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PubMed1985

Long term lorcainide therapy guided by electrophysiology studies.

One hundred patients inducible at electrophysiologic studies underwent serial drug testing with procainamide, lidocaine and lorcainide to determine comparative efficacy. Acute intravenous administration was followed by repeat programmed electrical stimulation (PES) studies on separate days for each antiarrhythmic drug. Lorcainide prevented VT induction in 69% of the 100 patients studied, procainamide was effective in 50% of the 75 patients studied, and lidocaine prevented VT induction in 30% of 53 patients. Following PES and serial drug testing, 46 patients were started on lorcainide, 9 patients on procainamide, and 45 patients were started on other antiarrhythmic drug regimens. Seventy percent of the patients have remained on lorcainide therapy, while 47% have continued on other drug therapies started over a 20.5 +/- 3.2 month mean follow-up period. Despite sleep-wake disturbances and a need for sedation at night, lorcainide therapy was tolerated well in this population and remained an effective antiarrhythmic with prolonged administration.

Administration, Oral↗
PubMed1980

[Pharmacokinetics of anti-arrhythmics. 2. Clinical applications].

The clinical usage of antiarrhythmic drugs may pose problems which could be solved by the direct application of the basic principles of pharmacokinetics. These problems involve the calculation of intravenous infusion rates and or oral dosages. Examples are provided by the rate of initial infusion of lignocaine in order to obtain a concentration within the therapeutic range, the eventual adjustment of this rate of infusion and the calculation of a loading dose. As regards the oral route, the calculation of the doses of procainamide is taken as an example. The estimation of the serum procainamide is a method for determining whether the dose should be increased or whether the drug is ineffective when no clinical result is observed. The pharmacokinetics of the main antiarrhythmic drugs are reviewed; procainamide, quinidine, propanolol, phenytoin, disopyramide. The therapeutic dose, clearance, extraction coefficient, bioavailability and half-life are the object of particular study. The fractioning of the dose and the total dose in a 24 hour period depend on these factors. The effects of cardiac, renal and hepatic failure on the clearance of each drug are recalled. These pharmacokinetic principles help the clinician not only in the prescription of an antiarrhythmic drug but also in deciding on the indications for drug serum concentration, estimations which are particularly useful in some difficult clinical situations, and in interpreting the results.

Administration, Oral↗
PubMed1982

Antiarrhythmic activity of the O-demethyl metabolite of encainide.

Clinical trials of the new antiarrhythmic agent encainide have demonstrated a high degree of efficacy in association with marked slowing of intracardiac conduction (prolongation of QRS). Indirect evidence has strongly suggested that at least some of these effects are mediated by the O-demethyl metabolite. The activity of a series of dosages of O-demethyl encainide, encainide and procainamide were compared against aconitine-induced ventricular arrhythmias in rats. Effective dosages were lowest for O-demethyl encainide and highest for procainamide: a 25% increase in the time to aconitine-induced ventricular tachycardia was produced by 0.02, 0.46 and 13 microM/kg of O-demethyl encainide, encainide and procainamide, respectively. QRS prolongation correlated well (r greater than 0.7, p less than .001) with enhanced survivorship for each agent tested and the cycle length of the ventricular tachycardia induced was lengthened in a dose-related fashion. Post-mortem plasma analysis showed that concentrations of the metabolite usually associated with pharmacological activity were present after encainide administration. However, encainide itself produced antiarrhythmic and electrocardiographic effects even when its metabolism was blocked. We conclude that both O-demethyl encainide and encainide exert antiarrhythmic actions in this model, but the metabolite is active at much lower dosages.

Aconitine↗
PubMed1980

Drug-induced systemic lupus erythematosus.

