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PubMed1992

Age and gender influence the stereoselective pharmacokinetics of propranolol.

The effect of age and gender on the stereoselective pharmacokinetics of propranolol was studied in 12 young (25 to 33 years old) and 12 elderly (62 to 79 years old) healthy nonsmoking volunteers, half of whom were female. Racemic propranolol was administered (80 mg p.o.) each 8 hr for seven doses. Serum was obtained just before (0 time) and at 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hr after the final dose and analyzed for propranolol enantiomers. The serum concentration of alpha-1 acid glycoprotein was determined before propranolol administration. The binding of each enantiomer to serum proteins was determined in samples obtained before propranolol administration and two hr after the final dose of propranolol. We found that the intrinsic hepatic clearance of S-propranolol was about 30% smaller in the elderly than in the young, whether it was calculated for total or unbound drug. Additionally, the elimination half-lives of both enantiomers were 2- to 3-fold prolonged in the elderly compared with the young. In all subjects regardless of age or sex the intrinsic hepatic clearance of the total (bound plus free) S-isomer was smaller than that of the R-isomer. There was no age-related difference in alpha-1 acid glycoprotein concentration or protein binding of either enantiomer of propranolol. However, there was a gender-related difference with the females having significantly greater binding of the S-enantiomer than the males.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1987

Nifedipine-propranolol interaction: dependence of cardiovascular effects on plasma drug concentrations.

The relationships between plasma drug concentrations and cardiovascular effects during combined administration of nifedipine and propranolol were evaluated in dogs anesthetized with thiopental. Three received small intravenous (i.v.) doses of nifedipine followed by propranolol, and 6 were given higher doses of nifedipine followed by propranolol; in 5, the order of drug doses was reversed, with propranolol administration followed by nifedipine. When dosing regimens that produced stable plasma levels of both drugs were used, the observed effects were closely related to the plasma concentrations of the individual agents. When small doses of nifedipine were combined with propranolol, at plasma levels associated with a significant degree of beta-adrenoceptor blockade, moderate decreases in spontaneous heart rate and cardiac output as well as increases in atrioventricular conduction time were produced. With higher doses of nifedipine, combined infusion with propranolol resulted in more pronounced depression in cardiac function, characterized by decreases in cardiac output, heart rate, and mean pulmonary arterial pressure, as well as increases in atrioventricular conduction time. When propranolol administration was followed by nifedipine, similar dose-dependent cardiovascular effects resulted, with profound toxicity apparent when large doses of nifedipine were used. These studies in an acute anesthetized dog model suggest that the magnitude of cardiovascular depression resulting from nifedipine and propranolol in combination is dependent on the plasma concentrations of both agents. Furthermore, in the presence of beta-adrenoceptor blockade, the direct effects of nifedipine on myocardial conducting tissue, which are usually absent when this calcium antagonist is given alone, may become apparent and result in depression of atrioventricular and sinoatrial nodal functions.

Animals↗
PubMed1989

[Effect of intracoronary and intravenous administration of propranolol on coronary vasomotility at rest and during exercise].

