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PubMed1987

The cellular electropharmacology of the simultaneous administration of propranolol and mexiletine: a class I and II antiarrhythmic drug combination.

The addition of propranolol to mexiletine may reduce the adverse effects of mexiletine and possibly increase its efficacy. We compared the cellular electrophysiologic effects of this combination with mexiletine and propranolol alone, over concentration ranges of 3.2 to 100 microM mexiletine and 0.80 to 25.0 microM propranolol, using standard microelectrode techniques and a stimulation frequency of 1.5 Hz. Mexiletine and propranolol both depressed the rate of rise of phase 0 (Vmax) with concentration-response curves of similar slope and a relative potency of 8:1, propranolol to mexiletine. Thus, combinations of 8:1 molar ratios of mexiletine to propranolol were assessed. The combination depressed Vmax to the same extent as mexiletine or propranolol alone. Mexiletine, propranolol and the combination all shortened action potential duration (APD) to the same extent. At low concentration mexiletine, propranolol and the combination shortened effective refractory period (ERP). At 25 microM mexiletine, this effect reversed and ERP began lengthening. The effect of the combination paralleled mexiletine while with propranolol alone the reversal did not occur until the highest concentration was reached. Mexiletine prolonged ERP relative to APD, an effect not shared by propranolol and attenuated with the combination (P less than 0.05). We conclude that combining propranolol with mexiletine does not alter any of the cellular electrophysiologic effects of mexiletine except the prolongation of ERP relative to APD. Although this may be an important antiarrhythmic effect, the extent by which in vivo concentrations of propranolol may reduce the clinical antiarrhythmic efficacy of mexiletine is likely to be negligible.

Action Potentials↗
PubMed1980

Massive propranolol metabolite retention during maintenance hemodialysis.

Eight outpatients on long-term hemodialysis receiving propranolol therapy were studied on a nondialysis day, 11 +/- 1 hr after the last dose. Steady-state daily dosage of propranolol averaged 225 +/- 36 mg (range, 80 to 400). Plasma concentrations of propranolol and three of its metabolites were measured by gas chromatography--mass spectrometry (x +/- SEM): propranolol, 47 +/0 17 ng/ml; propranolol glucuronide, 2.119 +/0 597 ng/ml; 4-hydroxypropranolol glucuronide, 789 +/- 149 ng/ml; and naphthoxylactic acid, 4,357 +/- 727 ng/ml. The plasma levels of these metabolites were 18, 20, and 29 times, respectively, as high as in patients with normal renal function and correlated well with the dose of propranolol. The total concentration of these metabolites exceeded the concentration of propranolol to 239 times (range 74 to 476). Four long-term hemodialysis patients on propranolol were hospitalized to ensure compliance. Plasma levels of propranolol and of the three metatolites were followed during a dosage interval. Plasma propranolol correlated well with dose (r = 0.94) and declined with approximately normal half-lifes of 3.2 to 5.4 hr. There was little variation in the extremely high plasma levels of the three metabolites during a dosage interval. The total metabolite to propranolol plasma concentration ratio in these four patients ranged from 109 to 705. The correlation between total metabolite concentrations and propranolol dose was striking (r = 0.997). Massive retention of propranolol metabolites occurs uniformly in uremia, is highly predictable from the dose, and could have important clinical implications.

Adult↗
PubMed1996

Ryanodine receptor/calcium release channel conformations as reflected in the different effects of propranolol on its ryanodine binding and channel activity.

1. Propranolol, a beta-blocker, inhibited or stimulated ryanodine binding to both the membrane-bound and purified ryanodine receptor (RyR) depending on the assay conditions. At high NaCl concentrations, propranolol increased the number of ryanodine-binding sites (Bmax) with no effect on the binding affinity. In the presence of 0.2 M NaCl, ryanodine binding was inhibited by propranolol. Half-maximal inhibition was obtained at 1.2 mM and complete inhibition at 2 mM propranolol. The inhibitory effect of propranolol obtained at low NaCl concentration was not restored by increasing the NaCl concentration to 1 M. 2. Modulators of the RyR that are known to alter its conformational states, such as adenine nucleotides, Ca2+ concentration and pH, modified the effect of propranolol on ryanodine binding. In the presence of propranolol and at low NaCl concentrations, ryanodine binding was inhibited and showed no Ca(2+)-, pH-, or time-dependence. 3. Propranolol immediately and completely blocked the channel opening of RyR reconstituted into a planar lipid bilayer. Propranolol-modified non-active channel was reactivated to a subconductive state (about 40% of the control conductance) by ATP. 4. Competition experiments between lidocaine (a stimulatory drug) or tetracaine (an inhibitory drug) and propranolol at 0.2 or 1.0 M NaCl, respectively, suggest the existence of different interaction sites for local anaesthetics and propranolol. 5. These results suggest that propranolol interacts directly with the RyR and modifies its ryanodine binding and single-channel activities. Propranolol effects are altered by the RyR conformational state, suggesting its possible use as a conformational probe for RyR.

