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PubMed1990

[Can sudden death be prevented by drugs?].

Sudden cardiac death continues a major health problem. It is the leading cause of mortality in patients with coronary artery disease. In patients with the most malignant forms of ventricular tachyarrhythmias (ventricular tachycardia with syncope or aborted sudden death), anti-arrhythmics have been shown to be effective in preventing recurrences of these arrhythmias when tested according to a systematic protocol. Empiric therapy, on the other hand, is ineffective and dangerous because of the limited efficacy and the pro-arrhythmic potency of all anti-arrhythmic drugs. Asymptomatic ventricular arrhythmias, especially complex forms, after myocardial infarction characterize patients at increased risk for sudden cardiac death. In this situation most anti-arrhythmics do not improve prognosis. Amiodarone is so far the only anti-arrhythmic drug which has been shown to be beneficial in postinfarct patients, whereas Flecainide and Encainide were deleterious in a population at relatively low risk. Beta blocking agents, however, are effective in reducing mortality and incidence of sudden cardiac death in patients after myocardial infarction.

Adrenergic beta-Antagonists↗
PubMed1991

Clinical pharmacology and beta-blocking efficacy of propafenone.

Propafenone, like encainide and flecainide, is an antiarrhythmic drug characterized by slow kinetics of interaction with cardiac sodium channels. In addition, it shares structural similarities with propranolol and has been shown to exert consistent beta-blocking action in vitro. On the other hand, the extent of beta-blockade noted after oral administration of propafenone in vivo has been reported to range from undetectable to clinically significant. Although the explanation for this discrepancy was initially unclear, recent work has convincingly demonstrated that the degree of beta-blockade during propafenone therapy reflects genetically determined variations in the metabolism of the parent drug, which has greater beta-blocking potency than do its metabolites. At lower dosages, beta-blockade is significantly greater and more likely to be clinically noticeable in the small percentage of patients who have poor metabolism and in whom deficient 5-hydroxylation is associated with higher plasma propafenone concentrations. Because this metabolic pathway is saturable, at the usual highest clinical dosage (900 mg/24 h) plasma propafenone concentration rises disproportionately in patients with normal 5-hydroxylation, and more comparable degrees of beta-blockade are noted in both metabolizer types. Beta-blockade during propafenone therapy, which can contribute both to the genesis of side effects and to the suppression of arrhythmias, is a potentially important drug effect that can largely be predicted by genetic variations in the metabolism of the drug.

Adrenergic beta-Antagonists↗
PubMed1991

Combination of antiarrhythmic drugs.

Antiarrhythmic treatment with single agents is often ineffective and can be limited by dose-dependent side effects. Therefore, combinations of antiarrhythmic drugs in smaller and well-tolerated doses are advocated in cases refractory to single antiarrhythmic drugs. Basically, substances belonging to the same electrophysiologic class should not be combined. However, drugs of different subsets of class I may be combined. Agents that have pharmacokinetic interactions, such as quinidine and amiodarone, should not be given together because this combination may be associated with a considerable proarrhythmic effect. A combination of beta-adrenoreceptor blockers with class I antiarrhythmic drugs may be effective, mainly in cases in which the arrhythmia is dependent on adrenergic stimulation. The combination of class III and IB substances can be useful in some cases, from the electrophysiological and clinical point of view. Among the successful combinations of this type are amiodarone and mexiletine, sotalol and mexiletine, or sotalol and tocainide. In 34 patients, the reduction of ventricular premature beats by sotalol alone was 28%, and by sotalol plus mexiletine or tocainide was 79%. Complex ventricular arrhythmias were suppressed by sotalol alone by less than 40% and by sotalol plus mexiletine or tocainide by more than 80%. There was no difference in the effectiveness of mexiletine and tocainide (both of them being class IB drugs) in this combination. However, mexiletine was associated with fewer adverse effects than was tocainide. In patients refractory to amiodarone alone or to a combination with mexiletine, the combined treatment with amiodarone and class IC drugs such as flecainide and encainide prolongs the cycle length of ventricular tachycardia, but does not suppress induction of ventricular tachycardia during programmed stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Clinical pharmacology of antiarrhythmic drugs: variability of metabolism and dose requirements.

