OBJECTIVETo study the pharmacokinetics of propranolol and metoprolol in rats after acute exposure to high altitude.

METHODSWistar rats were randomly assigned into 4 groups for treatment with intragastric administration of propranolol or metoprolol after acute exposure to high altitude (4010 m) or normal altitude (50 m). Venous blood samples were collected from the rats at different time points after drug administration to determine the drug concentrations in the plasma and plasma ultrafiltrate using liquid chromatography-mass spectrometry (LC-MS/MS).

RESULTSThe protein binding rate of propranolol was significantly increased but that of metoprolol remained unchanged after acute exposure to high altitude. Compared with the rats exposed to normal altitude, the rats with acute exposure to high altitude showed significant alterations in the pharmacokinetic parameters of the drugs, shown by increased Cmax and AUC, prolonged t1/2 and MRT, and lowered Clz/F of propranolol, and by increased Tmax and prolonged t1/2 and MRT of metoprolol without obvious changes of the parameters of the compartmental model.

CONCLUSIONSignificant changes in the pharmacokinetics of propranolol and metoprolol occur in rats after acute exposure to high altitude possibly in relation to, apart from the changes in plasma protein binding ratio and blood gas, alterations in metabolic enzyme activities, increased blood viscosity, and species and general conditions of the animals.

Altitude ; Animals ; Chromatography, Liquid ; Metoprolol ; pharmacokinetics ; Propranolol ; pharmacokinetics ; Protein Binding ; Rats ; Rats, Wistar ; Tandem Mass Spectrometry

OBJECTIVE: To study the effect of CYP2D610 (c.100 C>T) on plasma trough concentrations of metoprolol and its metabolite α-hydroxy metoprolol, blood pressure and heart rate in patients with coronary artery disease. METHODS: The patients with coronary artery disease taking metoprolol tablets (=128) and those taking metoprolol sustained-release tablets (=126) were genotyped for CYP2D610 using Taqman real-time quantitative PCR. The trough concentrations of metoprolol and α-hydroxy metoprolol were determined with UPLC-MS/MS, and the dose-normalized concentrations (C/D) were compared among the patients with different CYP2D610 genotypes in both groups. Resting blood pressure and heart rate were recorded in all the patients when the concentration of metoprolol reached the steady state and were compared among the patients with different genotypes. RESULTS: In patients taking metoprolol sustained-release tablets, the plasma trough concentration of α-hydroxy metoprolol was significantly associated with the systolic blood pressure (=0.0204). The CYP2D610 poor metabolizers showed a significant association with the C/D of metoprolol and α-hydroxy metoprolol ( < 0.01) in patients receiving metoprolol in both formulations, and in both groups, the C/D of metoprolol was significantly higher in the patients with a TT genotype than in those with a CC or CT genotype ( < 0.01); compared with those with the CT genotype, the patients with the TT genotype had a significantly lower C/D of α-hydroxy metoprolol ( < 0.01). In patients taking metoprolol sustained-release tablets, those with the CT (=0.0281) and TT (=0.0196) genotypes had lower diastolic blood pressure than patients with the CC genotypes, but the systolic blood pressure or heart rate did not differ significantly among them. CONCLUSIONS CYP2D610T allele mutation can reduce the metabolism of metoprolol, increase the C/D of metoprolol and decrease the C/D of α-metoprolol and diastolic blood pressure in patients with coronary artery disease, but CYP2D610 variation does not significantly affect systolic blood pressure or heart rate in the patients when the concentration of metoprolol reaches a steady state.
Adrenergic beta-Antagonists ; Chromatography, Liquid ; Coronary Artery Disease ; Cytochrome P-450 CYP2D6 ; Genotype ; Humans ; Metoprolol ; Tandem Mass Spectrometry