Adrenergic beta-Antagonists↗
PubMed2002

Attenuation of aortic banding-induced cardiac hypertrophy by propranolol is independent of beta-adrenoceptor blockade.

OBJECTIVE: Racemic propranolol attenuates cardiac hypertrophy secondary to abdominal aortic banding-induced pressure overload by a mechanism independent of its effect on cardiac work load. This was only observed, however, using doses of propranolol that were much higher than those needed to induce beta-adrenoceptor blockade. Thus, the question remains as to whether the antihypertrophic effect of propranolol depends on its ability to antagonize cardiac beta-adrenoceptor-mediated action (positive chronotropic effect, trophic effect) or on beta-adrenoceptor-independent action. METHODS: In a rat model of chronic pressure overload induced by abdominal aortic banding, we evaluated the effects on left ventricular hypertrophy (LVH) of the propranolol isomers, L-propranolol and D-propranolol, which compared to L-isomer is approximately 50-fold less potent as a beta-adrenoceptor antagonist, but is similarly potent as a membrane-stabilizer, as well as of timolol, a non-selective beta-adrenergic antagonist devoid of membrane stabilizing activity, and disopyramide, which is a membrane stabilizer, but not a beta-adrenoceptor blocker. RESULTS: Compared to sham-operated rats, banded rats had 30% greater left ventricular to body weight (LVW/BW) ratio (P < 0.01). The increase in LVW/BW ratio was significantly attenuated by treatment with 40 and 80 (but not 10) mg/kg per day of L-propranolol. Left ventricular hypertrophy was also prevented by D-propranolol, 40 and 80 mg/kg per day, and disopyramide, 50 mg/kg per day, whereas timolol, 30 and 60 mg/kg per day, showed no antihypertrophic effect. In separate groups of banded rats in which the reduction in heart rate induced by propranolol (80 mg/kg per day) was prevented by chronic cardiac pacing at 375 b.p.m., hypertrophy was again prevented, indicating that the effects of L-propranolol on LVH are not related to a reduction in cardiac work load. CONCLUSIONS: In the aortic banding-induced model of LVH: (i) the antihypertrophic effect of propranolol is independent of its beta-adrenergic blocking activity; and Iii) since disopyramide and D-propranolol also proved to be able to antagonize banding-induced LVH, the hypothesis is proposed that membrane-stabilizing activity, among the ancillary properties of propranolol, most likely accounts for the antihypertrophic effect of this drug.

Adrenergic beta-Antagonists↗
PubMed1995

Identification of human CYP isoforms involved in the metabolism of propranolol enantiomers--N-desisopropylation is mediated mainly by CYP1A2.