Despite some confusion in the literature, drug-induced SLE is a well defined reversible clinical entity. The lupus syndromes induced by procainamide, hydralazine, and isoniazid have been well studied and the data obtained have been convincing. Other drugs may also induce a lupus syndrome, but adequate prospective studies have not been done. Furthermore, many other drugs previously incriminated appear to activate spontaneous SLE rather than induce the de novo lupus syndrome. The mechanism by which procainamide, hydralazine, and isoniazid exert their effect is not known, and animal studies have been unrewarding. However, hydralazine and procainamide are capable of complexing with nuclear antigens in vitro and possibly in vivo and may evoke antinuclear antibody responses in this way. A number of defined factors influence the development of the clinical syndrome, including the cumulative drug dosage, the acetylator phenotype of the individual, and the biochemical nature of the drug. Studies to date have not revealed how these drugs induce the clinical disease. While these agents may induce antinuclear antibodies in many individuals, genetic influences may be important in determining which patients will develop clinical symptoms. Further study of drug-induced systemic lupus erythematosus is necessary in order to resolve these problems regarding pathogenesis. The resolution of these problems may shed light on the pathogenesis of spontaneous SLE.

Antibodies, Antinuclear↗
PubMed1994

[Acute atrial fibrillation in the emergency room. Which is the best drug for a rapid sinus rhythm conversion?].

PURPOSE: To evaluate differences between amiodarone, procainamide and quinidine in the time delay necessary to convert acute atrial fibrillation (AF) to sinus rhythm. METHODS: Sixty patients with acute AF were randomized in three groups (G) and treated with: quinidine (QG)-(21 patients) i.v. digital + quinidine up to 600 mg; procainamide (PG)-(23 patients) i.v. digital + i.v. procainamide, 10 mg/kg; amiodarone (AG)-(16 patients) i.v. amiodarone, 5 mg/kg. To evaluate time delay to conversion, all patients have their rhythm recorded by Holter system during four hours. Statistics were done with x2, considering significant a p < 0.05. RESULTS: There were no differences between groups regarding to age, gender and delay from symptoms initiation and medical assistance. Conversion to sinus rhythm occurred, in QG-71.4% cases; PG-47.8% and AG-50% (p > 0.05). Time delay in minutes to conversion were, respectively (media +/- SD): QG-112 +/- 43; PG-44.1 +/- 28; AG-20 +/- 13, significantly lower in PG and AG related to QG (p = 0.001). Although not significant, side effects were observed mostly in PG. CONCLUSION: Amiodarone is a good choice to convert, very quickly, acute AF. Otherwise, quinidine has the best rate of conversion but with a longer time delay.

Acute Disease↗
PubMed1999

Persistence of autoreactive T cell drive is required to elicit anti-chromatin antibodies in a murine model of drug-induced lupus.

Long-term treatment with procainamide and numerous other medications is occasionally associated with the development of drug-induced lupus. We recently established a murine model for this syndrome by disrupting central T cell tolerance. Two intrathymic injections of procainamide-hydroxylamine (PAHA), a reactive metabolite of procainamide, into (C57BL/6 x DBA/2)F1 mice resulted in the appearance of chromatin-reactive T cells and anti-chromatin autoantibodies. The current study explores in this model the role of autoreactive T cells in autoantibody production and examines why autoantibodies after a single intrathymic drug injection were much more limited in isotype and specificity. Injection of as few as 5000 chromatin-reactive T cells into naive, syngeneic mice induced a rapid IgM anti-denatured DNA response, while injection of at least 100-fold greater number of activated T cells was required for induction of IgG anti-chromatin Abs, suggesting that small numbers of autoreactive T cells can be homeostatically controlled. Mice subjected to a single intrathymic PAHA injection after receiving splenic B cells from an intrathymic PAHA-injected syngeneic donor also developed anti-chromatin Abs, but adoptive transfer of similarly primed T cells or of B cells without intrathymic PAHA injection of the recipient failed to produce an anti-chromatin response. However, anti-chromatin Abs developed after a single intrathymic PAHA injection in Fas-deficient C57BL/6-lpr/lpr mice, suggesting that activation-induced cell death limited autoimmunity in normal mice. Taken together, these results imply that chromatin-reactive T cells produced by intrathymic PAHA created a B cell population primed to somatically mutate and Ig class switch when subjected to a heavy load or second wave of autoreactive T cells.

