Advances in antiarrhythmic drug therapy.
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Anti-Arrhythmia Agents↗
Biomedical subjects
M B Bottorff
Publications and source records attributed to M B Bottorff.
Pharmacokinetic interactions with calcium channel antagonists (Part I).
Calcium channel antagonists are a diverse class of drugs widely used in combination with other therapeutic agents. The potential exists for many clinically significant pharmacokinetic interactions between these and other concurrently administered drugs. The mechanisms of calcium channel antagonist-induced changes in drug metabolism include altered hepatic blood flow and impaired hepatic enzyme metabolising activity. Increases in serum concentrations and/or reductions in clearance have been reported for several drugs used with a number of calcium channel antagonists. A number of reports and studies of calcium channel antagonist interactions have yielded contradictory results and the clinical significance of pharmacokinetic changes seen with these agents is ill-defined. The first part of this article deals with interactions between calcium antagonists and marker compounds, theophylline, midazolam, lithium, doxorubicin, oral hypoglycaemics and cardiac drugs.
Anti-Arrhythmia Agents↗
Pharmacokinetic interactions with calcium channel antagonists (Part II).
Since calcium channel antagonists are a diverse class of drugs frequently administered in combination with other agents, the potential for clinically significant pharmacokinetic drug interactions exists. These interactions occur most frequently via altered hepatic blood flow and impaired hepatic enzyme activity. Part I of the article, which appeared in the previous issue of the Journal, dealt with interactions between calcium antagonists and marker compounds, theophylline, midazolam, lithium, doxorubicin, oral hypoglycaemics and cardiac drugs. Part II examines interactions with cyclosporin, anaesthetics, carbamazepine and cardiovascular agents.
Anesthetics↗
Labetalol pharmacokinetics and pharmacodynamics: evidence of stereoselective disposition.
Labetalol pharmacokinetics and pharmacodynamics were evaluated in nine subjects before and during enzyme inhibition with cimetidine. Pharmacologic response was assessed by use of standardized treadmill tests during 24 hours after administration of oral labetalol. Oral clearance of labetalol decreased with cimetidine administration (58.7 +/- 23.3 to 32.9 +/- 13.2 ml/min/kg; p less than 0.05), thereby causing a 79% increase in area under the curve. Labetalol systemic clearance also decreased (23.2 +/- 5.3 to 17.7 +/- 3.7 ml/min/kg; p less than 0.05), but the volume of distribution was unchanged. Labetalol caused significant beta-blockade for 8 hours after the last oral dose, but cimetidine did not alter pharmacologic response. The Emax model provided a good description of the concentration-effect relationship. At peak labetalol concentrations after oral administration, (R,R)-labetalol concentrations were significantly lower than those of the other three stereoisomers (p less than 0.05). Cimetidine caused an increase in the concentrations of each stereoisomer, but the difference was significant (p less than 0.05) for only the (S,R)-, (S,S)-, and (R,S)-isomers. This first evidence of labetalol stereoselective disposition is consistent with the findings of previous (R,R)-labetalol pharmacokinetic studies and with previous pharmacodynamic investigations of labetalol and (R,R)-labetalol.
Administration, Oral↗
Effects of age on the protein binding and disposition of propranolol stereoisomers.
Previous studies of the effects of age on the disposition of propranolol have produced variable results. We evaluated the stereoselective disposition and protein binding of propranolol enantiomers in 10 young (mean age, 28 years) and 10 older (mean age, 64 years) healthy subjects. After receiving racemic propranolol orally for 6 days, the oral clearances of d-propranolol and l-propranolol were lower by 13% and 17% in the older group compared to the young group, but these differences were not statistically significant. The older subjects had higher alpha 1-acid glycoprotein concentrations (p less than 0.05) and lower unbound fractions of l-propranolol (p less than 0.05). After protein binding was accounted for, the unbound oral clearance of each enantiomer was similar in both groups. l-Propranolol was more highly protein bound than d-propranolol (p less than 0.05) in both young and older subjects. The unbound oral clearance d/l ratio was not different from unity in either group, indicating that the stereoselective differences in oral clearance were largely attributable to the stereoselective differences in protein binding.
Adult↗
Effects of calcium channel blockers on the pharmacokinetics of propranolol stereoisomers.
