Plasma Verapamil Levels Research Articles

Lack of Correlation of Verapamil Plasma Level with Cumulative Protective Effects Against Halothane-Epinephrine Ventricular Arrhythmias

The effect of verapamil, 0.2 mg/kg i.v. over 30 s, on the amount of epinephrine required to elicit a reproducible ventricular arrhythmia during 0.9% halothane in oxygen anesthesia was investigated in two groups of dogs after three consecutive doses of verapamil given at 90 (group I) and 120 min (group II) intervals, respectively. Verapamil caused a stepwise cumulative increase in the arrhythmogenic dose of epinephrine in both groups despite plasma verapamil levels that declined to low levels (28 and 22 ng/ml, respectively) between doses. Control epinephrine arrhythmogenic doses were 2.89 +/- 0.54 and 2.74 +/- 0.19 microgram/kg/min (mean +/- SEM), respectively, for groups I and II, and rose to 4.58 +/- 0.72 and 4.55 +/- 0.30 microgram/kg/min after the first verapamil dose, to 6.20 +/- 0.74 and 6.13 +/- 0.40 microgram/kg/min after the second verapamil dose, and 8.16 +/- 0.85 and 8.09 +/- 0.95 microgram/kg/min after the third verapamil dose, respectively. All postverapamil epinephrine arrhythmogenic dose values were significantly elevated above control and above the preceding values, although there was no significant difference between the two groups. Changes in heart rate or blood pressure were similar among the three doses of verapamil in each group. These results can be interpreted to indicate that, unlike hemodynamic effects that appear to parallel plasma verapamil concentrations, the protective effects of verapamil against halothane--epinephrine ventricular arrhythmias may not be accurately reflected by plasma verapamil levels and may be significantly present when plasma levels are too low to cause measurable hemodynamic effects.

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); only 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. The differences between the effects of oral and intravenous verapamil on atrioventricular conduction may be the result of stereoselective hepatic inactivation of verapamil's /-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.

Lack of correlation of verapamil plasma level with cumulative protective effects against halothane--epinephrine ventricular arrhythmias.

The effect of verapamil, 0.2 mg/kg i.v. over 30 s, on the amount of epinephrine required to elicit a reproducible ventricular arrhythmia during 0.9% halothane in oxygen anesthesia was investigated in two groups of dogs after three consecutive doses of verapamil given at 90 (group I) and 120 min (group II) intervals, respectively. Verapamil caused a stepwise cumulative increase in the arrhythmogenic dose of epinephrine in both groups despite plasma verapamil levels that declined to low levels (28 and 22 ng/ml, respectively) between doses. Control epinephrine arrhythmogenic doses were 2.89 +/- 0.54 and 2.74 +/- 0.19 microgram/kg/min (mean +/- SEM), respectively, for groups I and II, and rose to 4.58 +/- 0.72 and 4.55 +/- 0.30 microgram/kg/min after the first verapamil dose, to 6.20 +/- 0.74 and 6.13 +/- 0.40 microgram/kg/min after the second verapamil dose, and 8.16 +/- 0.85 and 8.09 +/- 0.95 microgram/kg/min after the third verapamil dose, respectively. All postverapamil epinephrine arrhythmogenic dose values were significantly elevated above control and above the preceding values, although there was no significant difference between the two groups. Changes in heart rate or blood pressure were similar among the three doses of verapamil in each group. These results can be interpreted to indicate that, unlike hemodynamic effects that appear to parallel plasma verapamil concentrations, the protective effects of verapamil against halothane--epinephrine ventricular arrhythmias may not be accurately reflected by plasma verapamil levels and may be significantly present when plasma levels are too low to cause measurable hemodynamic effects.

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.

Systemic availability of oral verapamil and effect on PR interval in man.

1 The plasma levels of verapamil and its major metabolite norverapamil were related to its effect as a Ca-antagonist on atrio-ventricular (AV) conduction, judged from prolongation of the PR interval in six normal volunteers. 2 Intravenous administration (0.1 mg kg-1) was compared to oral administration (120 mg) in each subject. 3 Intravenous verapamil showed a mean distribution half-life (alpha) of 8.5 min and elimination half-life (beta) of 2.0 h. The volume of distribution was about 112.1. Oral dosage gave an elimination half-life of 2.7 h, and a norverapamil half-life which averaged 4.6 h. The bioavailability of the oral dose averaged 22% (17 to 29%). 4 After the oral dose the percentage change in PR interval in the five appropriate subjects correlated significantly with the log plasma verapamil level (r = 0.732), but not with the log plasma norverapamil level (r = 0.078); norverapamil could not be detected after the intravenous dose. One subject developed Wenckebach type second degree AV block after each dose.

Verapamil disposition kinetics in chronic atrial fibrillation.

Verapamil disposition was studied in 12 patients with chronic and fibrillation. After an intravenous bolus of 15 mg plasma concentration was determined and the data fit in a three-compartment model. Model independent parameters were calculated and values for half-life (t 1/2), clearance, and steady-state distribution volume were 6.3 +/- 4 hr, 13.3 +/- 7.7 ml/min/kg, and 4.3 +/- 1.9 l/kg. The model was used to design a multistep infusion scheme, which was employed successfully to achieve predetermined plasma concentrations. Following single oral doses of 120 mg, plasma levels of verapamil and norverapamil were determined. The elimination t 1/2 for verapamil and norverapamil were 8.3 +/- 6.1 and 10.5 +/- 5.6 hr, respectively. The bioavailability of oral verapamil was 35 +/- 16%. During long-term oral therapy the mean verapamil plasma concentration was twice the value predicted from the single-dose studies. This suggests that verapamil may have reduced clearance during long-term oral use.

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.

Clinical utility of plasma verapamil levels in patients with hypertrophic cardiomyopathy

Clinical utility of plasma verapamil levels in patients with hypertrophic cardiomyopathy

Measurement of Verapamil Concentrations in Plasma by Gas Chromatography and High Pressure Liquid Chromatography

Summary: 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 < 0.001). Either assay procedure appears satisfactory for use in measurement of verapamil levels in plasma.

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.

Verapamil plasma levels and ventricular rate response in patients with atrial fibrillation and flutter.

The acute effect of verapamil on the ventricular rate in atrial fibrillation and flutter was studied in 15 patients, 13 of whom had heart rate inadequately controlled with digitalis. Plasma concentrations were measured 5 and 10 min after intravenous doses of 0.075 mg/kg and 0.15 mg/kg verapamil. In 9 patients who were clinically compensated, the 0.075-mg dose alone decreased the ventricular rate to under 100/min (responders); in the remaining 6, who had acute congestive heart failure manifested by orthopnea, rales, and pulmonary congestion, ventricular rates were above 100/min after the 0.075-mg dose (nonresponders). The 6 nonresponders received the 0.15-mg dose 30 min later. In all, the response was greater when plasma drug concentration rose after the high dose, although the rate decrease was smaller than in the 9 compensated patients who received the low dose. These results can be explained by assuming an antagonism of the verapamil effect by sympathetic stimulation in nonresponders.