piperidines and Bradycardia

Remifentanil is a selective mu-opioid receptor agonist characterized by a rapid onset and ultrashort predictable duration of action providing intense analgesia without prolonged respiratory depression. Remifentanil has been implicated in the causation of intraoperative bradyarrhythmias and asystole both in adults and in pediatric patients. Electrophysiological studies in humans and animals show that remifentanil provokes a dose-dependent depressor effect on sinus and AV node function, manifested by a significant prolongation of sinus node recovery time, sino-atrial conduction time and Wenckebach cycle length. These electrophysiologic effects of remifentanil suggest that it should be used with attention in vulnerable patients with predisposition to bradiarritmias during anesthesia.

Topics: Analgesics, Opioid; Animals; Atrioventricular Node; Bradycardia; Electrophysiological Phenomena; Heart Conduction System; Heart Rate; Humans; Piperidines; Receptors, Opioid, mu; Remifentanil; Sinoatrial Node; Treatment Outcome

The 'second-generation' cholinesterase inhibitors (ChEIs), donepezil, galantamine and rivastigmine, are a class of medications that are currently approved for the treatment of mild-to-moderate Alzheimer's disease (AD). These medications have proven efficacy in improving cognition, behaviour, activities of daily living, and global functioning in mild-to-moderate AD. They have also been shown to reduce caregiver stress and to delay time to nursing home placement. Two separate meta-analyses have indicated that ChEIs confer a modest but significant therapeutic benefit in the treatment of AD, despite higher rates of treatment discontinuation and side effects than placebo. There is growing evidence to support their efficacy in treating moderate-to-severe AD. ChEIs are generally well-tolerated, with side effects that tend to be dose-related and are most problematic during dose titration. The most common adverse effects, related to cholinergic stimulation in the brain and peripheral tissues, include gastrointestinal, cardiorespiratory, extrapyramidal, genitourinary, and musculoskeletal symptoms, as well as sleep disturbances. Few clinically significant drug-drug interactions with ChEIs have been identified. Three head-to-head trials of ChEIs in the treatment of AD have been published to date, but are limited due to their open-label design, rates of titration, and the drug dosage levels utilised. Further study is needed to examine other indications for ChEIs, as well as their combination with newer treatments, such as memantine.

Topics: Aged; Alzheimer Disease; Animals; Basal Ganglia Diseases; Bradycardia; Central Nervous System Diseases; Cholinesterase Inhibitors; Clinical Trials as Topic; Comorbidity; Donepezil; Double-Blind Method; Drug Evaluation; Drug Interactions; Female; Galantamine; Gastrointestinal Diseases; Humans; Indans; Institutionalization; Longitudinal Studies; Male; Memantine; Meta-Analysis as Topic; Mice; Middle Aged; Nootropic Agents; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Single-Blind Method; Sleep Wake Disorders; Treatment Outcome

Drugs can cause cardiac arrhythmias in a number of clinical situations, and many of the implicated agents are used to treat non-cardiac conditions. These adverse effects are frequently idiosyncratic, but are often mediated via triggered activity causing torsade de pointes. Drugs being used for treatment of cardiac conditions may promote arrhythmias by re-entrant mechanisms or via triggered activity. Many drugs may cause cardiac arrhythmic complications when taken in excessive amounts. Keys to reducing the incidence of drug-induced cardiac arrhythmias include increased awareness among the medical, pharmaceutical and nursing professions of the potential problems in using certain agents, especially in specific situations. Appropriate monitoring when such treatment is essential and, after diagnosis, prompt withdrawal of the offending agent and treatment for the arrhythmia should be initiated.

Topics: Amiodarone; Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Anti-Infective Agents; Arrhythmias, Cardiac; Bradycardia; Cisapride; Digitalis Glycosides; Electrocardiography; Gastrointestinal Agents; Histamine H1 Antagonists; Humans; Incidence; Piperidines; Sotalol; Tachycardia, Ventricular; Torsades de Pointes

Alectinib, a central nervous system (CNS)-active ALK inhibitor, has demonstrated efficacy and safety in ALK+ non-small-cell lung cancer that has progressed following crizotinib treatment. Other ALK inhibitors have shown concentration-dependent QTc prolongation and treatment-related bradycardia. Therefore, this analysis evaluated alectinib safety in terms of electrophysiologic parameters.. Intensive triplicate centrally read electrocardiogram (ECG) and matched pharmacokinetic data were collected across two alectinib single-arm trials. Analysis of QTcF included central tendency analysis [mean changes from baseline with one-sided upper 95% confidence intervals (CIs)], categorical analyses, and relationship between change in QTcF and alectinib plasma concentrations. Alectinib effects on other ECG parameters (heart rate, PR interval and QRS duration) were also evaluated.. Alectinib did not cause a clinically relevant change in QTcF. The maximum mean QTcF change from baseline was 5.3 ms observed pre-dose at week 2. The upper one-sided 95% CI was <10 ms at all time points. There was no relevant relationship between change in QTcF and alectinib plasma concentrations. Alectinib treatment resulted in a generally asymptomatic exposure-dependent decrease in mean heart rate of ~11 to 13 beats per minute at week 2. No clinically relevant effects were seen on other ECG parameters. Approximately 5% of patients reported cardiac adverse events of bradycardia or sinus bradycardia; however, these were all grade 1-2.. Alectinib does not prolong the QTc interval or cause changes in cardiac function to a clinically relevant extent, with the exception of a decrease in heart rate which was generally asymptomatic.

Topics: Algorithms; Anaplastic Lymphoma Kinase; Bradycardia; Carbazoles; Carcinoma, Non-Small-Cell Lung; Dose-Response Relationship, Drug; Electrocardiography; Heart Function Tests; Heart Rate; Humans; Long QT Syndrome; Lung Neoplasms; Monitoring, Physiologic; Piperidines; Receptor Protein-Tyrosine Kinases

Successful external cephalic version (ECV) for breech presenting fetus reduces the need for Caesarean section (CS). We aimed to compare the success rate of ECV with either spinal anaesthesia (SA) or i.v. analgesia using remifentanil.. In a double-phased, stratified randomized blinded controlled study we compared the success rates of ECV, performed under spinal anaesthesia (SA), i.v. analgesia (IVA) using remifentanil or no anaesthetic interventions. In phase I, 189 patients were stratified by parity before randomization to ECV, performed by blinded operators, under SA using either hyperbaric bupivacaine 9 mg with fentanyl 15 µg, i.v. remifentanil infusion 0.1 µg kg min(-1), or Control (no anaesthetic intervention). Operators performing ECV were blinded to the treatment allocation. In phase 2, patients in the Control group in whom the initial ECV failed were further randomized to receive either SA (n=9) or IVA (n=9) for a re-attempt. The primary outcome was the incidence of successful ECV.. The success rate in Phase 1 was greatest using SA [52/63 (83%)], compared with IVA [40/63 (64%)] and Control [40/63 (64%)], (P=0.027). Median [IQR] pain scores on a visual analogue scale (range 0-100), were 0 [0-0] with SA, 35 [0-60] with IVA and 50 [30-75] in the Control group (P<0.001). Median [IQR] VAS sedation scores were highest with IVA [75 (50-80)], followed by SA, [0 (0-50)] and Control [0 (0-0)]. In phase 2, 7/9 (78%) of ECV re-attempts were successful with SA, whereas all re-attempts using IVA failed (P=0.0007). The incidence of fetal bradycardia necessitating emergency CS within 30 min, was similar among groups; 1.6% (1/63) in the SA and IVA groups and 3.2% (2/63) in the Control group.. SA increased the success rate and reduced pain for both primary and re-attempts of ECV, whereas IVA using remifentanil infusion only reduced the pain. There was no significant increase in the incidence of fetal bradycardia or emergency CS, with ECV performed under anaesthetic interventions. Relaxation of the abdominal muscles from SA appears to underlie the improved outcomes for ECV.

Topics: Adult; Anesthesia, Obstetrical; Anesthesia, Spinal; Anesthetics, Intravenous; Anesthetics, Local; Bradycardia; Breech Presentation; Bupivacaine; Cesarean Section; Female; Fentanyl; Heart Rate, Fetal; Humans; Infant, Newborn; Pain Measurement; Piperidines; Pregnancy; Remifentanil; Version, Fetal

Breech presentation occurs in up to 3% of pregnancies at term and may be an indication for caesarean delivery. External cephalic version can be effective in repositioning the fetus in a cephalic presentation, but may be painful for the mother. Our aim was to assess the efficacy of remifentanil versus placebo for pain relief during external cephalic version.. A randomized, double-blind, controlled trial that included women at 36-41 weeks of gestation with non-cephalic presentations was performed. Women were randomized to receive either a remifentanil infusion at 0.1 μg/kg/min and demand boluses of 0.1 μg/kg, or saline placebo. The primary outcome was the numerical rating pain score (0-10) after external cephalic version.. Sixty women were recruited, 29 in the control group and 31 in the remifentanil group. There were significant differences in pain scores at the end of the procedure (control 6.5 ± 2.4 vs. remifentanil 4.7 ± 2.5, P = 0.005) but not 10 min later (P = 0.054). The overall success rate for external cephalic version was 49% with no significant differences between groups (remifentanil group 54.8% vs. control group 41.3%, P = 0.358). In the remifentanil group, there was one case of nausea and vomiting, one of drowsiness and three cases of fetal bradycardia. In the control group, there were three cases of nausea and vomiting, one of dizziness and nine cases of fetal bradycardia.. Intravenous remifentanil with bolus doses on demand during external cephalic version achieved a reduction in pain and increased maternal satisfaction. There were no additional adverse effects, and no difference in the success rate of external cephalic version or the incidence of fetal bradycardia.

Topics: Adult; Analgesia; Analgesics, Opioid; Bradycardia; Breech Presentation; Dizziness; Double-Blind Method; Female; Fetal Diseases; Humans; Nausea; Pain; Pain Management; Patient Satisfaction; Piperidines; Placebos; Pregnancy; Remifentanil; Treatment Outcome; Version, Fetal; Vomiting

Remifentanil is an ultrashort-acting synthetic opioid, and the metabolism of which is not influenced by hepatic or renal function. This study aims to compare the efficacy of two remifentanil doses during procedures in ventilated preterm infants.. Prospective, randomized, double-blind, noninferiority trial.. Neonatal ICU.. Preterm infants who were supported by a mechanical ventilator with tracheal tube and requiring central venous access.. Two remifentanil dosages were administered in mechanically ventilated preterm infants during peripherally inserted central catheter insertion. Fourteen preterm infants were randomly assigned to low-dose (0.1 μg/kg/min) or high-dose (0.25 μg/kg/min) remifentanil infusion. The Premature Infant Pain Profile was used to score pain during the procedure, and changes in the Premature Infant Pain Profile score between needle puncture and baseline were analyzed to investigate the noninferiority of low-dose to high-dose remifentanil. Occurrence of cardiorespiratory complications was also recorded.. The median gestational age (minimum, maximum) was 26 weeks (24, 31), and the median birth weight was 825 g (610, 1,280). Changes in Premature Infant Pain Profile in the high-dose and low-dose groups were 1.43 ± 3.10 and -0.60 ± 5.32, respectively. The difference in changes in the Premature Infant Pain Profile score between the high-dose and low-dose groups was -2.03 ± 4.13. The corresponding lower limit of one-tailed 97.5% CI was -7.24, below the noninferiority margin. Apneic events and bradycardia did not occur in the low-dose group; however, there were three episodes of apnea (42.9%) and one of bradycardia (14.3%) in the high-dose group (p = 0.683 and 0.366, respectively).. For mechanically ventilated preterm infants, the use of remifentanil at 0.25 μg/kg/min as an analgesic for short procedures represents a therapeutic option. Our pilot study suggests the need for larger randomized trials.

Topics: Analgesics, Opioid; Apnea; Birth Weight; Bradycardia; Catheterization, Central Venous; Double-Blind Method; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Male; Pain; Pain Measurement; Piperidines; Prospective Studies; Remifentanil; Respiration, Artificial

Maintaining blood pressure (BP) and heart rate (HR) after laryngoscopy and tracheal intubation has always been a concern in injured patients. Opioids can attenuate or stop an increase in these two parameters if administered with proper doses or targets in target-controlled infusion (TCI). Remifentanil and sufentanil are widely used for this purpose because their cardiac side effects are low and, especially in traumatic patients, they are tolerated well. A comparison of the benefits and limitations of these two opioids in TCI is much needed. A literature review in electronic data bases revealed few results.. 40 normotensive patients were enrolled to this randomized clinical trial study. After BIS guided anesthesia with a target-controlled propofol infusion and muscle relaxation with cisatracurium, remifentanil and sufentanil were infused using TCI with 2 and 0.2 ng.ml-1 targets respectively. BP and HR were recorded for five data points and compared with Fischer's exact test.. Systolic, mean and diastolic arterial pressure and HR in different points of the study remained below baseline values but were out of control in some cases, however the out-of-control values showed significant difference between the two groups only for heart rate changes. The relative risk for producing out-of-control changes with remifentanil compared to sufentanil is significantly more than 1 for HR decrease.. Sufentanil produced more common pre-intubation hypotension than remifentanil in propofol anesthetized patients but this hypotension disappeared sooner than remifentanil after tracheal intubation. Both opioids prevent an increase in BP and HR after tracheal intubation but the side effects (hypotension and bradycardia) may be a cause for concern (IRCT138710011361N3).