1. Studies using human liver microsomes and six recombinant human CYP isoforms (i.e. CYP1A2, 2A6, 2B6, 2D6, 2E1 and 3A4) were performed to identify the cytochrome P450 (CYP) isoform(s) involved in the ring 4-hydroxylation and side-chain N-desisopropylation of propranolol enantiomers in humans. 2. alpha-Naphthoflavone and 7-ethoxyresorufin (selective inhibitors of CYP1A1/2) inhibited the N-desisopropylation of R- and S-propranolol by human liver microsomes by 20 and 40%, respectively, while quinidine (a selective inhibitor of CYP2D6) abolished the 4-hydroxylation of both propranolol enantiomers almost completely. In contrast, sulphaphenazole (CYP2C8/9 inhibitor), S-mephenytoin (CYP2C19 inhibitor), troleandomycin (CYP3A3/4 inhibitor) and diethyldithiocarbamate (CYP2E1 inhibitor) elicited only weak inhibitory effects on propranolol metabolism via the two measured metabolic pathways. 3. Significant (P < 0.01) correlations were observed between the microsomal N-desisopropylation of both propranolol enantiomers and that for the O-deethylation of phenacetin among the 11 different human liver microsome samples (r = 0.98 and 0.77 for R- and S-propranolol, respectively). A marginally significant (r = 0.60, P congruent to 0.05) correlation was also observed between N-desisopropylation of S-, but not of R-propranolol and the 4'-hydroxylation of S-mephenytoin. No significant correlations were observed between the N-desisopropylation of propranolol enantiomers and the 2-hydroxylation of desipramine, the hydroxylation of tolbutamide or the 6 beta-hydroxylation of testosterone. 4. Significant (P < 0.01) correlations were observed between the microsomal 4-hydroxylation of R- and S-propranolol and the 2-hydroxylation of desipramine (r = 0.85 and 0.98, respectively). A weak (r = 0.66), albeit significant (P < 0.05) correlation was observed between the 4-hydroxylation of R-, but not of S-propranolol and the hydroxylation of tolbutamide. No significant correlations were observed between the 4-hydroxylation of propranolol enantiomers and the oxidation of other substrates for CYP1A2, 2C19, and 3A3/4. 5. Recombinant human CYP1A2 and CYP2D6 exhibited comparable catalytic activity with respect to the N-desisopropylation of both propranolol enantiomers; only expressed CYP2D6 exhibited a marked catalytic activity with respect to the 4-hydroxylation of both propranolol enantiomers.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed2004

The effect of propranolol on glyceryltrinitrate-induced headache and arterial response.

Prophylactic drug trials in migraine are long-lasting and expensive and require long-term toxicology information. A human migraine model would therefore be helpful in testing new drugs. Immediate headache and delayed migraine after glyceryltrinitrate (GTN) has been well characterized. We have recently shown that sodium valproate has prophylactic effect in the GTN model. Here we report our experience with propranolol in this model. Nineteen subjects with migraine without aura and 16 sex- and aged-matched healthy subjects were included in a two-centre randomized double-blind cross-over study. Fourteen migraine subjects and 14 healthy subjects completed the study and results from comparison of the 28 subjects are reported. Randomly propranolol 160 mg or placebo were each given daily for 14 days to both migraine and healthy subjects. A 20-min intravenous infusion of GTN 0.25 microg/kg per min was administered on a study day at the end of both pretreatment periods. Headache was registered for 12 h after GTN infusions. Its intensity was scored on a numerical verbal rating scale from 0 to 10. Fulfilment of International Headache Society (HIS) criteria was recorded for 24 h. Radial and superficial temporal artery diameters and blood velocity of both middle cerebral arteries were measured. All migraine subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 5, range 0-7) compared with placebo (median 5, range 0-10) (P = 0.441). Eight of the 14 completing migraine subject developed IHS 1.1 migraine after GTN, two subjects on both days, three subjects only after placebo, and three subjects only after propranolol. No reduction of GTN-induced migraine was found after propranolol compared with placebo (5 vs. 5, P = 1.000). All healthy subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 2, range 1-5) compared with placebo (median 1, range 1-7) (P = 0.315). Two subjects fulfilled IHS criteria 1.1 for migraine without aura after propranolol but not after placebo. The fulfilment was short lasting and did not require rescue medication. Headache after GTN was more pronounced in migraine subjects than in healthy subjects both with (P = 0.003) and without pretreatment with propranolol (P = 0.017). We found that 2 weeks of propranolol constricted the radial artery in healthy subjects but not in migraine subjects. GTN-induced vasodilatation abolished this difference. Mean maximum blood flow velocity in the middle cerebral artery was higher in healthy subjects than in migraine patients (P = 0.003-0.033) and unaffected by propranolol. We observed no effect of propranolol on GTN-induced headache and migraine. This could indicate that GTN induces migraine at a deeper level of the pathophysiological cascade of migraine than the prophylactic effect of propranolol. Propranolol does not constrict cerebral arteries, which therefore cannot be part of its mechanism of action in migraine.

Adult↗
PubMed1981

Effect of oral propranolol on rest and exercise left ventricular ejection fraction, volumes, and segmental wall motion in patients with angina pectoris. Assessment with equilibrium gated blood pool imaging.

