Plasma Propranolol Concentrations Research Articles

Plasma Drug Concentration of Propranolol and Genetic Study in Chinese Han Patients With Infantile Haemangioma.

Background and PurposeThis study was conducted to explore the plasma drug concentration of propranolol in Chinese Han patients with infantile haemangioma (IH) and the influencing factors, as well as the relationship among plasma drug concentrations of propranolol, β1-AR mutation and CYP2D6 188C>T, efficacy, and safety.Experimental ApproachFrom January 2018 to April 2019, 140 patients with IH who were admitted to the hospital for oral propranolol and agreed to have their plasma concentration of propranolol tested, including 112 patients with β1-AR and CYP2D6 gene tested.Key Results and Conclusions and ImplicationsThe mean peak blood levels of propranolol, 4-hydroxypropranolol (4-OH-P), and N-deisopropylpropranolol (NDP) were 60.35 ± 37.90, 1.90 ± 2.37, and 0.24 ± 0.18 ng/ml, respectively. The mean trough blood levels of propranolol, 4-OH-P, and NDP were 24.98 ± 17.68, 0.45 ± 0.52, and 0.05±0.05 ng/ml, respectively. The higher the dose of propranolol, the higher the plasma concentration of propranolol (p = 0.031). The plasma concentration of propranolol was not related to the treatment efficacy.

A Review on Pharmacokinetic and Pharmacodynamic Drug Interactions of Adrenergic β-blockers with Clinically Relevant Drugs-An Overview

Adrenergic β-blockers are used to treat many conditions, including hypertension, cardiac arrhythmias, heart failure, angina pectoris, migraine, and tremors. The majority of the β-blockers including Propranolol, Metoprolol, Acebutolol, Alprenolol, Betaxolol, Carvedilol, Nebivolol and Oxprenolol are metabolised majorly by CYP2D6, and Bisoprolol is primarily metabolised by CYP3A4 enzymes. The drugs inhibiting or inducing them may alter the pharmacokinetics of those β-blockers. The plasma concentrations of Propranolol might be elevated by the concomitant use of drugs, such as SSRIs (Fluoxetine, Paroxetine), SNRIs (Duloxetine) and Cimetidine, while the plasma concentrations of Metoprolol increased by the concurrent use of SSRIs (Fluoxetine, Paroxetine), Amiodarone, Celecoxib, Cimetidine, Terbinafine, and Diphenhydramine. β-blockers can also interact pharmacodynamically with drugs, including fluoroquinolones, antidiabetic agents and NSAIDs. In addition, β-blockers may interact with herbs, such as curcumin, Ginkgo biloba, Schisandra chinensis, green tea, guggul, hawthorn, St. John's wort and Yohimbine. This article focuses on clinically relevant drug interactions of β-blockers with commonly prescribed medications. In addition to Pharmacokinetics and Pharmacodynamics of the drug interactions, recommendations for clinical practice are highlighted. The prescribers and the pharmacists are needed to be aware of the drugs interacting with β-blockers to prevent possible adverse drug interactions.

Propranolol Therapy in Infantile Hemangioma: It Is Not Just About the Beta.

Propranolol, a nonselective β-adrenergic receptor antagonist, is approved by the U.S. Food and Drug Administration to treat problematic infantile hemangiomas, but a subset of patients experience treatment complications. Parents wary of long-term use and side effects consult plastic surgeons on surgical options or as a second opinion. Understanding the mechanism(s) of action of propranolol will allow plastic surgeons to better inform parents. A systemic literature search was performed to query published translational and basic science studies on propranolol effects on infantile hemangiomas and cells derived from these lesions. In experimental studies, propranolol was antiproliferative and cytotoxic against hemangioma endothelial and stem cells and affected infantile hemangioma perivascular cell contractility. Propranolol inhibited migration, network formation, vascular endothelial growth factor A production, and vascular endothelial growth factor receptor 2 activation and down-regulated PI3K/AKT and mitogen-activated protein kinase signaling in hemangioma endothelial cells, but it increased ERK1/2 activity in hemangioma stem cells. At effective clinical doses, measured propranolol plasma concentration is 100 times higher than necessary for complete β-adrenergic receptor blockade, yet was 10 to 100 times less than required to induce hemangioma stem cell death. Propranolol targets multiple cell types in infantile hemangiomas by means of β-adrenergic receptor-dependent and -independent mechanisms. Plasma concentration played a significant role. At clinically relevant doses, incomplete infantile hemangioma suppression may explain the rebound phenomenon and worsening ulceration, and propranolol off target effects may lead to commonly reported adverse effects, such as sleep and gastrointestinal disturbances. Propranolol limitations and complications underscore the importance of surgical treatment options in cases of rebound and severe adverse effects. Surgical intervention remains an important treatment choice when parents are hesitant to use propranolol.

