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At least 19 recordsLinked to original sources
PubMed1979

Propranolol glucuronide cumulation during long-term propranolol therapy: a proposed storage mechanism for propranolol.

The comparative disposition of propranolol glucuronide (PG) and propranolol was determined in 35 patients with hypertension or coronary artery disease during initiation of propranolol therapy, during steady-state conditions, and after discontinuation of propranolol (dose range, 40 to 960 mg daily, every 6 hr). The 2.3-fold PG cumulation in plasma was identical to propranolol cumulation. PG plasma levels were about 4 times as high as propranolol levels over the whole dose range. Unexpectedly slow terminal elimination rate of propranolol (t1/2 approximately 16 to 24 hr) on discontinuation of propranolol appeared to be related to equally slow PG elimination. PG and propranolol could be detected in plasma and urine up to 3 to 5 days after propranolol discontinuation. The PG formed in man was deconjugated to propranolol in the dog after intravenous administration, suggesting that PG may serve as a storage pool for propranolol. Observations consistent with systemic and enteric deconjugation of PG, including enterohepatic recirculation, may, at least in part, explain the observed propranolol cumulation as well as the slow elimination of propranolol after its discontinuation. PG renal clearance (29 to 70 ml/min) and PG plasma levels were highly dependent on glomerular filtration rate, suggesting that PG may cumulate abnormally in patients with severe renal disease.

Adolescent↗
PubMed1978

Pathways of propranolol metabolism. Use of the stable isotope twin-ion GC-MS technique to examine the conversion of propranolol to propranolol-diol by 9000g rat liver supernatant.

The metabolic conversion of propranolol to propranolol-diol [1-(1-naphthyloxy)-2,3-propyleneglycol] by rat liver 9000g supernatant was demonstrated to proceed through the intermediate 3-naphthyloxy-2-hydroxypropionaldehyde. Using side chain deuterated propranolol-d5 as substrate, propranolol-diol-d4 was produced, indicating an obligatory aldehyde intermediate. Analysis of desisopropylpropranolol obtained in the same incubation showed no loss of deuterium indicating that the possibility of rapidly tautomerizing imine intermediate did not make a significant contribution in this metabolic conversion. Desisopropylpropranolol, added in small amounts to the incubation mixture is more rapidly converted to the propranolol-diol than is propranolol, indicating that the major pathway of conversion of propranolol to its diol metabolite is through the desisopropylpropranolol intermediate.

Animals↗
PubMed1978

The contribution of propranolol metabolites to the fluorometric assay of propranolol in human plasma.

1. Studies were undertaken to determine the fluorescent properties of several propranolol metabolites under the conditions of the fluorometric propranolol assay. Of the metabolites studied, propranolol glycol and N-desisopropylpropranolol had significant molar fluorescent coefficients relative to propranolol (72 and 79% respectively). N-desisopropylpropranolol was extracted with the same efficiency as propranolol (greater than 90%) wheras the glycol metabolite had only 34% extraction efficiency. Addition of each metabolite to samples of human plasma containing propranolol produced the predicted increase in fluorescent intensity. 2. Gas chromatographic analysis of plasma collected from 22 hypertensive patients chronically receiving oral propranolol revealed low concentrations of propranolol glycol and N-desisopropylpropranolol relative to propranolol. The results of these studies indicate that fluorescent metabolites of propranolol are not present in sufficient concentration to significantly interfere with the fluorometric assay of propranolol.

Chromatography, Gas↗
PubMed1979

Measurement of propranolol, 4-hydroxypropranolol and propranolol glycol in human plasma.

An HPLC method for the quantitative determination of propranolol, 4-hydroxypropranolol, and propranolol glycol in human plasma is described. The limits of sensitivity for the method were: 1 ng/ml propranolol; 5 ng/ml 4-hydroxypropranolol; and 1 ng/ml propranolol glycol. Data obtained from 6 healthy volunteers given a single 160 mg oral dose of propranolol revealed mean (+/- SEM) peak plasma levels of 31 +/- 10 ng/ml for 4-hydroxypropranolol and 9 +/- 2 ng/ml for propranolol glycol. These plasma levels were less than the peak concentrations recorded for propranolol (123 +/- 34 ng/ml. The rates of plasma decay of these two metabolites were greater than that observed for propranolol.

