Lipids and lipoproteins during antihypertensive drug therapy. Comparison of doxazosin and atenolol in a randomized, double-blind trial: the Alpha Beta Canada Study.

A randomized double-blind trial comparing the alpha-adrenergic blocker doxazosin and the beta-adrenergic blocker atenolol was completed by 131 patients with mild to moderate hypertension. Blood pressure and fasting blood lipids were determined at baseline and 4, 12, and 24 weeks of treatment. At entry, plasma lipids and lipoproteins were similar in those patients randomized to doxazosin or atenolol. After 24 weeks of treatment with atenolol, there were significant (P < .05) decreases in high-density lipoprotein cholesterol (HDL-C) and increases in triglycerides and very-low-density triglycerides (VLDL-T). In contrast, doxazosin was associated with significant (P < .05) increases in HDL-C and decreases in triglycerides and VLDL-T. There were no significant differences in HDL apolipoprotein (apo) A-I or low-density lipoprotein apoB between the drugs, but atenolol decreased the ratio of HDL-C to apoA-I, and doxazosin increased this ratio, differences that were statistically significant (P < .002). Neither apoA-I nor apoB concentration at baseline nor apoE phenotype was predictive of the lipid responses during antihypertensive treatment with either drug. Thus, there are significant favorable changes in HDL-C, total triglycerides, and VLDL-T between patients with mild to moderate hypertension and normal plasma lipids when treated with the alpha-blocker doxazosin compared with the beta-blocker atenolol. Plasma lipid or apo concentrations were not predictive of their lipid response during antihypertensive therapy with either of these agents.

Evaluation and application of the linear variable differential transformer technique for the assessment of human dorsal hand vein alpha-receptor activity.

Diurnal, day-to-day, intrasubject, and intersubject variability of responsiveness of dorsal hand veins to norepinephrine has been investigated in healthy young subjects through the use of a novel technique in which a linear variable differential transformer (LVDT) is placed directly over the vein. Under constant operating conditions, control vein diameter remained consistent. There is a log dose responsiveness to norepinephrine infused directly into the hand vein. There was little diurnal, day-to-day, or intrasubject variability in the dose of norepinephrine required to induce 50% constriction of hand vein diameter. The responsiveness to norepinephrine of different veins in either hand was also consistent. However, there was wide intersubject variability, apparently unrelated to age, gender, or other subject characteristics. We conclude that the LVDT method is reproducible and reliable and offers a relatively noninvasive means of assessing the effects of disease and drugs on the human dorsal hand vein in vivo. The LVDT technique has been applied to study the rate of onset, magnitude of effect, dose responsiveness, and duration of action of intravenous dihydroergotamine, 0.1, 0.2, and 0.4 mg, on human dorsal hand veins. Despite systemic intravenous administration, there was an average delay in maximum response of 30 minutes to 1 hour. Venoconstriction was incomplete, with a maximum reduction of approximately 50% of vein diameter after each of the larger doses. There was no significant difference between the effects produced by 0.2 or 0.4 mg, which persisted for 6 hours after dosing.

Interaction between oral verapamil and beta-blockers during submaximal exercise: relevance of ancillary properties.

The interaction between verapamil and beta-blockers may involve negative chronotropic, inotropic, and dromotropic effects. Three randomized, double-blind, crossover trials evaluated standardized submaximal exercise hemodynamics after oral verapamil (120 mg) and beta-blocker, alone and in combination, in groups of eight healthy men. The beta-blockers were propranolol (80 mg), metoprolol (100 mg), and pindolol (5 mg). During submaximal exercise, each beta-blocker produced similar reductions in heart rate. Likewise, each verapamil and beta-blocker combination caused greater decreases in heart rate and prolongation of PR interval than did either drug alone. Only the verapamil and propranolol combination produced greater reduction of systolic blood pressure and prolongation of rate-adjusted PR interval. All verapamil and beta-blocker combinations caused frequent adverse events, predominantly exercise fatigue and resting first-degree heart block. Although the verapamil and metoprolol or pindolol combinations produced lesser negative dromotropic or inotropic effects compared with verapamil and propranolol, coadministration of verapamil and any beta-blocker should be performed cautiously.