The clinical use of the presently available antiarrhythmic agents is rendered difficult by narrow therapeutic ranges, highly variable drug elimination kinetics, and complex dose-concentration-effect relations. Because of their electrophysiological mechanisms of action, these drugs may produce proarrhythmic effects, conduction disturbances, and myocardial depression even at the assumed optimum therapeutic serum levels. Several antiarrhythmic drugs, such as procainamide, quinidine, propafenone, encainide, and amiodarone, are transformed to pharmacologically active metabolites, which may contribute to their antiarrhythmic and toxic effects. In addition to marked genetic differences in hepatic metabolism rates (polymorphic hydroxylation and acetylation), some drugs, e.g., quinidine, propafenone, and amiodarone, produce an inhibition of hepatic metabolizing enzymes and thus cause practically relevant drug interactions. A careful dosage adaptation in individual patients is therefore required to achieve maximum therapeutic benefit and to reduce the risk of unwanted side effects. Serum drug concentration measurements may contribute to an improved use of antiarrhythmic agents, but monitoring alone does not replace the electrophysiological assessment of therapeutic efficacy.

Anti-Arrhythmia Agents↗
PubMed1991

Effects of class I anti-arrhythmic drugs in infarcted tissue.

An in vitro model was used to examine the electrophysiological effects of anti-arrhythmic drugs in infarcted tissue. After 24 h of coronary artery occlusion in the dog, endocardial preparations were removed from the infarcted zone. Intracellular action potentials recorded from surviving Purkinje fibres on the endocardial surface showed reduced maximum upstroke velocity (Vmax), increased action potential duration and enhanced automaticity. The rate-dependent effect of lidocaine on Vmax and conduction was more prominent in Purkinje fibres that survived myocardial infarction than in normal Purkinje fibres. Tocainide, flecainide, and O-demethyl encainide reduced Vmax in both normal Purkinje fibres and Purkinje fibres surviving infarction. Similar to lidocaine, these drugs showed the greatest reduction of Vmax in Purkinje fibres surviving infarction at the shortest stimulation cycle length tested. In contrast, maximal drug effects on action potential duration were observed when long stimulation cycle lengths were used. Our results indicate that most Class I anti-arrhythmic drugs showed rate-dependent properties in normal Purkinje fibres as well as in Purkinje fibres surviving infarction. The increased sensitivity of the ischemic myocardium to anti-arrhythmic drugs resulting in greater reductions of Vmax and conduction may contribute to a greater potency of anti-arrhythmic drugs in the suppression of arrhythmias associated with ischemia. Conversely, while slowing of conduction can abolish re-entry arrhythmias by producing a bidirectional block, further slowing of conduction by anti-arrhythmic drugs can favour the development of new re-entry pathways and may contribute to their pro-arrhythmic effects.

Action Potentials↗
PubMed1991

[How should ventricular arrhythmia be treated?].

Antiarrhythmic therapy of ventricular arrhythmias in patients after myocardial infarction, even if it reduces the incidence of arrhythmias, does not influence the mortality, as demonstrated in the American CAST study where the most effective antiarrhythmic drugs class Ic, encainide and flecainide, were used. As a result of proarrhythmogenic action therapy may even enhance the risk. The authors present a classification of ventricular arrhythmias and recommend therapeutic strategies. They draw attention to the fact that the proarrhythmogenic action may develop in the early as well as in the late stage of treatment. Beta-blockers still remain the only group of drugs which markedly reduce the incidence of sudden death in patients after myocardial infarctions.

Arrhythmias, Cardiac↗
PubMed1991

[Possibilities and limitations of treatment for arrhythmia].