Development and Evaluation of a Physiologically Based Pharmacokinetic Drug-Disease Model of Propranolol for Suggesting Model Informed Dosing in Liver Cirrhosis Patients.

AimThe study was aimed to understand the underlying causes for the differences in propranolol pharmacokinetics (PK) between healthy and cirrhosis populations by using a systematic whole-body physiologically based pharmacokinetic (PBPK) model-building approach for suggesting model informed propranolol dosing in liver cirrhosis patients with different stages of disease severity.MethodsA whole-body PBPK model was developed by using population simulator PK-Sim® by using reported physicochemical and clinical data for propranolol in healthy and liver cirrhosis populations. The model evaluation was done by visual verification and comparison of PK parameters using their observed/predicted ratios (Robs/pred).ResultsThe developed model has effectively described the disposition of propranolol after intravenous and oral application in healthy and liver cirrhosis populations. All the model predictions were comparable to the observed clinical data and the Robs/pred for all the PK parameters were within a 2-fold range. A significant increase in plasma concentration of propranolol and decrease in drug clearance was observed in progressive stages of liver cirrhosis. The developed model after evaluation with the reported clinical PK data was used for suggesting model informed propranolol dosing in different stages of liver cirrhosis based on systemic unbound drug concentration.ConclusionThe developed PBPK model has successfully described propranolol PK in healthy and cirrhosis populations after IV and oral administration. The evaluated PBPK propranolol-cirrhosis model can have many implications in predicting propranolol dosing in liver cirrhosis patients with different stages of disease severity.

Intermittent β-adrenergic blockade downregulates the gene expression of β-myosin heavy chain in the mouse heart

Expression of the β-myosin heavy chain (β-MHC), a major component of the cardiac contractile apparatus, is tightly regulated as even modest increases can be detrimental to heart under stress. In healthy hearts, continuous inhibition of β-adrenergic tone upregulates β-MHC expression. However, it is unknown whether the duration of the β-adrenergic inhibition and β-MHC expression are related. Here, we evaluated the effects of intermittent β-blockade on cardiac β-MHC expression. To this end, the β-blocker propranolol, at the dose of 15mg/kg, was administered once a day in mice for 14 days. This dosing schedule caused daily drug-free periods of at least 6 h as evidenced by propranolol plasma concentrations and cardiac β-adrenergic responsiveness. Under these conditions, β-MHC expression decreased by about 75% compared to controls. This effect was abolished in mice lacking β1- but not β2-adrenergic receptors (β-AR) indicating that β-MHC expression is regulated in a β1-AR-dependent manner. In β1-AR knockout mice, the baseline β-MHC expression was fourfold higher than in wild-type mice. Also, we evaluated the impact of intermittent β-blockade on β-MHC expression in mice with systolic dysfunction, in which an increased β-MHC expression occurs. At 3 weeks after myocardial infarction, mice showed systolic dysfunction and upregulation of β-MHC expression. Intermittent β-blockade decreased β-MHC expression while attenuating cardiac dysfunction. In vitro studies showed that propranolol does not affect β-MHC expression on its own but antagonizes catecholamine effects on β-MHC expression. In conclusion, a direct relationship occurs between the duration of the β-adrenergic inhibition and β-MHC expression through the β1-AR.

