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Antidysrhythmic Drugs in Pediatrics
Published in Sam Kacew, Drug Toxicity and Metabolism in Pediatrics, 1990
Howard C. Mofenson, Thomas R. Caraccio, Kathleen Mimnagh, Peter Bruzzo
In 60% of patients (34 of 57) treated for ventricular dysrhythmias, propafenone effectively eliminated VT, reduced couplets by 90%, and achieved a 50 to 80% reduction in the frequency of ventricular premature beats.198 In a double-blind, placebo-controlled study, Hodges et al.199 noted an 80% or greater reduction in the frequency of PVCs in 58% (7 of 12) of patients receiving propafenone.
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Propafenone, a class Ic antiarrhythmic agent, has sodium channel blocking activity and slows intracardiac conduction (Bryson et al. 1993; Grant 1996; Siddoway et al. 1984). It also has β-adrenergic, potassium channel, and slight calcium channel blocking activity (Grant 1996). It is used clinically as a racemic mixture of S- and R-enantiomers. Although both enantiomers are equally potent in their activity as sodium channel blockers, the S-enantiomer has ~100-fold higher β-blocking activity than the R-enantiomer (Ki for the affinity to the human lymphocyte β2-adrenoceptors: 571 vs. 7.2 nM) (Kroemer et al. 1989a; Stoschitzky et al. 1990). The drug is an effective agent for the management of ventricular and supraventricular arrhythmias, particularly for Wolff–Parkinson–White syndrome (Grant 1996). Both enantiomers of propafenone exhibit distinct pharmacokinetics, with the R-enantiomer being cleared faster than the S-enantiomer (X. Chen et al. 2000; Kroemer et al. 1989a; Li et al. 1998). Propafenone undergoes extensive presystemic clearance that appears to be saturable, with bioavailability increasing as dosage increases. Nonlinear pharmacokinetics is observed with propafenone in humans (Connolly et al. 1983; Komura and Iwaki 2005). In humans, conjugates of hydroxylated derivatives of propafenone are present predominantly in the plasma postdosing (Hege et al. 1984). Propafenone is extensively metabolized by Phase I and Phase II reactions, resulting in at least 11 metabolites accounting for more than 90% of the dose administered (Hege et al. 1984). Propafenone is mainly metabolized by CYP2D6 via aromatic ring hydroxylation to 5-hydroxypropafenone and also by CYP1A2 and 3A4 to N-desalkylpropafenone to a minor extent (Figure 3.59) (Botsch et al. 1993; Zhou et al. 2003). Subsequent metabolism is via glucuronida-tion. 5-Hydroxypropafenone is pharmacologically active with similar electrophysiological profile to the parent drug (Haefeli et al. 1991; Malfatto et al. 1988; von Philipsborn et al. 1984). The major metabolites in feces and urine are glucuronide and sulfate conjugates of 5-hydroxypropafenone, N-desalkylpropafenone, and propafenone. Furthermore, propafenone undergoes oxidative deamination, resulting in a glycol and a lactic acid derivative (Hege et al. 1984). C–C splitting yields a relatively large amount of 3-phenyl-propionic acid, while cleavage of the ether group to a minor extent leads to a phenolic product.
Arrhythmias in Pregnancy
Published in Afshan B. Hameed, Diana S. Wolfe, Cardio-Obstetrics, 2020
Dana Senderoff Berger, Lee Brian Padove
The treatment in pregnancy is similar to nonpregnant patients (Figure 16.2). There is no benefit of rhythm control over rate control except when still symptomatic after rate control. In addition, in the majority of those presenting with a structurally normal heart, the first episode of atrial fibrillation typically converts quickly prior to any intervention, or within 24 hours with rate control [10,30]. And although pregnancy is thought to be a hypercoagulable state, a large retrospective study at Kaiser Permanente Southern California showed no cases of stroke despite low use of aspirin or anticoagulants in a relatively low risk group (average CHADVASC score 1.2) [22]. (See Table 16.3.) Rate control: First-line therapy is beta blockade. If hemodynamically stable, metoprolol IV 5 mg every 5 minutes up to 15 mg is used for heart rate control. If patient seems relatively dry, with history of poor oral intake, emesis, or marginal blood pressure, intravenous saline boluses are given. Second-line treatment includes intravenous diltiazem or digoxin [10,30]. Intravenous verapamil is typically not recommended due to potential to induce hypotension, which may lead to fetal hypoperfusion [30]. While digoxin has a large amount of safety data, it has a limited role as primary rate control and requires increased dosing in pregnancy and monitoring of levels. Nondihydropyridine calcium channel blockers have limited information, but some use verapamil as a third-line agent.Rhythm control: Rhythm control is indicated if patient remains symptomatic despite rate control. Flecainide has been used a great deal in the treatment of fetal SVT [20], with overall fetal safety demonstrated; therefore, we recommend it as the primary rhythm control agent in maternal atrial fibrillation with a structurally normal heart. We recommend starting low at 50 mg twice daily and increasing if needed. We usually will load while on maternal telemetry and will check a 12-lead ECG after the third dose. As expected, based on its use in fetal SVT, it does cross the placental barrier. Propafenone and sotalol can also be used in this situation, although propafenone has less data in pregnancy in the literature compared with flecainide, and sotalol is less preferable due to its effects on maternal blood pressure and heart rate. Amiodarone should be avoided due to potential fetal toxicity [30].If hemodynamically unstable, electrical cardioversion is the treatment of choice. Synchronized cardioversion is considered safe for the fetus in the same doses used in the nonpregnant state [43]. We typically use anticoagulation, either unfractionated heparin or low molecular weight heparin, if the duration of atrial fibrillation is unclear.
