Single Dose Of Verapamil Research Articles

Interaction potential of Carmegliptin with P-glycoprotein (Pgp) transporter in healthy volunteers

Objective:The primary objective of this study was to investigate the interaction potential of carmegliptin with P-glycoprotein transporter in vitro and in vivo. A secondary objective was to investigate the safety and tolerability of carmegliptin alone or co-administered with verapamil.Research design and methods:The inhibition potential of carmegliptin was tested in vitro and in a non-randomized open-label study in 16 healthy male volunteers. On day 1 a single dose of carmegliptin (150 mg) was given, followed by a single dose of verapamil (80 mg) on day 7, on day 10 a single dose of carmegliptin (150 mg) together with verapamil (80 mg t.i.d.), and verapamil (80 mg t.i.d.) on days 11–14. Finally, on day 15 a single dose of 150 mg carmegliptin together with 80 mg t.i.d. verapamil was administered. Pharmacokinetic and safety parameters were assessed.Results:Carmegliptin showed in vitro a low cell permeability and was a good substrate for human MDR1 cells. When carmegliptin was taken with verapamil, the mean exposure and Cmax to carmegliptin increased by 29% and 53%, respectively. Increases in exposure were slightly greater on the sixth day of verapamil dosing than on the first day. Verapamil Cmax was 17% lower on average when given with carmegliptin than when verapamil was taken alone, and similar trends were apparent in corresponding norverapamil pharmacokinetics. All reported adverse events (n = 28) were mild in intensity, and verapamil had no apparent effect on the pattern or incidence of events.Conclusions:In vitro, carmegliptin is a substrate but not an inhibitor of human Pgp. Consistently, the co-administration of carmegliptin with verapamil altered the pharmacokinetics of carmegliptin slightly and moderately increased the exposure. Peak exposure of verapamil and its metabolite norverapamil tended to be lower when co-administered with carmegliptin. The combination of carmegliptin and verapamil was generally well tolerated. Although the observed overall changes in pharmacokinetics were small and dose adjustments in clinics are currently not expected, co-administration of carmegliptin with Pgp inhibitors should be carefully monitored in future clinical trials.

Effects of verapamil on the pharmacokinetics and hepatobiliary disposition of fexofenadine in pigs

The pharmacokinetics (PK) of fexofenadine (FEX) in pigs were investigated with the focus on exploring the interplay between hepatic transport and metabolism when administered intravenously (iv) alone or with verapamil. The in vivo pig model enabled simultaneous sampling from plasma (pre-liver, post-liver and peripheral), bile and urine. Each animal was administered FEX 35mg iv alone or with verapamil 35mg. Plasma, bile and urine were analyzed with liquid chromatography–tandem mass spectrometry. Non-compartmental analysis (NCA) was used to estimate traditional PK parameters. In addition, a physiologically based pharmacokinetic (PBPK) model consisting of 11 compartments (6 tissues +5 sample sites) was applied for mechanistic elucidation and estimation of individual PK parameters. FEX had a terminal half-life of 1.7h and a liver extraction of 3%. The fraction of the administered dose of unchanged FEX excreted into the bile was 25% and the bile exposure was more than 100 times higher than the portal vein total plasma exposure, indicating carrier-mediated (CM) disposition processes in the liver. 23% of the administered dose of FEX was excreted unchanged in the urine. An increase in FEX plasma exposure (+50%) and a decrease in renal clearance (−61%) were detected by NCA as a direct effect of concomitant administration of verapamil. However, analysis of the PBPK model also revealed that biliary clearance was significantly inhibited (−53%) by verapamil. In addition, PBPK analysis established that metabolism and CM uptake were important factors in the disposition of FEX in the liver. In conclusion, this study demonstrated that CM transport of FEX in both liver and kidneys was inhibited by a single dose of verapamil.

