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PubMed1980

Effect of intracisternal application of 6-hydroxydopamine on the antihypertensive action of propranolol in the dog.

The antihypertensive effects of intravenous (i.v.) and intracisternal (i.cist.) dl-propranolol were studied in anesthetized hypertensive dogs pretreated with i.cist. administered 6-hydroxydopamine (6-OHDA, 600 micrograms/kg) one week previously. Acute neurogenic hypertension was elicited by sino-aortic denervation (deafferentation). In control (saline-pretreated) dogs, dl-propranolol given i.cist. (50 micrograms/kg) or i.v. (0.3 and 1 mg/kg) decreased both the rise in blood pressure and tachycardia induced by deafferentation. These hypotensive and negative chronotropic actions of i.v. (0.3 mg/kg) propranolol were suppressed by pretreatment with 6-OHDA. At a higher dose (1 mg/kg), i.v. propranolol always corrected hypertension and tachycardia in 6-OHDA-treated dogs as in control animals. After 6-OHDA, i.cist. propranolol (50 micrograms/kg) failed to decrease the rise in blood pressure in debuffered animals. Conversely, the bradycardia induced by i.cist. propranolol was more marked in 6-OHDA-treated dogs than in control animals. These results confirm that the antihypertensive action of propranolol can be partly explained by an action on the central nervous system. They support the hypothesis that the hypotension observed after intracisternal (and also after low does of i.v.) propranolol is dependent on the integrity of central catecholaminergic neurons. These studies suggest that the antihypertensive action of propranolol may be partly due to the blockade of central presynaptic beta-adrenoceptors.

Afferent Pathways↗
PubMed1988

Interaction of propranolol with central serotonergic neurons.

Central monoaminergic mechanisms are believed to be involved in cardiovascular regulation. The present study was designed to evaluate the involvement of central serotonergic pathways in the antihypertensive action of propranolol in pentobarbital anesthetized mongrel dogs. Ventriculocisternal perfusion of propranolol (25 ug/kg/min for 30 min) decreased serotonin turnover as indicated by a significant decrease in cerebrospinal fluid levels of 5-hydroxyindoleacetic acid (5-HIAA). This effect was accompanied by a significant reduction in mean arterial pressure and heart rate. These results indicate that propranolol decreases central serotonergic activity and suggests a possible role for central serotonergic pathways in the antihypertensive action of propranolol. Several studies have indicated that central serotonergic pathways participate in the regulation of blood pressure. Brainstem regions including the nucleus tractus solitarius, the raphe nucleus and the anterior hypothalamic preoptic region are involved in cardiovascular control and contain a dense population of serotonergic neurons. A centrally-mediated hypotensive effect of propranolol has been demonstrated. Centrally administered propranolol increases cerebrospinal fluid (CSF) levels of norepinephrine and reduces blood pressure possibly due to decreased peripheral sympathetic nerve activity. Central serotonergic pathways may also be involved in the antihypertensive action of some beta-adrenoceptor antagonists. Destruction of central serotonergic neurons with 5,7-dihydroxytryptamine and desipramine abolished the antihypertensive effect of intracisternal propranolol in sinoaortic denervated dogs. Acute administrations of (-)-propranolol and (-)-pindolol decreased the synthesis rate of serotonin, while acute administration of salbutamol, a beta 2-adrenoceptor agonist, increased 5-HIAA levels in rat brain structures. The present study was designed to evaluate the involvement of central serotonergic pathways in the antihypertensive action of propranolol.

Animals↗
PubMed1993

Racial differences in lymphocyte beta-receptor sensitivity to propranolol.

