Plasma Propranolol Concentrations Research Articles

Exercise and the pharmacokinetics of propranolol, verapamil and atenolol.

The volumes of distribution of the beta-adrenoceptor blocking agents propranolol and atenolol, and the calcium antagonist verapamil, during exercise have been investigated. Changes in the plasma concentrations of atenolol and propranolol during exhaustive exercise at 70% of maximal aerobic power were compared after 1 week of oral treatment (propranolol 80 mg b.d. and atenolol 100 mg once daily) in 12 healthy volunteers. In a second study the effect of 10 min exercise at 50% of maximal aerobic power on steady state plasma concentrations of propranolol, atenolol and verapamil was compared in 7 healthy subjects. The drugs were administered by a continuous intravenous infusion. The plasma concentration of atenolol was not changed by exercise in either study, but the plasma concentrations of propranolol and verapamil were significantly increased in both studies. However, after correction for changes in plasma volume during exercise, the plasma propranolol concentration was not significantly elevated in the second study. From the results it is concluded that exercise led to a reduction in the volume of distribution of propranolol during prolonged exercise (25 min) at 70% Wmax, which was not clearly demonstrable during 10 min exercise at 50% Wmax. The volume of distribution of verapamil was reduced during 10 min exercise at 50% Wmax. No change in the volume of distribution of atenolol during exercise could be shown. The changes in the volumes of distribution of propranolol and verapamil during exercise may contribute to preventing an increase in the half-life of these drugs in patients performing prolonged physical exercise.

Effects of the β-adrenoceptor antagonists atenolol and propranolol on human whole saliva flow rate and composition

The effects of β-adrenoceptor antagonists on salivary secretion have been extensively studied in animals but not in man. The aim here was to compare salivary flow rate and composition in man during 1 week of treatment with a non-selective (propranolol 80 mg b.i.d.) and a β 1-selective (atenolol 50 mg o.d.) antagonist with that of placebo. The randomized, double-blind, cross-over (“Latin square”) design was used and 42 healthy male volunteers were recruited to the study. The treatment periods were separated by a wash-out period of 2 weeks. Whole saliva was sampled on day 0 (before) and on day 7 during each treatment. The plasma concentration of propranolol and atenolol was determined from blood samples obtained on day 7. Resting saliva was assessed for flow rate, amylase activity and concentration of total protein, hexosamine and sialic acid. Stimulated saliva was assessed for flow rate, pH, buffer pH, amylase activity and concentration of total protein, Ca 2+, Mg 2+, Na +, K +, Cl − and PO 4 2−. In resting as well as stimulated whole saliva both the total protein concentration and the amylase activity were significantly decreased during the active treatment periods ( p < 0.05– p < 0.001). At lunchtime during atenolol treatment the hexosamine/total protein and the sialic acid/total protein ratios were significantly increased ( p < 0.05– p < 0.01), suggesting a possible effect on protein synthesis. In addition, the concentrations of Ca 2+, PO 4 2−, Cl − and Mg 2+ were significantly altered during the active treatment periods ( p < 0.05– p < 0.001). The results suggested that the ductal Na + and Cl − transport is under β-adrenoceptor control. Therapeutic doses of either the non-selective (propranolol) or the β 1-selective (atenolol) adrenoceptor antagonist thus significantly altered the composition of resting as well as stimulated whole saliva in healthy male volunteers, without affecting secretion rates.

