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PubMed1991

Polymorphous ventricular tachycardia associated with acute myocardial infarction.

BACKGROUND: During a 2.9-year period, 11 patients developed polymorphous ventricular tachycardia 1-13 days after acute anterior (seven patients) or inferior (four patients) myocardial infarction. None of the 11 patients had sinus bradycardia (mean heart rate, 90 +/- 23 beats/min), but three had a sinus pause immediately before the onset of polymorphous ventricular tachycardia. In all 11 patients, the QT interval and corrected QT interval (QTc) were normal or minimally prolonged (QT, 385 +/- 34 msec; QTc, 442 +/- 40 msec). None had significant hypokalemia (mean serum potassium concentration, 4.3 +/- 0.5 meq/l) or a grossly abnormal serum magnesium or calcium concentration (2.1 +/- 0.4 and 8.9 +/- 0.7 mg/dl, respectively). METHODS AND RESULTS: Immediately before the onset of polymorphous ventricular tachycardia, symptoms and/or electrocardiographic changes consistent with recurrent myocardial ischemia occurred in nine of 11 patients. One patient died before drug therapy could be initiated. Lidocaine was used in 10 patients and proved to be effective in only one. Intravenous procainamide was used in six patients: one improved, and five had recurrence of polymorphous ventricular tachycardia. Bretylium was used in five patients and was ineffective in all cases. Overdrive pacing was used in four patients and failed to suppress recurrent arrhythmias in all cases. Four patients with persistent polymorphous ventricular tachycardia unresponsive to lidocaine, procainamide, or bretylium responded to intravenous amiodarone. One patient with polymorphous ventricular tachycardia that was consistently preceded by ST segment elevation responded to intravenous nitroglycerin. Two patients with persistent polymorphous ventricular tachycardia and obvious recurrent ischemia unresponsive to pharmacological intervention responded to emergency coronary revascularization. A third patient who experienced recurrent angina and polymorphous tachycardia was initially stabilized with pharmacological therapy but subsequently underwent elective revascularization and has remained stable without antiarrhythmic therapy. CONCLUSIONS: Post-myocardial infarction polymorphous ventricular tachycardia is not consistently related to an abnormally long QT interval, sinus bradycardia, preceding sinus pauses, or electrolyte abnormalities. This arrhythmia has a variable response to class I antiarrhythmics but may be suppressed by intravenous amiodarone therapy. It is often associated with signs or symptoms of recurrent myocardial ischemia. Furthermore, coronary revascularization appears to be effective in preventing the recurrence of polymorphous ventricular tachycardia when associated with recurrent postinfarction angina.

Aged↗
PubMed1993

Comparative study on the proarrhythmic effects of some antiarrhythmic agents.

BACKGROUND: A main side effect of antiarrhythmic drug therapy is the tendency of these drugs to promote arrhythmia within the therapeutic concentration range, i.e., the proarrhythmic activity of these drugs. However, a model for in vitro assessment, quantification, and comparison of proarrhythmic drug activities was still lacking, and only sparse data were available. METHODS AND RESULTS: To analyze the arrhythmogenic risk of common antiarrhythmic drugs in a quantitative and comparative manner, isolated perfused rabbit hearts were treated with increasing concentrations of antiarrhythmic drugs corresponding to low, medium, and high therapeutic concentrations. For analysis of the epicardial activation process, an epicardial mapping (256 unipolar leads) was performed. For each electrode, the activation time was determined. From these data, the origins of epicardial activation ("breakthrough points" [BTP]) were determined. At each electrode, an activation vector (VEC) was calculated giving direction and velocity of the local excitation wave. The beat similarity of various heartbeats (under treatment) compared with control was evaluated by determination of the percentage of identical BTPs (deviation < or = 1 mm) and of similar VECs (deviation < or = 5 degrees). BTP and VEC were reduced by all antiarrhythmic agents tested (propafenone = flecainide > quinidine > ajmaline > procainamide > disopyramide > mexiletine = lidocaine > sotalol), indicating a more or less pronounced disturbance of the epicardial activation process. Treatment with propafenone, quinidine, and disopyramide and to a lesser extent sotalol prolonged the activation-recovery interval (ARI). ARI dispersion was greatly enhanced by flecainide and was reduced by sotalol. In addition, it could be shown that propranolol is able to reduce the proarrhythmic action of flecainide. This effect seemed to be due to a reduction of the flecainide-induced increase in ARI dispersion. CONCLUSIONS: From the results of our study, we propose the following rank order of the arrhythmogenic risk: flecainide > propafenone > quinidine > ajmaline > disopyramide > procainamide > mexiletine, lidocaine > sotalol. Moreover, we conclude that propranolol given additionally may be helpful in reducing the proarrhythmic risk of flecainide.