Differences between blacks and whites in their antihypertensive response to beta-blocker therapy are well recognized although the mechanisms of these response differences are not entirely understood. This study was performed to evaluate racial differences in in vitro sensitivity of lymphocyte beta-receptors to beta-blockade. Lymphocytes were isolated from whole blood of 10 white and 8 black healthy male volunteers and were exposed to isoproterenol concentrations ranging from 10(-8) M to 10(-2) M. Isoproterenol stimulation studies were performed in both the presence and absence of a typical therapeutic concentration of 1-propranolol (15 nM). Cyclic AMP content was determined by radioimmunoassay and was corrected to cAMP/10(6) cells. Sigmoid Emax and Emax models were fit to the cAMP response, isoproterenol concentration data by nonlinear regression analysis. Propranolol caused a nonsignificant increase in EC50 (median 3.2-fold) in blacks and a significant increase in EC50 (median 13.4-fold) in whites. The median calculated Ki values for propranolol were 9.2 nM in blacks and 1.2 nM in whites and median receptor occupancies at propranolol 15 nM were 64.3% in blacks and 92.5% in whites. A median propranolol concentration of 114 nM would have been needed in the black subjects to achieve a 92.5% receptor occupancy. These data suggest that the affinity of the beta-receptor for propranolol was greater in whites than blacks, thus equal propranolol concentrations resulted in greater beta-blockade in whites. This study suggested that for blacks and whites to achieve similar levels of beta-blockade, blacks needed a 7-fold higher concentration of propranolol. It is concluded racial differences in beta 2-receptor affinity for propranolol may help explain the documented racial differences in response.

Adult↗
PubMed1984

Reduction by propranolol of urinary hydroxyproline excretion in human hyperthyroidism: a beta-receptor blockade effect or a membrane stabilizing mechanism?

In order to investigate the mechanism whereby oral propranolol administration reduces the increased rate of urinary hydroxyproline excretion (UHxE) of patients with hyperthyroidism, a comparison was made of the effects of the oral administration of propranolol-timolol, propylthiouracil (PTU), and a placebo to patients with hyperthyroidism and to normal controls. Propranolol decreased the pulse rate (P less than 0.01), serum triiodothyronine (T3) level (P less than 0.05), and UHxE (P less than 0.01) without modifying the serum free thyroxine index (FT4I) or parathormone (PTH) level. Timolol decreased the pulse rate (P less than 0.01) to the same extent as propranolol, had no effect on T3, FT4I, or PTH, and failed to decrease UHxE. Administration of PTU decreased the T3 level (P less than 0.05) to a similar extent as propranolol without modifying the FT4I or PTH level and had no effect on UHxE. Placebo administration had no effect. These results suggest that the reduction of UHxE by propranolol is not due to the beta-receptor-blocking properties of propranolol nor mediated by the propranolol-induced decrease in the level of T3 but is probably due to the membrane-stabilizing properties of propranolol.

Adult↗
PubMed1989

Alteration of respiratory cycle timing by propranolol.

The present study was undertaken to explore the effect of propranolol on respiratory cycle timing and breathing pattern using mice and guinea pigs. Propranolol was administered via aerosol or via injection. Mice exposed to propranolol aerosols exhibited a breathing pattern that was characterized by a pause between breaths. The length of such pauses (TP) increased as the propranolol exposure concentration was raised. We also observed at increasing propranolol concentrations that the time of inspiration (TI) and time of expiration (TE) decreased. Thus, the respiratory rate of these animals was seen to increase, remain unchanged, or decrease depending on the balance between TP versus TI and TE. Guinea pigs also exhibited pauses between breaths during exposure to propranolol aerosols, but such pauses were not observed as consistently as in mice. TP again rose while TI and TE fell in guinea pigs exposed to increasing propranolol concentrations. This species was, however, less sensitive than mice. Intraperitoneal injections of propranolol failed to elicit such alterations in respiratory pattern or timing in either species. These changes in respiratory timing obtained with an aerosol of propranolol were most probably due to a local effect on vagal nerve endings or to its bronchoconstricting effect.

Administration, Inhalation↗
PubMed1979

Lethal synergism between morphine or other narcotic analgesics and propranolol.

Interactions of (+/-)-propranolol HCl with various narcotics were determined in albino rats. The 24-h intraperitoneal (i.p.) LD50 of morphine sulfate + saline was 15--16 times greater than for morphine + propranolol in both sexes although morphine was nearly twice as toxic to males as to females. The potency ratios for LD50's with saline vs. with propranolol were: codeine, 1.9, (+/-)-methadone, 6.0; (-)-alpha-acetylmethadol, 2.8 (72 h). The toxicity of levorphanol also was greatly increased with propranolol, but the dose-effect relationship showed non-parallelism vs. levorphanol + saline. Albino mice and mongrel dogs also showed synergism between morphine and propranolol. Mortality after morphine and propranolol was antagonized by naloxone or naltrexone in rats and mice. The potency ratio in rats for morphine + saline vs. morphine + practolol was 3.5. However, the synergism between propranolol and the narcotics probably was unrelated to beta-adrenergic blocking effects of propranolol because of the apparent equivalence of (+)-, (-)- and (+/-)-propranolol in rats for synergism with morphine.