Influence of the injection volume on the release pattern of intramuscularly administered propranolol to rats

The aim of this study was to investigate the relationship between the injection volume and the bioavailability of propranolol after i.m. administration. Aqueous solutions of propranolol (3 mg) were administered i.m. in 50, 100 or 200 μl and i.v. (1 mg) in 0.5 ml to rats. Intramuscular injections were given alternately into the left and right hind leg. Blood samples were taken at regular time intervals during a period of 24 h. Propranolol concentrations in plasma were determined by HPLC. Intravenous data were fitted according to either a mono- or a bi-exponential function. The amount of non-absorbed drug remaining at the i.m. injection site was calculated according to the method of deconvolution. Absorption rate constants ( k a ) were calculated from the initial phases (0–90 min) of the log fraction of drug not-adsorbed vs time curves. The area under the curve (AUC 0− t ) to 8 h post-injection was calculated by the linear trapezoidal rule. A Kendall's rank order test ( α = 0.05) was applied for correlation testing. Intramuscular data showed a biphasic decline of propranolol in the blood; at early times the curves were steep while at later times they became flatter. Mean initial absorption rate constants (± S.D) were 0.12 (± 0.02), 0.20 (± 0.04) and 0.27 (± 0.07) h −1 respectively, and mean AUC 0− t per g body weight (± S.D.) after i.m. injection of 50, 100 and 200 μl were 5.3 (± 1.2), 7.0 (± 1.1) and 9.2 (± 1.8) μg h 1 −1, respectively. Propranolol availability after intramuscular injection was incomplete. A positive correlation between either AUC 0− t, or k a and the injection volume was established. An increased absorption rate at large injection volumes was shown not to be in accordance with the diffusion-controlled absorption model. This, and the incomplete release after 8 h, could be attributed to the precipitation at or binding of the drug to the injection site. It is concluded that the absorption rate as well as the availability of intramuscularly injected propranolol from aqueous solutions is influenced by the injection volume.

Mechanisms of pharmacokinetic interaction between propranolol and quinidine in rats.

In order to study the mechanism of propranolol-quinidine interaction, the effects of quinidine on propranolol pharmacokinetics were examined in male Wistar rats. The concurrent oral administration of quinidine (10 mg/kg) markedly increased the plasma concentration of propranolol (2.5 mg/kg), and the area under the propranolol concentration-time curve increased about 3.6-fold. These results are consistent with previous observations in man and indicate the possible usefulness of the male Wistar rat as an animal model for investigating the mechanisms of the drug interaction. When propranolol was given intravenously, a concurrent administration of quinidine increased the apparent distribution volume of propranolol, mainly by decreasing its plasma protein binding. However, the systemic clearance of propranolol was not significantly altered by quinidine. Thus, quinidine increased the availability of oral propranolol from 13.8 +/- 2.2 to 44.2 +/- 4.6% (p less than 0.01). Furthermore, quinidine delayed the elimination of propranolol from the isolated perfused rat liver. These results indicate that quinidine reduces the presystemic elimination of propranolol in the liver, thereby increasing its systemic availability after oral administration.

Dual adrenergic control of renin during nonhypotensive hemorrhage in conscious dogs.

These experiments evaluated the contribution of renal alpha-adrenoceptors, renal beta-adrenoceptors, and extrarenal beta-adrenoceptors to increased plasma renin activity (PRA) during nonhypotensive hemorrhage in conscious dogs. Blood withdrawal at a rate of 16 g/kg body wt over 20 min increased PRA to nearly threefold control levels without decreasing mean arterial pressure. The PRA response to hemorrhage was reduced to a greater extent by simultaneous direct renal arterial (ira) infusion of phenoxybenzamine and propranolol than by propranolol alone. Phenoxybenzamine infusion ira did not block alpha-adrenoceptors located outside of the kidney. The PRA and heart rate responses to hemorrhage were both significantly reduced when propranolol was infused either ira or intravenously (iv) at a rate of 2 micrograms.kg-1.min-1 for 20 min followed by 0.5 microgram.kg-1.min-1 continuous infusion. Propranolol infusion at a lower rate (0.5 microgram.kg-1.min-1 for 20 min followed by 0.12 microgram.kg-1.min-1) had little effect on the magnitude of increase in PRA when infused either iv or ira. The calculated renal arterial plasma propranolol concentration was at least fivefold higher or more during ira than during iv propranolol infusion at each rate and was approximately the same during ira infusion at the lower rate (17.5 +/- 0.7 ng/ml) as during iv infusion at the higher rate (16.7 +/- 2.4 ng/ml). These data indicate that the hemorrhage-induced increase in PRA is mediated by renal alpha-adrenoceptors and extrarenal beta-adrenoceptors, whereas renal beta-adrenoceptors appear to play little or no role.