Adoptive Transfer↗
PubMed1992

Pharmacologic suppression of atrial flutter induced by atrial stimulation.

To examine the electrophysiologic properties of human atrial flutter and its response to various classes of antiarrhythmic drugs, 39 patients were identified as having inducible sustained atrial flutter with atrial extra-stimulation techniques. Measurement of intra-atrial, interatrial, atrioventricular node and His-Purkinje-conduction intervals, atrial refractory periods, and atrial flutter-cycle length were made before and after intravenous administration of verapamil, ouabain, or cedilanid, propranolol, and procainamide in these 39 patients, as well as in seven control patients. Verapamil significantly shortened flutter-cycle length but suppressed atrial-flutter induction in only one of seven patients. Two of nine patients who received propranolol proved resistant to flutter provocation; the seven patients who remained nonsuppressible exhibited greater prolongation of interatrial-conduction time. Ouabain and cedilanid suppressed flutter inducibility in four of seven patients, and flutter-cycle length increased in those patients remaining inducible. Procainamide suppressed flutter induction in nine of 11 patients. These results suggest that procainamide is the most effective agent of those agents tested in suppressing atrial flutter induced by atrial extra-stimulation. Verapamil and propranolol proved quite ineffective in suppressing inducible atrial flutter.

Adult↗
PubMed1983

Differentiation of septal from free wall accessory pathway location: observations during bundle branch block in reciprocating tachycardia in the presence of type I antiarrhythmic drugs.

In patients with Wolff-Parkinson-White syndrome, observations during bundle branch block (BBB) in reciprocating tachycardia are of value in accessory pathway localization. Most importantly, an increase in the ventriculoatrial (VA) interval of greater than or equal to 35 ms has indicated an ipsilateral free wall location and excluded a septal location. The present study examined whether data collected in the presence of type I antiarrhythmic drugs retained localizing value. Review of retrospective data showed that observations in the drug-free state were precluded by the need to suppress atrial arrhythmia during electrophysiologic study in 20% of patients with Wolff-Parkinson-White syndrome who underwent preoperative workup. Prospectively, in 15 patients with left free wall or posteroseptal pathways, we observed transient left BBB during tachycardia before and after administration of procainamide, disopyramide or quinidine. Serum drug levels ranged from 4.6 to 6.9 mg/liter, except in 1 patient with a serum procainamide level of 18 mg/liter. Drugs increased the VA interval during narrow QRS tachycardia by 17% (p less than 0.01). However, the change in the VA interval with left BBB was not significantly affected. The baseline and drug values averaged 73 ms (range 39 to 94) and 70 ms (range 39 to 90), respectively, for left free wall pathways (n = 8), and 19 ms (range 0 to 28) and 21 ms (range 2 to 35), respectively, for posteroseptal pathways (n = 7). Among the latter, the interval increased less than 30 ms during left BBB except in the patient with the high serum procainamide level, in whom the increase was 35 ms. Thus, the VA interval change that accompanied left BBB remained of localizing value with moderate blood levels of type I drugs, and an increase greater than or equal to 35 ms indicated a left free wall rather than posteroseptal pathway.

Adolescent↗
PubMed1978

Antibody deposition in the pleura: a finding in drug-induced lupus.

Pleural tissues from a group of 36 consecutive patients comprised of 15 malignancies, 3 tuberculous, 2 rheumatoid arthritis, 3 procainamide-induced systemic lupus erythematosus (SLE) syndromes, 1 infectious mononucleosis, and 12 nonspecific pleural effusions undergoing needle biopsy were studied by immunofluorescent techniques for antibody deposition. Specific nuclear fluorescence was detected only in procainamide-induced SLE and was characterized by in vivo staining with either IgG, IgM, and in one case, also C3. C1q could not be detected. Two other patients who had antinuclear antibodies (ANA) in their peripheral blood did not have detectable in vivo antinuclear staining in their pleural tissue. The presence of in vivo fixation of ANA in the pleura may be of etiologic and diagnostic significance in procainamide-induced SLE syndrome.