Analgesics, Opioid↗
PubMed1991

Comparison of the new alpha 1-blocker alfuzosin with propranolol as first-line therapy in hypertension.

The new alpha 1-blocker alfuzosin was compared with propranolol as monotherapy for hypertension in a double-blind, parallel group study of 8-week duration in 40 patients with essential hypertension. The patients (11 males, 29 females; mean age 47.8 +/- 2.2 years in the alfuzosin group and 46.6 +/- 2.4 years in the propranolol group) randomly received either alfuzosin from 2.5 mg b.i.d. up to 10 mg b.i.d. or propranolol from 40 mg b.i.d. up to 160 mg b.i.d. according to an individualized dose-titration schedule. The two groups were comparable with respect to disease history, cardiovascular risk factors, concomitant diseases, previous treatments and end-placebo blood pressure and heart rate values. Four patients did not complete the study, two patients in the alfuzosin group: one patient because of postural hypotension and the second one because of breast cancer; and two patients in the propranolol group: one patient for inefficacy and the second one lost to follow-up. At the end of the 8-week trial the mean daily doses were 12.2 +/- 0.61 mg and 196 +/- 9.82 mg for alfuzosin and propranolol, respectively. The antihypertensive effects of the two drugs were comparable. Upright and supine blood pressures decreased significantly with both treatments from the second week on (P less than 0.001 for all BP values). At the end of the 8-week double-blind trial, 83% of alfuzosin patients and 67% of propranolol patients were normalized. The two treatments differed significantly with respect to their effect on heart rate. Alfuzosin did not induce marked changes in heart rate: only a slight increase was observed. In contrast, propranolol caused bradycardia, more marked in the upright position. Palpitations, headache, asthenia and orthostatic hypotension were reported in the alfuzosin group. Asthenia and decreased libido were reported in the propranolol group. These data prove that alfuzosin has antihypertensive effects equivalent to propranolol and it is an interesting agent for the therapy of essential hypertension. It can be used as a first agent at doses between 5 and 20 mg/day with satisfactory therapeutic response and without relevant side-effects.

Adrenergic alpha-Antagonists↗
PubMed1977

The effects of oral propranolol, digoxin and combination therapy on the resting and exercise electrocardiogram.

The effects of propranolol, digoxin and combination therapy (/D) on the resting and exercise ECG were studied in ten normal subjects and 20 patients with coronary artery disease (CAD) given a sequence of oral placebo, propranolol, P/D, digoxin and placebo, for two week periods. Digoxin produced a significant decrease in T-wave amplitude and often resulted in ST segment depression in the resting ECG. Propranolol, digoxin, and P/D tended to decrease the QTc interval and prolong the PR interval. However, CAD patients were more sensitive to PR prolongation than normals while receiving propranolol or digoxin alone. Propranolol therapy did not significantly affect the ST segment of the exercise ECG in the normal subjects or the CAD patients without an ischemic control exercise ECG. By contrast, 50 per cent of the normal subjects developed "false-positive" ischemic ST segment responses to exercise while receiving digoxin of P/D and three of eight CAD patients without ischemic control exercise ST segments had a similar response to digoxin or P/D. In 12 CAD patients with ischemic control exercise ST segments, propranolol did not affect the amount of ST segment depression at the onset of angina or the maximum amount of ST segment depression. Digoxin or P/D both uniformly increased the maximum amount of ST segment depression which was greater with digoxin than P/D. However, the maximum heart rate on P/D was significantly reduced as compared to that on digoxin. It is concluded that (1) CAD patients are more sensitive to propranolol or digoxin-induced AV block than normals, (2) propranolol does not change the magnitude of ischemic exercise ST segment depression, (3) digoxin increases ischemic exercise ST segment depression and results in a high incidence of false-positive exercise tests, and (4) the addition of propranolol to digoxin attenuates the effects of digoxin on the exercise ST segment.

