Tenecteplase for treatment of acute myocardial infarction.

OBJECTIVE: To describe the pharmacology, pharmacokinetics, efficacy, and safety of tenecteplase in reducing mortality associated with acute myocardial infarction (AMI). DATA SOURCES: Published articles were identified from MEDLINE (from 1966 to December 2000) and Current Contents (all sections) searches. STUDY SELECTION AND DATA EXTRACTION: Dose-ranging and pivotal studies were included for analysis in the clinical trials section. DATA SYNTHESIS: Tenecteplase is a third-generation thrombolytic indicated for the reduction of mortality associated with AMI. Tenecteplase has a longer half-life that allows for single-dose, intravenous bolus administration. Data from clinical trials support that tenecteplase is similar to alteplase in reducing 30-day mortality rates in patients who have had an AMI. In the ASSENT-2 (Assessment of the Safety and Efficacy of a New Thrombolytic) trial, patients treated with tenecteplase required fewer blood transfusions and experienced fewer episodes of noncerebral bleeding compared with those treated with alteplase. CONCLUSIONS: Tenecteplase is an effective thrombolytic agent for the treatment of AMI. It can be given as a single weight-based dose; however, it appears to offer no significant advantage over other agents in terms of its efficacy or rate of intracranial hemorrhage.

New recommendations from the 1999 American College of Cardiology/American Heart Association acute myocardial infarction guidelines.

OBJECTIVE: To review literature relating to significant changes in drug therapy recommendations in the 1999 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for treating patients with acute myocardial infarction (AMI). DATA SOURCES: 1999 ACC/AHA AMI guidelines, English-language clinical trials, reviews, and editorials researching the role of drug therapy and primary angioplasty for AMI that were referenced in the guidelines were included. Additional data published in 2000 or unpublished were also included if relevant to interpretation of the guidelines. STUDY SELECTION: The articles selected influence AMI treatment recommendations. DATA SYNTHESIS: Many clinicians and health systems use the ACC/AHA AMI guidelines to develop treatment plans for AMI patients. This review highlights important changes in AMI drug therapy recommendations by reviewing the results of recent clinical trials. Insights into evolving drug therapy strategies that may impact future guideline development are also described. CONCLUSIONS: Several changes in drug therapy recommendations were included in the 1999 AMI ACC/AHA guidelines. There is emphasis on administering fibrin-specific thrombolytics secondary to enhanced efficacy. Selection between fibrin-specific agents is unclear at this time. Low response rates to thrombolytics have been noted in the elderly, women, patients with heart failure, and those showing left bundle-branch block on the electrocardiogram. These patient groups should be targeted for improved utilization programs. The use of glycoprotein (GP) IIb/IIIa receptor inhibitors in non-ST-segment elevation MI was emphasized. Small trials combining reduced doses of thrombolytics with GP IIb/IIIa receptor inhibitors have shown promise by increasing reperfusion rates without increasing bleeding risk, but firm conclusions cannot be made until the results of larger trials are known. Primary percutaneous coronary intervention (PCI) trials suggest lower mortality rates for primary PCI when compared with thrombolysis alone. However, primary PCI, including coronary angioplasty, is only available at approximately 13% of US hospitals, making thrombolysis the preferred strategy for most patients. Clopidogrel has supplanted ticlopidine as the recommended antiplatelet agent for patients with aspirin allergy or intolerance following reports of a better safety profile. The recommended dose of unfractionated heparin is lower than previously recommended, necessitating a separate nomogram for patients with acute coronary syndromes. Routine use of warfarin, either alone or in combination with aspirin, is not supported by clinical trials; however, warfarin remains a choice for antithrombotic therapy in patients intolerant to aspirin. Beta-adrenergic receptor blockers continue to be recommended, and emphasis is placed on improving rates of early administration (during hospitalization), even in patients with moderate left ventricular dysfunction. New recommendations for drug treatment of post-AMI patients with low high-density lipoprotein cholesterol and/or elevated triglycerides are included, with either niacin or gemfibrozil recommended as an option. Supplementary antioxidants are not recommended for either primary or secondary prevention of AMI, with new data demonstrating lack of efficacy vitamin E in primary prevention. Estrogen replacement therapy or hormonal replacement therapy should not be initiated solely for prevention of cardiovascular disease, but can be continued in cardiovascular patients already taking long-term therapy for other reasons. Bupropion has been added as a new treatment option for smoking cessation. As drug therapy continues to evolve in treating AMI, more frequent updates of therapy guidelines will be necessary.