Animals↗
PubMed1996

Mechanisms of drug-induced lupus. II. T cells overexpressing lymphocyte function-associated antigen 1 become autoreactive and cause a lupuslike disease in syngeneic mice.

Current theories propose that systemic lupus erythematosus develops when genetically predisposed individuals are exposed to certain environmental agents, although how these agents trigger lupus is uncertain. Some of these agents, such as procainamide, hydralazine, and UV-light inhibit T cell DNA methylation, increase lymphocyte function-associated antigen 1 (LFA-1) (CD11a/CD18) expression, and induce autoreactivity in vitro, and adoptive transfer of T cells that are made autoreactive by this mechanism causes a lupuslike disease. The mechanism by which these cells cause autoimmunity is unknown. In this report, we present evidence that LFA-1 overexpression is sufficient to induce autoimmunity. LFA-1 overexpression was induced on cloned murine Th2 cells by transfection, resulting in autoreactivity. Adoptive transfer of the transfected, autoreactive cells into syngeneic recipients caused a lupuslike disease with anti-DNA antibodies, an immune complex glomerulonephritis and pulmonary alveolitis, similar to that caused by cells treated with procainamide. These results indicate that agents or events which modify T cell DNA methylation may induce autoimmunity by causing T cell LFA-1 overexpression. Since T cells from patients with active lupus have hypomethylated DNA and overexpressed LFA-1, this mechanism could be important in the development of human autoimmunity.

Animals↗
PubMed1992

Postmortem changes and pharmacokinetics: review of the literature and case report.

OBJECTIVE: To review the mechanisms and sequence of events that occur during ischemia and cell death and following death of the human body. The impact of these postmortem events on the distribution and pharmacokinetic behavior of drugs is described. The case study presented illustrates a possible situation where such postmortem changes could have affected the pharmacokinetics of procainamide. DATA SOURCES: English-language journal articles and reference texts identified from pertinent data sources. DATA SYNTHESIS: Postmortem changes in the human body begin at the cellular level with the onset of ischemia. As the length of time of ischemia increases and death ensues, more changes occur and lead to deterioration in tissue and organ function. These changes may affect the pharmacokinetic and distribution behavior of certain drugs. Drugs particularly affected are those whose distribution is dependent on molecular size, lipophilicity, pH, energy-dependent transport, and tissue binding. Such drugs include the tricyclic antidepressants, digoxin, and cimetidine. Other drugs with similar characteristics, such as procainamide, may also demonstrate like changes in distribution and pharmacokinetics. CONCLUSIONS: When measuring drug concentrations after death, it is important to consider the phenomenon of postmortem redistribution. Postmortem drug concentrations may not be a true reflection of antemortem concentrations and as a result, wrong conclusions could be made about the cause of death. More studies characterizing the postmortem distribution and pharmacokinetic characteristics of specific drugs are necessary.

Antidepressive Agents, Tricyclic↗
PubMed1996

Possible pharmacokinetic interaction with quinidine: ciprofloxacin or metronidazole?