Familial studies of heritability of alpha1-adrenergic receptor responsiveness in superficial veins.

BACKGROUND: Studies of monozygotic and dizygotic twins indicate an important genetic influence on the variability of responsiveness to norepinephrine in superficial human vein. OBJECTIVES: Genetic aspects of variability of alpha1-adrenergic receptor responsiveness to norepinephrine in superficial veins were further investigated by studying the response to norepinephrine in the dorsal hand veins of parents and their children. METHODS: Subjects were healthy nonsmoking adults (n = 24; age range, 40 to 52 years) and their biological children (n = 20; age range, 15 to 26 years) who were free from medications likely to modify vascular tone. Superficial vein responsiveness to norepinephrine was assessed by the linear variable differential transformer technique. The dose of norepinephrine required to constrict superficial vein diameter by 50% from baseline (ED50) was calculated for each subject. Heritability was estimated by standard techniques of regression of mid-parent/child (natural logarithm) ED50 values. RESULTS: ED50 ranged from 5.6 to 254.6 ng/min in the parents and from 7.8 to 242.3 ng/min in the children. Heritability was calculated at 0.88. CONCLUSIONS: These data confirm wide variability in superficial vein responsiveness to norepinephrine. The results confirm a major genetic influence in biological responsiveness of superficial vein to norepinephrine in healthy humans. Heritability of vascular alpha-adrenergic receptor responsiveness may influence vascular regulation during sympathetic stimulation and blockade.

Cholestyramine and spironolactone and their combination in digitoxin elimination.

The effects of oral cholestyramine 4 gm 8 times daily and spironolactone 300 mg daily, given independently and in combination, on the elimination rate of digitoxin were studied in 6 healthy subjects pretreated with 0.1 or 0.15 mg oral digitoxin daily for 30 days before each intervention. The mean pretreatment digitoxin concentrations for the group ranged from 21 +/- 2.9 (SD) ng/ml to 28.5 +/- 6.9 ng/ml. The mean control digitoxin half-life (t 1/2) was reduced from 141.6 to 84.4 by treatment with cholestyramine alone. Treatment with spironolactone alone prolonged the mean digitoxin t 1/2 to 192.2 hr. The mean digitoxin t 1/2 after both active drugs was intermediate at 102.9 hr. Spironolactone did not fulfill the expectation from animal studies that it would enhance the clearance of digitoxin by cholestyramine. The prolongation of digitoxin elimination after spironolactone may contraindicate this drug in digitoxin intoxication.

Measurement of partial agonist activity of pindolol.

The partial agonist activity of pindolol was assessed by examining the action of cumulative doses on the heart rate of resting, standing, and exercising healthy men and by studying the interaction of pindolol with metoprolol, a beta blocker devoid of partial agonist activity. Pindolol did not affect resting or standing heart rates (RHR, SHR) but reduced the heart rate after vigorous exercise by approximately 25%. The flatter dose-response curve of pindolol for exercise heart rate (EHR) has been reported from practolol and oxprenolol, which also exert partial agonist activity. After extremely large doses of pindolol there was no evidence of enhancement of agonist activity on RHR, nor was there any evidence of dominance of agonist activity over antagonist activity on EHR. Metoprolol did not alter RHR but reduced SHR by approximately 20% and EHR by approximately 31%. The effects of pindolol on SHRs and EHRs were not enhanced by metoprolol, even though the drug itself induced greater reductions of both. The reduction of SHR by metoprolol was reversed by pindolol. Pindolol appears to have greater affinity than metoprolol for atrial beta adrenoceptors in man.

The influence of age on dorsal hand vein responsiveness to norepinephrine.

The influence of age on the responsiveness of dorsal hand vein alpha-receptors to local infusions of norepinephrine was investigated by the use of a novel technique, the linear variable differential transformer. Studies were conducted in two groups of healthy subjects, 26 elderly individuals (14 men and 12 women) 60 to 78 years old and 32 young individuals (24 men and eight women) 16 to 29 years old. There was wide interindividual variation in responsiveness to norepinephrine within both groups of subjects. The dose of norepinephrine required to produce 50% venoconstriction in the elderly ranged from 1.5 to 300 ng/min (geometric mean 24.0 ng/min). The dose required to produce 50% venoconstriction in younger individuals ranged from 1.6 to 360 ng/min (geometric mean 23.8 ng/min). These results suggest that there is no systematic influence of age on dorsal hand vein alpha-receptor responsiveness. A power calculation demonstrates a very small likelihood of a type II error.

