Atenolol: a long-acting beta 1- adrenoceptor antagonist.
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Adrenergic beta-Antagonists↗
Biomedical subjects
D G Shand
Publications and source records attributed to D G Shand.
Beta-adrenergic blocking drugs after acute myocardial infarction.
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Adrenergic beta-Antagonists↗
Effect of verapamil on malignant tissue blood flow in SMT-2A tumor-bearing rats.
We investigated the influence of the calcium antagonist verapamil on malignant and normal tissue blood flow using 25-micrometer 113Sn-labeled microspheres. Isogeneic Wistar-Furth rats were inoculated with a metastasizing mammary gland adenocarcinoma (SMT-2A) in the hindlimb musculature and mammary gland. Verapamil was administered as an i.v. bolus via an external jugular vein catheter followed by a supplemental constant infusion with a Harvard infusion pump. Plasma verapamil levels were determined by high performance liquid chromatography, and heart rate and systemic blood pressure were monitored. Verapamil in concentrations of 100 to 200 ng/ml resulted in an approximate 50% increase in tumor blood flow compared to control levels (p less than 0.001) regardless of the site of tumor implantation. These levels were not associated with a significant alteration in arterial blood pressure. These data suggest that verapamil in concentrations currently used in humans may provide a means of improving the delivery of chemotherapeutic agents to solid neoplasms and may also enhance the effectiveness of ionizing radiation treatment by increasing tumor oxygenation.
Adenocarcinoma↗
Clinical comparison of rapid infusion and multiple injection methods for lidocaine loading.
A rapid infusion regimen for lidocaine loading (150 mg infusion over 18 minutes following a 75 mg priming injection) was evaluated in 12 patients. This was compared with multiple injection loading method in six patients involving three 50 mg injections over 18 minutes following the same priming dose. Both loading regimens were followed by a maintenance infusion of 2 mg/min. Predictably, the multiple injection method produced wide variations in lidocaine concentrations compared to the rapid infusion method. Some evidence of lidocaine toxicity (drowsiness, tinnitus) was seen in 13 of the 18 patients after the priming injection. During multiple injection loading, all six patients experienced side effects (drowsiness, tinnitus, dysarthria, or paresthesias.) Only 1 of 12 patients experienced a side effect (drowsiness) during rapid infusion loading. The difference in incidence of adverse reactions was significantly greater with the multiple injection regimen (p less than 0.01) but was associated with measurably greater drug levels.
Adult↗
The ability of vascular tissue to produce prostacyclin decreases with age.
The ability of aortae from young and mature swine to produce prostacyclin (PGI2) has been determined. PGI2 was measured as its hydration product, 6-keto-PGF1 alpha and assayed by stable isotope dilution GCMS. There was no significant difference in 6-keto-PGF1 alpha production between intimal strips from young and mature aortae in the basal state. In the presence of saturating concentrations of arachidonic acid, however, intimal strips from young aortae synthesized twice as much 6-keto-PFG1 alpha as did older tissues. Fatty acid compositions of young and mature aortae were virtually identical, making dietary difference an unlikely explanation for the age-related decrease in PGI2 synthesis. Both young and mature vascular tissues produced essentially only PGI2; insignificant amounts of PGE2 and PGF2 alpha were found.
6-Ketoprostaglandin F1 alpha↗
Relationship between alpha 1-acid glycoprotein and lidocaine disposition in myocardial infarction.
The effects of myocardial infarction (MI) on lidocaine disposition were investigated in eight patients during a constant infusion of 2 mg/min. Plasma lidocaine binding and total plasma and free lidocaine concentrations were measured 12, 24, 36, and 48 hr after beginning therapy and were related to alpha 1-acid glycoprotein (AAG) concentrations. By 48 hr total plasma lidocaine and AAG concentrations had risen, as had plasma lidocaine binding. Because of enhanced binding, free lidocaine concentrations did not change significantly over this time. There was a correlation between AAG and the binding ratio for lidocaine (r = 0.87) and between AAG and total plasma lidocaine concentrations (r = 0.81). The data suggest that the rise in AAG seen after MI is responsible for enhanced plasma lidocaine binding and may, at least in part, be related to lidocaine cumulation.