Topics: Adult; Anesthesia; Anesthetics, Intravenous; Blood Pressure; Bradycardia; Dose-Response Relationship, Drug; Drug Monitoring; Female; Heart Rate; Humans; Hypotension; Intraoperative Complications; Intubation, Intratracheal; Male; Middle Aged; Outcome Assessment, Health Care; Piperidines; Remifentanil; Sufentanil; Wounds and Injuries

We randomly allocated 80 patients to intravenous dexmedetomidine (0.25, 0.5, or 1 μg.kg(-1) ) or placebo 15 min before anaesthetic induction. Dexmedetomidine 0.5 and 1.0 μg.kg(-1) significantly reduced the mean (95% CI) propofol effect-site concentrations by 0.83 (0.63-1.03) μg.ml(-1) , p = 0.001 and 1.29 (1.12-1.46) μg.ml(-1) , p = 0.0003 at intubation, by 1.05 (0.85-1.25 μg.ml(-1) , p = 0.0006 and 1.33 (1.15-1.51) μg.ml(-1) , p = 0.0002 when surgery started, and by 0.59 (0.39-0.79) μg.ml(-1) , p = 0.030 and 0.72 (0.57-0.87) μg.ml(-1) , p = 0.004 on completion of surgery, respectively. Patients' tracheas were extubated sooner after 0.5 and 1.0 μg.kg(-1) dexmedetomidine, by 5.36 (2.39-8.32) min, p = 0.009 and 7.37 (3.24-11.51) min p = 0.003, respectively. Tachycardic responses to intubation were present in five placebo patients and no dexmedetomidine patients. Bradycardia was treated after dexmedetomidine in six patients: five after 1.0 μg.kg(-1) ; and one after 0.25 μg.kg(-1) . Single-dose dexmedetomidine can reduce anaesthetic requirements, with both desirable and undesirable haemodynamic effects.

Topics: Adult; Analgesics, Opioid; Anesthesia; Anesthesia, General; Anesthesia, Intravenous; Bradycardia; Dexmedetomidine; Dose-Response Relationship, Drug; Female; Hemodynamics; Humans; Hypnotics and Sedatives; Infusions, Intravenous; Laryngoscopy; Male; Middle Aged; Monitoring, Intraoperative; Nerve Block; Piperidines; Propofol; Remifentanil; Sample Size; Tachycardia; Young Adult

This trial aimed to compare the maternal and neonatal effects of remifentanil given by patient-controlled analgesia (PCA) or continuous infusion for labour analgesia. Patient controlled analgesia was administered using increasing stepwise boluses from 0.1 to 0.4 μg.kg(-1) (0.1 μg.kg(-1) increment, 2 min lockout, n = 30). Continuous infusion used rates from 0.05 to 0.2 μg.kg(-1) .min(-1) (0.05 μg.kg(-1) .min(-1) increment, n = 30). Dose increments were given on request. Women reported lowest pain scores (median (IQR [range]) of 3 (2-4 [2-5]) for PCA and 4 (3-5.25 [3-7]) for continuous infusion (p = 0.004) at 60 min after the beginning of analgesia. The mean (SD) remifentanil umbilical vein/maternal artery ratio in the PCA and infusion groups were 0.74 (0.45) vs 0.70 (0.52), respectively (p = 0.776). The mean (SD) umbilical artery/umbilical vein ratios were 0.31 (0.12) vs 0.26 (0.07), respectively (p = 0.088). Maternal and neonatal adverse reactions of remifentanil were similar between the two groups. The total remifentanil consumption (median (IQR [range]) during PCA administration was lower than continuous infusion, 1.34 (1.22-1.48 [0.89-1.69]) mg vs 1.49 (1.35-1.61 [1.12-1.70] mg; p = 0.011). The results suggest that remifentanil PCA provides better pain relief and similar placental transfer compared with continuous infusion.

Topics: Adult; Analgesia, Obstetrical; Analgesia, Patient-Controlled; Analgesics, Opioid; Analysis of Variance; Blood Pressure; Bradycardia; Double-Blind Method; Female; Fetal Heart; Heart Rate; Humans; Infusions, Intravenous; Maternal-Fetal Exchange; Nausea; Pain Measurement; Patient Satisfaction; Piperidines; Pregnancy; Prospective Studies; Pruritus; Remifentanil; Treatment Outcome; Young Adult

Eighty patients undergoing elective ear-nose-throat surgery were enrolled in the present study to investigate the relationship between surgical pleth index (SPI) and stress hormones (ACTH, cortisol, epinephrine, norepinephrine) during general anaesthesia which was induced and maintained with propofol and remifentanil using a target-controlled infusion. The study concluded that the SPI had moderate correlation to the stress hormones during general anaesthesia, but no correlation during consciousness. Furthermore, SPI values were able to predict ACTH values with high sensitivity and specificity.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Aged; Anesthesia, Intravenous; Anesthetics, Intravenous; Arterial Pressure; Bradycardia; Consciousness; Epinephrine; Female; Heart Rate; Humans; Hydrocortisone; Male; Middle Aged; Norepinephrine; Otorhinolaryngologic Diseases; Piperidines; Propofol; Prospective Studies; Reference Values; Remifentanil; ROC Curve; Sensitivity and Specificity; Single-Blind Method; Statistics as Topic; Statistics, Nonparametric; Stress, Physiological; Young Adult

This study was conducted to examine whether pretreatment with intravenous atropine could prevent bradycardia and hypotension during induction of total intravenous anesthesia with propofol and remifentanil in a prospective randomized placebo-controlled manner. Seventy patients, aged 24-78 years, were randomly divided into two groups, and received 0.5 mg atropine or placebo saline 1 min before induction of intravenous anesthesia with remifentanil at 0.4 microg/kg/min, propofol at a target blood concentration of 3 microg/ml, and vecuronium 1.5 mg/kg. Immediately after tracheal intubation, the infusion rate of remfentanil and the target concentration of propofol were reduced to and kept at 0.1 microg/kg/min and 2 microg/ml, respectively, for 10 min. Noninvasive blood pressure (BP) and heartrate (HR) were measured and recorded every minute. Intravenous atropine could prevent a fall in HR, but not a fall in BP, during induction of intravenous anesthesia with propofol and remifentanil of our dosing regimen. Our data suggested that a fall in HR induced by propofol-remifentanil anesthesia was mainly caused by centrally mediated sympatholytic and/or vagotonic actions of propofol and remifentanil, whereas a fall in BP was mainly the result of their direct vasodilating actions.

Topics: Adult; Aged; Anesthesia, Intravenous; Anesthetics, Intravenous; Atropine; Bradycardia; Female; Humans; Hypotension; Male; Middle Aged; Parasympatholytics; Piperidines; Propofol; Prospective Studies; Remifentanil; Treatment Outcome; Young Adult

Succinylcholine is a popular muscle relaxant and one of its most common side effects is muscle fasciculation. The purpose of this study was to evaluate the efficacy of remifentanil in preventing succinylcholine-induced fasciculation in patients undergoing general anesthesia.. In aprospective, double blind study, 60 ASA I & II patients were randomly assigned into two groups (30 each) to receive either remifentanil 1 microg/kg (Group R), or saline 3 ml (Group S) as a pretreatment agent, one minute before induction of general anesthesia by propofol, fentanyl, and 1.5 mg/kg succinylcholine. The duration and the intensity of fasciculation were assessed using a four-point rating scale. Data were analyzed by Mann-Whitney U-test, Fisher exact test and Student-t-test using SPSS software.. In the remifentanil group the duration (p < 0.001) and the intensity (p < 0.001) of fasciculation were lower compared to the saline group. However the incidence of bradycardia was higher in the remifentanil group in comparison to the group which received normal saline.. Our findings indicate that remifentanil can reduce the duration and the intensity of succinylcholine induced fasciculation. However, it induces greater bradycardia.

Topics: Adult; Anesthesia, General; Anesthetics, Combined; Anesthetics, Intravenous; Bradycardia; Double-Blind Method; Fasciculation; Female; Fentanyl; Humans; Male; Middle Aged; Neuromuscular Depolarizing Agents; Piperidines; Propofol; Prospective Studies; Remifentanil; Severity of Illness Index; Statistics, Nonparametric; Succinylcholine; Young Adult

In neuroanesthesia practice, muscle relaxants may at times need to be avoided to facilitate intraoperative motor pathway monitoring. Our study's objective was to determine the optimal dose of remifentanil required to prevent movement after neurosurgical stimulation.. After Institutional Review Board approval and written informed consent, 132 patients undergoing elective craniotomy randomly received one of 12 remifentanil dose regimens (0.10 to 0.21 microg/kg/min). Remifentanil was started before induction with propofol and succinylcholine. Anesthesia was maintained with isoflurane (0.6% end-tidal) in air/oxygen. During the study, movement was assessed on predetermined criteria by the anesthesiology, nursing, and neurosurgical teams. Heart rate and blood pressure were recorded every 5 minutes. We assessed the relationship between movement, hypotension, bradycardia, and dose using probit analysis and logistic regression.. Sixty-five percent of the patients moved in response to surgical stimuli [95% confidence interval (CI): 49%-79%] at a remifentanil infusion rate of 0.10 microg/kg/min, and movement decreased to 21% (95% CI: 11-35) at 0.21 microg/kg/min. The probability of movement was 50% at an infusion rate (95% CI) of 0.13 (0.10 to 0.15) microg/kg/min remifentanil and decreased to 25% at an infusion rate of 0.19 (0.17 to 0.29) microg/kg/min. The probability of hypotension and bradycardia was 50% at 0.13 (0.10 to 0.15) microg/kg/min and 0.17 (0.15 to 0.21) microg/kg/min, respectively.. Higher doses of remifentanil lessen the risk of movement in the absence of muscle relaxants with surgical stimulation for elective craniotomy. Hypotension and bradycardia were common at higher doses. Even at the maximum dose (0.21 mcg/kg/min) there was a 20% chance of movement. Adjunctive therapy is needed to ablate movement reliably, and to counteract the hypotensive effect of remifentanil. These findings may be helpful for clinicians administering remifentanil and isoflurane during procedures, where muscle relaxants may not be desirable.

Topics: Adult; Anesthesia, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Blood Pressure; Bradycardia; Brain Neoplasms; Craniotomy; Dose-Response Relationship, Drug; Double-Blind Method; Female; Heart Rate; Humans; Hypotension; Intraoperative Complications; Intraoperative Period; Intubation, Intratracheal; Isoflurane; Male; Middle Aged; Movement; Neuromuscular Blockade; Neurosurgical Procedures; Piperidines; Prospective Studies; Remifentanil

We evaluated the use of continuous infusion of ketamine to reduce intraoperative remifentanil side effects, such as bradycardia and hypotension, and to improve postoperative analgesia from balanced anesthesia with remifentanil.. Forty patients undergoing spine surgery under remifentanil-based anesthesia were randomly assigned to intraoperative ketamine group and saline (control) group. Balanced anesthesia was maintained with infusion of propofol (2-4 mg x kg(-1) x hr(-1)), remifentanil (6-8 microg x kg(-1) hr(-1)) and vecuronium (60-80 microg x kg(-1) x hr(-1)) with nitrous oxide (60%) and with or without ketamine (300-400 microg x kg(-1) x hr(-)). All patients were given scheduled NSAIDs by their own doctor at the end of surgery. Intraoperative bradycardia (HR <50) and hypotension (SBP <80), and postoperative additional NSAIDs request were recorded.. Adverse events, such as bradycardia and hypotension, were less frequent in the ketamine group (P < 0.05). Less additional NSAIDs was required in the ketamine than in the control group (P < 0.05). Emergence time from anesthesia was within 5 min in both groups.. Remifentanil-based anesthesia with continuous ketamine decreases intraoperative side effects and postoperative NSAIDs request. Thus, intraoperative continuous ketamine may be a useful adjuvant to remifentanil.

Topics: Adjuvants, Anesthesia; Adult; Anesthesia, General; Anti-Inflammatory Agents, Non-Steroidal; Bradycardia; Humans; Hypotension; Infusions, Intravenous; Intraoperative Complications; Ketamine; Middle Aged; Pain, Postoperative; Piperidines; Remifentanil; Spine

A randomized and prospective study was performed to compare anaesthetic characteristics and stress hormone responses of two anaesthetic techniques.. Forty-two patients undergoing day case excisional biopsy of breast mass were randomly assigned to receive propofol-remifentanil or sevoflurane-N2O. Anaesthesia was induced and maintained either with sevoflurane and 50% N2O in oxygen or with target-controlled remifentanil and propofol in 50% oxygen and air. Anaesthetic depth was monitored by the bispectral index.. The times for induction (2.9 vs. 1.7 min) and for laryngeal mask insertion (5.7 vs. 3.3 min) were longer in the sevoflurane-N2O group than in the propofol-remifentanil group. However, apnoea (57.1% vs. 9.5%) and bradycardia (23.8% vs. 0%) were more prevalent with propofol-remifentanil. In the sevoflurane-N2O group, the emergence times to a verbal response (10.6 vs. 3.7 min), to extubation (11.8 vs. 4.0 min) and to orientation (14.7 vs. 4.8 min) were longer than in the propofol-remifentanil group. There were significantly more nausea (38.1% vs. 4.8%) and vomiting (19.2% vs. 0%) in the sevoflurane-N2O group than in the propofol-remifentanil group. The time to discharge was similar although there was less postoperative pain in the sevoflurane-N2O group. There were no differences in the perioperative cortisol responses in the two groups.. Smoother induction of anaesthesia was seen with sevoflurane-N2O. Propofol-remifentanil showed a quicker emergence with less nausea/vomiting. There were similar perioperative cortisol responses in the two anaesthetic techniques.

