Differential effects of d- and l-propranolol on dopamine turnover stimulated by oxotremorine in striatal and mesolimbic areas of rat brain

The effects of l-propranolol, d-propranolol and clonidine on homovanillic acid (HVA) concentrations in the corpus striatum and nucleus accumbens of rats were studied under normal conditions and after treatment with oxotremorine or haloperidol. Thile propranolol and clonidine given alone had no significant effect on HVA levels in either area, l-propranolol (1--10 mg/kg) and clonidine (0.1 mg/kg), both significantly inhibited the elevation of striatal HVA, found 60 min after oxotremorine administration. Both l- and d-propranolol (2.5 mg/kg), reduced the effect of oxotremorine in the nucleus accumbens. Neither l-propranolol no clonidine affected the rise in HVA in either brain area seen after haloperidol. Our results suggest that propranolol may reduce cholinergic activation of dopaminergic pathways by two different mechanisms. One is stereospecific for the l-isomer and operates in the striatum and another, which is shared by both isomers, occurs in the nucleus accumbens.     

Studies on the uptake and release of propranolol and the effects of propranolol on catecholamines in cultures of bovine adrenal chromaffin cells

Uptake and release of [3H]l-propranolol and the effects of propranolol on the uptake and release of [3H]norepinephrine were studied in cultures of isolated bovine adrenal chromaffin cells. [3H]l-Propranolol uptake increased with increasing [3H]l-propranolol concentration from 10(-7) M to 10(-3) M and was not saturable in this concentration range. [3H]l-Propranolol uptake was equally inhibited by l- and d-propranolol, indicating that the uptake is not stereoselective. [3H]l-Propranolol uptake differed from [3H]norepinephrine uptake in two respects: [3H]l-propranolol uptake was 44-50 times greater than [3H]norepinephrine uptake at early non-equilibrium time periods, and [3H]l-propranolol uptake was not Na+ dependent and was not inhibited by desipramine, indicating that [3H]l-propranolol is not taken up by the biogenic amine transport system. In cells preloaded with [3H]l-propranolol, two agents, veratridine and tyramine, stimulated an increased release of [3H]l-propranolol into the medium. However, veratridine-induced [3H]l-propranolol release was inhibited only slightly by the Na+ channel blocker tetrodotoxin, and tyramine-induced [3H]l-propranolol release was not inhibited by desipramine. In addition, K+, carbachol and the physiological mediator of adrenal catecholamine release, acetylcholine, failed to evoke [3H]l-propranolol release. Therefore, it is unlikely that propranolol is released in response to physiological stimulation of adrenal chromaffin cells in animals administered propranolol in vivo. l-Propranolol inhibited [3H]norepinephrine uptake by chromaffin cells with an IC50 for l-propranolol of 5 X 10(-6) M; d-propranolol was equally potent for this effect at lower propranolol concentrations. By themselves, neither l- nor d-propranolol had any effect on [3H]norepinephrine release from the cells. However, l-propranolol inhibited carbachol-induced [3H]norepinephrine release with an IC50 for l-propranolol of 5 X 10(-7) M to 10(-6) M. At these lower concentrations, d-propranolol had no effect on carbachol-induced [3H]norepinephrine release, indicating that the inhibition by l-propranolol may be mediated via beta-adrenoceptors on chromaffin cells.     

Effects of l- and d-propranolol on the ischemic myocardial metabolism of the isolated guniea pig heart, as studied by 31P-NMR

Using 31P nuclear magnetic resonance (NMR) spectroscopy (acquisition time of 3 min), we studied the effects of l- and d-propranolol on the ischemic derangement of myocardial energy metabolism in the isolated perfused guinea pig heart. The myocardial pH and concentration of high-energy phosphate were used as measures of the energy metabolism. Cardiac pH progressively declined during ischemia from 7.41 +/- 0.04 to 7.13 +/- 0.05, 6.91 +/- 0.04, 6.74 +/- 0.04, and 6.61 +/- 0.04 (before ischemia and 3, 6, 9, and 12 min after ischemia, respectively). After 3 min of reperfusion, pH rapidly returned to 7.42 +/- 0.04. Creatine phosphate (CP) and adenosine triphosphate (ATP) contents were reduced, while inorganic phosphate (Pi) contents were increased during ischemia. Whereas CP and Pi contents were restored to the normal values after reperfusion, the recovery of ATP contents was poor. Both l- and d-propranolol (10(-6) M) significantly suppressed the fall of the myocardial pH. Changes in the high-energy phosphate contents were also attenuated by l- and d-propranolol. These results suggest that not only l-propranolol, but also d-propranolol can produce beneficial effects on the ischemic derangements of myocardial energy metabolism.     