Cardiovascular and central nervous system (CNS) toxicity, including tachydysrhythmia, agitation, and seizures, may arise from cocaine or bupropion use. We report acute toxicity from the concomitant use of cocaine and bupropion in a 25-year-old female. She arrived agitated and uncooperative, with a history of possible antecedent cocaine use. Her electrocardiogram demonstrated tachycardia at 130 beats/min, with a corrected QT interval of 579 ms. Two doses of 5 mg intravenous metoprolol were administered, which resolved the agitation, tachydysrhythmia, and corrected QT interval prolongation. Her comprehensive toxicology screen returned positive for both cocaine and bupropion. We believe clinicians should be aware of the potential for synergistic cardiovascular and CNS toxicity from concomitant cocaine and bupropion use. Metoprolol may represent an effective initial treatment. Unlike benzodiazepines, metoprolol directly counters the pharmacologic effects of stimulants without respiratory depression, sedation, or paradoxical agitation. A lipophilic beta-blocker, metoprolol has good penetration of the CNS and can counter stimulant-induced agitation.
Adult ; Benzodiazepines ; Bupropion ; Central Nervous System ; Cocaine ; Dihydroergotamine ; Electrocardiography ; Female ; Humans ; Metoprolol ; Respiratory Insufficiency ; Seizures ; Tachycardia ; Toxicology

BACKGROUND: Postural tachycardia syndrome (POTS) is a common childhood disease that seriously affects the patient's physical and mental health. This study aimed to investigate whether pre-treatment baseline left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) values were associated with symptom improvement after metoprolol therapy for children and adolescents with POTS. METHODS: This retrospective study evaluated 51 children and adolescents with POTS who received metoprolol therapy at the Peking University First Hospital between November 2010 and July 2019. All patients had completed a standing test or basic head-up tilt test and cardiac echocardiography before treatment. Treatment response was evaluated 3 months after starting metoprolol therapy. The pre-treatment baseline LVEF and LVFS values were evaluated for correlations with decreases in the symptom score after treatment (ΔSS). Multivariable analysis was performed using factors with a P value of <0.100 in the univariate analyses and the demographic characteristics. RESULTS: A comparison of responders and non-responders revealed no significant differences in demographic, hemodynamic characteristics, and urine specific gravity (all P > 0.050). However, responders had significantly higher baseline LVEF (71.09% ± 4.44% vs. 67.17% ± 4.88%, t = -2.789, P = 0.008) and LVFS values (40.00 [38.00, 42.00]% vs. 36.79% ± 4.11%, Z = -2.542, P = 0.010) than the non-responders. The baseline LVEF and LVFS were positively correlated with ΔSS (r = 0.378, P = 0.006; r = 0.363, P = 0.009), respectively. Logistic regression analysis revealed that LVEF was independently associated with the response to metoprolol therapy in children and adolescents with POTS (odds ratio: 1.201, 95% confidence interval: 1.039-1.387, P = 0.013). CONCLUSIONS Pre-treatment baseline LVEF was associated with symptom improvement after metoprolol treatment for children and adolescents with POTS.
Adolescent ; Child ; Humans ; Metoprolol/therapeutic use* ; Postural Orthostatic Tachycardia Syndrome/drug therapy* ; Retrospective Studies ; Stroke Volume ; Ventricular Function, Left

OBJECTIVETo investigate the value of metoprolol injection at dobutamine-atropine stress echocardiography (DASE) for detection of coronary artery disease (CAD).

METHODSDASE was performed in 72 patients with suspected CAD. All the patients received rapid metoprolol injection immediately after getting peak heart rate at DASE (DASE-Meto) and were subjected to coronary angiography (CAG) within two weeks. Regional wall motion and haemodynamic parameters at peak heart rate during DASE and after metoprolol injection were analyzed, and DASE and DASE-Meto results were compared with CAG.

RESULTSThere were 35 patients with CAG positive and 37 negative. The sensitivity, specificity, accuracy and positive and negative predictive values of DASE for detecting CAD were 65.7%, 86.5%, 76.4%, 82.1% and 84.6%, respectively. There were 10 patients with positive result at CAG undetected by DASE but observed regional wall motion abnormality (RWMA) after metoprolol injection. So the sensitivity, specificity, accuracy and positive and negative predictive values of DASE-Meto for detecting CAD were 94.3%, 83.8%, 88.9%, 72.7%, 93.9%, respectively. After metoprolol injection, the symptoms caused by the medicine used in detection were alleviated soon and recovery time was shortened.

CONCLUSIONThe use of metoprolol at DASE can improve the accuracy and security of CAD detection.