Genetic aspects of variability in superficial vein responsiveness to norepinephrine.

Venoconstriction of the dorsal hand vein by local norepinephrine infusion was measured by the linear variable differential transformer method in 15 healthy unrelated subjects and eight pairs of monozygotic and six pairs of dizygotic twins. Incremental norepinephrine infusion produced dose-related venoconstriction. In unrelated subjects the doses of norepinephrine constricting basal vein diameter by 50% (ED50) ranged from 3.9 to 120.5 ng/min. There was a positive linear relationship between doses of norepinephrine infused and local steady-state plasma concentrations of norepinephrine achieved in each subject. The reciprocals of the slopes of these dose-concentration relationships, which reflect local norepinephrine clearance (disposition) in the vein, ranged from 0.47 to 1.86 ml/min. Plasma concentrations of norepinephrine associated with reduction of basal vein diameter by 50% (EC50) ranged from 1.4 to 110.2 ng/ml, with variability similar to that of ED50. There was a very high level of concordance in ED50, EC50, and clearance of norepinephrine within pairs of monozygotic twins but not within dizygotic twins. Differences in pharmacokinetics of infused norepinephrine exert a minor impact on overall intersubject variability. Genetic aspects of "tissue responsiveness" (i.e., vascular alpha-adrenoceptor response, smooth muscle contractility, and endothelial function) appear to be largely responsible for the wide intersubject variability in venoconstrictor responsiveness to norepinephrine.

Synergistic adverse hemodynamic interaction between oral verapamil and propranolol.

The interaction between oral verapamil and propranolol may involve negative chronotropic, inotropic or dromotropic effects. The immediate effects of orally administered verapamil (120 mg) and propranolol (80 mg), alone and combined, on submaximal exercise hemodynamics and on pharmacokinetics were studied in eight healthy male volunteers in a randomized, double-blind, crossover manner. Maximum effects on heart rate, systolic blood pressure, PR interval and rate-adjusted PR prolongation were greatest with the combined administration of verapamil and propranolol. The combination caused a high frequency of adverse drug events, predominantly exercise fatigue. Verapamil increased the AUC and Cmax and shortened the tmax of propranolol. Propranolol decreased the AUC and Cmax of verapamil. The greater reduction of heart rate with the combination of verapamil and propranolol was only partially explained by higher plasma concentrations of propranolol. The combination of propranolol and verapamil produced clinically important synergistic adverse effects during exercise. Negative dromotropic effects occurred primarily by direct AV node inhibition and were more important than previously recognized.

Grapefruit juice--felodipine interaction in the elderly.

BACKGROUND: Grapefruit juice can increase the oral bioavailability of a broad range of medications. This interaction has not been assessed in the elderly. METHODS: Twelve healthy elderly people (70 to 83 years of age) were administered 5 mg felodipine extended release with 250 mL grapefruit juice or water in a single-dose study. Subsequently, 6 of these people received 2.5 mg felodipine for 2 days, followed by 5 mg felodipine for 6 days with 250 mL grapefruit juice or water in a steady-state study. Plasma concentrations of felodipine and dehydrofelodipine metabolite, blood pressure, and heart rate were measured over 24 hours after single and final steady-state dose. RESULTS: Mean felodipine area under the curve and maximum concentration were 2.9-fold and 4.0-fold greater, respectively, with grapefruit juice in both studies. Interindividual variability in the extent of the interaction was high. Felodipine apparent elimination half-life was not altered. Dehydrofelodipine area under the curve and maximum concentration were increased and dehydrofelodipine/felodipine area under the curve ratio was reduced. Systolic and diastolic blood pressures were lower with grapefruit juice in the single-dose study, whereas they were not different between treatments in the steady-state study. Curvilinear relationships existed between plasma felodipine concentration and changes in systolic and diastolic blood pressures. Heart rates were higher with grapefruit juice in both studies; however, this effect was greater and more prolonged at steady state. CONCLUSIONS: A normal dietary amount of grapefruit juice produced a pronounced, unpredictable, and sustained pharmacokinetic interaction with felodipine by reducing its presystemic metabolism in the elderly. The different blood pressure results between the studies can be explained by felodipine concentration-blood pressure response relationships. The elderly should be particularly cautioned about concomitant grapefruit juice and felodipine ingestion.