Atrial fibrillation and cancer; understanding the mysterious relationship through a systematic review
Published in Journal of Community Hospital Internal Medicine Perspectives, 2020
Noman Lateef, Vikas Kapoor, Muhammad Junaid Ahsan, Azka Latif, Umair Ahmed, Mohsin Mirza, Faiz Anwar, Mark Holmberg
The potential mechanisms underlying the association between AFib and increased long-term cancer risk remain unclear. Shared risk factors (e.g., advanced age, obesity, diabetes, and smoking) for both cancer and AFib possibly explain this association [8]. Also, antiarrhythmic medications are guideline recommended first-line management of AFib. Recent studies have shown increased cancer risk with antiarrhythmic medication use particularly Amiodarone. The study by Su et al. found that amiodarone use was associated with increased risk of incident cancer in male patients with (SIR, 1.18; 95% CI, 1.02 to 1.36 [p = 0.022]). Similarly, in the study by Lim et al. Amiodarone was associated with an increased risk of malignant neoplasm of liver and intrahepatic bile ducts with an odds ratio of 1.60 (1.45–1.77). The latter study also found an association of increased risk of cancer with other antiarrhythmic medications like Quinidine and Propafenone; however, the adjusted ratios were not significant for these two drugs [17,24]. Few case reports have described hepatotoxicity arising from the use of Propafenone. Steatohepatitis, hepatocellular injury, and fibrosis leading to cirrhosis and HCC is proposed mechanism of action [19]. Furthermore, as suggested by the prominence of colon cancer, increased detection can be due to gastrointestinal bleeding with anticoagulation use (Figure 2).
The effects of cardiac drugs on human erythrocyte carbonic anhydrase I and II isozymes
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Onur Argan, Kübra Çıkrıkçı, Aybike Baltacı, Nahit Gencer
CAs are drug-target enzymes. The inhibitors of these enzymes are important compounds for discovering new therapeutic agents and understanding enzyme–drug interactions in detail at the molecular level. Propafenone is a sodium channel-blocking antiarrhythmic drug. It works by blocking the activity of particular electrical signals in the heart that can cause arrythmias. It is used to restore a normal heart rhythm and maintain regular beats in supraventricular tachyarrhythmias18. The effect of these cardiovascular drugs on CA has not been studied; however, the effects of some of these agents on aldehyde oxidase were studied. Propafenone (2.5 µM), amlodipine (5.5 µM), and nifedipine (79% inhibition at 50 µM) have been shown to inhibit aldehyde oxidase to a certain extent19.
Regioselective hydroxylation of an antiarrhythmic drug, propafenone, mediated by rat liver cytochrome P450 2D2 differs from that catalyzed by human P450 2D6
Published in Xenobiotica, 2019
Shotaro Uehara, Norie Murayama, Hiroshi Yamazaki, Hiroshi Suemizu
Propafenone is a sodium channel blocking agent used clinically to treat cardiac arrhythmias, atrial fibrillation and ventricular tachycardia (Capucci and Boriani 1995). Propafenone is mainly metabolised into two metabolites in human liver microsomes: 5-hydroxypropafenone, which is formed by P450 2D6, and N-despropylpropafenone, which is formed by both P450 3A4 and 1A2 (Botsch et al., 1993). Major clearance routes of propafenone administered in humans have been shown to incorporate the conjugates of 5-hydroxypropafenone and propafenone glucuronide (Hege et al., 1984). In contrast, the major metabolite of propafenone in rat liver perfusate is 4′-hydroxypropafenone (Tan et al., 1998). Metabolic clearance of propafenone is also higher in rat hepatocytes than in human hepatocytes (Komura and Iwaki, 2005). β-Naphthoflavone and dexamethasone, typical P450 1A and 3A inducers, respectively, increase propafenone N-despropylation activity in rat liver microsomes (Zhou et al., 2001). However, the overall roles of rat P450 enzymes in the regioselective metabolism of propafenone have not yet been investigated.