Clinical use of new antithrombotic therapies for medical management of acute coronary syndromes.

Prevention and management of acute coronary syndromes (ACS) are focal points of interest among health care providers. Acute coronary syndromes is an all-encompassing term that refers to unstable angina, non-Q wave myocardial infarction, and Q wave myocardial infarction. These syndromes are usually the result of atherosclerotic plaque rupture leading to thrombus formation in a coronary artery. Heparin and aspirin are traditional antithrombotic treatments. They typically are administered with antiischemic therapies and often with fibrinolytic agents for patients with ST segment elevation associated with acute myocardial infarction. Although aspirin and heparin are important, they have significant limitations that have prompted development of newer antithrombotic approaches. Adenosine diphosphate inhibitors have been evaluated as either alternatives or adjunctive treatment to aspirin. Glycoprotein IIb-IIIa receptor inhibitors, low-molecular-weight heparins, and direct thrombin inhibitors have been studied as concurrent therapy with, or as alternatives to, heparin.

Vitamins for the management of cardiovascular disease: a simple solution to a complex problem?

Attention is focusing on the relationship between homocysteine and cardiovascular disease and the role of vitamins in the management of this prevalent ailment. Epidemiologic studies have shown that a relationship between elevated homocysteine concentrations and cardiovascular disease may exist; however, a cause-and-effect relationship has not been proven. The B vitamins are key components of homocysteine metabolism, and the trend is toward their being increasingly prescribed for cardiovascular disease. Prescribing of antioxidant vitamins, vitamin E in particular, has increased as well. Vitamin E may decrease the risk of nonfatal myocardial infarction in patients with coronary artery disease, but its benefit in preventing fatal myocardial infarction has not been shown. Vitamin supplements are not warranted in all patients with cardiovascular disease but may have a place in therapy for selected patients.

Adjunctive intracoronary thrombolysis in complicated coronary angioplasty.

Percutaneous transluminal coronary angioplasty is complicated by abrupt closure in 4.4-9.5% of procedures. Although the etiology of closure is difficult to determine, arterial dissection and thrombus formation are often involved. When abrupt closure occurs, repeat balloon dilation of the affected vessel is the mainstay of treatment and results in a mean angiographic success rate of 44% (range 35-51%). Other interventions, such as stent implantation and atherectomy, may also be attempted. I.c. thrombolysis is an alternative rescue strategy for the treatment of abrupt coronary closure during angioplasty. Initial angiographic success with i.c. thrombolysis, in combination with repeat balloon dilation ranges from 52% to 90%. These results are encouraging, but vessel reocclusion occurs in up to 55% of patients, resulting in diminished clinical success. Two trials suggest thrombolysis is ineffective or detrimental in this patient population. Most studies evaluating i.c. thrombolysis are retrospective, noncomparative, lack standardized protocols, and evaluate dissimilar patient populations. Therefore, the contribution of confounding variable such as operator experience, balloon size, duration of balloon inflation, and investigator bias cannot be assessed. I.c. thrombolysis has a limited role in the treatment of abrupt closure. This therapy should be considered only if thrombus formation is definitively the cause of occlusion, and avoided if intimal dissection is present, due to possible detrimental effects. The results of thrombolysis as a sole rescue therapy for abrupt closure are disappointing. Therefore, repeat balloon dilation should always be performed concomitantly with drug administration. In select patients, streptokinase, alteplase, or urokinase may be given for abrupt closure. Urokinase is favored due to increased experience with this agent and decreased cost. Ambrose recommends 250,000-1,000,000 units of urokinase, infused for up to 30 minutes (average wholesale price $419-1676). Additional data indicate a lower dose of urokinase may be sufficient for closure resolution, but this has not been adequately assessed. I.c. rather than intravenous thrombolytic administration may cause fewer systemic effects; however, contraindications to thrombolytic therapy should always be evaluated and weighed against potential benefits. The future role of thrombolysis in the treatment of complicated coronary angioplasty is unclear. Only randomized, controlled trials can evaluate the merits of this treatment approach compared with other rescue strategies.

