Plasma Verapamil Levels Research Articles

SP27-1 Risk pathogens and PK/PD of antibiotics

The aim of this work was to compare the suitability of different pharmacodynamic models for PK–PD modeling of verapamil cardiovascular effects in aortic coarctated rats (ACo), a model of renovascular hypertension.A “shunt” microdialysis probe was inserted in a carotid artery of anaesthetized sham-operated (SO) and ACo rats for determination of verapamil plasma concentrations and their effects on blood pressure and heart rate after intravenous application (1 and 3 mg kg− 1). Correlation between verapamil plasma levels and their cardiovascular effects was established by fitting data to a linear, and a conventional and modified Emax model.No differences in verapamil volume of distribution were observed between experimental groups. Whilst clearance increased with dose in SO rats, no differences were found in verapamil clearance in ACo comparing both dose levels. A good correlation between verapamil plasma unbound concentrations and their hypotensive and chronotropic effects was found in both experimental groups using the tested PK–PD models. Although all pharmacodynamic models allowed a precise estimation of verapamil PK–PD parameters, linear and Emax model did not permit an accurate PK–PD parameter estimation for the hypotensive and chronotropic effect, respectively. Conversely, the modified Emax model allows both a precise and accurate estimation of PK–PD parameters for verapamil effects. Although, absolute verapamil blood pressure lowering effect was greater in ACo rats compared with SO rats, no differences were found in verapamil PK–PD parameters estimated for the hypotensive response.Side-by-side comparison of the tested pharmacodynamic models showed that accuracy of PK–PD parameters estimation by using the linear and classical Emax model depends on the magnitude of concentration–effect curve covered in the study. Conversely, the modified Emax model allowed both a precise and accurate estimation of PK–PD parameters, suggesting that the modified Emax pharmacodynamic model is the most suitable for verapamil PK–PD modeling.

Comparison of different pharmacodynamic models for PK–PD modeling of verapamil in renovascular hypertension

Introduction The aim of this work was to compare the suitability of different pharmacodynamic models for PK–PD modeling of verapamil cardiovascular effects in aortic coarctated rats (ACo), a model of renovascular hypertension. Methods A “shunt” microdialysis probe was inserted in a carotid artery of anaesthetized sham-operated (SO) and ACo rats for determination of verapamil plasma concentrations and their effects on blood pressure and heart rate after intravenous application (1 and 3 mg kg − 1 ). Correlation between verapamil plasma levels and their cardiovascular effects was established by fitting data to a linear, and a conventional and modified E max model. Results No differences in verapamil volume of distribution were observed between experimental groups. Whilst clearance increased with dose in SO rats, no differences were found in verapamil clearance in ACo comparing both dose levels. A good correlation between verapamil plasma unbound concentrations and their hypotensive and chronotropic effects was found in both experimental groups using the tested PK–PD models. Although all pharmacodynamic models allowed a precise estimation of verapamil PK–PD parameters, linear and E max model did not permit an accurate PK–PD parameter estimation for the hypotensive and chronotropic effect, respectively. Conversely, the modified E max model allows both a precise and accurate estimation of PK–PD parameters for verapamil effects. Although, absolute verapamil blood pressure lowering effect was greater in ACo rats compared with SO rats, no differences were found in verapamil PK–PD parameters estimated for the hypotensive response. Discussion Side-by-side comparison of the tested pharmacodynamic models showed that accuracy of PK–PD parameters estimation by using the linear and classical E max model depends on the magnitude of concentration–effect curve covered in the study. Conversely, the modified E max model allowed both a precise and accurate estimation of PK–PD parameters, suggesting that the modified E max pharmacodynamic model is the most suitable for verapamil PK–PD modeling.

Influence of famotidine on verapamil pharmacokinetics in rats

The effect of famotidine (4 mg/kg, p.o.) on the kinetic profile of co-administered verapamil (20 mg/kg(-1), p.o.) was studied in the rat. Plasma verapamil levels were collected serially for 12 h and measured using sensitive HPLC method. The pharmacokinetic parameters (elimination half-life, area under the plasma concentration-time curve, peak plasma levels and the times to attain these plasma levels) of verapamil were evaluated in the rat. The results indicate that co-administered famotidine did not significantly alter the pharmacokinetic profile of verapamil in the rat. The present finding suggests that famotidine may safely be co-administered with verapamil but clearly further studies in human subjects are needed to reliably rule out the potential interaction of these two drugs.