Topics: Adult; Ambulatory Surgical Procedures; Anesthesia Recovery Period; Anesthesia, General; Anesthetics, Intravenous; Apnea; Biopsy; Bradycardia; Breast; Electroencephalography; Female; Humans; Hydrocortisone; Methyl Ethers; Nitrous Oxide; Piperidines; Propofol; Prospective Studies; Remifentanil; Sevoflurane; Time Factors

Remifentanil is recommended for use in procedures with painful intraoperative stimuli but minimal postoperative pain. However, bradycardia and hypotension are known side-effects. We evaluated haemodynamic effects of i.v. glycopyrrolate during remifentanil-sevoflurane anaesthesia for cardiac catheterization of children with congenital heart disease.. Forty-five children undergoing general anaesthesia with remifentanil and sevoflurane were randomly allocated to receive either saline, glycopyrrolate 6 microg kg(-1) or glycopyrrolate 12 microg kg(-1). After induction of anaesthesia with sevoflurane, i.v. placebo or glycopyrrolate was administered. An infusion of remifentanil at the rate of 0.15 microg kg(-1) min(-1) was started, sevoflurane continued at 0.6 MAC and cisatracurium 0.2 mg kg(-1) was given. Heart rate (HR) and non-invasive arterial pressures were monitored and noted every minute for the first 10 min and then every 2.5 min for subsequent maximum of 45 min.. Baseline HR [mean (SD)] of 117 (20) beats min(-1) decreased significantly from 12.5 min onwards after starting the remifentanil infusion in the control group [106 (18) at 12.5 min and 99 (16) beats min(-1) at 45 min]. In the groups receiving glycopyrrolate, no significant decrease in HR was noticed. Glycopyrrolate at 12 microg kg(-1) induced tachycardia between 5 and 9 min after administration. Systolic and diastolic arterial pressures decreased gradually, but there were no significant differences in the pressures between groups.. I.V. glycopyrrolate 6 microg kg(-1) prevents bradycardia during general anaesthesia with remifentanil and sevoflurane for cardiac catheterization in children with congenital heart disease. Administering 12 microg kg(-1) of glycopyrrolate temporarily induces tachycardia and offers no additional advantage.

Topics: Adjuvants, Anesthesia; Anesthetics, Combined; Blood Pressure; Bradycardia; Cardiac Catheterization; Child, Preschool; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glycopyrrolate; Heart Defects, Congenital; Heart Rate; Humans; Infant; Intraoperative Care; Intraoperative Complications; Male; Methyl Ethers; Piperidines; Prospective Studies; Remifentanil; Sevoflurane

We compared the hemodynamic effects of a bolus administration of 1 microg/kg remifentanil for 1, 3, and 5 min (1, 0.33, and 0.2 microg. kg(-1). min(-1), respectively) in patients scheduled for coronary artery bypass grafting anesthetized with small-dose propofol. The study was terminated after only eight patients had been enrolled (three received remifentanil at a rate of 1.0 microg. kg(-1). min(-1), two at 0.33 microg. kg(-1). min(-1), and three at 0.2 microg. kg(-1). min(-1)) because of severe hemodynamic instability, which was particularly marked in four patients and consisted of severe bradycardia in one patient and severe hypotension with a reduction in systemic vascular resistance in three others. One patient showed evidence of myocardial ischemia. All patients responded to therapeutic interventions. The results show that remifentanil should be given only by slow infusion to such patients.. This study investigates the effect on the heart and blood vessels of various rates of administration of boluses of a relatively new potent opiate, remifentanil, to patients with coronary artery disease. The results show that remifentanil should be given only by slow infusion to such patients.

Topics: Anesthetics, Intravenous; Bradycardia; Coronary Artery Bypass; Depression, Chemical; Hemodynamics; Humans; Hypotension; Piperidines; Remifentanil

The single-dose effects of the cytochrome P-450 inhibitors erythromycin and ketoconazole on the steady-state pharmacokinetics and electrocardiographic repolarization pharmacodynamics of intranasal levocabastine, a potent and selective H1-receptor antagonist, were evaluated in healthy young male subjects. Two randomized, open-label, placebo-controlled, two-way crossover studies were performed. Levocabastine nasal spray was administered as two sprays per nostril (0.05 mg/spray) twice daily (for a total daily dose of 0.4 mg) for 6 days. On Day 7, a single dose of 0.2 mg was administered followed immediately by a single dose of either oral placebo, erythromycin 333 mg, or ketoconazole 200 mg. In all treatment groups, levocabastine was rapidly absorbed, with peak plasma concentrations reached at approximately 3 hours in the erythromycin study and 2.8 hours in the ketoconazole study. The mean terminal half-life was approximately 45 and 44 hours, respectively. In both studies, mean steady-state plasma concentrations and pharmacokinetics of levocabastine following the single doses of erythromycin or ketoconazole were not significantly different from corresponding values seen with the concomitant administration of the placebo. No clinically significant mean changes from baseline in QT or QTc (QT corrected for heart rate) intervals occurred in any of the treatment groups, and none of the subjects in either study experienced abnormally prolonged QTc intervals. Intranasal levocabastine was well tolerated, with no difference in the incidence of adverse events between treatment groups in either study; adverse events were generally mild in severity. Since levocabastine undergoes only minimal hepatic metabolism and is not a substrate for or an inhibitor of cytochrome P-450, the likelihood of systemic drug interactions with drugs affecting the cytochrome P-450 system is minimal.

Topics: Administration, Intranasal; Adolescent; Adult; Anti-Bacterial Agents; Anti-Infective Agents; Area Under Curve; Biological Availability; Bradycardia; Cross-Over Studies; Drug Interactions; Electrocardiography; Erythromycin; Headache; Heart Block; Histamine H1 Antagonists; Humans; Ketoconazole; Male; Middle Aged; Piperidines; Rhinitis; Time Factors; Virus Diseases

The objectives of this phase I study were to evaluate the toxic effects and the maximum tolerated dose (MTD) of S9788, a new modifier of multidrug resistance (MDR), when given alone and in combination with doxorubicin to patients with advanced solid tumors; to achieve a potentially active plasma concentration of S9788; and to study the pharmacokinetics of both drugs.. A total of 26 patients (median age 58 years) entered the study. S9788 was given alone as a 30-min infusion at day 1 and in combination with a 50-mg/m2 bolus of doxorubicin at days 8 and 29. Dose levels of S9788 were escalated from 8 to 96 mg/m2 according to the modified Fibonacci scheme. Plasma samples were taken predose as well as during and up to 48 h after the beginning of infusion for S9788 and doxorubicin quantitation. Fractionated urine samples were also collected for up to 24 h for S9788 determination.. The dose-limiting side effects of S9788 consisted of bradycardia, sometimes associated with faintness or dizziness. The MTD of S9788 was 96 mg/m2. No enhancement of doxorubicin toxicity was observed. One partial response (duration 140 days) was observed at 96 mg/m2 in a patient with multiple lung metastases from a refractory urothelial carcinoma. Pharmacokinetic studies were performed in 24 patients. Since the mean apparent elimination half-life of S9788 was 46 +/- 23 h and the last plasma sampling time was 48 h, only model-independent parameters were considered. Plasma levels of S9788 were below the limit of quantitation (4 x 10[-3] microM) before each drug administration. S9788 plasma levels of up to 3.7 microM could be obtained with this administration schedule. The urinary elimination of the unchanged drug was negligible, whatever the collection period. In spite of the large inter- and intraindividual variability, plasma pharmacokinetics of S9788 given as a 30-min i.v. infusion were linear up to 96 mg/m2 and were not modified by doxorubicin administration. Doxorubicin pharmacokinetic parameters did not seem to be influenced by S9788 coadministration.. The dose-limiting toxicity of S9788 consisted of bradycardia or clinical symptoms suggesting a vasovagal impact such as faintness or dizziness. The MTD of S9788 was 96 mg/m2. The pharmacokinetic parameters of doxorubicin in this study were close to those usually described and were not influenced by escalation of the S9788 dose. No pharmacokinetic interaction was observed between S9788 and doxorubicin. The clinical tolerability of the combined treatment is in good agreement with the pharmacokinetic findings, since no enhancement of doxorubicin toxicity was observed.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Bradycardia; Dose-Response Relationship, Drug; Doxorubicin; Drug Interactions; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Middle Aged; Neoplasms; Piperidines; Triazines

Topics: Antipsychotic Agents; Bradycardia; Humans; Piperazines; Piperidines; Schizophrenia

Alectinib is one of the targeted therapies commonly given to patients with advanced non-small cell lung cancer (NSCLC) with mutations in the ALK gene. The most common adverse effects of alectinib are fatigue, constipation, edema, myalgia and anemia. Meanwhile, bradycardia was reported as a very common adverse effect, but generally asymptomatic, unlike the reported patient in this case report. This case report's purpose is to increase awareness of the possibility of adverse effects due to alectinib administration that require immediate intervention in order to improve the quality of life and patient survival, especially in patients with advanced NSCLC.

Topics: Anaplastic Lymphoma Kinase; Bradycardia; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Quality of Life; Receptor Protein-Tyrosine Kinases

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Bradycardia; China; Electrocardiography; Humans; Male; Piperidines; Severity of Illness Index; Sinoatrial Node

In vivo stimulation of cardiac vagal neurons induces bradycardia by acetylcholine (ACh) release. As vagal release of ACh may be modulated by autoreceptors (muscarinic M2 ) and heteroreceptors (including serotonin 5-HT1 ), this study has analysed the pharmacological profile of the receptors involved in histamine-induced inhibition of the vagal bradycardic out-flow in pithed rats. For this purpose, 180 male Wistar rats were pithed, artificially ventilated and pre-treated (i.v.) with 1 mg/kg atenolol, followed by i.v. administration of physiological saline (1 ml/kg), histamine (10, 50, 100 and 200 μg/kg) or the selective histamine H1 (2-pyridylethylamine), H2 (dimaprit), H3 (methimepip) and H4 (VUF 8430) receptor agonists (1, 10, 50 and 100 μg/kg each). Under these conditions, electrical stimulation (3, 6 and 9 Hz; 15 ± 3 V and 1 ms) of the vagus nerve resulted in frequency-dependent bradycardic responses, which were (i) unchanged during the infusions of saline, 2-pyridylethylamine, dimaprit or VUF 8430; and (ii) dose-dependently inhibited by histamine or methimepip. Moreover, the inhibition of the bradycardia caused by 50 μg/kg of either histamine or methimepip (which failed to inhibit the bradycardic responses to i.v. bolus injections of acetylcholine; 1-10 μg/kg) was abolished by the H3 receptor antagonist JNJ 10181457 (1 mg/kg, i.v.). In conclusion, our results suggest that histamine-induced inhibition of the vagal bradycardic out-flow in pithed rats is mainly mediated by pre-junctional activation of histamine H3 receptors, as previously demonstrated for the vasopressor sympathetic out-flow and the vasodepressor sensory CGRPergic (calcitonin gene-related peptide) out-flow.

Topics: Animals; Bradycardia; Heart Rate; Histamine; Histamine Agonists; Histamine H3 Antagonists; Imidazoles; Male; Piperidines; Pyridines; Rats; Rats, Wistar; Receptors, Histamine H3; Vagus Nerve

Although the induction of anaesthesia with remifentanil often causes bradycardia, the relationship between the effect-site concentration (Ce) of remifentanil and instantaneous heart rate (HR) has remained unclear. The present study examined the relationship between instantaneous HR and remifentanil Ce at the induction of anaesthesia with and without propofol hypnosis, to facilitate safe management of anaesthesia induction with remifentanil. Instantaneous HR was calculated every 5 s using an electrocardiographic real-time analysis system (MemCalc/Makin2; GMS, Tokyo, Japan). At the beginning of anaesthesia induction, continuous infusion of remifentanil (1 μg min

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Anesthesia; Anesthetics, Intravenous; Blood Pressure; Bradycardia; Electrocardiography; Female; Heart Rate; Humans; Hypnotics and Sedatives; Male; Middle Aged; Piperidines; Propofol; Remifentanil; Time Factors

The aim was to evaluate the clinical profile and effectiveness of ECT in women. A retrospective chart review was carried out to identify female patients who had received ECT during the period September 2013-February 2015. Details regarding their sociodemographic, clinical, and treatment data were extracted from these records for the present study. The total number of patients, admitted to our psychiatry inpatient clinic during the survey period, was 802. During this period, 26 (3.24 %) female patients received ECT. Patients who received ECT were mostly in age group of 25-44 years (76.9 %). Twenty percent of patients were in the postpartum period. Psychotic disorders (46.1 %) was the most common diagnosis for which ECT was used, followed by bipolar affective disorder, current episode manic (19.2 %). At the end of ECT courses, 70 % of the patients showed good response with a CGI-I of 1 or 2, and 30 % showed minimal response with a CGI-I score of 3. The most common side effects were post-ECT confusion (15.4 %) and prolonged seizure (11.5 %). This rate of prolonged seizure was higher the rates reported in the literature. The bronchospasm related with remifentanil, post-ECT bradycardia, hypertensive crisis and oligohydramnios were also reported in one case each. ECT is a safe and effective treatment option in women with severe psychiatric disorders and disorders in the perinatal/postpartum period are a major area of ECT use. The female gender may be a contributing factor for the higher rates of prolonged seizure.