Antiarrhythmic therapy for tachyarrhythmias is more effective, but at the same time more complicated, than it was a few years ago. This is equally true for the indication of therapy in general, for the decision to apply a particular therapeutic tool, and for the control of antiarrhythmic treatment itself. An effective, long-lasting control of cardiac arrhythmias requires carefully selected therapeutic approaches. Primary treatment aims at the underlying disease. The causal therapy must, of course, be directed to the conditions responsible for the disease, that is, for example, therapy for coronary artery disease, treatment of myocarditis, elimination of glycoside intoxication or electrolyte disturbances, normalization of thyroid dysfunction, or revision of an ineffective pacemaker. The symptomatic therapy for cardiac arrhythmias is subdivided into drug therapy, electro-therapeutic measures (cardiac pacemaker, implantable cardioverter/defibrillator, fulguration) and antiarrhythmic surgery or, in special cases even heart transplantation. In the pharmaceutical sector, progress has been made by introducing new antiarrhythmic substances, such as encainide and flecainide, tocainide, amiodarone, sotalol, and especially by the combination of antiarrhythmic agents. The combination of antiarrhythmic substances allows the use of smaller dosage of one or both of the drugs. Despite potential proarrhythmic effects with combination of antiarrhythmic agents, this risk seems to be lower by using reduced dosages. Thus, the conventional spectrum of antiarrhythmic therapy has to be reconsidered with respect to new approaches in the control of cardiac dysrhythmias.

Anti-Arrhythmia Agents↗
PubMed1991

Flecainide toxicity in a neonate with supraventricular tachycardia.

Class IC antiarrhythmic drugs, specifically encainide and flecainide, have been used with increasing frequency in children and young adults with both atrial and ventricular tachyarrhythmias. As a result of the recent findings from the Cardiac Arrhythmia Suppression Trial (CAST) study, their use in adults as well as children has been questioned. Because of their potential and often dangerous side effects, the child receiving a class IC drug must be monitored very closely. We report a case of flecainide toxicity in a 2 1/2-week-old neonate who was being treated for incessant supraventricular tachycardia.

Electrocardiography↗
PubMed1990

[Chronic non-paroxysmal supraventricular tachycardia in children].

The paper provides the criteria for diagnosis and the results of conservative and surgical treatments for chronic supraventricular tachycardia. The author identifies 3 nosological entities for this type of tachycardia. These are: 1) sustained borderline reciprocal tachycardia; 2) atrial ectopic tachycardia; and 3) ectopic tachycardia. In sustained borderline reciprocal tachycardia, the promising drugs were found to be propaphenone, encainide, and phencainide. The surgical management of this tachycardia aimed at abolishing retrograde conduction and accessory pathways. The most beneficial procedure was shown by usage of cryotherapy in the area of the coronary sinus, this producing nearly 100% responses. The surgical management was less effective in patients with borderline ectopic tachycardia or the so-called His' tachycardia.

Adolescent↗
PubMed1990

[Can sudden cardiac death be prevented by treatment with anti-arrhythmia drugs?].

Sudden cardiac death is defined as death due to a primary cardiac cause or mechanism, occurring within one hour of the onset of acute illness in a person thought to be free of, or with symptomatically mild, heart disease, or simply prehospital death. Of persons dying suddenly, 90% have coronary artery disease, less commonly, dilated cardiomyopathy or hypertrophic cardiomyopathy, preexcitation syndrome, long QT-syndrome, conduction disturbances, congenital or valvular heart disease as well as cardiac tamponade are responsible. In the USA, the incidence of sudden cardiac death is approximately 450,000 per year, in the Federal Republic of Germany the number lies at about 70,000 to 80,000. The most important risk factors for sudden cardiac death are impaired left ventricular ejection fraction, myocardial ischemia and arrhythmias. In general, sudden cardiac death is caused by ventricular fibrillation which arises mainly by degeneration of ventricular tachycardia (VT). The terminal arrhythmia, it is assumed, is precipitated by premature ventricular beats originating in an arrhythmogenic substrate. MEDICAL ANTIARRHYTHMIC TREATMENT IN PATIENTS WITH CORONARY ARTERY DISEASE AFTER MYOCARDIAL INFARCTION: STUDIES WITH CLASS I DRUGS: The results of nine large, randomized , controlled studies are available in which the mortality of patients on antiarrhythmic treatment has been studied (Table 1). Two studies each were carried out with aprindine, phenytoin, mexiletine and tocainide as well as one study with endainide, flecainide or morizicine. With the exception of the CAST study, no study showed a significant difference between treated patients and the control group with respect to mortality or incidence of sudden cardiac death. The CAST study was terminated after ten months because the administration of flecainide and encainide led to overall mortality of 7.7% vs. 3.0% in the control group and the rate of sudden cardiac death at 4.5% was significantly higher in the treatment group than the 1.2% incidence found in controls (Table 2). For nearly all of the studies described, the patient groups were not sufficiently large and subgrouping according to patient characteristics was not carried out such that possibly, inhomogeneity of the entire collective may not have been recognized precluding identification of some individuals who may have shown benefit from antiarrhythmic treatment. The necessity for treatment in many of those receiving drugs is questionable since generally the rhythm profile of the patients was not taken into consideration for the decision to treat. Proarrhythmic effects, accordingly, were also not assessed. Individual treatment and dosage adjustment by monitoring with effectiveness criteria was carried out in one study only in which, even here, criteria for effectiveness were arbitrarily capable of eliciting antiarrhythmic actions. Calculation of mortality rates was carried out on the basis of the total number of deaths in the respective groups without taking into consideration that by the end of the study, in the treatment group the medication had been discontinued in up to 40% of the patients. STUDIES WITH CLASS II DRUGS: For treatment with beta-receptor blockers there are 15 large, controlled, randomized, long-term studies available in which total mortality and the incidence of sudden cardiac death were studied.(ABSTRACT TRUNCATED AT 400 WORDS)