Propranolol kinetics in plasma from severely burned adults

ObjectivesThe aim of this study was to determine the appropriate propranolol dosing strategy for reducing heart rate in severely burned adults. MethodsA total of 26 patients (≥18 years) with burns covering ≥30% of the total body surface area were included in this IRB-approved study. Plasma propranolol concentrations were determined in a placebo group (n=10) or following one of three dosing strategies: Q6 (n=4), Q8 (n=6), and Q24 (n=6). Blood was collected just before dosing and at regular intervals over two dosing periods with corresponding heart rate and blood pressure recordings. Statistical significance was determined by one-way ANOVA followed by the appropriate post-hoc test. ResultsHeart rate was 86±2 bpm for Q6, 93±3 bpm for Q8, and 90±4 bpm for Q24. The Q8 group had a significantly higher heart rate than the Q6 group (p=0.0001). Plasma propranolol concentrations were significantly higher in the Q6 dosing strategy than in the Q8 dosing strategy (p=0.02). ConclusionsHeart rate can be decreased to a similar degree with Q6 and Q24 dosing strategies, with the Q8 dosing strategy being less effective. Q6 dosing is recommended to maintain reduced heart rate throughout dosing periods.

Population Pharmacokinetics Of Propranolol in Patients with Liver Cirrhosis

Since propranolol, a nonselective β-blocker, is known to a high extraction drug and mainly metabolized in the liver after oral administration, the pharmacokinetics may be markedly affected by the hepatic function. The aim of this study is to develop a population pharmacokinetic model and evaluate the effects of covariates including hepatic impairment. Single oral dose of 40mg propranolol was administered and plasma concentrations of propranolol and metabolite concentrations were measured over 8h after dosing. The population pharmacokinetics was analyzed using NONMEM for 468 plasma concentrations of propranolol and metabolite from 42 noncirrhotic and 36 cirrhotic subjects. Volume of distribution of parent drug (Vp/F) was set equal to volume of distribution of metabolite. The parameters were estimated using the first-order conditional estimation method with interaction. Covariates were tested with exponential relationship by stepwise covariate model building. The final model was a one-compartment for both parent and metabolite model with two depot compartments: the dose enters not only into the parent compartment at a rate Ka with a fraction F1(0.25 fix) but also into the metabolite compartment at a rate Kam with a fraction F2(0.315 fix). Final parameter estimates (%inter-individual variability, IIV) were as follows; Vp/F = 14.8 L (187.8%), clearance of propranolol (CL) = 44.8 L/hr (130.4%), clearance of 4-OH propranolol (CLm) = 1060 L/hr (75.6%), and the metabolic rate constant of propranolol to 4-OH propranolol (Km) = 0.215 hr-1 (47.6%). The platelet count showed an influence on propranolol PK parameters; Vp/F, CL, CLm and Km. The visual predictive check and the fits of a bootstrap with 1000 replicates of the data set demonstrated the adequateness and robustness of the developed model. A population PK model reflecting the first-pass effect was successfully developed and we evaluated the effects of covariates on the pharmacokinetic parameters.

Pharmacokinetic Parameters and Over-Responsiveness of Iranian Population to Propranolol.

Purpose: Propranolol is the most widely used treatment for cardiovascular diseases. Dosage range in our patients is usually less than the amount mentioned in references. The aim of the present study was to clarify whether pharmacokinetic differences are able to justify the need for the fewer doses in our patients or not.Methods: Twenty healthy volunteers (10 male) at heart center of Mazandaran University of Medical Sciences were studied. Samples of blood were collected before a single oral dose (40 mg) of Propranolol. Blood samples were taken up to 9 hours after dose. Total plasma concentration of Propranolol was measured by HPLC. Population Pharmacokinetic analysis was performed using population pharmacokinetics modeling software P-Pharm.Results: The mean value for oral plasma clearance (CL/F) was 126.59 ml/hr. The corresponding values for apparent volume of distribution (V/F), t1/2 beta, maximum blood concentration (C max), and time to reach the maximum blood concentration (T max) were 334.12 Lit, 1.98 hr, 40.25 ng/ml, and 1.68 hr, respectively. The observed mean values of V/F of propranolol in the present study were comparable with those reported in the literature. However, the mean values of CL/F of propranolol in current study was significantly higher than those reported in other population (P-value<0.001).Conclusion: This study has confirmed that the pharmacokinetic differences are not able to justify over-responsiveness of Iranian population to propranolol. Pharmacodynamic differences in responding to beta blocker drugs by Renin secretion or having a different sensibility to beta receptors might play a role in making our population have a different response to propranolol.

