Plasma Concentrations Of Diltiazem Research Articles

Comparative Bioavailability of Diltiazem in Prolonged-Release Oral Preparations

This study was conducted to compare the bioavailability of two prolonged-release pharmaceutical forms containing 300 mg of diltiazem. The test formulation is a new design of tablets with a hydrophilic matrix, and the reference formulation is capsules containing prolonged liberation microgranules, in the same dose, that are commercially available in the pharmaceutical market. Diltiazem plasma concentrations were analyzed by high-performance liquid chromatography (HPLC), which involves solid-phase extraction for plasma sample preparation. Twelve healthy volunteers participated in the study, which had a single-dose, two-treatment, two-sequence-crossover, randomized design. The preparations were compared using pharmacokinetic parameters such as the area under the plasma concentration-time curve AUC(0–36), peak plasma concentration Cmax, and Cmax/AUC(0–36) ratio as a measure for the absorption rate. No statistically significant difference was observed for any of the parameters, and the 90% confidence intervals calculated for the ratio of the logarithmically transformed AUC(0–36) and Cmax/AUC(0–36) values of both formulations were within the bioequivalence limit of 0.80–1.25. Moreover, an in vitro study of dissolution according to USP 23 was conducted, and the in vitro parameters were calculated.

No effect of diltiazem on the hepatic clearance of indocyanine green in the rats.

In order to investigate the effect of the pretreatment with various doses of diltiazem (DTZ) on the pharmacokinetics of indocyanine green (ICG) at steady state, especially the hepatic blood clearance due to the change of hepatic blood flow, the following experiments were carried out with ICG, a hepatic function test marker, not metabolized in liver and only excreted in bile. The intravenous bolus injection (3,780 micrograms/kg) and the constant-rate infusion (10,100 micrograms/kg/hr) of ICG into the left femoral vein were made in order to check the steady-state plasma concentration (Css of 10 micrograms/ml) of ICG at 20, 25 and 30 min. Following a 90-min washout period, the intravenous bolus injection (108, 430, 860 and 1,720 micrograms/kg) and the constant-rate infusion (108, 433, 866 and 1,730 micrograms/kg/hr) of DTZ into the right femoral vein were made and the achievement of the steady-state plasma levels (Css of 50, 200, 400 and 800 ng/ml) of DTZ were conformed at 60, 70 and 80 min. During the steady state of DTZ, the intravenous bolus injection (3,780 micrograms/kg) and the constant-rate infusion (10,200 micrograms/kg/hr) of ICG into the left femoral vein were made and also the steady-state plasma concentration of ICG was checked at 20, 25 and 30 min. The plasma concentrations of DTZ and ICG were determined using a high performance liquid chromatographic technique. At the steady state, the hepatic blood clearance of ICG was obtained from the plasma concentration and blood-to-plasma concentration ratio (RB) of ICG. The pretreatment with various doses of DTZ did not influence the plasma concentrations, RB and plasma free fraction (fp) of ICG. So the hepatic blood clearance of ICG was independent of concentration of DTZ. The hepatic blood clearance of ICG could be affected by both hepatic blood flow and hepatic intrinsic clearance. But there was no change of the hepatic blood clearance of ICG between the control and the DTZ-pretreated rats in this study. So it may be suggested that DTZ does not influence hepatic blood flow.

Pharmacokinetics and hypotensive effect of diltiazem in rabbits after a single intravenous administration: effect of phenobarbital.

