Elizabeth L. Todd

Verapamil Pharmacodynamics and Disposition in Young and Elderly Hypertensive Patients: Altered Electrocardiographic and Hypotensive Responses

We studied verapamil pharmacodynamics and disposition in seven young, ten elderly, and seven very elderly hypertensive males. Maximal decrease in mean (+/- SD) blood pressure tended to be greater in the elderly (-13.5 +/- 5.9 mm Hg) and the very elderly patients (-15.9 +/- 9.6 mm Hg) compared with that in young patients (-7.3 +/- 4.2 mm Hg). Disparate effects on heart rate responses were noted with reflex tachycardia in young patients compared with decreases in heart rate among the elderly and very elderly. Sensitivity to verapamil-induced prolongation in electrocardiographic P-R interval was less in the very elderly, and maximal prolongation in P-R interval induced by verapamil was less in the elderly and very elderly. Verapamil disposition was also age related. Total verapamil clearance was decreased in elderly (10.5 +/- 3.5 mL/min X kg; p less than 0.05) and very elderly (8.0 +/- 4.1 mL/min X kg; p less than 0.01) when compared with that in young patients (15.5 +/- 4.5 mL/min X kg). Elimination half-life was prolonged in the elderly (7.4 +/- 3.3 h; p less than 0.01) and very elderly (8.0 +/- 1.2 h; p less than 0.01) compared with that in young patients (3.8 +/- 1.1 h). Our data indicate age- and hypertension-related physiologic changes result in predictable pharmacokinetic changes. However, the complex alterations in verapamil pharmacodynamic responses indicate an interaction between direct drug effects and age- and disease-related changes in hemodynamic and autonomic nervous system function.

Comparison in young and elderly patients of pharmacodynamics and disposition of labetalol in systemic hypertension

Pharmacodynamics and pharmacokinetics of labetalol, a combined alpha- and beta-adrenoceptor antagonist drug, were studied in elderly and young hypertensive patients. After receiving intravenous labetalol, elderly patients had a greater maximal mean decrease in systolic blood pressure (BP) (39 +/- 8 vs 25 +/- 13 mm Hg, p less than 0.02); however, maximal decrease in diastolic BP was similar in elderly (18 +/- 10 mm Hg) and young (17 +/- 6 mm Hg) patients. After receiving oral labetalol, elderly patients had a greater maximal decrease in standing systolic BP (41 +/- 16 vs 16 +/- 14 mm Hg, p less than 0.001) and similar decreases in standing diastolic BP (21 +/- 7 vs 17 +/- 9 mm Hg). Sitting maximal BP decreases after oral labetalol treatment were similar in elderly and young patients (12 +/- 16 vs 17 +/- 7 mm Hg systolic and 24 +/- 6 vs 12 +/- 7 diastolic). The decrease in heart rate was greater in young patients after intravenous labetalol administration. To evaluate labetalol pharmacodynamics, a linear model was used. Slope of labetalol concentration vs systolic BP for elderly vs young patients was 0.928 +/- 1.05 vs 0.326 +/- 0.490 ng/ml X mm Hg-1 (difference not significant). The slope of labetalol concentration vs heart rate for elderly vs young patients was 0.176 +/- 0.063 vs 0.406 +/- 0.303 ng/ml X beats/min-1 (p less than 0.05), with 2 elderly patients showing no decrease in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxidation of hydrazine metabolites formed from isoniazid

Studies in rats indicate that the metabolic activation of acetylhydrazine, a metabolite of isoniazid, is a critical determinant of the hepatotoxicity of isoniazid. As demonstrated in that model, the formation of 14CO2 after the administration of 14C‐acetylisoniazid reflects the activity of the toxic pathway. A similar approach in man should make it possible to demonstrate the presence and to assess the quantitative importance of this toxifying pathway, and thus to evaluate its role in the pathogenesis of isoniazid hepatitis. We gave 300 mg isoniazid together with 10 µCi 14C‐acetylisoniazid (12 mg) to 17 healthy subjects and determined the time course of the plasma concentrations of isoniazid, acetylisoniazid, acetylhydrazine, and diacetylhydrazine and of the exhalation of 14CO2. The time course of 14CO2 in breath closely paralleled the plasma concentration‐time curve of acetylhydrazine but not those of acetylisoniazid or diacetylhydrazine, indicating that the 14CO2 originated directly from the metabolism of acetylhydrazine. The cumulative exhalation of 14CO2 increased with decreasing rate of acetylation of isoniazid, such that slow acetylators generated more 14CO2 than rapid acetylators. Simulation studies demonstrated that even if the data are corrected for the different formation of acetylisoniazid from isoniazid in slow and rapid acetylators, the slow acetylators still generated more 14CO2. The data therefore indicate that a substantial fraction of the acetylhydrazine formed from isoniazid passes through a pathway that has been shown in animals to generate highly reactive and hepatotoxic intermediates. The observation that slow acetylators metabolize more isoniazid via the toxic pathway, together with recent data showing an exceptionally high incidence of hepatitis in slow acetylators receiving large therapeutic doses of isoniazid, further support the hypothesis that the metabolic activation of acetylhydrazine from isoniazid is an important determinant of the hepatotoxicity of isoniazid in man.