The effect of oral propranolol on left ventricular ejection fraction, left ventricular volumes, cardiac output, and segmental wall motion was assessed with multigated blood pool imaging both at rest and during supine exercise in 15 patients with angina pectoris. Propranolol had no effect on resting left ventricular ejection fractions. Before propranolol, they did not change during exercise, whereas after propranolol the ejection fractions increased slightly. Exercise left ventricular ejection fractions increased with propranolol in three patients with resting left ventricular ejection fractions of less than 40 per cent. More specifically, left ventricular end-diastolic volume index, end-systolic volume index, stroke volume index, and cardiac index were not altered significantly at rest or during exercise by propranolol. Exercise left ventricular ejection fractions were increased in five and unchanged in eight patients by propranolol. Those patients with increases in left ventricular ejection fractions had a greater change in left ventricular end-diastolic volume indices and a greater change in left ventricular end-systolic volume indices during exercise while on propranolol. Left ventricular segmental wall motion was not altered significantly during exercise by propranolol. We conclude that: (1) Left ventricular functional responses to propranolol during exercise are heterogeneous and not easily predicted; (2) propranolol causes no consistent deterioration in exercise left ventricular ejection fraction even in patients with resting ventricular ejection fractions less than 40 per cent; (3) increased exercise left ventricular ejection fraction with propranolol is contributed to by significant increases in end-diastolic volume during exercise; and (4) gated blood pool imaging is a useful method for characterising rest and exercise left ventricular ejection fractions and left ventricular volumes during propranolol therapy.

Adult↗
PubMed1985

Enhancement of the antiaggregatory activity of prostacyclin by propranolol in human platelets.

The beta-adrenergic antagonist propranolol has been found to inhibit platelet aggregation. We investigated the possibility that propranolol exerts this action by stimulating the synthesis or enhancing the antiaggregatory activity of prostaglandin (PG) I2. The media from cultures of human endothelial cells inhibited thrombin-induced platelet aggregation, an effect attributed to PGI2 production by the cells. When endothelial cells were incubated with dl- or d-propranolol, the media had two to three times the inhibitory activity of control media. However, this increased activity was not due to increased synthesis of PGI2 because control and propranolol-treated cultures synthesized similar amounts of the PGI2 metabolite, 6-keto-PGF1 alpha. Instead, propranolol enhanced the antiaggregatory activity of PGI2. Propranolol (1 microM) and PGI2 (0.05 nM), when tested separately, inhibited aggregation by 19% and 13%, respectively, whereas the combination inhibited aggregation by 51%. PGI2 inhibited platelet aggregation and thromboxane (Tx) B2 production but stimulated cyclic AMP formation. The adenyl cyclase inhibitor 2',5'-dideoxyadenosine (DDA) had no effect of its own on these parameters, but blocked the actions of PGI2. Propranolol inhibited aggregation and TxB2 synthesis without changing cyclic AMP levels. Unlike PGI2, propranolol's effects were not altered by DDA. While the combination of propranolol and PGI2 inhibited aggregation to a greater extent than either agent alone, this enhanced effect with the combination did not extend to TxB2 or cyclic AMP production. Propranolol, PGI2, and the combination inhibited TxB2 synthesis to a similar extent, and PGI2 produced a similar increase in cyclic AMP in the presence and absence of propranolol. These findings indicate that propranolol and PGI2 inhibit platelet aggregation through cyclic AMP-independent and dependent mechanisms, respectively. While propranolol does not alter the synthesis of PGI2, it enhances the inhibition of aggregation by PGI2, and this may contribute to its antiplatelet effect.

Cells, Cultured↗
PubMedDate not supplied

Pharmacokinetic drug interactions with propranolol.

Propranolol is widely used in clinical practice and is frequently administered along with other drugs. The co-administration of propranolol and other drugs may result in either propranolol-induced changes in the disposition of other drugs or in effects of the other drugs on the pharmacokinetics of propranolol. These changes may be due to alteration in absorption, metabolism or to haemodynamic effects such as altered liver blood flow. Understanding the pharmacokinetics of propranolol is important to the rational interpretation of the effects of other drugs on propranolol's disposition. The absorption, protein binding and metabolism of propranolol may all be affected by the co-administration of other drugs. Induction of propranolol's metabolism by halofenate, phenytoin, phenobarbitone, rifampicin and alcohol have all been implicated in altering propranolol clearance, while inhibition of hepatic drug metabolising enzymes by chlorpromazine and cimetidine appear to reduce propranolol clearance. Propranolol may also affect the metabolism of other drugs such as antipyrine, chlorpromazine, theophylline and thyroid hormones. Suggestions that propranolol may alter quinidine's elimination have not been substantiated. By reducing liver blood flow propranolol may reduce the systemic clearance of other high extraction drugs such as lignocaine.