OBJECTIVE: To discuss a potential pharmacokinetic interaction between quinidine, ciprofloxacin, and metronidazole. CASE SUMMARY: A 51-year-old black woman was admitted for shortness of breath, abdominal pain, and atrial fibrillation. Procainamide and diltiazem were begun for the atrial fibrillation and ciprofloxacin and metronidazole for suspected diverticulitis. The therapy was switched to quinidine on day 5 because of adverse events associated with procainamide. A trough serum quinidine concentration (SQC) on day 7 was 6.3 micrograms/mL (normal 2-5) with normal QT and QTc intervals. On day 8, the patient was discharged in normal sinus rhythm. She took her last doses of antibiotics on day 15 and a follow-up SQC on day 18 was 2.3 micrograms/mL. DISCUSSION: The possible explanations for the changes in SQCs include: (1) laboratory error, (2) compliance with medication regimen, and (3) altered hepatic metabolism. The first two are not likely in this case. The laboratory verified the elevated SQC and the patient had her prescriptions refilled within appropriate time limits. The third explanation seems more plausible. Quinidine is metabolized by the hepatic mixed-function oxidase system, specifically cytochrome P450 (CYP) 3A4. We found that metronidazole has been shown to inhibit CYP3A activity and ciprofloxacin has been shown to inhibit certain isozymes in the cytochrome P450 system as well. CONCLUSIONS: When metronidazole and ciprofloxacin are administered concomitantly with quinidine, clinicians should be aware of this potential interaction. Quinidine concentrations should be monitored and patients should be assessed for signs and symptoms of quinidine toxicity.

Anti-Arrhythmia Agents↗
PubMed1997

Pharmacologic management of supraventricular tachycardias in children. Part 1: Wolff-Parkinson-White and atrioventricular nodal reentry.

OBJECTIVE: To review the literature regarding the use of antiarrhythmic agents in the management of Wolff-Parkinson-White (WPW) syndrome and atrioventricular nodal reentry tachycardia (AVNRT) in infants and children, and to discuss the advantages and disadvantages of specific agents in each arrhythmia in an effort to develop treatment guidelines. DATA SOURCES: A MEDLINE search encompassing the years 1966-1996 was used to identify pertinent literature for discussion. Additional references were found in the articles that were retrieved via MEDLINE. STUDY SELECTION: Clinical trials that address the use of antiarrhythmic agents for the treatment of the supraventricular tachycardias WPW and AVNRT in children were selected. Literature pertaining to dosage, pharmacokinetics, efficacy and toxicity of antiarrhythmic agents in children were considered for possible inclusion in the review, and information judged to be pertinent by the authors was included in the discussion. DATA EXTRACTION: Although there are numerous reports of antiarrhythmic use in children, very few large studies are designed to evaluate an individual antiarrhythmic agent for a specific arrhythmia. Controlled, comparison trials of antiarrhythmic agents in children are virtually nonexistent. Ideally, controlled clinical trials are used to develop clinical guidelines; however, in this situation, most data and information must be obtained from case series of children treated. Although the results from these type of studies may be useful in developing guidelines for the optimal use of these agents, controlled trials are required for establishing standard treatment guidelines for all patients. DATA SYNTHESIS: Despite limited scientific evaluation of conventional agents in the treatment of WPW and AVNRT in children, they continue to be used as standard of care. Most information regarding the use of conventional agents in children has been extrapolated from the adult literature. Little justification for the use of agents or dosing in children is available. Controlled trials regarding the use of new antiarrhythmic agents (propafenone, amiodarone, flecainide) are available; however, the variance in dosing schemes, presence of structural heart disease, and patient age make the development of recommendations difficult. CONCLUSIONS: Because of greater clinical experience with these conventional antiarrhythmic agents, they continue to be first-line therapy in the management of most supraventricular tachycardia (SVT) in children. The management of SVT in children with WPW syndrome should begin with the use of a beta-blocker with the addition of digoxin or procainamide for treatment failures. The use of digoxin monotherapy, although frequently used by many practitioners in infants and children with WPW, cannot be recommended. For failures to conventional agents, flecainide is the preferred agent, while therapy with propafenone, amiodarone, and sotalol remains to be elucidated. The management of AVRNT is similar to that of WPW; however, digoxin is the agent of first choice. Trials of beta-blockers and procainamide should follow for treatment failures with flecainide again being the preferred "newer" antiarrhythmic for use in resistant cases. Additional well-designed, controlled trials are needed to further evaluate the comparative efficacy of antiarrhythmics in the management of WPW and AVNRT in children, as well as to evaluate dosing and toxicity in various age groups.

