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PubMed1988

Serotonergic blockade compared with beta-adrenergic blockade in systemic hypertension: a double-blind comparison of ketanserin with propranolol.

The safety and efficacy of ketanserin, a competitive serotonin blocking agent, and propranolol were compared in 33 patients with mild to moderate hypertension (sitting diastolic blood pressure [DBP] 95-115 mm Hg) using a placebo run-in, randomized, double-blind parallel study design. All patients received placebo for 4 weeks, then were randomized to receive increasing doses of either ketanserin (20, 40 mg twice daily) or propranolol (40, 80 mg twice daily) to achieve a goal sitting DBP less than 90 mm Hg. Patients not achieving the goal blood pressure with either drug as monotherapy, received the other drug in combination. At the end of the active monotherapy phase (week 10 of the study), propranolol demonstrated a greater decrease in DBP from baseline, as compared to ketanserin (-7.9 +/- 10.9 mm Hg with propranolol, P less than 0.05; -1.0 +/- 7.2 mm Hg with ketanserin, P = NS). Four out of 16 patients achieved goal response on propranolol, compared to 3/17 for ketanserin. With combination treatment, 9/18 patients reached the goal response; the addition of propranolol to ketanserin in non-responders resulted in further reduction of sitting DBP of -10.3 +/- 6.3 compared to monotherapy (P less than 0.001), while the addition of ketanserin to non-responders produced no significant response in sitting DBP. Propranolol showed a consistent effect in slowing heart rate. Ketanserin displayed less frequent side effects than propranolol. Propranolol used twice daily appears to be more effective than twice daily ketanserin use in patients with mild to moderate hypertension.

Adrenergic beta-Antagonists↗
PubMed1988

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.

Adult↗
PubMed1988

Suppression of pentylenetetrazol-elicited seizure activity by intraosseous propranolol in pigs.

The intraosseous (IO) route provides a rapid and effective alternative venous access in the pediatric population when the conventional intravenous (IV) route cannot be easily obtained. DL-propranolol, a beta-adrenoceptor antagonist, exhibits antiepileptic activity in various animal seizure models. This study assessed the efficacy of IO propranolol in suppressing pentylenetetrazol (PTZ)-induced seizure activity in pigs. Domestic swine (13-20 kg) were prepared for recordings of arterial blood pressure, ECG and electrocortical activity. Seizure activity was induced by pentylenetetrazol (PTZ; 100 mg/kg; IV). Sixty seconds after the onset of seizure activity, the animals either received no drug (control) or propranolol (IV or IO via an 18-gauge spinal needle placed in the right proximal tibia). A transient increase (16.3-50.0%) in the mean arterial blood pressure (MAP) was observed following PTZ administration. Both IO and IV propranolol significantly suppressed the seizure duration (SD) (sec/min interval) at 1 min following drug administration; SD control, 36.3 +/- 4.8; IV propranolol, 12.3 +/- 5.1; IO propranolol, 18.3 +/- 6.0. In addition, both IV and IO propranolol produced a maximal decrease of 32-38% in the basal heart rate; and reduced the transient increase in MAP elicited by PTZ, with no significant effect on the basal MAP. The data demonstrate that 1) propranolol possesses anticonvulsant activity against PTZ-induced seizure in the pig, and 2) the intraosseous route is a rapid and effective alternative venous access for propranolol administration in swine.

Animals↗
PubMed1982

Stereoselective disposition and glucuronidation of propranolol in humans.

Following oral dosing to steady state, the disposition of S(-)- and R(+)-propranolol and their corresponding glucuronide conjugates was studied in 4 healthy adults using doses from 40 to 320 mg/day of the racemate. Steady -state plasma concentrations of S(-)-propranolol and its corresponding glucuronide conjugate were greater than that for R(+)-propranolol and its corresponding conjugate. The average steady-state concentration of both enantiomers increased disproportionately to dose. There was a 52+/- 7 (mean +/- SD) % decrease in the intrinsic clearance (clint) of S(-)-propranolol and a 65 +/- 22% decrease in the Clint of R(+)-propranolol over the dosing range studied. The terminal elimination half-lives of S(-)-propranolol and its glucuronide conjugate were longer than for the R(+)-enantiomer at all doses. The formation of glucuzonide conjugates of S(-)- and R(+)-propranolol was best described by a saturable process in all subjects. Within individuals, the ratio of Vmax/Km for the glucuronide conjugate of S(-)-propranolol was from 2.1-to 4.9-fold greater than for the conjugate of the R(+)-enantiomer. These studies demonstrate for the first time, that propranolol undergoes stereoselective disposition in humans.