Metabolism of the widely used calcium antagonist diltiazem (DTZ) is an important contributing factor to its therapeutic effects. In order to study the effects of CYP3A induction on the pharmacokinetics and haemodynamic effect of DTZ, it was administered as a single 5 mg/kg dose i.v. to two groups of New Zealand white rabbits (n = 6 in each group). Prior to the injection, one of the groups received phenobarbital 20 mg/kg s.c. two times a day for 3 days to ensure CYP3A induction, and the other received normal saline. A third group of animals (n = 6) received neither phenobarbital nor DTZ, and served as the control. Blood samples, systolic and diastolic blood pressure (SBP and DBP), and heart rate (HR) recordings were obtained from each rabbit up to 7 h, and urine samples for 48 h post-dose. Plasma concentrations of DTZ and its metabolites were determined by HPLC. The results showed that phenobarbital increased the Cl and Vdss of DTZ from 24 +/- 14 to 51 +/- 4.9 ml/min/kg and from 1.9 +/- 1.2 to 3.8 +/- 0.7 l/kg, respectively (p < 0.05). It also decreased the plasma concentrations of DTZ and all the measured metabolites in this study. Both phenobarbital and DTZ decreased SBP and DBP significantly without affecting the HR.

Cardioprotective effects of diltiazem during acute rejection on heterotopic heart transplants.

In the presence of severe rejection, cardiac allograft perfusion has been shown to be impaired. Since a functionally reversible vasoconstrictor component has been identified in this condition and rejection does not reverse if ischemia does not, we hypothesized that diltiazem may be beneficial in this condition. Experiments were performed on dogs with heterotopic heart transplants and chronic instrumentation for the assessment of allograft perfusion. Two groups of cardiac allograft recipients were studied: untreated recipients and recipients treated with the calcium antagonist diltiazem (180 mg twice daily, orally). Allograft blood flow was monitored daily along with plasma diltiazem levels. The lymphoproliferative response to mitogens was studied at selected intervals until terminal rejection. Contractile function of the graft was assessed daily by palpation. Without immunosuppression, terminal rejection was observed within 7 days. Rejection was confirmed by histology; cellular infiltration and myocyte necrosis were present in all cardiac allografts but to a significantly lesser degree in diltiazem-treated recipients. The mean blood flow of heterotopically implanted hearts was in the range of 35-50 ml/min, which decreased steadily in untreated recipients. In contrast, significant improvement of allograft perfusion was observed in diltiazem-treated recipients at days 4-6 after transplantation. Diltiazem also significantly attenuated mitogen-induced lymphocyte proliferation at peak sensitivity (2 days after transplantation). Diltiazem plasma concentrations were in the therapeutic range (30-60 ng/ml) before and after cardiac transplantation. Results of the present study demonstrate beneficial effects of diltiazem in the course of severe cardiac rejection. Such findings support its use during rejection when maintenance of graft blood flow and myocyte protection may be important for myocardial function and viability.

Effect of phenobarbital pretreatment on the pharmacokinetics and metabolism of diltiazem in rats.

In order to study the effect of cytochrome P-450 isozyme induction on the pharmacokinetics and metabolism of diltiazem (DTZ), male Sprague-Dawley rats weighing 300-600 g were randomly assigned to two groups. The enzyme induction group (n = 4) received phenobarbital 60 mg/kg i.p. once daily for 4 days, whereas the control group (n = 6) received normal saline for the same duration. Each rat then received a single oral dose of DTZ in solution (20 mg/kg). Blood samples (0.5 ml) were collected from each rat via an implanted polyethylene catheter (0.040" i.d.) in the right carotid artery at 0 (just before dosing), 0.25, 0.5, 1,2,3,4,6,8 and 10 h post-dose. Arterial plasma concentrations of DTZ and its metabolites M(A), M1, M2, M4 and M6 were determined by HPLC. Pharmacokinetics parameters were calculated using non-linear regression. The results showed that both mean Cmax and AUC of DTZ were lower (871.6 vs 79.8 ng/ml; 1171 vs 101.9 ng-h/ml), but the mean Cmax of the primary metabolites M1 and M(A) was higher after phenobarbital (M1 413.0 vs 648.9 ng/ml; M(A) 683.0 vs 814.8 ng/ml). The highest increase was seen in the mean Cmax and AUC of the secondary metabolite M2 (837.5 vs 2585.7 ng/ml; 3312.1 vs 13156.5 ng-h/ml). In contrast, plasma concentrations of the O-desmethylated metabolites M4 and M6 did not increase after phenobarbital. These results suggest that both deacetylation and N-demethylation of DTZ in rats are catalyzed by drug metabolizing enzymes inducible by phenobarbital.

