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PubMed1999

Propranolol stereoisomer plasma concentrations and portal haemodynamic response in patients with liver cirrhosis.

BACKGROUND: The haemodynamic effect of propranolol on portal pressure in patients with portal hypertension is highly variable and does not correlate with propranolol racemate plasma concentrations. AIM: To investigate the stereoselective metabolism of the propranolol enantiomers and its impact on portal haemodynamics in patients with liver cirrhosis since only S-propranolol is haemodynamically active. METHODS: Twenty patients with liver cirrhosis and portal hypertension received 40 mg propranolol orally. Portal blood velocity (PBV) and propranolol stereoisomer plasma concentrations were determined. RESULTS: During the 4 h examination period we observed a significant reduction in PBV (18.3 +/- 2.2%, P < 0.0001) vs. baseline. The area under the curve (AUC) during the study period was significantly different for the two isomers (S-propranolol 1217.0 +/- 118.5 nmol.h/L; R-propranolol 728.8 +/- 103.8 nmol.h/L, P < 0.0001). Seven patients (35%) were portal haemodynamic non-responders to propranolol. Propranolol stereoisomer AUC values were no different between responders (S-propranolol 1133. 3 +/- 132.0 nmol.h/L; R-propranolol 718.0 +/- 129.7 nmol.h/L) and non-responders (S-propranolol 1371.8 +/- 250.5 nmol.h/L; R-propranolol 746.9 +/- 200.3 nmol.h/L); neither was there a correlation between propranolol enantiomer plasma concentrations and the portal haemodynamic effect. CONCLUSIONS: Our data demonstrate a stereoselective metabolism of propranolol enantiomers in liver cirrhosis. However, following oral propranolol administration, stereoisomer plasma concentrations do not predict the portal haemodynamic effect.

Adrenergic beta-Antagonists↗
PubMed1986

Interaction between oral hydralazine and propranolol. II. Assessment of altered splanchnic blood flow as the determinant of altered presystemic extraction.

Coadministration of p.o. hydralazine and d-propranolol or dl-propranolol in six conscious dogs caused a significant increase in peak plasma concentration and area under the p.o. plasma concentration-time curve of propranolol (P less than .01, P less than .01, peak plasma concentration; P less than .01 and P less than .05, area under the plasma concentration-time curve; d-propranolol and dl-propranolol, respectively). Coadministration of p.o. hydralazine with p.o. dl-propranolol resulted in a small trend toward an increase in systemic clearance of i.v. dl-[3H]propranolol; however, this did not reach statistical significance (P less than .2, P less than .1, d-propranolol and dl-propranolol, respectively). When a mixture of d-propranolol and 14C-labeled dl-propranolol was administered into the jejunum of seven anesthetised dogs, the absorption into portal vein of the 14C-labeled dl-propranolol paralleled closely that of d-propranolol both in terms of time to peak and absorption as measured by a percentage of total area under the plasma concentration-time curve at an arbitrary time (10 min) postdose. Assessment of hepatic extraction (E) showed similar close parallels (d-propranolol, E = 0.85 +/- 0.02; dl-[14C]propranolol, E = 0.86 +/- 0.03: mean +/- S.E.M., n = 5, P less than .70). Hepatic extraction of propranolol and blood flow in mesenteric artery and hepatic artery were measured in 23 anesthetised dogs given a constant infusion of d-propranolol into portal vein (11 micrograms/kg/min), made up to 6 control and 17 hydralazine-treated dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1976

Stereospecific radioimmunoassay for propranolol isomers.

Antisera against propranolol were produced in rabbits immunized with propranolol conjugated to bovine serum albumin. The antiserum against dl-propranolol recognized both d- and l-propranolol to the same degree. However, antiserum against l-propranolol was able to discriminate the l-propranolol selectively. The antisera were used to develop radioimmunoassays for dl-propranolol and l-propranolol. The assay can detect as little as 10 pg of propranolol. Metabolites of propranolol do not interfere with the assay unless concentrations are very high. Serum and heart levels of l-propranolol and the d-isomer were determined in the rat after i.v. injection (1 mg/kg) of dl-propranolol. l-Propranolol declines rapidly in the blood after the injection. Concomitantly, there is a rapid accumulation of l-propranolol by the heart. The d-form of propranolol remains in the blood and is metabolized rapidly as reflected by a shorter half-life (23.8 minutes) than the one found for l-propranolol (5.20 minutes).

