Plasma Propranolol Research Articles

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.

Simultaneous Determination of Propranolol Enantiomers in Plasma by High-Performance Liquid Chromatography with FIuorescence Detection

A simple, rapid, and sensitive assay for the simultaneous quantification of the (−)- and (+)-propranolol in human and dog plasma is described using a reversed-phase high-performance liquid chromatography (HPLC) system with fluorescence detection. The method involves extraction of propranolol enantiomers from plasma into 1% 1-butanol in n-hexane at basic pH, followed by evaporation of the organic phase and the formation of diastereomeric derivatives with the chiral reagent (−)-menthyl chloroformate. (+)-Flecainide is used as the internal standard. The limiting concentration of each enantiomer that can be detected is 1 ng/mL plasma. In six normal human volunteers, who received a single oral dose of 80 mg of racemic propranolol, the plasma levels of the (−)-enantiomer were always higher than those of the (+)-enantiomer with a mean (−):(+) ratio of 1.38. The half-lives of both the enantiomers were similar (3.5 ± 0.3 h). In six normal male mongrel dogs given a single intraportal dose of 40 mg of racemic propranolol, the plasma levels of the (−)-enantiomerwere always lower than those of the (+)-enantiomer with a mean (−):(+) ratio of 0.48. The half-life of the (−)-enantiomer (73.3 ± 16.2 min) was shorter than that of the (+)-enantiomer (87.1 ± 18.1 min).

Determination of total and free concentration of propranolol in human plasma by displacement electrophoresis in a two-layer polyacrylamide gel using fluorimetric detection.

A new method based on displacement electrophoresis has been developed for the determination of the total and free concentration of propranolol, a beta-adrenergic blocker drug, in plasma. To determine the total concentration the drug is extracted from human plasma into a chloroform + heptane mixture in the presence of ammonia. After evaporation of the solvent mixture the residue is submitted to displacement electrophoresis in a glass tube containing a two-layer polyacrylamide gel. When the propranolol electrophoretically leaves the gel column it is transferred by a buffer flow to the cuvette of a fluorimeter for continuous detection and quantification. The concentration of the free non-protein bound drug can be determined by the same displacement electrophoresis technique following extraction of the plasma sample into the above organic solvent mixture in the absence of ammonia. Alternatively the extraction procedure can be exchanged for dialysis for 1 h. To decrease the risk that large size material might comigrate with propranolol two layers of polyacrylamide are used, one having small pores to retard such material. In addition, we use fluorimetric detection which means that many possible contaminants are not recorded and therefore do not affect a quantitative determination of propranolol.

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.

Racial Differences in Drug Response

To determine whether the pharmacokinetics and pharmacodynamics of beta-blockade differ among racial groups, we gave 10 men of Chinese descent and 10 American white men 10, 20, 40, and 80 mg of propranolol every eight hours; the dosages were given in random order, and each dose was given for one day. The degree of beta-blockade was measured as the reduction in the heart rate and blood pressure in the supine and upright positions and during treadmill exercise testing. The Chinese subjects had at least a twofold greater sensitivity to the beta-blocking effects of propranolol than the white subjects, as indicated by the mean (+/- SEM) plasma concentrations producing a 20 percent reduction in the heart rate in both the supine position (197 +/- 31 vs. 536 +/- 58 nmol per liter; P less than 0.05) and the upright position (131 +/- 27 vs. 343 +/- 39 nmol per liter; P less than 0.05) and after exercise testing (96 +/- 12 vs. 185 +/- 23 nmol per liter; P less than 0.05). In addition, the Chinese subjects had much greater sensitivity to the hypotensive effects of propranolol, as shown by the concentrations that reduced blood pressure by 10 percent in the supine position (73 +/- 5 vs. 748 +/- 7 nmol per liter; P less than 0.01) and in the upright position (89 +/- 5 vs. 401 +/- 6 nmol per liter; P less than 0.01). No difference in beta-receptor density or affinity of lymphocytes was found between the groups. The Chinese group had a 45 percent higher free fraction of propranolol in plasma, which may have contributed to the increased drug effect but cannot explain it entirely. This group metabolized propranolol more rapidly than the white group, which resulted in a 76 percent higher clearance of an oral dose (3740 +/- 737 vs. 2125 +/- 214 ml per minute; P less than 0.05) because of increased metabolism through multiple metabolic pathways. We conclude that Chinese men have greater sensitivity than white men to the effects of propranolol on heart rate and blood pressure. Decreased protein binding may be responsible in part, but most of the effect remains to be explained.

Binding of prazosin and propranolol at variable alpha 1-acid glycoprotein and albumin concentrations.