Aged ; Coronary Disease ; diagnostic imaging ; Echocardiography, Stress ; methods ; Female ; Humans ; Male ; Metoprolol ; Middle Aged ; Predictive Value of Tests ; Sensitivity and Specificity

Adrenergic beta-Antagonists ; analysis ; Analgesics, Opioid ; analysis ; Chromatography, High Pressure Liquid ; methods ; Humans ; Metoprolol ; analysis ; Tramadol ; analysis

OBJECTIVES: The use of anticholinergic drugs in the elderly may lead to negative events such as falls, delirium, urinary retention and cognitive decline, and the higher the number of anticholinergic drugs use, the more such negative events occur. This study aims to analyze the risk factors associated with the prescription of total anticholinergic drugs in elderly outpatients and evaluate the rationality of anticholinergic drugs, and to provide a reference for reducing the adverse effects of anticholinergic drugs. METHODS: A list of drugs with anticholinergic activity based on the Beers criteria was established. The basic information (such as age and gender), clinical diagnosis, and medications of elderly outpatient were extracted from hospital electronic medical records, and the Anticholinergic Cognitive Burden (ACB) Scale was used to calculate the anticholinergic burden for each patient. Logistic regression analysis was used to identify the potential risk factors for the occurrence of problems such as multiple medication and insomnia. RESULTS: A total of 1 840 prescriptions for elderly patients were reviewed. Of these patients, ACB score was more than or equal to 1 in 648 (35.22%) patients. Number of prescription medication (95% CI: 1.221 to 1.336) and insomnia (95% CI: 3.538 to 6.089) were independent factors affecting ACB scores (both P<0.01). Medications for patients of ACB scores were most commonly treated with the central nervous system drugs (such as alprazolam and eszopiclone) and for the cardiovascular system drugs (such as metoprolol and nifedipine). CONCLUSIONS There is a high rate of ACB drugs use in geriatric patients, and the clinical focus should be on multiple medication prescriptions, especially on the central nervous system drugs (such as alprazolam and eszopiclone) and cardiovascular system drugs (such as metoprolol and nifedipine). The prescription review should be emphasized to reduce adverse reactions to anticholinergic drugs in elderly patients.
Humans ; Aged ; Cholinergic Antagonists/adverse effects* ; Outpatients ; Metoprolol ; Alprazolam ; Eszopiclone ; Nifedipine ; Sleep Initiation and Maintenance Disorders ; Risk Factors

OBJECTIVE: To analyze the disease spectrums underlying orthostatic intolerance (OI) and sitting intolerance (SI) in Chinese children, and to understand the clinical empirical treatment options. METHODS: The medical records including history, physical examination, laboratory examination, and imagological examination of children were retrospectively studied in Peking University First Hospital from 2012 to 2021. All the children who met the diagnostic criteria of OI and SI were enrolled in the study. The disease spectrums underlying OI and SI and treatment options during the last 10 years were analyzed. RESULTS: A total of 2 110 cases of OI and SI patients were collected in the last 10 years, including 943 males (44.69%) and 1 167 females (55.31%) aged 4－18 years, with an average of (11.34±2.84) years. The overall case number was in an increasing trend over the year. In the OI spectrum, postural tachycardia syndrome (POTS) accounted for 826 cases (39.15%), followed by vasovagal syncope (VVS) (634 cases, 30.05%). The highest proportion of SI spectrum was sitting tachycardia (STS) (8 cases, 0.38%), followed by sitting hypertension (SHT) (2 cases, 0.09%). The most common comorbidity of OI and SI was POTS coexisting with STS (36 cases, 1.71%). The highest proportion of treatment options was autonomic nerve function exercise (757 cases, 35.88%), followed by oral rehydration salts (ORS) (687 cases, 32.56%), metoprolol (307 cases, 14.55%), midodrine (142 cases, 6.73%), ORS plus metoprolol (138 cases, 6.54%), and ORS plus midodrine (79 cases, 3.74%). The patients with POTS coexisting with VVS were more likely to receive pharmacological intervention than the patients with POTS and the patients with VVS (41.95% vs. 30.51% vs. 28.08%, χ²= 20.319, P < 0.01), but there was no significant difference in the proportion of treatment options between the patients with POTS and the patients with VVS. CONCLUSION POTS and VVS in children are the main underlying diseases of OI, while SI is a new disease discovered recently. The number of children with OI and SI showed an increasing trend. The main treatment methods are autonomic nerve function exercise and ORS. Children with VVS coexisting with POTS were more likely to take pharmacological treatments than those with VVS or POTS only.
Child ; Electrolytes ; Female ; Humans ; Male ; Metoprolol ; Midodrine ; Orthostatic Intolerance/therapy* ; Postural Orthostatic Tachycardia Syndrome/diagnosis* ; Retrospective Studies ; Salts ; Sitting Position ; Syncope, Vasovagal/diagnosis* ; Tilt-Table Test