Anti-Arrhythmia Agents↗
PubMed1990

[Determination of oxidative phenotype in a sample population and correlation with the pharmacokinetics of propafenone].

UNLABELLED: Propafenone, like other cardioactive drugs (metoprolol, propranolol, encainide) is submitted to oxidative metabolism, evaluable by assessment of debrisoquine oxidative capacity. Two phenotypes have been described: extensive and poor oxidizers, with interethnic differences in the prevalence of poor oxidizers. Aims of this study were: 1) to assess the oxidative phenotype in a sample of the Italian population and 2) to evaluate the relationships between oxidative capacity and propafenone pharmacokinetics or pharmacodynamics. The ratio between debrisoquine (D) and 4-hydroxy-debrisoquine (4-OH-D) in the urines after D administration (10 mg) was employed to characterize oxidative phenotype in 90 subjects (42 arrhythmia patients and 48 healthy volunteers). In 10 patients, extensive oxidizers of debrisoquine, we studied propafenone (P) and 5-hydroxy-propafenone (5-OH-P) kinetics after acute oral administration (450 mg) and chronic oral treatment (300 mg tid for 2 weeks), followed by wash out. RESULTS: 1) the prevalence of poor oxidizers (D/4-OH-D ratio greater than 12.6) in our population resulted to be 6.6%, like in other studies in Caucasians; 2) propafenone kinetics was strictly related to oxidative capacity since D/4-OH-D ratio strictly correlated with the ratio of P and 5-OH-P areas under curve in acute (r = 0.91) and in chronic administration (r = 0.90) and with P half-life in acute (r = 0.82) and in chronic administration (r = 0.82); 3) QRS widening both during chronic treatment and after acute administration correlated with oxidative capacity (r = -0.78 and -0.68 with D/4-OH-D ratio respectively) and with 5-OH-P areas under curve (r = 0.84 and 0.70 respectively); it did not correlate with P areas under curve. In conclusion both kinetics and electrophysiological effects of propafenone strictly correlate with oxidative capacity, even in extensive oxidizers. Thus even a small reduction in oxidative capacity may have relevant consequences during propafenone oral treatment.

Adult↗
PubMed1989

Second generation antidysrhythmic agents.