Absorption↗
PubMed1992

Propranolol, a phosphatidate phosphohydrolase inhibitor, also inhibits protein kinase C.

Propranolol, a beta-adrenergic receptor antagonist, also inhibits phosphatidate phosphohydrolase, the enzyme that converts phosphatidic acid into diacylglycerol. This latter effect has prompted recent use of propranolol in studies examining the importance of diacylglycerol and phosphatidic acid in cellular signalling events. Here, we show that propranolol is also an inhibitor of protein kinase C. At concentrations greater than or equal to 20 microM, propranolol reduced [3H]phorbol dibutyrate binding (IC50 = 200 microM) and phorbol myristate acetate-stimulated superoxide anion release (IC50 = 130 microM) in human neutrophils. Scatchard analysis showed that propranolol lowers the number of phorbol diester binding sites without significantly affecting their affinity. In vitro kinetic analysis, performed in a mixed micellar assay with protein kinase C purified from human neutrophils, suggested a competitive inhibition of propranolol with the cofactor phosphatidylserine. Complex kinetic patterns were observed with respect to diacylglycerol and ATP, approximating competitive and noncompetitive inhibition, respectively. Taken together, these results suggest that the drug interacts at the level of the regulatory domain of the enzyme. Fifty % inhibition occurred at approximately 150 microM propranolol. Similar levels of inhibition were obtained using exogenous (histone) and endogenous (p47-phox, a NADPH oxidase component) substrates. Protein kinase C-alpha and protein kinase C-beta, two protein kinase C isozymes present in human neutrophils, were inhibited by propranolol in a comparable manner. In the range of concentrations tested (30-1000 microM), neither cAMP-dependent protein kinase nor neutrophil protein tyrosine kinases were affected. The racemic form of propranolol and the (+) and the (-) stereoisomers were equally active, and other beta-adrenergic receptor antagonists (pindolol) and agonists (isoproterenol) were inactive. This suggests that the inhibitory action of propranolol on protein kinase C is related to the amphipathic nature of the drug rather than to its beta-adrenergic receptor blocking ability. Analogs of propranolol were synthesized and found to be more potent protein kinase C inhibitors, with IC50 values in the 10-20 microM range. We conclude that the ability of propranolol to inhibit both protein kinase C and PA phosphohydrolase complicates interpretation of results when this drug is used in signal transduction studies. In addition, propranolol may be a useful prototype for the synthesis of new protein kinase C inhibitors.

Cells, Cultured↗
PubMedDate not supplied

Human albumin and alpha 1-acid glycoprotein binding of propranolol in the presence of a perfluorochemical blood substitute.

Propranolol binding to human albumin (HSA) and to mixtures of alpha 1-acid glycoprotein (AGP) and HSA was examined in the presence of a perfluorochemical (PFC) blood substitute. The per cent free propranolol was determined using a dialysis exchange method at 37 degrees C. In 4% HSA solutions the per cent free propranolol was 51.9% and 53.6% at propranolol concentrations of 100 and 500 ng/ml, respectively. Buffer dilutions of 4% HSA solutions resulted in an increase in free propranolol. However, dilution of the HSA solutions with the PFC emulsion resulted in a significant decrease in free propranolol. In solutions containing 4% HSA with 0.067% AGP, the per cent free propranolol was 22.6% and 23.5% for 100 and 500 ng/ml propranolol, respectively. Again, the per cent free propranolol increased upon plasma protein dilution with buffer solution and decreased upon dilution with the blood substitute. A centrifugation method was utilized to determine the per cent bound propranolol associated with the PFC emulsion droplets in the presence of the proteins. Propranolol was significantly bound by the PFC emulsion even in the presence of a mixture of AGP and HSA. These results indicate that the overall affinity of the PFC blood substitute for propranolol is very substantial. Thus, administration of this PFC blood substitute may not result in the significant increase in per cent free propranolol normally associated with plasma protein dilution.