Diltiazem and verapamil inhibit oxidative drug metabolism both in vivo and in vitro. We compared their effects on the stereoselective pharmacokinetics and protein binding of propranolol in 12 subjects. After 6 days of coadministration with racemic propranolol, diltiazem caused decreases of 27% and 24% in d-propranolol and 1-propranolol oral clearances, respectively (p less than 0.05 versus control). With verapamil, d-propranolol oral clearance decreased 32% (p less than 0.05), and 1-propranolol oral clearance decreased 26% (p less than 0.05). The unbound fraction of d-propranolol was higher than that of 1-propranolol (p less than 0.05), but the protein binding was not altered by diltiazem or verapamil. Both drugs therefore decreased the unbound oral clearance of each propranolol enantiomer (p less than 0.05). Verapamil caused a stereoselective effect and increased the d/l ratio of propranolol serum concentrations (p less than 0.05) and decreased the d/l ratio of oral clearance (p less than 0.05).
Adult↗
Altered beta-adrenergic sensitivity and protein binding to 1-propranolol in the elderly.
The elderly are reported to be less sensitive to the beta-blocking effects of propranolol. However, age-related changes in the stereoselective pharmacokinetics or protein binding of propranolol enantiomers could have confounded the results of previous studies because only 1-propranolol contributes significantly to the beta-blocking effects of the racemate. To avoid these confounding variables, we studied 10 young (mean 28 years) and 10 elderly (mean 64 years) subjects, and determined the cardiac beta-receptor sensitivity in terms of unbound, active 1-propranolol. The doses of isoproterenol required to increase heart rate (HR) by 25 beats/min were determined before and during a continuous infusion of propranolol. The serum concentration of 1-propranolol was determined by enantioselective high-performance liquid chromatography (HPLC), and the unbound fraction was determined by equilibrium dialysis. The apparent in vivo receptor dissociation constant for unbound 1-propranolol increased from 0.066 +/- 0.047 ng/ml in the young to 0.218 +/- 0.264 ng/ml in the older group (p less than 0.05). The unbound fraction was decreased in the older subjects (0.141 +/- 0.023 vs. 0.121 +/- 0.025, p less than 0.05) because of an increase in alpha 1-acid glycoprotein concentration (55 +/- 11 mg/dl vs. 72 +/- 19 mg/dl, p less than 0.05). Advancing age was associated with a decreased sensitivity to isoproterenol (rs = 0.76, p less than 0.05) and to unbound 1-propranolol (rs = 0.45, p less than 0.05). We conclude that the older subjects have (a) decreased sensitivity to the beta-blocking effects of 1-propranolol and to the agonist effects of isoproterenol, and (b) a lower unbound fraction of 1-propranolol.
Adult↗
The effects of encainide versus diltiazem on the oxidative metabolic pathways of antipyrine.
The effects of diltiazem and encainide on the pharmacokinetics and metabolism of antipyrine were compared in nine healthy male volunteers. Diltiazem 90 mg every 8 hours for 5 days decreased the oral clearance of antipyrine from 2.34 to 1.86 L/hour (p less than 0.05) and increased half-life from 12.7 to 15.9 hours (p less than 0.05). Diltiazem reduced the formation rate constants for 3-hydroxymethylantipyrine by 27% (p less than 0.05) and 4-hydroxyantipyrine by 37% (p less than 0.05). There was also a 21% reduction in the formation rate constant for norantipyrine (0.05 less than p less than 0.10). Encainide 25 mg every 8 hours for 5 days had no apparent effect on the oral clearance or half-life of antipyrine, or on the formation rate constants for metabolites of antipyrine. In contrast to a previously published report in rats, encainide, unlike diltiazem, does not inhibit the oxidative metabolism of antipyrine in humans.
Adult↗
Pharmacokinetics and pharmacodynamics of dilevalol.
The pharmacokinetics and pharmacodynamics of dilevalol, the R,R stereoisomer of labetalol, were evaluated in nine subjects. Dilevalol was given as a single 50 mg intravenous dose and as a 400 mg daily oral dose for 7 days. To study the effects of hepatic enzyme inhibition, each subject received dilevalol in the presence of and absence of cimetidine. Cardiac beta-blockade was assessed by use of standardized treadmill tests for 48 hours after oral dilevalol. The three-compartment model analysis showed that systemic clearance (29.8 +/- 5.7 ml/min/kg), volume of distribution (16.6 +/- 4.1 L/kg), and terminal half-life (11.7 +/- 2.7 hours) were not altered by cimetidine. However, there was a 20% increase in the area under the curve (p less than 0.05) and an 11% increase in systemic bioavailability (p less than 0.05) after oral administration. Dilevalol caused significant cardiac beta-blockade for more than 24 hours, but these effects were not altered by cimetidine. The pharmacokinetic changes are consistent with a decrease in first-pass extraction of a high clearance drug.
Administration, Oral↗
The effect of diltiazem on the disposition of encainide and its active metabolites.