Adult↗
The artifactual nature of heparin-induced drug protein-binding alterations.
Our purpose was to determine whether the reported alteration of protein drug binding after heparin administration in man was artifactual as a result of continued in vitro activity of triglyceride lipases. The lipoprotein lipase inhibitors protamine (14 mg/ml) and ethylenediaminetetraacetic acid (10 mg/ml) were added to blood samples from 11 healthy subjects before and 15 min after 100 USP units of intravenous heparin. Heparin elevated total nonesterified fatty acid (NEFA) concentration (P less than 0.001) and free fractions of lidocaine, diazepam, and propranolol (P less than 0.001 for all). The presence of the lipase inhibitors diminished the heparin-induced elevation of NEFA (P less than 0.001) and free fractions of lidocaine (P less than 0.001) and diazepam (P less than 0.001), but these values were still greater than control. The inhibitors reduced propranolol binding in control samples and did not diminish the effects of heparin. The change in NEFA concentrations correlated with the free fraction changes of all three ligands (r = 0.739 to 0.849). These data suggest that the heparin-induced protein binding changes are to, a large extent, in vitro artifacts.
Adult↗
Reduced verapamil clearance during long-term oral administration.
Plasma concentrations of verapamil and its metabolite, norverapamil, were measured in six patients with supraventricular tachycardia after the first and seventh dose of a regimen consisting of 120 mg every 8 hr by month. Steady state was reached by the seventh dose and the area under the concentration-time curve (AUC) at steady state (1999 +/- 435[SD] ng/ml . hr) was greater than that after the first dose (788 +/- 224, P less than 0.001). This unexpected cumulation was associated with prolongation of verapamil half-life (t1/2) from 2.75 +/- 1.14 to 4.52 +/- 1.10 hr. Norverapamil AUC also rose from 1225 +/- 405 to 2312 +/- 963 ng/ml/hr during the attainment of steady state. We conclude that verapamil cumulates to a greater extent than predicted from its t1/2, due to reduction in hepatic clearance.
Administration, Oral↗
The method of separate exponentials: a simple aid to devising intravenous drug-loading regimens.
Stimulation of complex dosage regimens for drugs with multicompartmental kinetics is described using the method of separate exponentials. This approach requires that alpha- and beta-phases are treated separately throughout and summed only at the end of the stimulation. The method was used to devise a loading regimen for pirmenol, comprising a priming injection, and a rapid loading infusion, followed by a maintenance infusion. The regimen was tested in a patient with excellent agreement. The method of separate exponentials is mathematically simple and of informational value in that it demonstrates when the early distribution phase is important. Its use can avoid the potentially dangerous assumption of one-compartmental kinetics in the design of intravenous loading regimens.
Anti-Arrhythmia Agents↗
Sex-related differences in the plasma protein binding of lignocaine and diazepam.
1 The percentage of lignocaine free in the plasma of ten females receiving oral contraceptive medication was significantly greater than in 17 males of similar age (18--42 years). 2 In the same subjects the percentage of diazepam free in plasma was significantly greater in the contraceptive treated group than in 11 contraceptive-free females and significantly greater in contraceptive-free females than in males. 3 The differences in lignocaine binding were almost completely attributable to changes in alpha 1-acid glycoprotein concentration, which is reduced by oestrogens. The binding of diazepam was significantly related to albumin, alpha 1-acid glycoprotein and non-esterified fatty acid concentrations which together were related to 55% of the variation in the binding of this basic compound.
Adult↗
Lignocaine disposition in blood in epilepsy.
1 The plasma concentration of alpha 1-acid glycoprotein (AAG) was significantly greater in 27 epileptic subjects receiving anticonvulsants compared with 27 age- and sex-matched drug-free control subjects. 2 Increased AAG concentration was associated with enhanced lignocaine binding in the plasma of epileptics. 3 Increased AAG concentration was also associated with a redistribution of lignocaine out of red cells and into plasma thus lowering the blood to plasma concentration ratio. 4 Enhanced lignocaine binding in epileptics receiving anticonvulsant therapy may result in lower free (unbound) plasma concentrations of the drug compared to normal subjects with equivalent total plasma lignocaine concentrations.
