Kegg Pathway: Antiarrhythmic drugs

Int J Legal Med. 2008 Jul 19;
Hikiji W, Kudo K, Nishida N, Ishida T, Usumoto Y, Tsuji A, Ikeda N

A fatal case of intentional poisoning with two Antiarrhythmic agents, pilsicainide, a pure sodium channel blocker, and atenolol, a selective beta1 blocker, is presented. A woman in her twenties was found dead at home and empty pill packages of pilsicainide, atenolol, and aspirin were found near by. Hesitation marks were found on the wrist, and strong fibrous degeneration was observed in the cardiomyocytes of the sinoatrial node. The blood concentrations of pilsicainide and atenolol were 7.83 and 4.94 mug/ml, respectively, both far above the reported therapeutic levels. According to these results, we concluded that death was due to cardiac arrhythmia caused by poisoning with pilsicainide and atenolol. This is the first report of fatal poisoning attributable to an overdose of the combination of these two Antiarrhythmic drugs.

Anesth Analg. 2008 Jul; 107(1): 37-50
Matyal R

The assumption that males and females are physiologically similar has led to females being clinically evaluated and treated as males. However, there is growing evidence in the literature that, other than the reproductive system, there are other fundamental physiological differences between the two genders. The manifestation of these differences starts soon after puberty and becomes more pronounced with age. The differences in body mass and volume and renal and liver metabolism account for the difference in therapeutic efficacy and side effects of commonly used cardiovascular drugs. Women have smaller coronary arteries, more frequent diastolic dysfunction, present with vague symptoms of coronary artery disease and do worse than men after revascularization procedures. Women also have a shorter cardiac cycle and are more prone to develop arrhythmias and react differently to Antiarrhythmic drugs. Most epidemiological trials that have assessed the utility of pharmacological myocardial protection or outcomes after noncardiac surgery have either been performed on men only or women were not identified as a separate group. Recent evidence is suggestive that coronary vasospasm may be the dominant etiology of acute myocardial ischemia in women. This may explain the poor sensitivity and specificity of the routine myocardial perfusion tests. Having considered all this evidence, it has become very essential to view the operative risk stratification as being gender-based. This approach may involve a shift in our present day paradigm of patient management.

Herzschrittmacherther Elektrophysiol. 2008 Jun; 19(2): 27-32
Nölker G, Brachmann J

Atrial fibrillation is a relevant challenge for health care systems in Europe and North America. Interventional treatment of atrial fibrillation in terms of ablation of atrial structures including isolation of the pulmonary veins is nowadays established as an alternative to drug therapy, especially if treatment with Antiarrhythmic drugs has been ineffective. Recently published European and North American guidelines support this strategy.This article describes different techniques of atrial fibrillation ablation including intracardiac echo-guided pulmonary vein isolation. Potential complications, success rates and different follow-up strategies are specified. Furthermore interventional treatment of atrial fibrillation of heart failure patients is discussed.

Vasc Health Risk Manag. 2008; 4(1): 67-73
Cuspidi C, Negri F, Zanchetti A

Left ventricular hypertrophy (LVH) and atrial fibrillation (AF) are strong predictors of cardiovascular (CV) morbidity and mortality, independently of blood pressure levels and other modifiable and nonmodifiable risk factors. The actions of circulating and tissue angiotensin II, mediated by AT1 receptors, play an important role in the development of a wide spectrum of cardiovascular alterations, including LVH, atrial enlargement and AF. Growing experimental and clinical evidence suggests that antihypertensive drugs may exert different effects on LVH regression and new onset AF in the setting of arterial hypertension. Since a number of large and adequately designed studies have found angiotensin II receptor blockers (ARBs) to be more effective in reducing LVH than beta-blockers and data are also available showing their effectiveness in preventing new or recurrent AF, it is reasonable to consider this class of drugs among first line therapies in patients with hypertension and LVH (a very high risk phenotype predisposing to AF) and as adjunctive therapy to Antiarrhythmic agents in patients undergoing pharmacological or electrical cardioversion of AF.