Chronopharmacokinetics of beta-receptor blocking drugs of different lipophilicity (propranolol,metoprolol, sotalol,atenolol) in plasma and tissues after single and multiple dosing in the rat

Summary Comparative pharmacokinetic studies with the -receptor blocking drugs propranolol, metoprolol, sotalol and atenolol, differing greatly in lipophilicity, and their main route of elimination were performed in light-dark-synchronized rats after equimolar single (6 moles/kg) or multiple (6x6 moles/kg) drug application. Drug concentrations were determined in plasma and various target organs of the drugs, e.g. heart, muscle, lung and brain, after drug application in the light period (L) and dark period (D), respectively. After single drug administration pharmacokinetic parameters of all drugs depended on the L and D conditions. Elimination half-lives in plasma and organs were shorter during D than during L. No L-D-differences were found in initial drug concentrations of the hydrophilic drugs sotalol and atenolol. In contrast, C₀-values of the lipophilic propranolol in highly perfused organs (muscle, lung, brain) and of metoprolol in muscle tissue were significantly higher in D than in L. No obvious temporal dependency was found in other pharmacokinetic parameters (AUC, plasma clearance,V _d) with the exception inV _d of propranolol. Due to the different physico-chemical properties of the compounds inter-drug-differences in pharmacokinetic parameters including drug accumulation into lung and brain tissue were observed. Multiple drug dosing abolished the circadian-phase-dependency in the elimination half-lives of the drugs due to an increase in D. Only for the highly lipophilic propranolol half-lives in highly perfused organs were still shorter in D than in L. It is concluded that L-D-differences in drug half-lives after single dose application are mainly due to circadian variations in drug elimination with a higher hepatic (propranolol, metoprolol) or renal (sotalol, atenolol) elimination in the activity period of rats during D. Additional studies with propranolol on heart rate of conscious rats revealed that a maximum in -receptor blockade was achieved at 10 moles/kg in L but not in D. Thus, it is assumed that abolition of circadian-phase-dependency in half-lives after 6x6 moles/kg of the drugs may be due to the longer lasting and more pronounced -receptor blockade after multiple drug dosing over a period of several hours in D. Thereby, liver-flow-dependent elimination of propranolol and metoprolol and renal elimination of sotalol and atenolol is reduced to base-line levels found in L.Parts of this work were presented at the 22nd Spring Meeting (Lemmer 1981) and at the Joint Meeting (Lemmer et al. 1983a) of the German Pharmacological Society     

Effect of enantiomers of propranolol on desipramine-induced anti-immobility in the forced swimming test in the rat

The effect of d- and l-enantiomers of propranolol on desipramine-induced anti-immobility effects and on brain desipramine levels was studied in the rat. Intraperitoneal propranolol and desipramine were administered three times, 25, 6, 2 and 24, 5, 1 h respectively, before the test. It was found that l-propranolol but not d-propranolol, at the same doses (2.5 and 5 mg/kg), antagonized 20 mg/kg desipramine without altering desipramine brain levels. It is suggested that blockade of beta-adrenergic receptors rather than membrane-stabilizing or pharmacokinetic effects is responsible for the antagonism of propranolol toward desipramine.     

An opposing role for the adrenals in the hypotensive effects of propranolol in the spontaneously hypertensive rat.

d,l-Propranolol (1 and 5 mg/kg s.c.) did not cause a fall in blood pressure and induced only a limited decrease in heart rate in conscious spontaneously) hypertensive rats (SHR). In contrast, after bilateral adrenalectomy, d,l-propranolol induced a rapid and profound decrease in blood pressure and heart rate. Decreases in heart rate and blood pressure in the individual animals were not correlated. The effects were mainly caused by l-propranolol but an additional effect of d-propranolol cannot be excluded. The decrease in blood pressure was not observed after removal of the adrenal medulla. Heart rate decreased only slightly in these animals. After treatment of adrenalectomized SHR with corticosterone (1 mg/kg b.w./h) the decrease in blood pressure due to d,l-propranolol was completely abolished. The fall in heart rate was diminished. Central injection of d,l-propranolol into the lateral brain ventricle of adrenalectomized SHR caused cardiovascular changes which were less pronounced than those following peripheral injection of comparable doses. The inhibitory effects of d,l-propranolol also occurred in adrenalectomized normotensive Wistar Kyoto rats. However, no significant changes in blood pressure and only a limited fall in heart rate were observed in adrenalectomized normotensive and renal hypertensive Wistar rats. It is concluded that the presence of the adrenal cortex, but not of the adrenal medulla prevents acute hypotension and bradycardia after propranolol in the conscious SHR.     