Oxandrolone Coadministration Does Not Alter Plasma Propranolol Concentrations in Severely Burned Pediatric Patients.

The systemic impact of severe burn injury results in a variety of disorders that require therapeutic intervention. Propranolol, a nonselective β1, β2-adrenergic receptor antagonist, reduces resting heart rate and cardiac work caused by elevated circulating catecholamines. Oxandrolone, a testosterone mimetic, promotes protein synthesis and anabolism to counter muscle wasting. Coadministration of these drugs is expected to synergistically improve patient outcomes. Testosterone administration is known to alter β-adrenergic receptor-mediated signaling. Here, we determined whether the coadministration of oxandrolone alters plasma propranolol concentrations. Ninety-two pediatric patients with burns covering ≥30% of the TBSA were enrolled in this institutional review board-approved study and randomized to receive propranolol (n = 49) or oxandrolone + propranolol (n = 43). Plasma propranolol concentrations were determined following two dosing strategies: Q6 (liquid formulation; n = 86) and Q24 (extended-release capsule; n = 22). Samples were drawn before drug administration and at regular intervals throughout the next two dosing periods. Heart rate and blood pressure were recorded throughout the study. Propranolol half-life was 3.3 hours for the Q6 drug dosing frequency (P < .0001) and 11.2 hours for the Q24 strategy (P < .0001). Percentage of predicted heart rate declined by 2.8% for each doubling of the propranolol concentration in the Q6 dosing schedule (P < .0001). Percentage of predicted heart rate declined by 2.5% for each doubling of propranolol concentration on the Q24 dosing schedule (P < .0001). Maximum and minimum propranolol plasma concentrations were similar with either dosing regimen. The addition of oxandrolone did not affect any of the measured parameters. Oxandrolone coadministration does not alter propranolol’s plasma concentration, half-life, or effect on heart rate. This study is registered at clincialtrials.gov: NCT00675714.

Effects of Dosing Protocol on Distribution of Propranolol in Periocular Tissues after Topical Ocular Instillation

ABSTRACTPurpose: Our previous study demonstrated that topical ocular instillation can deliver effective concentrations of propranolol in the periocular tissues, and may be superior to oral propranolol in the treatment of periocular capillary hemangiomas. The objective of this study was to investigate the effects of dosing protocol on the distribution of propranolol in the periocular tissues and plasma after topical ocular instillation.Methods: Each rabbit received propranolol 0.5% ophthalmic solution using one of the following dosing protocols: three drops of 50 μL, one drop of 50 μL, or one drop of 25 μL. The periocular tissues (e.g. eyelids and extraocular muscles) and blood were collected and assayed for propranolol at 1 h after dosing.Results: Decreasing the concentration of eye drops (1% to 0.5%), decreasing the number of eye drops during dosing (three drops to one drop), or decreasing the instilled volume (50 µL to 25 µL) generally lowered the concentration of propranolol in the periocular tissues. Nevertheless, therapeutic levels of propranolol (> 0.4 μg/g) were delivered to the periocular tissues at 1 h after dosing using any of the three protocols examined. Dose-dependent concentrations in some periocular tissues and plasma were observed over the dose range of 0.125 mg to 1.5 mg. The plasma concentration of propranolol was not measurable when a single 25 μL of propranolol 0.5% was instilled in the eye.Conclusions: The dosing protocol of topical ocular instillation can be tailored to achieve the desired therapeutic concentrations of propranolol in the periocular tissues while minimizing systemic exposure.