The effect of intracoronary and intravenous propranolol on coronary vasomotion was evaluated in 30 patients with coronary artery disease. Luminal area of a normal and a stenotic coronary segment was determined at rest, during supine bicycle exercise and 5 min after 1.6 mg sublingual nitroglycerin administered at the end of the exercise test using biplane quantitative coronary arteriography. Patients were divided into 3 groups: Group I (n = 12) served as control Group II consisted of 10 patients with intracoronary administration of 1 mg propranolol and Group III of 8 patients with intravenous administration of 0.1 mg/kg propranolol prior to the exercise test. In the control Group there was coronary vasodilation (+23%, p less than 0.01) of the normal and coronary vasoconstriction (-29%, p less than 0.001) of the stenotic vessel segment during bicycle exercise. After sublingual administration of 1.6 mg nitroglycerin there was vasodilation of both normal (+40%, p less than 0.001 vs rest) and stenotic (+12%, NS vs rest) segments. In Group II intracoronary propranolol was not accompanied by a change in coronary area but both normal (+13%, p less than 0.05) and stenotic (+22%, p less than 0.05) segments showed coronary vasodilation during bicycle exercise. After sublingual nitroglycerin there was further vasodilation of both normal (+31%, p less than 0.001 vs rest) and stenotic (+45%, p less than 0.01 vs rest) arteries. In Group III intravenous administration of propranolol was associated with a decrease in coronary luminal area of both normal (-24%, p less than 0.001) and stenotic (-41%, p less than 0.001) segments. During dynamic exercise there was coronary vasodilation of both segments when compared to the data after intravenous injection of propranolol but there was no change in luminal area (normal vessel-2%, NS vs rest; stenotic vessel-3%, NS vs rest) when compared to the resting data. After sublingual administration of 1.6 mg nitroglycerin both normal (+21%, p less than 0.001) and stenotic (+46%, p less than 0.001) segments showed coronary vasodilation. It is concluded that supine bicycle exercise in patients with coronary artery disease is associated with vasodilation of the normal and vasoconstriction of the stenotic coronary arteries. Intravenous administration of propranolol is followed by coronary vasoconstriction of both normal and stenotic coronary arteries probably due to secondary mechanisms (reduction in heart rate and contractility) because it is not observed after intracoronary injection of propranolol and it is overridden by bicycle exercise and sublingual nitroglycerin.

Adult↗
PubMed1988

Enhanced exercise noradrenaline concentrations during propranolol treatment: a limiting factor in cardiac beta-adrenoceptor blockade.

Treatment with beta-adrenoceptor blocking drugs may result in augmented plasma concentrations of noradrenaline during exercise. The effect of propranolol on exercise heart rate and its relationship to plasma concentrations of propranolol and noradrenaline were examined in 10 hospitalized volunteers following treatment with propranolol, in doses of 80 mg and 320 mg daily. Responses to submaximal treadmill exercise during propranolol treatment and following discontinuation of the higher dose were compared to pre-drug and post drug placebo values. Exercise noradrenaline was increased by 67% over baseline values by treatment with the 320 mg daily dose of propranolol; this increment was present at 4 h and returned to baseline by 16 h after drug administration. Augmentation of exercise noradrenaline was correlated with plasma propranolol concentrations; the threshold concentration for this effect was 10-fold higher than the threshold for reduction in exercise heart rate. The effect of propranolol on heart rate was blunted in relation to the augmentation of exercise noradrenaline (P less than 0.001). These relationships suggest that, in patients taking high doses of propranolol, drug induced augmentation of plasma levels of noradrenaline during exercise may have physiologic importance. Enhanced effects on adrenergic receptors could have clinical relevance in certain groups of patients.

Adult↗
PubMed1985

Cardiovascular responses to verapamil and propranolol in hypertensive patients.

Since there is concern that the potentially useful antihypertensive combination of verapamil and propranolol might lead to adverse cardiovascular responses, we have investigated its effects, not only on blood pressure, but also on electrocardiographic and echocardiographic variables. Fourteen hypertensive patients participated in a double-blind, randomized, crossover comparison of verapamil 360 mg, propranolol 240 mg, verapamil 360 mg + propranolol 240 mg, and placebo, each given for 4 weeks. The antihypertensive effect of verapamil + propranolol was greater than that of either drug alone. Pulse rate was reduced by propranolol but not verapamil. However, addition of verapamil to propranolol led to further reduction in pulse rate. The PR interval was prolonged by verapamil + propranolol when compared with all other treatments. The active drugs increased ventricular dimensions and the effect of the combination was statistically significant. Thus, verapamil + propranolol is an effective antihypertensive combination, but heart rate, atrio-ventricular conduction and left ventricular function may be affected adversely, necessitating careful monitoring of therapy.

Adult↗
PubMedDate not supplied

Quantitative account of propranolol metabolism in urine of normal man.