Undersea Hyperb Med. 2008 May-Jun; 35(3): 159-61
Weisher DD

We report two interesting cases in which both divers sustained a very serious Type II decompression sickness. This involved substantial neurological impairment which was successfully treated despite having a delayed treatment time 12 hours or more. The treatment used hyperbaric oxygen recompression therapy with the addition oflidocaine i.v. drip. This first case was in November 2007 and the second was in December 2007 and both patients made excellent recoveries.

Int Heart J. 2008 May; 49(3): 281-93
Ishiguro H, Ikeda T, Abe A, Tsukada T, Mera H, Nakamura K, Yusu S, Yoshino H

In the treatment of arrhythmia, beta-blockers are mainly used to regulate the heart rate. However, beta-blockers are also known as drugs with an Antiarrhythmic effect due to the suppression of sympathetic activity. We evaluated the Antiarrhythmic effects of a highly selective beta(1)-blocker, bisoprolol, in patients with diurnal paroxysmal atrial fibrillation (P-AF). A total of 136 patients with symptomatic diurnal P-AF were enrolled. Patients were divided into a diurnal-specific P-AF group and a diurnal & nocturnal P-AF group, as well as into a bisoprolol single use group and a combined use group with an Antiarrhythmic drug. The effects of bisoprolol were evaluated in 3 categories: subjective symptom improvement, quality of life (QOL) improvement, and elimination of P-AF episode in Holter electrocardiograms (ECGs). For patients with effective treatment, a long-term effect up to 24 months was evaluated. Five patients (3.7%) discontinued bisoprolol due to side effects. Following administration of bisoprolol, 109 patients (80%) experienced subjective symptom improvement, 103 patients (76%) experienced QOL improvement, and elimination of P-AF episodes in ECGs was observed in 84 patients (62%). The elimination rate of P-AF episodes in ECGs was higher in the diurnal P-AF group than in the diurnal & nocturnal P-AF group (P = 0.042). There was no significant difference between the bisoprolol single use group and the combined use group. A long-term suppressive effect by bisoprolol was observed in 70 of 83 patients (84%). The results demonstrate that bisoprolol has an Antiarrhythmic effect against sympathetic diurnal P-AF, improving subjective symptoms and QOL and eliminating P-AF episodes in ECGs.

Pharmazie. 2008 Jun; 63(6): 480-4
Maciag D, Bednarski M, Filipek B, Pociecha T, Szkaradek N, Marona H

A series of aroxyethylamines (1-10) have been previously evaluated for antihypertensive and adrenolytic properties. Of the derivatives tested, four (compounds 4, 7, 8 and 10) displayed significant antihypertensive activity and binding affinities for alpha- and beta-adrenergic receptors. As a continuation of our study, we present here the in vivo and in vitro Antiarrhythmic activity of compounds 1-10, as well as their electrocardiographic properties. Only compounds 4, 7, 8 and 10 demonstrated strong Antiarrhythmic activity in adrenaline induced arrhythmia after intravenous and oral administration. In addition, compounds 4 and 7 significantly decreased heart rhythm disturbances in arrhythmia induced by coronary artery occlusion and reperfusion. The pharmacological results and receptor binding studies suggest that the Antiarrhythmic activity of the compounds tested may be related to their adrenolytic properties. Moreover, the presence of a methoxyphenylpiperazine moiety seems to be required for their pharmacological activity.