The Effect of Licorice Drink on the Systemic Exposure of Verapamil in Rabbits

The effect of licorice root drink (aqueous extract of Glycyrrhiza glabra Fabaceae) on plasma concentration of verapamil, using rabbits as animal model, was investigated. Two groups of locally inbred New Zealand male rabbits were used. The first group was given a single dose of licorice drink (4 ml/kg body weight) concomitantly with 30 mg/kg verapamil, and the second group was given a daily dose of licorice drink (4 ml/kg body weight) for two weeks, with single doses of verapamil on days, 7 and 14. Single dose treatment resulted in a nonsignificant decrease in mean C(max) by 33.2% (P = 0.41), but in a significant decrease of AUC(0-24) and AUC(0-infinity) by 60.5% and 63.6%, respectively (P = 0.01). First period of multiple dose treatment study (7 days), resulted in a significant reduction in mean C(max), AUC(0-24) and AUC(0-infinity) by 55.0%, 47.0% and 45.7%, respectively (P = 0.02, 0.03 and 0.03, respectively). A more pronounced effect was seen at second period of multiple dose treatment study (14 days), where the corresponding decrease was, 85.4%, 76.8% and 73.3%, respectively (P < 0.01). Mean T(max) was significantly increased 4.2-fold over control period at day 14 of multiple dose study (P = 0.02). In conclusion, licorice root drink decreased verapamil systemic exposure both after single dose and after daily doses for 14 days.

Verapamil-associated cardiogenic shock in a 71-year-old man with myasthenia gravis: a case report

IntroductionMyasthenia gravis is a rare neuromuscular disorder associated with a reduction in the availability of acetylcholine receptors at the post-synaptic membranes of skeletal muscles. This is caused by the production of anti-acetylcholine receptor antibodies at the neuromuscular junction due to an autoimmune insult, leading to a compromised neuromuscular transmission. Verapamil can influence, in a dose-dependent fashion, the neuromuscular transmission in myasthenia gravis.Case presentationWe report a 71-year-old Caucasian man with myasthenia gravis suffering from a cardiogenic shock following a single dose of verapamil. The patient had uncontrolled atrial fibrillation with a heart rate of 120 beats/min. Atenolol 100 mg was started. The next day, verapamil SR 240 mg was started. Two hours after the first dose of verapamil, the patient complained of weakness and dyspnea with signs of shock; his blood pressure was 70/50 mm Hg and heart rate at 101 beats/min. An echocardiogram showed diffuse hypokinesis of both ventricles with an ejection fraction of 20%. Cardiac catheterization was performed and coronary arteries appeared without significant stenosis, but there was a diffuse hypokinesis. Verapamil was stopped and the patient received intravenous glucagon and calcium chloride. Both the anti-acetylcholine receptor and anti-striated muscle antibodies tested positive. A few hours later, another echocardiogram showed an improvement in the ventricular function, which returned to normal five days later.ConclusionCaution is needed when administering verapamil to patients with myasthenia gravis, especially when the anti-acetylcholine receptor and anti-striated muscle antibodies titres are positive.

Impact of food on the pharmacokinetics and electrocardiographic effects of sustained release verapamil in normal subjects

To evaluate the impact of food on the pharmacokinetics and electrocardiographic effects of sustained release (SR) verapamil tablets, 9 healthy men each received 3 single doses of verapamil in a randomized, crossover manner: 10 mg of intravenous verapamil, 240 mg SR verapamil on an empty stomach, and 240 mg SR verapamil with a standardized meal. PR intervals and racemic verapamil serum concentrations were measured serially over 30 hours after administration. The time to peak concentration was longer (7.5 ± 3.0 vs 4.4 ± 2.3 hours), resulting in a lower peak verapamil serum concentration (118 ± 43 vs 175 ± 50 ng/ml) when SR verapamil was administered with food (p < 0.05). Food tended to decrease the bioavailability of SR verapamil (34 ± 12 vs 49 ± 14%), although this difference did not reach statistical significance (p = 0.065). Precipitous or exaggerated release of verapamil from the SR tablet was not observed in any subject during the fasting state. Prolongation of the PR interval paralleled these alterations in serum concentration. The maximal change in the PR interval was greater (21 ± 8 vs 14 ± 5%; p < 0.05) when SR verapamil was given in the fasting state. Although an exaggerated verapamil release or effect was not observed, food significantly altered the absorption and electrocardiographic effects of a single dose of SR verapamil. Manipulation of the administration condition may be helpful in achieving desired outcomes.

Differences in response to single dose and steady-state therapy with verapamil in stable angina

Ten patients with stable effort angina were studied in a randomized double-blind and placebo-controlled trial to compare the antianginal efficacy of “acute” and “chronic” (after reaching a steady-state level) treatment with verapamil. Efficacy was assessed by exercise testing after a 120 mg single-dose and at the end of a seven-dose course of 120 mg of verapamil given thrice daily. Three daily exercise tests were performed the first, second and fifth day of the study protocol at 8, 12 and 16 hours. Eight hours after the last dose was given, exercise time increased by 54 ± 30 sec after a single-dose of verapamil and by 156 ± 31 sec after seven-doses of verapamil ( P < 0.05 as compared to single-dose verapamil). The time to 1 mm depression of the ST segment increased by 30 ± 20 sec after a single-dose of verapamil and by 66 ± 28 sec after seven-doses of verapamil ( P < 0.01 as compared to single dose verapamil). Six of the ten patients became free from angina on treadmill exercise after a seven-dose course of verapamil, but only one patient became free from angina after acute testing with a single-dose of verapamil. It is concluded that several doses of verapamil are required to achieve an optimal anti-ischemic effect, as suggested by the pharmacodynamic properties of this drug. Once steady-state is achieved, the effects of verapamil remain for at least 8 hours, so that an administration schedule of three times daily protects the patient for a 24-hour period.