Adrenergic beta-Antagonists↗
PubMed1997

Pharmacologic management of supraventricular tachycardias in children. Part 2: Atrial flutter, atrial fibrillation, and junctional and atrial ectopic tachycardia.

OBJECTIVE: To review the literature regarding the use of antiarrhythmic agents in the management of atrial flutter (AF), atrial fibrillation (Afib), junctional ectopic tachycardia (JET), and atrial ectopic tachycardia (AET) in infants and children. To discuss the advantages and disadvantages of specific agents in each type of arrhythmia in an effort to develop treatment guidelines. DATA SOURCE: A MEDLINE search encompassing the years 1966-1996 was used to identify pertinent literature for discussion. Additional references were found in the articles, which were retrieved via MEDLINE. STUDY SELECTION: Clinical trials that address the use of antiarrhythmic agents for the treatment of supraventricular tachycardia, AF, Afib, JET, and AET in children were selected. Literature pertaining to dosage, pharmacokinetics, efficacy, and toxicity of antiarrhythmic agents in children were considered for possible inclusion in the review; information judged to be pertinent by the authors was included in the discussion. DATA EXTRACTION: Although there are numerous reports of antiarrhythmic use in children, there are very few large studies designed that evaluate the use of specific antiarrhythmic agents in the treatment of AF, Afib, JET, or AET. Ideally, controlled clinical trials are used to develop clinical guidelines; however, in this situation, most data and information must be obtained from case series of children treated. Although the results from these types of studies may be useful in developing guidelines for the optimal use of these agents for the treatment of AF, Afib, JET, and AET, controlled trials are required for establishing standard treatment guidelines for all patients. DATA SYNTHESIS: Despite limited scientific evaluation of conventional agents in the treatment of AF, Afib, JET, or AET in children, they continue to be the standards of care. Most information regarding the use of conventional agents in children has been extrapolated from the adult literature. Little justification for the use of the agents or dosing in children is available. Controlled trials regarding the use of newer antiarrhythmic agents (propafenone, amiodarone, flecainide) are available; however, the variance in dosing schemes, presence of structural heart disease, and patient age may confound the results. CONCLUSIONS: Because of greater clinical experience, conventional antiarrhythmic agents generally remain as first-line therapy in the management of most supraventricular tachycardias in children. Atrial pacing or cardioversion to reestablish sinus rhythm is indicated for initial episodes of AF in infants, followed by chronic prophylactic therapy in those with significant structural heart disease or in infants in whom AF recurs. Attempts to eliminate AF in children outside the neonatal or infancy period should begin with trials of traditional agents such as digoxin or procainamide, and if unsuccessful, subsequent trials of amiodarone. Digoxin and beta-blockers remain the mainstay of therapy for children with Afib, followed by procainamide for treatment failures. Intravenous amiodarone, the newest addition to our antiarrhythmic armamentarium, is the most promising agent in the treatment of postoperative JET. This arrhythmia has been traditionally managed with corporal cooling and/or digoxin therapy; however, intravenous amiodarone may now be a valuable option. Although relatively unsuccessful in the management of congenital JET and AET, conventional agents are typically used prior to the initiation of long-term therapy with potentially more toxic agents such as amiodarone or propafenone. Additional well-designed, controlled trials are needed to further evaluate the comparative efficacy of agents such as flecainide, sotalol, moricizine, propafenone, and amiodarone in the management of AF, Afib, JET, and AET in children, as well as to evaluate the dosing and toxicity in various age groups.

Anti-Arrhythmia Agents↗
PubMed1983

Quantitative analysis of the antiarrhythmic effect of drugs on canine ventricular arrhythmias by the determination of minimum effective plasma concentrations.