HPLC/MS findings in a fatality involving sustained-release verapamil

A fatality involving verapamil, a calcium channel blocker agent, is presented. A 51-year old male ingested 7200 mg of sustained-release (SR) verapamil at T0 and died 40 hours later of refractory, mixed shock and multiorgan failure. The symptoms displayed during hospitalization were quite typical and involved altered consciousness, hypotension, bradycardia, atrioventricular block, metabolic acidosis and renal failure. Verapamil and its primary metabolite, norverapamil, were assayed on eight plasma and two urine samples, successively taken between the admission to the ICU (T0 + 4 hours) and time of death, using an original high-performance liquid chromatography/mass spectrometry (HPLC/MS) procedure with verapamil-d3 as internal standard. Plasma verapamil and norverapamil levels on admission were 0.94 and 1.36 microg/mL, respectively, then verapamil remained practically unchanged throughout the hospitalization (0.85 microg/mL at T0 + 40 hours). The discussion focuses on the detrimental role of SR formulations in overdose, with special emphasis on the risk of pharma-cobezoar development already reported with SR-verapamil. To our knowledge, this is the first report of a verapamil fatality documented by repeated plasma measurements of the drug during the antemortem period.

Simplified reversed-phase HPLC method with spectrophotometric detection for the assay of verapamil in rat plasma

A high-performance liquid chromatographic (HPLC) method was developed for the assay of verapamil in rat plasma. After deproteinization of the plasma sample with an acetonitrile-perchloric acid (8:2) mixture containing dextromethorphan, the internal standard, an aliquot of the supernatant was directly analyzed on a cyanopropylsilane column with methanol-acetonitrile-triethylamine acetate buffer (10:30:60) as the mobile phase and detection at 235 mm. At a flow rate of 1.5 ml min −1, a complete analysis was completed in less than 6 min. The method was linear for verapamil concentrations in the range 0.5–10 μg ml −1 ( r=0.9999). Recoveries for the same drug concentrations from spiked rat plasma ranged from 85.6-93.0% ( n=8). The mean RSD values for intraday and interday assay reproducibility ( n=3) were, in both cases, less than 0.9%. The limit of detectability was about 0.1 μg ml −1. The method was found useful to monitor the plasma levels of verapamil in rats that had received this drug by the nasal, oral and intravenous routes of administration.

Verapamil and Norverapamil Plasma Levels in Infants and Children During Chronic Oral Treatment

Verapamil and norverapamil trough plasma levels were measured in 22 children, aged from 15 days to 17 years, under chronic oral treatment with the drug (mean daily dose +/- SD: 4.9 +/- 1.4 mg/kg) for supraventricular tachyarrhythmias (n = 20) or hypertrophic cardiomyopathy (n = 2). Overall, 67 determinations were available (1 to 11 per patient) and the mean concentration values (+/- SD) were 43.3 +/- 36.4 ng/ml for verapamil and 41.7 +/- 28.9 ng/ml for norverapamil. Verapamil and norverapamil trough concentrations were correlated with the daily dose (p < 0.05) but a wide intersubject variability was present at any given dose and the regression line did not pass through the origin of axes (x-axis intercept: 1.2 mg/kg for verapamil, 0.9 mg/kg for norverapamil). To study the influence of age on drug kinetics, verapamil plasma concentrations corrected by daily dose/kg ([V]/D) and norverapamil to verapamil concentration ratios (N/V) (taken as an index of metabolic clearance) were divided according to age quartiles. The median [V]/D was higher in the first and in the fourth age quartile than in the other two age groups. On the contrary, median N/V ratio increased with age, suggesting that drug metabolism was improving during the first year of life. Four children developed typical adverse reactions to the drug (bradycardia, AV block, hypotension). In one case verapamil plasma levels were definitely high (294 ng/ml). In the other three cases, concomitant factors (such as very young age and heart disease) seem to have contributed to drug toxicity.