Pharmacokinetics and local safety profile of propranolol eye drops in rabbits.

Oral propranolol, a nonselective β-blocker, is able to reduce the progression of retinopathy of prematurity in newborns, but it appeared unsafe. This study aimed to find, in rabbits, a propranolol eye drop concentration able to induce lower plasma but higher retinal concentrations than those obtained after oral administration. Male New Zealand white rabbits were treated with oral propranolol (0.25 mg/kg/6 h) for 5 d, and propranolol concentrations were measured after 1, 2, 3, and 6 h in plasma, aqueous humor, vitreous humor, and retina. These concentrations were compared with those obtained after the administration of one drop of 25 μl of propranolol 0.1% prepared in saline, applied every 6 h to both eyes for 5 d. A Draize eye test and histological analyses were performed to assess eye drop tolerability. The administration of eye drops produced retinal concentrations similar to, but plasma concentrations significantly lower than, those measured after oral administration. The local tolerability profile was excellent. Propranolol eye drops are able to ensure high retinal and low plasma concentrations of propranolol, and this finding opens the perspective of possible topical treatment with propranolol in newborns with retinopathy of prematurity.

Propranolol inhibited angiogenesis via down-regulating the expression of vascular endothelial growth factor in hemangioma derived stem cell

Oral propranolol (PRN) has recently been shown to be highly effective for infantile hemangiomas (IHs), and is currently recommended as the first-line treatment of complicated IHs. However, no pharmacokinetic parameters have ever been reported for infants who received PRN treatment for IHs, and the therapeutic mechanism(s) still remain unclear. In this study, we found that plasma PRN concentration was affected by the frequency of administration of PRN. A single daily administration of PRN (1mg/kg/d) resulted in an early elevation of plasma PRN compared to administration of the same dose divided into two times daily.

Effects of physiological and biochemical factors based on aging, pathological conditions and drug combinations on propranolol pharmacokinetics using physiologically-based pharmacokinetic model in humans

Sensitivity of physiological and biochemical parameters based on aging, pathological conditions and drug combinations on propranolol pharmacokinetics was investigated to define factors contributing to larger inter-individual variability on propranolol pharmacokinetics after oral administration than that after intravenous (iv) administration. Using a physiologically-based pharmacokinetic model, plasma propranolol concentration was simulated with wide-ranging physiological and biochemical parameters. Then calculated AUC and half-life (t1/2) were compared with those obtained from the basic condition. It was found that the total blood flow through the body (Qtot), hepatic volume, unbound fraction in the blood and metabolic parameters affected propranolol AUC. Except for Qtot, effects were greater with after oral administration than iv administration. The propranolol AUC decreased by half with a two-fold increase in hepatic volume after oral administration possibly because of the increased first-pass metabolism. By contrast, some distribution parameters such as the skin tissue-to-blood distribution ratio and blood-to-plasma concentration ratio affected propranolol t1/2. Finally, propranolol plasma concentrations were simulated in the case that metabolizing activity decreased to one half and one fifth with an assumption of metabolic enzyme inhibition. The simulated propranolol curves correlated well with the previously reported plasma concentration in the absence and presence of quinidine, which is well known to be a potent and selective CYP2D6 inhibitor. Thus, plasma propranolol pharmacokinetics was affected by parameters which related to the hepatic metabolism and the distribution, especially after oral administration.