Pharmazie. 2008 Jun; 63(6): 475-9
Xu L, Huang C, Chen J, Jiang X, Li X, Bett GC, Rasmusson RL, Wang S

As the major component of I(to) (slow), Kv1.4 channel plays an important role in repolarization of cardiac myocytes. C-type inactivation is one of Kv1.4 inactivation and can be affected by open channel blockers. We used the two-electrode voltage clamp technique to observe the effect of amiodarone on Kv1.4 C-type inactivation and compare amiodarone's effects on Kv1.4 with propafenone and verapamil. Our data show that those three Antiarrhythmic drugs blocked fKv1.4 delta N (N-terminal deleted Kv1.4 channel from ferret heart) in voltage- and frequent-dependent manners. The amiodarone's IC50 was 489.23 +/- 4.72 microM, higher than that of propafenone (98.97 +/- 1.13 microM) and verapamil (263.26 +/- 6.89 microM) for fKv1.4 delta N channel (+50 mV). After application of amiodarone, propafenone and verapamil, fKv1.4 delta N inactivation becomes bi-exponential: the faster portion of inactivation (drug-induced inactivation) and the slower portion of inactivation (C-type inactivation). Amiodarone and verapamil fastened C-type inactivation in fKv1.4 delta N, but propafenone did not. Unlike propafenone that had no effect on fKv1.4 delta N recovery, amiodarone and verapamil slowed recovery in fKv1.4 delta N.

J Thorac Cardiovasc Surg. 2008 Jul; 136(1): 100-7, 107.e1
Blaufox AD, Sleeper LA, Bradley DJ, Breitbart RE, Hordof A, Kanter RJ, Stephenson EA, Stylianou M, Vetter VL, Saul JP,

OBJECTIVES: Our objective was to determine the relationship between functional outcome and abnormalities of heart rate and rhythm after the Fontan operation. METHODS: The National Heart, Lung, and Blood Institute Pediatric Heart Network conducted a cross-sectional analysis of patients who had undergone a Fontan procedure at the 7 network centers. Analysis was based on 521 patients with an electrocardiogram (n = 509) and/or bicycle exercise test (n = 404). The Child Health Questionnaire parent report and the oxygen consumption at the anaerobic threshold were used as markers of functional outcome. RESULTS: Various Fontan procedures had been performed: intracardiac lateral tunnel (59%), atriopulmonary connection (14%), extracardiac later tunnel (13%), and extracardiac conduit (11%). Prior volume unloading surgery was performed in 389 patients: bidirectional Glenn (70%) and hemi-Fontan (26%). A history of atrial tachycardia was noted in 9.6% of patients and 13.1% of patients had a pacemaker. Lower resting heart rate and higher peak heart rate were each weakly associated with better functional status, as defined by higher anaerobic threshold (R = -0.18, P = .004, and R = 0.16, P = .007, respectively) and higher Child Health scores for physical functioning (R = -0.18, P < .001, and R = 0.17, P = .002, respectively). Higher anaerobic threshold was also independently associated with younger age and an abnormal P-axis. Resting bradycardia was not associated with anaerobic threshold or Child Health scores. CONCLUSIONS: In pediatric patients (6-18 years) after the Fontan procedure, a lower resting heart rate and a higher peak heart rate are each independently associated with better physical function as measured by anaerobic threshold and Child Health scores. However, these correlations are weak, suggesting that other, nonrhythm and nonrate, factors may have a greater impact on the functional outcome of pediatric patients after the Fontan operation.

Pharmacol Ther. 2008 Jun 13;
Vik T, Pollard C, Sager P

Drug-induced arrhythmias or QT interval prolongation is one of the two most common reasons for drugs to be denied regulatory approval or to have warnings imposed on their clinical labelling. The assessment of torsades de pointes (TdP) risk during clinical development of a new pharmaceutical compound has been an issue of debate since the original description of drug-induced proarrhythmia. TdP risk assessment is complicated by the very low incidence (e.g., <1/100,000 patient years of exposure) of clinical events for non-Antiarrhythmic agents and thus the improbable likelihood of observing even one event during clinical development. Thus surrogate methods of determining risk are necessary. A clinical approach to the issue of TdP risk assessment during drug development has been developed and implemented internationally. These efforts have markedly reduced the likelihood that drugs with unknown TdP risks will be commercialized, have resulted in fostering extensive productive pre-clinical and clinical research, and subsequent improved understanding of drug-induced proarrhythmia. Current research efforts are directed to increasing the efficiency of clinical QT assessment and the impact of pre-clinical assessment on clinical development. This article describes the clinical evaluation of TdP risk during drug development and how pre-clinical assessment can impact the early clinical development TdP risk assessment.