Pamatolol: phase I evaluation of the pharmacodynamics of a cardioselective beta adrenoceptor blocking drug.

A Phase I evaluation of a new adrenoceptor blocker, pamatolol, was performed in 10 healthy male volunteers. Minor reductions in standing and exercise and isoproterenol-induced increases in heart rate were observed with the 10-mg oral dose and appeared maximal with the 400-600 mg dose. The rate of decline of effect averaged 1.5% of the exercise heart rate/hr. Neither resting systolic time intervals nor post-exercise pulmonary function was affected by this dose range of pamatolol. Based on the latter responses and the isoproterenol dose response curve, we tentatively conclude that pamatolol is relatively cardioselective in man.

Ineffectiveness of beta-adrenergic blockers on ventilatory response to carbon dioxide.

The effects of the beta-adrenoceptor blockers atenolol, metoprolol, pindolol, and propranolol on the ventilatory response to carbon dioxide rebreathing have been determined in a double-blind randomized manner. Eight healthy, male, nonsmoking subjects received cumulative doses of each drug over a 10-hr period. The effects of each drug on heart rate and carbon dioxide sensitivity were determined at intervals of 2 hr and were related to plasma concentrations of each drug. Maximum reduction of exercise heart rate was achieved with all four beta blockers and plasma concentrations were in the usual therapeutic range for these drugs. There was considerable intersubject and within-subject variability in ventilatory responsiveness to inhaled carbon dioxide, but we were not able to discern any alteration in central sensitivity to increasing carbon dioxide concentrations.

Kinetics of pamatolol, a cardioselective beta adrenoreceptor blocker.

The systemic bioavailability, elimination half-life (t1/2), and plasma concentration--response relationships of pamatolol, a relatively cardioselective beta adrenoceptor blocker, have been measured in healthy subjects. Pamatolol is rapidly and completely absorbed after oral dosing. Elimination t1/2 ranged from 2.9 to 4.6 hr after oral doses and from 2.2 to 5.6 hr after intravenous doses. There was a clear relationship between log plasma pamatolol concentration and sympathetic blockade assessed by reduction of exercise heart rate. Concentration-response curves were essentially identical after oral and intravenous doses. There is no evidence of a first-pass effect, nor is there any evidence of metabolite activity.

Respiratory and cardiac effects of metoprolol and bevantolol in patients with asthma.

The effects on standing heart rate and respiratory function of two relatively selective beta 1-adrenoceptor antagonists, metoprolol and bevantolol, were compared in a double-blind, randomized, crossover study of 16 patients with asthma. After control observations on 2 separate days, the patients received approximately equivalent cardiac beta-adrenoceptor antagonist doses of metoprolol, 12.5, 25, 50, and 100 mg, and bevantolol, 18.75, 37.5, 75 and 150 mg, at intervals of 2 hours. Dosing was stopped if symptoms warranted or if there was a fall of greater than or equal to 20% in the forced expiratory volume in 1 second. In general, the cumulative dosing regimen proved a safe and effective means of assessing bronchial responsiveness to these beta-blockers in asthma, but one patient had to be dropped from the study because of severe bronchoconstriction after the first dose. Of the 15 patients studied who were taking both drugs, seven patients were withdrawn prematurely. In these seven patients, the average maximum tolerated cumulative doses were 45.5 mg bevantolol and 26.8 mg metoprolol, doses that are much lower than those usually required for therapeutic activity. The respiratory response to either drug could not be predicted.

Correlation between plasma diphenhydramine level and sedative and antihistamine effects.