Evaluation of potential pharmacodynamic and pharmacokinetic interactions between verapamil and propranolol in normal subjects.

1. Potential pharmacodynamic and pharmacokinetic interactions between verapamil and propranolol were evaluated in two double-blind, randomised, balanced, crossover studies employing the same six healthy males. 2. The first study examined the effect of repeated propranolol administration on the pharmacodynamics and pharmacokinetics of verapamil after single oral and intravenous doses. The second explored the pharmacodynamics and pharmacokinetics of verapamil and propranolol alone and in combination after single and repeated oral doses. 3. The magnitude of the prolongation of PR interval induced by oral and intravenous verapamil was not affected by pre-treatment with propranolol. When verapamil and propranolol were co-administered as single doses, effects on PR interval were additive but, following repeated doses, a trend towards greater than additive prolongation was seen. The arithmetic sum of the effects of the two drugs was 23% (95% C.I. 8-38%) but the measured increase after the combination was 40% (95% C.I. 26-54%). 4. The extent of reduction in heart rate and blood pressure at rest and after exercise following repeated doses of propranolol was not influenced by single oral or intravenous doses of verapamil. The heart rate and blood pressure responses to single and repeated oral doses of verapamil and propranolol in combination were significantly greater than those after either drug alone and approximated to the arithmetic sum of the individual responses. 5. Although repeated administration of propranolol reduced hepatic blood flow as assessed by indocyanine green clearance, there was no evidence of an interaction between the drugs at this level. 6. The pharmacokinetics of verapamil and norverapamil were not significantly affected by prior propranolol. After single doses of verapamil and propranolol in combination, the maximum plasma concentration of propranolol was increased and the oral clearance of verapamil reduced. No pharmacokinetic interaction was observed after repeated doses. 7. These findings provide little evidence of a pharmacodynamic or pharmacokinetic interaction between verapamil and propranolol in normal subjects. Most of the haemodynamic responses to these drugs in combination can be explained by additive drug effects but an interaction affecting AV conduction after repeated doses cannot be excluded. The minor pharmacokinetic interaction between the drugs is unlikely to be relevant to the pharmacodynamic changes.

Mechanism for the Enhancement Effect of Fatty Acids on the Percutaneous Absorption of Propranolol

The effects of a series of fatty acids on the percutaneous absorption of propranolol (PL) through rabbit skin and the mechanism by which fatty acids facilitate the skin penetration of PL were examined in vitro and in vivo using a gel base. Lauric and myristic acids, at the fatty acid:PL molar ratio of 1:1 were the most potent agents in increasing the skin penetration, giving the largest penetration rate (Js and penetration coefficient (Kp) of PL. The molar ratio of 2:1 also exerted a large enhancing effect, comparable to that with a molar ratio of 1:1. When the enhancing effects of lauric acid, its amide, and its methyl ester were compared, the free acid gave the highest Js and Kp values. The plasma PL concentrations were significantly higher and more sustained after a single percutaneous application of the formulation with lauric acid than those after the formulation without the acid. The mechanism for the enhancing effect was examined by measuring IR and 13C NMR spectra, the solubility in buffer, and the apparent partition coefficient of PL. Additionally, the penetration of PL and lauric acid, as co-penetrants, through rabbit skin and shed snake skin were evaluated. The IR spectra of the mixture of PL with lauric acid (molar ratio, 1:1) was characterized by an extreme shift of the CO peak. Comparison of the NMR spectra of PL, lauric acid, and the mixture suggested that the carbonyl group of lauric acid interacted with the amino and hydroxyl groups of PL, probably by charge interaction. The apparent partition coefficient of PL between n-octanol and water was significantly higher for the mixture with lauric acid than for PL alone or the mixture with methyl laurate. Lauric acid and PL penetrated through snake skin, a model of the stratum corneum, at almost the same rate, while the penetration rate of lauric acid across whole rabbit skin was one-tenth that of PL. These results indicate that a significant portion of PL will penetrate across the stratum corneum by forming a complex with a fatty acid, and that the complex will dissociate to each component in the interface between the corneum and viable epidermis, where PL partitions into this water-rich tissue.