Blood Substitutes↗
PubMed1976

The use of drug concentration measurements in studies of the therapeutic response to propranolol.

The dose of propranolol which produces the optimal therapeutic effect in patients with angina pectoris has been found to vary widely among patients. Because the plasma concentration of propranolol also differs markedly due to interpatient variability in absorption it seemed possible that this might be the reason for the wide range of effective doses in angina and that plasma propranolol might provide a useful guide to therapeutic response. To examine this possibility we selected ten patients with coronary artery disease complicated by angina and studied them at varying propranolol doses to a maximum of 320 mg/day. Exercise capacity was tested on a treadmill and plasma propranolol concentration was measured by gas liquid chromatography. In seven normal subjects beta-blockade was quantified precisely as inhibition of exercise tachycardia and was related to plasma propranolol levels at various doses. Maximal beta-blockade occurred at 100 ng/ml of plasma propranolol, but the dose response curve of blockade was relatively flat and the ED50 of plasma propranolol was 8+/-1 ng/ml. In the patients maximal therapeutic benefit from propranolol occurred at 30+/-7 ng/ml and at a dose of 144 mg/day. This resulted in an increase in exercise capacity from an estimated 12-7+/-0-8 ml/kg/min of oxygen consumption during control to 17-2+/-1-1 ml/kg/min on the drug. Thus, there was a wide variation of both dose and concentration among these patients at the maximum therapeutic response. However, when plasma propranolol was related to pharmacologic activity, the maximum therapeutic response was observed between 64 and 98% of total blockade. These studies indicated the extent of beta-blockade necessary to produce an effective therapeutic response in angina, but demonstrate that plasma drug levels provide no practical guide to therapy in patients with angina pectoris. A further study was conducted measuring plasma propranolol in twenty hypertensive patients to investigate the fall in blood pressure in relations to the change in plasma renin activity and the inhibition of cardiac adrenergic receptors. The inhibition of plasma renin closely resemble the response seen in heart rate inhibition in that the maximum response is seen at 100 ng/ml and the ED50 was 11 ng/ml. In contrast propranolol is shown only to begin to have a significant effect on blood pressure at a plasma level of 30 ng/ml and the effect becomes progressively greater as the plasma level increases. This suggests that the hypotensive effect of propranolol may be dissociated from the beta-blocking effects of cardiac and renin releasing receptors.

Angina Pectoris↗
PubMed2000

Stereoselective propranolol metabolism in two drug induced rat hepatic microsomes.

AIM:To study the influence of inducers BNF and PB on the stereoselective metabolism of propranolol in rat hepatic microsomes.METHODS:Phase I metabolism of propranolol was studied by using the microsomes induced by BNF and PB and the non induced microsome as the control.The enzymatic kinetic parameters of propranolol enantiomers were calculated by regression analysis of Lineweaver-Burk plots. Propranolol concentrations were assayed by HPLC.RESULTS:A RP-HPLC method was developed to determine propranolol concentration in rat hepatic microsomes. The linearity equations for R(+)propranolol and S(-) propranolol were A = 705.7C+311.2C (R = 0.9987) and a = 697.2C+311.4C (R = 0.9970) respectively. Recoveries of each enantiomer were 98.9%, 99.5%, 101.0% at 60&mgr;mol/L, 120&mgr;mol/L, 240&mgr;mol/L respectively. At the concentration level of 120&mgr;mol/L, propranolol enantiomers were metabolized at different rates in different microsomes. The concentration ratio R(+)/S(-) of control and PB induced microsomes increased with time, whereas that of microsome induced by BNF decreased. The assayed enzyme parameters were: 1. Km. Control group: R(+)30 plus minus 8, S(-)18 plus minus 5; BNF group: R(+)34 plus minus 3, S(-)39 plus minus 7; PB group: R(+)38 plus minus 17, S(-)36 plus minus 10. 2. Vmax. Control group: R(+)1.5 plus minus 0.2, S(-)2.9 plus minus 0.3; BNF group: R(+)3.8 plus minus 0.3, S(-)3.3 plus minus 0.5; PB group: R(+)0.07 plus minus 0.03, S(-)1.94 plus minus 0.07. 3. Clint. Control group: R(+)60 plus minus 3, S(-)170 plus minus 30; BNF group: R(+)111.0 plus minus 1, S(-) 84 plus minus 5; PB group: R(+)2.0 plus minus 2, S(-)56.0 plus minus 1. The enzyme parameters compared with unpaired t tests showed that no stereoselectivity was observed in enzymatic affinity of three microsomes to enantiomers and their catalytic abilities were quite different and had stereoselectivities.Compared with the control, microsome induced by BNF enhanced enzyme activity to propranolol R(+)enantiomer, and microsome induced by PB showed less enzyme activity to propranolol S(-)enantiomer which remains the same stereoselectivities as that of the control.CONCLUSION:Enzyme activity centers of the microsome were changed in composition and regioselectivity after the induction of BNF and PB, and the stereoselectivities of propranolol cytochrome P450 metabolism in rat hepatic microsomes were likely due to the stereoselectivities of the catalyzing function in enzyme.CYP1A subfamily induced by BNF exhibited pronounced contribution to propranolol metabolism with stereoselectivity to R(+)enantiomer.CYP2B subfamily induced by PB exhibited moderate contribution to propranolol metabolism, but still had the stereoselectivity of S(-)enantiomer.