Antibody Formation↗
PubMed1996

Atrial flutter: a newly recognized complication of pediatric lung transplantation.

BACKGROUND AND METHODS: Atrial flutter after pediatric lung transplantation has not previously been reported. We reviewed the records of 78 children who underwent lung transplantation at our institution to characterize the incidence and clinical course of postoperative atrial flutter. The diagnosis was based on either a surface or transesophageal electrocardiogram that demonstrated a fixed cycle length atrial tachycardia that did not require ventricular participation. RESULTS: Atrial flutter occurred in seven of 62 (11.3%) patients who underwent bilateral sequential lung transplantation, zero of 10 patients after single lung transplantation, and zero of six patients after heart-lung transplantation. Ages of the patients with atrial flutter ranged from 2.5 months to 14 years. Electrocardiographic findings among patients varied with respect to p-wave morphology and atrioventricular conduction. No patient had a prior atrial arrhythmia or coexisting structural cardiac disease. None had atrial flutter in relation to a rejection episode. Two patients had atrial flutter transiently during the first postoperative day, but it resolved spontaneously. Five patients had recurrent atrial flutter that began 13 +/- 7 days after the operation. The mean cycle length of atrial flutter was 196 +/- 65 msec. The arrhythmia was unresponsive to digoxin in four patients to whom it was administered. It was controlled with procainamide in four patients and with flecainide in one. At 1 and 6 months after lung transplantation, procainamide was discontinued in two patients without recurrence. One patient died of bronchiolitis obliterans 6 months after the operation while still receiving flecainide. Two patients continue to receive procainamide 4 and 7 months after transplantation. CONCLUSIONS: (1) Atrial flutter commonly occurs after bilateral lung transplantation in children. (2) Electrocardiographic manifestations are variable. (3) Type 1 antiarrhythmic agents provide satisfactory control.

Adolescent↗
PubMedDate not supplied

Effects of antiarrhythmic drugs on AV nodal and intraventricular conduction as assessed in the isolated, blood-perfused AV node preparation of the dog.

The effects of seven antiarrhythmic drugs on atrioventricular (AV) nodal and intraventricular (His-Purkinje-ventricular muscle) conduction were investigated in the isolated, blood-perfused AV node preparation of the dog. When injected into the posterior septal artery (PSA), which supplies mainly the AV node, quinidine, ajmaline, disopyramide, lidocaine, mexiletine, phenytoin, and procainamide increased AV nodal conduction time; and in high doses, these drugs produced second- or third-degree AV conduction block. However, quinidine, ajmaline, disopyramide, and lidocaine had less propensity to induce second- or third-degree AV conduction block than did phenytoin, mexiletine, and procainamide. When injected into the anterior septal artery (ASA), which supplies the His-Purkinje-ventricular muscle, all seven drugs prolonged intraventricular conduction time. The relative suppressant effects of these drugs on AV nodal and intraventricular conduction varied. Quinidine, disopyramide, and ajmaline suppressed AV nodal conduction as much as intraventricular conduction. Lidocaine and mexiletine suppressed AV nodal conduction more than intraventricular conduction, and phenytoin suppressed AV nodal conduction much more than intraventricular conduction. In contrast, procainamide suppressed intraventricular conduction rather than AV nodal conduction. All drugs increased blood flow in the ASA and the PSA.

Animals↗
PubMed1987

Effects of antiarrhythmic drugs on premature action potential duration in canine ventricular muscle fibers.