Antiarrhythmic effects and minimum antiarrhythmic plasma concentrations (min PC) were examined using three canine ventricular arrhythmia models, i.e., two-stage coronary ligation arrhythmia (Cor), halothane-adrenaline arrhythmia (Adr) and digitalis arrhythmia (Dig). Disopyramide suppressed these three arrhythmias and its min PCs were 5.3 +/- 1.8 (Cor), 4.2 +/- 1.1 (Adr) and 1.7 +/- 0.4 micrograms/ml (Dig). Procainamide suppressed coronary ligation arrhythmia and its min PC was 27.1 +/- 4.0 micrograms/ml, but was not effective on adrenaline arrhythmia. Aprindine was effective on three arrhythmias and its min PCs were 1.6 +/- 0.3 (Cor), 1.0 +/- 0.4 (Adr) and 0.8 +/- 0.4 micrograms/ml (Dig). Lidocaine was not effective on coronary ligation arrhythmia, but was effective on adrenaline arrhythmia and its min PC was 15 micrograms/ml. Phenytoin was effective on three arrhythmias and its min PCs were 9.8 +/- 2.0 (Cor), 12.1 +/- 3.1 (Adr) and 11.3 +/- 3.0 micrograms/ml (Dig). It was not specifically effective on canine digitalis arrhythmia. Propranolol and other beta-blockers were effective on adrenaline arrhythmia, but very high doses were necessary for suppressing coronary ligation and digitalis arrhythmias. Verapamil was only effective on adrenaline arrhythmia and its min PC was 0.03 +/- 0.01 microgram/ml. Canine min PCs of drugs were almost the same as those reported in man except for procainamide and lidocaine. Membrane stabilizing effects seem to be important for suppressing canine ventricular arrhythmias.

Animals↗
PubMed1991

Ventricular tachycardia with congenital ventricular diverticulum.

A 24-year-old man presented with symptomatic, recurrent, sustained ventricular tachycardia (VT). He was found to have a basal inferior left ventricular diverticulum. His sustained VT was reproduced by programmed electrical stimulation and was unresponsive to procainamide, tocainide, propafenone, and flecainide. Endocardial mapping followed by resection and cryoablative surgery was performed. The patient had only one recurrence after 18 months, with subsequent control with procainamide for over 14 months.

Adult↗
PubMed2004

Murine models of lupus induced by hypomethylated T cells.

CD4+ T-cell DNA hypomethylation may contribute to the development of drug-induced and idiopathic human lupus. Inhibiting DNA methylation in mature CD4+ T cells causes autoreactivity specific to the major histocompatibility complex in vitro. The lupus-inducing drugs hydralazine and procainamide also inhibit T-cell DNA methylation and induce autoreactivity, and T cells from patients with active lupus have hypomethylated DNA and a similarly autoreactive T-cell subset. Further, T cells treated with DNA methylation inhibitors demethylate the same sequences that demethylate in T cells from patients with active lupus. The pathological significance of the autoreactivity induced by inhibiting T-cell DNA methylation has been tested by treating murine T cells in vitro with drugs that modify DNA methylation, then injecting the cells into syngeneic female mice. Mice receiving CD4+ T cells demethylated by a variety of agents, including procainamide and hydralazine, develop a lupuslike disease. This chapter describes the protocols for inducing autoreactivity in murine T cells in vitro and using the cells to induce autoimmunity in vivo.

Adoptive Transfer↗
PubMed1987

Cardiovascular effects of a new phenoxyalkylamine derivative, 2-isopropyl-5-[3-(2-methoxyphenoxy)propylamino]-2-(3,4,5-trimethoxy phenyl) valeronitrile fumarate (HV-525), in cross-circulated dog atrial preparations.