Lack of interaction between verapamil and cimetidine

Nine healthy normal subjects received verapamil, 10 mg iv, before (control) and during cimetidine dosing (300 mg every 6 hours), and verapamil, 120 mg po, twice in the same manner. After intravenous doses, the t½ (X̄ ± SE: control, 3.60 ± 0.40 hours; cimetidine trial, 4.30 ± 0.60 hours), volume of distribution (5.8 ± 0.6 vs. 6.6 ± 0.9 L/kg), and total clearance (19.2 ± 1.5 vs. 18.4 ± 1.6 ml/min/kg) did not change during cimetidine dosing. After oral doses, the t½ (4.25 ± 0.57 vs. 4.60 ± 0.70 hours), plasma AUC (585 ± 113 vs. 506 ± 82 ng/ml · hr) and absolute bioavailability (35% ± 7% vs. 30% ± 5%) did not differ between control and cimetidine trials, respectively. Five of the subjects also received lidocaine, 25 mg iv, once in the control state and once during the cimetidine regimen described above. Lidocaine clearance fell (665 ± 216 vs. 527 ± 134 ml/min; P < 0.05) during cimetidine therapy, resulting in a trend toward a longer t½ (1.81 ± 0.41 vs. 2.44 ± 0.42 hours; 0.1 > P > 0.05) with no change in volume of distribution (1.77 ± 0.66 vs. 1.99 ± 0.81 L/kg). Verapamil pharmacodynamics (ECG PR interval, blood pressure, and heart rate) were evaluated after intravenous doses. A decrease in mean arterial pressure (8 ± 1 vs. 9 ± 2 mm Hg) and a reflex increase in heart rate (14 ± 3 vs. 17 ± 2 bpm) were no different in the control and cimetidine trials. After intravenous doses under a sigmoid Emax pharmacodynamic model, verapamil concentration at 50% maximal prolongation of PR interval from baseline did not differ between trials (27.5 ± 2.8 [control] vs. 24.3 ± 2.1 ng/ml), nor did the maximal PR prolongation differ (94 ± 36 [control] vs. 85 ± 20 msec). After oral verapamil doses under a linear pharmacodynamic model, the slope of the line describing the verapamil concentration vs. PR interval relationship (1.10 ± 0.61 [control] vs. 1.15 ± 0.56 msec/ng · mg−1) and the defined y‐intercept (−37 ± 21 [control] vs. − 28 ± 15 msec) were no different between trials. Our data indicate that neither a pharmacokinetic nor a pharmacodynamic interaction between verapamil and cimetidine occur in vivo in man when therapeutic doses are administered, and that verapamil hepatic extraction after oral dosing is not affected by cimetidine, unlike extraction processes described for other high‐clearance drugs.

Verapamil and norverapamil determination in human plasma by gas-liquid chromatography using nitrogen-phosphorus detection: Application to single-dose pharmacokinetic studies

A sensitive (to 0.5 ng/ml) and specific method for the determination of verapamil and norverapamil which utilizes gas-liquid chromatography with nitrogen-phosphorus detection is described. A basic extraction with acid back-wash and final basic reextraction is used for the preparation of plasma samples. Standard curves using alpha-isopropyl-alpha-[(N-methyl-N-homoveratryl)-beta-aminoethyl]- 3,4- dimethoxyphenylacetonitrile hydrochloride (D-517) are linear for concentrations from 0.5 to 200 ng/ml for both verapamil and norverapamil. Within-day and between-day reproducibility is good with a coefficient of variation less than 10% for all concentrations. Recovery is complete for both verapamil and norverapamil. Application of the method is demonstrated by a pharmacokinetic study in a normal volunteer who received 10 mg verapamil hydrochloride by intravenous infusion.