Clinical Pharmacokinetics of Buffered Propranolol Sublingual Tablet (Promptol™)—Application of a New “Physiologically Based” Model to Assess Absorption and Disposition

Sublingual administration of certain buffered propranolol may improve the rate and extent of absorption compared to oral administration. The main objectives of this study were to (1) compare the plasma propranolol concentrations (Cp-prop) following sublingual administration of a specially buffered formulation (Promptol™) to that following oral administration of Inderal(®) and (2) evaluate the utility of a special pharmacokinetic model in describing the Cp-prop following sublingual administration. Eighteen healthy volunteers received 10mg sublingual Promptol™ or oral Inderal(®). Multiple Cp-prop were determined and their pharmacokinetics compared. Additional data following sublingual 40mg Promptol™ or Inderal(®) were utilized for evaluation of a special advanced compartmental absorption and transit (ACAT) model. For model simulation, the physicochemical parameters were imported from AMET predictor, whereas the pharmacokinetic parameters were calculated and optimized by Gastroplus(®). Based on this model, the quantity of drug absorbed via buccal/sublingual mucosa was estimated. Cp-prop was higher at earlier times with 3-fold greater relative bioavailability following sublingual Promptol™ compared to that from oral Inderal(®). The special ACAT model provided excellent goodness of fit of Cp-prop-time curve and estimated a 56.6% increase in absorption rate from Promptol™ and higher initial Cp-prop compared to the regular formulation. The modified ACAT model provided a useful approach to describe sublingual absorption of propranolol and clearly demonstrated an improvement of absorption of Promptol™. The sublingual 10mg Promptol™ achieved not only a similar systemic exposure as 30mg oral Inderal(®) but an earlier effective Cp-prop which may be advantageous for certain clinical conditions.

The effect of rectal ozone on the portal vein oxygenation and pharmacokinetics of propranolol in liver cirrhosis (a preliminary human study)

The aim of this study was to investigate the effect of rectal ozone on portal vein oxygenation and the pharmacokinetic changes of propranolol in patients with liver cirrhosis. Fifteen patients with liver cirrhosis were included They were given a fixed oral dose of propranolol 80mg on the morning of day 1 after overnight fasting. Blood samples were collected at fixed time intervals for 24h. Patients were given 12 sessions of rectal ozone of 300ml of 40% ozone/oxygen mixture. On day 14 another oral dose of 80mg propranolol was given and blood samples were collected as on day 1. Plasma concentrations of propranolol were measured by HPLC. Portal vein oxygen tension and saturation were measured before and after rectal ozone. Plasma concentrations of propranolol were reduced after ozone therapy with pronounced decreases in the maximum plasma concentration and the area under the plasma concentration-time curve. The changes were consistent with a decrease in propranolol bioavailability. There was a decrease in the elimination half-life and mean residence time. Portal vein oxygenation significantly increased after rectal ozone. The changes in the pharmacokinetics of propranolol probably reflect an increase in the rate and extent of its metabolism resulting from improved portal vein oxygenation attributable to the ozone therapy. The present work highlights that ozone can be an alternative medical measure to improve portal vein oxygenation in liver cirrhosis.

Modification of propranolol’s bioavailability by Eurycoma longifolia water-based extract

Eurycoma longifolia (E. longifolia), a herb commonly consumed for its aphrodisiac properties, is widely used by Asian males. This may include hypertensive patients receiving propranolol which may cause sexual dysfunction as one of its side-effects. There is no published study of the potential pharmacokinetic interaction between propranolol and the herb. To study propranolol's pharmacokinetics when E. longifolia is consumed, comparing volunteers given either propranolol or a placebo. This is a placebo-controlled randomized single-blinded crossover study of the effect of a water-based extract of E. longifolia on the pharmacokinetics of a single dose of proporanolol (Inderal(®)) in 14 healthy non-smoker young males. Eighty milligram of propranonol was orally administered with (i) placebo (Lactose) or (ii) 200 mg of water-based extract of E. longifolia (0·0272 ± 0·0026%eurycomanone) following an overnight fasting. Blood samples were collected at 0, 0·5, 1, 1·5, 2, 3, 4, 6, 8 and 10 h for propranolol's plasma concentration determinations using a validated high-performance liquid chromatography (HPLC) method. When propranolol was administered with E. longifolia, its bioavailability (AUC0-∞) decreased by 29% while C(max) was reduced by 42% and T(max) was significantly prolonged by almost 86%. The terminal elimination half-life, however, was not significantly affected. The bioavailability of propranolol is significantly decreased when consumed together with E. longifolia. The interaction is due to a reduction in absorption, rather than an increase in propranolol's metabolism. Although the pharmacodynamics of propranolol was not affected in healthy volunteers, caution is still advisable with co-administration of the drug and the herb.

