Biomedical subjects

J J Krukemyer

Publications and source records attributed to J J Krukemyer.

6 recordsLinked to original sources

PubMed1990

Comparison of hypersensitivity to adrenergic stimulation after abrupt withdrawal of propranolol and nadolol: influence of half-life differences.

To test whether a beta-blocker's pharmacokinetics has an effect on the development of the beta-blocker withdrawal syndrome, we compared response to exercise and isoproterenol after abrupt withdrawal of two beta-blockers, one with a short half-life (propranolol) and one with a long half-life (nadolol). Eight normal males participated in the randomized cross-over trial. They took propranolol, 40 mg every 6 hours for 6 days, and nadolol, 80 mg daily for 7 days. Exercise- and isoproterenol-induced changes in heart rate and pulse pressure were significantly less than control values during treatment with both drugs (p less than 0.05). Significant hypersensitivity of heart rate response was seen on days 2, 3, and 7 after propranolol withdrawal (p less than 0.05) and on day 6 after nadolol withdrawal (p less than 0.005). Hypersensitive responses to isoproterenol were seen after propranolol withdrawal; no evidence of hypersensitivity to isoproterenol was seen after nadolol withdrawal. The area under the heart rate response, time curve after nadolol withdrawal was significantly less than that after propranolol withdrawal (20.3 beats/min.day vs 44.9 beats/min.day, respectively, (p less than 0.05). There was a significant inverse correlation between the degree of hypersensitivity and nadolol pharmacokinetic half-life (r = -0.80, p less than 0.02). We conclude that abrupt withdrawal of a beta-blocker with a long half-life may protect against the development of the beta-blocker withdrawal syndrome.

Adult↗

PubMed1990

Comparison of single-dose and steady-state nadolol plasma concentrations.

The pharmacokinetics of nadolol have been previously reported to be linear between single and steady-state dosing. Data from a study in our laboratory suggested greater than expected beta-blockade with nadolol at steady state. Because the early potency studies were single-dose studies, we hypothesized there was a nonlinearity in nadolol pharmacokinetics which produced higher than expected plasma concentrations at steady state. Six normal volunteers from the previous study (steady state) volunteered to participate in the single-dose study. Plasma concentrations were determined for 24 hr following a single dose of nadolol, 80 mg. A simple, inexpensive, and accurate method for determination of nadolol in plasma or serum by HPLC with fluorometric detection is described. The AUC0-tau at steady state was greater than the AUC0-infinity following a single dose in five of the six subjects. The mean ratio of AUCss/AUCsd was 2.54. This value would be unity in the presence of linear pharmacokinetics. We conclude that the principle of superposition is not applicable for nadolol.

Adult↗

PubMed1990

Use of beta-adrenergic blocking agents in congestive heart failure.

The use of beta-adrenergic blocking agents in patients with congestive heart failure (CHF) is reviewed. The sympathetic nervous system plays an important compensatory role in maintaining inotropic support of the failing heart; therefore, beta blockers have long been considered contraindicated in CHF patients. However, prolonged excessive activation of the sympathetic nervous system may be detrimental. Several clinical trials have shown improved functional status and hemodynamic indices in some patients with dilated cardiomyopathy who received beta blockers. The maximum effect required up to 12 months. Two studies also showed trends toward improved survival. Aspects of study design that appear to be associated with the observation of a favorable response to beta blockade in CHF patients are a low initial dosage, gradual adjustment of the dosage, and a sufficient duration of therapy. Trials with unfavorable results lacked one or more of those design characteristics. Mechanisms proposed to underlie the beneficial effects of beta blockers in CHF patients include up-regulation of beta-receptors, reduction in cardiac energy requirements, protection of the myocardium against norepinephrine toxicity, and anti-arrhythmic effects. Most studies were conducted in patients with idiopathic dilated cardiomyopathy; it is unknown whether beta-blocker therapy is equally beneficial in patients with CHF arising from other causes. Metoprolol is the agent for which there is the most experience; comparative efficacy trials have not been conducted. Beta-adrenergic blockers appear to be beneficial in some patients with CHF. Further trials are needed to identify the patients most likely to respond and the drugs most likely to work.

Adrenergic beta-Antagonists↗

PubMed1989

Drug- or hormone-induced adaptation: model of adrenergic hypersensitivity.

A pharmacokinetic/pharmacodynamic model of hypersensitivity to adrenergic stimulation following abrupt withdrawal of chronic beta blockade was developed. The model employs the Hill equation, a term which describes the competition between isoproterenol and l-propranolol for beta receptors, and a kinetic term which characterizes the appearance and disappearance rates of up-regulated beta receptors. The model predicted peak chronotropic hyperresponsiveness to isoproterenol 48 hr following abrupt withdrawal of chronic treatment with daily propranolol doses of 160 mg, and a drug half-life of 3.5 hr. The model also predicted that increasing the dose rate and prolonging the half-life of propranolol delayed and decreased the extent of adrenergic hypersensitivity. The time-course of adrenergic hypersensitivity simulated by our model was in excellent agreement with that observed in studies which were published earlier by our laboratory. The model underestimated the extent of adrenergic hypersensitivity. The results of our simulation are consistent with a beta agonist-receptor-effector system, which involves spare receptors, amplification of response by second and third messengers, and beta agonist- antagonist-induced receptor regulation.

Adaptation, Physiological↗

PubMed1989

Biphasic pattern of hypersensitivity following acute propranolol withdrawal in normal subjects.

The effect of abrupt propranolol withdrawal on exercise-induced changes in heart rate and blood pressure was studied in six normal volunteers. Response to exercise was measured on two occassions during propranolol treatment and 1, 2, 3, 4, 5 and 7 days after the last dose of propranolol. Exercise-induced changes in heart rate were significantly lower than control during propranolol treatment (p less than 0.005). Following propranolol cessation, all subjects showed a biphasic pattern of hypersensitivity. Heart rate response was significantly greater than control 2, 3 and 7 days after the last propranolol dose (p less than 0.05) and not significantly different from control 1, 4 and 5 days after the last dose of propranolol. Exercise-induced changes in pulse pressure showed a biphasic pattern similar to the changes in heart rate.

Adult↗

PubMed1987

Lovastatin: a new cholesterol-lowering agent.

Lovastatin is a potent new drug for lowering serum cholesterol through inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme for cholesterol biosynthesis. Metabolic studies with lovastatin in healthy volunteers and patients with hypercholesterolemia suggest reduced synthesis of low-density lipoprotein cholesterol (LDL-C) as well as enhanced catabolism LDL-C mediated through LDL receptors as the principal mechanisms for lipid-lowering effects. Total cholesterol and LDL-C are reduced by 30% or more on average when added to baseline therapy, with the effects being more pronounced in nonfamilial than in familial hypercholesterolemia. Optimal dosing appears to be 20 mg given twice a day. The most common adverse effects are gastrointestinal, while the most serious are elevated transaminase levels and the potential for lens opacities. Lovastatin is the first of a new class of lipid-lowering agents, and is effective when added to diet therapy or in combination with other drugs.

Cholesterol↗