Adult↗
PubMed1995

Effects of a Finnish sauna on the pharmacokinetics and haemodynamic actions of propranolol and captopril in healthy volunteers.

The effects of a Finnish sauna on propranolol pharmacokinetics and on the pharmacodynamics of propranolol and captopril were studied in healthy, young volunteers (2 males, 6 females) in a double-blind, cross-over trial. The subjects received single oral doses of placebo, propranolol (40 mg) or captopril (12.5 mg) in sauna and control sessions at a one-week interval. The sauna sessions consisted of three repetitive 10-min stays in a sauna (85-100 degrees C, relative humidity 25-35%) separated by two 5-min rest periods in a cool room. Sauna bathing started 35, 50 and 65 min after ingestion of the drugs. Venous blood for plasma propranolol measurement were collected before and 15, 30, 45, 60, 75, 90 min and 2, 3, 4, 5, 7 and 24 h after drug intake. The sauna significantly increased the maximum concentration (Cmax 41 vs. 28 ng.ml-1) of propranolol and the mean plasma propranolol concentration 60 and 90 min, and 2 and 3 h after drug administration. It also significantly increased the AUC0-5h (119 vs 71 micrograms.h.l-1) of propranolol from 0 to 5 hours tmax, t1/2 beta and AUC0-24h of propranolol did not differ between the control and sauna sessions. The higher propranolol levels during and after the cessation of sauna bathing did not lead to significant changes in blood pressure or heart rate compared to the control period. Captopril had no major effects on these parameters during the post-sauna phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Influence of vitamin C on the absorption and first pass metabolism of propranolol.

The effect of ascorbic acid on the availability of propranolol has been examined. After oral administration of propranolol 80 mg with or without ascorbic acid pretreatment (2 g), the plasma concentrations and urinary excretion of propranolol and its metabolites, 4-hydroxy-propranolol and propranolol-conjugated, were determined by HPLC. Compared to controls, vitamin C decreased the maximum concentration of propranolol from 463 to 334 nmol.l-1, and the area under the propranolol concentration-time curve (from 0 to 24 hours) from 3.13 to 1.96 mumol.l-1.h. The time to reach maximum propranolol concentration was increased from 1.9 to 2.7. The total amount of drug recovered in urine has also significantly diminished (from 12.6 to 4.29 mg). No change in elimination rate was observed, indicating that ascorbic acid had affected both the absorption process and the first pass metabolism. The heart-rate decreased less when propranolol was administered with ascorbic acid in comparison to control subjects, although this interaction has little biological importance.

Administration, Oral↗
PubMed1979

Propranolol in conscious spontaneously hypertensive rats. II. Disposition after subcutaneous and intracerebroventricular administration.

The disposition of dl-propranolol was studied in spontaneously hypertensive rats (SHR), both after subcutaneous (s.c.) and intracerebroventricular (i.c.v.) injection of 1 mg/kg. 1. Upon s.c. injection propranolol appeared rapidly in plasma. A maximum concentration of 374 +/- 33 ng/ml (N = 10) was reached 5 min after injection. After a distribution phase with a half-life of t 1/2 alpha = 17 min propranolol was eliminated with a t 1/2 beta = 59 min. 2. Both propranolol and its metabolites were taken up rapidly into all tissues studied. Highest concentrations (10.4 +/- 1.5 micrograms/g, N = 5) were found in lungs 30 min after injection. 3. Neither propranolol nor its metabolites accumulated in any of the tissues examined. 4. Upon i.c.v. injection of propranolol, a maximal concentration of 573 +/- 47 ng/ml (N = 3) was reached in plasma already 2 min after injection. In this case t 1/2 alpha was 13 min and t 1/2 beta was 80 min. 5. Dialysis experiments indicated that propranolol is bound to plasma proteins for 92% in the concentration range of 20--100 ng/ml. With increasing concentrations binding diminishes progressively. At the highest concentration tested (345 ng/ml) only 76% was bound. It is concluded that s.c. and i.c.v. injection of an identical dose of propranolol gives a similar plasma concentration-time profile. Moreover, it is suggested that the pharmacokinetic behaviour of propranolol in SHR does not explain the delayed antihypertensive effect of this drug.