Animals↗
PubMed1980

Effect of dose and uremia on plasma and urine profiles of propranolol metabolites.

The relationship between plasma levels of 4 propranolol metabolites--naphthoxylactic acid (NLA), 4-hydroxypropranolol (4-OH), naphthoxyacetic acid (NAA), and propranolol glycol (PG)--and propranolol plasma levels was determined in healthy, adult male subjects after increasing single oral doses of propranolol. NLA was present at plasma levels 6 to 25 times that of propranolol. More than 90% of circulating NLA was in the plasma fraction, where it was 95% protein bound. The ratio of plasma concentrations of the pharmacologically active metabolite 4-OH to propranolol approached unity 0.5 hr after propranolol, 160 mg or 320 mg orally, but fell rapidly. Plasma levels of NAA were in the same range as propranolol, especially as time progressed. PG circulated at plasma levels less than 12% of propranolol. As oral doses of propranolol were increased from 20 to 320 mg, there was a decrease in intrinsic plasma clearance (Cli) from 425 to 200 1/hr. Half-life rose from 3 to 5 hr. Urinary recovery of 4-OH fell as Cli rose. Urinary recovery of propranolol conjugates, NLA, and N-desisopropylpropranolol (NDIPP) rose as Cli fell. Our results suggest that naphthalene ring oxidation of propranolol represents a high-affinity low-capacity enzymatic pathway(s) that plays an important role in the extensive hepatic extraction of propranolol after small doses orally. Plasma NLA and plasma NAA were determined before and after hemodialysis in 14 uremic patients receiving long-term propranolol therapy. Mean plasma NLA was 4.372 ng/ml, and mean plasma NAA level was 238 ng/ml when mean plasma propranolol level was 15 ng/ml.

Absorption↗
PubMed1996

Racial differences in propranolol enantiomer kinetics following simultaneous i.v. and oral administration.

1. Racial differences in propranolol enantiomer kinetics following oral dosing were previously documented in our laboratory. The purpose of this study was to more completely describe propranolol kinetics in black and white subjects with the goal of gaining a better understanding of the mechanism(s) responsible for racial differences in oral propranolol kinetics. 2. Twelve white and 13 black healthy males were included in the study. Poor metabolizers of dextromethorphan and mephenytoin were excluded. Subjects took oral propranolol 80 mg every 8 h for 16 doses and received an intravenous dose of radiolabelled propranolol with the 16th dose. Serum and urine samples were collected for 24 h after the 16th dose. Serum concentrations of R- and S-propranolol and urine concentrations of its three primary metabolites were determined by h.p.l.c. 3. Apparent oral clearances of R- and S-propranolol were higher (P < 0.05) in blacks than whites (R-propranolol: 5036 +/- 4175 ml min-1 vs 2854 +/- 879 ml min-1; S-propranolol 3255 +/- 1723 ml min-1 vs 2125 +/- 510 ml min-1; blacks vs whites). 4. R- and S-propranolol clearances were higher in blacks than whites (R-propranolol 1069 +/- 316 ml min-1 vs 841 +/- 161 ml min-1; S-propranolol 947 +/- 271 ml min-1 vs 771 +/- 142 ml min-1; blacks vs whites, P < 0.05). 5. There were trends (P > 0.05 < 0.10) toward higher side chain oxidation, 4-hydroxylation and R-propranolol glucuronidation in blacks compared with whites. Ethnic differences in the enantiomeric ratios of partial metabolic clearance values were not observed. 6. We conclude the higher propranolol oral clearances in black subjects are explained by blacks having slightly higher hepatic metabolism via all three of its major metabolic pathways. Higher propranolol clearances among black subjects were also observed and we conclude this finding is explained largely by the higher hepatic metabolism, but also by slightly higher liver blood flow among black subjects.