Severe Diltiazem Poisoning with Intestinal Pseudo-Obstruction: Case Report and Toxicological Data

This case report concerns a 30-year-old man who survived a 4.2 g diltiazem overdose. He sustained vasoplegic shock with a junctional escape rhythm which required high doses of norepinephrine and epinephrine. Among other complications, ileus with paralytic intestinal pseudo-obstruction developed on day three. Cecal distention was demonstrated by abdomen computed tomodensitometry. The ileus resolved on day seven following the poisoning. Diltiazem plasma concentrations were determined during the first three days. The possible role of other medications, activated charcoal and sufentanil, is noted.

Comparative Pharmacokinetics and Bioavailability of Dilacor XR and Cardizem CD in Healthy Volunteers.

The objective of this investigation was to compare the single-dose and steady-state pharmacokinetic profiles of Dilacor XR to Cardizem CD. The study enrolled 24 healthy males and was divided into three parts: a single intravenous 25-mg bolus dose of diltiazem HCl (Cardizem Injectable) followed by a two-way crossover comparison of single and multiple once-daily 240-mg oral doses of Dilacor XR and Cardizem CD. Plasma samples were analyzed for diltiazem using a specific and sensitive HPLC assay. Statistical analysis and deconvolution were performed on the data. A 1- and 3-hour lag time in diltiazem absorption was noted following the administration of Dilacor XR and Cardizem CD, respectively. Statistically significant differences were noted in mean single- and multiple-dose t(max) values with Cardizem CD taking approximately twice as long as Dilacor XR to reach C(max). Dilacor XR was equivalent to Cardizem CD with respect to AUC((0--infty infinity)) and C(max). Equivalent minimum and average steady-state plasma diltiazem concentrations were noted after multiple-dose administration. Deconvolution of the single-dose data also showed similar mean bioavailabilities for the respective formulations but revealed dissimilarities in each product's absorption profile that may reflect observed differences in absorption lag time and t(max).

Plasma concentrations of diltiazem in coronary artery surgery

Plasma concentrations of diltiazem in coronary artery surgery

Pharmacokinetics of Multiparticulate Sustained-Release Diltiazem Preparations in Dogs

The in vivo performance of multiparticulate sustained-release diltiazem preparations [HER-SR(A,B,C)] coated with water-insoluble polymer (ethylcellulose), to control the in vitro dissolution rate, was evaluated in dogs. With a decrease in dissolution rate, HER-SR maintained sustained-release characteristics, although the bioavailability decreased slightly. The bioavailability of HER-SR(A,B,C) was comparable with that of a conventional diltiazem tablet (HER). Plasma diltiazem concentrations for the HER-SR preparations were analyzed with a two-fraction absorption model and the pharmacokinetic characteristics were discussed. From the results, it was considered that HER-SR(B) preparation had desirable pharmacokinetic characteristics as sustained-release diltiazem preparations. The absorption site of the slow-release component of HER-SR(B) in the gastrointestinal tract was examined. Almost all of the component had reached the colon within 5 h of administration, the diltiazem content remaining in the component being approximately 60% of the initial amount. Thus, it was shown that the HER-SR(B) preparation had particular absorption characteristics that resulted in the colon being the part of the gastrointestinal tract most receptive to its release. In vivo release profiles of diltiazem from the HER-SR(B) preparation were calculated by the Wagner-Nelson method, and in vitro and in vivo release profiles of HER-SR(B) were further analyzed with a two-fraction release equation. A close correlation of in vitro and in vivo release profiles of HER-SR(B) was found.

Pharmacokinetics of diltiazem and its metabolites in dogs after oral administration of a multiparticulate sustained-release preparation.