Bronchoconstriction of the asthmatic airway by inhaled and ingested propranolol

Responsiveness to inhaled histamine and DL propranolol hydrochloride was measured in 31 adult asthmatics and compared with bronchoconstriction provoked by acute oral propranolol dosing (max 160 mg). Twelve asthmatics developed greater than or equal to 15% reduction in the forced expired volume in 1 s (FEV1), 2 h after less than or equal to 100 mg oral propranolol; cardiac beta-adrenoceptor blockade was confirmed by cycle exercise tests in the 19 without airway response. The provocative inhaled dose of each aerosol causing a 20% fall in FEV1 (PC20) was lower, histamine 0.43 mg.ml-1, propranolol 3.12 mg.ml-1, in the 12 with a positive oral test compared with the 19 with a negative test, PC20 histamine 1.65 mg.ml-1, PC20 propranolol 16.2 mg.ml-1 (P less than 0.001 for both aerosols). A correlation was demonstrated between the PC20 values for asthmatics with a negative oral test (r = 0.72, P less than 0.001, n = 19) but not for the remainder (r = 0.14, P greater than 0.05, n = 12). Plasma propranolol concentrations (CL, ng.ml-1) after the final oral dose did not correlate with the % delta FEV1 (26.3) (r = -0.28) when an airway response was provoked or with the reduction in exercise tachycardia (25.9%) (r = 0.31) when no bronchoconstriction occurred. CL exceeded the limit of detection after the final inhaled propranolol dose (7.5 ng.ml-1) and was weakly related to the PC20 propranolol value (r = 0.53, P = 0.01, n = 27). The prevalence of a positive oral challenge was low in this group (39%).(ABSTRACT TRUNCATED AT 250 WORDS)

Design of a polyvinyl alcohol hydrogel containing phospholipid as controlled-release vehicle for rectal administration of (±)-propranolol HCl

Polyvinyl alcohol hydrogels which contained phospholipid, egg yolk lecithin or hydrogenated soya lecithin were designed as a transrectal delivery system for propranolol hydrochloride. The hydrogel preparations containing phospholipid were prepared by a low-temperature crystallization method. The release profile of propranolol from hydrogel preparations containing phospholipid complied with Fickian diffusion (Higuchi model). The release of propranolol from the hydrogel preparation decreased with higher contents of phospholipid (approximately 2% w/w). In rats plasma concentrations of propranolol after rectal administration of hydrogel preparations containing phospholipid (1 and 2% w/w) were prolonged compared with those of rats receiving preparations without phospholipid.

Circadian influence on effect of propranolol on exercise-induced tachycardia in healthy subjects

Following a cross-over design propranolol 20 mg p.o. was given to 7 healthy subjects at 09.00 h and 21.00 h at an interval of 1 week. Heart rate (HR) during submaximal ergometer exercise was measured at four intervals during 10 h after treatment. Plasma propranolol concentrations were also determined. The suppressive effect (%R) of propranolol on the rise in HR during exercise after the morning dosage was significantly greater at 1.5 h and tended to be greater 3 h after administration than at comparable times in the evening trial. Mean plasma propranolol concentrations during the early phase were higher after the morning than the evening dose. The maximum plasma concentration (Cmax), area under the plasma concentration-time curve from 0 to 10 h (AUC (0-10] and absorption rate constant (ka) were significantly greater after the morning dose. The time to maximum concentration (tmax) and elimination half-life (t 1/2) of the morning and evening dosages did not differ. A significant correlation was observed between plasma propranolol concentration and %R in HR during exercise in the morning (r = 0.74) and evening (r = 0.63) trials, and the regression lines of the morning and evening treatments did not differ.(ABSTRACT TRUNCATED AT 250 WORDS)

Alteration of propranolol pharmacokinetics and pharmacodynamics by quinidine in man.