Chromatography, High Pressure Liquid↗
PubMed1978

Plasma propranolol levels in beagle dogs after administration of propranolol hemisuccinate ester.

The hemisuccinate ester of propranolol was administered to beagle dogs to test its applicability as a potential prodrug of propranolol. Following oral administration of propranolol hemisuccinate, plasma propranolol levels were eight times higher than after an equivalent dose of propranolol hydrochloride. The hemisuccinate was absorbed rapidly, with peak plasma levels observed at 0.5--1 hr. Following intravenous dosing, the disappearance half-life of the prodrug from the plasma was 0.5 hr while the propranolol half-life was 1.7 hr. This study demonstrated the potential usefulness of the prodrug approach when a highly metabolized drug such as propranolol is protected from first-pass elimination.

Animals↗
PubMed1979

Plasma concentrations of propranolol and 4-hydroxypropranolol during chronic oral propranolol therapy.

1 The plasma levels of propranolol and 4-hydroxypropranolol have been measured in 17 hypertensive patients receiving chronic oral therapy with propranolol. 2 The range of plasma propranolol concentrations was from 5.3 to 300 ng/ml, and that of 4-hydroxypropranolol was from 2.1 to 36.0 ng/ml. 3 The mean (+/- s.d.) plasma concentration ratio of 4-hydroxypropranolol to propranolol was 0.130 (+/- 0.005); however, a very wide range was observed with individual values ranging from 0.057 to 0.241. 4 A statistically significant correlation was observed between the plasma concentration of 4-hydroxypropranolol and that of propranolol. 5 Propranolol and 4-hydroxypropranolol plasma concentrations were each significantly, but poorly, correlated with daily propranolol dose. 6 The clinical significance of the results has been discussed.

Adult↗
PubMed1979

Comparison of a once daily long-acting formulation of propranolol with conventional propranolol given twice daily in patients with mild to moderate hypertension.

The effect of conventional propranolol tablets given twice daily has been compared with an equivalent dosage of a long-acting formulation of propranolol ('Inderal' LA)p given once daily in twenty-nine patients with mild to moderate hypertension. The study lasted 10 weeks. There was no significant difference in clinical response to the two treatments which were equally effective and well tolerated. A once daily dosage schedule should greatly aid patient compliance.

Adult↗
PubMed1975

Some haemodynamic effects of compound AH 5158 compared with propranolol, propranolol plus hydrallazine, and diazoxide: the use of AH 5158 in the treatment of hypertension.

1. Intravenous administration of compound AH 5158, which possesses alpha- and beta-adrenergic receptor-blocking properties, produces haemodynamic effects similar to those seen from the combined effects of propranolol and hydrallazine. 2. Chronic oral administration has demonstrated that compound AH 5158 is an effective hypotensive agent capable of controlling the blood pressure in patients previously requiring large doses of drugs such as methyldopa. Some postural and exercise hypotension may be seen with larger doses.

Blood Pressure↗
PubMed1978

Propranolol in thyrotoxicosis. Cardiovascular changes during thyroidectomy in patients pre-treated with propranolol.

The cardiovascular changes during anaesthesia and thyroidectomy have been studied in seven thyrotoxic patients prepared with propranolol. The heart rate and cardiac rhythm remained very stable throughout surgery. A 20% increase in mean arterial pressure occurred during surgical stimulation. A decrease in cardiac output, due to decreased stroke volume, occurred during surgical stimulation. A decrease in cardiac output, due to decreased stroke volume, occurred during surgery, reaching a maximum of 21% during ligation of the thyroid vessels and returning to pre-operative values by the end of surgery. The fall in cardiac output was accompanied by raised central venous pressure and raised total peripheral resistance.