Non-invasive haemodynamic study in hypertensive subjects after treatment with verapamil slow release

Aim of this study is to investigate the haemodynamic effects, after the short and long-term antihypertensive treatment. After a wash-out period and a placebo treatment period, 30 hypertensive patients received verapamil SR (slow release, 240 mg o.d.) for 30 days. A significant decrease in systolic and diastolic blood pressure was obtained already 4 h after the first administration of verapamil; it was more evident and persistent throughout the study. No significant changes of heart rate or PR interval in ECG were observed. A significant decrease in total vascular resistances, were observed. A significant decrease in total vascular resistances, both supine and upright, was evident already 4 h after the drug intake and observed throughout the study. The major effect was obtained after one month. No significant changes of cardiac output, cardiac index and stroke volume were recorded. Furthermore, plasma verapamil levels were measured to confirm that the haemodynamic effects are obtained by low drug concentrations. The present study provides evidence that the antihypertensive effect of verapamil, whose mechanism is the reduction of total vascular resistances, is progressive, long acting and achieved by low plasma levels, when slow release formulation is considered.

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.

Steady-state cerebrospinal fluid transfer of verapamil and metabolites in patients with schizophrenia.

Cerebrospinal fluid (CSF) and plasma levels of verapamil and its two metabolites, norverapamil and D-620, were measured in seven patients with schizophrenia under steady-state conditions. Simultaneous sampling of CSF and plasma just before the dose during week 4 of the trial showed that verapamil, norverapamil, and D-620 partition in the CSF and reflect 7%, 5%, and 12% of the corresponding levels in plasma, respectively. There was a significant decrease in the mean unbound fraction of verapamil in schizophrenic patients as compared with normal subjects (0.058 vs. 0.11; p less than 0.001). Estimates of the mean unbound fraction obtained from CSF/plasma verapamil concentrations and the pH partition hypothesis showed excellent agreement with that measured by equilibrium dialysis (0.055 vs. 0.058) in these patients. Although systemic pool protein concentrations in schizophrenic patients were within normal range, an excellent positive correlation was observed between the ratio of the bound/free verapamil concentration and alpha 1-acid glycoprotein levels (r = 0.86; p less than 0.05). Determination and development of correlations between plasma and CSF may enhance our understanding of the central nervous system effects of verapamil.

Failure of episodic high-dose oral verapamil therapy to convert supraventricular tachycardia: A study of plasma verapamil levels and gastric motility

The practicality of administering large oral doses of verapamil tablets to terminate supraventricular tachycardia (SVT) was investigated in 10 patients. A pilot study in four patients howed that unexpectedly low plasma levels (< 40 ng/ml) were obtained 60 minutes after administering 160 mg or 240 mg of verapamil during SVT. Nuclear studies in the six other patients showed that fractional liquid gastric emptying times (T) were significantly prolonged in SVT compared to sinus rhythm (SR), p < 0.05 from T1/3 onward. Further verapamil absorption studies (200 to 360 mg) performed during SVT and SR in five of six patients showed that peak verapamil levels in four patients in SVT were 23% to 71% lower than in sinus rhythm, where they had peaked at >250 ng/ml 60 minutes post verapamil ingestion, and areas under the plasma concentration time curves were 26% to 100% (mean 67%) less in SVT than in SR for all five patients. SVT was terminated by verapamil in one patient after 40 minutes and the rate of SVT was slowed after 90 minutes in two other patients. Thus plasma verapamil levels are considerably reduced during SVT as compared to SR, and changes in gastric emptying are likely a contributing cause. Since SVT was converted to sinus rhythm in only 1 of 10 patients within 1 hour, large oral doses of verapamil tablets appear unsatisfactory for the episodic treatment of SVT.

Verapamil and adriamycin in the treatment of drug-resistant ovarian cancer patients.