Analysis of the vasodilator action of alprenolol

The effect of alprenolol and other beta-adrenoceptor antagonists, including d-isomers, on blood flow in femoral, coronary and mesenteric vascular beds was measured in anesthetized dogs. Under conditions of constant perfusion pressure, intra-arterial injection of beta-adrenoceptor antagonists produced vasodilation. Propranolol and alprenolol were approximately equipotent in coronary and mesenteric beds but alprenolol was significantly more potent in the femoral bed. Practolol was virtually inactive in all beds. The vasodilating potency of d-alprenolol and d-propranolol was not significantly different from that of the respective racemic mixtures. The vasodilator response to alprenolol was not affected by pretreatment with atropine, diphenhydramine or propranolol. In conscious normotensive dogs i.v. injections of d,l- and d-alprenolol produced dose-dependent decreases in blood pressure and increases in heart rate. Under similar conditions, i.v. d,l-propranolol was without effect on either measurement. The results suggest that the hypotensive action of alprenolol in dogs may derive from its vasodilator activity.     

Biphasic effects of propranolol on a temporal generalization gradient in the rat

Rats were trained on a fixed interval (FI 20 s) schedule of food reinforcement, then subjected to drug trials on an ABBA design. Responses, recorded in 2 s post-reinforcement bins, formed a temporal generalization gradient. d,l-propranolol (7.5 mg/kg, intraperitoneally) decreased responding in bins two to four, in which control response rates were relatively low, but increased responding in bins five to eight, in which control response rates were higher. The effect was weaker at 5 mg/kg, non-significant at 2.5 mg/kg and absent at 1 and 10 mg/ kg. A similar effect was seen in a single trial of d,l-propranolol (7.5 mg/kg) on FI 40. I- propranolol (3.75 mg/kg) reproduced this effect in part, whereas d-propranolol (7.5 mg/kg) and the peripherally acting beta-blocker, atenolol (10, 20 mg/kg), were without any effect.     

Induction of propranolol metabolism by rifampicin

The effect of rifampicin on the blood concentration-time curve of propranolol at steady-state following oral administration of 120 mg every 8 h was investigated in six normal, young, male subjects. After an initial 2 week dosing period, all individuals additionally received 600 mg rifampicin daily for 3 weeks followed by a 4 week period during which again only the propranolol was given. In four of the subjects the effects of 900 and 1200 mg rifampicin daily was also studied. Changes in disposition were assessed by estimation of propranolol's oral clearance and elimination half-life during the dosage interval. Rifampicin (600 mg/day) caused a large increase in propranolol's oral clearance (35.7 +/- 16.3 vs 96.1 +/- 26.9 ml min-1 kg-1, mean +/- s.d.), but neither the elimination half-life nor extent of plasma binding were affected. Increasing the daily dosage to 900 and 1200 mg did not cause any additional changes in oral clearance. Four weeks after discontinuing rifampicin, propranolol's oral clearance had essentially returned to its pre-induction level. The oral clearance of propranolol was significantly smaller (89.5 +/- 14.4%) during the dosage interval immediately after administration of the last rifampicin dose than the value measured 24 h later. The findings are consistent with rifampicin causing induction of the drug metabolizing enzymes responsible for propranolol's biotransformation. The marked reduction in the steady-state propranolol blood concentration that results from chronic rifampicin administration would be expected to result in a significant change in clinical effectiveness of the beta-adrenoceptor blocker when the two drugs are used concurrently.     