1. The effect of variable alpha 1-acid glycoprotein (AAG) and albumin (HSA) concentrations on the binding of prazosin and propranolol was assessed in plasma after surgery and in mixtures of AAG/HSA with concentrations mimicking those found in vivo. 2. On the pre-operative day the binding of prazosin and propranolol was 94.8% and 89.0%, respectively and 97.3% and 93.2%, respectively, 5 days after surgery. 3. In solutions containing mixtures of highly purified AAG and HSA representing the pre-operative state, 88.6% and 83.9% binding of prazosin and propranolol was observed, whereas for solutions mimicking post-operative plasma, the equivalent values were 94.6% and 91.4%, respectively. 4. The ratios between bound and unbound concentrations of both drugs were closely correlated to the concentrations of AAG, but not to the concentrations of HSA. 5. The present study demonstrates that AAG is responsible for the binding variability of prazosin and propranolol in plasma from post-operative patients.

Enantioselective drug monitoring of ( R)- and ( S)-propranolol in human plasma via derivatization with optically active ( R,R)-O,O-diacetyl tartaric acid anhydride

A sensitive high-performance liquid chromatographic method was developed for the stereoselective assay of ( R)- and ( S)-propranolol in human plasma. The method involves diethyl ether extraction of the drugs and a racemic internal standard, N- tert.-butylpropranolol, followed by derivatization of the compounds with the chiral reagent ( R,R)-O,O-diacetyl tartaric acid anhydride. The resulting diastereomeric derivatives were separated isocratically on a reversed-phase column. Quantitation was achieved by the peak-height ratio method with reference to the internal standard. The assay was accurate and reproducible in the concentration range 1–100 ng of ( R)- and ( S)-propranolol per ml plasma, using fluorescence detection at λ ex 290 nm and λ em 335 nm. The applicability of this method was demonstrated for the determination of concentration-time profiles of propranolol enantiomers in the course of comparative pharmacokinetic studies.

Determination of ( R)- and ( S)-propanolol in plasma by high-performance liquid chromatography using N-benzoxycarbonylglycyl- l-proline as chiral selector in the mobile phase

A normal-phase chromatographic method for the determination of ( R)- and ( S)-propranolol in plasma is described. The chiral separation is performed by adding an optically active complexing agent, N-benzoxycarbonylglycyl- l-proline, to the mobile phase (dichloromethane). The solid phase is LiChrosorb DIOL. After adjustment of the pH of the plasma, the propranolol enantiomers are extracted into hexane-dichloromethane- n-butanol (72:18:10). The organic phase is evaporated and the residue dissolved in the mobile phase before injection on to the column. Quantifications are performed by using internal standardization, giving a precision of better than 2% (coefficient of variation). The method employs 1-ml plasma samples and has linear calibration graphs ( r=0.999) over the concentration range studied, 9.2–288 nmol/l. Injections of sample solutions with a composition different from that of the mobile phase gave system peaks that might affect the shape of the solute peaks. Several possibilities for avoiding these disturbing system peaks in the chromatogram by changing the mobile phase composition are discussed.

Determination of propranolol and 4-hydroxypropranolol in human plasma by high-performance liquid chromatography.

A high-performance liquid chromatographic method was developed to determine the levels of propranolol and its major metabolite, 4-hydroxypropranolol, in human plasma. The limits of determination are 10 ng ml-1 of propranolol and 5 ng ml-1 of 4-hydroxypropranolol using a 0.5-ml plasma sample. The stability of plasma samples stored at -30 degrees C for up to 2 months was also tested. No stabilising antioxidants were added to the samples.

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.

Routine Methods in Toxicology and Therapeutic Drug Monitoring by High-Performance Liquid Chromatography. IV. A Rapid Microscale Method for Determination of Propranolol and 4-Hydroxypropranolol in Plasma

A fast, simple, and sensitive method for the simultaneous determination of total and free propranolol and its active metabolite 4-hydroxypropranolol in plasma by high performance liquid chromatography is described. Both propranolol and 4-hydroxypropranolol are detected by fluorescence at one wavelength detector setting. The limit of sensitivity of the method is 2 ng/ml for 4-hydroxypropranolol and 1 ng/ml for propranolol. The method is fast since it involves a single extraction step followed by evaporation of organic solvent and chromatography of the residue. The method takes only 10 min per sample and thus can be set up in a therapeutic drug-monitoring laboratory for monitoring propranolol levels routinely.

Triazolam kinetics: interaction with cimetidine, propranolol, and the combination.