Eight patients with refractory ovarian cancer were treated on a pilot protocol of verapamil plus Adriamycin (Adria Laboratories, Columbus, OH). This trial was based on our previous laboratory studies which demonstrated that Adriamycin resistance in human ovarian cancer cell lines could be partially reversed by exposure of the cells to high concentrations of verapamil (3,000 ng/mL). Patients were treated in an intensive care unit with continuous cardiovascular monitoring. The dose of verapamil was escalated in each patient until hypotension or heart block developed, and this dose was maintained for 72 hours. Adriamycin (50 mg/m2) was infused over 24 hours during the second day of the verapamil infusion and verapamil alone was administered on the third day in an effort to block efflux from drug-resistant cells. This intensive approach led to a median plasma verapamil level of 1,273 ng/mL (range, 720 to 2,767). However, the high infusion rates of verapamil (9 micrograms/kg/min) required to achieve these plasma levels produced an unacceptable degree of cardiac toxicity. Two patients developed transient atropine-responsive complete heart block and four patients developed transient congestive heart failure with increases in pulmonary capillary wedge pressure. There was no evidence that the noncardiac toxicities of Adriamycin were enhanced by verapamil. There were no objective responses to therapy. Future studies should use less cardiotoxic calcium channel blockers that can be safely administered to produce the plasma levels required for in vitro sensitization of drug resistant cells.

The cardiovascular and adrenergic actions of verapamil or diltiazem in combination with propranolol during halothane anesthesia in the dog.

Continuous infusions of verapamil and diltiazem were established in halothane-anesthetized dogs (1.15-1.35% end tidal concentration) with or without a concomitant propranolol infusion to investigate changes: in cardiovascular function, in reflex activation as reflected in circulating catecholamine levels, and in the chronotropic response to the exogenously administered beta agonist, isoproterenol. Verapamil plasma levels of approximately 100 and 250 ng X ml-1, diltiazem plasma levels of approximately 140 and 325 ng X ml-1, and propranolol levels of approximately 70 ng X ml-1 were tolerated individually in the presence of halothane, although atrioventricular conduction was prolonged in the verapamil and diltiazem groups. Catecholamine levels were increased in the high verapamil group. However, when propranolol was combined with the lower levels of verapamil or diltiazem, the result was decreased heart rate, blood pressure, left ventricular maximum rate of tension development (dP/dt), and cardiac index with increased systemic vascular resistance. When the attempt was made to proceed to the increased plasma levels of verapamil or diltiazem in the presence of propranolol, 6/6 animals in the verapamil-propranolol group and 4/6 animals in the diltiazem-propranolol group were unable to maintain a mean arterial blood pressure of greater than 50 mmHg, and many developed 2 degrees or higher heart block.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. IV. Chronically administered oral verapamil and halothane, enflurane, and isoflurane.

Dogs were chronically instrumented to measure aortic and left atrial blood pressures, left ventricular maximal rate of tension development (dP/dt), cardiac output, and carotid, coronary and renal blood flows. Measurements were taken with the animals awake and during steady-state low and high concentrations of halothane (1.2%, 2.4%), enflurane (2.4%, 4.0%), and isoflurane (1.6%, 3.0%) with and without at least 2 weeks of oral verapamil, 120 mg, three times per day. Plasma verapamil levels varied widely, with means of 500-700 ng X ml-1 in awake animals and lower (300-400 ng X ml-1) at the time of hemodynamic measurements during anesthesia. Chronic oral verapamil in awake dogs produced predominantly tachycardia. The hemodynamic effects of low-dose halothane and isoflurane before and after oral verapamil were unchanged except for decreased renal blood flow after oral verapamil and no coronary vasodilation nor tachycardia. However, left atrial pressure was increased and cardiac output and coronary blood flow were decreased by low concentrations of enflurane with oral verapamil compared to without. The combination of oral verapamil with low (clinical) doses of enflurane was more depressant to the cardiovascular system of healthy dogs than was the combination of verapamil and halothane or isoflurane.