The effects of quinidine on pharmacokinetics and pharmacodynamics of propranolol were investigated in a double-blind, placebo-controlled design. Healthy subjects of group A (n = 5) and group B (n = 11) were given oral propranolol (dose: group A 10 mg, group B 20 mg) with placebo or propranolol with quinidine (dose: group A 100 mg, group B 200 mg) on separate occasions. Quinidine induced a significant rise in the plasma concentrations of propranolol, and the area under the propranolol concentration-time curves (AUC) was also increased about 3-fold in both groups, indicative of an alteration of propranolol pharmacokinetics. In order to estimate the pharmacodynamic action of the pharmacokinetic interaction, the change in the heart rate during treadmill exercise testing was studied in group A. A significant inhibition of exercise-induced tachycardia was observed after administration of propranolol alone, but in combination with quinidine an even greater suppression was evident. These results indicate that the coadministration of propranolol and quinidine provides not only the potentiation of quinidine action by propranolol, which has been reported, but also the enhancement of propranolol action by quinidine, due to an increased plasma concentration of propranolol.

Efficacy of intravenous propranolol for suppression of inducibility of ventricular tachyarrhythmias with different electrophysiologic characteristics in coronary artery disease

The efficacy of intravenous propranolol for suppression of inducibility of sustained ventricular tachyarrhythmias (VT) was studied in 24 patients who had failed ≥1 membrane-active antiarrhythmic drug (mean 2.2 ± 1.2 drugs/patient). The response to propranolol was compared in 13 patients who had only stable monomorphic VTs inducible at baseline and another 11 patients who had ≥1 episode of electrically unstable VTs (polymorphic VT, ventricular flutter or ventricular fibrillation) at baseline. Seven patients (29%) became noninducible (responders) and 17 patients (71%) remained inducible to sustained VT (nonresponders) after propranolol. The basal heart rate was faster in responders than in nonresponders (101 ± 14 vs 86 ± 11 beats/min, p < 0.01). The magnitude of heart rate reduction was also greater after propranolol in responders (from 101 ± 14 to 80 ± 9 beats/min, p < 0.001) than in nonresponders (from 86 ± 11 to 74 ± 9 beats/min, p < 0.01) (p < 0.05 between the groups), despite equal plasma propranolol concentrations (84 ± 50 vs 88 ± 43 ng/ml, difference not significant). Seven of 11 patients (64%) who had ≥1 episode of unstable VTs inducible at baseline responded to intravenous propranolol, whereas none of the patients with only stable monomorphic VTs became noninducible after β blockade (p < 0.001). Responders had shorter cycle length of inducible VTs than nonresponders (225 ± 38 vs 302 ± 66 ms, p < 0.001). Thus, intravenous propranolol appears to be efficacious in suppressing fast, electrically unstable VTs, compared to monomorphic VTs with slower rates.

Interindividual differences in β-receptor density contribute to variability in response to β-adrenoceptor antagonists

To determine the role of changes in receptor density and the considerable interindividual variability in the response to beta-adrenergic antagonists, we determined the relationship between the beta-blockade produced by propranolol and the beta-adrenergic receptor density (Bmax) in 16 healthy subjects who received 10, 20, 40, and 80 mg propranolol every 8 hours for 1 day at each dosage level. The extent of beta-blockade produced was assessed as the reduction in exercise tachycardia. The extent of beta-blockade correlated with pretreatment lymphocyte Bmax (30 mg/day: r = 0.6290, p less than 0.05; 60 mg/day: r = 0.5279, p less than 0.05; 120 mg/day: r = 0.5888, p less than 0.01; 240 mg/day: r = 0.6783, p less than 0.005). When the extent of beta-blockade was corrected for plasma propranolol concentrations, the correlation was further improved (30 mg/day: r = 0.7636, p less than 0.001; 60 mg/day: r = 0.7218, p less than 0.002; 120 mg/day: r = 0.7814, p less than 0.001; 240 mg/day: r = 0.6899, p less than 0.005). We conclude that the density of beta-adrenergic receptors is one of the principal factors that control beta-receptor response to antagonists in human beings.