Animals↗
PubMed1985

Receptor binding of propranolol is the missing link between plasma concentration kinetics and the effect-time course in man.

In a double-blind, placebo-controlled study in 6 healthy volunteers, the correlation between beta-adrenoceptor binding, the time course of the effect and plasma concentration kinetics was investigated from 0 to 48 h after a single oral dose of propranolol 240 mg. First, the in vitro beta-adrenoceptor interaction of propranolol was investigated. Propranolol inhibited beta-adrenoceptor binding to rat parotid (beta 1) and reticulocyte (beta 2) membranes in the presence of pooled human plasma with a Ki of about 8 ng/ml plasma. After oral administration of 240 mg propranolol, concentration kinetics in plasma could be described by a Bateman function with a fictive concentration at time 0 of 275 ng/ml plasma, and a mean elimination half-life of 3.5 h. Using the concentration kinetics of propranolol in plasma together with its in vitro beta-adrenoceptor binding characteristics in the presence of placebo plasma from each individual, the time course of antagonism against beta-adrenoceptor mediated effects was predicted. The latter was in agreement with the time course of propranolol-induced inhibition of tachycardia due to orthostasis. After bicycle ergometry, however, the time course of inhibition of tachycardia was shorter than was predicted. Plasma sampled at various times after propranolol administration inhibited beta-adrenoceptor binding of the radioligand 3H-CGP 12177 to rat reticulocyte membranes in a fashion reflecting the time course of inhibition of exercise tachycardia observed in the volunteers. A direct, linear relation was shown between the in vitro inhibition of beta-adrenoceptor binding by the plasma samples withdrawn after propranolol administration and the inhibition of exercise tachycardia observed in parallel. The results show that the concentrations of antagonist present in plasma are representative of the concentrations in the effect compartment. Deep compartments of drug distribution appear irrelevant to the effects of the drugs. The relation between the plasma concentration of propranolol and the reduction in heart rate at various levels of physical effort shows no significant inhibition at rest and increasing IC50-values from orthostasis to 2 min and to 4 min of ergometry. IC50-values after orthostasis are in the range of the Ki-values from in vitro receptor binding studies, whereas the IC50-values after exercise are shifted 2- to 3-fold to the right relative to the Ki-values. This finding is in agreement with increased beta-adrenoceptor stimulation with increasing effort (release of endogenous noradrenaline), which shifts the antagonist concentration-effect curve to the right.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1981

Correlation between propranolol in plasma and urine, renin-aldosterone system and blood pressure in essential hypertension.

Thirty patients with mild or moderate essential hypertension, and a fixed elevation of diastolic blood pressure, were randomly allocated to three groups and treated with propranolol 40 mg x 4 (Group 1), 80 mg x 4 (group 2) and 160 mg x 4 (Group 3). Blood pressure (BP), pulse rate (PR), plasma renin activity (PRA), plasma aldosterone concentration (PAC), total plasma propranolol (tPP), free plasma propranolol (fPP), and 24 h urinary propranolol excretion (UP) were determined at the end of four consecutive periods: (A) after four weeks without any treatment; (B) after two to three weeks during which the propranolol dose was gradually increased to the intended level; (C) after four weeks, and (D) after eight weeks of unchanged treatment. The maximum reduction in diastolic BP occurred after period B, and in systolic BP after Period C, for Groups 2 and 3, and for all groups together; for Group 1, however, the maximum diastolic BP reduction was first seen after period C. PR was reduced to the same level in all groups after period B. After period B, PRA an PAC fell in all groups, and remained reduced during C and D Group 1. After periods C and D, PRA and PAC in Groups 2 and 3 did not differ significantly from the levels after period A; tPP, fPP and UP were significantly correlated with the propranolol dose, and were lowest in Group 1 and highest in Group 3; UP was negatively correlated with systolic but not diastolic BP in Periods B, C and D. In contrast neither fPP nor tPP were correlated with systolic or diastolic BP. There was no significant correlation between PRA, PAC and changes in PRA or PAC on the one hand and tPP, fPP, UP, BP or changes in BP on the other. It was concluded that propranolol effectively reduced BP, but diastolic BP reduction was most rapidly obtained at 320 and 640 mg daily, that the activity of the renin -aldosterone system was initially suppressed in all group, but for unknown reasons it increased towards the control level after seven to eleven weeks of therapy with 320 and 640 mg/day, and that the reduction in systolic BP increased with higher doses of propranolol and with increasing urinary propranolol excretion.