Improving sublingual delivery of weak base compounds using pH max concept: Application to propranolol

The purpose of the present work was to provide theoretical and experimental support in generating an optimal pH (pH max) for a representative weak base compound (propranolol), that can lead to enhanced sublingual absorption. Initially equations for pH-solubility and pH-permeability profiles were derived and compared to the profiles obtained experimentally. Excellent correlation ( R 2 = 0.999) of solubility profiles was obtained using non-linear regression, and the permeability profiles further predicted that at certain pH (pH max), optimal mucosal permeation could be achieved. Subsequently, in a pharmacokinetics study, a buffered sublingual propranolol tablet, designed to achieve its pH max (when dissolved in saliva), were compared to that from a marketed product (Inderal ® which could not achieve pH max) in 8 healthy subjects. Each subject received the products sublingually for 15 min followed by swallowing the remaining drug–saliva. The plasma propranolol concentrations of AUC during first 30 min from the buffered tablet were significantly higher than that from the Inderal ® tablet ( p < 0.05), and no significant differences in the remaining AUC were observed. These in vitro and in vivo results on propranolol provided experimental confirmation of the pH max concept as well as its utility in sublingual drug delivery. Such an approach may be applicable to other similar compounds to improve sublingual drug delivery.

Chronic effects assessment and plasma concentrations of the β-blocker propranolol in fathead minnows ( Pimephales promelas)

The presence of many human pharmaceuticals in the aquatic environment is now a worldwide concern, yet little is known of the chronic effects that these bioactive substances may be having on aquatic organisms. Propranolol, a non-specific beta adrenoreceptor blocker (β-blocker), is used to treat high blood pressure and heart disease in humans. Propranolol has been found in surface waters worldwide at concentrations ranging from 12 to 590 ng/L. To test the potential for ecologically relevant effects in fish in receiving waters, short-term (21 days) adult reproduction studies were conducted, in which fathead minnows were exposed to nominal concentrations of propranolol hydrochloride [CAS number 318-98-9] ranging from 0.001 to 10 mg/L (measured concentrations typically from 78 to 130%). Exposure of fish to 3.4 mg/L (measured) over 3 days caused 100% mortality or severe toxicity requiring euthanasia. The most sensitive endpoints from the studies were a decrease in hatchability (with regard to the number of days to hatch) and a concentration-related increase in female gonadal somatic index (GSI), giving LOEC hatchability and LOEC female GSI values of 0.1 mg/L. Concentration-related decreases in weights of male fish were also observed, with LOEC male wet weight value of 1.0 mg/L, and the LOEC reproduction value was 1.0 mg/L. Collectively, these data do not suggest that propranolol was acting as a reproductive toxin. Plasma concentrations of propranolol in male fish exposed to nominal concentrations of 0.1 and 1.0 mg/L were 0.34 and 15.00 mg/L, respectively, which constitutes 436 and 1546% of measured water concentrations. These compare with predicted concentrations of 0.07 and 0.84 mg/L, and thus to a degree support the use of partition coefficient models for predicting concentrations in plasma in fish. In addition, propranolol plasma concentrations in fish exposed to water concentrations of 0.1 and 1.0 mg/L were greater than the human therapeutic plasma concentration and hence these data very strongly support the fish plasma model proposed by Huggett et al. [Huggett, D.B., Cook, J.C., Ericson, J.F., Williams, R.T., 2003a. A theoretical model for utilizing mammalian pharmacology and safety data to prioritize potential impacts of human pharmaceuticals to fish. Hum. Ecol. Risk Assess. 9, 1789–1799].