Administration, Oral↗
PubMed2000

Lack of interaction between lansoprazole and propranolol, a pharmacokinetic and safety assessment.

Due to the prevalence of both gastrointestinal and cardiovascular diseases, it is likely that patients may be coprescribed gastric parietal cell proton pump inhibitors and beta-adrenergic antagonists. Therefore, the objectives of this phase I study were to assess the potential effects of the coadministration of lansoprazole on the pharmacokinetics of propranolol and to evaluate the safety of propranolol with concomitant lansoprazole dosing. In a double-blind fashion, 18 healthy male nonsmokers were initially randomized to receive either 60 mg oral lansoprazole, each morning for 7 days, or an identical placebo (period 1). On day 7, all subjects were concomitantly administered oral propranolol, 80 mg. After a minimum of 1 week following the last dose of either lansoprazole or placebo, subjects were crossed over to the opposite treatment for another 7 days (period 2). Subjects were again administered oral propranolol on day 7. During both treatment periods, blood samples for the determination of plasma propranolol and 4-hydroxy-propranolol were obtained just before the dose and at 0.5, 1, 2, 3, 4, 6, 8 12, 16, 20, and 24 hours postdose. Plasma propranolol and 4-hydroxy-propranolol concentrations were determined by using HPLC with fluorescence detection. The Cmax, tmax, AUC0-infinity, and t1/2 values for propranolol, as well as the AUC0-infinity for 4-hydroxy-propranolol, were calculated and compared between the lansoprazole and placebo regimens. The mean age of the 15 subjects who successfully completed the study was 31 years (range: 24-38 years), and their average weight was 174.8 pounds (range: 145-203 pounds). There were no statistically significant differences between the lansoprazole and placebo regimens for the propranolol Cmax, tmax, AUC0-infinity, and t1/2 values. Also, there were no statistically significant differences between regimens for the 4-OH-propranolol AUC0-infinity. Safety evaluations, which included adverse events, vital signs, clinical laboratory determinations, ECG, and physical examinations, revealed no unexpected clinically significant findings and did not suggest a drug-drug interaction. In conclusion, lansoprazole does not significantly alter the pharmacokinetics of propranolol, suggesting that it does not interact with the CYP2D6- or CYP2C19-mediated metabolism of propranolol. Modification of a propranolol dosage regimen in the presence of lansoprazole is not indicated, based on the pharmacokinetic analysis and the lack of a clinically significant alteration in the pharmacodynamic response.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1994

Electrophysiological analysis of effect of propranolol in rabbit S2 proximal straight tubule.

The effect of dl-propranolol on the basolateral membrane potential (Vb) of in vitro microperfused S2 proximal straight tubules of the rabbit kidney was examined using conventional microelectrode techniques. In the steady-state condition, the average of 23 measurements of Vb was -44.8 +/- 2.0 mV. Addition of 10(-4) mol/l of dl-propranolol to the basolateral solution rapidly depolarized Vb by 12.1 +/- 1.3 mV in 20 sec (n = 15). The same dose of d-isomer of propranolol, which has no beta-blocking effect, also depolarized Vb to a similar extent. The non-selective beta-blocker nadolol, which possesses no membrane stabilising activity, had no effect on Vb. Depolarization of Vb by dl-propranolol in 20 seconds (propranolol-induced delta Vb) occurred in a dose-dependent manner. In the presence of 1 mmol/l Ba++ in basolateral solution, propranolol-induced delta Vb was strongly inhibited. The stilbene derivative DIDS at 1 mmol/l did not change propranolol-induced delta Vb, whereas the elimination of Cl- from the ambient conditions increased propranolol-induced delta Vb. The minimization of the luminal Na(+)-coupled organic solute transporter by collapsing of the lumen did not inhibit propranolol-induced delta Vb, indicating the lack of effect of propranolol on luminal Na(+)-coupled transporters. Ouabain at 10(-3) mmol/l in the bath did not eliminate propranolol-induced delta Vb, indicating the presence of a target transporter other than Na+/K+ ATPase for propranolol. These results suggest the following; 1) propranolol has a depolarizing effect on Vb in proximal tubule; 2) the effect of propranolol is independent of Cl- transport or Na(+)-coupled transporters in the luminal membrane; 3) propranolol depolarizes Vb by inhibiting the K+ channel in the basolateral membrane of S2 proximal tubule.