The range of premature action potential duration (APDs) during the first 100 ms of electrical restitution was determined in canine ventricular muscle fibers (VM) in the presence of lidocaine (4 and 8 micrograms/ml), mexiletine (8 micrograms/ml), flecainide (2 and 4 micrograms/ml), procainamide (50 micrograms/ml), quinidine (10 micrograms/ml), and disopyramide (10 micrograms/ml). The drug effects on the characteristics of action potential at the basic cycle lengths (BCLs) of 500 and 1,000 ms were similar to those reported previously. At control, the range of premature APDs was approximately 40 ms at BCL of 1,000 ms and approximately 30 ms at BCL of 500 ms. It was decreased 26-52% by lidocaine, mexiletine, and flecainide, not changed significantly by procainamide, and increased 17-53% by quinidine and disopyramide. The range of premature APDs at control and in the presence of drugs in ventricular muscle was smaller than in Purkinje fibers at the same or lower drug concentrations (Varro et al., J Pharmacol Exp Ther 1985;233:304). The four factors influencing the premature APD range in the Purkinje fibers operated in the VM as follows: The difference between the duration of effective refractory period (ERP) and the APD at BCL (APDb) (i.e., the ERP-APDb interval) was increased by lidocaine, mexiletine, and flecainide; normalized restitution curve was shifted toward longer premature APD values only by flecainide; the kinetics of restitution were slowed only by procainamide; and APD at BCL of 1,000 ms was shortened by lidocaine and mexiletine, and prolonged at BCLs of 1,000 and 500 ms by the other four drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1988

Comparative effects of antiarrhythmic drugs on the ventricular fibrillation threshold.

The purpose of this study was to compare the effects of several different antiarrhythmic drugs on the ventricular fibrillation threshold (VFT). Experiments were performed on open-chest dogs anesthetized with pentobarbital. The VFT was measured on the right ventricle by scanning the vulnerable period with a single 10-ms electrical stimulus. The following antiarrhythmic drugs were each given intravenously to eight different dogs: procainamide (25 mg/kg), lidocaine (2 mg/kg + 70 micrograms/kg/min), flecainide (3 mg/kg), timolol (0.1 mg/kg), clofilium (1 mg/kg), dl-sotalol (5 mg/kg), and bethanidine (4 mg/kg). The drugs resulted in the following increases in the VFT: procainamide, 33 +/- 13%; lidocaine, 21 +/- 5%; flecainide, 38 +/- 10%; timolol, 19 +/- 6%; clofilium, 14 +/- 6%; sotalol, 33 +/- 10%; and bethanidine, 69 +/- 15%. The changes in VFT were all significant (p less than 0.01) except for clofilium. Only procainamide and sotalol caused stimulus-induced runs of nonsustained polymorphic ventricular tachycardia that spontaneously reverted to sinus rhythm after 4 s or more. In individual experiments, the occurrence of nonsustained polymorphic tachycardia that resembled ventricular fibrillation could not be correlated with a change in the VFT. In addition, there appeared to be no relationship between a drug-induced increase of the VFT and alterations in the QRS duration, the QT interval, or the ventricular effective refractory period. Bethanidine had the greatest effect on the VFT, in spite of the fact that this drug shortened the ventricular effective refractory period.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Investigation of class I anti-arrhythmic drug actions on guinea-pig cardiac mitochondrial lactate dehydrogenase activity.

1. The effects of the Class I anti-arrhythmic drugs quinidine, procainamide, lidocaine, phenytoin and tocainide on mitochondrial lactate dehydrogenase activity were compared in guinea-pig heart preparations. 2. All the tested drugs inhibited the enzyme activity in a concentration-dependent fashion, exhibiting varying profiles in their actions. Lidocaine exhibited inhibitory concentration 20% (IC20) and IC50 values of 0.52 +/- 0.02 mmol/L and 25.6 +/- 0.5 mmol/L, procainamide 6.0 +/- 0.2 mmol/L and 108 +/- 7.2 mmol/L, phenytoin 3.4 +/- 0.06 mumol/L and 0.34 +/- 0.02 mmol/L, quinidine 39.2 +/- 1.2 mumol/L and 9.8 +/- 0.8 mmol/L and tocainide 2.7 +/- 0.3 mmol/L and 44.6 +/- 2.5 mmol/L. 3. According to the IC50 values, this is the order of their inhibitory potencies: phenytoin > quinidine > lidocaine > tocainide > procainamide. This trend is in general agreement with the lipophilicity rank of the drugs. 4. It is concluded, therefore, that inhibition of mitochondrial lactate dehydrogenase is a property shared by most Class I anti-arrhythmic drugs which may depend on their lipophilicity and possibly their membrane stabilizing effects.