Influence of pH changes on the actions of verapamil on cardiac excitation-contraction coupling

Langendorff preparations of Sprague-Dawley rat hearts were perfused with calcium-free Krebs solution of pH 7.48 (control), 7.26 (acidosis) or 7.69 (alkalosis) containing either adrenaline or potassium. The responses of the force of contraction, coronary perfusion pressure and heart rate to graded doses of calcium preceded by a single dose of verapamil were measured. Contractile responsiveness to calcium was reduced during acidosis in both adrenaline- and potassium-stimulated hearts but was increased or reduced during alkalosis with adrenaline- or potassium stimulation, respectively. The efficacy of verapamil as a calcium antagonist increased during acidosis or alkalosis in both adrenaline- and potassium-stimulated hearts. In conclusion, acidosis or alkalosis inhibits potassium-stimulated contractions of the heart and enhances the effects of verapamil on potassium- and adrenaline-mediated contractions. Acidosis inhibits and alkalosis enhances adrenaline-stimulated contractions.

Evaluation of potential pharmacodynamic and pharmacokinetic interactions between verapamil and propranolol in normal subjects.

1. Potential pharmacodynamic and pharmacokinetic interactions between verapamil and propranolol were evaluated in two double-blind, randomised, balanced, crossover studies employing the same six healthy males. 2. The first study examined the effect of repeated propranolol administration on the pharmacodynamics and pharmacokinetics of verapamil after single oral and intravenous doses. The second explored the pharmacodynamics and pharmacokinetics of verapamil and propranolol alone and in combination after single and repeated oral doses. 3. The magnitude of the prolongation of PR interval induced by oral and intravenous verapamil was not affected by pre-treatment with propranolol. When verapamil and propranolol were co-administered as single doses, effects on PR interval were additive but, following repeated doses, a trend towards greater than additive prolongation was seen. The arithmetic sum of the effects of the two drugs was 23% (95% C.I. 8-38%) but the measured increase after the combination was 40% (95% C.I. 26-54%). 4. The extent of reduction in heart rate and blood pressure at rest and after exercise following repeated doses of propranolol was not influenced by single oral or intravenous doses of verapamil. The heart rate and blood pressure responses to single and repeated oral doses of verapamil and propranolol in combination were significantly greater than those after either drug alone and approximated to the arithmetic sum of the individual responses. 5. Although repeated administration of propranolol reduced hepatic blood flow as assessed by indocyanine green clearance, there was no evidence of an interaction between the drugs at this level. 6. The pharmacokinetics of verapamil and norverapamil were not significantly affected by prior propranolol. After single doses of verapamil and propranolol in combination, the maximum plasma concentration of propranolol was increased and the oral clearance of verapamil reduced. No pharmacokinetic interaction was observed after repeated doses. 7. These findings provide little evidence of a pharmacodynamic or pharmacokinetic interaction between verapamil and propranolol in normal subjects. Most of the haemodynamic responses to these drugs in combination can be explained by additive drug effects but an interaction affecting AV conduction after repeated doses cannot be excluded. The minor pharmacokinetic interaction between the drugs is unlikely to be relevant to the pharmacodynamic changes.

The Pharmacokinetics of Racemic Verapamil in Patients with Impaired Renal Function

The pharmacokinetics of verapamil were studied in patients with renal failure who were undergoing maintenance hemodialysis and in normal subjects after an IV infusion of 10 mg and a single oral dose of 120 mg. Plasma levels of verapamil and its active metabolite, norverapamil, were analyzed by a sensitive and specific HPLC procedure. Severe renal failure requiring hemodialysis did not change the time course of verapamil and norverapamil plasma concentrations after either the IV or oral dose. The terminal elimination rate constant, clearance, volume of distribution, and bioavailability of verapamil were not significantly different between the two groups of subjects. In addition, the apparent maximal plasma concentration, terminal elimination rate constant, and area under the curve for norverapamil were similar in patients with renal failure and normal subjects. The study showed that the plasma disposition of verapamil and norverapamil was not affected in patients with impaired renal function. Furthermore, this study does not indicate that any change in dosage is necessary when single doses of verapamil are administered to patients with renal failure.