Animals↗
PubMedDate not supplied

Effects of diltiazem on the disposition and metabolism of the enantiomers of propranolol in the dog during multiple oral dosing.

The intravenous and oral dose kinetics and metabolism of the enantiomers of propranolol were investigated in five dogs during steady-state oral racemic propranolol dosing (5 mg/kg, every 8 hr for 3 days). These results were compared with those obtained during concomitant administration of oral diltiazem (2.5 mg/kg, every 8 hr for 3 days) in the same animals. The oral and intravenous propranolol test doses consisted of a pseudoracemic mixture of equal amounts of hexadeuterated-(R-(+))- and dideuterated-(S-(-))-propranolol. Propranolol metabolism in the urine was evaluated by coadministering 150 muCi of [4'-3H]racemic propranolol HCl, along with the deuterium-labeled compounds. Plasma concentrations of the deuterated enantiomers were measured by HPLC-thermospray MS, using undecadeuterated racemic propranolol as the internal standard. Diltiazem coadministration had no significant effects on either the systemic clearance, renal clearance, the apparent volume of distribution, or the elimination half-lives of either enantiomer. On the other hand, concomitant diltiazem treatment significantly reduced the oral clearance of S-(-)- and R-(+)-propranolol by 58 and 61%, respectively. These reductions resulted in an increase in their respective apparent steady-state oral availabilities of 129 and 106%. The S/R enantiomeric ratio of the oral availability of propranolol was not significantly changed from control. The urinary propranolol metabolites were isolated and purified by solvent extraction and HPLC and quantitated by radioactivity. Twelve metabolites, including propranolol, were isolated and quantitated in the urine. A significant reduction in the percentage of ring oxidation products and a significant increase in the percentage of naphthoxylactic acid and propranolol glucuronide excreted in the urine occurred in the diltiazem-treated animals. The S/R enantiomeric ratios of urinary excreted propranolol, propranolol glucuronide, 4'-hydroxypropranolol glucuronide, and its sulfate were not altered by diltiazem. These results suggest that the decreased oral clearances of the enantiomers of propranolol by diltiazem is caused by a selective decrease in the formation of ring-oxidized products.

Animals↗
PubMed1984

Ethanol-induced inhibition of hepatic uptake of propranolol in perfused rat liver and in man.

Studies were conducted to determine the mechanism whereby ethanol alters the hepatic disposition of propranolol. In eight isolated perfused rat livers, ethanol (mean = 40.1 mmol/l diminished the clearance of dl-propranolol (1.93 +/- 0.43 to 1.24 +/- 0.22 ml/min/g liver, p less than 0.05); increased its t1/2 (12.8 +/- 1.5 to 20.7 +/- 3.25 min, p less than 0.01); and decreased the proportion metabolized (68.7 +/- 4.7% to 34.3 +/- 10.3%, p less than 0.01). These results suggest that ethanol could substantially increase the oral bioavailability of propranolol in humans. However, in normal human volunteers administered 80 mg of propranolol orally, alone, or preceded and followed by ethanol to maintain breath ethanol concentrations of 800-1000 mg/l, increases in propranolol AUC were smaller than anticipated. Seven subjects had increases in free propranolol AUC0-8h (32%, range: 12-61%) (p less than 0.05), while total propranolol AUC0-8h increased by a mean 22% (range: -4-+49%). Propranolol free fraction varied with time and was higher after ethanol (mean = 0.090 vs 0.084) (p less than 0.077). The extent of the propranolol-induced slowing of heart rate was not influenced by ethanol (mean decrease from baseline of 13 bpm at peak propranolol effect vs 9 bpm without ethanol); mean heart rates following propranolol with ethanol were higher at all times (mean of 7.5 bpm) (p less than 0.001) than after propranolol alone. Ethanol inhibits the hepatic oxidative metabolism of propranolol in vitro; however, any effect on heart rate of higher concentrations of propranolol induced by ethanol in humans is offset by the cardio-acceleratory effect of ethanol.