Topics: Adult; Aged; Anesthetics, Intravenous; Bipolar Disorder; Bradycardia; Bronchial Spasm; Depression, Postpartum; Depressive Disorder; Electroconvulsive Therapy; Female; Hospitals, Psychiatric; Humans; Hypertension; Middle Aged; Oligohydramnios; Piperidines; Pregnancy; Pregnancy Complications; Psychotic Disorders; Puerperal Disorders; Remifentanil; Retrospective Studies; Treatment Outcome; Turkey; Young Adult

Remifentanil stimulates the parasympathetic nervous system, and patients with increased parasympathetic tone may be at greater risk of bradycardia after its administration. We aimed to establish if adult patients with increased baseline parasympathetic tone were at higher risk of bradycardia and hypotension when given a bolus dose of remifentanil. Seventy adults (age 20-60 years and ASA physical status 1 or 2) were given remifentanil 1 μg.kg(-1) . A Holter ECG monitor was used to assess heart rate changes. Heart rate variability in the frequency domain during the 5 min after remifentanil administration was analysed. Multivariate analysis demonstrated that baseline heart rate was the only independent predictor of remifentanil-induced bradycardia [odds ratio (95% CI) 0.877 (0.796-0.966)]. The vagotonic action of remifentanil does not appear to be related to baseline autonomic tone in adult patients.

Topics: Adult; Anesthetics, Intravenous; Autonomic Nervous System; Blood Pressure; Bradycardia; Electrocardiography, Ambulatory; Female; Heart Rate; Humans; Hypotension; Male; Middle Aged; Piperidines; Remifentanil; Young Adult

A 69-year-old woman undergoing treatment for hypertension and epilepsy was scheduled to undergo cataract surgery. All preoperative examination results were within normal limits. Despite being tense, she walked to the operating room. Approximately 2 minutes after an intravenous line was established by an anesthesia resident, severe hypoxia and bradycardia developed, and she lost consciousness. Cardiopulmonary resuscitation was initiated immediately, and after 1 minute, she regained consciousness, and her breathing and circulation recovered. After admission to the intensive care unit, emergency coronary angiography was performed. The blood flow in all the coronary arteries was normal. However, a decrease in the apical left ventricular wall motion and an increase in the basal wall motion were observed. Based on these findings, Takotsubo cardiomyopathy was diagnosed. The wall motion gradually improved and the patient was discharged from the hospital on postoperative day 15. The respiratory depression and bradycardia were thought to be due to an inadvertent bolus of remifentanil. We surmised that the patient had received a slight amount of retained medication when the anesthesia resident established the intravenous line, which caused severe respiratory depression. It is important to note that adverse effects such as severe respiratory depression and bradycardia can be caused by even small doses of remifentanil.

Topics: Aged; Analgesics, Opioid; Anesthesia, General; Bradycardia; Cardiopulmonary Resuscitation; Cataract Extraction; Coronary Angiography; Electrocardiography; Epilepsy; Epinephrine; Female; Humans; Hypertension; Piperidines; Remifentanil; Respiratory Insufficiency; Takotsubo Cardiomyopathy; Vasoconstrictor Agents

Patients suffering from Alzheimer's disease, Parkinson's disease and dementia with Lewy bodies can be treated well with the cholinesterase inhibitors rivastigmine or donepezil, and because of the increasing number of these patients undergoing surgery in general anaesthesia we find it urgent to draw attention to possible complications such as severe bradycardia or third-degree heart block when propofol and remifentanil are being used.

Topics: Aged; Anesthesia, General; Anesthetics, Intravenous; Bradycardia; Cholinesterase Inhibitors; Dementia; Donepezil; Drug Interactions; Drug Therapy, Combination; Electrocardiography; Humans; Indans; Male; Piperidines; Propofol; Remifentanil

Although cholinesterase inhibitors have been frequently used in the treatment of Alzheimer disease, its effects on serum cholinesterase concentrations have been rarely described. We described significant depression of serum cholinesterase levels due to cholinesterase inhibitor toxicity from redundant use of donepezil and rivastigmine in a 78-year-old man. Recovery of serum cholinesterase level was noted upon drug discontinuation and cholinergic symptom resolution. Serum cholinesterase level can be used as a biomarker for central cholinesterase inhibitor toxicity.

Topics: Aged; Bradycardia; Cholinesterase Inhibitors; Cholinesterases; Donepezil; Humans; Indans; Lewy Body Disease; Male; Miosis; Parkinson Disease; Phenylcarbamates; Piperidines; Rivastigmine

We report a patient with concealed sick sinus syndrome who developed intraoperative bradycardia and asystole. An 81-year-old man was scheduled to undergo total gastrectomy under general and epidural anesthesia. There was no history of syncope, and preoperative 12-lead ECG showed normal sinus rhythm. Anesthesia was induced with propofol and remifentanil, maintained with sevoflurane, remifentanil and thoracic epidural infusion of lidocaine, fentanyl and levobupivacaine. Bradycardia was detected on ECG 110 minutes after the start of surgery. Intravenous atropine (0.5 mg, repeated up to a total dose of 1.5 mg) was ineffective in restoring a normal heart rhythm. Ten minutes later, the ECG changed to asystole lasting for about 15 seconds. Regular chest compression and intravenous administration of dopamine (5 microg x kg(-1) x min(-1)) resulted in successful recovery of sinus rhythm. Postoperative ECG showed sinus rhythm. The final diagnosis by a cardiologist was concealed sick sinus syndrome. Many anesthetic agents have some effects on the cardiac conduction system. Remifentanil may have played a role in the development of asystole in this patient. The existence of concealed sick sinus syndrome should be kept in mind even in patients who show no clinical abnormalities on preoperative assessment.

Topics: Aged, 80 and over; Anesthesia, Epidural; Anesthesia, General; Atropine; Bradycardia; Dopamine; Electrocardiography; Gastrectomy; Heart Arrest; Humans; Infusions, Intravenous; Intraoperative Complications; Male; Piperidines; Remifentanil; Sick Sinus Syndrome; Stomach Neoplasms

Donepezil is a centrally-acting, reversible acetylcholinesterase inhibitor that is used in the treatment of Alzheimer disease. Altered mental status, nausea, vomiting, and bradycardia have been reported in therapeutic and supratherapeutic ingestions of donepezil, though pediatric exposures have not been well-described. We report a case of prolonged altered mental status and recurrent bradycardia in a child with a single-pill ingestion of donepezil.. A 14-month-old boy was brought to the Emergency Department 3 hours after ingesting one of his grandfather's donepezil tablets (10 mg). Upon arrival, he was somnolent and drooling, with multiple episodes of vomiting and diarrhea. Pupils were normal. Initial vitals: temperature, 36.8°C; blood pressure, 103/56 mmHg; heart rate, 140/min; respiratory rate, 36/min; oxygen saturation, 97%. His drooling, vomiting, and diarrhea resolved, but he remained intermittently agitated. Over the course of the following four days, he had intermittent, episodes of asymptomatic bradycardia to a low of 55/min, primarily when sleeping. A transient episode of junctional rhythm was observed. Serum donepezil level 97 hours post-ingestion was 10 ng/ml. He did not require atropine treatment, and was discharged in stable condition on hospital day 5.. Donepezil has a prolonged elimination of half-life in adults of approximately 70 hours. Despite its relative specificity for central AChEs, peripheral cholinergic symptoms have been described. We report a case of a symptomatic ingestion of donepezil in a child.. Even after a single-tablet ingestion, donepezil may cause prolonged altered mental status and bradycardia in young children.

Topics: Accidents, Home; Bradycardia; Cholinesterase Inhibitors; Donepezil; Emergency Service, Hospital; Humans; Indans; Infant; Male; Nootropic Agents; Piperidines; Psychoses, Substance-Induced; Severity of Illness Index; Sleep Stages; Vomiting

Donepezil is a commonly used drug in older people that due to its procholinergic effects can provoke bradycardia and neurocardiogenic syncope. Donepezil is metabolized by the cytochrome P450 isozyme 3A4 (CYP3A4). Clarithromycin is a potent inhibitor of CYP3A4, and patients taking both of these drugs may be at increased risk of cardiac adverse events.. The aim of this study was to evaluate the association between recent use of clarithromycin and adverse cardiovascular events in elderly patients receiving donepezil.. A population-based, nested case-control study using provincial healthcare databases was conducted. The base cohort was made up of persons 66 years of age or older who were prescribed donepezil and also were prescribed clarithromycin, erythromycin, azithromycin, cefuroxime, moxifloxacin or levofloxacin. Cases were those members of the base cohort hospitalized for bradycardia, syncope or complete atrioventricular block. For each case patient, five controls were matched according to age, sex and residence (community or long-term care).. Between July 2002 and March 2010, 17,712 patients continuously receiving donepezil were prescribed one of the antibacterials. In 1400 person-years of follow-up, 59 cases were identified. As compared with azithromycin, there was no statistically significant association between use of clarithromycin in donepezil users and subsequent adverse cardiovascular events (odds ratio 0.67; 95% CI 0.28, 1.63). There was no significant risk associated with exposure to either cefuroxime or respiratory quinolones.. The use of clarithromycin in elderly donepezil users did not significantly increase the risk of adverse cardiovascular outcomes. However, our study cannot rule out a possible small increase in risk. Although antibacterials can be beneficial, care should be taken in selecting antibacterials for use in older people receiving donepezil.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Atrioventricular Block; Bradycardia; Cardiovascular Diseases; Case-Control Studies; Cholinesterase Inhibitors; Clarithromycin; Cohort Studies; Cytochrome P-450 CYP3A Inhibitors; Donepezil; Drug Interactions; Drug Prescriptions; Enzyme Inhibitors; Female; Humans; Indans; Macrolides; Male; Ontario; Piperidines; Syncope

We encountered three patients who showed ECG changes, suggesting cardiac conduction abnormality, immediately after the induction of general anesthesia with remifentanil and thiamylal. The first patient was a 42-year-old man (172cm and 75kg). The second patient was a 75-year-old woman (153 cm and 62 kg) and the last patient was 16-year-old woman (166 cm and 46 kg). Remarkable past history was not noted and pre-anesthetic evaluations including 12 lead electrocardiogram demonstrated no abnormality in all patients. Immediately after the induction of anesthesia, atrioventricular dissociation, sinus arrest and atrioventricular junctional rhythm were diagnosed by monitoring electrocardiogram, respectively. The conduction abnormalities were not followed by severe bradycardia and hypotension, and observed without drug administration. In the first and second patient, sinus rhythm returned within 15 to 20 min after the induction. The junctional rhythm in the third patient continued during the operation; however, the recovery to sinus rhythm was observed at the end of operation lasting about 1 hr. No severe adverse clinical complication was found; however, careful monitoring might be required to pre vent circulatory depression with combination of remifentanil and thiamylal.

Topics: Adolescent; Adult; Aged; Anesthesia, General; Anesthetics, Intravenous; Bradycardia; Electrocardiography; Female; Heart Conduction System; Humans; Male; Monitoring, Intraoperative; Piperidines; Remifentanil

The reverse rate dependence (RRD) of actions of I(Kr)-blocking drugs to increase the action potential duration (APD) and beat-to-beat variability of repolarization (BVR) of APD is proarrhythmic. We determined whether inhibition of endogenous, physiological late Na(+) current (late I(Na)) attenuates the RRD and proarrhythmic effect of I(Kr) inhibition.. Duration of the monophasic APD (MAPD) was measured from female rabbit hearts paced at cycle lengths from 400 to 2000 milliseconds, and BVR was calculated. In the absence of a drug, duration of monophasic action potential at 90% completion of repolarization (MAPD(90)) and BVR increased as the cycle length was increased from 400 to 2000 milliseconds (n=36 and 26; P<0.01). Both E-4031 (20 nmol/L) and d-sotalol (10 μmol/L) increased MAPD(90) and BVR at all stimulation rates, and the increase was greater at slower than at faster pacing rates (n=19, 11, 12 and 7, respectively; P<0.01). Tetrodotoxin (1 μmol/L) and ranolazine significantly attenuated the RRD of MAPD(90,) reduced BVR (P<0.01), and abolished torsade de pointes in hearts treated with either 20 nmol/L E-4031 or 10 μmol/L d-sotalol. Endogenous late I(Na) in cardiomyocytes stimulated at cycle lengths from 500 to 4000 milliseconds was greater at slower than at faster stimulation rates, and rapidly decreased during the first several beats at faster but not at slower rates (n=8; P<0.01). In a computational model, simulated RRD of APD caused by E-4031 and d-sotalol was attenuated when late I(Na) was inhibited.. Endogenous late I(Na) contributes to the RRD of I(Kr) inhibitor-induced increases in APD and BVR and to bradycardia-related ventricular arrhythmias.

Topics: Acetanilides; Action Potentials; Animals; Anti-Arrhythmia Agents; Bradycardia; Disease Models, Animal; Enzyme Inhibitors; Female; Heart Rate; Long QT Syndrome; Models, Cardiovascular; Myocardial Contraction; Myocytes, Cardiac; Patch-Clamp Techniques; Piperazines; Piperidines; Pyridines; Rabbits; Ranolazine; Sodium; Sodium Channel Blockers; Sodium Channels; Tetrodotoxin; Torsades de Pointes

The cholinesterase inhibitors donepezil, rivastigmine and galantamine have a modest and transient benefit in Alzheimer's disease. Their known adverse effects include bradycardia. A Canadian case-control study conducted between 2003 and 2008 showed a statistically significant increase in the risk of hospitalisation for bradycardia among patients who had been taking a cholinesterase inhibitor for less than 3 months, compared with patients who had stopped taking a cholinesterase inhibitor more than 6 months previously. After hospital discharge, more than half of these patients were again prescribed a cholinesterase inhibitor, and 4% of them were re-admitted for bradycardia. In practice, when an adverse effect has been identified and treated, this information must be shared and taken into account by all those involved in the patient's subsequent management.