Combined Effects of Verapamil and Isoflurane on Coronary Blood Flow and Myocardial Metabolism in the Dog

The effects of three different plasma levels of verapamil on coronary hemodynamics and myocardial metabolism in the presence of 1.61 +/- 0.05% end-tidal concentration of isoflurane (mean +/- SEM) were studied in a canine model, using a thermodilution coronary sinus catheter to measure coronary sinus blood flow and pressure and to provide coronary sinus plasma samples. A control group receiving only isoflurane was also studied (n = 6). Plasma arterial verapamil levels of 55 +/- 7 (n = 6); 134 +/- 7 (n = 10); and 301 +/- 37 ng X ml-1 (n = 5), were achieved by a loading dose followed by a continuous infusion for 30 min. The only changes with time in the isoflurane group were decreases in left ventricular maximum rate of tension development (dP/dt) and left ventricular stroke work index compared with control after 90 min without changes in myocardial oxygen balance. The low plasma verapamil level caused reductions in heart rate, mean and diastolic arterial pressure, and left ventricular dP/dt without changes in myocardial oxygen supply or myocardial metabolism. Intermediate verapamil concentrations produced a transient initial increase in heart rate and a reduction in stroke volume index. With the intermediate and the highest levels of verapamil, mean and diastolic arterial pressure, left ventricular dP/dt, and cardiac index were decreased. An increase in arterial norepinephrine plasma levels was seen in the intermediate and the highest levels of verapamil; however, a transient coronary vasodilation occurred without changes in myocardial oxygen balance. Significant prolongation of the PR interval was observed in all verapamil groups, with second or third degree heart block in some of the higher-dose animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Twice-Daily Administration of Oral Verapamil in the Treatment of Essential Hypertension

The antihypertensive effect of twice-daily administration of verapamil hydrochloride was evaluated in 21 adult patients with mild to moderate essential hypertension. Following four weeks of placebo therapy, verapamil was given for four weeks with a treatment goal of sitting diastolic blood pressure (BP) of less than 90 mm Hg, or to a maximum dose of 160 mg twice daily. Sitting and standing BPs, heart rate, and verapamil plasma levels were determined weekly, ten to 12 hours post dose. At the maximal dose (mean, 154 +/- 19.2 mg), heart rate was not affected, side effects were minimal, and sitting diastolic BP was significantly reduced from placebo baseline, with 12 of 21 patients having a fall in sitting diastolic BP of 10 mm Hg or more or less than 90 mm Hg. A trough verapamil plasma level of greater than 80 ng/mL was associated with a good hypotensive response. These data indicate the safety and utility of twice-daily verapamil administration for the treatment of essential hypertension and suggest the value of obtaining verapamil plasma levels as a guide to dosage determination.

Kinetics and dynamics of calcium entry antagonists in systemic hypertension

The calcium-entry antagonists verapamil, diltiazem and nifedipine (and their analogs) are all eliminated by hepatic metabolism and the rate of disposition is dependent on the rate of liver blood flow. During long-term administration, the profound hemodynamic effects of these agents result in changes in hepatic blood flow in association with decreases in arterial pressure, and either increases or decreases in measured cardiac output. This alters the drug's rate of delivery to the site of elimination, with concomitant changes in systemic clearance and a prolongation in elimination half-life. The pharmacokinetic data determined after initial single doses, therefore, only suggest the kinetic characteristics during long-term administration, because this profile depends on the drugs' sustained effects on liver blood flow. The elimination half-life of all 3 prototypical calcium antagonists is probably significantly prolonged during long-term dosing with clinically effective regimens. Patients with hepatic disorders in which liver blood flow is altered, such as cirrhosis, have profound changes in pharmacokinetics with both short- and long-term administration of verapamil and are likely to have similar changes with other calcium antagonists. During short-term administration, the plasma concentrations of verapamil and other calcium antagonists relate closely to the observed hemodynamic (and electrophysiologic) effects. With long-term administration, however, these correlations are much less impressive. When given in tablet form, nifedipine lowers blood pressure roughly in proportion to plasma levels between 20 and 200 ng/ml; verapamil plasma levels between 80 and 800 ng/ml are associated with antihypertensive efficacy. Plasma level measurements, therefore, are not of clinical importance as guides to antihypertensive therapy, except to identify noncompliance or abnormal patterns of drug handling.