Increase of myocardial pH by 1- and d-propranolol during ischemia of the heart in dogs

Myocardial pH was measured continuously with a micro pH electrode inserted into the left ventricular wall in dogs. Anterior descending coronary flow was reduced to about 1/3 of the original flow by partial occlusion of the coronary artery. Myocardial pH decreased from 7.50--7.60 to 7.06--7.24 after partial occlusion. Drugs were injected intravenously during ischemia of the heart caused by partial occlusion. l-Propranolol (1 mg/kg) reduced heart rate and increased the pH from 7.06 +/- 0.04 to 7.48 +/- 0.04 (P less than 0.01). d-Propranolol (1 mg/kg) reduced heart non-significantly and increased the pH from 7.24 +/- 0.05 TO 7.56 +/- 0.05 significantly (P less than 0.05). In other studies, the effect of l- and d-propranolol on both heart rate and metabolic responses to isoproterenol (500 micrograms/kg i.p.) was studied. Isoproterenol increased heart rate and also elevated the blood levels of glucose and lactate. l-Propranolol inhibited these responses to isoproterenol. d-Propranolol did not inhibit the heart rate response but inhibited the blood lactate response to isoproterenol significantly. The blood glucose response to isoproterenol was inhibited by d-propranolol non-significantly. The action of both l- and d-propranolol on ischemic myocardial pH may be related to their action on cardiac metabolism as well as to their local anesthetic action.     

The antihypertensive action of several beta-adrenoreceptor-blocking drugs.

The antihypertensive and pulse-slowing effects of racemic propranolol, oxprenolol, pindolol, practolol and d-propranolol were assessed in 54 hypertensive patients. Drug dosage was selected to be proportionate to beta-adrenoreceptor-blocking potency; d-propranolol dosage equalled approximately that of racemic propranolol. D-propranolol had onlyslight antihypertensive effect; the four other drugs were found to have a considerable and approximately equal antihypertensive effect. The degree of slowing of heart rate varied with the different drugs, being greatest with racemic propanolol. The effect on pulse rate did not correlate with the effect on blood pressure for most of the drugs. The falls in blood pressure induced by racemic propanolol were strongly correlated with those induced by each of the other drugs. The small falls in blood pressured induced by d-propranolol correlated also with those induced by practolol (which had no membrane activity) and are presumably due to its weak beta-adrenoreceptor-blocking action. The beta-adrenoreceptor-blocking action per se is responsible for the antihypertensive action of these drugs.     

A comparison of the effects of flosequinan, a new vasodilator, and propranolol on sub-maximal exercise in healthy volunteers.

1. The effects of steady state flosequinan, a new vasodilator, and propranolol, on glucose mobilisation, lipolysis and plasma potassium concentration during sub-maximal exercise testing were investigated in a double-blind, randomised, three-way crossover study in 12 healthy volunteers. 2. Plasma glucose, potassium and free fatty acid concentration during and after exercise on flosequinan were similar to those on placebo. Exercise heart rates were 7% (+9.2 beats min-1) higher on flosequinan compared with placebo (P less than 0.05). During exercise on propranolol plasma glucose concentrations were comparable with those on placebo but plasma potassium concentrations were higher (mean increase 0.26 mmol l-1, P less than 0.01) whereas free fatty acid concentrations were lower (mean decrease 0.10 mmol 1-1, P less than 0.01). As expected the heart rate on exercise was 25% less (-35 beats min-1) on propranolol (P less than 0.05). 3. These data suggest that, in contrast to propranolol, flosequinan does not adversely affect the mobilisation of the two major sources of energy during sub-maximal exercise.     

Drug- or hormone-induced adaptation: model of adrenergic hypersensitivity

A pharmacokinetic/pharmacodynamic model of hypersensitivity to adrenergic stimulation following abrupt withdrawal of chronic beta blockade was developed. The model employs the Hill equation, a term which describes the competition between isoproterenol and l-propranolol for beta receptors, and a kinetic term which characterizes the appearance and disappearance rates of up-regulated beta receptors. The model predicted peak chronotropic hyperresponsiveness to isoproterenol 48 hr following abrupt withdrawal of chronic treatment with daily propranolol doses of 160 mg, and a drug half-life of 3.5 hr. The model also predicted that increasing the dose rate and prolonging the half-life of propranolol delayed and decreased the extent of adrenergic hypersensitivity. The time-course of adrenergic hypersensitivity simulated by our model was in excellent agreement with that observed in studies which were published earlier by our laboratory. The model underestimated the extent of adrenergic hypersensitivity. The results of our simulation are consistent with a beta agonist-receptor-effector system, which involves spare receptors, amplification of response by second and third messengers, and beta agonist- antagonist-induced receptor regulation.     