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.

Sotalol: a breakthrough antiarrhythmic?

OBJECTIVE: To review the pharmacology, pharmacokinetic, dosing, adverse effects, and therapeutic uses of sotalol. DATA IDENTIFICATION: Articles were identified with an English-language literature computer search via Knowledge Finder, using the term sotalol, and with an extensive search of bibliographies of identified articles. STUDY SELECTION: Relevant or representative animal studies, human trials, and case reports were selected for evaluation. DATA EXTRACTION: The literature was assessed for quality, methodology, and outcome information. DATA SYNTHESIS: Sotalol is a racemic compound with Class II (beta-blocking properties) and Class III (prolonged action potential) antiarrhythmic activity. It has been suggested that the plasma concentration associated with QTc prolongation (a measure of the Class III action) is much greater than that associated with beta-blockade. Therefore, sotalol is categorized as a Class III antiarrhythmic agent. The 1-isomer is responsible for the beta-blocking activity, whereas both isomers have Class III properties. After oral dosing in fasting patients with normal renal function, sotalol is > 90 percent absorbed, achieves peak serum concentrations in 2-4 h, is excreted unchanged 80-90 percent in the urine, has a volume of distribution of 1-2 L/kg, and has an elimination half-life of about 12 h. Sotalol is effective in patients with life-threatening ventricular arrhythmias that have been refractory to other conventional antiarrhythmic drugs. In general, sotalol appears to be well tolerated, with many of its adverse effects caused by beta-blocking activity. As with other antiarrhythmic agents, the possibility of proarrhythmia (frequently torsade de pointes) exists. CONCLUSIONS: Racemic sotalol is an effective Class III antiarrhythmic agent approved by the Food and Drug Administration for the treatment of documented life-threatening ventricular arrhythmias. Investigations continue with racemic sotalol in the management of supraventricular arrhythmias. Trials with the d-isomer are also ongoing.

Concomitant amiodarone and the implantable cardioverter-defibrillator: is there a place?

OBJECTIVE: To discuss the controversy surrounding concomitant therapy with amiodarone and the implantable cardioverter-defibrillator (ICD). DATA SOURCES: A MEDLINE search identified English-language literature sources, including nonhuman studies. STUDY SELECTION: Studies included those that specifically addressed the use of amiodarone plus the ICD as well as reviews of the ICD. DATA EXTRACTION: Studies were evaluated for design, type of defibrillation electrode or defibrillator, method of defibrillation, amiodarone loading and maintenance dosages, duration of amiodarone therapy, and study endpoints. DATA SYNTHESIS: Because the ICD functions by delivering energy to depolarize a mass of myocardium, concomitant use of antiarrhythmic agents that elevate the defibrillation threshold (DFT) beyond an ICD's energy capability may adversely effect patient outcome. Amiodarone has been shown to both increase and decrease the DFT. Trials examining the use of amiodarone plus the ICD have not provided strong evidence that amiodarone will decrease the number of ICD discharges or favorably affect the mortality rate. Amiodarone is also expensive and toxic. Although the cost of the ICD is relatively high, continuing improvements in battery life will decrease long-term costs. CONCLUSIONS: Controlled trials are required to substantiate the improved survival rate with the ICD and to determine the role of antiarrhythmic agents in conjunction with the device. At present, there are no data to support the combination of amiodarone and an ICD in terms of improved quality or duration of life.