We examined the expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNAs upon isoproterenol (Iso)-induced cardiac hypertrophy in rats. Then, we tried to investigate the effects of sympatholytics to see if they can modulate the expression of ANP and BNP. In this study, RT-PCR technique was used to characterize the expression of ANP and BNP in right atrium (RA) and left ventricle (LV) of the hypertrophied rat heart. Histologic findings indicated that stimulation of beta-adrenoceptors with Iso for 5 days was sufficient to induce cardiac hypertrophy in rats. A continuous stimulation with Iso for 7 days resulted in an increase of the ANP and BNP expression in the LV and BNP expression in the RA. The increased expressions of ANP and BNP in the LV were slightly inhibited, and the increased expressions of BNP in the RA were markedly inhibited by a continuous treatment with propranolol, metoprolol, and clonidine for 7 days. Overall, our data present a differential expression of the natriuretic peptides in Iso-induced cardiac hypertrophy, and that the mechanisms involved in this differential ANP and BNP gene expression could be mediated via sympathetic nervous system.
Animals ; Atrial Natriuretic Factor ; Cardiomegaly* ; Clonidine ; Gene Expression ; Heart ; Heart Atria ; Heart Ventricles ; Isoproterenol ; Metoprolol ; Natriuretic Peptide, Brain ; Natriuretic Peptides ; Propranolol ; Rats* ; RNA, Messenger* ; Sympathetic Nervous System ; Sympatholytics

INTRODUCTION: An  aorto-enteric  fistula  is  a  fistulous communication  between  the  duodenum  and  the  aorta. The  non-traumatic  form,  or  primary  aorto-enteric  fistula (PAEF), is rare and fatal if untreated.  This is a case of PAEF in a Filipino patient who presented with upper gastrointestinal bleeding (UGIB).
CLINICAL PRESENTATION: A  62-year-old  Filipino  sought consult  for  hematemesis  and  melena.  He  had  just  been discharged the previous day and sent home on empiric H. pylori eradication therapy after a week of workup, which included an unremarkable esophagogastroduodenoscopy (EGD). He claimed to be hypertensive but was not taking any maintenance anti-hypertensive medication.
PHYSICAL FINDINGS: Blood  pressure  was  80/50  mmHg,and  cardiac  rate  of  94  bpm.  He  had  pale  palpebral  conjunctivae,  and  pale  nailbeds.Abdominal  exam  was  unremarkable.  Rest  of  physical  exam  was  normal.  Stat hemoglobin was 63 g/dL.
RESULTS: Exploratory  laparotomy  revealed  the  primary aortoduodenal  fistula  at  the  anterolateral  aspect  of  the fourth  segment  of  the  duodenum  (PADF).  Patient  was  started  on  metoprolol  and  atorvastatin.  Axillary  femoro-femoral  bypass,  ligation  of  aorta,  wedge  resection  of  aortoduodenal fistula, duodenorrhaphy, tube jejunostomy completed  was  done.  Post-operative  course  was  complicated by peritonitis and sepsis, and eventually went into arrest on his third week.
SIGNIFICANCE: This is the first case of PAEF in our institution,and possibly in the country. It is an extremely rare condition that has an annual incidence of 0.007 per million. Since its description in 1843, only 250 cases have been reported in literature.
RECOMMENDATIONS: A  high  index  of  suspicion  is  key  to  its diagnosis  and  management.Massive  UGIB,  a  negative  endoscopy, and known aortic aneurysm should raise the suspicion  for  PAEF,  as  prompt  surgical  intervention  is  the only chance for survival among these patients.

Human ; Male ; Middle Aged ; Melena ; Metoprolol ; Hematemesis ; Atorvastatin Calcium ; Aortic Aneurysm ; Duodenal Diseases ; Intestinal Fistula ; Aortic Diseases ; Aorta ; Peritonitis ; Sepsis ; Duodenum ; Hemoglobins