Several new antidysrhythmic agents have been or are about to be approved for the prevention and/or treatment of life-threatening or symptomatic ventricular arrhythmias. Prior to use in clinical practice, however, their relative risk/benefit ratio must be assessed. Whereas relief of bothersome symptoms of ventricular dysrhythmias may improve the patient's return to a more active role in society, one must be aware, at the same time, that these antidysrhythmics have adverse effects of their own that may significantly limit their effectiveness. None of these new antidysrhythmic agents has been shown to prevent suddent cardiac death in controlled trials. At the present time, studies are being conducted to assess the efficacy of these agents in preventing sudden cardiac death. The new antidysrhythmic agents are highly effective in treating a wide variety of ventricular, and in some cases, supraventricular dysrhythmias. These agents are orally effective and, because of their unique pharmacokinetic profile, can often be prescribed less often per day than first generation antidysrhythmics. Side effects, for the most part, are predictable and involve the gastrointestinal and central nervous systems. In most cases, such side effects are reversible with dosage reduction. Upon treating a patient for a potentially lethal dysrhythmia, a Class IC agent such as encainide, flecainide, or propafenone, may be considered as the first-line therapy. Class IB agents, although less effective when used alone, show augmented antidysrhythmic efficacy with a reduction in side effects when administered concomitantly with a Class IA agent, such as quinidine or procainamide.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Arrhythmia Agents↗
PubMed1988

Update on antiarrhythmic drugs in emergency medicine.

Most patients presenting to the Emergency Department with acute arrhythmias can be adequately treated with the available, conventional antiarrhythmics. Recent studies have taught us to use them with better understanding. In the future, several new antiarrhythmics look promising for use in the Emergency Department when given by the intravenous route; particularly, pirmenol, encainide, esmolol, amiodarone, sotalol, and magnesium. However, there have been few comparison studies between various antiarrhythmics, and experience must be gained for a full understanding of the benefits and risks of these agents.

Adrenergic beta-Antagonists↗
PubMed1987

Antiarrhythmic, electrophysiologic and hemodynamic effects of ACC-9358.

The antiarrhythmic, electrophysiologic and hemodynamic effects of a new antiarrhythmic agent, ACC-9358, were evaluated. In anesthetized dogs, ACC-9358 converted ouabain-induced ventricular tachycardia to normal sinus rhythm at a cumulative dose equal to encainide or flecainide and less than disopyramide. In 24-hr coronary artery ligated dogs, ACC-9358 suppressed spontaneous ventricular arrhythmias for up to 6 hr after oral or i.v. administration. The antiarrhythmic effect and plasma concentrations of ACC-9358 correlated well for both oral (r = 0.88) and i.v. (r = 0.87) administration. ACC-9358, flecainide and disopyramide were equieffective in converting crush-stimulation-induced atrial flutter in anesthetized dogs to normal sinus rhythm. In alpha-chloralose-anesthetized, closed-chest dogs, ACC-9358 slowed impulse conduction through the atria, atrioventricular node, His-Purkinje system and ventricles and prolonged atrial functional refractory period. In conscious dogs, ACC-9358 increased heart rate, reduced stroke volume and had no effect on mean arterial pressure, systemic vascular resistance or cardiac output. In alpha-chloralose-anesthetized dogs, ACC-9358-induced sinus tachycardia was unaffected by propranolol but was blocked by hexamethonium or vagotomy. In isolated cat ventricular muscle, the IC50 for the negative inotropic effect of ACC-9358 was significantly greater than flecainide or disopyramide. These results indicate that ACC-9358 is a potent, broad-spectrum, long-acting, orally and intravenously active class Ic antiarrhythmic agent that 1) may be devoid of active metabolites, 2) exerts little or no vascular effects and 3) has less direct cardiodepressant activity than flecainide or disopyramide.

Animals↗
PubMed1985

Purification and characterization of the human liver cytochromes P-450 involved in debrisoquine 4-hydroxylation and phenacetin O-deethylation, two prototypes for genetic polymorphism in oxidative drug metabolism.

Two forms of cytochrome P-450 were purified to apparent homogeneity from several different preparations of human liver microsomes. One form, designated P-450DB, had relatively high catalytic activity towards the drugs debrisoquine, sparteine, bufuralol (both the (+)- and (-)-isomers), encainide, and propranolol and appears to be the enzyme involved in the polymorphic distribution of oxidative activities towards these substrates in humans. The other form, designated P-450PA, had relatively high phenacetin O-deethylase activity and appears to be involved in the variation of this activity among humans. Polyclonal antibodies raised to the two enzymes were specific for the antigens as judged by immunoelectrophoresis and immuno-inhibition studies. The two enzymes and their activities were distinguished by chromatographic separation, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, amino acid composition, immuno-inhibition studies, and steady-state kinetic assays. Immunochemical studies suggest that each form represents only a small fraction of the total cytochrome P-450 in human liver microsomes. These biochemical studies provide a basis for better understanding the mechanisms which underlie genetic polymorphisms involving P-450 cytochromes in humans.