The pharmacist's role in thrombolytic therapy.

The pharmacist's role in the administration, appropriate use, and evaluation of thrombolytic agents is discussed. Thrombolytic drugs have been shown to be efficacious when given early in the development of an acute myocardial infarction (AMI). If the drug is to be reconstituted in a central area, there must be immediate response from the pharmacy. If reconstitution is not the pharmacist's responsibility, the pharmacist should still play a role in establishing guidelines for patient selection, drug reconstitution, patient-specific dosing regimens, and concomitant therapy. Pharmacists must also participate in drug-use evaluation. The three thrombolytic agents currently available for the management of AMI are streptokinase, alteplase, and anistreplase. Dosing and reconstitution guidelines for each of these agents are given, and current investigations concerning optimum regimens are summarized. Some of the relative contraindications now used in patient selection need to be examined. It is possible that certain patient subgroups excluded in some trials may benefit from thrombolytic agents. Future clinical trials will provide guidance for the use of thrombolytic agents in these populations. The advent of thrombolytic therapy offers pharmacy an opportunity to expand its role in the drug-use process and to ensure the appropriate use of these agents.

Antihypertensive monotherapy with tablet (prompt-release) diltiazem: multicenter controlled trials.

The tablet formulation of diltiazem has been available for the treatment of angina pectoris but has not been comprehensively evaluated in hypertension. This study's aim was to evaluate the efficacy, dose-response characteristics, and duration of action of tablet (prompt-release) diltiazem in mild to moderate hypertension. Three placebo-controlled trials were designed. The first (trial #1) evaluated the dose response of 120, 240, and 360 mg/day (q12h regimen) of diltiazem in parallel fixed-dose fashion using hourly blood pressures. The second (trial #2) evaluated a q12h titration from 240 to 360 mg/day, which could be switched to q8h. The third (trial #3) evaluated a q8h titration from 180 to 270 to 360 mg/day, followed by conversion to a q12h regimen. The goal was a supine diastolic blood pressure of less than 90 mmHg and 10 mmHg less than baseline. With doses of diltiazem increasing from 120 to 240 to 360 mg/day, there was a progressive decrease in the average mean arterial pressure, describing a dose response with 120 mg/day as the ineffective dose. The peak effect for each dose regimen was found at 6 hours, with significant reductions lasting over 10 hours in the 240 mg/day and 360 mg/day groups. Peak plasma concentrations occurred at 3 hours. The residual effect at the trough of the 240 mg/day and 360 mg/day doses was 48% and 53% of the peak effect, respectively. When titration was carried out on a q8h regimen, both systolic and diastolic blood pressures were significantly decreased. When the regimen was switched from q8h to q12h, the effect was not maintained.(ABSTRACT TRUNCATED AT 250 WORDS)

Sustained-release diltiazem: duration of antihypertensive effect.

The antihypertensive activity of a sustained-release preparation of diltiazem (given each 12 hours) was assessed in 96 patients with supine diastolic blood pressure (BP) between 95 and 110 mm Hg in a multicenter, randomized, double-blind, placebo run-in, parallel-group trial comparing optimally titrated doses of diltiazem and placebo. The aim was to assess the onset of action as well as the extent and variability of BP control of this formulation during the 12-hour interval. Diltiazem was titrated from 120 mg bid to 180 mg bid as necessary to lower BP. At baseline, on the first day of titration, and at the end of 8 weeks, BP was evaluated at 0, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours after dosing. The onset of action was within 2 hours, and the effect was maintained throughout the 12-hour period. Mean BP for the diltiazem group at baseline was 154/101 mm Hg. At week 8, BP was 148/93 mm Hg at hour "0" (P less than .02 and P = .0001 for systolic and diastolic BP vs. placebo), 139/84 mm Hg at the nadir at hour 5 (P = .0001), and 149/91 mm Hg at the end of the 12-hour period (P less than .02 and P = .0001 for systolic and diastolic BP). Diltiazem was significantly more effective than placebo (P = .0001) with 50% of patients controlled to a diastolic pressure of less than 90 mm Hg at 7 of the 10 evaluation points, including the evaluation point of 12 hours post-dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic effects of antihypertensive therapy with a calcium antagonist.