Administration, Oral↗
PubMed2000

The combination of propranolol and magnesium does not prevent postoperative atrial fibrillation.

BACKGROUND: Atrial fibrillation is a common complication of cardiovascular surgery. Beta-blockers have been shown to decrease the incidence of postoperative atrial fibrillation. However, the use of magnesium is more controversial. It was our hypothesis that adjunctive magnesium sulfate would improve the efficacy of beta-blockers alone in the prevention of postoperative atrial fibrillation. METHODS: We prospectively randomized 167 coronary artery bypass patients (mean age 61+/-10 years, 115 men) to receive propranolol alone (20 mg four times daily) or propranolol and magnesium (18 g over 24 hours). Magnesium was begun intraoperatively, and propranolol was started on admission to the intensive care unit. RESULTS: Using an intention-to-treat analysis, the incidence of postoperative atrial fibrillation was 19.5% in the propranolol-treated patients and 22.4% in propranolol + magnesium-treated patients (p = 0.65). Because combination therapy resulted in an excess of postoperative hypotension, which required withholding doses of propranolol, an on-treatment analysis was also performed. In this analysis, the incidence of atrial fibrillation was still not significantly different (18.5% in propranolol-treated patients and 10.0% in propranolol + magnesium-treated patients, p = 0.20). CONCLUSIONS: Adjunctive magnesium sulfate, in combination with propranolol, does not decrease the incidence of postoperative atrial fibrillation.

Administration, Oral↗
PubMed1989

Improved myocardial oxygen utilization following propranolol infusion in adolescents with postburn hypermetabolism.

The purpose of this study was to determine if propranolol (0.5 mg/kg and 1 mg/kg), administered intravenously (IV) at the height of the postburn hypermetabolic response, would decrease myocardial oxygen requirements, without adversely affecting overall oxygen delivery or total body oxygen consumption. To test this hypothesis, six nonseptic patients age 17 +/- 3 years with burns over 82% +/- 11% total body surface area were given propranolol with continuous hemodynamic monitoring. Propranolol was administered to these patients 20 +/- 15 days postburn. Two clinically derived indices of myocardial oxygen consumption, pressure-work index (PWI) and rate-pressure product (RPP), were used to estimate the energy expenditure of the working heart. Both PWI and RPP were significantly decreased from baseline after 0.5 mg/kg propranolol, 31% for PWI (P less than .001) and 30% for RPP (P less than .01). Similarly, a decrease from baseline was seen after 1.0 mg/kg propranolol, 32% for PWI (P less than .001) and 35% for RPP (P less than .01). Cardiac index (L/min/m2) demonstrated no significant change [7.4 +/- 1.1 (prepropranolol), 6.5 +/- 1.3 (after 0.5 mg/kg propranolol), and 6.8 +/- 1.0 (after 1.0 mg/kg propranolol)] and exceeded the upper limits of normal (hyperdynamic state) throughout the study. Oxygen delivery index (962 +/- 209 mL/min/m2) and oxygen consumption indices [(254 +/- 78 mL/min/m2 by Fick method and 236 +/- 78 mL/min/m2 by inspired and expired gases)] were elevated at baseline and unaffected by propranolol. The decrease in PWI and RPP was achieved mainly by propranolol's effect to lower both heart rate and BP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1976

Propranolol effect on plasma glucose, free fatty acid, insulin, and growth hormone in Graves' disease.