Adult↗
PubMed1986

Comparison of enalapril and propranolol in essential hypertension.

In 40 patients with essential hypertension, enalapril was compared with propranolol as an antihypertensive agent in a double-blind study. The patients were randomly given either enalapril 5-10-20 mg bid or propranolol 40-80-120 mg bid in a treatment consisting of step-by-step increases in dosage. When the diastolic blood pressure remained greater than 90 mm Hg on the highest dosage, hydrochlorothiazide was added. Both enalapril and propranolol reduced blood pressure, although the patients tended to achieve lower blood pressures while on enalapril. More patients on propranolol required additional diuretic therapy than patients on enalapril. Propranolol reduced heart rate; with enalapril there were no changes in heart rate. Both drugs increased serum potassium and urea. Plasma renin substrate was reduced by enalapril, but raised by propranolol. Enalapril increased plasma renin activity and angiotensin I, while propranolol reduced both. Converting enzyme activity was lowered with enalapril but was unchanged with propranolol. Both drugs reduced angiotensin II. Plasma aldosterone concentration was more suppressed with propranolol than with enalapril.

Adult↗
PubMed1996

Exercise increases plasma concentrations of (R)- and (S)-propranolol.

OBJECTIVE: We recently reported a highly stereoselective increase in plasma concentrations of (S)-atenolol during exercise which is most likely due to a release of the drug from adrenergic cells. The objective of the present study was to investigate the influence of physical exercise on plasma concentrations of the (R)- and (S)-enantiomers of propranolol. METHODS: Blood samples were taken immediately before and at the end of exercise in 12 patients receiving chronic treatment with racemic (R, S)-propranolol. Plasma concentrations of (R)- and (S)-propranolol were determined by HPLC. RESULTS: In contrast to atenolol, mean plasma concentrations of (S)-propranolol were significantly higher (+20%) than those of (R)-propranolol at rest. During exercise there was an increase in plasma concentrations of both (R)-propranolol (+129%) and (S)-propranolol (+109%). CONCLUSION: Based on information from in vitro studies we conclude that the increase in plasma concentrations of (S)-propranolol during exercise is caused by a release of the drug from adrenergic nerves, whereas the reason for the increase in (R)-propranolol remains to be determined. This release of the beta-adrenoceptor blocking (S)-enantiomer directly at the synaptic gaps might be one reason for the poor correlation between plasma concentration and effect of beta-adrenoceptor antagonists repeatedly described in the literature.

Adrenergic beta-Antagonists↗
PubMed1983

Thallium-201 myocardial imaging during maximal and submaximal exercise: comparison of submaximal exercise with propranolol.

Propranolol is an effective drug for patients with angina and has been shown to favorably alter exercise ejection fraction and myocardial perfusion images in patients with coronary disease. A characteristic effect of propranolol is reduction in exercise heart rate (HR). Twenty men with coronary disease (10 with prior infarction), angina-limited exercise tests, abnormal myocardial blood flow distribution images (MBFDI) (201thallium) during exercise, and normal resting ejection fractions underwent treadmill exercise testing with imaging on three occasions. Control maximal exercise was performed initially with measurement of MBFDI. Propranolol, 40 mg by mouth four times a day, was administered for a week with exercise repeated to the same workload. A third study, with men off propranolol, was undertaken with exercise continued only to the HR obtained while the men were taking propranolol (submaximal exercise). All men had improvement in MBFDI while receiving propranolol (men without infarction +780 +/- 88 [average +/- SEM] normalized count rate difference between control and propranolol; men with infarction +724 +/- 73 normalized counts). Greater count differences were noted when control exercise and HR-controlled, submaximal exercise MBFDI were compared with a greater difference in men with infarction (+1094 +/- 89 normalized counts) than for men without infarction (+896 +/- 88 normalized counts). Results suggest that propranolol improves MBFDI during exercise in men with angina, but that submaximal exercise results in more normal MBFDI than does propranolol for exercise to the same HR.

Angina Pectoris↗
PubMed1982

Calcium channel blockade as primary therapy for stable angina pectoris. A double-blind placebo-controlled comparison of verapamil and propranolol.