The effect of diuretics to increase serum glucose, low-density lipoprotein cholesterol and triglycerides, as well as the adverse changes in triglycerides and high-density lipoprotein cholesterol produced by nonselective beta blockers, have been largely ignored in the treatment of hypertension. However, a number of trials have shown that reductions in serum lipids can alter cardiovascular mortality. Calcium antagonists have become major drugs in the treatment of hypertension, and some data suggest that calcium antagonists may increase serum glucose levels. Significantly less data on lipid effects have been published. Lipid and glucose effects were examined in an 8-week antihypertensive study using a sustained-release preparation of diltiazem titrated from 240 to 360 mg/day in a twice-daily regimen in a randomized, double-blind, placebo-controlled parallel trial in 96 patients. Average supine blood pressure at week 8 was 156/98 mm Hg, standing blood pressure with placebo 152/100 mm Hg, and with diltiazem 147/91 and 144/93 mm Hg. There were no statistically significant changes in serum lipids or glucose in the diltiazem or placebo group or between the groups. Mean values (mg/dl) at baseline and week 8 in the diltiazem group were, respectively, for cholesterol 215 and 218, high-density lipoprotein cholesterol 50 and 51, low-density lipoprotein cholesterol 128 and 133, triglycerides 169 and 175, and glucose 113 and 110. Thus, this large and placebo-controlled study shows that diltiazem is among the antihypertensives with no adverse long-term lipid or glucose effects.

Paradoxical increase of ventricular fibrillation threshold in response to coronary sinus obstruction.

We determined the ventricular fibrillation threshold (VFT) changes in response to graded coronary sinus (CS) obstruction in 13 chloralose-anesthetized dogs with fixed heart rate (150 min-1, mean systemic arterial pressure (80 mm Hg), and cardiac index (100 ml/min.kg-1 body weight). VFT in milliamperes (VFTmA) increased linearily with CS pressure (CSP) increases up to 41.2 +/- 1.4 mm Hg (VFTmA = 6.5 + 0.14 CSP mm Hg, p less than 0.01). Total coronary venous effluent (CBF) did not change significantly, suggesting compensatory coronary vasodilation. Myocardial O2 consumption also remained unchanged. At higher CSP, both CBF and VFT declined precipitously (VFTmA = 20.9 - 0.27 CSP mm Hg, p less than 0.02). With simultaneous increases of systemic arterial along with CSP, VFT increased again along with the CSP-induced reduction of gradient until it reached 42.8 +/- 3.2 mm Hg. We conclude that with coronary venous obstruction, despite coronary perfusion gradient reduction to about 40 mm Hg, CBF remains constant. This constant flow vasodilation is associated with substantial (82%) VFT increase. The mechanism may involve enhanced homogeneity of CBF distribution and increased extracellular fluid.

The disposition of recainam hydrochloride during and after intravenous loading and maintenance infusion in cardiac patients.

Recainam hydrochloride is a newly synthesized propylurea compound demonstrating potent antidysrhythmic effects. Recainam was administered as a loading dose of 3 mg/kg/40 minutes followed by a continuous infusion of 0.9 mg/kg/hr for 23 hours and 20 minutes to ten patients with cardiac disease and frequent PVCs (more than 30/hr). A total of 15 plasma samples were drawn over 36 hours during and after the infusion. Plasma recainam concentration was determined by high performance liquid chromatography (HPLC). The mean (+/- SD) postload and 24-hour plasma concentrations were 5.19 +/- 0.51 and 3.41 +/- 0.71 micrograms/mL, respectively. The data were best described by a two-compartment model yielding the following mean (+/- SD) pharmacokinetic parameters: lambda 1 = 2.62 +/- 0.68 hr-1, lambda 2 = 0.144 +/- 0.014 hr-1, t1/2 lambda 2 = 4.84 +/- 0.46 hr, CLT = 0.268 +/- 0.057 L/hr/kg, CLR = 0.143 +/- 0.052 L/kg/hr, CLNR = 0.125 +/- 0.041 L/hr/kg, Vdss = 1.3 +/- 0.19 L/kg, and Vd lambda 2 = 1.9 +/- 0.43 L/kg. There were no adverse reactions. Based on these data, recainam can be safely administered as a loading dose followed by a continuous infusion in patients with stable cardiac disease without significant ventricular dysfunction.