Adult↗
High-performance liquid chromatographic analysis of sulfinpyrazone and its metabolites in biological fluids.
A rapid, senstivie, and specific high-performance liquid chromatographic method is described for the quantitative analysis of sulfinpyrazone and its sulfone and p-hydroxy metabolites in plasma and urine. The method uses two different procedures for sample preparation: (1) a rapid and convenient procedure using a single extraction with 1-chlorobutane and subsequent back-extraction into sodium hydroxide solution for the analysis of sulfinpyrazone and its sulfone metabolite, and (2) a more time consuming procedure using triple extraction with ethylene dichloride, a buffer wash, and back extraction into the base for the additional analysis of the p-hydroxy metabolite. The lower limit of sensitivity for fulfinpyrazone is 50 ng/ml. Concentrations of sulfinpyrazone between 0.05 and 0.1 and 50 micrograms/ml were measured with an average coefficient of variation of 3.9%, ranging from 1.5 to 6.1%.
Butanes↗
The sympathetic response to profound hypothermia and circulatory arrest in infants.
It has been suggested that the increased incidence of ventricular arrhythmias recognized below 30 degrees C might be catecholamine mediated. Elevate catecholamine concentrations have been reported in experimentally induced hypothermia in animals. Plasma concentrations of epinephrine and norepinephrine were measured during profound hypothermia and total circulatory arrest in infants under one year of age undergoing surgical correction of congenital cardiac defects. There was no significant change in either epinephrine or norepinephrine levels during surface cooling to 28 degrees C. Circulatory arrest and exsanguination at 18 degrees C were not associated with a rise in catecholamine levels. However, there was a striking rise in the levels of both epinephrine and norepinephrine with the recommencement of bypass and rewarming. The mean plasma norepinephrine concentration rose from 466 pg/ml (SE +/- 81) at circulatory arrest to 4543 pg/ml (SE +/- 2058) on rewarming bypass (p less than 0.02), while the mean plasma epinephrine concentration rose from 218 pg/ml (SE +/- 54) at circulatory arrest to 3724 pg/ml (SE +/- 1064) on rewarming bypass (p less than 0.02). The plasma catecholamine concentrations fell once cardiopulmonary bypass was discontinued, when the infant's temperature was 37 degrees C. It would, therefore, appear unlikely that the ventricular irritability recognized below 30 degrees C is due to catecholamine excess. The accumulation of catecholamines and/or metabolic products in the infants during circulatory arrest with their subsequent release into the circulation during rewarming may account for the elevation of catecholamine levels during rewarming bypass.
Body Temperature↗
Lidocaine plasma protein binding.
The percent of unbound lidocaine in the plasma of 24 healthy subjects was measured by equilibrium dialysis after addition of 3 microgram/ml C14 lidocaine hydrochloride. The percentage of unbound lidocaine varied from 19.9 to 38.8 (30.2 +/- 5, mean +/- SD) was inversely related to the concentration of alpha 1-acid glycoprotein (AAG) in the plasma (r = -0.931, p less than 0.001). The binding ratio (number of moles bound divided by number of moles unbound) of lidocaine was directly related to the plasma AAG concentration (r = 0.960, p less than 0.001). The binding ratio of lidocaine in solutions containing AAG but no albumin, prepared from the plasma of subjects in the study, was also directly related to the concentration of this acute-phase protein (r = 0.909, p less than 0.001). Human serum albumin solution (4 gm/100 ml) bound lidocaine to the extent of 20% under the same conditions. There was no relationship between the binding ratio of lidocaine and the albumin concentration in the plasma of the 24 subjects. In 7 normal subjects variation in AAG between 2 samples collected at least 1 mo apart was associated with a concomitant change in plasma lidocaine binding (r = 0.943, p less than 0.01). Thus even in normal subjects there is considerable interindividual and intraindividual variation in lidocaine binding, and measurements of AAG concentration in plasma may be a useful predictor of the extent of lidocaine plasma binding.