A newly developed phenoxyalkylamine derivative, 2-isopropyl-5-[3-(2-methoxyphenoxy)propylamino]-2-(3,4, 5-trimethoxyphenyl)-valeronitrile fumarate (HV-525), was investigated in intact dogs and in isolated dog atria perfused with anesthetized donor dog's arterial blood. When 0.3 mg/kg of HV-525 was intravenously administered to the donor dog, a depressor effect without significant changes in heart rate was observed in donor dogs and a decrease in developed tension was observed in the isolated atrium. At 1 mg/kg, HV-525 caused a depressor response in donor dogs and decreases in developed tension and atrial rate in isolated atria. The decrease in systemic blood pressure seen following 1 mg/kg of HV-525 was between 15-40 mmHg. These effects continued for about 60 min. When HV-525 was administered into the cannulated sinus node artery of the isolated atrium, dose related negative inotropic and chronotropic actions were observed. Occasionally, HV-525 induced slight, brief positive chronotropic and inotropic effects followed by long-lasting negative effects. The threshold dose for inducing the negative chronotropic effect was approximately 3 micrograms while the negative inotropic one was approximately 1 microgram. A large dose of 100 micrograms of HV-525 caused a profound deceleration but not atrial arrest. The order of potencies for inducing a negative chronotropic effect in dog atria was verapamil greater than propranolol much greater than HV-525 greater than or equal to lidocaine greater than or equal to quinidine greater than phenytoin greater than disopyramide greater than procainamide, and that for inducing a negative inotropic effect was verapamil greater than or equal to propranolol greater than HV-525 greater than lidocaine greater than phenytoin greater than disopyramide greater than procainamide greater than or equal to quinidine. HV-525 did not induce a significant effect on sinoatrial conduction time. HV-525 at the doses studied, uniformly suppressed the frequency-force relationship, while verapamil, one of the phenoxyalkylamine derivatives, caused a marked depression of high frequency-induced contraction. Thus, it is concluded that HV-525 has mild depressant properties on the cardiovascular system and may have characteristics different from those of verapamil.

Animals↗
PubMed1992

Drug-specific immune responses induced by immunization with drugs in guinea pigs and mice.

In order to develop a system for evaluating the allergenicity of drugs in clinical use, we tested drugs for the ability to induce drug-specific immune responses in guinea pigs and mice. Test drugs were benzylpenicillin, procainamide, hydralazine, isoniazid, alpha-methyldopa, D-penicillamine, captopril, sulfamethoxazole and 2,4-dinitrochlorobenzene (DNCB), which are known to induce allergic responses in man including hypersensitivity reactions and drug-induced auto-immune responses. Guinea pigs were immunized with an emulsion of complete Freund's adjuvant (CFA) and 25 mg of each drug. Mice were immunized with an emulsion of CFA and 2 mg of each drug or a mixture of aluminum hydroxide gel and 2 mg of each drug. In order to examine drug-specific immune responses, we employed detection of antibodies by enzyme-linked immunosorbent assay (ELISA) and passive cutaneous anaphylaxis tests, active systemic anaphylaxis (ASA) tests and delayed type hypersensitivity (DTH) tests. In guinea pigs, drug-specific antibodies were detected following immunization with benzylpenicillin, procainamide, hydralazine, isoniazid, captopril, sulfamethoxazole or DNCB. Some of these drugs were also positive in DTH tests and/or ASA tests. In mice, however, only DNCB gave positive results. Therefore, our system involving immunization of guinea pigs with CFA emulsion of a drug and detection of drug-specific immune responses is considered to be an effective test method for evaluating drug allergenicity.

Animals↗
PubMed2005

Wide QRS tachycardia caused by severe hyperkalaemia and digoxin intoxication.

We report the case of a 78-year-old woman, with previous narrow QRS atrial fibrillation, who in the presence of mild digoxin intoxication and severe hyperkalaemia, caused by chronic renal failure and usage of potassium sparing drugs, presented on her ECG two distinct wide QRS tachycardias. Initial treatment with low doses of procainamide resulted in severe bradycardia. Her original rhythm was restored after partial correction of hyperkalaemia with haemodialysis under continuous infusion of lidocaine. The electrocardiographic manifestations of hyperkalaemia and digoxin intoxication as well as the effect of lidocaine and procainamide on hyperkalaemia-induced wide QRS tachycardias are discussed.

Aged↗
PubMed1988

Clinical pharmacokinetics in heart failure. An updated review.