Sex and age differences in the effect of verapamil on rat cardiac function

The author reports that a relatively high dose of verapamil produces sex-related cardiac effects, especially on the conducting system in adult rats. A single dose of verapamil (0.5-1 mg/kg, i.v.) caused a marked AV block and a reduction in heart rate to 50-60% in adult males, but not in females. There was no sex difference in the hypotensive effect of verapamil. At 3, 5 or 7 weeks of age, verapamil (1 mg/kg, i.v.) induced a 10-20% reduction of the heart rate without AV block in both male and female rats. In 8-week-old male rats, the reduction in the heart rate became apparent, and AV block appeared following a single i.v. injection of verapamil. The adult pattern in cardiac response to verapamil was observed at 11 weeks of age and afterward. Castration in adult male and female rats resulted in an intermediate pattern of the response to verapamil in intact male and female rats. Acute treatment with testosterone (20 mg/kg, s.c.) in castrated male and female rats induced a decrease in the basal heart rate and increased the cardiac responsiveness to verapamil in castrated female rats. Estradiol-17 beta failed to alter the responsiveness of castrated rats to verapamil. These results suggest that testosterone may play a role in the sex difference of the cardiac responses to verapamil in rats.

Verapamil effects on left ventricular performance in patients with congestive heart failure studied with echocardiography before and after cardiac surgery.

Cardiac effects of a single dose of verapamil was studied with digitalization of M-mode echocardiograms in 6 patients before and after surgery, along with pharmacological examinations. Corresponding to the different distribution volume and excretion pre- and postoperatively, the cardiodepressive effect on the contraction of the left ventricle was more pronounced and lasted longer postoperatively. Probably due to initial reduction of peripheral resistance, there was an initial improvement of ventricular contractility indices. Obviously depending on serum concentration, maximal cardiodepression occurred at 35-40 ng/ml, and no effect could longer be found as the values reached 20 ng/ml, pre- as well as postoperatively.

Effects of verapamil on thermal trauma depressed cardiac output in the anaesthetized dog

Thermal trauma to the anaesthetized dog results in an immediate, significant decrease in cardiac output, an increase in peripheral resistance and no significant change in mean arterial blood pressure. The administration of verapamil 1.0 mg/kg by slow intravenous injection produced a rapid increase in cardiac output and a decrease in peripheral resistance. Mean arterial pressure fell and returned to or nearly to pre-injection values within 30 min. The duration of the increase in cardiac output after a single dose of verapamil was approximately 1.5-2.0 h. Administration of a second 0.5 mg/kg dose of verapamil, 1.5 h after the first dose, increased cardiac output and decreased peripheral resistance. After the second dose of verapamil, cardiac output was significantly greater and peripheral resistance was significantly less than in untreated animals for at least 2 h.

Electrophysiologic effects of verapamil in children.

The electrophysiologic effects of verapamil, a slow channel blocker, were investigated during diagnostic cardiac catheterization in 24 children premedicated with lytic cocktail. The ages ranged from 50 days to 12 years. Twenty had congenital and 4 had rheumatic heart disease. Surface EKG, high intra-atrial and His bundle electrograms were obtained in all before and 5 min after a single dose of verapamil (0.15 mg/Kg, max 5 mg iv). In 14 cases complete electropysiologic studies were performed using the atrial pacing and extrastimulus technique. Due to variability of the resting heart rates and the effect of cycle length on refractory periods each paced with identical S1-S1 interval before and after verapamil, thus allowing each case to serve as his own control. Verapamil prolonged the corrected AH interval in all (mean +/- SD; from 116 +/- 37 to 152 +/- 41 msec, p less than 0.01) and shortened the HV interval in 15/24 (mean +/- SD: from 55 +/- 13 to 47 +/- 9.9 msec, p less than 0.05). The effective and functional refractory periods of the total conduction system, the AV node (ERPAVN) and atrium (ERPA) increased significantly in 10/14. The most profound effect was on ERPAVN and ERPA (25.54 +/- 29 and 19.27 +/- 21.81 percent mean percent increase +/- SD respectively, p less than 0.01 and p less than 0.02). Our findings show that verapamil prolongs the effective and functional refractory periods of the cardiac conduction system with maximal effects on the AV node, thus suggesting the mechanism of its effectiveness in the treatment of reentrant supraventricular arrhythmias.