The sedative and antihistamine effects of diphenhydramine were assessed in relation to plasma concentration after placebo, diphenhydramine 50 mg intravenously, and diphenhydramine 50 mg orally to each of 6 healthy volunteers on three separate occasions. Diphenhydramine plasma elimination t1/2 was 3.0 to 4.3 hr, volume of distribution was 188 to 336 L, and clearance was 637 to 1,014 ml/min. Systemic bioavailability of the oral preparation ranged from 0.26 to 0.60. The sedative effect of intravenous diphenhydramine differed from that of placebo only during the first 3 hr. Antihistamine effect, as measured by reduction of histamine provoked skin wheal diameter, was significantly different from that of placebo for at least 8 hr. There was a positive correlation between plasma diphenhydramine level and sedative and antihistamine effects, but wide variation in the extent and rate of change of these effects were observed between the subject. There appears to be a concentration range of 25 to 50 ng/ml, within which there is significant antihistamine effect without significant sedation.

Influence of intrinsic sympathomimetic activity and cardioselectivity on beta adrenoceptor blockade.

Dose-response curves for propranolol and oxprenolol were studied in healthy volunteers, with a standardized excercise test and percentage reduction in excercise heart rate (EHR) as the index of drug effect. The dose-response curves obtained were compared with similar curves previously reported for sotalol, practolol, and atenolol with identical experimental methods. Two distinct types of response were identified: in the first, shown by propranolol and sotalol, increasing doses of the beta adrenoceptor-blocking drug continued to produce increasing effects to the limits of the dose levels examined; with the second (oxprenolol and practolol), increasing the dose initially resulted in substantial increase in effect but subsequently larger doses produced almost no increase in effect. Consideration of the additional properties of these beta adrenoceptor-blocking drugs revealed that both practolol and oxprenolol have intrinsic sympathomimetric activity (ISA), whereas propranolol and sotalol do not. In addition, practolol is cardioselective. Further investigation of the possible influence of ISA or cardioselectivity on beta adrenoceptor-blocking activity was undertaken by studying the effects of combinations of drugs on EHR. Sotalol produced greater effect when given 2 hr after sotalol, oxprenolol, practolol, or atenolol. When oxprenolol was given after sotalol or oxprenolol, or practolol was given after sotalol or practolol, there was no further increase in percentage reduction in EHR. When atenolol was given, the combinations of sotalol and atenolol together with two doses either of sotalol or atenolol all induced increases and similar final percentage reductions in EHR. Thus atenolol induces effects like those of sotalol, which are quite different from those of oxprenolol or practolol. The presence or absence of ISA would appear to be the important difference between these two groups of drugs: ISA would, therefore, appear to be demonstrated in man by flattening of the dose-response curves with exercise.

Quinidine interaction with nifedipine and felodipine: pharmacokinetic and pharmacodynamic evaluation.

Conflicting findings suggest that serum quinidine concentrations may be decreased or increased by nifedipine. We performed a double-blind, placebo-controlled trial of Latin-square design. Twelve healthy men received 3 days of pretreatment with nifedipine prolonged action (20 mg twice a day) or felodipine extended release (10 mg every day), another dihydropyridine calcium antagonist, followed by coadministration of quinidine (400 mg). Quinidine pharmacokinetics were not changed by either dihydropyridine. However, 3-hydroxyquinidine area under the concentration-time curve (AUC) and 3-hydroxyquinidine/quinidine AUC ratio were decreased by felodipine, consistent with reduced metabolite formation. Heart rates and adverse events were higher with felodipine, demonstrating lack of bioequivalence with nifedipine. The QTc interval did not deviate from that expected for the observed quinidine concentration, suggesting the pharmacokinetics of active quinidine metabolites were not markedly altered among treatments. Quinidine disposition did not appear to be changed sufficiently to be clinically important by sustained-release nifedipine and felodipine.

Clinical pharmacologic observations on atenolol, a beta-adrenoceptor blocker.