Pharmacokinetics is the study of the effect that the body has on drug absorption, distribution, metabolism and excretion. The pharmacokinetics of a specific drug are assessed by the volume of distribution, bioavailability, clearance and elimination half-life. Elimination half-life is directly related to the volume of distribution and inversely related to clearance. Any 1 or more of these parameters may be altered by physiological changes such as ageing, or disease states such as congestive heart failure. Congestive heart failure is associated with hypoperfusion to various organs including the sites of drug clearance, i.e. the liver and kidneys. It also leads to organ congestion as seen in the liver and gut. The main changes in drug pharmacokinetics seen in congestive heart failure are a reduction in the volume of distribution and impairment of clearance. The change in elimination half-life consequently depends on whether both clearance and the apparent volume of distribution change, and the extent of that change. Pharmacokinetic changes are not always predictable in congestive heart failure, but it seems that the net effect of reduction in the volume of distribution and impairment of clearance is that plasma concentrations of drugs are usually higher in patients with congestive heart failure than in healthy subjects. The changes in pharmacokinetics assume importance only in the case of drugs with a narrow therapeutic ratio (e.g. digoxin) and some of the antiarrhythmics such as lignocaine (lidocaine), procainamide and disopyramide. This necessitates reduction in both the loading and maintenance doses. Prolongation of the elimination half-life leads to delay in reaching steady-state, and therefore dose increments must be made more gradually. Plasma concentration measurements of the drugs concerned are a good guide to therapy and help to avoid toxicity. Pharmacokinetic changes are of less importance in the case of drugs with immediate clinical response, e.g. diuretics and intravenous vasodilators such as nitrates and phosphodiesterase inhibitors. The dose in the latter group can be titrated to the desired effect. Not all adverse reactions to drugs that may occur in heart failure are the result of alterations in pharmacokinetics; rather, some may be due to important drug interactions. An interaction may occur directly e.g. reduction of renal clearance of digoxin by captopril and quinidine; or indirectly, e.g. through diuretic-induced hypokalaemia, which exacerbate arrhythmias associated with digoxin and antiarrhythmics such as quinidine and procainamide.

Animals↗
PubMed1997

Ibutilide. A review of its pharmacological properties and clinical potential in the acute management of atrial flutter and fibrillation.

Ibutilide is the first 'pure' class III antiarrhythmic drug to become available. Its predominant action is prolongation of the myocardial action potential duration. This appears to be achieved by a unique ionic mechanism of action that involves activation of a late inward sodium current and possibly blockade of the rapidly activating component of the cardiac delayed rectifier potassium current. Intravenous ibutilide 0.01 to 0.025 mg/kg or 1 to 2 mg successfully converted atrial flutter or fibrillation to sinus rhythm in 33 to 49% of patients in 2 placebo-controlled trials involving 439 patients with sustained arrhythmia. In a third trial in 300 patients who developed atrial flutter or fibrillation after cardiac surgery, ibutilide 2 mg successfully converted the arrhythmia in 57% of patients. The mean times to conversion were < or = 30 minutes in these trials. In 3 comparative trials, ibutilide was significantly more effective than racemic sotalol or procainamide in terminating atrial flutter or fibrillation. The pretreatment duration of the arrhythmia is an important predictor of the success of ibutilide treatment; the greatest conversion rates are achieved when the arrhythmia is of recent onset (i.e. < or = 30 days' duration). Ibutilide is more effective in terminating atrial flutter than atrial fibrillation. Adverse events associated with ibutilide are predominantly cardiovascular. Sustained polymorphic ventricular tachycardia developed in 1.7%, and non-sustained polymorphic ventricular tachycardia in 2.7%, of 586 patients treated with ibutilide in clinical trials. However, no proarrhythmia-related deaths have been reported with the use of ibutilide. The drug has minimal haemodynamic effects and is associated with few noncardiovascular adverse events. Thus, ibutilide is a useful agent for the pharmacological cardioversion of recent-onset atrial fibrillation or flutter, provided that adequate steps are taken to monitor for proarrhythmic events. The drug causes few noncardiovascular adverse events and has minimal haemodynamic effects. Furthermore, it appears to be more effective than procainamide (especially in patients with atrial flutter) and racemic sotalol.

Anti-Arrhythmia Agents↗
PubMed1995

Adsorption of charged non-albumin bound drugs by amorphous silica.