The effectiveness and safety of the beta-adrenergic blocking agent propranolol and the calcium channel antagonist verapamil were compared in 22 patients with chronic stable angina pectoris using a double-blind randomized placebo-controlled crossover protocol. The double-blind phase was preceded by a 2 week single-blind placebo period, followed by randomization to either 4 weeks' therapy with verapamil, 360 mg/day, or propranolol, 240 mg/day, followed by crossover to the other drug. Both verapamil and propranolol increased exercise tolerance (5.5 +/- 0.4 minutes with placebo, 7.8 +/- 0.5 minutes with propranolol [p less than 0.001], and 9.1 +/- 0.5 minutes with verapamil [p less than 0.001]), but the increase with verapamil was significantly greater (p less than 0.01). Both drugs prolonged the exercise duration to 1 mm S-T depression (3.3 +/- 0.4 minutes with placebo, 5.7 +/- 0.5 minutes with propranolol [p less than 0.001] and 5.5 +/- 0.6 minutes with verapamil [p less than 0.001]); the degree of improvement was similar with both active drugs. Both drugs decreased the resting heart rate (76 +/- 3 beats/min with placebo, 56 +/- 2 beats/min with propranolol [p less than 0.001], and 71 +/- 3 beats/min with verapamil [p less than 0.01]), but the heart rate decreased more with propranolol than with verapamil (p less than 0.001). Neither drug produced significant adverse reactions. This study, along with 8 similar double-blind placebo-controlled randomized investigations which have compared verapamil with propranolol, indicate that verapamil is as effective and safe as propranolol in relieving symptoms and improving exercise tolerance in patients with chronic stable angina pectoris and may be considered a first-line therapeutic agent in patients with ischemic heart disease.

Adrenergic beta-Antagonists↗
PubMed1981

Interaction of propranolol with model phospholipid membranes. Monolayer, spin label and fluorescent spectroscopy studies.

The interaction of propranolol with model phospholipid membranes was studied using various experimental techniques. The partition coefficient of propranolol in the negatively charged membranes of vesicles prepared from phosphatidylserine and phosphatidic acid was found to be more than 20-times higher than in neutral phosphatidylcholine membranes. Preferential interaction of propranolol with acidic phospholipid membranes was confirmed using the monolayer compression isotherm technique and the spin-labelling method. Phosphatidylserine monolayers were markedly expanded even at a relatively low drug concentration (5 . 10(-6) M). In contrast, the effect of propranolol on phosphatidylcholine monolayers was much smaller, being detectable only at a higher concentration of the drug (1 . 10(-4) M). Spin-labeling experiments show that propranolol exerts marked ordering effect on bilayers prepared from acidic phospholipids and does not change the order parameter of phosphatidylcholine membranes. The dependence of the propranolol fluorescence spectrum on the polarity of the solvent allowed us to identify the intercalation region of the drug in the membrane. The fluorophore moiety of propranolol was found to be localized in the lipid polar head groups region of the bilayer. The role of electrostatic and hydrophobic effects in propranolol-membrane interaction is discussed and the effect of propranolol on the ordering of phospholipid bilayers is compared with the effects of other anesthetic-like molecules.

Electron Spin Resonance Spectroscopy↗
PubMed1987

Propranolol inhibition of the neutral phospholipases A of rat heart mitochondria, sarcoplasmic reticulum and cytosol.

Membrane damage caused by phospholipase A action is thought to be an important factor in ischemic myocardial injury. Propranolol has been shown previously to have beneficial effects in both animal experiments and clinical trials, and it has membrane-stabilizing properties in vitro. To investigate the possibility that these effects might be due, in part, to effects on phospholipases, we determined the effects of propranolol on rat heart phospholipases A at physiological pH using small unilamellar liposomes of di[1-14C]oleoylphosphatidylcholine as substrate. Propranolol inhibited heart phospholipases A in vitro. The concentration required to give 50% inhibition was 0.2 mM for the mitochondrial and cytosolic phospholipases A and 2.9 mM for sarcoplasmic reticulum phospholipase A. The binding of [4-3H]propranolol to fresh membrane preparations was studied using an ultracentrifugation method. Propranolol bound readily to both membrane fractions in vitro with no significant difference in the saturation number (0.20 to 0.28 mol drug per mol phospholipid) but the association constant, KA, was higher for mitochondrial membranes (3760 +/- 350) than for the sarcoplasmic reticulum (2190 +/- 390). Our results show that propranolol inhibited heart phospholipases A in vitro at physiological pH. The mitochondrial and cytosolic phospholipases A were more susceptible to inhibition than the phospholipase A of sarcoplasmic reticulum. Propranolol bound to mitochondria and sarcoplasmic reticulum in vitro, suggesting the possibility that propranolol binding to heart membranes in vivo could result in drug concentrations in these membranes high enough to inhibit phospholipase A. This could represent an additional mechanism by which propranolol exerts beneficial effects in myocardial ischemia.