Topics: Alzheimer Disease; Bradycardia; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Risk; Rivastigmine

The concept of opioid-induced hyperalgesia has recently gained prominence as a contributing factor for long-term treatment failure.. To evaluate possible differences of opioids used in anaesthesia, cumulative doses of sufentanil and remifentanil were compared with escalating doses of the oripavine derivative etorphine, in awake and trained canines. This was followed by naloxone unmasking a possible hyperalgesic state, which had developed during opioid administration. Heart rate, blood pressure and propagation of nociceptive volleys in somatosensory-evoked potentials as well as the skin-twitch reflex were evaluated.. Opioid-related hypotension and bradycardia were reversed by naloxone with a late (30 min) overshoot of R43 and R17% after remifentanil and sufentanil, respectively. Following etorphine, overshoot in mean blood pressure was R9%, whereas heart rate still remained below S9% when compared with control. Peak hyperalgesia, as detected in the somatosensory-evoked potential and skin-twitch, increased by R70% after remifentanil and by R43% after sufentanil. This reflected a significant (P<0.005) increase in propagation of nociceptive afferents as late as 30 min after naloxone reversal. Such potentiation was not observed in the etorphine group, as peak somatosensory-evoked potential deflection and skin-twitch remained below S80% when compared with control.. The pure mu-agonists sufentanil or remifentanil seem to induce a 'bimodal' inhibitory followed by an excitatory effect. The latter is unmasked by naloxone in the postadministration period. In contrast, this is not seen with etorphine, a close congener of buprenorphine. The proposed mode of action of such hyperexcitatory effects may involve second-messenger-mediated G-protein activation, originally proposed by others. Ligands of the oripavine series may present an alternative for prevention of opioid-induced hyperalgesia in patients.

Topics: Afferent Pathways; Analgesics, Opioid; Animals; Blood Pressure; Bradycardia; Dogs; Dose-Response Relationship, Drug; Etorphine; Evoked Potentials, Somatosensory; Heart Rate; Hyperalgesia; Hypotension; Naloxone; Narcotic Antagonists; Piperidines; Remifentanil; Substance Withdrawal Syndrome; Sufentanil

Topics: Airway Obstruction; Anesthetics, Intravenous; Bradycardia; Cardiotonic Agents; Cholangiopancreatography, Endoscopic Retrograde; Choledocholithiasis; Decerebrate State; Flumazenil; GABA Agonists; Humans; Hypnotics and Sedatives; Hypoxia; Intraoperative Complications; Intubation, Intratracheal; Male; Midazolam; Middle Aged; Naloxone; Piperidines; Propofol; Remifentanil; Sleep Apnea, Obstructive

Stimulation of the dorsolateral periaqueductal gray matter (dlPAG) and the B3 cell group inhibits the cardiovagal component of the baroreflex in rats. Our aim was to determine whether the defence reaction induces similar modulatory effects on the cardiac response of the von Bezold-Jarisch reflex and the carotid chemoreceptor reflex. We examined the effects of dlPAG stimulation on the reflex bradycardia triggered by systemic administration of phenylbiguanide or potassium cyanide. Electrical and chemical stimulation of the dlPAG produced marked inhibition of the cardiovagal components of the von Bezold-Jarisch and the carotid chemoreceptor reflexes. In addition, as 5-HT(3), NK(1) and GABA(A) receptor activation blocks cardiac reflex responses, we studied whether these receptors were involved in the dlPAG-induced inhibitory effects. We found that, after microinjection of granisetron (a 5-HT(3) receptor antagonist), bicuculline (a GABA(A) receptor antagonist) and GR-205171 (an NK(1) receptor antagonist) into the nucleus of the solitary tract (NTS), reflex bradycardic responses were preserved during dlPAG stimulation. Finally, activation of the B3 region also inhibited both reflex bradycardic responses, and these effects were prevented by prior blockade of 5-HT(3) receptors in the NTS. The inhibitory effect of dlPAG stimulation on the cardiac reflex responses was prevented by inhibition of neurons in the medullary B3 region. In conclusion, 5-HT(3), GABA(A) and NK(1) receptors in the NTS appear to be involved in the inhibition of the von Bezold-Jarisch reflex and the carotid chemoreceptor reflex bradycardia evoked by activation of neurons in the dlPAG and the raphé magnus.

Topics: Animals; Bicuculline; Biguanides; Bradycardia; Carotid Arteries; Chemoreceptor Cells; GABA Antagonists; Granisetron; Immunohistochemistry; Male; Microinjections; Parasympathetic Nervous System; Periaqueductal Gray; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, Neurokinin-1; Receptors, Serotonin, 5-HT3; Reflex; Serotonin Agents; Solitary Nucleus; Sympathetic Nervous System; Tetrazoles

To quantify the association between cholinesterase inhibitors (ChE-Is) and a new diagnosis of bradycardia and to evaluate the clinical significance of bradycardia.. Cox proportional hazards with time-dependent exposures were used to evaluate the association and examine the dose effect for donepezil and bradycardia.. New England Veterans Affairs Healthcare System.. Patients with dementia who received care between January 1999 and June 2007 (N=11,328).. Bradycardia was defined using three methods using a combination of International Classification of Diseases, Ninth Revision, codes and recorded heart rates of less than 60 beats per minute.. A greater risk for bradycardia was found in patients taking any ChE-Is than in the no-treatment group (adjusted hazard ratio (HR)=1.4, 95% confidence interval (CI)=1.1-1.6). A dose-response effect was observed for donepezil, with the highest-dose group at greatest risk (HR=2.1, 95% CI=1.5-2.9). Results were consistent regardless of bradycardia definition. Patients with bradycardia were more likely to fall, experience syncope, or need a pacemaker implantation than those without.. Using a large cohort, a modestly greater risk of bradycardia was found in patients with dementia taking ChE-Is than in those not taking these drugs. In patients taking donepezil, the risk of bradycardia may increase with increasing doses. Because of the potential clinical consequences, monitoring for bradycardia may be warranted in patients with dementia treated with ChE-Is.

Topics: Alzheimer Disease; Bradycardia; Cholinesterase Inhibitors; Cross-Sectional Studies; Dementia; Donepezil; Dose-Response Relationship, Drug; Drug Therapy, Combination; Galantamine; Heart Rate; Hospitals, Veterans; Humans; Incidence; Indans; Massachusetts; Nootropic Agents; Phenylcarbamates; Piperidines; Risk; Rivastigmine; Veterans

Topics: Adult; Anesthesia, General; Anesthetics, Intravenous; Bradycardia; Bronchial Spasm; Cholinesterase Inhibitors; Drug Interactions; Drug Therapy, Combination; Humans; Hypotension; Male; Myasthenia Gravis; Piperidines; Preanesthetic Medication; Propofol; Pyridostigmine Bromide; Remifentanil; Thymectomy

Topics: Age Factors; Anesthesia, Intravenous; Anesthetics, Intravenous; Bradycardia; Child; Clinical Trials as Topic; Contraindications; Female; Humans; Infusions, Intravenous; Injections, Intravenous; Intraoperative Complications; Multicenter Studies as Topic; Myasthenia Gravis; Perfusion; Piperidines; Remifentanil; Thoracoscopy; Thymectomy

Recently, attention has been drawn to compounds that activate the human ether-a-go-go channel potassium channel (hERG), which is responsible for the repolarizing rapid delayed rectifier potassium current (I(Kr)) in the mammalian myocardium. The compound NS3623 [N-(4-bromo-2-(1H-tetrazol-5-yl)-phenyl)-N'-(3'-trifluoromethylphenyl) urea] increases the macroscopic current conducted by the hERG channels by increasing the time constant for channel inactivation, which we have reported earlier. In vitro studies suggest that pharmacological activation is an attractive approach for the treatment of some arrhythmias. We present here data that support that NS3623 affects native I(Kr) and report the effects that activating this potassium current have in the intact guinea pig heart. In Langendorff-perfused hearts, the compound showed a concentration-dependent shortening of action potential duration, which was also detected as concentration-dependent shorter QT intervals. There was no sign of action potential triangulation or reverse use dependence. NS3623 decreased QT variability and distinctly decreased the occurrence of extrasystoles in the acutely bradypaced hearts. Taken together, the present data strongly support the concept of using hERG activators as a treatment for certain kinds of arrhythmias and suggest further investigation of this new approach.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Bradycardia; Electrocardiography; Ether-A-Go-Go Potassium Channels; Guinea Pigs; Heart; Heart Rate; In Vitro Techniques; Perfusion; Phenylurea Compounds; Piperidines; Pyridines; Tetrazoles; Ventricular Function

Topics: Anesthetics, Intravenous; Bradycardia; Child, Preschool; Craniocerebral Trauma; Humans; Male; Piperidines; Remifentanil

Blockade of sodium channels located in the sinoatrial node can slow diastolic depolarisation rate, recorded in vitro. The objective was therefore to determine whether these blockers could slow heart rate in vivo. The heart rate was firstly measured in spontaneously beating, isolated rat heart atria in the presence of different voltage gated sodium channel blockers. Tetrodotoxin and lidocaine slightly reduced heart rate whereas KC 12291 and R 56865, which mainly interact with the persistent component of the sodium current, concentration dependently and potently induced bradycardia. In the pithed rat, tetrodotoxin induced statistically significant decreases heart rate, maximal effects were: -32.2+/-6.1 beat per min. KC 12291 and R 56865 dose-dependently induced bradycardia (Delta heart rate obtained, -55.1+/-5.2 beat per min, P<0.05, and -71.9+/-8.5 bpm, P<0.05, respectively). In conclusion, voltage gated sodium channel blockers rather selective for the persistent current, exert a potent bradycardic effect in the rat.

Topics: Animals; Benzothiazoles; Bradycardia; Heart Atria; Heart Rate; Lidocaine; Male; Piperidines; Rats; Rats, Sprague-Dawley; Sinoatrial Node; Sodium Channel Blockers; Sodium Channels; Tetrodotoxin; Thiadiazoles; Thiazoles

Sinus node inhibitors reduce the heart rate presumably by blocking the pacemaker current If in the cardiac conduction system. This pacemaker current is carried by four hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels. We tested the potential subtype-specificity of the sinus node inhibitors cilobradine, ivabradine, and zatebradine using cloned HCN channels. All three substances blocked the slow inward current through human HCN1, HCN2, HCN3, and HCN4 channels. There was no subtype-specificity for the steady-state block, with mean IC50 values of 0.99, 2.25, and 1.96 microM for cilobradine, ivabradine, and zatebradine, respectively. Native If, recorded from mouse sinoatrial node cells, was slightly more efficiently blocked by cilobradine (IC50 value of 0.62 microM) than were the HCN currents. The block of I(f) in sinoatrial node cells resulted in slower and dysrhythmic spontaneous action potentials. The in vivo action of these blockers was analyzed using telemetric ECG recordings in mice. Each compound reduced the heart rate dose-dependently from 600 to 200 bpm with ED50 values of 1.2, 4.7, and 1.8 mg/kg for cilobradine, ivabradine, and zatebradine, respectively. beta-Adrenergic stimulation or forced physical activity only partly reversed this bradycardia. In addition to bradycardia, all three drugs induced increasing arrhythmia at concentrations greater than 5 mg/kg for cilobradine, greater than 10 mg/kg for zatebradine, or greater than 15 mg/kg for ivabradine. This dysrhythmic heart rate is characterized by periodic fluctuations of the duration between the T and P wave, resembling a form of sick sinus syndrome in humans. Hence, all available sinus node inhibitors possess an as-yet-unrecognized proarrhythmic potential.

Topics: Animals; Arrhythmias, Cardiac; Benzazepines; Bradycardia; Cardiotonic Agents; Cloning, Molecular; Electrocardiography; Humans; Ivabradine; Mice; Mice, Inbred C57BL; Piperidines; Sinoatrial Node; Up-Regulation

Topics: Alzheimer Disease; Bradycardia; Cholinesterase Inhibitors; Cognition; Donepezil; Heart Block; Humans; Indans; Piperidines

Topics: Anesthetics, Intravenous; Bradycardia; Child; Female; Humans; Intraoperative Complications; Medication Errors; Piperidines; Remifentanil

Topics: Anesthetics, Intravenous; Apnea; Bradycardia; Child, Preschool; Coronary Angiography; Female; Humans; Piperidines; Remifentanil

Methods to correct the QT interval for heart rate are often in disagreement and may be further confounded by changes in autonomic state. This can be problematic when trying to distinguish the changes in QT interval by either drug-induced delayed repolarization or from autonomic-mediated physiological responses. Assessment of the canine dynamic QT-RR interval relationship was visualized by novel programming of the dynamic beat-to-beat confluence of data or "clouds". To represent the nonuniformity of the clouds, a bootstrap sampling method that computes the mathematical center of the uncorrected beat-to-beat QT value (QTbtb) with upper 95% confidence bounds was adopted and compared with corrected QT (QTc) using standard correction factors. Nitroprusside-induced reflex tachycardia reduced QTbtb by 43 ms, whereas an increase of 55 and 16 ms was obtained using the Bazett (QTcB) and Fridericia (QTcF) formulae, respectively. Phenylephrine-induced reflex bradycardia increased QTbtb by 3 ms but decreased QTcB by 20 ms and QTcF by 12 ms. Delayed repolarization with E-4031 (1-[2-(6-methyl-2-pyridyl)ethyl]-4-methylsulfonylaminobenzoyl)-piperidine), an inhibitor of rectifier potassium current, increased QTbtb by 26 ms but QT prolongation calculations using QTcF and QTcB were between 12 and 52% less, respectively, when small decreases in heart rate (5-8 beats per minute) were apparent. Dynamic assessment of beat-to-beat data, using the bootstrap method, allows quantification of QT interval changes under varying conditions of heart rate, autonomic tone, and direct repolarization that may not be distinguishable with use of standard correction factors.