Triazolam kinetics: interaction with cimetidine, propranolol, and the combination

Nineteen healthy volunteers received a single 0.5-mg oral dose of triazolam on four occasions under the following conditions: (1) triazolam alone; (2) triazolam with cimetidine, 300 mg four times daily; (3) triazolam with propranolol, 40 mg four times daily; (4) triazolam with both cimetidine and propranolol. Triazolam kinetics were determined from multiple plasma concentrations measured during 24 hours after each dose. Compared with control, peak plasma triazolam concentration (Cmax) was significantly increased by cimetidine (5.4 versus 3.9 ng/mL), total area under the plasma concentration curve (AUC) increased (21.3 versus 16.1 ng/mL X hr), and oral clearance decreased (485 versus 668 mL/min). However triazolam half-life was not increased. During propranolol alone, triazolam Cmax (4.1 ng/mL), AUC (14.3 ng/mL X hr), and clearance (759 mL/min) did not differ significantly from control, whereas kinetic variables for triazolam with cimetidine plus propranolol were similar to those with cimetidine alone. Plasma free fraction for triazolam (17 to 18% unbound) did not differ significantly among the four treatment conditions. Mean steady-state plasma cimetidine concentrations during trials 2 and 4 were similar (1.04 versus .98 micrograms/mL), whereas plasma propranolol was significantly higher during cimetidine plus propranolol than with propranolol alone (47 versus 29 ng/ml, P less than .001). Thus cimetidine coadministration significantly inhibits triazolam clearance, causing increased triazolam AUC and Cmax, but without a prolongation in half-life. Propranolol itself does not impair triazolam clearance, nor does propranolol potentiate the inhibitory effect of cimetidine alone.     

Pharmacokinetics ofl-propranolol during repetitive dosing in normal and uranyl nitrate-induced renal failure rats

The effect of experimental renal failure on the intravenous and oral pharmacokinetics of l-propranolol was studied in rats. Renal failure was induced by a single intravenous injection of uranyl nitrate (5 mg/kg). Pharmacokinetic studies were carried out on the fifth day after injection of the renal toxin (renal failure group or saline (control group). Serum concentration time course of l-propranolol was characterized after a single intravenous or oral dose as well as after five consecutive doses of the drug given at 3-hr intervals. During repetitive intravenous drug administration, steady state was reached by the second dose, i.e., within 6hr after initiation of repetitive dosing. No significant difference in the serum concentration time course of l-propranotol was observed between control and renal failure animals. In both groups the AUCover the steady-state dosing interval was on the average 21–27%higher than the AUCafter a single dose, indicating a slight decrease in the systemic clearance of l-propranolol during repetitive intravenous drug administration. An approximately two- to three-fold higher serum l-propranolol concentration was observed in renal failure animals as compared to the normal controls after both single or repetitive oral dosing. The apparent reduction in oral clearance probably reflected an inhibition of the hepatic first-pass metabolism of l-propranolol in the renal failure rat. An unexpectedly high and protracted accumulation of serum l-propranolol concentration was observed during repetitive oral drug administration. Continuing accumulation was still evident after the fifth oral dose, i.e., a period of 15hr or approximately 10 half-lives. The mean AUCover the last dosing interval was 32.0 and 17.8 times higher than the predicted steady-state estimate based on single oral dose data for control and renal failure rats, respectively. The substantial reduction in the oral clearance during repetitive drug administration may be due to an auto-inhibition of l-propranolol metabolism.This work was supported by Grant HL-25797 from the National Heart, Lung and Blood Institute, the National Institutes of Health.     

Effects of long-acting propranolol on blood pressure and heart rate in hypertensive Chinese.

In a double-blind, balanced and randomised study we used treadmill exercise to assess the effects of long-acting propranolol (LA propranolol) 160 or 320 mg or placebo, given once daily for 4 weeks, on heart rate (HR) and blood pressure (BP) in 15 Chinese subjects with mild primary hypertension (PHT). We used 24 h ECG monitoring to assess drug effects on HR. Another 18 patients were similarly assessed without exercise. Steady-state plasma propranolol concentrations after LA propranolol 160 and 320 mg were comparable to those after ordinary propranolol 80 and 160 mg daily measured in 11 and 12 separate patients. LA propranolol 160 and 320 mg reduced HR and BP before and during vigorous exercise. LA propranolol 160 and 320 mg reduced HR for 17.6 and 21.4 h of the day, and 320 mg significantly reduced the mean 24 h HR, and the mean maximum HR. The drug effects on BP and HR, and the average plasma propranolol levels after LA propranolol were similar to those reported in European subjects.     