Animals↗
PubMed1989

Effects of alpha-1-acid glycoprotein administration on propranolol binding and beta blockade in rats.

Alpha-1-acid glycoprotein (AAG), 750 mg/kg, was administered to rats to determine its effect on propranolol binding and beta blockade. Anesthetized rats received [3H]propranolol i.v., followed in 15 min by human AAG or bovine serum albumin, 750 mg/kg. AAG treatment produced a human AAG concentration in serum of 7.76 +/- 1.17 mg/ml, several times higher than the endogenous serum AAG concentration in stressed rats. AAG treatment significantly increased the heart rate response to isoproterenol, compared to albumin (95.4 +/- 19.6 vs 28.3 +/- 16.7% of baseline value, measured 45 min after propranolol, P less than 0.001). AAG-treated rats had greater [3H]propranolol binding in serum (93.0 +/- 3.2 vs 76.7 +/- 3.0%, P less than 0.01) and a lower calculated unbound [3H]propranolol concentration in serum (2.7 +/- 1.3 vs 7.4 +/- 3.1 X 10(6) dpm/ml, P less than 0.001) than albumin-treated rats. These data demonstrate that AAG can alter propranolol pharmacokinetics and pharmacodynamics even when administered after the propranolol effect is evident. Because the reported affinity of propranolol for cardiac beta receptors is 10,000 times greater than its affinity for AAG, these data suggest that AAG acted by altering propranolol disposition rather than by directly competing with beta receptors for drug.

Animals↗
PubMed1992

A possible mechanism of the impairment of hepatic microsomal monooxygenase activities after multiple administration of propranolol in rats.

The mechanism of selective inhibition of propranolol hydroxylations after multiple administration of the drug was investigated by metabolic inhibition studies in rat liver microsomes. The time course of irreversible binding of a reactive metabolic intermediate(s) of propranolol to liver microsomal protein, which was proposed as the cause of the impairment of enzymatic activities, had a delayed phase followed by a rapid linear rise, while the unmetabolized propranolol remaining in the reaction mixture showed a rapid linear decrease immediately after the onset of incubation. Thus, it was conceivable that the reactive intermediate(s) was not always formed directly from the parent drug, propranolol. Among four primary metabolites of propranolol, 4-hydroxypropranolol was the most potent inhibitor of propranolol hydroxylase activities, and this inhibition was much enhanced by preincubation of 4-hydroxypropranolol with NADPH. The type of inhibition kinetics of propranolol 5- and 7-hydroxylase activities by 4-hydroxypropranolol was changed from a competitive type to a non-competitive type by the preincubation. These results suggest that a reactive metabolite(s) of propranolol which impaired propranolol hydroxylase activities is a further metabolite(s) of 4-hydroxypropranolol.

Animals↗
PubMed1977

Studies on the contribution of active metabolites to the anticonvulsant effects of propranolol.

The anticonvulsant activity of propranolol and two selected metabolites, propranolol glycol and N-desisopropylpropranolol were compared in mice against 4 types of experimentally induced seizures: pentylenetetrazol, strychnine, low frequency and maximal electroshock. Both metabolites possessed significant anticonvulsant activity with propranolol glycol being 1/2 to 1/3 as potent and N-desisopropylpropranolol being 1/6 as potent as propranolol. The possible contribution of these two active metabolites to the acute anticonvulsant efficacy of propranolol was assessed in time course studies. Maximal anticonvulsant activity occurred between 2.5--10 min after propranolol (5-20 mg/kg, i.v.) and was significantly diminished after 30 min. Following propranolol, brain levels of both metabolites were extremely low ( less than 10 ng/g) at the onset of anticonvulsant action and reached peak levels between 15-30 min at which time anticonvulsant activity was already declining. In contrast, brain levels of propranolol were similar in time course to that observed for its anticonvulsant effect and there was significant positive correlation between these two parameters in 3 of the 4 seizure models. These data indicate that although these two metabolites are pharmacologically active, they do not contribute significantly to the acute anticonvulsant actions observed after propranolol administration.

Animals↗