Verapamil Does Not Alter Succinylcholine-Induced Increases in Serum Potassium during Halothane Anesthesia in Normal Dogs

Six dogs were studied to determine whether verapamil pretreatment exacerbates the increase in serum potassium levels associated with succinylcholine. Dogs were anesthetized with halothane, 1.26 +/- 0% (mean +/- SEM; end tidal). Arterial blood-gas tensions, blood pressure, heart rate, temperature, and serum potassium levels were measured. Each dog underwent control and experimental studies separated by seven days. In the experimental study, a 0.15 mg/kg bolus of verapamil was followed by a 4.0 micrograms X kg-1 X min-1 continuous infusion of verapamil. Normal saline was used in the control study. Succinylcholine, 1 mg/kg bolus, was given 10 min after the initial saline or verapamil bolus. Vital signs again were measured 1, 3, 5, 10, and 15 min after succinylcholine, and plasma verapamil levels were measured 8 and 15 min after verapamil administration. Serum potassium concentrations increased from 3.9 +/- 0.2 to 5.0 +/- 0.2 mEq/L in control studies and from 3.7 +/- 0.2 to 4.8 +/- 0.3 mEq/L in animals pretreated with verapamil. Verapamil pretreatment does not alter the increase in serum potassium induced by succinylcholine in normal dogs.

Pharmacokinetics of verapamil in patients with renal failure.

The pharmacokinetics of verapamil was studied in patients with end-stage chronic renal failure and in normal subjects after i.v. injection of 3 mg and a single oral dose of 80 mg. Plasma levels of verapamil and its active metabolite norverapamil were measured by HPLC. After i.v. injection, the terminal phase half-life and total plasma clearance of verapamil in both groups were similar. Haemodialysis did not change the time course of plasma verapamil levels after i.v. administration. After a single oral dose, the plasma levels of verapamil and norverapamil in both groups of subjects were similar. Subsequently, normal volunteers and patients with renal failure were treated for 5 days with oral verapamil 80 mg t.d.s. There was no difference between the 2 groups of subjects in the trough and peak levels of verapamil or of norverapamil. Intravenous and oral administration of the calcium channel blocking agent had similar effects on blood pressure, heart rate and the PR-interval in the electrocardiogram in both groups. The study demonstrated that the disposition of verapamil was similar in normal subjects and in patients with renal failure.

Rapid gas—liquid chromatographic method for plasma verapamil level determination

Verapamil is a newly marketed antiarrhythmic drug. It has a significant presystemic elimination when administered orally and, therefore, intravenous therapy is often recommended. Optimum therapeutic effect is obtained when verapamil plasma concentrations are between 100 and 400 ng/ml. Several chromatographic procedures for the determination of verapamil in biological fluids have been described in the literature [l-11]. Some of the procedures have also quantitated verapamil metabolites [l, 6, 7 1. The highperformance liquid chromatographic (HPLC), as well as the gas-liquid chromatographic (GLC) procedures are sensitive but require lengthy and tedious multiple extraction steps especially when the metabolites are quantitated. This report describes a rapid, sensitive and accurate GLC procedure with thermionic specific detection for the determination of verapamil in dog plasma. This procedure also has a potential use in controlled clinical pharmacokinetic studies of this antiarrhythmic agent in humans.

Plasma verapamil levels and exercise performance.

Our study in 10 patients with stable, exercise-related angina under a double-blind, placebo-controlled protocol correlated plasma verapamil levels after single oral doses of 120 and 240 mg and exercise performance. Plasma verapamil levels peaked at 2 hr in seven patients and 4 hr in three patients and declined thereafter, with a mean plasma t1/2 of 3.22 and 4.54 hr after the 120- and 240-mg dose. Despite the relatively short t1/2s, total exercise duration and time to onset of angina and S-T segment depression were longer than placebo values for 4 hr after the 120-mg dose and for 8 hr after the 240-mg dose. Percentage increase in treadmill time and log of plasma verapamil levels correlated. All patients with plasma levels above 100 ng/ml had at least a 50% increase in exercise duration. Thus measurement of plasma verapamil levels are useful in patients who fail to respond to a dose of verapamil. If the level is below 100 ng/ml, increasing the dose of verapamil may improve response.