The disposition of encainide is under genetic control. In extensive metabolizers, the drug undergoes extensive first-pass metabolism to form the active metabolites O-desmethylencainide (ODE) and 3-methoxy-O-desmethylencainide (MODE). Because diltiazem is a known inhibitor of hepatic oxidative metabolism, the disposition of encainide and its metabolites was studied in eight extensive metabolizers and one poor metabolizer before and after administration of 90 mg diltiazem every 8 hours for 10 days. After diltiazem, the encainide serum AUC values increased in seven of the eight extensive metabolizers, and the percent recovery of encainide in urine increased by 69%. There were no apparent changes in the serum AUC values of the metabolites, suggesting that diltiazem may alter both the formation and the elimination clearances of the metabolites to a similar degree. In the poor metabolizer, encainide serum AUC increased 33% during treatment with diltiazem, but ODE and MODE could not be reliably quantitated. The subjects had no change in QRS, QTc, or JTc intervals after administration of diltiazem. Diltiazem inhibited the first-pass metabolism of encainide, resulting in increased bioavailability. This appeared to be caused by the inhibition of debrisoquin 4-hydroxylase and impairment of other unmeasured metabolic pathways for encainide. However, because no change occurs in the systemic exposure to the active metabolites, dosage adjustments in extensive metabolizers are probably not required for patients receiving combination encainide and diltiazem therapy.
Adult↗
A high-performance liquid chromatographic method for the determination of encainide and its major metabolites in urine and serum using solid-phase extraction.
A high-performance liquid chromatography (HPLC) procedure used to quantitate encainide and two of its active metabolites, O-desmethylencainide (ODE) and 3-methoxy-O-desmethylencainide (MODE), is described. All three compounds were simultaneously extracted from urine and serum using an octyl (C-8) solid-phase extraction column. The compounds were then separated by reverse-phase HPLC on a cyanopropylsilane column using ultraviolet detection at 260 nm. Serum samples were quantified over a concentration range of 25-400 ng/ml and urine over a range of 150-10,000 ng/ml. Total run time for the assay was less than 12 min. Within-day and between-day precision and relative error were less than 10% in serum and less than 13% in urine for all three compounds. The lower limit of quantitation was 10 ng/ml for encainide and ODE and 15 ng/ml for MODE. This HPLC procedure represents a quick and reliable method of measuring encainide and its major metabolites in both urine and serum, making the assay applicable as an aid for therapeutic drug monitoring of patients receiving encainide therapy.
Anilides↗
Calcium channel blockers as inhibitors of drug metabolism.
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Adrenergic beta-Antagonists↗
Pharmacokinetics and pharmacodynamics of urapidil in severe hypertension.
The clinical response and pharmacokinetics of intravenous urapidil were studied in patients with uncontrolled severe hypertension. Six of nine patients achieved a diastolic blood pressure (DBP) of 100 mm Hg after initial administration of serial bolus doses and were then placed on maintenance infusions. Three of these six patients maintained a DBP 100 mm Hg or lower at infusion rates of 10 to 20 mg/hr, whereas the remaining three patients experienced a loss of DBP control despite rates of 40 mg/hr. Mean DBP was significantly reduced from 126 +/- 6 mm Hg (N = 9) to 105 +/- 15 mm Hg after the bolus phase (N = 9, P less than .05) and 99 +/- 18 mm Hg after the infusion phase (N = 6, P less than .05). Significant reductions in systolic blood pressure were also achieved after bolus and infusion phases. Adverse reactions included drowsiness, tachycardia, nausea and vomiting but were considered mild. Estimated pharmacokinetic parameters included Vz (0.80 +/- 0.20 L/kg), CL (2.53 +/- 0.99 mL/min/kg) and t1/2 (4.0 +/- 1.5 hr). Urapidil safely reduces blood pressure in patients with severe hypertension. An alternative dosing regimen is suggested.
Adolescent↗
The relative predictive performance of two theophylline pharmacokinetic dosing programs.
The predictive performance of 2 theophylline pharmacokinetic dosing programs (Abbott and Simkin) was evaluated using a group of 44 inpatients who had 2 serum concentrations (TSC) measured during hospitalization. Bias was assessed with the median prediction error (PE) and precision was assessed with the median absolute PE. The Abbott program was significantly less biased than the Simkin program in predicting the first TSC (PEs 0.1 and -1.3 micrograms/ml, respectively; p less than 0.05). No significant difference in bias was observed in predicting the second TSC, or in precision in predicting either the first or second TSC. Both programs exhibited small improvements in prediction precision when the first TSC was used to predict the second. Correlations of predicted versus measured TSC also improved with the second prediction. These programs may be useful in dosing theophylline; however, TSC monitoring and the application of sound clinical judgment are warranted.
