardiogram. Verapamil dosing resulted in progressive prolongation of the PR interval as plasma drug levels increased from 40 to 250 ng/ml; at higher drug levels, complete atrioventricular block occurred. At the highest plasma concentrations used, the maximal vasodilation produced by both drugs was approximately equal, with mean aortic pressure levels falling to 50–60% of control values. The effects of the two agents on cardiac pump performance, however, differed: nifedipine administration produced dose-related increases in cardiac output at all plasma drug concentrations studied; the effects of verapamil were critically dependent upon drug levels in plasma, with cardiac output increased above control values at drug concentrations between 40 and 250 ng/ml, and progressively depressed at higher plasma levels of the drug. As a result, the calculated systemic vascular resistance declined progressively during nifedipine administration, while after verapamil doses, this parameter varied inversely with observed effects on cardiac output. These in vivo data illustrate the potent and generalized vascular effects of both nifedipine and verapamil, and, in addition, emphasize fundamental differences between these two agents, which derive from the direct myocardial depressant effects of verapamil.

Cardiodepressant actions of combined diltiazem and propranolol in dogs.

Summary The cardiovascular actions of combined intravenous (i.v.) diltiazem and propranolol were studied in barbiturate-anesthetized dogs. When given alone, diltiazem increased cardiac output (CO) and P-R interval duration (P-R) while decreasing mean arterial pressure (MAP), heart rate (HR), and systemic vascular resistance (SVR). Propranolol alone decreased CO and HR while increasing SVR. With the same i.v. doses, combined infusion of diltiazem and propranolol rapidly resulted in depression of CO to levels similar to those achieved with propranolol β-adrenoceptor blockade alone. The combination decreased MAP to levels achieved with diltiazeminduced calcium channel blockade. P-R increased beyond the durations produced by either drug given alone. Pharmacokinetic interactions were not apparent, although slight increases in propranolol plasma concentrations were observed during combined drug infusions. These studies support clinical observations that the cardiovascular effects resulting from a combination of diltiazem and propranolol may be attributed to the characteristic cardiovascular actions of each individual drug.

Hemodynamic and pharmacokinetic aspects of the interactions between verapamil and pindolol

Combined administration of verapamil, a phenylalkylamine calcium-entry antagonist, with a pure beta-adrenoceptor blocker, propranolol, produces profound cardiovascular depression associated with decreased hepatic clearance of both drugs. We have therefore studied the combination of verapamil and pindolol, a beta-adrenoceptor blocker with intrinsic sympathomimetic activity (ISA), to evaluate whether or not the property of ISA will confer protection from the usual toxic effects observed with verapamil and a beta-adrenoceptor blocking agent. In an anesthetized dog model, dosing regimens which produced stable plasma concentrations of either verapamil and/or pindolol resulted in drug effects which were closely related to the plasma levels of the individual agents. When pindolol was combined with verapamil, profound depression of cardiac pump function occurred, similar to that previously found with propranolol. Further, plasma concentrations of verapamil promptly increased into a toxic range during combined administration with pindolol. In summary, since the cardiovascular depression resulting from verapamil and pindolol in combination is similar to that which occurs with verapamil and propranolol, ISA does not appear to obviate the toxic effects of verapamil and a beta-adrenoceptor agent in combination.