Pharmacokinetics of diltiazem and its six metabolites were compared after oral administration in dogs of a multiparticulate sustained-release diltiazem preparation (HER-SR, QD) and a conventional diltiazem preparation (HER, TID). The plasma concentration of diltiazem, its two active basic metabolites (M1, N-monodesmethyl diltiazem; M2, deacetyl diltiazem), and four acidic metabolites [A1, (+)-(2S,3S)-2-(4-methoxyphenyl)-3-acetoxy-4-oxo-2,3,4,5,-tetrahydro-1,5- benzothiazepin-5-acetic acid; A2, 3-deacetyl-A1; A3, O-demethyl-A1; A4, O-demethyl-3-deacetyl-A1] following several administration routes were determined using high-performance liquid chromatography with UV detector (UV-HPLC). Following the oral administration of HER to dogs, plasma concentrations were in the descending order of A2, diltiazem, M1, and M2. The absolute bioavailability of diltiazem was about 30%. Diltiazem conversion to its metabolites (M1, M2, A2) was 31.0, 2.1, and 14.6%, respectively. Following intraduodenal and mesenteric venous administration of diltiazem, M1 and A2 were produced mainly in the intestine and liver. Oral administration of HER-SR and HER to dogs resulted in almost-identical plasma concentrations of A2, diltiazem, M1, and M2 (descending order). Supported evidence was the effective absorption of diltiazem from all gastrointestinal tract regions and similar formation ratios of diltiazem basic metabolites (M1, M2) from the duodenum, ileum, and colon.

Concentrations plasmatiques du diltiazem et de ses métabolites en chirurgie coronarienne : relation avec le traitement préopératoire

Preoperative oral administration of calcium channel blocking agents has been found ineffective to prevent perioperative myocardial ischaemia. Our hypothesis was that low plasma concentrations may account for this inefficiency. Twenty-three male patients, scheduled for surgical myocardial revascularisation, were administered their usual anti-anginal treatment, including 180 to 360 mg of diltiazem since more than one week. The usual dosage was given at 8.00 p.m. on the day before surgery. On the morning of surgery, after withdrawal of a first blood sample, 60 mg of diltiazem were administered per mouth before the induction of anaesthesia. The anaesthesia was obtained with fentanyl, midazolam or flunitrazepam, pancuronium and isoflurane as required. The cardiopulmonary bypass (CPB) was associated with total haemodilution with Ringer's Lactate and a membrane oxygenator. A second blood sample was withdrawn after CPB. Plasma concentrations of diltiazem and its two active metabolites, N-monodemethyldiltiazem (MA) and desacetyldiltiazem (M1), were assessed by HPLC. Plasma diltiazem concentrations decreased from 78 ± 66 (mean ± SD) to 51 ± 42 μg · l −1 (p < 0.05) with wide individual variations. These concentrations were under therapeutic levels in 18 out of 23 patients before (p < 0.05) with wide individual variations. These concentrations were under therapeutic levels in 18 out of 23 patients before induction and in 22 patients after CPB. The metabolite/diltiazem ratios remained constant. A dosage-plasma concentration relationship was observed preoperatively with diltiazem and MA. It is concluded that plasma concentrations of diltiazem should be optimized preoperatively in order to prevent myocardial ischaemia.

Pharmacokinetic analysis of an oral sustained-release diltiazem preparation using multifraction absorption models.

Application of multifraction absorption models to pharmacokinetic analysis of an oral sustained-release diltiazem preparation (HER-SR) was investigated. The plasma diltiazem concentrations after oral administration of the HER-SR preparation were analyzed using both the two-fraction absorption model and the two-step discontinuous absorption model. The two-fraction absorption model was suitable for the pharmacokinetic analysis of the HER-SR preparation, whereas the two-step discontinuous absorption model is often unsuitable for the analysis of sustained-release preparations which disintegrate into fractions with different release characteristics in the gastrointestinal tract. The two-step discontinuous absorption model is usually not applicable to plasma concentration data when the first peak is sharp. MFA-MULTI(V) was shown to be useful for the prediction of the bioavailability in each fraction of HER-SR. It was further demonstrated that a two-fraction absorption model is useful for the comparison of in vitro and in vivo release profiles or evaluating the influence of food on the absorption behavior of HER-SR. In addition, the application of a two-fraction absorption model to population pharmacokinetics of HER-SR was investigated.