A recent study, identifying several sulfate conjugates, appears to have led to a full qualitative account of propranolol metabolism in man. The objective of the present investigation was to determine the quantitative fate of propranolol, including the relationship between the primary metabolic pathways, i.e. glucuronidation, side-chain oxidation and ring oxidation. Single 80-mg oral doses of propranolol together with [3H]propranolol were administered to seven normal subjects. Urinary metabolites were determined by HPLC with radiometric detection after hydrolysis of glucuronic acid conjugates and fractionation by solvent extraction. About 90% of the dose was recovered in urine. Twelve metabolites accounted for 91% of the recovered dose. When examining the metabolites based on the primary metabolic pathways, 17% of the dose (range, 10-25%) was going through glucuronidation, 41% (range, 32-50%) through side-chain oxidation, and 42% (range, 27-59%) through ring oxidation. These data show that the net elimination of propranolol is largely due to oxidative metabolism. The relative contribution of the primary pathways is well reflected by the four major propranolol metabolites, i.e. propranolol glucuronide, naphthoxylactic acid, and the glucuronic acid and sulfate conjugates of 4'-hydroxypropranolol. These observations should greatly facilitate future studies of the biochemical mechanisms of propranolol disposition.

Adult↗
PubMedDate not supplied

Failure of propranolol to prevent chronic hyperthyroid induced cardiac hypertrophy and multifocal cellular necrosis in the rat.

The effect of excess thyroid and thyroid plus propranolol on right and left ventricular structure was examined. Perfusion fixed hearts from untreated adults and those treated for 10 weeks with thyroid, propranolol, and thyroid plus propranolol were embedded in plastic and sectioned for light and electron microscopy. Hyperthyroidism stimulated a significant increase in heart rate, oxygen consumption, and systolic blood pressure. Propranolol was effective in normalizing the heart rate of hyperthyroid rats, but did not affect oxygen consumption or blood pressure. Both left and right ventricular weight increased similarly in thyroid and thyroid-propranolol treated animals, but right ventricular mass increased more than left ventricular mass in both groups. The majority (21 of 24) of right ventricles from thyroid and thyroid-propranolol treated animals had multifocal areas of histologically detected fibrosis. Left ventricular fibrosis was absent or minimal in both hyperthyroid groups. Neither left nor right ventricular fibrosis was observed in control or propranolol only treated animals. We conclude that beta adrenergic stimulation is unnecessary for thyroid induced cardiomegaly, and excess thyroid hormones induce right ventricular fibrosis which is not prevented by propranolol.

Animals↗
PubMed1987

[Comparative study of the effects of verapamil and propranolol therapy in 16 cases of obstructive hypertrophic myocardiopathy].

In a randomized, double-blind, cross-over study with plasma drug assays, 16 patients (11 men, 5 women; mean age 48.56 +/- 3.61 years) presenting with hypertrophic obstructive cardiomyopathy confirmed by echocardiography, left ventriculography and left intraventricular gradient measurement were treated with verapamil 480 mg/day or propranolol 320 mg/day. Both treatments produced functional improvement (p less than 0.01) which was more distinct with verapamil (NS). No changes in cardiothoracic index, echocardiographic parameters and Sokolow's index were observed. Mean total heart work during exercise, which was 1,197.27 +/- 135.89 watts before treatment, increased to 1,260.91 +/- 146.60 watts under propranolol (NS) and to 1,344.09 +/- 171.06 watts under verapamil (NS). Maximum heart rate during exercise, which was 162.3 +/- 3.46 beats/min before treatment, was reduced to a greater extent by propranolol (122.1 +/- 6.6 beats/min; p less than 0.001) than by verapamil (147.7 less than 5.08 beats/min; p +/- 0.01). The two treatments did not significantly modify ventricular arrhythmia, arterial and capillary pulmonary pressures, mean aortic pressure and left ventricular end-systolic pressure. Cardiac index, unchanged under verapamil, fell from 2.98 +/- 0.16 1 X min-1 X m-2 to 2.60 +/- 0.11 1 X min-1 X m-2 under propranolol (p less than 0.05). The left intraventricular gradient present in 5 patients at rest and during exercise, was reduced by both drugs. The gradient under isoprenaline (n = 16), which was 162.07 +/- 18.77 mmHg before treatment, fell to 93.86 +/- 24.48 mmHg with propranolol (p less than 0.05) and to 128.86 +/- 18.22 mmHg with verapamil (p less than 0.05). Left ventricular ejection fraction, mean circumferential fibre shortening speed and compliance coefficient remained unchanged under both drugs (NS). Left ventricular diastolic function, evaluated by radioisotope angiography in the last 9 patients, was most often improved by verapamil (NS). Verapamil was better tolerated generally and by the heart than propranolol. No correlation was observed between plasma verapamil levels and clinical results. Low plasma propranolol levels were often noted in non-responders, suggesting a need for treatment with high doses. It is concluded that at the dosage level used in this study propranolol and verapamil were equally effective, but there were individual variations in best response to one or the other of these two drugs.