Doxepin-cimetidine interaction: increased doxepin bioavailability during cimetidine treatment

The influence of concurrent cimetidine administration on the disposition of doxepin was evaluated in 10 healthy volunteers. Each subject ingested 100 mg of doxepin on two different occasions, once while otherwise drug free and once while receiving cimetidine, 300 mg every 6 hours. Doxepin absorptive parameters--time to peak doxepin plasma concentration (2.3, control, vs. 2.4 hours during cimetidine co-administration) and peak concentration achieved (43.3. vs. 55.5 ng/ml)--were not changed during cimetidine administration. Likewise, doxepin elimination half-life was similar in the control state (12.5 hours) and during cimetidine administration (13.2 hours). However, doxepin area under the plasma concentration-time curve (AUC) was increased during concurrent cimetidine administration (533 vs. 695 ng/ml . hour; p less than 0.05), resulting in a trend toward decreased doxepin oral clearance (4404 vs. 3278 ml/min; 0.05 less than p less than 0.1). Relative bioavailability during concurrent cimetidine treatment was 123% of that during the control trial. Desmethyldoxepin AUC was no different between trials (478, control, vs. 433 ng/ml . hour during cimetidine ingestion). Plasma protein binding of doxepin was similar between trials (percent unbound; 10.5, control, vs. 11.2%) and therefore did not influence calculated AUC. These data indicate that doxepin relative bioavailability is increased during concurrent cimetidine administration and suggest that doxepin hepatic extraction is impaired by cimetidine after oral administration. During chronic doxepin therapy, addition of cimetidine to a therapeutic regimen may result in increased doxepin plasma concentration.

Effects of intravenous ethanol on diameter of epicardial coronary arteries

T here is controversy concerning the effects of ethanol on the coronary vasculature. In animals, ethanol causes inte;lse coronary arterial vasoconstriction.‘,2 In contrast, in man, intracoronary ethanol increases coronary blood flow without changing epicardial coronary arterial dimensions, presumably by dilating the small resistance vessels.3 Because of these conflicting results, we performed this study to assess the influence of intravenous ethanol on heart rate, systemic arterial pressure, and epicardial coronary arterial dimensions in humans. . . . We studied 16 patients (13 men and 3 women, aged 37 to 67 years) undergoing cardiac catheterization for the evaluation of chest pain. The protocol was approved by the Human Subjects Review Committee of the University of Texas Southwestern Medical Center, and all patients gave written, informed consent. No subject had a previous or ongoing problem with alcohol abuse. Antianginal medications were discontinued for >12 hours before the study; no patient smoked for >3 hours before study. All patients were studied in the fasting state after premeditation with oral diazepam 5 to 10 mg. An 8Fr sheath was inserted percutaneously in the femoral artery, through which a Judkins catheter was advanced to the ostium of the left coronary artery. Systemic arterial pressure was measured through the catheter, and heart rate was determined electrocardiographically. The heart rate-systolic arterial pressure product was used as an estimate of myocardial oxygen demand.4 An initial cineangiogram was performed to exclude narrowing of the left main coronary artery. Provided that

Labetalol Analysis in Human Plasma Using Liquid Chromatography with Electrochemical Detection: Application to Pharmacokinetic Studies

Abstract Labetalol determination in human plasma by a sensitive (to 2.5 ng/ml) and selective method using liquid chromatography with electrochemical detection is described. Plasma is extracted with diethyl ether under mildly basic (pH 9) conditions, back-extracted into an aqueous acidic buffer, then injected directly on column. Standard curves using propranolol as an internal standard are linear for concentrations from 2.5 to 200 ng/ml. Within-day and between-day reproducibility is satisfactory with coefficient of variation less than 8% for all concentrations. Sample recovery from the extraction is complete at all concentrations. Utility of the method is demonstrated by a pharmacokinetic study in a hypertensive volunteer who received 43.75 mg labetalol by 10 minute intravenous infusion.

Steady State Verapamil Tissue Distribution in the Dog: Differing Tissue Accumulation

Plasma, heart, and extracardiac tissue verapamil concentrations were measured after sustained intravenous infusions in 11 dogs to determine the differential tissue accumulation of verapamil. A steady state verapamil concentration of 327 +/- 50 ng/ml decreased the mean arterial blood pressure from 104 +/- 9 to 90 +/- 6 mm Hg (p = 0.08) and the P-R interval increased from 118 +/- 4 to 176 +/- 13 ms (p less than 0.001) with second-degree atrioventricular block developing in 6 animals. Verapamil accumulated in organs in the following order: Lung much greater than kidney greater than spleen greater than ventricular myocardium = liver greater than atrial myocardium greater than cerebral cortex greater than fat = skeletal muscle. Levels in the ventricular free wall were consistently greater than atrial levels, but no difference was observed between left versus right-sided cardiac chambers. In summary, affinity of different organs for verapamil is highly variable and organ-specific; furthermore, differential intracardiac chamber accumulation occurs.