Hollow fibers as an oral sustained-release delivery system using propranolol hydrochloride.

Fibers were spun by the downward configuration of the wet spinning technique. This configuration is capable of encapsulating nonspherical and/or coarse particles. We examined encapsulation of propranolol hydrochloride and the ability of the fibers to act as a sustained-release delivery system for propranolol hydrochloride as a model drug. The U.S.P. basket dissolution method was used to evaluate the in vitro drug release kinetics and the effect of the aspect ratio (length/diameter) on drug release. For in vivo evaluation, selected fibers were administered to dogs in gelatin capsules. The results of these in vitro and in vivo studies were compared to those obtained with a marketed sustained-release propranolol product (Inderal LA). The fiber delivery system provided a sustained-release profile of plasma propranolol concentrations similar to that observed with Inderal LA.

Relationship among beta-adrenergic blockade, propranolol concentration, and liver function in patients with cirrhosis.

In 20 patients with cirrhosis we studied the relationship among the efficiency of beta-adrenergic blockade induced by oral administration of 40 mg propranolol, the plasma level of propranolol, and the liver function. The beta-adrenergic blockade was studied 2 h and 8 h after propranolol administration and assessed by the cardiac chronotropic response to isoprenaline. Liver function was evaluated by a standard liver function test and the Child-Turcotte or Pugh score. The beta-adrenergic blockade and propranolol plasma concentration were higher 2 h than 8 h after propranolol administration. The beta-adrenergic blockade and the propranolol plasma concentration varied widely among patients. No significant correlation was found between the efficiency of beta-blockade and propranolol concentration. The beta-adrenergic response before propranolol administration was correlated with bilirubin level and Child scores, but no significant correlation was found between the beta-blockade and the severity of liver disease. These results suggest that in patients with cirrhosis, differences in response to propranolol are not related to differences in the severity of the liver disease or to differences in propranolol concentration.

The percutaneous absorption of propranolol and prediction of the plasma concentration.

In order to avoid first-pass metabolism and to maintain therapeutically effective concentration of propranolol (PL) for a prolonged time, ointments of PL were prepared and the percutaneous (p.c.) absorption was investigated in rabbits. To describe the plasma PL concentration profile during repeated p.c. administrations, a simple pharmacokinetic model, including a first-order absorption process, was applied. The p.c. absorption of PL from both macrogol (400:4000, 30:40, g/g) and Carbopol 934 ointments was significantly increased by adding Azone (AZ). Effective plasma levels were sustained for about 10-20 h, but the absorption of PL from the macrogol ointment was relatively slow. The bioavailability of PL in the 5% PL Carbopol ointment with AZ was 13%. The plasma level of PL after application of Carbopol ointment was enhanced as PL was increased in the ointment, 3 to 5%. The repeated p.c. absorption studies were carried out by applying the 5% PL ointment daily for 3 d. The use of the pharmacokinetic model was justified by good agreement with the observed data after repeated applications of the ointment. Thus, the plasma PL concentration profile during repeated p.c. administrations can be predicted using the model.

The effect of propranolol on exercise induced tachycardia is determined by plasma concentration and the density of adrenergic receptors on leukocytes.