Cardiomyopathy, Hypertrophic↗
PubMed1987

[Inhibitory effect of propranolol on myocardial relaxation not mediated by beta blockade].

The effect of d- and d,l-propranolol (10(-5)M) on myocardial relaxation was studied in the isolated cat heart beating at constant rate and perfused at constant coronary flow. Infusion of d,l-propranolol 10(-5)M produced a significant decrease in maximal velocity of contraction (+T) of 48 +/- 1.5%, P less than 0.05, and a proportionally greater decrease in maximal velocity of relaxation (-T) of 58 +/- 2%, with a significant increase in the ratio between both maximal velocities (+T/-T) of 28.4 +/- 6.2% (from 1.35 +/- 0.03 to 1.74 0.09). The time constant of tension decline computed from the time of -T (Tau) was significantly prolonged by 64 +/- 17.5% (from 38 +/- 1.4 to 61 +/- 6 msec) (P less than 0.05). Similar results were obtained with d-propranolol (10(-5)M). A decrease in +T of 52.2 +/- 4.1% elicited by perfusion with low calcium (0.05 mM) also produced a slight increase in +T/-T and Tau by 11 +/- 4.5% and 27 +/- 6% respectively, P less than 0.05). These increases were, however, lower than those produced by both d,l- and d-propranolol (P less than 0.05). The effect of low calcium on +T, +T/-T and Tau were fully reversible, whereas the complete reversal by calcium of the negative inotropic effect of d- and d,l-propranolol did not reverse the significant decrease in -T and increase in +T/-T, and Tau elicited by the drug. Similar results were obtained in catecholamine depleted hearts. d-propranolol (10(-5)M) did not affect the calcium sensitivity of the chemically skinned cat right ventricular trabeculae. The calcium uptake of cat cardiac sarcoplasmic reticulum was significantly inhibited by d-propranolol from a concentration of 3 X 10(-4) M. The results suggest that propranolol 10(-5)M has an antirelaxant effect, not mediated by its negative inotropic action and independent of its beta blocking action. This antirelaxant effect might be mediated by the SR calcium uptake inhibition produced by the drug and might be a possible mechanism by which high concentrations of these agents negatively affect myocardial contractility.

Animals↗
PubMed1988

[Verapamil versus propranolol in stable effort angina. Randomized, crossed, double-blind study].

A randomised, crossover, double-blind study was carried out in sixteen coronary patients with stable effort angina to compare the effects of verapamil (360 mg) and propranolol (120 mg). All the patients received placebo for 2 days, underwent a coronary angiography which confirmed coronary heart disease and were then randomised into two groups to receive an initial treatment of either verapamil or propranolol for three days. The patients then took placebo for 3 days, then the second drug after cross-over also over 3 days. The therapeutic efficacy was assessed by stress testing on a treadmill (Bruce protocol) with automated analysis of the results (Case-Marquette), carried out on the last day of each of the phases with placebo and the test drug. The duration of the stress test increased significantly with propranolol (p less than 0.01) and verapamil (p less than 0.05) with respect to placebo. In comparison with placebo, propranolol and verapamil resulted in a similar decrease in ST segment depression at the time of maximum effort (p less than 0.01). The resting systolic blood pressure decreased with propranolol (p less than 0.02) and verapamil (p less than 0.01), whereas resting diastolic blood pressure only decreased with verapamil (p less than 0.01). Resting heart rate decreased during the propranolol phase (p less than 0.001). The systolic blood pressure at the time of maximum effort decreased especially with propranolol (p less than 0.05), whereas the diastolic blood pressure on exertion decreased during the verapamil phase (p less than 0.01). Heart rate during exertion only showed a significant decrease with propranolol (p less than 0.001) as compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Labetalol compared with propranolol in the treatment of black hypertensive patients.