The effects of chronic oral diltiazem and cimetidine dosing on the pharmacokinetics and negative dromotropic action of intravenous and oral diltiazem in the dog.

The kinetics and negative dromotropic action of intravenous (1 mg kg-1) and oral (5 mg kg-1) diltiazem were studied in dogs after acute doses, after treatment for 3 days with oral diltiazem (5 mg kg-1, t.i.d.), and after 3 days' treatment with oral diltiazem (5 mg kg-1 t.i.d.) and cimetidine (200 mg t.i.d.). Plasma concentrations of diltiazem and two of its metabolites, desacetyldiltiazem and desmethyldiltiazem were measured by HPLC. Chronic oral dosing significantly lowered both the systemic and oral clearance of diltiazem, with no changes in either the volume of distribution or blood binding of diltiazem. Cimetidine treatment resulted in a significant reduction in diltiazem oral clearance from chronic control with no effect on its systemic clearance. The AUCs of both metabolites increased by greater than threefold from acute to chronic oral dosing; however, the ratio of each metabolite's AUC to that of diltiazem AUC was not significantly altered. Cimetidine treatment significantly lowered these ratios. The negative dromotropic potency of diltiazem after the acute oral dose was three times greater than that after intravenous or chronic control dosing. Cimetidine treatment resulted in further lowering chronic oral diltiazem potency. These data indicate that the disposition and negative dromotropic action of diltiazem is dependent both on the route of administration and the duration of treatment, and can be altered by co-administration with cimetidine.

Rate-dependent effects of diltiazem on human atrioventricular nodal properties.

Tachycardia enhances the channel-blocking effects of antiarrhythmic drugs. In contrast to the extensive data regarding the rate-dependent effects of sodium channel blockers in humans, little is known about the frequency-dependent effects of calcium channel blockers on human atrioventricular (AV) nodal properties. Accordingly, the purpose of this study was to evaluate the importance of heart rate in modulating the electrophysiological effects of diltiazem in humans. Electrophysiological studies were performed in 25 patients. Sinus node, atrial, and AV nodal function were evaluated at multiple atrial rates under control conditions and after administration of one of three intravenous doses of diltiazem designed to produce low, intermediate, and high stable plasma concentrations (designated doses 1, 2, and 3, respectively). Results were analyzed in terms of the longest and shortest cycle lengths obtainable in each patient under control and drug conditions. Plasma concentrations of diltiazem were stable and averaged 43 +/- 4, 73 +/- 6, and 136 +/- 11 ng/ml for doses 1, 2, and 3, respectively. Sinus node recovery time, intra-atrial conduction time, atrial effective refractory period, and HV interval were unaffected by diltiazem infusion. Effects of diltiazem were limited to changes in AV nodal parameters. Stable, dose-dependent increases in Wenckebach cycle length were observed after all three doses of diltiazem (increases of 54 +/- 13, 84 +/- 18, and 174 +/- 33 msec for doses 1, 2, and 3, respectively). Small nonsignificant increases in AH interval and atrioventricular effective refractory period (AVERP) were observed after dose 1 of diltiazem. At long cycle lengths, diltiazem caused modest increases in AH interval (3 +/- 4 and 25 +/- 8 msec for doses 2 and 3, respectively) and AVERP (36 +/- 12 and 70 +/- 25 msec). Drug effects were far greater at short cycle lengths (45 +/- 17 msec, 58 +/- 12 msec for AH interval and 80 +/- 24 msec, 163 +/- 41 msec for AVERP; p less than 0.05 versus values at long cycle lengths). At rapid rates, effects of diltiazem on AVERP substantially exceeded those on AV conduction, a result that could account for the beneficial effects of diltiazem during paroxysmal AV reentrant tachycardia by decreasing the excitable gap. Depressant effects of diltiazem on human AV nodal function are highly dependent on atrial rate; the rate-dependent actions on AV nodal refractoriness probably contribute to beneficial effects of diltiazem in patients with supraventricular arrhythmias.

