Release Of Propranolol Research Articles

Depolarization-induced release of propranolol and atenolol from rat cortical synaptosomes.

The accumulation and release of [3H]-propranolol and [3H]-atenolol were examined in synaptosomes from rat cerebral cortex. Synaptosomes accumulated 20 pmol propranolol and 0.6 pmol atenolol mg-1 protein when incubated at 30 degrees C with radiolabelled drugs (0.1 microM). Exposure of propranolol-loaded synaptosomes to elevated K+, Rb+ or Cs+ evoked a concentration-dependent increase in propranolol efflux. The action of these ions in releasing propranolol was highly correlated with their ability to produce synaptosomal membrane depolarization, as estimated with the voltage-sensitive dye diS-C3-(5). Elevated K+ also promoted atenolol release from synaptosomes in a concentration-dependent manner. Veratridine (10 microM) released propranolol and atenolol from synaptosomes and these effects were antagonized by tetrodotoxin (1 microM). Under Ca2+-free conditions, K+-induced release of propranolol was reduced by 37% and atenolol release was diminished by 68%. The results support the concept that both polar and non-polar beta-adrenoceptor blocking drugs may be accumulated by nerve endings for release by membrane depolarization and suggest that neural storage and release of these molecules may influence their concentrations at localized sites of action.

Effects of cholestyramine and colestipol on the plasma concentrations of propranolol.

The effect of equivalent hypolipidaemic doses of cholestyramine (8 g) or colestipol (10 g) on the plasma concentrations of propranolol and 4'-hydroxypropranolol was studied in 12 normal volunteers following the oral administration of 120 mg of normal release propranolol tablets. When two doses of either cholestyramine or colestipol were administered prior to the propranolol, the peak plasma concentrations and area under the curve for both propranolol and the metabolite 4'-hydroxypropranolol were reduced significantly (P less than 0.05). We conclude that the drug interaction between cholestyramine or colestipol and propranolol leads to significant reductions in plasma concentrations of propranolol and 4'-hydroxypropranolol which may cause a clinically diminished effect for a given dosage. Therefore, patients should be observed when either of these resins are added to or deleted from a therapeutic regimen.

Differential effects of hypoxia on the disposition of propranolol and sodium taurocholate by the isolated perfused rat liver.

Although the adverse effect of hypoxia on drug metabolism is well documented in subcellular systems, its effect on drug clearance by the intact liver has not been defined. This study was undertaken in the isolated perfused rat liver to examine the effects of acute hypoxia on the hepatic elimination of two highly cleared substances--propranolol and sodium taurocholate. Hypoxia was established by equilibrating the perfusate with 100% nitrogen rather than 100% oxygen. This led to a fall in portal vein pO2 from 300 to 30 mm Hg, and a 10-fold rise in hepatic venous lactate:pyruvate ratio, indicating a profound alteration in hepatic cellular redox state. In bolus dose studies, propranolol uptake was unimpaired by hypoxia, with a monoexponential decline in perfusate concentrations from 2,000 to 30 ng per ml, (t1/2 uptake = 2.5 min). After 20 min of hypoxia, perfusate propranolol concentrations rose from 30 to 80 ng per ml, indicating release of propranolol from liver back into the perfusate. Reoxygenation of perfusate restored hepatic extraction of propranolol to normal (t1/2 uptake = 2.37 +/- 0.19 min vs. 2.55 +/- 0.60 min p greater than 0.1) such that perfusate concentrations were undetectable by 30 min. In steady-state studies, perfusate propranolol concentrations rose from 1.55 +/- 0.50 to 4.08 +/- 1.47 micrograms per ml (p less than 0.005), after 1 hr of hypoxia indicating a change in propranolol clearance from 15 ml per min to less than 6 ml per min. Reoxygenation resulted in a fall in perfusate propranolol concentrations towards control values (2.78 +/- 1.13 vs. 1.80 +/- 0.41 micrograms per ml, p greater than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Stable oral availability of sustained release propranolol when co‐ administered with hydralazine or food: evidence implicating substrate delivery rate as a determinant of presystemic drug interactions.