Nineteen healthy volunteers received a single 0.5-mg oral dose of triazolam on four occasions under the following conditions: (1) triazolam alone; (2) triazolam with cimetidine, 300 mg four times daily; (3) triazolam with propranolol, 40 mg four times daily; (4) triazolam with both cimetidine and propranolol. Triazolam kinetics were determined from multiple plasma concentrations measured during 24 hours after each dose. Compared with control, peak plasma triazolam concentration (Cmax) was significantly increased by cimetidine (5.4 versus 3.9 ng/mL), total area under the plasma concentration curve (AUC) increased (21.3 versus 16.1 ng/mL X hr), and oral clearance decreased (485 versus 668 mL/min). However triazolam half-life was not increased. During propranolol alone, triazolam Cmax (4.1 ng/mL), AUC (14.3 ng/mL X hr), and clearance (759 mL/min) did not differ significantly from control, whereas kinetic variables for triazolam with cimetidine plus propranolol were similar to those with cimetidine alone. Plasma free fraction for triazolam (17 to 18% unbound) did not differ significantly among the four treatment conditions. Mean steady-state plasma cimetidine concentrations during trials 2 and 4 were similar (1.04 versus .98 micrograms/mL), whereas plasma propranolol was significantly higher during cimetidine plus propranolol than with propranolol alone (47 versus 29 ng/ml, P less than .001). Thus cimetidine coadministration significantly inhibits triazolam clearance, causing increased triazolam AUC and Cmax, but without a prolongation in half-life. Propranolol itself does not impair triazolam clearance, nor does propranolol potentiate the inhibitory effect of cimetidine alone.

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.

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.

Quantitative determination of propranolol in plasma and pharmaceutical preparations by agar-based cation-exchange chromatography utilizing the native anion groups in the agaropectin moiety.

A new cost-effective method for determining the amount of total propranolol (free and protein-bound) in plasma samples and the amount of the drug in tablets and injection solutions has been developed. The method is based on cation-exchange chromatography at pH 8.5 on an inexpensive column of agar, the native sulfate (and carboxylic) groups of which interact with the positively charged propranolol (this interaction is reinforced by the 'aromatic adsorption' characteristic of the agar matrix). The method can be used for quantitative analyses at both low (1 x 10(-2) mg/L) and high (5 x 10(3) mg/L) concentrations of the drug. For analyses of plasma and tablets--but not for injection solutions--extraction of the propranolol is required. The extraction time was 6 min. On a 6(ID) mm x 9 mm agar column the run time was less than 10 min.

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.

Plasma Propranolol Levels and Their Effect on Plasma Thioridazine and Haloperidol Concentrations

The relationship between chronic oral dosage with a long-acting formulation of propranolol and plasma propranolol levels 22 to 23 hours later is described in 12 adult male patients with organic brain disease. Separately, the effects on plasma levels of thioridazine plus metabolites with concomitant rising dose long-acting propranolol administration were studied in five patients. Significant dose-related increases in levels of thioridazine and metabolites were found when long-acting propranolol was given. No changes in haloperidol levels were found in three patients studied in a similar protocol.

Rapid high-performance liquid chromatographic method for the determination of propranolol in plasma.

An HPLC method has been developed that can determine propranolol and its chief metabolite, 4-hydroxypropranolol, in plasma without the necessity for a pre-injection clean-up step. Sample clean-up is achieved by using a pre-column in conjunction with a column-switching device so that proteinaceous and other contaminants by-pass the analytical column. Accurate determinations were possible in the range 20–1000 ng ml–1. A method is also described for improving the minimum detection level by the on-column concentration of analytes.

Improved high-performance liquid chromatographic method for the simultaneous determination of propranolol and 4-hydroxypropranolol in plasma with fluorescence detection

Improved high-performance liquid chromatographic method for the simultaneous determination of propranolol and 4-hydroxypropranolol in plasma with fluorescence detection

The Effect of ??-Adrenergic Blockade on the Cardiovascular Response to Diltiazem or Verapamil in Dogs

Diltiazem or verapamil were each given at two different infusion rates to pentobarbital-anesthetized dogs with or without a concurrent infusion of propranolol. Changes in cardiovascular function, in reflex activation as reflected by circulating catecholamine levels, and in the chronotropic response to an exogenous beta-adrenergic agonist, isoproterenol, were measured. When administered alone, diltiazem or verapamil, at plasma concentrations of 160 and 370 ng/ml, or 230 and 500 ng/ml, respectively, prolonged atrioventricular conduction and caused systemic vasodilation with a decrease in mean arterial pressure. Cardiac index increased, associated with an increase in arterial norepinephrine level. Heart rate increased with the lower level of verapamil; left ventricular dP/dt increased with both levels of verapamil and at the higher level of diltiazem. Plasma propranolol levels of approximately 35 ng/ml were well tolerated in the absence of diltiazem or verapamil. When added to diltiazem or verapamil, propranolol resulted in an increase in systemic vascular resistance to near control values; a decrease in cardiac index, left ventricular dP/dt, and heart rate; and worsened atrioventricular conduction. Three of nine animals in the high verapamil-propranolol group were unable to maintain a mean arterial pressure greater than 50 mm Hg, and developed a low cardiac index with an elevated systemic vascular resistance, despite very high levels of circulating catecholamines. Compared to the anesthetized state, greater amounts of isoproterenol were needed to effect the same increase in heart rate with the addition of diltiazem, verapamil, or propranolol alone.(ABSTRACT TRUNCATED AT 250 WORDS)