We investigated the in vitro drug adsorption of PQ 10150 sodium silicate gel (AIS, Santa Clara, CA) with particle size of 230 microns and surface area of 400 m2/g. We observed 99% to 88% adsorption of gentamicin; a mean 91% of disopyramide; a mean 89% of quinidine at low concentration, falling to 75% at higher concentration. Insulin was 88% adsorbed at low concentrations but less so (65%) at higher concentrations. We observed a mean 83% adsorption of procainamide, a mean 84% of N-acetyl procainamide, 74% of lidocaine, 73% of amitriptyline, and 44% of desipramine. We found an average of 14% reduction of total digoxin concentration when serum containing digoxin (2 to 33 ng/mL) was exposed to sodium silicate, while the reduction in free digoxin concentration was 16%. Five percent ethosuximide was also removed. The adsorption of theophylline, phenobarbital, acetaminophen, phenytoin, ethylene glycol, methotrexate, salicylate, thiocyanate and diazepam was minimal and not significant. We conclude that significant amounts of charged, non-albumin bound drugs can be removed by PQ 10150 sodium silicate gel.

Adsorption↗
PubMed1981

Exercise-triggered paroxysmal ventricular tachycardia. A repetitive rhythmic activity possibly related to afterdepolarization.

Electrophysiologic study, isoproterenol infusion, and serial treadmill exercise tests before and after administration of propranolol, verapamil, lidocaine, and procainamide were done in three patients with exercise-triggered ventricular tachycardia. In all three patients, organic heart diseases were absent. Ventricular tachycardia was reproducibly provoked with exercise and with isoproterenol infusion. Propranolol (tested in three patients) and lidocaine (tested in two patients) effectively prevented exercise provocation of tachycardia. Verapamil terminated tachycardia in all three patient and successfully prevented exercise provocation of tachycardia in only two patients. Procainamide was ineffective in one patient and was partially effective in two patients. In the latter two patients, ventricular ectopies, couplets, and short salvos remained provocable with exercise. Electrical stimulations with incremental ventricular pacing and ventricular extrastimulus testing failed to induce tachycardia in all three patients. These findings strongly suggest that repetitive rhythmic activities related to the catecholamine-sensitive afterdepolarizations are probably responsible for the exercise-triggered ventricular tachycardia.

Adult↗
PubMed1999

Cimetidine transport in brush-border membrane vesicles from rat small intestine.

In previous studies, sulfoxide metabolite was observed in animal and human intestinal perfusions of cimetidine and other H2-antagonists. A sequence of follow-up studies is ongoing to assess the intestinal contributions of drug metabolism and drug and metabolite transport to variable drug absorption. An evaluation of these contributions to absorption variability is carried out in isolated fractions of the absorptive cells to uncouple the processes involved. In this report, data is presented on the drug entry step from a study on [3H]cimetidine uptake into isolated brush-border membrane vesicles from rat small intestine. A saturable component for cimetidine uptake was characterized with a Vmax and Km (mean +/- S.E.M.) of 6.1 +/- 1.5 nmol/30s/mg protein and 8.4 +/- 2.0 mM, respectively. Initial binding, and possibly intravesicular uptake, was inhibited by other cationic compounds including ranitidine, procainamide, imipramine, erythromycin, and cysteamine but not by TEA or by the organic anion, probenecid. Initial uptake was not inhibited by amino acids methionine, cysteine, or histidine, by the metabolite cimetidine sulfoxide, or by inhibitors of cimetidine sulfoxidation, methimazole, and diisothiocyanostilbene-2,2'-disulfonic acid. Equilibrium uptake was inhibited by ranitidine, procainamide, and cysteamine but not by erythromycin or imipramine. Initial cimetidine uptake was stimulated by an outwardly directed H+ gradient, and efflux was enhanced by an inwardly directed H+ gradient. Collapse of the H+ gradient as well as voltage-clamping potential difference to zero significantly reduced initial cimetidine uptake. The data is supportive of both a cimetidine/H+ exchange mechanism and a driving-force contribution from an inside negative proton or cation diffusion potential.

Animals↗