Topics: Adrenergic beta-Agonists; Animals; Bradycardia; Dogs; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Heart Rate; Humans; Isoproterenol; Long QT Syndrome; Nitroprusside; Phenylephrine; Piperidines; Potassium Channels, Voltage-Gated; Pyridines; Tachycardia

Previous data showed that in the nucleus tractus solitarius (NTS), 5-HT(3) receptors are critically involved in the inhibition of cardiac baroreceptor reflex response occurring during the defense reaction. Since stimulation of NTS NK(1) receptors has been found to inhibit the baroreflex bradycardia, we examined in this study whether this reflex response is inhibited during the defense reaction via an interaction between NK(1) and 5-HT(3) receptors.. For this purpose, we analyzed in urethane-anaesthetized rats the effects of intra-NTS GR205171, a selective NK(1) receptor antagonist, on the baroreflex bradycardia inhibition observed either during the defense reaction triggered by electrical stimulation of the dorsal periaqueductal grey matter (dPAG) or after NTS 5-HT(3) receptor activation.. Intra-NTS GR205171, reversed, in dose-dependent manner, the inhibitory effect of dPAG stimulation on baroreflex bradycardia. This reversion was of 49% when both sinus carotid and aortic baroreceptors were stimulated by phenylephrine, and of 84% when aortic depressor nerve was stimulated. Similarly, intra-NTS GR205171 reversed partially or almost totally the inhibitory effect of local microinjections of phenylbiguanide, a 5-HT(3) receptor agonist, on baroreflex bradycardia induced either by phenylephrine administration or aortic nerve stimulation, respectively.. These results strongly suggest that NK(1) receptors contribute downstream to the 5-HT(3) receptor-mediated inhibition of the aortic but not carotid cardiac baroreflex response occurring during the defense reaction, therefore implying that baroreceptor afferent inputs may be differentially modulated depending on their origin. This differentiation may be useful for a better understanding of baroreflex dysfunction in disease-induced conditions.

Topics: Animals; Aorta; Baroreflex; Bradycardia; Electric Stimulation; Escape Reaction; Granisetron; Male; Microinjections; Neurokinin-1 Receptor Antagonists; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists; Solitary Nucleus; Substance P; Tetrazoles

We have compared the effect of two distinct Ih inhibitors on the temporal properties of the ERG response that, as previously shown, correlates well with the HCN activation in rods. The present results confirm the notion that cilobradine is more effective than zatebradine in inducing bradycardia. Importantly, the doses of cilobradine that reduce the heart rate to values comparable to, or lower than, those obtained with higher doses of zatebradine have little effect on the frequency response of the ERG. While more potent than zatebradine in its bradycardic action, cilobradine appears comparatively less effective on the visual response. A possible explanation is that the affinity of cilobradine for the HCN channels in the heart is higher than that for the HCN channels of retinal neurons.

Topics: Animals; Benzazepines; Bradycardia; Cardiotonic Agents; Dose-Response Relationship, Drug; Electroretinography; Heart; Heart Rate; Ion Channels; Membrane Potentials; Piperidines; Rats; Rats, Long-Evans; Retina; Retinal Ganglion Cells; Retinal Rod Photoreceptor Cells; Tachycardia

Decreasing heart rate might be beneficial for improvement of myocardial energetics and could reduce the severity of myocardial ischemia. We examined the contribution of heart rate reduction by cilobradine (DK-AH 269), a direct sinus node inhibitor, on left ventricular function and peripheral vasomotion in anesthetized rabbits with experimental myocardial infarction. The rabbits were randomized to receive either placebo (n=10) or cilobradine (n=7). Cilobradine decreased significantly heart rate from 163 +/- 33 to 131 +/- 13 bpm, p< 0.05, without any inotopic or vascular effects. After 60 min coronary occlusion and 30 min reperfusion, both systolic and diastolic ventricular function were more reduced in the cilobradine group; i.e. maximal left ventricular pressure significantly decreased to 62 +/- 11 mmHg, p < 0.05 (placebo: 77 +/- 9 mmHg); dP/dt(min) significantly decreased to -904 +/- 247 mmHg, p < 0.05 (placebo: -1106 +/- 242 mmHg). However, infarct size in the cilobradine group was significantly smaller compared with the placebo group. In conclusion, cilobradine reduced heart rate without any negative inotropic effect and reduced infarct size. On that account, this bradycardic agent might open a promising therapeutical avenue to treat postischemic dysfunction.

Topics: Animals; Benzazepines; Bradycardia; Heart Rate; Myocardial Ischemia; Piperidines; Rabbits

Our objective was to identify the sites of interaction of cannabinoids with cardiovascular sympathetic regulation in the rat. Effects on sympathetic tone were first determined in anaesthetised animals following i.v. administration of the drugs. Central effects were evaluated in anaesthetised rats receiving microinjections of cannabinoids into brain stem nuclei. Peripheral effects were identified in pithed rats with electrically stimulated sympathetic outflow. In anaesthetised and artificially ventilated rats, i.v. injection of the cannabinoid agonists WIN55212-2 and CP55940 decreased mean arterial pressure, heart rate and the plasma noradrenaline concentration. These effects were antagonized by the CB(1) cannabinoid receptor antagonist SR141716A. The bradycardia was abolished by the muscarinic acetylcholine receptor antagonist methylatropine. The decreases in mean arterial pressure and heart rate caused by cannabinoids in ventilated rats were much less pronounced than in spontaneously breathing rats. Microinjection of WIN55212-2 into the nucleus tractus solitarii had no effect. Microinjected into the rostral ventrolateral medulla oblongata, WIN55212-2 lowered mean arterial pressure slightly without changing other parameters. In pithed rats, WIN55212-2 inhibited the increases in mean arterial pressure, heart rate and the plasma noradrenaline concentration evoked by electrical stimulation of the sympathetic outflow. Our results show that activation of CB(1) cannabinoid receptors induces sympathoinhibition and enhancement of cardiac vagal tone, leading to hypotension and bradycardia. Presynaptic inhibition of noradrenaline release from terminals of postganglionic sympathetic neurons is the major component of the sympathoinhibition, but an effect in the rostral ventrolateral medulla oblongata may also contribute. The cannabinoid-evoked cardiovascular depression depends strongly on the respiratory state of the animals.

Topics: Animals; Atropine Derivatives; Benzoxazines; Bradycardia; Cannabinoids; Cardiovascular System; Cyclohexanols; Disease Models, Animal; Dose-Response Relationship, Drug; Hypotension; Male; Medulla Oblongata; Microinjections; Morpholines; Naphthalenes; Norepinephrine; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Sympathetic Fibers, Postganglionic; Sympathetic Nervous System

In the present study, we examined cardiac and regional haemodynamic effects of endothelin-1 (ET-1), a potent vasoconstrictive factor, in a rat model of pressure-controlled irreversible haemorrhagic shock resulting in the death of all control animals within 30 min. Experiments were carried out in male ethylurethane-anaesthetised Wistar rats subjected to hypotension of 20-25 mmHg, which resulted in bradycardia, an extreme decrease in cardiac index (CI) and an increase in total peripheral resistance index (TPRI), with reductions in renal (RBF), hindquarters (HBF) and mesenteric blood flow (MBF). ET-1 (50, 200 pmol/kg) administered intravenously at 5 min of critical hypotension produced increases in mean arterial pressure (MAP) and heart rate (HR), which were significantly higher than those in normotensive animals, and a 100% survival at 2 h after treatment. The effects were accompanied by a rise in CI, a decrease in TPRI, with increases in RBF and HBF and persistently lowered MBF, and an increase in circulating blood volume 20 min after treatment. The cardiovascular effects of ET-1 were inhibited by the ETA receptor antagonist BQ-123 (1 mg/kg), while the ETB receptor antagonist BQ-788 (3 mg/kg) had no effect. In conclusion, ET-1 acting via ETA receptors produces reversal of haemorrhagic hypotension in rats due to the mobilisation of blood from venous reservoirs, with the improvements in cardiac function and the perfusion of peripheral tissues.

Topics: Animals; Blood Pressure; Bradycardia; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hemodynamics; Hemorrhage; Hindlimb; Hypotension; Injections, Intravenous; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin A; Renal Circulation; Shock, Hemorrhagic; Sodium Chloride; Splanchnic Circulation; Time Factors; Vascular Resistance

To report and discuss a case of fetal bradycardia in a parturient under anesthesia for cholecystectomy despite normal maternal oxygenation and arterial blood pressure.. A 27-yr-old woman (gravida 2 para 1), with a fetus of 34 weeks gestation, received general anesthesia for cholecystectomy. After anesthesia induction and tracheal intubation, anesthesia was maintained with oxygen, sevoflurane and iv remifentanil infusion. While preparing for surgery, the fetal heart rate decreased within about half a minute to 70 beats x min(-1) and remained at that level. The maternal blood pressure, heart rate and oxygen saturation were normal. An emergency Cesarean delivery was performed. The infant had Apgar scores of 1 at one minute, 5 at five minutes, 7 at ten minutes and required resuscitation after birth.. Ideally, women having non-obstetric surgery during the third trimester of pregnancy will have intraoperative fetal heart rate monitoring.

Topics: Adult; Anesthesia, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Apgar Score; Blood Pressure; Bradycardia; Cesarean Section; Cholecystectomy; Female; Fetal Distress; Fetal Monitoring; Heart Rate; Heart Rate, Fetal; Humans; Infant, Newborn; Methyl Ethers; Oxygen; Piperidines; Pregnancy; Remifentanil; Severity of Illness Index; Sevoflurane

A 79-year-old woman with Alzheimer's disease was admitted due to acute cholinergic symptoms induced by overdose (45 mg) of donepezil (DPZ). Physical examination showed bradycardia, sinus arrhythmia, vomiting and respiratory insufficiency. She was treated with atropine intravenously and her cholinergic symptoms subsided in the next evening. After 5 days she was discharged from the hospital and DPZ was withholded for about 4 weeks. The plasma concentration of DPZ was 54.6 ng/ml on admission and gradually decreased to the normal limits in about 90 hours. The calculative half-life of DPZ was about 55 hours. Since the half-life of DPZ is long and differs between individuals, hospitalization and treatment with atropine is recommended for cholinergic side effects induced by overdose of DPZ. It is important to prevent dosing errors in cooperation with medical providers, patients and families.

Topics: Aged; Alzheimer Disease; Arrhythmia, Sinus; Bradycardia; Cholinesterase Inhibitors; Donepezil; Drug Overdose; Electrocardiography; Female; Humans; Indans; Piperidines; Vomiting

We describe three cases of patients with Alzheimer's disease who presented with cardiac syncope soon after initiation of a cholinesterase inhibitor therapy (donepezil). Bradyarrhythmia was documented in two patients, considered probable in one, and was presumed related to the cholinergic therapy. Pacemaker implantation seemed justified rather than donepezil cessation. More over, it permitted an increase in donepezil dosage.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Bradycardia; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Pacemaker, Artificial; Piperidines; Syncope

The pharmacokinetics of lerisetron, a novel 5HT(3) antagonist, are studied together with its efficacy in inhibiting the serotonin (5-HT)-evoked transient bradycardia reflex (von Bezold-Jarisch reflex) in Sprague Dawley rats. [(14)C]Lerisetron (50, 100, and 200 microg/kg) was given to rats by intravenous (iv) injection and plasma levels of unchanged (UL) and total (unchanged + changed, TL) drug were measured by liquid chromatography with radioactivity monitoring and scintillation counting, respectively. Linearity of UL and TL pharmacokinetics over the dose range was established by noncompartmental analysis. Protein binding of lerisetron was measured in vitro by ultrafiltration. The unbound fraction was 14.4 +/- 1.4%. A nonlinear mixed effects ("population") bicompartmental pharmacokinetic analysis showed that volume of distribution and clearance (CL) were high for both forms of the drug, but CL was significantly smaller for TL [(mean +/- SEM) 0.014 +/- 0.03 L/min for UL versus 0.006 +/- 0.03 L/min for TL, p < 0.05)]. Large interindividual variabilities were observed for both forms. The response to lerisetron administration (inhibition of bradycardia) was evaluated at different doses (2, 3, 5, 6, and 10 microg/kg, iv) at times 2-180 min after dose administration and related to simulated concentrations. Inhibition was 100% 5 min after the 10-microg/kg dose and, 3 h later, it was still > 10%. Response to lerisetron was dose related in the range studied. Pharmacodynamic parameters were estimated by a sigmoid E(max) naive-pooled model. The parameters were also different between the two forms: EC(50) was 0.44 ng/mL (CV = 5.9%) for UL and 0.88 ng/mL (CV = 4.9%) for TL. We conclude that UL and TL pharmacokinetics were linear and that the differences in the kinetics and dynamics between the two forms suggest the presence of at least one metabolite.

Topics: Animals; Benzimidazoles; Bradycardia; Dose-Response Relationship, Drug; Female; Male; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists

To discover a highly selective M(3) antagonist, a combinatorial library was prepared. The library was designed to identify a novel structural class of M(3) antagonists by exploring the spatial arrangement of the pharmacophores in known M(3) antagonists. After the evaluation of 1000 library members, a potent M(3) antagonist, 14a (K(i) = 0.31 nM), with novel structural features was identified. Compound 14a showed high selectivity for M(3) receptors over the other muscarinic receptor subtypes (M(1)/M(3) = 380-fold, M(2)/M(3) = 98-fold, M(4)/M(3) = 45-fold, M(5)/M(3) = 120-fold).