Hemodynamic effect of calcium channel blockade during anesthesia for coronary artery surgery

Because the choice of anesthetic technique does not influence the incidence of perioperative myocardial ischemia, reduction of ischemic risk may require specific antianginal therapy. Calcium entry blockers are effective drugs in antianginal therapy. Diltiazem reduces myocardial oxygen demand through decreases in heart rate, inotropy, and systolic function, while increasing myocardial oxygen delivery through coronary vasodilation. These potentially beneficial effects of diltiazem were evaluated in 15 of 29 patients (diltiazem v placebo, double-blind study) scheduled for coronary artery bypass graft surgery. Continuous infusion of diltiazem (0.15 mg/kg bolus followed by 2 μg/kg/min), during anesthesia and surgery before cardiopulmonary bypass, significantly reduced the major MV02 determinants during anesthesia with moderate doses of fentanyl and a benzodiazepine (midazolam in 8 of 14 control patients and 9 of 15 treated patients, or flunitrazepam in the others). Heart rate, mean arterial pressure, and inotropy were decreased during the most stressful events of surgery when plasma diltiazem concentrations were in the therapeutic range (>96 ng/mL). The number of patients with perioperative ischemia was 2 of 15 in the treated group and 4 of 14 in the control group. Provided that diltiazem plasma concentrations are sufficient, it can contribute to lowering the ischemic burden during anesthesia for coronary artery surgery.

The effect of CPR on plasma diltiazem concentrations in dogs

To determine the effect of cardiac arrest with CPR on diltiazem concentrations in dogs. Prospective, double-blind, randomized trial. Laboratory at a large university-affiliated medical center. Twenty mongrel dogs. Following administration of anesthesia, catheters were placed in the pulmonary artery, aortic arch, left ventricle, and right ventricle. Dogs were randomized to receive diltiazem (0.5 mg/kg) either 60 minutes before or during cardiac arrest with CPR. After 13 minutes of cardiac arrest, defibrillation was attempted. Frequent blood samples for diltiazem concentrations were obtained before, during, and after cardiac arrest. The mean diltiazem concentration rose 70% during CPR in the group that received diltiazem before cardiac arrest. The group that received diltiazem during CPR had concentrations five times greater than expected during sinus rhythm. Increased diltiazem concentrations are observed during CPR and are probably related to altered distribution encountered during CPR.

The determinants of response to diltiazem in hypertension

We examined factors (blood pressure, plasma renin activity, and age) influencing the antihypertensive response in essential hypertensive patients given 240 mg/day of slow-release diltiazem in an unblinded study after a placebo run-in period. Subjects provided a range of diastolic blood pressures (90 to 115 mm Hg), of age (31 to 70 years), and of plasma renin activity (0.1 to 2.7 ng angiotensin I/ml/hr) on a 70 to 150 mEq sodium diet. Blood pressure, plasma renin activity, and plasma diltiazem concentrations were measured after the first (n = 21) and final dose (n = 19) of 120 mg diltiazem, twice daily for 4 weeks. Multiple linear stepwise regression of change in blood pressure versus age, plasma renin activity, and baseline blood pressure showed baseline blood pressure was the only predictor of response (p = 0.0002). For each increase of 10 mm Hg in baseline pressure there was a 7 mm Hg greater decrease in diastolic blood pressure. We conclude that patient age and plasma renin activity are not clinically significant predictors of antihypertensive response to diltiazem in hypertension.