Adult↗
PubMed1979

Propranolol in angina pectoris: duration of improved exercise tolerance and circulatory effects after acute oral administration.

The duration of the effects of single oral doses of 80 and 160 mg of propranolol was studied in 11 patients with stable, exercise-induced angina pectoris. After administration of both doses, plasma propranolol levels peaked at 2 hours in 8 of the 11 patients and thereafter declined exponentially with an average plasma half-life of 3.98 hours (range 1.4 to 4.3) after the 80 mg dose and 4.28 hours (range 1.9 to 5.4) after the 160 mg dose. There was wide interindividual variation in plasma propranolol concentration at any given time after each dose. Treadmill walking time to the onset of angina, the total duration of exercise and the total external work performed were significantly greater by 1 hour after each dose of propranolol than after placebo. This improvement in exercise tolerance persisted unchanged for 8 hours (P less than 0.001) and was still significant although less marked at 12 hours (P less than 0.05). Improvement in exercise tolerance after propranolol was associated with a significant reduction in S-T segment depression during exercise. Both at rest and during exercise, heart rate, systolic blood pressure and rate-pressure product decreased after propranolol, and these circulatory effects persisted for 12 hours. Changes in walking time, heart rate and systolic blood pressure were similar after 80 and 160 mg of propranolol. Despite the increase in exercise duration and in total work performed after propranolol, the rate-pressure product at the onset of angina was lower after propranolol. In view of the prolonged effects of single oral doses of 80 and 160 mg of propranolol, it is suggested that administration of propranolol twice daily should be adequate in treating patients with stable angina pectoris. These studies also demonstrate that routine measurement of plasma propranolol levels is of little practical value in the management of patients with angina pectoris.

Administration, Oral↗
PubMed1979

Effect of furosemide on plasma concentration and beta-blockade by propranolol.

Although propranolol and furosemide are used together for hypertension, the effects of furosemide on plasma levels and beta-blocking action of propranolol are not known. Ten healthy subjects received propranolol 40 mg orally; the mean plasma propranolol levels in 60, 90, 180, and 300 min were 85 +/- 16, 90 +/- 7, 82 +/- 8, and 58 +/- 8 ng/ml. Propranolol was then given together with furosemide (25 mg orally) and the propranolol blood level was measured. Mean propranolol plasma levels were 106 +/- 11 ng/ml at 60 min, 120 +/- 12 ng/ml at 90 min (p less than 0.01), 102 +/- 8 ng/ml at 180 min (p less than 0.05), and 78 +/- 8 ng/ml at 300 min (p less than 0.01). Six additional subjects were given an infusion of 1 microgram/min isoproterenol increased by 0.5 microgram/min every 2 min until the heart rate rose by 25% after oral administration of furosemide 25 mg. This procedure was repeated after propranolol (40 mg orally) and propranolol with furosemide (25 mg orally). The amount of isoproterenol which raised the heart rate by 25% was 2.6 +/- 0.3 micrograms after furosemide alone and 17.7 +/- 2 micrograms after propranolol (p less than 0.01). After propranolol with furosemide the dose of isoproterenol required to elevate heart rate by 25% was 109 +/- 15 micrograms (p less than 0.001).

Adolescent↗
PubMedDate not supplied

Increased diastolic time: a possible important factor in the benefical effect of propranolol in patients with coronary artery disease.