Journal Article↗
PubMedDate not supplied

Assessment of beta-adrenergic blockade with propranolol in patients with cirrhosis.

Fourteen patients with cirrhosis and bleeding esophageal varices were treated with propranolol. The dose of propranolol was determined by decreasing the resting heart rate by 25% 12 hr after an oral dose of propranolol which was given twice a day. Significant decreases in the hepatic venous pressure gradient and cardiac output after 1 month of propranolol administration was observed. To assess beta-adrenergic blockade, the isoproterenol test and plasma propranolol levels were evaluated. Increasing doses of isoproterenol were injected to increase the resting heart rate 25 beats per minute (chronotropic dose 25 or CD25 ). Plasma propranolol concentrations were measured in blood samples drawn 4 hr after the last oral dose. The mean CD25 was 5 +/- 2 micrograms before and 146 +/- 84 micrograms after 1 month of propranolol administration. The plasma propranolol level after 1 month of drug administration was 0.69 +/- 0.47 microM per liter i.e. 2.33 +/- 1.59 micrograms per ml. A significant correlation was found between the CD25 measured after continuous propranolol administration and plasma propranolol level. In conclusion, the efficacy of beta-adrenergic blockade was estimated by the isoproterenol test which correlates with the plasma propranolol level in patients with cirrhosis. This study suggests that the isoproterenol test is useful in assessing beta-adrenergic blockade with propranolol in patients with cirrhosis.

Cardiac Output↗
PubMedDate not supplied

Comparative pharmacodynamics and pharmacokinetics of conventional and long-acting propranolol.

This investigation was conducted to compare the pharmacokinetic and pharmacodynamic effects of single and multiple doses of conventional propranolol and long-acting propranolol in healthy human volunteers. Two double-blind, randomized, double-crossover, Latin square studies were carried out. One study evaluated long-acting propranolol 160 mg/d, conventional propranolol 40 mg qid, or placebo for seven days in 24 men. The other study compared long-acting propranolol 80 mg/d, conventional propranolol 20 mg qid, or placebo for seven days in 27 men. At specific times after the administration, blood samples were obtained, and heart rate and blood pressure were measured; exercise tests were done both on the first day and at steady state (day 7). In both studies, the area under the plasma propranolol concentration-time curve and the peak concentration were significantly less (P less than .0001) after the administration of long-acting propranolol compared with conventional propranolol on both day 1 and day 7; in addition, the elimination half-life was longer after administration of the long-acting preparation (9 hr) compared with that following the conventional dosage form (4 hr). Both conventional and long-acting propranolol significantly decreased the exercise heart rate at each of the selected time points (P less than .05) compared with placebo. Reduction in exercise heart rate was greater with conventional propranolol than with the long-acting formulation, but the differences were not statistically significant, when exercise was performed only at trough levels of the conventional drug. The decreases in exercise heart rate were correlated with plasma propranolol concentrations.

Adolescent↗
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↗
PubMed2005

A double blind, randomized trial on augmentation of labour with a combination of intravenous propranolol and oxytocin versus oxytocin only.