A 3-hr glucose tolerance test was performed in 12 thyrotoxic patients before and after propranolol treatment for 30 days (120 mg/day). Plasma glucose, free fatty acid, insulin, and growth hormone levels were determined on each test and compared to each other and against nine clinically healthy volunteers. In eight thyrotoxic patients (subgroup A) an improvement in carbohydrate tolerance was observed after propranolol treatment, along with a fall in the previously elevated fasting FFA; no change in plasma insulin levels was observed. Plasma growth hormone levels were higher than normal both before and after propranolol; however, a 46% glucose-induced suppression was seen in both instances. In the other four patients (subgroup B) (who had had a marked and rapid weight loss) a deterioration of the previously normal glucosnificant changes in insulin levels. Elevated fasting plasma free fatty acids remained so despite propranolol treatment. Plasma growth hormone was higher than normal before and after propranolol; a late suppression (at 120 min) and no suppression at all were seen, respectively. After propranolol treatment, subgroup B had higher plasma free fatty acid than subgroup A in the fasting state and at 30 and 180 min. It is proposed that the improvement or deterioration in carbohydrate tolerance after propranolol treatment might be related to whether or not a satisfactory propranolol-induced lipolytic blockade is achieved, leading to a decrease in plasma free fatty acid levels, improved insulin sensitivity, and better peripheral glucose utilization. Therefore, a uniform dose of propranolol will not always be sufficient to obtain adequate lipolytic blockade, particularly if the thyrotoxic patient has had a marked and rapid weight loss.

Adolescent↗
PubMed1993

Propranolol in the prevention of recurrent upper gastrointestinal bleeding in patients with cirrhosis undergoing endoscopic sclerotherapy. A randomized controlled trial.

The purpose of this study was to investigate the possible value of continuous administration of propranolol in the prevention of recurrent upper gastrointestinal bleeding in patients with cirrhosis undergoing chronic endoscopic sclerotherapy. Among 239 patients admitted for acute variceal bleeding, 85 with cirrhosis were randomized to receive sclerotherapy either alone (40) or in combination with propranolol (45). Sclerotherapy was carried out with an intravariceal injection of 5% ethanolamine oleate through a fiberoptic endoscope. The procedure was performed every week, until the esophageal varices at the gastroesophageal junction were too small for any further injections. Varices were reinjected if they recurred. Propranolol was given orally twice a day until heart rate was reduced by 25% in the resting position. The mean follow-up period was 23.2 and 24.2 months for sclerotherapy and the sclerotherapy plus propranolol groups, respectively. During this period a significant (P = 0.001) reduction in the recurrence of esophageal varices was observed in patients treated with the combination of sclerotherapy plus propranolol compared with those treated with sclerotherapy alone. However, the time of rebleeding from any source or from esophageal varices did not differ significantly between the two groups. In the sclerotherapy group 21 patients rebled (35 bleeding episodes) compared with 14 (22 episodes) in the combination therapy group. Patients in the sclerotherapy group were more prone to bleed from gastric varices and congestive gastropathy than patients treated with the combination of sclerotherapy plus propranolol (P = 0.012). Twenty-five patients in the endoscopic sclerotherapy group developed complications attributed to sclerotherapy compared with 23 patients in the sclerotherapy plus propranolol group. Complications directly attributable to propranolol were observed in 11 patients. Three of these patients stopped taking the drug due to heart failure (1) and flapping tremor (2). Eight patients (17.8%) died in the latter group while the corresponding figure in the sclerotherapy group was nine (22.5%). It is concluded that the continuous administration of propranolol may reduce incidences of recurrent upper gastrointestinal hemorrhage from gastric sources in patients with cirrhosis undergoing chronic sclerotherapy.

Aged↗
PubMed2000

Direct high-performance liquid chromatographic determination of (R)- and (S)-propranolol in rat microdialysate using on-line column switching procedures.

Two different column-switching HPLC systems (CSWs), employing restricted access material for initial pretreatment of biological samples, were developed for the determination of propranolol enantiomers in microdialysate. CSW 1 was a single-pump set-up based on an initial sample clean-up step with a RP-18 ADS precolumn coupled with an ovomucoid analytical column for direct drug enantioseparation. For the two-pump column set-up (CSW 2), a teicoplanin analytical column was applied for the enantioselective assay after initial sample pretreatment using a RP-8 ADS precolumn. The inter-day precision of the CSW 1 ranged from 0.5 to 5.1% for (R)-propranolol and from 5.1 to 10.5% for (S)-propranolol. The limit of detection (LOD) was set at 10 ng/ml and 15 ng/ml for (R)- and (S)-propranolol, respectively. Inter-day relative standard deviation values of the CSW 2 ranged from 1.1 to 9.9% for (R)-propranolol and from 1.3 to 9.6% for (S)-propranolol. The LOD of the method was 3.0 ng/ml for (R)-propranolol and 2.5 ng/ml for (S)-propranolol. Both approaches were successfully applied for stereoselective monitoring of unbound propranolol levels in rat microdialysates.