Diastolic time (DT) calculated as the cycle length minus electromechanical systole (QS2) has a nonlinear relationship to heart rate (HR), increasing rapidly as rates fall below 75. The effect of propranolol on DT was studied in 150 patients with coronary artery disease. Patients were divided into three groups. Group I included patients with stable angina pectoris: propranolol (2.5 mg, i.v.) significantly increased DT from 411 +/- 18 to 527 +/- 22 msec (p less than 0.001) in 23 patients of group I; therapy with propranolol (mean daily dose 200 +/- 15 mg) increased DT from 446 +/- 29 to 766 +/- 26 msec (p less than 0.001) in 15 patients with stable angina. Group II was made up of patients with acute myocardial infarction: Propranolol (2.5 mg, i.v.) increased DT from 379 +/- 16 to 458 +/- 24 (p less than 0.001) in 18 of these patients. Group III included patients with recent coronary bypass surgery: propranolol (2.5 mg, i.v.) increased DT from 323 +/- 9 to 468 +/- 24 msec (p less than 0.001) in 14 patients 7 days after surgery. In addition, DT at 15 hr and 2 weeks after surgery was compared in 30 patients maintained on propranolol (mean daily dose, 155 +/- 11 mg preoperative and 68 +/- 9 mg postoperative) and 50 other patients who underwent coronary bypass surgery not on propranolol. DT was greater in propranolol patients (546 +/- 21 vs. 388 +/- 16 msec, p less than 0.001), preoperative and 396 +/- 15 vs. 320 +/- 12 msec, p less than 0.001, postoperative). Changes in DT after propranolol are mainly attributed to decreased HR. Changes in QS2 were much less profound and always less (p less than 0.01) than changes in DT. Thus propranolol significantly increased DT per beat in patients with coronary artery disease, which allowed more time for coronary perfusion; this effect of propranolol could well be as important as the reduction of myocardial oxygen consumption.

Adult↗
PubMed1978

Radionuclide assessment of ventricular performance during propranolol withdrawal prior to aortocoronary bypass surgery.

The effects of oral propranolol upon left ventricular performance were assessed in 18 patients with angiographically documented coronary artery disease in whom propranolol was tapered prior to elective aortocoronary bypass surgery. Left ventricular ejection fraction, ejection rate, and regional wall motion were obtained on three occasions with first-pass radionuclide angiocardiographic techniques. Patients were studied at peak propranolol dose ( +/- SEM) 224 +/- 29 mg./day; serum propranolol level, 85 +/- 22 ng./ml.), intermediate dose (99 +/- 9 mg./day; serum propranolol, 30 +/- 6 ng./ml.), and 24 hours following discontinuation of propranolol therapy. Heart rate increased significantly (62 +/- 2.3 vs 67 +/- 3.0 vs 73 +/- 2.3 beats/minute, p less than 0.001) during propranolol withdrawal, while systolic blood pressure did not change significantly (114.7 +/- 4.3 vs 110.3 +/-3.0 vs 113 +/- 3.0 mm. Hg, p greater than 0.05). There was no significant change in ejection fraction (59.1 +/- 2.4 vs 60.4 +/- 2.0 vs 59.2 +/- 2.5 per cent) or ejection rate 2.80 +/- 0.18 vs 2.87 +/- 0.18 vs 2.92 +/- 0.20 sec.-1) as propranolol was tapered (p greater than 0.05). No patient demonstrated a change in regional wall motion in response to propranolol withdrawal. The results of this study suggest that oral propranolol in commonly used clinical dosages does not significantly affect radionuclide measures of left ventricular performance in the basal state.

Administration, Oral↗
PubMed1977

Beneficial effect of propranolol in a histologically appropriate model of postischemic acute renal failure.