OBJECTIVE: To compare the combination of intravenous propranolol and oxytocin with oxytocin only in augmentation of labour. STUDY DESIGN: A prospective randomized double-blind study in an obstetric department of a large university hospital in Finland. A total of 107 parturients with arrested first stage of labour owing to inadequate uterine contractility were randomized to receive intravenously once or twice a 2 mg dose of propranolol or placebo combined with oxytocin infusion. The main outcome measure was the effect of intravenous propranolol on the frequency of Caesarean section among parturients with arrested labour. The secondary outcome measures were the duration of labour, the required dosage of oxytocin, CTG readings, neonatal outcome and maternal and cord plasma levels of beta-adrenoceptor-binding component of propranolol. Categorial variables between the groups were compared using Chi square and Fisher's exact tests. Continuous variables were compared using the Mann-Whitney U-test and Student's t-test. RESULTS: No reduction in Caesarean section rate was found in the propranolol group. Seventy-three percent of the parturients in the propranolol group and 85% in the placebo group had spontaneous vaginal delivery, RR=0.86 (95% CI 0.70-1.05). The percentage proportion of the augmented part of labour was significantly shorter in the propranolol group than in the placebo group. No differences in the required oxytocin dosage or CTG pathology were found between the groups. Propranolol was found to be safe for the neonates. The concentrations of its beta-adrenoceptor-binding component after a 2mg intravenous dose were quite similar in parturients and neonates at the time of delivery. The active drug component crossed placental barriers with an average neonate umbilical artery/parturient venous plasma ratio of 0.7. After a 4 mg dose the active drug concentrations in parturients were rather similar to those measured after 2 mg dose, whereas in neonates there were signs of drug accumulation. No picture could be obtained from the kinetics of the beta-adrenoceptor-binding component of propranolol from the data. CONCLUSIONS: Propranolol (2 or 4 mg i.v.) combined with oxytocin, as treatment for arrested labour did not affect the Caesarean section rate compared with placebo plus oxytocin. The percentage proportion of the augmented part of labour was significantly shorter after propranolol. Propranolol was safe for the neonates and can be used as an additional medication among parturients with arrested labour.

Adult↗
PubMed1976

Residual effects when chronic propranolol therapy is discontinued within 48 hours of cardiopulmonary bypass.

Recommendations regarding the safe waiting period between discontinuing chronic oral propranolol therapy and beginning cardiopulmonary bypass have varied from a few hours to 2 weeks. In the present study, utilizing adult dogs, propranolol was discontinued 8 or 48 hours prior to surgery. A reduction in cardiac output and elevations of left ventricular end-diastolic pressure, peak systolic pressure, and systemic resistance were noted when cardiac function was evaluated following the induction of anesthesia and prior to undertaking cardiopulmonary bypass. The magnitude of these differences was directly related to the degree of volume loading and inversely related to the interval between the last dose of propranol and the determination of cardiac function. Reduction of heart rate was the most evanescent of propranolol's hemodynamic effects as the marked bradycardia which persisted throughout the course of propranolol therapy was no longer evident 8 hours after the last oral dose of the drug. Following total cardiopulmonary bypass of 1 hour's duration, undertaken 8 hours after the last oral dose of propranolol, cardiac output and left ventricular end-diastolic pressure had returned to normal but peak systolic pressure and systemic resistance remained significantly elevated, When 48 hours had elapsed between discontinuing propranolol and beginning cardiopulmonary bypass, postbypass cardiac function was essentially normal with only slight persistent elevations of peak systolic pressure and systemic resistance detected. When the combined effects of ischemic heart disease and propranolol therapy, the altered metabolic and hemodynamic effects of different routes of drug administration, and the varying durations of cardiopulmonary bypass are taken into consideration, some of the discrepancies between previously reported clinical and experimental findings regarding the duration of persistent propranolol effects can be understood. The clinical course is usually benign in patients who have received propranolol to within a few hours of surgery without specific indication. However, it is often complicated when the drug is continued until just prior to surgery in patients dependant on propranolol for pain or arrhythmia control. In patients demonstrating propranolol dependence, control of symptoms with intra-aortic balloon counterpulsation is recommended followed by the gradual withdrawal of propranolol and elective aortocoronary bypass surgery.

Administration, Oral↗