Circ Res. 2008 Jul 3;
Barajas-Martínez HM, Hu D, Cordeiro JM, Wu Y, Kovacs RJ, Meltser H, Kui H, Elena B, Brugada R, Antzelevitch C, Dumaine R

Brugada syndrome has been linked to mutations in SCN5A. Agents that dissociate slowly from the sodium channel such as flecainide and ajmaline unmask the Brugada syndrome electrocardiogram and precipitate ventricular tachycardia/fibrillation. Lidocaine, an agent with rapid dissociation kinetics, has previously been shown to exert no effect in patients with Brugada syndrome. We characterized a novel double mutation of SCN5A (V232I in DI-S4+L1308F in DIII-S4) identified in a rare case of lidocaine (1 mg/kg)-induced Brugada syndrome. We studied lidocaine blockade of INa generated by wild-type and V232I+L1308F mutant cardiac sodium channels expressed in mammalian TSA201 cells using patch clamp techniques. Despite no significant difference in steady-state gating parameters between V232I+L1308F and wild-type sodium currents at baseline, use-dependent inhibition of INa by lidocaine was more pronounced in V232I+L1308F versus wild-type (73.0+/-0.1% versus 18.23+/-0.04% at 10 micromol/L measured at 10 Hz, respectively). A dose of 10 micromol/L lidocaine also caused a more negative shift of steady-state inactivation in V232I+L1308F versus wild-type (-14.1+/-0.3 mV and -4.8+/-0.3 mV, respectively). The individual mutations produced a much less accentuated effect. We report the first case of lidocaine-induced Brugada electrocardiogram phenotype. The double mutation in SCN5A, V232I, and L1308F alters the affinity of the cardiac sodium channel for lidocaine such that the drug assumes Class IC characteristics with potent use-dependent block of the sodium channel. Our results demonstrate an additive effect of the 2 missense mutations to sensitize the sodium channel to lidocaine. These findings suggest caution when treating patients carrying such genetic variations with Class I Antiarrhythmic drugs.

BMJ. 2008; 337: a424
Leitz N, Khawaja Z, Been M

Tidsskr Nor Laegeforen. 2008 Jun 26; 128(13): 1532-3
Gjesdal K

In former days, amiodarone was mainly used as high-dose prescription for serious ventricular arrhythmias. The indication was life-saving and a high incidence of adverse effects was consequently accepted. Such patients are currently protected by an implantable cardioconverter-defibrillator (ICD), and the typical amiodarone patient receives low-dose treatment for atrial fibrillation. In this situation, the tolerance for adverse effects is lower. Increased photosensitivity is often bothersome and the thyroid function is frequently affected. Cough and dyspnoe may still indicate drug-induced interstitial lung disease and is a feared complication that may have a lethal outcome, but it rarely occurs due to the lower doses prescribed. The pharmacokinetics of amiodarone are peculiar, and there are interactions with many drugs. Treatment must therefore be guided by a specialist of internal medicine or cardiology. Despite these limitations, amiodarone is a useful drug, both in the emergency setting and in the atrial fibrillation patients who respond poorly to conventional treatment. Amiodarone may prove beneficial in the primary prevention of atrial fibrillation, to convert fibrillation, to prevent recurrency, and finally, to reduce a fast ventricular rate that does not respond to standard therapy.