Animals↗
PubMed1990

Inhibition kinetics of cationic drugs on N'-methylnicotinamide uptake by brush border membrane vesicles from the dog kidney cortex.

The effect of cationic drugs on the uptake of the prototypical organic cation N'-methylnicotinamide has been evaluated. Using purified brush border membrane vesicles prepared from dog kidney cortex and applying a rapid Millipore filtration technique, cationic drugs apparent inhibitory constants (Ki) were calculated from kinetic analysis of N'-methylnicotinamide uptake corrected for noncarrier-mediated transport (10 s uptake; outwardly directed H+ gradient; pH 7.4, 25 degrees C). All of the cationic drugs tested exhibited competitive inhibition of N'-methylnicotinamide uptake suggesting that they all share the organic base transport system at the renal proximal tubule. The Ki values were as follows, in order of decreasing apparent affinity: quinidine (0.7 microM), trimehoprim (1.3 microM), cimetidine (2.0 microM), famotidine (3.0 microM), quinine (7.0 microM), amiloride (5.8 microM), procainamide (21 microM), and nizatidine (30 microM). The different relative affinities of the drugs for the organic base transport system may explain the mutual competition for renal tubular secretion observed when cationic drugs are administered concurrently in vivo, e.g., trimethoprim--procainamide and cimetidine--procainamide. The approach outlined in the present study should prove useful to predict complex drug interactions in clinical pharmacology.

Animals↗
PubMed1997

Safety of atrial defibrillation shocks synchronized to narrow and wide QRS complexes during atrial pacing protocols simulating atrial fibrillation in dogs.

BACKGROUND: The potential ventricular proarrhythmic effect of atrial defibrillation shocks (ADS) remains a concern with automatic internal atrial defibrillation. Optimal R-wave synchronization alone may not be sufficient to prevent the induction of ventricular fibrillation (VF). METHODS AND RESULTS: The proarrhythmic effect of ADS synchronized to normally conducted QRS complexes (NQRS) and to supraventricular complexes with left or right bundle-branch block (L/RBBB) was investigated in a canine atrial pacing study. Short-long-short, single premature, and burst pacing protocols from the high right atrium were performed at baseline, during isoproterenol infusion, and after intravenous procainamide. The ADS were delivered between decapolar catheters in the coronary sinus and lateral right atrium. They were initially delivered 20 milliseconds (ms) after the end of the last conducted QRS complex and then scanned decrementally through that complex until VF was induced. For NQRS complexes, VF occurred only when the ADS were delivered at or before the onset of the QRS complex and never during the complex itself. In the presence of LBBB or RBBB, VF was induced by ADS delivered at the onset of or within the first 45 ms of the QRS complex in 16 animals. The longest RR (VV) intervals preceding ADS-induced VF were 345 ms at baseline and 380 ms after procainamide. CONCLUSIONS: In this study, ADS synchronized to NQRS complexes appeared to be safe regardless of the preceding RR interval. In the presence of LBBB or RBBB, RR intervals preceding the ADS of >345 ms at baseline and >380 ms in the presence of procainamide would have been required to avoid VF. Alternatively, ADS delivered 50 ms after the onset of the RV electrogram appeared to be safe in all circumstances regardless of the preceding RR interval.

Animals↗
PubMed2006

Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2.