A study was made of the influence of hydralazine on the oral availability of a sustained release formulation of propranolol (Inderal LA). Sustained release propranolol 160 mg was given orally either alone or in combination with oral hydralazine 25 mg on separate occasions to six healthy volunteers. Blood and urine samples were collected post-dosing over 34 h. Peak concentrations of propranolol, time to peak and area under the plasma concentration-time curve (AUC) were not altered by co-administration of hydralazine with sustained release propranolol. Similarly, there was no change in recovery of 11C-labelled propranolol and metabolites in those individuals to whom tracer label was given. These results contrast with previous reports of marked interaction between the conventional formulation of propranolol and hydralazine or food. Interactions were confirmed between hydralazine and conventional propranolol in three subjects who had been studied previously with sustained release propranolol. Analysis of metabolite profiles in one of these subjects established that the major metabolites do change under hydralazine stimulus. These results indicate that substrate delivery rates may determine presystemic drug interactions, suggesting capacity limitations of hydroxylation processes or short-term flow redistribution following hydralazine, resulting in functional shunting past the hydroxylation enzymes. These results exclude global or lasting enzyme inhibition by hydralazine or simple flow-sensitivity of presystemic clearance.

Ambulatory blood pressure during administration of atenolo, metoprolol, pindolol, and slow release propranolol

Ambulatory blood pressure during administration of atenolo, metoprolol, pindolol, and slow release propranolol

Temporal relationship between cardiac performance and myocardial uptake of dl-propranolol in man.

1. The temporal relationship between the myocardial arteriovenous difference of plasma propranolol concentration and heart rate and left ventricular dp/dt maximum was examined for 30 min after intravenous administration of 10mg (0.04 mmol) dl-propranolol in nine patients with ischaemic heart disease. 2. Very large positive myocardial a.v. differences of propranolol within the first 5 min became negative after 5 min, indicating a rapid, avid uptake with subsequent release of propranolol from the heart. 3. The heart rate and left ventricular dp/dt maximum increased 1 min after propranolol administration and did not change after the fifth min of the observation period. 4. The data suggest that a large number of unspecific binding sites for propranolol are present in the heart in addition to the specific beta-receptors.

Once daily administration of sustained release propranolol capsules in the treatment of angina pectoris

The effect of once daily administration of sustained release capsules of propranolol 160 mg was compared with treatment with standard 40 mg tablets four times daily, in eight patients with stable angina pectoris, in a four week, double blind crossover, random treatment-order trial. Clinical evaluation and submaximal bicycle ergometry were performed before propranolol therapy and on the last day of each treatment period. Serum propranolol concentration over a 24 hour period on those two days ranged from 34.4 to 65.5 ng/ml for the tablets, and 27.7–76.0 ng/ml for the capsules. The peak increase in heart rate on exercise fell from 59 beats per minute to 43 and 41 bpm following the tablets and capsules, respectively (p<0.05). The degree of ST segment depression decreased from 1.94 mm to 0.94 mm and 0.63 mm, respectively (p<0.05). Serum propranolol concentrations were significantly correlated with the reduction in peak heart rate (r=0.58, p<0.05), and in heart rate-pressure product (r=0.83, p<0.01). Clinical attacks and nitroglycerin requirements were equally reduced by both formulations. Sustained release capsules of propranolol 160 mg given once daily were as effective as standard 40 mg tablets given four times daily in the treatment of stable angina pectoris in patients requiring this dose range.

Proceedings: the effect of food on the in vivo release of propranolol from a PVC matrix tablet in the dog.

Journal Article The effect of food on the in vivo release of propranolol from a PVC matrix tablet in the dog Get access R U Grundy, R U Grundy Pharmaceutical Research Department, ICI Limited, Pharmaceuticals Division, Alderley Park, Macclesfield, Cheshire, UK Search for other works by this author on: Oxford Academic Google Scholar J McAinsh, J McAinsh Pharmaceutical Research Department, ICI Limited, Pharmaceuticals Division, Alderley Park, Macclesfield, Cheshire, UK Search for other works by this author on: Oxford Academic Google Scholar D C Taylor D C Taylor Pharmaceutical Research Department, ICI Limited, Pharmaceuticals Division, Alderley Park, Macclesfield, Cheshire, UK Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 26, Issue Supplement_1, December 1974, Pages 65P–66P, https://doi.org/10.1111/j.2042-7158.1974.tb10088.x Published: 12 April 2011