Propranolol Increases the Threshold for Lidocaine-Induced Convulsions in Awake Rats: A Direct Effect on the Brain

Propranolol is a beta-adrenoceptor antagonist used clinically. Local anesthetics are used for controlling pain, whereas propranolol is concomitantly given to treat hypertension and tachycardia. However, there are few studies examining the effects of propranolol on the toxicity of local anesthetics. We investigated the effect of propranolol on lidocaine-induced convulsions in awake, spontaneously breathing rats. Male Sprague-Dawley rats were randomly divided into six groups (n = 8, each group). Rats were pretreated with intracerebroventricular saline (cerebroventricle-control: CV-C group), 10 or 30 microg/kg of (S)-(-)-propranolol (propranolol) (cerebroventricle-small dose: CV-S and cerebroventricle-large dose: CV-L groups, respectively) or i.v. saline (IV-control: IV-C group), 1 or 3 mg/kg of propranolol (IV-small dose: IV-S and IV-large dose: IV-L groups, respectively). Three minutes later, lidocaine was administered i.v. at 4 mg x kg(-1) x min(-1) until tonic-clonic convulsions occurred. The convulsive dose of lidocaine in the CV-L group was significantly larger than that in the CV-C group (30.6 +/- 5.1 vs 23.5 +/- 2.2 mg/kg, respectively, P = 0.008). Plasma concentrations of total and protein-unbound lidocaine, concentrations of lidocaine in the brain at the onset of convulsions were also significantly higher in the CV-L group than those in the CV-C group (36.1 +/- 4.8 vs 26.0 +/- 3.8 microg/mL, 22.5 +/- 3.5 vs 13.7 +/- 2.6 microg/mL, 82.7 +/- 7.1 vs 57.3 +/- 5.7 microg/g, P < 0.001 for all). The convulsive dose, plasma concentrations of total and protein-unbound lidocaine, and brain lidocaine in the IV-L group were also significantly larger than those in IV-C group and comparable with those in the CV-L group. The plasma concentration of propranolol before starting an infusion of lidocaine in the IV-L group was approximately 60-fold higher than that in the CV-L group (554.7 +/- 104.6 and 9.3 +/- 6.7 ng/mL, respectively). Propranolol increased the threshold for lidocaine-induced convulsions by directly acting on the brain.

PROPRANOLOL PLASMA MONITORING IN CHILDREN SUBMITTED TO SURGERY OF TETRALOGY OF FALLOT BY A MICROMETHOD USING HIGH PERFORMANCE LIQUID CHROMATOGRAPHY

To evaluate the analytical micromethod using liquid chromatography for the quantification of propranolol in children submitted to surgery of tetralogy of Fallot (TLF). Only 0.2 mL of plasma is required for the assay. Peaks eluted at 8.4 (Propranolol) and 17.5 min (verapamil, internal standard) from a C18 column, with a mobile phase 0.1 M acetate buffer, pH 5.0, and acetonitrile (60:40, v/v) at flow rate 0.7 mL/min, detected at 290 nm (excitation) and 358 nm (emission). Surgery was started 776 min of drug administration (8.7 mg, mean); seven blood samples were collected from six patients (4M/2F; 2.1 yrs;11.5 kg; 0.80 m; 18.9 kg/m(2)). Confidence limits of the method showed high selectivity and recovery, sensitivity of 0.02ng/mL, good linearity (0.05-1000 ng/mL), precision of 8.6% and accuracy of 3.1%. The mean duration of surgery was 283.2 min, with the patients remaining under cardiopulmonary bypass (CPB) for 114 min. A declining curve of propranolol plasma concentration was obtained after the last dose in the night that preceded the day of surgery. Plasma concentration also was normalized with hematocrit due to the hemodilution caused by the CPB procedure. On the other hand a decrease on drug plasma concentration was obtained between periods, the beginning of surgery to the postoperative day 2 (7.09 ng/mL and 0.05 ng/mL, p<0.05 respectively) and from the end of CPB to the postoperative day 2 (2.79 ng/mL e 0.05 ng/mL, p<0.05). Propranolol monitoring of plasma concentrations of children (TLF) normalized after the last preoperative dose revealed a decline from the beginning of surgery to the second postoperative day, suggesting that, once redistribution was restored, propranolol washout was complete.