Topics: Acetylcholine; Animals; Bradycardia; Bronchoconstriction; Carbachol; CHO Cells; Cholinergic Agents; Combinatorial Chemistry Techniques; Cricetinae; Dipeptides; Heart Atria; Humans; In Vitro Techniques; Muscarinic Antagonists; Piperidines; Rats; Receptor, Muscarinic M3; Receptors, Muscarinic; Structure-Activity Relationship

To examine the effect of changes in plasma alpha1-acid glycoprotein (AAG) levels on the pharmacokinetics (PK) and pharmacodynamics (PD) of lerisetron, a novel serotonin 5-HT3 receptor antagonist, in the rat.. After subcutaneous administration of turpentine oil, AAG was significantly elevated compared with controls. The PK of unchanged lerisetron (UL; high-performance liquid chromatography with radioactivity monitoring) and total lerisetron (TL; unchanged + changed, scintillation counting) was characterized post intravenous (i.v.) 14C lerisetron (50 microg/kg) in control and turpentine oil pretreated rats. The PK (0-180 min) was described by a two-compartmental model. Protein binding of lerisetron in vitro was measured using an ultrafiltration technique. The effect of lerisetron (5 microg/kg, i.v.) over 180 min was measured in anesthetized rats (control and pretreated) with the Bezold-Jarisch reflex (inhibition of bradycardia after 16 microg/kg serotonin i.v.) as the endpoint. PD parameters were estimated by sigmoid Emax models.. The unbound fraction was significantly diminished in pretreated rats (mean +/- SEM) (6.60 +/- 1.23% vs. control 14.4 +/- 1.40%, P < 0.05). Volume of distribution (V) and clearance for UL and TL were significantly decreased when compared to the controls (P < 0.0001 for UL and P < 0.05 for TL). Plasma clearance based on unbound concentration for UL did not differ between groups but the unbound V and steady-state unbound V remained decreased (P < 0.05 and P < 0.0001). Pretreated rats showed a significantly diminished drug effect: the area under the E-t curve over 180 min was (mean +/- SEM) 5,189 +/- 657.7 in control animals vs. 3,486 +/- 464.4 in the pretreated group (P < 0.05). The EC50 (concentration at half maximum effect) for UL and TL were increased in pretreated rats and were not compensated when the unbound concentration was used.. An increase in AAG causes alterations in the PK and PD of lerisetron, and because this is not compensated with the unbound concentration, we suggest that mechanisms not linked to protein binding may be involved.

Topics: Animals; Benzimidazoles; Bradycardia; Female; Orosomucoid; Piperidines; Protein Binding; Rats; Rats, Sprague-Dawley; Serotonin Antagonists

Carotid endarterectomy can be performed under general or locoregional anesthesia. If locoregional anesthesia is chosen, the state of awareness of the patient allows for direct viewing of the effect of vascular clamping of the corresponding neurological territory. We present the results of an anesthetic procedure using only an analgesic in patients who were intubated and ventilated but with a level of consciousness that allowed us to view the effect of carotid clamping on motor functions.. Forty-eight patients, ASA II-III, underwent surgical carotid endarterectomy. The anesthetic protocol began with preoxygenation for 2 min; induction with remifentanil 0.75-1 microgram kg-1 for 2 min., followed by perfusion of 1 microgram/kg-1.min-1 of remifentanil and propofol 1 microgram/kg-1; and orotracheal intubation by local anesthesia of the glottis with 5% lidocaine spray. Ventilation was with FiO2 100%, FR 12 min. and VT 8 ml. kg-1. For maintenance the dose of remifentanil was regulated to obtain a coordinated motor response (maximum 1.5 microgram/kg-1.min-1, minimum 0.35 microgram/kg-1. min-1). For all patients we monitored hemodynamics continuously and non-invasively, including aortic output by the transesophageal Doppler echocardiography.. The objective of anesthesia was reached in all the patients. The most common hemodynamic alterations were bradycardia (28), arterial hypotension (25), elevated blood pressure (3) and altered aortic output. All changes were corrected quickly with the treatment used, guided by the evolution of hemodynamic parameters. Postanesthetic recovery came in less than 4 min. The only episodes of hyper -and hypotension consisted of a few episodes of mild hyper- (12) and hypotension (1), which were soon corrected. No alterations attributable to hemodynamic instability occurred. During surgery, an intracarotid shunt was necessary in only one patient. Three suffered surgically-related neurological complications after the operations. No complications could be attributed to anesthesia.. An advantage of this technique is that the duration of anesthesia is not limited, with adequate ventilation and maintenance of an adequate state of consciousness for clinical evaluation of the repercussions of carotid clamping. Hemodynamic monitoring detected the appearance of imbalances requiring therapeutic intervention. The procedure is interesting provided it is performed according to a strict protocol, with continuous clinical and instrumental monitoring of the patient's status.

Topics: Aged; Aged, 80 and over; Alprazolam; Anesthesia Recovery Period; Anesthesia, Intravenous; Anesthetics, Intravenous; Bradycardia; Cardiac Output; Endarterectomy, Carotid; Female; Hemodynamics; Humans; Hydroxyzine; Hypnotics and Sedatives; Hypotension; Intraoperative Complications; Male; Middle Aged; Monitoring, Intraoperative; Piperidines; Postoperative Complications; Preanesthetic Medication; Propofol; Remifentanil; Treatment Outcome

Topics: Aged; Aged, 80 and over; Analgesics, Opioid; Bradycardia; Female; Humans; Piperidines; Remifentanil

Systemically administered cannabinoids elicit marked cardiovascular effects, and the role of the central and the peripheral nervous system in these effects is not clarified. The aim of this study was to characterize the actions of cannabinoids on cardiovascular regulatory centers in conscious rabbits. A catheter for administration of drugs into the cisterna cerebellomedullaris and an electrode for recording renal sympathetic nerve activity were implanted under halothane anesthesia. Experiments were carried out later in conscious animals. Two cannabinoid receptor agonists were injected intracisternally: the aminoalkylindole WIN55212-2 (0.1, 1, and 10 microg kg(-1)) and the bicyclic Delta(9)-tetrahydrocannabinol analog CP55940 (0.1, 1, and 10 microg kg(-1)). WIN55212-2 and CP55940 dose dependently increased renal sympathetic nerve activity and the plasma noradrenaline concentration and also lowered the heart rate. The highest doses of WIN55212-2 and CP55940 increased blood pressure. In contrast, intracisternal injection of WIN55212-3 (0.1, 1, and 10 microg kg(-1)), an enantiomer of WIN55212-2 with very low affinity for cannabinoid binding sites, had no effects. The CB(1) cannabinoid receptor antagonist SR141716A (0.5 mg kg(-1), i.v. ) attenuated the effects of intracisternally administered WIN55212-2 (0.1, 1, and 10 microg kg(-1)). The results indicate that cannabinoids, acting directly on cardiovascular regulatory centers, elicit sympathoactivation and bradycardia. These effects were likely mediated by CB(1) cannabinoid receptors, because they were elicited by two cannabinoid agonists belonging to different chemical classes (WIN55212-2 and CP55940), but not by the inactive enantiomer WIN55212-3, and because they were attenuated by the CB(1) cannabinoid receptor antagonist SR141716A.

Topics: Animals; Benzoxazines; Blood Pressure; Bradycardia; Cannabinoids; Cyclohexanols; Drug Interactions; Female; Heart Rate; Injections, Intraventricular; Kidney; Male; Morpholines; Naphthalenes; Norepinephrine; Piperidines; Pyrazoles; Rabbits; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Stereoisomerism; Sympathetic Nervous System

The cardiovascular response to 5-hydroxytryptamine (5-HT) challenge has been previously described in cattle. Abrupt bradycardia, followed by tachycardia, triphasic systemic blood pressure response, and pulmonary hypertension were the major changes elicited by 5-HT. The purpose of the present study was to determine whether the cardiovascular response to 5-HT in calves was attributable to 5-HT2 receptors. A specific 5-HT2 antagonist (metrenperone, 0.05 mg/kg) was administered intramuscular to six unsedated Friesian calves 30 min before the animals were given a 5-min intravenous 5-HT infusion. Mean systemic arterial (SAP), mean pulmonary arterial (PAP), pulmonary capillary wedge (PW) pressures were obtained by means of fluid-filled catheters, and cardiac output (CO) was measured by the thermodilution technique. Heart rate, stroke volume, systemic (SVR) and pulmonary (PVR) vascular resistances were calculated. Administration of 5-HT after metrenperone induced a short-lasting period of severe bradycardia followed by tachycardia and increased CO. The systemic blood pressure response was exclusively hypotensive and associated with a decrease in SVR. Conversely, PAP, PW, and PVR were not modified by 5-HT administration. The results establish that 5-HT induced systemic as well as pulmonary hypertension is mediated through the activation of type-2 serotonergic or alpha-adrenergic receptors, or both. In contrast, neither apnoea, bradycardia and hypotension, nor the positive chronotropic effect induced by 5-HT in cattle are mediated through such receptors.

Topics: Animals; Body Temperature; Bradycardia; Cardiovascular System; Cattle; Hypotension; Kinetics; Muscle, Skeletal; Piperidines; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Sleep Stages

1. The aim of the present study was to analyse the cardiovascular actions of the synthetic CB1/CB2 cannabinoid receptor agonist WIN55212-2, and specifically to determine its sites of action on sympathetic cardiovascular regulation. 2. Pithed rabbits in which the sympathetic outflow was continuously stimulated electrically or which received a pressor infusion of noradrenaline were used to study peripheral prejunctional and direct vascular effects, respectively. For studying effects on brain stem cardiovascular regulatory centres, drugs were administered into the cisterna cerebellomedullaris in conscious rabbits. Overall cardiovascular effects of the cannabinoid were studied in conscious rabbits with intravenous drug administration. 3. In pithed rabbits in which the sympathetic outflow was continuously electrically stimulated, intravenous injection of WIN55212-2 (5, 50 and 500 microg kg(-1)) markedly reduced blood pressure, the spillover of noradrenaline into plasma and the plasma noradrenaline concentration, and these effects were antagonized by the CB1 cannabinoid receptor-selective antagonist SR141716A. The hypotensive and the sympathoinhibitory effect of WIN55212-2 was shared by CP55940, another mixed CB1/CB2 cannabinoid receptor agonist, but not by WIN55212-3, the enantiomer of WIN55212-2, which lacks affinity for cannabinoid binding sites. WIN55212-2 had no effect on vascular tone established by infusion of noradrenaline in pithed rabbits. 4. Intracisternal application of WIN55212-2 (0.1, 1 and 10 microg kg(-1)) in conscious rabbits increased blood pressure and the plasma noradrenaline concentration and elicited bradycardia; this latter effect was antagonized by atropine. 5. In conscious animals, intravenous injection of WIN55212-2 (5 and 50 microg kg(-1)) caused bradycardia, slight hypotension, no change in the plasma noradrenaline concentration, and an increase in renal sympathetic nerve firing. The highest dose of WIN55212-2 (500 microg kg(-1)) elicited hypotension and tachycardia, and sympathetic nerve activity and the plasma noradrenaline concentration declined. 6. The results obtained in pithed rabbits indicate that activation of CB1 cannabinoid receptors leads to marked peripheral prejunctional inhibition of noradrenaline release from postganglionic sympathetic axons. Intracisternal application of WIN55212-2 uncovered two effects on brain stem cardiovascular centres: sympathoexcitation and activation of cardiac vagal fibres. The highest dose of

Topics: Analgesics; Animals; Benzoxazines; Blood Pressure; Bradycardia; Cannabinoids; Cardiovascular Physiological Phenomena; Cisterna Magna; Consciousness; Cyclohexanols; Decerebrate State; Dose-Response Relationship, Drug; Electric Stimulation; Female; Heart Rate; Infusions, Intravenous; Injections; Injections, Intravenous; Kidney; Male; Morpholines; Naphthalenes; Norepinephrine; Piperidines; Pyrazoles; Rabbits; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Stereoisomerism; Sympathetic Nervous System; Sympathomimetics

1. The effect of microinjecting angiotensin II (ANGII) into the nucleus of the solitary tract (NTS) on both baroreceptor and peripheral chemoreceptor reflexes was compared. 2. Experiments were performed in a working heart-brainstem preparation of rat. Baroreceptors were stimulated by raising perfusion pressure and chemoreceptors were activated with aortic injections of sodium cyanide (0.025 %, 25-75 microl). Reflex changes in phrenic nerve activity and heart rate were measured after bilateral NTS microinjection (50 nl) of ANGII (0.5-5000 fmol). 3. NTS microinjection of 5 fmol ANGII elicited a transient (28.2 +/- 6 s; mean +/- s.e.m.) bradycardia (-18 +/- 3 beats min-1), and decreased phrenic nerve activity cycle length and amplitude (P < 0.05). At higher doses of ANGII a similar respiratory response was seen but heart rate changes were inconsistent. 4. The baroreceptor reflex bradycardia was depressed significantly by NTS microinjections of ANGII (5-5000 fmol) in a dose-dependent manner with the reflex gain decreasing from 1.7 +/- 0.16 to 0.66 +/- 0.1 beats min-1 mmHg-1 (P < 0.01) at 5000 fmol. Although the chemoreceptor reflex bradycardia was depressed at a low dose of ANGII (5 fmol), all higher doses (50-5000 fmol) produced a dose-dependent potentiation of the reflex bradycardia (maximally +64 +/- 8 %). The respiratory component was unaffected. The effects of ANGII on both reflexes were blocked by an ANGII type 1 (AT1) receptor antagonist, losartan (20 microM). 5. The potentiating action of ANGII on the chemoreceptor reflex cardiac response was abolished by a neurokinin type 1 (NK1) receptor blocker (CP-99,994, 5 microM) but this had no effect on the baroreceptor reflex. 6. AT1 receptors in the NTS can depress the baroreceptor reflex bradycardia which is independent of NK1 receptors. The ANGII effect on the cardiac component of the chemoreceptor reflex is bi-directional being inhibited at low concentrations and potentiated at higher concentrations; the latter involves NK1 receptors and presumably results from release of substance P.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Bradycardia; Chemoreceptor Cells; Heart Rate; Losartan; Microinjections; Neurokinin-1 Receptor Antagonists; Phrenic Nerve; Piperidines; Pressoreceptors; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Reflex; Respiration; Respiratory Physiological Phenomena; Solitary Nucleus; Substance P