The chronotropic response to a single oral dose of propranolol in 23 healthy subjects has been related to the plasma propranolol concentration and the density of beta-adrenoceptors on peripheral polymorphonuclear leucocytes. The percentage reduction in exercise-induced tachycardia was significantly correlated with the log plasma propranolol concentration within subjects but not between subjects. Taking the concentration of the active metabolite 4-hydroxypropranolol into account did not improve the interindividual correlation. The reduction in exercise-induced tachycardia was significantly correlated with the maximum binding density of (125I)-hydroxybenzylpindolol on polymorphonuclear leucocyte membrane fragments measured before medication. A response index (% reduction in exercise-induced tachycardia/plasma propranolol concentration) was correlated with the maximum binding density of (125I)-hydroxybenzylpindolol (pre-drug) at 2 h (rs = 0.72), 4 h (rs = 0.84) and 6 h (rs = 0.73) after dosing. The data suggest that interindividual variation in the response to propranolol after a single oral dose is determined by interindividual differences both in plasma propranolol and adrenoceptor density.

Decreased bioavailability of propranolol due to interactions with adsorbent antacids and antidiarrhoeal mixtures

The interaction of propranolol (50–160 mg/100 ml) with recommended doses of magnesium trisilicate, kaolin-pectin and bismuth subsalicylate suspensions was studied. Magnesium trisilicate and bismuth subsalicylate were found to adsorb propranolol with a limiting adsorptive capacity of 112 and 97 mg/g, respectively. Kaolin-pectin suspension adsorbed practically all of the drug. The effect of these interactions on the bioavailability of propranolol in rats was determined. The extent, but not the rate. of propranolol absorption was decreased on concomitant administration of the adsorbents. Peak propranolol plasma concentrations decreased by 2924̄5% and a parallel decrease of 35–44% in AUC values was observed. These interactions suggest possible clinically important differences in propranolol bioavailability.

In support of cardiac chronotropic beta 2 adrenoceptors

The effects of atenolol (50 mg) and propranolol (40 mg) on exercise- and isoproterenol-induced heart rate increments were studied in 9 male volunteers. Propranolol reduced maximal heart rate from 187 ± 4 to 146 ± 7 beats/min and atenolol reduced it to 138 ± 6 beats/min. There was no difference between the drugs at any point during exercise. Isoproterenol sensitivity was measured as the dose of isoproterenol required to increase resting heart rate by 25 beats/min (CD-25). Propranolol increased the CD-25 from 1.8 ± 0.3 μg after placebo to 39 ± 8 μg and atenolol increased the CD-25 to 8 ± 2 μg. The increase by propranolol was significantly greater than that of atenolol. Intravenous atropine (0.04 mg/kg) did not alter the isoproterenol CD-25 during placebo or atenolol. The CD-25 with propranolol decreased after atropine (39 ± 8 versus 25 ± 5 μg) and was due to diminished plasma propranolol concentrations as the drug sensitivity (measured by Ka) was unchanged before (12 ± 2 ml/ng) and after (10 ± 3 ml/ng) atropine. These data support the hypothesis that moderate exercise is primarily a β 1-mediated response and therefore equally antagonized by cardioselective and nonselective blockers, but that isoproterenol stimulates both β 1 and β 2 receptors. The greater ability of the nonselective agent to antagonize isoproterenol tachycardia with no significant change after atropine suggests the presence of cardiac β 2 chronotropic receptors. The physiologic and pathologic importance of these receptors has yet to be determined.

Quantitative determination of propranolol in plasma and plasma water from normal subjects and patients with angina pectoris by high-performance liquid chromatography

A precise and sensitive high-performance liquid chromatographic method using a column packed with porous polystyrene gel is described for the determination of propranolol in plasma and plasma water from normal subjects and patients with angina pectoris. Propranolol in the samples was extracted with an n-heptane—isoamylalcohol (98.5:1.5) mixture after addition of penbutolol used as an internal standard. The extracts were chromatographed and detected with a spectrofluorophotometer. The quantitative limit of propranolol was 1 ng using 1 ml of plasma or 0.5 ml of plasma water. The present method should be useful for monitoring propranolol concentrations in plasma and plasma water during drug therapy and for pharmacokinetic study of propranolol.