Animals↗
PubMedDate not supplied

The inhibition of sexual behavior in male rats by propranolol is stereoselective.

We have previously reported that administration of racemic mixtures of propranolol was associated with a marked inhibition of mating behavior in male rats. To compare the effects of (+)-propranolol, (-)-propranolol, and (+/-)-propranolol in sexually experienced males, rats ejaculating in four or more mating tests were divided into three groups (N = 16 per group) such that no differences in parameters of copulatory behavior were evidence in preexperimental tests. No major effect of propranolol on parameters of behavior associated with initiation of sexual behavior was evident. In contrast, other measures of behavior were profoundly modified. The ejaculatory threshold, indicated by the number of intromissions preceding ejaculation, was increased after (+)- and (+/-)-propranolol, but not (-)-propranolol. The number of mounts without intromission preceding ejaculation was increased only after (+/-)-propranolol. A decrease in copulatory efficacy was evident after (-)- or (+/-)-propranolol, but not after (+)-propranolol. Increases in ejaculation latency, intercopulatory interval, and postejaculatory interval were observed after (-)- and (+/-)-propranolol, but not after (+)-propranolol. In summary, the present data indicate that the (-) isomer of propranolol is the active form necessary for the inhibitory effects of propranolol on male sexual function. We suggest that this inhibition is due to specific receptor-mediated mechanisms, involving beta-adrenoceptors and 5-HT1A receptor interactions.

Animals↗
PubMed1984

Stereoselective clearance and distribution of intravenous propranolol.

Our objective was to determine the kinetics of (+)- and (-)-propranolol after intravenous doses of racemic drug. Five normal subjects received 0.1 mg/kg of a pseudoracemate of propranolol that consisted of deuterium-labeled (+)-propranolol and unlabeled (-)-propranolol. Plasma concentrations of (+)- and (-)-propranolol as measured by gas chromatography-mass spectrometry demonstrated enantiomeric differences in systemic clearance (Cls) [(+)-propranolol, 1.21 +/- 0.15 l/min; (-)-propranolol, 1.03 +/- 0.12 l/min; P less than 0.01] and apparent volume of distribution (Vd) [(+)-propranolol, 4.82 +/- 0.34 l/kg; (-)-propranolol, 4.08 +/- 0.33 l/kg; P less than 0.001], but no difference in distribution or elimination t1/2s (t1/2 beta 3.5 hr). The higher Cls of (+)-propranolol suggests stereoselective hepatic elimination. The higher apparent Vd of (+)-propranolol is mainly related to its lower plasma binding [(+)-propranolol, 20.3 +/- 0.8% unbound; (-)-propranolol, 17.6 +/- 0.7% unbound; P less than 0.001]. There was no stereoselective uptake by red blood cells. These findings demonstrate that multiple stereoselective mechanisms are involved in the disposition of propranolol and determine the access of the drug to active sites.

Adult↗
PubMed1999

The effects of propranolol on heterogeneity of rat cerebral small vein oxygen saturation.