Adult↗
Nonlinear accumulation of propranolol enantiomers.
The accumulation of (+)- and (-)-propranolol was investigated in nine subjects who received 160 mg of racemic propranolol as a single dose and then once daily for 7 days. The serum concentrations of propranolol enantiomers were measured by h.p.l.c. using a novel chiral stationary phase allowing direct resolution of underivatized propranolol. The (+)-propranolol AUC increased from 412 +/- 223 ng ml-1 h after single doses (0-infinity) to 584 +/- 279 ng ml-1 h at steady-state (0-24 h) (P less than 0.05). Similarly, (-)-propranolol AUC increased from 609 +/- 304 to 777 +/- 370 ng ml-1 h (P less than 0.05). The AUC ratio (-)/(+) was 1.52 +/- 0.36 and 1.32 +/- 0.17 after single doses and steady-state, respectively (P greater than 0.05). Therefore, nonlinear accumulation occurs with both enantiomers although there is a trend for the (-)/(+) ratio to decrease at steady-state.
Adult↗
Nonlinear pharmacokinetics of unbound propranolol after oral administration.
After multiple oral doses, propranolol has been reported to accumulate to a greater degree than expected based on its terminal elimination rate constant and dosage interval. To determine whether the decrease in presystemic elimination can be attributed solely to a decrease in unbound intrinsic clearance or possibly a decrease in unbound fraction, we studied the pharmacokinetics of unbound propranolol in nine healthy subjects who were given 160 mg of regular or sustained-release propranolol orally as single doses, and once daily for 7 d. Unbound propranolol concentrations were calculated by HPLC and equilibrium dialysis on each serum sample. With regular propranolol, the mean unbound oral clearance (CLoral) decreased 29%, from 503 +/- 281 after a single dose to 359 +/- 143 mL/min/kg at steady state (p less than 0.05). Similarly, CLoral decreased 33% with sustained-release propranolol from 1077 +/- 514 to 721 +/- 385 mL/min/kg (NS). The corresponding accumulation ratios for regular and sustained-release propranolol were 1.39 +/- 0.49 and 1.61 +/- 0.81, respectively (NS). Therefore, the mean bioavailability of sustained-release relative to that of regular propranolol was 0.52 +/- 0.23 and 0.54 +/- 0.17 for single doses and at steady-state, respectively. The percent unbound of propranolol ranged from 6.8 to 14.0 with an average of 10.1. Neither the percent unbound nor alpha 1-acid glycoprotein (AAG) serum concentrations were statistically different between single and multiple doses. The binding ratio was significantly correlated to AAG concentration (r = 0.776, p less than 0.05). The data support a decrease in unbound intrinsic clearance of propranolol with no change in unbound fraction, leading to an increase in bioavailability at steady state.
Administration, Oral↗
Lidocaine protein binding in preeclampsia.
The effect of preeclampsia on the binding of lidocaine to serum proteins was studied in 25 term parturients with severe preeclampsia and in 21 normal parturients serving as controls. There were no statistically significant differences in mean lidocaine free fraction, binding ratio, or serum AAG levels in the control vs preeclamptic patients, respectively. Binding ratio was strongly correlated with AAG concentration for the control (r = 0.91) and preeclamptic (r = 0.85) patients. A statistically significant difference was observed in the slopes of the lines relating binding ratio to AAG. Preeclampsia had little affect on serum AAG concentrations and lidocaine binding ratio. Preeclampsia may alter the interaction of lidocaine with binding sites on AAG without a significant change in lidocaine free fraction.
Blood Proteins↗
Propranolol pharmacokinetics and pharmacodynamics after single doses and at steady-state.
The duration and extent of cardiac beta-blockade and their relationship to propranolol pharmacokinetics were assessed in nine healthy volunteers. Each subject received 160 mg of regular propranolol (R), 160 mg of sustained-release propranolol (SR) and no drug (control), both as single doses and once daily for 7 days. After single doses and at steady-state, both products caused a decrease in exercise heart rate for at least 24 h, compared to control. The time course of effect was similar to the time course of serum propranolol concentration. The oral clearance of propranolol decreased from single doses to steady-state for both R and SR; however, the difference achieved statistical significance only for R. These changes were reflected in mean accumulation ratios (AUC steady-state 0-24 h/AUC single dose 0-infinity) of 1.49 and 1.68 for R and SR, respectively. The pharmacokinetic data are consistent with a decrease in intrinsic hepatic clearance of propranolol, leading to an increase in bioavailability at steady-state. Despite a two-fold difference in the bioavailability of R and SR, there was no difference in the area under the effect-time curve at steady-state.
Administration, Oral↗