A double-blind parallel group study was conducted to examine the effects of oral labetalol, in doses from 100 to 800 mg BID, and propranolol, 40 to 320 mg, in patients with mild to moderate hypertension. The doses of labetalol (n = 74) and propranolol (n = 79) were titrated weekly to achieve a sitting diastolic blood pressure (DBP) of less than 90 mmHg or at least a 10-mmHg decrease from placebo baseline on two consecutive visits. A 2-month fixed-dose maintenance phase followed in which a diuretic could be added if the sitting DBP was greater than or equal to 100 mmHg on maximum doses of either drug. BP and heart rate were measured 8-12 hours after a dose in the sitting and standing positions. Labetalol was significantly more effective at the end of monotherapy than propranolol was in lowering both the sitting (p less than .05) and standing (p less than .04) DBP. The reduction in the systolic, although more pronounced for those on labetalol, was not significantly different; 53% of patients had a "good" response to labetalol compared with 30% of the propranolol group. Propranolol significantly (p less than 0.01) lowered heart rate compared with labetalol. Nine patients in the labetalol group and 10 in the propranolol group required a diuretic. The decrease in BP after the addition of a diuretic was comparable. Changes in plasma lipids were not significant, but HDL increased 9% with labetalol and decreased 2% with propranolol. Triglycerides increased 25% with labetalol and 31% with propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Inhibition of quinidine-propranolol elevation of the ventricular fibrillation threshold by bilateral stellectomy+vagotomy in the anesthetized dog.

The antiarrhythmic potentiation that occurs with the coadministration of quinidine-propranolol has been attributed to propranolol-induced cardiac beta adrenergic receptor blockade. That this may not be the sole mechanism, however, is suggested by the finding that sotalol, pronethalol and practolol fail to potentiate quinidine in some antiarrhythmic tests. Thus, in the present experiments, the influence of bilateral stellectomy + vagotomy on quinidine-propranolol antiarrhythmic activity was studied in the anesthetized dog. Antiarrhythmic activity was determined as elevation of the electrical ventricular fibrillation threshold (VFT) when the left ventricle was stimulated directly with 60 Hz, 6 msec and varying mA for 2 sec. The increase in VFT produced by quinidine-propranolol (5 + 0.2 mg/kg, i.v.) was significantly reduced when the heart was subsequently denervated by bilateral stellectomy + vagotomy. The cardiac denervation did not significantly reduce the elevation of VFT that had been produced by prior administration of propranolol 0.4 mg/kg or sotalol. In other groups with prior bilateral stellectomy + vagotomy, the separate administration of propranolol 0.4 mg/kg or quinidine 5 mg/kg failed to significantly elevate the VFT although the VFT was increased by propranolol 0.8 mg/kg. The results indicate that the action of quinidine-propranolol to elevate the VFT may be dependent in part upon an intact nerve supply to the heart.

Anesthesia↗
PubMed1979

Steady-state disposition of propranolol and its total metabolites in the spontaneously hypertensive rat: chronic subcutaneous vs. intracerebroventricular infusion with osmotic minipumps.

The steady-state disposition of propranolol and its total metabolites was measured after 6 day continuous subcutaneous (1 mg/kg/day) or intracerebroventricular (i.c.v., 0.01 and 1 mg/kg/day) infusion of dl-[3H]propranolol with osmotic minipumps in spontaneously hypertensive rats. After 2 days daily excretion of total radioactivity was 70% or more of the total dose infused each day. Steady-state plasma concentrations (day 3 and 6) of propranolol and its total metabolites did not differ significantly during subcutaneous or i.c.v. infusion of 1 mg/kg/day. During i.c.v. infusion with 0.01 mg/kg/day these concentrations were only 0.01 to 0.02 times as high. Propranolol and its total metabolite concentrations did not differ significantly in peripheral tissues during subcutaneous or i.c.v. infusion of 1 mg/kg/day, whereas brain propranolol concentrations were 40- to 600-fold higher during i.c.v. infusion. During i.c.v. infusion with 0.001 mg/kg/day, peripheral propranolol and total metabolite concentrations were only 0.003 to 0.02 times those following 1 mg/kg/day. Brain propranolol concentrations after 0.01 mg/kg/day i.c.v. were in the same range as those following 1 mg/kg/day subcutaneously. The data suggest that the osmotic minipump is a useful tool for creating and maintaining a steady-state for propranolol in spontaneously hypertensive rats. Moreover, by i.c.v. placement of the pump outlet the brain can be selectively perfused with this agent for a prolonged period of time.