Anaesthesia. 2008 Jul; 63(7): 719-25
Thwaites CL, Yen LM, Cordon SM, Thwaites GE, Loan HT, Thuy TT, White NJ, Soni N, Macdonald IA, Farrar JJ

Severe tetanus is characterised by muscle spasms and autonomic dysfunction. We recently reported the results of a randomised placebo controlled trial of magnesium sulphate infusions for the treatment of severe tetanus which showed magnesium was associated with improved muscle spasm and cardiovascular control. We hypothesised that magnesium controlled autonomic dysfunction by reducing catecholamine release and thus urinary excretion. Urinary adrenaline and noradrenaline concentrations were measured during the first 24 h of therapy in 180 adults with severe tetanus randomised to treatment with magnesium (n = 92) or placebo (n = 88). Magnesium therapy was associated with lower urinary adrenaline excretion and higher urinary noradrenaline excretion. High urinary adrenaline concentrations were associated with documented autonomic dysfunction. Patients given magnesium had significantly less autonomic dysfunction, required less cardiovascular stabilising drugs, and had lower urinary concentrations of adrenaline. These findings suggest adrenaline is important in the pathophysiology of severe tetanus and magnesium controls autonomic dysfunction by reducing adrenaline release.

Anesthesiology. 2008 Jul; 109(1): 118-23
Martin F, Cherif K, Gentili ME, Enel D, Abe E, Alvarez JC, Mazoit JX, Chauvin M, Bouhassira D, Fletcher D

BACKGROUND: The analgesic effect of perioperative low doses of intravenous lidocaine has been demonstrated after abdominal surgery. This study aimed to evaluate whether a continuous intravenous low-dose lidocaine infusion reduced postoperative pain and modified nociceptive pain threshold after total hip arthroplasty. METHODS: Sixty patients participated in this randomized double-blinded study. Patients received lidocaine 1% (lidocaine group) with a 1.5 mg/kg intravenous bolus in 10 min followed by a 1.5 mg . kg . h intravenous infusion or saline (control group). These regimens were started 30 min before surgical incision and stopped 1h after skin closure. Lidocaine blood concentrations were measured at the end of administration. In both groups, postoperative analgesia was provided exclusively by patient-controlled intravenous morphine. Pain scores, morphine consumption, and operative hip flexion were recorded over 48 h. In addition, pressure pain thresholds and the extent of hyperalgesia around surgical incision were systematically measured at 24 and 48 h. RESULTS: In comparison with the placebo, lidocaine did not induce any opioid-sparing effect during the first 24 h (median [25-75% interquartile range]; 17 mg [9-28] vs. 15 mg [8-23]; P = 0.54). There was no significant difference regarding the effects of lidocaine and placebo on pain score, pressure pain thresholds, extent in the area of hyperalgesia, and maximal degree of active hip flexion tolerated. Mean plasma lidocaine concentration was 2.1 +/- 0.4 mug/ml. CONCLUSION: Low dose perioperative intravenous lidocaine after total hip arthroplasty offers no beneficial effect on postoperative analgesia and does not modify pressure and tactile pain thresholds.

Anesthesiology. 2008 Jul; 109(1): 72-80
Lange M, Smul TM, Redel A, Lotz C, Jazbutyte V, Schnupp V, Roewer N, Kehl F