Adult↗
Diazepam and N-desmethyldiazepam redistribution after heparin.
The effects of heparin, 1,000 U intravenously, on the blood, plasma, and free concentrations of diazepam and its metabolite, N-desmethyldiazepam, have been investigated 3 hr after oral administration of 10 mg diazepam to 5 normal subjects. The percent free diazepam and N-desmethyldiazepam increased 15 min after heparin from 1.66 +/- 0.35 to 3.99 +/- 1.88 (mean +/- SD; p less than 0.05) in the case of diazepam anolite. The actual free concentration of diazepam rose from 3.6 +/- 1.04 to 6.9 +/- 1.33 ng/ml (p less than 0.05) 15 min after heparin while total blood concentration was unchanged (144 +/- 54 vs 130 +/- 57 ng/ml). Free concentrations of N-desmethyldiazepam rose from 0.62 +/- 0.17 to 1.01 +/- 0.34 but the effect, though consistent, was not statistically significant. Blood concentrations did not change (15 +/- 3.2 vs 14 +/- 3.9 ng/ml). That free drug level rose without a change in blood or total plasma levels suggests that factors other than simple plasma binding displacement are involved in this drug interaction.
Adult↗
Propranolol disposition in renal failure.
1 Previous studies of propranolol disposition in renal failure have been conflicting. 2 Using simultaneous administration of [3H]-propranolol intravenously and unlabelled propranolol orally the principal determinants of drug distribution were calculated in normals, patients with severe renal impairment (creatinine clearance 14.5 +/- 2.8 ml/min) but not on haemodialysis and patients on haemodialysis (creatinine clearance less than 5 ml/min). 3 The effect of haemodialysis on propranolol binding and free fraction was also examined. The percentage of propranolol unbound rose from 7.1% to 9.9%. (P less than 0.001) 20 min following heparinization and beginning haemodialysis. This was accompanied by a large rise in free fatty acids from 0.567 +/- 0.059 to 3.326 +/- 0.691 mumol/ml (P less than 0.005). 4 The blood to plasma concentration ratios of propranolol were significantly higher in patients with renal failure (P less than 0.02) and on haemodialysis (P less than 0.001) and were significantly negatively correlated (P less than 0.001) with the haematocrit. 5 Although the half-life propranolol was significantly shortened in the patients with renal failure (P less than 0.02), there was no change in the apparent liver blood flow, extraction ratio or the principal determinants of steady-state drug concentrations in blood namely oral and intravenous clearance from blood. 6 There is, therefore, no pharmacokinetic basis to adjust the dosage of propranolol in patients with renal failure.
Administration, Oral↗
Increased plasma propranolol binding in myocardial infarction.
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Blood Proteins↗
Uptake of propranolol by the lung and its displacement by other drugs: involvement of the alveolar macrophage.
The role of the alveolar macrophage in the uptake of 3H-propranolol by the isolated perfused rabbit lung and displacement of 3H-propranolol from this site has been investigated. Removal of 3H-propranolol (100 microgram) by the lung was characterized by a rapid distribution phase (t1/2 min) and a slower elimination phase with a clearance of 22.4 ml/min (t1/2 = 47 min). Addition of chlorpromazine (1 mg) at 30 min was followed by a twofold increase in perfusate concentrations of 3H-propranolol which was also associated with a reduction of 3H-propranolol in macrophages recovered from lungs at the end of perfusion experiments. Experiments using isolated alveolar macrophages demonstrated uptake of propranolol and marked inhibition by 100-fold higher concentrations of chlorpromazine and imipramine. In the intact dog, injection of imipramine (1 mg/kg) 60-70 min after bolus injection of 3H-propranolol (0.3 mg/kg) was associated with an immediate increase in blood levels of 3H-propranolol consistent with tissue redistribution. It is concluded that chlorpromazine and imipramine can displace propranolol from the lung,and that the alveolar macrophage is involved in this process.
Animals↗