The effects of oral and intravenous administration of atenolol were studied in healthy volunteers. The oral administration of a series of single doses of atenolol reduced an exercise tachycardia. After a 200-mg dose, the effect on an exercise tachycardia was maximal at 3 hr and declined linearly with time at a rate of approximately 10% per 24 hr. The peak plasma atenolol concentration occurred at 3 hr and thereafter declined exponentially with time with an elimination half-life of 6.36 +/- 0.55 hr: 43 +/- 3.9% of the dose was excreted in the urine within 72 hr. There was a correlation between the reduction in an exercise tachycardia and the logarithm of the corresponding plasma concentration. The intravenous administration of atenolol reduced exercise tachycardia with a significant correlation between effect and plasma concentration. After 50 mg intravenously, 100% of the dose was recovered from the urine, and the clearance was 97.3 ml/min. Comparison of AUC O leads to chi after oral and intravenous administration of 50 mg showed the bioavailability to be 63% after oral drug. Repeated oral administration of atenolol 200 mg daily either as a single dose or in divided 12 hourly doses for 8 days maintained reduction of an exercise tachycardia of at least 24% during the period of drug administration. The plasma elimination half-life, area under the plasma concentration-time curve, and peak plasma concentration after 200 mg atenolol were not changed by chronic dosing for 8 days.

Elevation of serum total cholesterol and triglyceride levels during amiodarone therapy.

Over the last decade there has been increasing awareness that some cardiovascular medications may adversely affect serum cholesterol concentrations. It has been suggested previously that amiodarone may alter serum cholesterol, triglyceride and glucose concentrations, but no substantive data support this observation. During the course of a 1-year study of adverse effects in patients taking amiodarone, 21 patients with normal total serum cholesterol before entry in the study were prospectively investigated for changes in lipid metabolism. A statistically significant sustained rise of 17% in total serum cholesterol occurred from a baseline of 178 +/- 7 mg/dl (4.6 +/- 0.2 mmol/liter) to 208 +/- 9 mg/dl (5.4 +/- 0.2 mmol/liter). Ten of the patients developed elevations of cholesterol above the 75th percentile for their age and sex. This group experienced a sustained rise of 20% in mean cholesterol concentration from baseline, had statistically significant elevations of triglyceride concentrations and had higher glucose and desethylamiodarone concentrations than patients who did not develop elevations in cholesterol greater than the 75th percentile. It may be possible to predict these differences in response as early as 4 to 8 weeks after starting therapy. Because amiodarone is increasingly used in patients without ischemic heart disease or life-threatening arrhythmias, the potential atherogenic risk of these metabolic abnormalities merits further investigation.

Relation of amiodarone hepatic and pulmonary toxicity to serum drug concentrations and superoxide dismutase activity.

Hepatic enzymes, pulmonary function, serum amiodarone and desethylamiodarone (DEA) concentrations and erythrocyte superoxide dismutase (SOD) activity were monitored at regular intervals for 1 year in 30 patients receiving amiodarone. Subclinical hepatotoxicity developed in 5 patients. These patients had higher baseline alanine transaminase values (42.6 +/- 6.8 vs 22.9 +/- 1.8 U/liter) and had an increase in serum aspartate transaminase from 27 +/- 4.1 at baseline to 147 +/- 77.3 U/liter at 12 months. The other patients had little variation in aspartate transaminase. Six patients with normal baseline carbon monoxide diffusing capacity had subclinical pulmonary toxicity develop with a mean decrease in diffusing capacity to 0.7 +/- 0.05 of the baseline value, which correlated with decreasing erythrocyte SOD activity. Mean carbon monoxide diffusing capacity and SOD activity remained unchanged in the other patients. The mechanisms of hepatic and pulmonary injury remain unknown, but appear to be associated with exposure to higher total serum concentrations of amiodarone plus DEA. Patients who had hepatic and/or pulmonary abnormalities develop received higher doses of amiodarone (440 +/- 27 vs 340 +/- 18 mg/day), but also had a higher amiodarone:DEA ratio suggesting that dose-dependent kinetics contributed to the higher concentrations. Elevated baseline alanine transaminase may indicate increased risk for hepatotoxicity while a progressive decrease in erythrocyte SOD may be an early indication of pulmonary toxicity. The latter finding indicates a need to investigate the role of free radicals in the pathogenesis of amiodarone pulmonary toxicity.