A cDNA coding a new H+/organic cation antiporter, human kidney-specific multidrug and toxin extrusion 2 (hMATE2-K), has been isolated from the human kidney. The hMATE2-K cDNA had an open reading frame that encodes a 566-amino acid protein, which shows 94, 82, 52, and 52% identity with the hMATE2, hMATE2-B, hMATE1, and rat MATE1, respectively. Reverse transcriptase-PCR revealed that hMATE2-K mRNA but not hMATE2 was expressed predominantly in the kidney, and hMATE2-B was ubiquitously found in all tissues examined except the kidney. The immunohistochemical analyses revealed that the hMATE2-K as well as the hMATE1 was localized at the brush border membranes of the proximal tubules. HEK293 cells that were transiently transfected with the hMATE2-K cDNA but not hMATE2-B exhibited the H+ gradient-dependent antiport of tetraethylammonium (TEA). Transfection of hMATE2-B had no affect on the hMATE2-K-mediated transport of TEA. hMATE2-K also transported cimetidine, 1-methyl-4-phenylpyridinium (MPP), procainamide, metformin, and N1-methylnicotinamide. Kinetic analyses demonstrated that the Michaelis-Menten constants for the hMATE2-K-mediated transport of TEA, MPP, cimetidine, metformin, and procainamide were 0.83 mM, 93.5 microM, 0.37 mM, 1.05 mM, and 4.10 mM, respectively. Ammonium chloride-induced intracellular acidification significantly stimulated the hMATE2-K-dependent transport of organic cations such as TEA, MPP, procainamide, metformin, N1-methylnicotinamide, creatinine, guanidine, quinidine, quinine, thiamine, and verapamil. These results indicate that hMATE2-K is a new human kidney-specific H+/organic cation antiporter that is responsible for the tubular secretion of cationic drugs across the brush border membranes.

Alternative Splicing↗
PubMed2000

Antiarrhythmic agents: drug interactions of clinical significance.

The management of cardiac arrhythmias has grown more complex in recent years. Despite the recent focus on nonpharmacological therapy, most clinical arrhythmias are treated with existing antiarrhythmics. Because of the narrow therapeutic index of antiarrhythmic agents, potential drug interactions with other medications are of major clinical importance. As most antiarrhythmics are metabolised via the cytochrome P450 enzyme system, pharmacokinetic interactions constitute the majority of clinically significant interactions seen with these agents. Antiarrhythmics may be substrates, inducers or inhibitors of cytochrome P450 enzymes, and many of these metabolic interactions have been characterised. However, many potential interactions have not, and knowledge of how antiarrhythmic agents are metabolised by the cytochrome P450 enzyme system may allow clinicians to predict potential interactions. Drug interactions with Vaughn-Williams Class II (beta-blockers) and Class IV (calcium antagonists) agents have previously been reviewed and are not discussed here. Class I agents, which primarily block fast sodium channels and slow conduction velocity, include quinidine, procainamide, disopyramide, lidocaine (lignocaine), mexiletine, flecainide and propafenone. All of these agents except procainamide are metabolised via the cytochrome P450 system and are involved in a number of drug-drug interactions, including over 20 different interactions with quinidine. Quinidine has been observed to inhibit the metabolism of digoxin, tricyclic antidepressants and codeine. Furthermore, cimetidine, azole antifungals and calcium antagonists can significantly inhibit the metabolism of quinidine. Procainamide is excreted via active tubular secretion, which may be inhibited by cimetidine and trimethoprim. Other Class I agents may affect the disposition of warfarin, theophylline and tricyclic antidepressants. Many of these interactions can significantly affect efficacy and/or toxicity. Of the Class III antiarrhythmics, amiodarone is involved in a significant number of interactions since it is a potent inhibitor of several cytochrome P450 enzymes. It can significantly impair the metabolism of digoxin, theophylline and warfarin. Dosages of digoxin and warfarin should empirically be decreased by one-half when amiodarone therapy is added. In addition to pharmacokinetic interactions, many reports describe the use of antiarrhythmic drug combinations for the treatment of arrhythmias. By combining antiarrhythmic drugs and utilising additive electrophysiological/pharmacodynamic effects, antiarrhythmic efficacy may be improved and toxicity reduced. As medication regimens grow more complex with the aging population, knowledge of existing and potential drug-drug interactions becomes vital for clinicians to optimise drug therapy for every patient.

Animals↗