Animals↗
PubMed1979

Effects of propranolol in chronic two-kidney Goldblatt hypertension in rats.

Propranolol administered subcutaneously in a dise of 30 mg/kg twice a day for 3 weeks did not significantly lower systolic tail blood pressure (STBP) in chronic two-kidney Goldblatt hypertension in rats. Plasma renin activity (PRA) measured at the end of the treatment was not significantly different in propranolol treated and dextrose treated rats, although there was marked bradycardia in propranolol treated rats. However, 3 out of 10 propranolol treated hypertensive rats had pressures in the normotensive range during the last week of therapy. PRA values in these three rats were significantly lower than those in dextrose treated hypertensive rats. STBP on day 20 showed a positive correlation with PRA in both propranolol (r = 0.90, p less than 0.01) and dextrose (r = 0.85, p less than 0.01) treated hypertensive rats. Hypertension was associated with an increase in heart weight, which was significantly blunted but not abolished by propranolol treatment. Thus, propranolol did not decrease blood pressure in most rats with chronic two-kidney Goldblatt hypertension; when it did lower blood pressure, its antihypertensive effect appeared related to its renin suppression effect. Furthermore, propranolol mitigated hypertension induced cardiac hypertrophy, independently of its antihypertensive effect.

Animals↗
PubMedDate not supplied

In vivo study of propranolol and metabolite(s) disposition in rat liver.

To investigate the intrahepatic disposition of drugs subjected to the first-pass effect, propranolol (0.002 mg/kg and 5 mg/kg) was injected into the portal vein of rats. At various times the drug was measured in liver homogenate, cytosol, smooth microsomal, and Golgi fractions. The results suggest that hepatic uptake of propranolol is an extremely rapid process and essentially complete, independently of the dose. Effectively at 0.5 min, 70% and 85% of the low and high doses, respectively, were recovered in the liver homogenate. Furthermore following the 0.002-mg/kg dose, 96% of the recovered drug equivalents in the suprahepatic blood consisted of metabolites. An additional experiment demonstrated that the uptake of a 0.002-mg/kg dose of propranolol was not modified by a loading dose of 25 mg/kg. The pattern of propranolol distribution correlated with the intracellular localization of phospholipids and proteins. The amount of propranolol found in subcellular fractions relative to liver homogenate remained constant throughout the study, suggesting a rapid equilibrium. Low doses of propranolol were cleared from the hepatic cells almost completely by biotransformation. However, high doses saturated the metabolic clearance. Propranolol metabolites accumulated preferentially in the cytosol fraction. The intracellular elimination of the metabolites appeared to be a saturable process. The Golgi apparatus does not seem to be involved in the elimination of propranolol or its polar metabolites.

Animals↗
PubMed1980

Sustained cardiac beta adrenoceptor blockade in vitro and increased vulnerability to aconitine-induced arrhythmias in vivo after propranolol withdrawal in rats.

The present study was undertaken in order to investigate the possibility of cardiac hypersensitivity to norepinephrine (NE) after propranolol withdrawal in rats. The effect of NE was studied on heart rate and left intraventricular pressure development (maximal dP/dt) in the isolated perfused heart at various time periods after termination of the propranolol feeding. Also, the influence of propranolol withdrawal on vulnerability to aconitine-induced arrhythmias in vivo was evaluated in anesthetized rats. No hypersensitivity to NE was seen in the perfused rat heart 1 and 3 days after propranolol withdrawal. Rather, a depressed response to NE was registered suggesting a long half-life for the disappearance of beta adrenoceptor blockade. Increased vulnerability to aconitine-induced arrhythmias was observed 1 and 3 days after treatment with propranolol had ceased. Rats receiving propranolol continuously until experimentation exhibited an elevated threshold to aconitine-induced arrhythmias. These data indicate that a hypothetical rebound phenomenon after withdrawal of propranolol is not associated with an increase in mechanical performance of the heart in response to NE. A decreased threshold for development of arrhythmias appears, however, to be at hand, perhaps due to an inbalance in the transmembrane sodium flux in the heart in the early time course after propranolol withdrawal.