UNLABELLED: beta-Adrenergic receptors are involved in altering cerebral metabolism and blood flow. This study was performed to determine whether propranolol would alter the microregional O2 balance in the brain. Rats were anesthetized with 1.4% isoflurane. Isotonic sodium chloride solution (control group), propranolol 2 mg/kg (low propranolol group) or propranolol 20 mg/kg (high propranolol group) was administered IV to the rats. Twenty minutes later, regional cerebral blood flow (rCBF) was measured using the 14C-iodoantipyrine autoradiographic technique. Small (diameter <70 microm) arterial and venous oxygen saturation (SaO2 and SvO2, respectively) was determined using microspectrophotometry in the alternate slices of the tissue sections used to measure rCBF. In both the low and high propranolol groups, average cortical rCBF was 35% lower than that in the control group. The average O2 consumption of the cortex of the propranolol groups was significantly lower than control (low propranolol: -41%, high propranolol: -49%). In all groups, SaO2 was almost identi-cal. The heterogeneity of the microregional SvO2 expressed as the coefficient of variation (CV = 100 x sD/mean) was significantly lower in the propranolol groups (low propranolol: 8.0+/-2.3, high propranolol: 7.3 +/- 2.9) than in the control group (13.4 +/- 3.5). The proportion of cortical veins with Svo2 <55% was significantly smaller in the low and high propranolol groups (4 of 60 and 3 of 60, respectively) than that in the control group (15 of 60). In the other brain regions, the data followed a similar pattern. Our data demonstrated that propranolol is effective in decreasing O2 consumption, improving microregional O2 balance, and reducing its heterogeneity in the brain. IMPLICATIONS: Our data suggest that the linkage of O2 supply and consumption is not tightly coupled under isoflurane anesthesia. beta-Adrenergic blockers may tighten this linkage and reduce the number of low O2-saturated microregions.

Adrenergic beta-Antagonists↗
PubMed1989

Halothane inhibition of propranolol metabolism is stereoselective.

Propranolol, like many drugs, is used clinically as a racemic mixture. The major pharmacodynamic effects of propranolol, however, are mediated by the (-)-isomer, which is 100 times as potent as the (+)-isomer. The two isomers also differ in their pharmacokinetic characteristics. To determine whether halothane anesthesia stereo-selectively inhibits the metabolism of racemic propranolol, eight male mongrel dogs were studied. On the first day of the study, 40 mg racemic propranolol was infused into the portal vein and arterial blood samples were obtained over the following 4 h for the measurements of (+)- and (-)-propranolol concentrations by HPLC. The study was repeated 24 h later during 2 MAC halothane anesthesia, when the intrinsic clearance of total propranolol was decreased by 67.5 +/- 5%, from 6.14 +/- 1.1 1/min to 1.84 +/- 0.4 1/min (P less than 0.05). The decrease in intrinsic clearance was stereoselective, (-)-propranolol being affected to a greater extent than (+)-propranolol; thus, the decrease in the clearance of (-)-propranolol, from 10.96 +/- 2.71/min to 2.6 +/- 0.71/min (73 +/- 5%) was significantly (P less than 0.05) greater than the decrease in the clearance of (+)-propranolol, (62 +/- 3%) from 4.3 +/- 0.8 1/min to 1.5 +/- 0.3 1/min. Furthermore, the ratio of the intrinsic clearance of (-)-propranolol to the intrinsic clearance of (+)-propranolol was significantly (P less than 0.05) reduced by halothane anesthesia, from 2.42 +/- 0.29 to 1.69 +/- 0.11. Stereoselective inhibition of propranolol metabolism results in proportionally higher concentrations of (-)-propranolol during halothane anesthesia than are present in awake dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Inhalation↗
PubMed1996

(S)-4'-hydroxypropranolol causes product inhibition and dose-dependent bioavailability of propranolol enantiomers in the isolated perfused rat liver and in rat liver microsomes.