Amino Acids↗
PubMedDate not supplied

E- and Z-10-hydroxylation of nortriptyline by human liver microsomes--methods and characterization.

To enable in vitro characterization of nortriptyline 10-hydroxylase activity of microsomal fractions of human liver, methods for the determination of E- and Z-10-hydroxynortriptyline were developed. High performance liquid chromatography (HPLC) with UV-detection or HPLC separation followed by quantitation by gas chromatography-mass spectrometry were used. The microsomal 10-hydroxylation of nortriptyline was linear to 60 min with a protein concentration of 1 mg x ml-1. In 15 human livers a 5-fold variation in activity was found. The formation of the Z-isomer comprised 13 +/- 3% (mean +/- SD) of the total 10-hydroxylase activity. The 10-hydroxylation was inhibited by debrisoquine, sparteine, propranolol, and encainide. No effect or a stimulation of the activity was seen with p-nitroanisole and acetanilide.

Adult↗
PubMed1984

Polymorphic drug oxidation in humans.

Genetic polymorphisms in the oxidative metabolism of debrisoquine, mephenytoin, phenformin, sparteine, and tolbutamide have been discovered during recent years. Among these pharmacogenetic conditions, polymorphic oxidation of debrisoquine and sparteine has been intensively studied. Two phenotypes, the extensive (EM) and the poor (PM) metabolizers, have been observed in all populations so far investigated. The PM phenotype exhibits a grossly impaired or nearly absent capacity to metabolize these drugs. The incidence of the PM phenotype in European populations ranges from 5 to 9%. Pronounced variations in the incidence of the PM phenotype have been demonstrated among different ethnic groups. The metabolism of debrisoquine and sparteine is determined by two alleles at a single gene locus; PMs are homozygous for an autosomal recessive gene. Because of markedly impaired metabolism, the PM phenotype develops side effects if normal doses of debrisoquine and sparteine are administered. Defective metabolism in the PM phenotype is not restricted to debrisoquine and sparteine. Impaired metabolism of guanoxan , phenformin, perhexiline, methoxyamphetamine, phenacetin, encainide, metoprolol, alprenolol, bufuralol, nortriptyline, and desipramine have been described. As a consequence of impaired metabolism of these drugs, toxicity and therapeutic failure are observed in the PMs. With regard to molecular mechanisms, studies with microsomes from human liver provide evidence that in the PM phenotype a cytochrome P-450 isozyme is either missing or functionally inadequate.

Cytochrome P-450 Enzyme System↗
PubMed1982

[Clinically significant inherited differences in the mode of action of drugs].

An important source of interindividual differences in drug action are inherited differences in the pharmacokinetics and pharmacodynamics of many drugs. For most enzymatic reactions of drug biotransformation in the liver, genetic polymorphisms have been observed which lead to a decreased rate of metabolism and/or a different pattern of metabolites in certain subpopulations, ethnic groups or families. Examples of frequent polymorphisms in drug-metabolizing enzymes are deficient N-acetyltransferase (50-70% of the population) and deficient debrisoquine hydroxylase (10% of the population). "Slow acetylators" inactivate isoniazid, hydralazine, procainamide, phenelzine, dapsone, sulfamethazine (sulfadimidine), sulfapyridine and nitrazepam at a decreased rate. The molecular genetic defect causing deficient debrisoquine hydroxylation is still unclear and also affects the metabolism of phenytoin, phenacetin, guanoxan, sparteine, methoxyamphetamine, nortriptyline, encainide, perhexiline and probably other drugs. A relationship has been observed between the defect of metabolism and the clinical effects and toxicity of the drugs involved.

Acetyltransferases↗