Adrenergic beta-Antagonists↗
PubMed2000

Uniform-sized molecularly imprinted polymer material for (S)-propranolol.

A uniform-sized molecularly imprinted polymer for (S)-propranolol has been prepared by a multi-step swelling and thermal polymerization method using methacrylic acid (MAA) and ethylene glycol dimethacrylate (EDMA) as a host functional monomer and cross-linker, respectively. The obtained (S)-propranolol imprinted MAA-EDMA materials were evaluated using aqueous-rich eluents by HPLC. The (S)-propranolol imprinted MAA-EDMA materials had specific recognition for (S)-propranolol and moderate recognition for some structurally related beta-adrenergic antagonists (especially, pindolol and alprenolol), but had no recognition for other basic compounds, and neutral and acidic compounds. Enantioseparations of propranolol and some structurally related beta-adrenergic antagonists were attained with the imprinted MAA-EDMA materials. Hydrophobic interaction of the naphthyloxy and isopropyl groups of propranolol, and ionic interaction of the isopropylamino group of propranolol with the (S)-propranolol imprinted MAA-EDMA materials could play an important role in enantioselective recognition of propranolol.

Acetonitriles↗
PubMed2000

Comparison of the effect of verapamil and propranolol on response of coronary vasomotion to cold pressor test in symptomatic patients with hypertrophic cardiomyopathy.

Impaired endothelium-dependent vasodilatation of coronary resistance vessels has been demonstrated in patients with hypertrophic cardiomyopathy (HC). The aim of this study was to compare the effect of verapamil and propranolol on the response of diastolic coronary blood flow velocity (CBFV) and coronary vascular resistance index to the cold pressor test (CPT) in symptomatic HC patients. In 15 patients with HC, the CBFV was measured in the distal portion of the left anterior descending coronary artery using high-sensitivity transthoracic Doppler echocardiography. Peak diastolic CBFV and coronary vascular resistance index (calculated as ratio of mean aortic pressure/CBFV ratio) were measured at baseline and after CPT. Changes of these parameters induced by the CPT (expressed as percentage of baseline values) were compared after verapamil and propranolol treatment in a crossover study. The same measurements were obtained in nine healthy control subjects. CPT induced an increasing pattern of CBFV during verapamil therapy, which was absent in CPT after propranolol administration (10.1 +/- 5.6% vs. -0.9 +/- 4.1%, P < 0.01). In healthy controls CBFV increased in response to CPT more than in HC patients receiving verapamil or propranolol (23.1+/- 12.8% P < 0.01 and P < 0.05, respectively). The coronary vascular resistance index increased during the CPT significantly less on verapamil than on propranolol treatment (3.5 +/- 9.2% vs. 18.1 +/- 13.5%, P < 0.01). In healthy controls the coronary vascular resistance index decreased during CPT -4.5 +/- 8.5% (P < 0.05 vs. verapamil and P < 0.01 vs. propranolol). Verapamil improved the coronary vasomotor response to CPT in relation to propranolol. Verapamil blunted the increase of the coronary vascular resistance index to the CPT in comparison with its change at CPT after propranolol. Thus, coronary endothelial dysfunction in symptomatic HC patients may be partially reduced by verapamil in comparison with propranolol treatment.

Adrenergic beta-Antagonists↗
PubMed1980

4-Hydroxypropranolol and its glucuronide after single and long-term doses of propranolol.