Aconitine↗
PubMed1984

Effects of propranolol and hemodialysis on the response of glucose, insulin, C-peptide and cyclic AMP to glucagon challenge.

Hypoglycemia is frequently reported in hemodialysis patients on propranolol. We studied the influence of propranolol on carbohydrate metabolism in sixteen hemodialysis patients (eight on propranolol and eight not) with pre-dialysis oral glucose tolerance tests (OGTT) and pre- and post-dialysis glucagon tests. Propranolol was shown to have significant suppressive effect on the insulin response during OGTT. With glucagon challenge pre- and post-dialysis, despite a similar cAMP response, patients on propranolol had significantly lower glucose response than those not receiving propranolol and it is postulated that this is due to post-receptor post-cAMP inhibition of hepatic glycogenolysis. Moreover, while the glucose response in patients not on propranolol significantly increased after dialysis, no significant change was found in patients on propranolol. The significantly higher C-peptide, insulin and cAMP responses to glucagon challenge in the hemodialysis patients as compared to normal controls may be due to delayed clearance of glucagon, and the further increased responses after dialysis may be due to the removal of a dialyzable factor suppressing these responses.

Adult↗
PubMed1983

Propranolol-hydralazine combination in essential hypertension.

The efficacy of a propranolol-hydralazine combination tablet was compared with that of each of its two components in the twice-daily treatment of mild to moderate essential hypertension (diastolic blood pressure: 100 to 125 mmHg). After a three-week, single-blind, placebo period, a 9- to 18-week, single-blind, dose-finding phase with the combination was performed. The daily doses of propranolol/hydralazine were 40 mg/25 mg, 80 mg/25 mg, 80 mg/50 mg, 120 mg/50 mg, 160 mg/50 mg, and 160 mg/100 mg. Of 83 patients, 73 (88%) had decreases in diastolic blood pressure equal to or greater than 10 mmHg. Thirty-eight (46%) patients had a diastolic blood pressure equal to or less than 90 mmHg while taking 80 mg propranolol/50 mg hydralazine or less given BID. Mean systolic and diastolic pressures were reduced by 16.8 mmHg (10.9%) and 17.6 mmHg (16.7%), respectively (P less than 0.001). A ten-week, double-blind, parallel-treatment phase followed in which patients were randomly assigned to the combination tablet or to propranolol or hydralazine. There were significantly larger increases in mean systolic (P less than 0.01) and mean diastolic (P less than 0.03) blood pressure when the components were taken alone than with the combination from the mean of the last three weekly dose-finding visits to the mean of the last four biweekly parallel-treatment visits. The changes in systolic/diastolic blood pressures were: hydralazine (n = 30), 14.43/8.62 mmHg; propranolol (n = 24), 9.87/6.09 mmHg; and the combination (n = 27), 1.47/1.53 mmHg. During the parallel-treatment phase, the proportions of patients with new complaints were: hydralazine, 16/31 (52%); propranolol, 10/25 (40%); and the combination, 11/27 (41%). In the hydralazine group, three patients had cardiovascular events (severe tachycardia, mild palpitations, and skipped heart beats) and two patients had mild anxiety; no such occurrences were noted in the propranolol or combination group. The mean change (increase) in heart rate from the end of dose-finding to the end of the double-blind period was significantly larger for patients taking hydralazine than for patients taking propranolol or the combination. Mean changes for these groups were: hydralazine, 12.4 beats/min; propranolol, 2.9 beats/min; and the combination, 1.8 beats/min (P = 0.0001). This study found the combination of propranolol plus hydralazine to be safe and more effective than either component.

Adult↗