Acute renal failure caused in the rabbit by clamping one renal pedicle for 1 hour and removing the opposite kidney produced a histologic picture very similar to that observed in "hypotensive" acute renal failure in man. Intravenous infusion of propranolol, a drug which prevents renin release, at 1 mg/kg for 70 minutes beginning at time of pedicle clamping resulted in significantly lower serum creatinine in this model (2.8 +/- 0.2 mg% at 48 hours with propranolol versus 5.2 +/- 0.8 mg% without). Renin stimulation by dehydration or feeding a low-salt diet enhanced the difference between treated and untreated groups (2.6 +/- 0.4 mg% with propranolol versus 6.2 +/- 1.8 mg% without, after dehydration; 3.5 +/- 1.0 mg% with propranolol versus 7.6 +/- 1.4 mg% without, after low-salt diet).Suppression of renin production by saline feeding eliminated propranolol's beneficial effect (5.6 +/- 0.9 mg% with propranolol versus 4.0 +/- 0.6 mg% without). In rabbits with a normal food and water intake, renal denervation using phenol also eliminated propranolol's effect (creatinine 8.6 +/- 1.4 mg% with propranolol versus 8.6 +/- 1.8 mg% without). In rabbits with intact kidneys, flow probe recording of renal blood flow showed a significantly higher blood flow immediately after unclamping in the propranolol-treated animals, and renal angiograms showed less vasoconstriction in this group after unclamping. In this model of acute renal failure, renal vasoconstriction plays an important role following the initial ischemic insult. Propranolol lessens the severity of this vasoconstriction and the resulting acute renal failure. Its probable action is interference with neurogenically stimulated renin release.

Acute Kidney Injury↗
PubMed1977

Pathophysiologic and pharmacokinetic determinants of the antihypertensive response to propranolol.

The tendency for patients with essential hypertension to differ markedly in antihypertensive response to propranolol could arise from pathophysiologic or pharmacokinetic differences between them. This possibility was investigated in 23 men with mild to moderately severe essential hypertension. At each of three propranolol doses, 40 mg, 80 mg, and 320 mg daily, approximately a 20-fold range in steady-state plasma propranolol concentrations was observed. Clinical response however was unrelated to plasma propranolol: oral dose ratio, since patients with higher plasma levels were less sensitive to the existing plasma drug concentration. When falls in blood pressure and plasma propranolol concentration were compared overall, a biphasic dose-response relationship was noted, with a first component at plasma propranolol concentrations of 3 to 30 ng/ml and a second at concentrations above 30 ng/ml. Only patients with increased sympathetic nervous system activity and high plasma renin activity (PRA) had substantial falls in pressure at propranolol levels of 3 to 30 ng/ml. Cardiac beta adrenergic receptor blockade, not suppression of PRA, seemed to be the antihypertensive mechanism. This relation of pretreatment sympathetic nervous activity and PRA to antihypertensive response existed only at lower plasma propranolol concentrations. With a propranolol dose of 320 mg daily, both plasma norepinephrine concentration and PRA were unrelated to the clinical response.

Adolescent↗
PubMed1979

Effects of atenolol and propranolol when added to long-term antihypertensive diuretic therapy.

The antihypertensive effects of atenolol and propranolol were compared in a double-blind crossover study of 19 patients with essential hypertension (World Health Organization, I and II) who were receiving long-term diuretic treatment (chlorthalidone, 50 mg daily) during the study. After a 3-wk placebo period, a beta-adrenergic antagonist was administered once daily (atenolol, 50 mg daily, or propranolol, 80 mg daily) for a week. If the MAP was more than 108 mm Hg at the end of the week, dosage of the beta-blocker was doubled the following week; when necessary, doubling was repeated to a maximum dose of 640 mg propranolol and 400 mg atenolol daily. Fifty milligrams atenolol had a greater effect than 80 mg propranolol and was as effective as 160 mg propranolol. The dose-response curve flattened off after 160 mg propranolol and 50 mg atenolol daily. The two highest doses of atenolol lowered MAP more than the highest doses of propranolo. Heart rate slowing was the same for both drugs and did not correlate with the fall in blood pressure. PRA was suppressed by all doses of propranolol, whereas atenolol suppressed PRA only at the 2 highest doses, (200 and 400 mg daily). With the lower propranolol doses, the percent MAP change correlated weakly with the percent PRA change (80 mg--r = 0.41, p less than 0.1; 160 mg--r = 0.64, p less than 0.05). Side effects were minimal, and were noted only with 640 mg propranolol; with this exception, the percentage of patients with no complaints rose when placebo was replaced by beta-blockers.

Administration, Oral↗