Topics: Anesthetics, Combined; Anesthetics, Intravenous; Bradycardia; Child, Preschool; Female; Humans; Piperidines; Propofol; Remifentanil

Vagal activation influences various cardiac functions as well as occurrence of arrhythmias. Inhibition of a rapid type of delayed rectifier K+ current (I[Kr]) has been reported to be effective for the treatment of both ventricular and supraventricular arrhythmias. However, it is unknown how I[Kr] inhibition modulates the cardiac responses to vagal activation in situ. We analyzed the effects of I[Kr] inhibitors, dofetilide and E-4031, and a class I antiarrhythmic agent, disopyramide, on electrical cardiac responses to vagus stimulation in anesthetized dogs. Dofetilide (0.003-0.3 micromol/kg, i.v.), E-4031 (0.01-1 micromol/kg, i.v.) and disopyramide (2.9-29 micromol/kg, i.v.) prolonged sinus cycle length (SCL), right atrial effective refractory period (AERP) and ventricular effective refractory period (VERP) dose-dependently. During cervical vagus stimulation-induced prolongation of SCL, atrio-His (AH) interval and VERP and shortening of AERP, dofetilide and E-4031 inhibited the prolongation of SCL but potentiated the shortening of AERP. Dofetilide and E-4031 did not affect prolongations of AH interval and VERP. On the other hand, disopyramide inhibited all electrical cardiac responses to vagus stimulation. These results suggest that I(Kr) inhibition differentially modulate cardiac responses to vagus activation probably due to a different role of I(Kr) in each cardiac function in the heart in situ.

Topics: Animals; Anti-Arrhythmia Agents; Bradycardia; Disease Models, Animal; Disopyramide; Dogs; Dose-Response Relationship, Drug; Electric Stimulation; Electrophysiology; Female; Heart Conduction System; Male; Phenethylamines; Piperidines; Potassium Channel Blockers; Pyridines; Sulfonamides; Vagus Nerve

Topics: Anesthetics, Intravenous; Bradycardia; Humans; Male; Middle Aged; Piperidines; Remifentanil

A 2-month-old infant with gastroesophageal reflux was treated with cisapride. Bradycardia developed and an electrocardiogram revealed 2:1 atrioventricular conduction and a prolonged QT interval. After cessation of cisapride therapy, both the rhythm and the QT interval returned to normal. Prolonged QT interval during treatment with cisapride may occur in children as in adults.

Topics: Adult; Age Factors; Bradycardia; Cisapride; Electrocardiography; Female; Gastroesophageal Reflux; Humans; Infant; Long QT Syndrome; Piperidines

p-Dimethoxyaryl analogs of certain potent catechol-derived dopaminergic agonists show dopaminergic properties for which no structure-activity relationship has yet been defined. (S)-3-(3-Hydroxyphenyl)-N-n-propylpiperidine (1, S-"3-PPP") is a dopaminergic autoreceptor agonist, and at high doses it also exhibits postsynaptic antagonism. (R)-1 is a postsynaptic agonist. In a continuation of studies of effects of the p-dimethoxy moiety at dopamine receptors, synthesis and resolution of the 2,5-dimethoxy analog 3 of 3-PPP was undertaken. The two enantiomers and the racemic modification showed cardiovascular effects consistent with actions at DA-2 receptors. The potency of all three compounds was much lower than that of 3-PPP, although they displayed approximately the same duration of action. Absolute configuration does not seem to be a major determinant of these compounds' ability to interact with DA-2 receptors.

Topics: Animals; Bradycardia; Dopamine Agents; Hypotension; Piperidines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship

Diphemanil can be useful in some neonates presenting with bradycardia due to vagal hyperreflectivity. Paradoxically, this drug may induce atrio-ventricular (AV) block in premature babies.. Case no 1. A premature neonate suffering from acute respiratory distress from birth required respiratory support, antibiotics and caffeine. Despite this treatment, he underwent many episodes of apnea, and bradycardia that appeared on day 4 and did not respond to IV doxapram (1 mg/kg/h). He was given diphemanil on day 9 (10 mg/kg/d) and permanent bradycardia with complete AV block and a normal QT interval appeared 2 days later. Cessation of diphemanil and administration of IV isoprenaline led to a normal sinusal rhythm, but there were bladder, intestinal and ocular signs of atropinic intoxication. A complete definitive recovery occurred 5 days after cessation of diphemanil. Case no 2. A premature neonate developed episodes of apnea 2 days after birth. These episodes persisted and were complicated by bradycardia on day 4 despite administration of caffeine. Vagal stimulation on day 7 was positive and the infant was then given diphemanil (10 mg/kg/d). Permanent bradycardia occurred 2 days later, with partial AV block and a normal QT interval. The child recovered a normal sinusal rhythm 2 days after cessation of diphemanil.. Anticholinergic therapy may cause permanent bradycardia due to AV block in premature infants. This therapy should not be given to premature infants without a prior ECG. Doses lower than those used in infants are recommended.

Topics: Bradycardia; Bronchodilator Agents; Drug Administration Schedule; Heart Block; Humans; Infant, Newborn; Infant, Premature; Male; Parasympatholytics; Piperidines; Respiratory Distress Syndrome, Newborn

The pharmacokinetics of diphemanil methylsulphate was evaluated after oral administration of a single 3 mg.kg-1 dose to 5 infants being treated for symptomatic bradycardia. The mean pharmacokinetic parameters of oral diphemanil methylsulphate in infants were similar to those in adults. The mean half-life was 8.6 h. This would allow administration three times a day in infants instead of four to six times a day, as currently prescribed. The mean residence time decreases significantly with age (Spearman's r' = -1), and there is a trend for the half-life to decrease with age (r' = -0.9; NS), suggesting an influence of maturation on its elimination.

Topics: Administration, Oral; Bradycardia; Drug Administration Schedule; Half-Life; Humans; Infant; Parasympatholytics; Piperidines

Four premature infants presenting with episodes of bradycardia in the first weeks of life were given diphemanil. One of them received an overdose accidentally. Paradoxically, this induced a permanent bradycardia leading to the discovery of a grade II A-V block as well as a prolonged QT interval. Discontinuation of the drug resulted in a prompt normalization of these changes. It is felt that this anticholinergic therapy may have caused a prolongation of the QT interval and, therefore, a partial A-V block in case of sinus tachycardia. Thus, such a therapy should not be given to young premature infants without having checked the QT interval on a ECG tracing and having made sure that it is adapted to the actual heart rate. It is also advised to reduce usual doses.

Topics: Bradycardia; Electrocardiography; Female; Heart Block; Humans; Infant, Newborn; Infant, Premature, Diseases; Male; Parasympatholytics; Piperidines

We report a case of vagal hypertonia syndrome in a newborn infant, developed after surgical repair of an aortic coarctation combined with banding of the pulmonary artery trunk. The parasympathetic activity had adverse repercussions on haemodynamics. The diagnosis was confirmed by prolonged asystole on the oculocardiac reflex and by concomitant arrhythmia and disorders of conduction demonstrated by Holter recordings. To our knowledge, no other case of vagal hypertonia associated with a congenital cardiopathy has yet been reported. Infants with this syndrome are at a high risk of sudden death. Treatment with vagolytic drugs is of questionable value, and prolonged supervision of the patient is mandatory.

Topics: Bradycardia; Cranial Nerve Diseases; Follow-Up Studies; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant, Newborn; Male; Parasympatholytics; Piperidines; Sudden Infant Death; Syndrome; Vagus Nerve

For a period of 20 months, 50 consecutive infants (mean age: 11 months) were given Diphemanil (atropine like synthetic drug) for reflex symptomatic bradycardia of probable vagal origin. Treatment's results were evaluated with the study of oculo-cardiac reflex (OCR) and Holter monitoring performed before and 3 months after the beginning of Diphemanil. If tolerance was generally good, it was not possible to demonstrate the clinical efficacy of the treatment on the whole group. However, assertive success was seen on individual cases. Holter and OCR data improved statistically. The other therapeutical means aiming at warning possible complications of the hypertonic vagal reflex were reviewed: inserting a cardiac pace-maker does not always prevent sudden death; a nodal sinus surgical selective denervation might be justified in certain exceptional cases, because of the severity of the spontaneous evolution or of the resistance to medical treatment.

Topics: Bradycardia; Child, Preschool; Cranial Nerve Diseases; Female; Humans; Infant; Infant, Newborn; Male; Parasympatholytics; Piperidines; Sudden Infant Death; Vagus Nerve

The hypotension and bradycardia observed after intravenous injection of dextran sulfate in rabbits was prevented by prior depletion of circulating platelets, but was not prevented by depletion of the third component of complement or Hageman factor. Dextran sulfate injection caused immediate thrombocytopenia with temporary localization of platelets within lungs. Morphological analysis revealed platelet aggregates in lung capillaries. The platelets had changed shape and were in the process of degranulating. Serotonin and histamine levels in blood increased approximately 5-fold and 7-fold, respectively, after dextran sulfate injection. The cardiovascular events following dextran sulfate injection were mimicked by intravenous serotonin but not by intravenous histamine injection, although a combination of serotonin and histamine reproduced the pattern of blood pressure changes better than did either agent alone. Quantification of platelets trapped in lung revealed that the potential release of serotonin from trapped platelets could account for the rise in plasma serotonin concentration and the hemodynamic changes observed. Both the dextran sulfate-induced cardiovascular effects and serotonin-induced hypotension were markedly diminished by cutting vagus and depressor nerves, and were virtually abolished by carotid ligation in addition to nerve section. These results support the concept that platelet activation within rabbit lungs may cause hypotension via serotonin-induced chemoreflexes.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Autonomic Nervous System; Blood Platelets; Bradycardia; Chemoreceptor Cells; Cimetidine; Complement C3; Dextran Sulfate; Dextrans; Factor XII; Histamine; Histamine Release; Hypotension; Injections, Intravenous; Ketanserin; Leukocyte Count; Lung; Male; Methysergide; Piperidines; Rabbits; Serotonin

High dosages of narcotic analgesics are frequently utilized as the sole anaesthetic agents for patients requiring open-heart surgery. The purpose of this study was to investigate the effect of high dosages of fentanyl and piritramide upon the cardiovascular system. In anaesthetized dogs (N2O:O2=2:1; 0.5 vol% halothane) 0.03 mg/kg fentanyl (=8) and 1.5 mg/kg piritramide (n=8) respectively were given intravenously as a bolus. After the administration of fentanyl there was a slight decrease in blood pressure (10%). The hypotension was the result of a decrease in cardiac output (thermodilution technique) by 13% due to bradycardia. Total peripheral resistance and myocardial contractility remained unaffected. Similar effects were only found late after injection of piritramide, since there was an initial cardiovascular response to piritramide characterized by a marked fall in blood pressure (29%). The major cause of arterial hypotension was peripheral vasodilatation. Load data and the decrease in max dp/dt however indicated also a slight myocardial depression. The altered haemodynamics led to a decrease in myocardial oxygen consumption with both narcotics, which was nearly paralleled by a reduction in coronary blood flow. The narrowing of arteriovenous oxygen difference of the heart proved coronary dilatatory properties of fentanyl and especially of piritramide. This study indicated that high dosages of fentanyl have advantages in comparison to high dosages of piritramide. The clinical implications of the results are discussed.

Topics: Animals; Blood Pressure; Bradycardia; Cardiac Output; Coronary Circulation; Dogs; Female; Fentanyl; Heart; Heart Rate; Isonipecotic Acids; Male; Myocardial Contraction; Myocardium; Oxygen Consumption; Piperidines; Vascular Resistance

Topics: Adolescent; Adult; Aged; Androstanes; Bradycardia; Electrocardiography; Female; Heart Rate; Humans; Male; Middle Aged; Neuromuscular Nondepolarizing Agents; Piperidines; Premedication; Succinylcholine; Toxiferine; Tubocurarine

Topics: Animals; Antidotes; Atropine; Bradycardia; Carbachol; Central Nervous System; Cholinesterase Inhibitors; Female; Guinea Pigs; Hallucinogens; Heart Rate; Mandelic Acids; Methacholine Compounds; Mice; Parasympatholytics; Peripheral Nerves; Phosphates; Piperidines; Pupil; Quaternary Ammonium Compounds; Rabbits; Scopolamine; Seizures; Trihexyphenidyl

Topics: Analgesics; Analgesics, Non-Narcotic; Antipyretics; Bradycardia; Droperidol; Fentanyl; Hypotension; Mice; Morphine; Mortality; Nalorphine; Pharmacology; Piperidines; Research; Toxicology