1. Previous evidence suggests that the dose-dependent bioavailability of racemic propranolol may be partly due to product inhibition. We have examined this further by studying the individual enantiomers of propranolol in the perfused rat liver (IPRL) and in rat liver microsomes. 2. In recirculating IPRL experiments, (R)-propranolol (n = 7) or (S)-propranolol (n = 4) were infused at rates of 75, 150 and 231 nmol/min for three sequential 36-min phases. In single-pass experiments, (R)-propranolol (n = 4) or (S)-propranolol (n = 4) were administered at rates of 80, 136 and 239 nmol/min for three sequential 30-min phases. Steady-state bioavailability increased 10-20-fold over this dose range with both enantiomers in both recirculating and single-pass experiments. At the higher administration rates of (S)-propranolol, bioavailability in recirculating experiments was significantly greater than that in single-pass experiments, whereas there was no significant difference for (R)-propranolol. This suggests product inhibition of (S)- but not (R)-propranolol metabolism. 3. Of the metabolites examined, racemic 4'-hydroxypropranolol (4-OHP) inhibited the formation of 4-OHP, 5'-hydroxypropranolol (5-OHP) and desisopropylpropranolol (DIP) from (S)-propranolol and (R)-propranolol in microsomal studies (IC50 20 microM). Tissue levels of (S)-4-OHP in recirculating experiments (28.0 microM) at the highest dose (239 nmol/ min) of (S)-propranolol were greater than its IC50 of 20 microM, suggesting that 4-OHP is the inhibiting metabolite in the intact liver. The absence of evidence for product inhibition with (R)-propranolol in perfused livers suggests that (S)-4-OHP inhibits 4-hydroxylation of each isomer but (R)-4-OHP does not. 4. We conclude that in the recirculating IPRL, product inhibition of propranolol metabolism is evident with the (S)-isomer, but not he (R)-isomer, and that the inhibiting metabolite is (S)-4-OHP.

Animals↗
PubMed2002

[Decrease in the sensitivity to the anti-ischemic effect of propranolol and prospects for correcting it in patients with stable angina pectoris].

AIM: To study incidence of low sensitivity to an antiischemic effect of propranolol and feasibility of its correction with a metabolic drug--trimetazidine. MATERIAL AND METHODS: Paired treadmill and bicycle exercise tests were made until depression of segment ST > 1 mm and a typical angina episode. The trial included 147 men with ischemic heart disease, stable angina pectoris (functional class II-III). The antiischemic effect of propranolol single doses 40 or 80 mg were assessed in 117 patients. Single doses of propranolol 40 mg, trimetazidine 20 mg and their combination were examined for an antiischemic effect in 30 patients. The absence of the above effect of propranolol was stated in 20 patients who participated in a double blind, randomised, placebo-controlled study with conduction of 2-week courses of regular administration of propranolol in a dose 120 mg/day, trimetazidine 60 mg/day and their combination. Echo-CG was made initially and in the end of each course. RESULTS: Propranolol's antiischemic effect of a single dose 40 mg was not found in 45.3% patients, 40-80 mg--in 21%. Among 20 patients without effect of the single propranolol dose, an increment of the threshold load made up 20.7 +/- 15.7 s, after intake of trimetazidine 16.3 +/- 18.6 s. The combination of these drugs significantly increases the increment of the threshold load duration to 90.8 +/- 80.4 s. The same picture was observed in the course treatment. The above increment in the course administration of propranolol was 46.3 +/- 15.3 s, of trimetazidine 22.8 +/- 20.2 s, of their combination 122.7 +/- 21.8 s (p = 0.02). In the absence of propranolol effect, echo-CG registered deterioration of disorder of left ventricular diastolic function. 10 patients with effect of the single propranolol dose this deterioration was not observed in combined use of propranolol and trimetazidine. CONCLUSION: The antiischemic effect of propranolol in a single dose 40 mg was not recorded in about half of the examined anginal patients. Combined use of propranolol and trimetazidine in cases with no propranolol effect provides a synergetic effect both in single and course administration.

Adrenergic beta-Antagonists↗
PubMed1995

Contribution of the small intestine to the first-pass uptake and systemic clearance of propranolol in rabbits.