The disposition of the pharmacologically active 4-hydroxypropranolol (HO-P), its glucuronic acid conjugate (HO-P-G), and propranolol were compared after single intravenous and oral doses of propranolol in 6 normal subjects and after long-term therapy in 32 patients with hypertension or coronary artery disease. The areas under the plasma concentration/time curves (AUCoo, ng . hr/ml) after 4-mg intravenous doses of propranolol were 6.6 +/- 2.2 (mean +/- SEM) for HO-P and 55 +/- 11 for propranolol. After 20- and 80-mg oral doses the AUCoo for HO-P were 59 +/- 9 and 162 +/- 21 and for propranolol were 72 +/- 9 and 306 +/- 46. Peak HO-P concentrations were reached at 1 to 1.5 hr after the oral doses. Although there was a rapid decline in plasma HO-P between 1.5 and 3 hr when HO-P-G was still rising to levels above HO-P levels 3.5- to 5-fold, the apparent half-lifes (t1/2s) after 3 hr were in the same range for HO-P, HO-P-G, and propranolol (3.0 to 4.2 hr). While during long-term therapy plasma HO-P rose over the whole dose range (40 to 960 mg daily) in an apparently linear fashion, the HO-P/propranol plasma level ratio fell from 1.07 +/- 0.13 at 40 mg daily to only 0.09 +/- 0.01 at 640 mg daily. Plasma HO-P-G rose exponentially with dose and demonstrated significant cumulation. HO-P and HO-P-G in urine accounted for about 9% of long-term propranolol doses. This study suggests a significant contribution of HO-P to pharmacologic effects, in particular at low single and long-term oral doses of propranolol and saturation of naphthalene ring oxidation as a main determinant of propranolol bioavailability.

Administration, Oral↗
PubMed1983

Total and free propranolol levels in sensitive and resistant patients.

The clinical effects of the beta-adrenergic inhibitor, propranolol, are believed to correlate best with circulating levels of free drug, the component of total drug concentration that is not bound to plasma proteins and is therefore free to interact with tissue beta receptors. We used the radioreceptor assay for propranolol to determine total and free propranolol levels in 32 hospitalized patients receiving a wide range of doses (40 to 1280 mg/day). Free propranolol was determined by equilibrium dialysis and by the erythrocyte drug level. Erythrocyte levels were found to correlate strongly with free drug, as determined by equilibrium dialysis. Mean percent free propranolol was 16.9 +/- 2.4 ng/ml (SEM) by equilibrium dialysis and 18.8 +/- 2.3 ng/ml (SEM) by the red cell level. Despite considerable variability in the actual level achieved at any given dose, total and free propranolol concentrations were related to dose. A weaker correlation for free drug concentration resulted from variability in free drug among responsive patients (mean +/- SD free propranolol was 13.5 +/- 8.8 ng/ml), and suggested a threshold level of free drug required to achieve clinical effects. Six patients were resistant to high doses of propranolol. Excessive protein binding was noted in four, suggesting abnormalities at the level of protein-drug interaction. Several other possible mechanisms for propranolol resistance became apparent.

Drug Resistance↗
PubMed1985

Propranolol antagonism of phenylpropanolamine-induced hypertension.

Phenylpropanolamine (PPA) overdose can cause severe hypertension, intracerebral hemorrhage, and death. We studied the efficacy and safety of propranolol in the treatment of PPA-induced hypertension. Subjects received propranolol either by mouth for 48 hours before PPA or as a rapid intravenous infusion after PPA. PPA, 75 mg alone, increased blood pressure (31 +/- 14 mm Hg systolic, 20 +/- 5 mm Hg diastolic), and propranolol pretreatment antagonized this increase (12 +/- 10 mm Hg systolic, 10 +/- 7 mm Hg diastolic). Intravenous propranolol after PPA also decreased blood pressure. Left ventricular function (assessed by echocardiography) showed that PPA increased the stroke volume 30% (from 62.5 +/- 20.9 to 80.8 +/- 22.4 ml), the ejection fraction 9% (from 64% +/- 10% to 70% +/- 7%), and cardiac output 14% (from 3.6 +/- 0.6 to 4.1 +/- 1.0 L/min). Intravenous propranolol reversed these effects. Systemic vascular resistance was increased by PPA 28% (from 1710 +/- 200 to 2190 +/- 700 dyne X sec/cm5) and was further increased by propranolol 22% (to 2660 +/- 1200 dyne X sec/cm5). We conclude that PPA increases blood pressure by increasing systemic vascular resistance and cardiac output, and that propranolol antagonizes this increase by reversing the effect of PPA on cardiac output. That propranolol antagonizes the pressor effect of PPA is in contrast to the interaction in which propranolol enhances the pressor effect of norepinephrine. This is probably because PPA has less beta 2 activity than does norepinephrine.

Administration, Oral↗