Effect of CGP 17/582, a selective beta-adrenoceptor antagonist, on the haemodynamic and hypokalaemic response to adrenaline.

1. CGP 17/582B is a new beta-adrenoceptor antagonist which on experimental studies appears to combine selective beta 1-adrenoceptor blockade with partial agonist activity (ISA). Assessing beta-adrenoceptor selectivity and the degree of partial agonist activity in vivo can be difficult. 2. In a double-blind placebo controlled crossover study we have compared the effect of oral pretreatment for 7 days with CGP (100 mg twice daily), with propranolol (non-selective beta-adrenoceptor blocker with no ISA) and metoprolol (selective beta-adrenoceptor blocker with no ISA) on resting heart rate and heart rate response to submaximal exercise on a bicycle ergometer to assess the degree of beta-adrenoceptor blockade and also the changes in blood pressure, heart rate and potassium during the intravenous infusion of (-)-adrenaline to determine the degree of beta 2-adrenoceptor blockade. 3. Subjects underwent submaximal exercise testing on the second and fifth day of each treatment period and on the seventh day received a 2 h infusion of (-)-adrenaline (0.06 microgram kg-1 min-1). Heart rate, blood pressure, plasma potassium and catecholamines were measured throughout the study period. 4. All three active treatments significantly reduced exercise induced tachycardia. The (-)-adrenaline infusion significantly reduced plasma noradrenaline levels following propranolol and metoprolol and to a lesser extent with placebo but were unaltered on CGP. Baseline heart rate was unaltered by CGP but was significantly reduced by metoprolol and propranolol. Adrenaline significantly reduced plasma potassium levels following placebo and CGP pretreatment but plasma potassium was unaltered by adrenaline with metoprolol and propranolol pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Roles of hepatic blood flow and enzyme activity in the kinetics of propranolol and sotalol.

1 The roles of the hepatic blood flow and the drug oxidizing enzyme system in eliminating oral propranolol and sotalol were studied in twelve subjects with biopsy proven liver parenchymal disease. 2 The apparent plasma clearance of propranolol was closely related both to the in vivo (antipyrine test) and in vitro (cytochrome P-450) indices of the activity of the hepatic mixed function oxidase system. 3 Propranolol clearance had also a clear relationship to the estimated liver blood flow. Altered flow was, however, suggested to be a minor factor when compared with changes in the enzyme system. 4 The elimination rate of sotalol had no correlation to the indices of hepatic drug metabolism or to the estimated liver blood flow. 5 It is concluded that both the deteriorated sinusoidal perfusion and the decreased mass of drug metabolizing enzymes may be responsible for the impaired elimination of oral propranolol in subjects with parenchymal liver disease.     

Circadian changes in the pharmacokinetics and cardiovascular effects of oral propranolol in healthy subjects

Summary Four subjects were synchronized with activity from 07 to 23 h and were given a single oral dose of 80 mg racemic propranolol at fixed times (08, 14, 20 and 02 h) at weekly intervals.ANOVA revealed significant circadian changes in the peak propranolol concentration (C_max), with a maximum at 08 h and a minimum at 02 h after drug intake; t_max was not dependent on the circadian phase. The elimination half-life varied significantly with the time of day, being shortest at 08 h (3.3 h) and longest at 20 h (4.9 h). The stereospecificity of the propranolol pharmacokinetics was not dependent on the time of drug intake. No circadian variation was found in the maximum decrease in heart rate, but the time to peak effect was dependent on the time of drug intake; t_max was 2.3 h at 08 h and 7.0 h at 02 h. Thus, the time to peak drug concentration did not coincide with the time to peak effect on heart rate at different times of day. Circadian changes were also found in the systolic blood pressure and in the double product.The results show a significant daily variation in the pharmacokinetics and cardiovascular effects of propranolol. However, chronokinetics cannot explain the circadian changes in the effects of the drug. It is concluded that circadian variation in sympathetic tone and vascular reactivity is mainly responsible for the circadian changes in the effects of propranolol.     

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.