トレッドミルテスト施行時におけるｄｉｌｔｉａｚｅｍの薬効と体内動態に関するデータ解析

To adapt therapeutic drug monitoring to clinical practice, a pharmacokinetic and pharmacodynamic data analysis of the effects of diltiazem during treadmill tests in 22 patients with angina pectoris was performed. Scattered data obtained from the treadmill tests, pharmacokinetic parameters for diltiazem, indicators of diltiazem sensitivity, and plasma diltiazem concentrations, and effects at standard dose (60mg) were statistically analyzed, and their mutual relationships were examined by a correlation analysis and a multiple regression analysis. In addition, we derived predictive models for the effects of diltiazem from the results of the multiple regression analysis and then examined the predictive performance of these models. The patients' ages were correlated with plasma diltiazem concentrations, suggesting that plasma diltiazem concentration increases with increasing age for the same dose and after the same lapse time of following administration. On the other hand, plasma dilitiazem concentration was correlated with exercise time (Ext) at 3hr and with pressure-rate product during rest (RestPRP) at 1.5 or 3hr after administration, but not with pressure-rate product at maximum exercise (MaxPRP). The variables most correlated with Ext, RestPRP and MaxPRP were the indicators of diltiazem sensitivities calculated from the relationships between effects and plasma diltiazem concentration. An elimination rate constant (Ke) was found to affect indicators of diltiazem sensitivity during exercise, suggesting that the effects of diltiazem during exercise depend on the tissue distribution of diltiazem. The reproducibility of the predictive models derived from the multiple regression analysis was satisfactory, suggesting that these models may be useful in predicting the effects of diltiazem in individual cases by analyzing plasma diltiazem concentration data.

Diltiazem Overdose: Pharmacokinetics Of Diltiazem and Its Metabolites and Effect Of Multiple Dose Charcoal Therapy

We describe a 38 year-old female who ingested 900 mg of diltiazem. She experienced hypotension, bradycardia and heart block but responded well to supportive care that included normal saline infusion and vasopressors. Calcium administration was not beneficial. Serial plasma concentrations of diltiazem, N-demethyldiltiazem and desacetyldiltiazem were quantified. By comparing the elimination half-life for diltiazem with historical controls, it is concluded that multiple dose charcoal therapy was not beneficial for our patient.

Determinants and significance of diltiazem plasma concentrations after acute myocardial infarction

A total of 1,975 plasma diltiazem concentrations were obtained from 1,067 patients enrolled in a multicenter secondary intervention study of diltiazem after acute myocardial infarction. To evaluate the determinants and significance of diltiazem concentrations in this patient population, we related drug concentrations to a variety of clinical variables recorded on the case history forms. Multiple linear regression analysis showed that (1) time from the last drug dose, (2) drug dose taken, (3) patient height (an index of lean body weight), and (4) patient age were important determinants of plasma concentration. For an equivalent dose, plasma diltiazem concentrations in a 75-year-old patient were about double those of a 25-year-old patient. Total weight and drug dose prescribed did not significantly affect plasma concentrations. Whereas drug concentrations were higher (p = 0.01) among patients with left-sided heart failure, they were not altered by renal dysfunction, hepatic disease or β blockers. Diltiazem concentrations were a significant determinant of diastolic arterial pressure (p < 10 −9), but neither systolic pressure nor heart rate were significantly related to diltiazem concentration. The overall incidence of adverse experiences was not related to drug concentrations, but the occurrence of second- and third-degree atrioventricular block in the coronary care unit and the need for a temporary pacemaker were substantially higher among patients with a drug concentration >150 ng/ml (7.4 and 1.9%, respectively) than among patients with lower concentrations (2.6% for atrioventricular block, 0.3% for pacemaker; p = 0.02 for each). The risk of atrioventricular block was particularly increased by high diltiazem concentrations in the face of acute inferior infarction. These results suggest that diltiazem's pharmacologic and clinical effects in a large population are concentration-related, and that the consideration of patient size, age, and left ventricular function in selecting a diltiazem dose may allow for effective drug therapy with a reduced likelihood of adverse effects.