Epithelial cells of the intestine enclose isozymes able to metabolize propranolol, raising the possibility that the gut contributes with the liver to the first-pass uptake and systemic clearance of propranolol. To assess the role of the liver in the first-pass uptake, propranolol was injected into the jugular vein and a mesenteric vein of anesthetized New Zealand rabbits, and blood samples were drawn from the abdominal aorta, or it was injected into the intestine and samples were drawn simultaneously from the portal vein and the abdominal aorta. Extraction of propranolol by the liver was estimated to be 96-97%. To assess the intestinal extraction of oral propranolol, a porto-cava transposition was conducted in two groups of animals, and propranolol was injected into the first 30 cm of the small intestine or into the jugular vein and samples were withdrawn from the abdominal aorta; propranolol extraction by the intestine was 43%. To document the contribution of the intestine in the systemic clearance of propranolol, propranolol was injected into the jugular vein and blood samples were drawn simultaneously from the abdominal aorta (before the gut) and from the portal vein (after the gut); propranolol extraction from the systemic circulation by the intestine was 24%. Only the liver generated detectable amounts of conjugated metabolites of propranolol. In the in vitro studies, it was shown that propranolol was rapidly metabolized by the liver, yielding 4-hydroxypropranolol and conjugates of propranolol; propranolol metabolism in the proximal small intestine was slower and yielded only 4-hydroxypropranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1984

Effects of chlorpromazine on the disposition and beta-adrenergic blocking activity of propranolol in the dog.

The effects of chlorpromazine (100 mg p.o., 2 hr before propranolol) on the disposition and beta-adrenergic blocking actions of both intravenous (6 mg) and oral (40 mg) propranolol were studied in the dog. Chlorpromazine pretreatment significantly reduced (69%) the oral clearance of propranolol, resulting in significant increases in propranolol bioavailability (159%), and in the total beta-adrenergic blocking activity (111%) after the oral dose. The increase in the total beta-adrenergic blocking activity of oral propranolol after chlorpromazine pretreatment was mostly due to an increased contribution from the parent compound; the apparent activity from active propranolol metabolites was not affected by chlorpromazine. Chlorpromazine pretreatment had no significant influence on the systemic clearance, elimination half-life, apparent volume of distribution, and plasma binding of propranolol, or on the apparent hepatic blood flow. After intravenous propranolol, chlorpromazine pretreatment had no effect on either the total amount of beta-adrenergic blocking activity or the amount of activity attributable to active metabolites. The decreased oral propranolol clearance by chlorpromazine was seen as a shift to the left in the propranolol dose vs. AUC relationship, eliminating the apparent nonlinear kinetic behavior of oral propranolol, and reducing the apparent oral threshold dose. Chlorpromazine's major, if not only, effect on propranolol disposition was to reduce the presystemic elimination of propranolol, possibly through inhibition of its metabolism via a pathway other than ring oxidation.

Animals↗
PubMed1985

Combination propranolol and bepridil therapy in stable angina pectoris.

The safety and efficacy of bepridil plus propranolol therapy were investigated in a placebo-controlled, parallel-design, double-blind trial in 56 patients who were not responding to propranolol alone. Patients entering the study were receiving an average propranolol dosage of 131 mg/day (range 20 to 240). For the first 2 weeks of the study they were given placebo in addition to their propranolol dose, and then were randomized to receive continued placebo plus propranolol or bepridil plus propranolol therapy. The bepridil dosage was adjusted over the 8 weeks of active treatment to an average of 273 mg/day (range 200 to 400). The double-blind treatment period was followed by a 3-week washout period during which all patients received propranolol and placebo. The effects of treatment on the frequency of angina attacks, nitroglycerin consumption, exercise performance (treadmill-modified Bruce protocol) and Holter electrocardiogram (ECG) were assessed. Propranolol and bepridil plasma levels also were obtained. Improved antianginal efficacy and reduced nitroglycerin consumption were noted when bepridil was added to propranolol (p less than 0.01). During 8 weeks of combination treatment, exercise tolerance increased 1.0 +/- 1.2 minutes from a baseline of 7.3 +/- 2.2 with bepridil plus propranolol compared with an increase of 0.02 +/- 1.3 minutes from a baseline of 7.6 +/- 2.9 with placebo plus propranolol (p less than 0.01). With bepridil plus propranolol, there were also increases in exercise time to onset of angina (p less than 0.04), exercise time to 1-mm electrocardiographic ST-segment depression (p less than 0.06) and total work (p less than 0.03) compared with placebo plus propranolol therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