BACKGROUND: Anesthetic preconditioning is mediated by beta- adrenergic signaling. This study tested the hypotheses that desflurane-induced preconditioning is dose-dependently blocked by metoprolol and mediated by calcium/calmodulin-dependent protein kinase II (CaMK II). METHODS: Pentobarbital-anesthetized New Zealand White rabbits were instrumented for measurement of systemic hemodynamics and subjected to 30 min of coronary artery occlusion followed by 3 h of reperfusion. Rabbits were assigned to receive vehicle (control), 0.2, 1.0, 1.75, or 2.5 mg/kg metoprolol for 30 min, or the CaMK II inhibitor KN-93 in the absence or presence of 1.0 minimum alveolar concentration desflurane. Protein expression of CaMK II, phospholamban, and phospho-phospholamban was measured by Western blotting. Myocardial infarct size and area at risk were measured with triphenyltetrazolium staining and patent blue, respectively. RESULTS: Baseline hemodynamics were not different among groups. Infarct size was 60 +/- 3% in control and significantly (* P < 0.05) decreased to 33 +/- 2%* by desflurane. The CaMK II inhibitor KN-93 did not affect infarct size (55 +/- 4%) but blocked desflurane-induced preconditioning (57 +/- 3%). Metoprolol at 0.2 and 1.0 mg/kg had no effect on infarct size (55 +/- 3% and 53 +/-3%), whereas metoprolol at 1.75 and 2.5 mg/kg reduced infarct size to 48 +/- 4%* and 39 +/- 5%*, respectively. Desflurane-induced preconditioning was attenuated by metoprolol at 0.2 mg/kg, leading to an infarct size of 46 +/- 5%*, and was completely abolished by metoprolol at 1.0, 1.75, and 2.5 mg/kg, resulting in infarct sizes of 51 +/- 3%, 52 +/- 3%, and 55 +/- 3%, respectively. CONCLUSIONS: Desflurane-induced preconditioning is dose-dependently blocked by metoprolol and mediated by CaMK II.

N Engl J Med. 2008 Jun 26; 358(26): 2829-31
Pyeritz RE

N Engl J Med. 2008 Jun 26; 358(26): 2787-95
Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC

BACKGROUND: Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan's syndrome. Recent data from mouse models of Marfan's syndrome suggest that aortic-root enlargement is caused by excessive signaling by transforming growth factor beta (TGF-beta) that can be mitigated by treatment with TGF-beta antagonists, including angiotensin II-receptor blockers (ARBs). We evaluated the clinical response to ARBs in pediatric patients with Marfan's syndrome who had severe aortic-root enlargement. METHODS: We identified 18 pediatric patients with Marfan's syndrome who had been followed during 12 to 47 months of therapy with ARBs after other medical therapy had failed to prevent progressive aortic-root enlargement. The ARB was losartan in 17 patients and irbesartan in 1 patient. We evaluated the efficacy of ARB therapy by comparing the rates of change in aortic-root diameter before and after the initiation of treatment with ARBs. RESULTS: The mean (+/-SD) rate of change in aortic-root diameter decreased significantly from 3.54+/-2.87 mm per year during previous medical therapy to 0.46+/-0.62 mm per year during ARB therapy (P<0.001). The deviation of aortic-root enlargement from normal, as expressed by the rate of change in z scores, was reduced by a mean difference of 1.47 z scores per year (95% confidence interval, 0.70 to 2.24; P<0.001) after the initiation of ARB therapy. The sinotubular junction, which is prone to dilation in Marfan's syndrome as well, also showed a reduced rate of change in diameter during ARB therapy (P<0.05), whereas the distal ascending aorta, which does not normally become dilated in Marfan's syndrome, was not affected by ARB therapy. CONCLUSIONS: In a small cohort study, the use of ARB therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial.

Eur Rev Med Pharmacol Sci. 2008 Mar-Apr; 12(2): 113-6
Facchini G, Forte S, Podda P, Piro F, Carlone S

Authors describe a case of pulmonary masses and estensive skin pigmentation: "blue-gray syndrome" occurred in a patient in amiodarone therapy who presented with progressive dyspnea, cough, and fever. The diagnosis was suspected by detection of a high attenuation of the pulmonary masses on the nonenhanced chest computed tomography (CT) and lots of foamy macrophages in the bronchoalveolar lavage fluid. Relief of respiratory symptoms and radiological improvement was achieved when amiodarone treatment was stopped.

Ann Thorac Surg. 2008 Jul; 86(1): 350-1; author reply 351-2
Pai RK, Conant AR, Dihmis WC