Effect of phenytoin on serum disopyramide concentrations.

The effects of phenytoin on serum disopyramide concentrations in 10 volunteers were studied. Leading to the study was the case of a 59-year-old man who received phenytoin and disopyramide and who required unusually high doses of disopyramide and an unusually high serum concentration of this drug to control his ventricular tachycardia. Ten healthy men 23-36 years of age each received a single oral dose of disopyramide phosphate 300 mg. Periodic blood samples were obtained for 24 hours after the dose. On day 2, the subjects began a 13-day course of oral phenytoin sodium 300 mg/day, and on day 14 each again received a single oral dose of disopyramide, after which blood samples were obtained. Serum disopyramide concentrations were determined by enzyme-mediated immunoassay and gas chromatography and serum phenytoin concentrations by fluorescence polarization immunoassay. Pharmacokinetic values before and after phenytoin administration were calculated. The mean area under the serum concentration-time curve for disopyramide and the disopyramide half-life and elimination rate constant were significantly different before and after phenytoin treatment. The maximum serum disopyramide concentrations were not significantly different. After phenytoin therapy, subjective complaints of anticholinergic effects increased in number and severity. An interaction between disopyramide and phenytoin appears to exist and to be caused by an increase in the hepatic metabolism of disopyramide.(ABSTRACT TRUNCATED AT 250 WORDS)

Initial and long-term outpatient experience with pirmenol for control of ventricular arrhythmias.

Pirmenol, a new class IA antiarrhythmic agent, has shown promise in short-term trials, but long-term efficacy has not been documented. We thus evaluated 11 patients with frequent (greater than or equal to 60/h) premature ventricular complexes (PVC) given oral pirmenol for 25-727 days. Ten of 11 patients entering the long-term open trial had shown greater than or equal to 70% (mean 83%) PVC suppression during in-hospital pirmenol dose ranging. Long-term pirmenol was given in divided doses of 100-600 mg/day. Mean PVC frequency during baseline was 13,078/24 h (range, 3,218-32,718); couplets averaged 481/24 h (1-2,829) and runs 45/24 h (0-334). Ambulatory monitoring was performed at 1, 3, 6, and 12 months, then semiannually. Mean absolute PVC suppression at 1 month averaged 75% (p less than or equal to 0.02). Median individual percentage PVC suppression was 94%. During the first 3 months, 8 patients (73%) continued to show a favorable response (greater than or equal to 70% suppression), and 3 had arrhythmia recurrence and were dropped. One responder was withdrawn after the onset of paroxysmal atrial fibrillation, and another early responder was withdrawn after 3 months because of arrhythmia relapse. Six patients have been treated for over 1 year, with 99% mean PVC suppression. Mean couplet and run frequencies at 1 month decreased by means of 76% (p less than or equal to 0.05) and 92% (p = 0.001) respectively. At 1 year, couplets were suppressed 99.8% and runs by 99.7% in the 6 patients remaining on pirmenol.(ABSTRACT TRUNCATED AT 250 WORDS)

Flecainide: a new prototype antiarrhythmic agent.

Flecainide acetate is the first class IC antiarrhythmic agent marketed in the United States. In vitro, animal and human studies have shown that the drug markedly prolongs conduction and has minimal effect on repolarization. Efficacy trials have shown flecainide to be effective in a wide range of ventricular and selected atrial arrhythmias. The drug is generally well tolerated, although minor adverse effects are common. These generally are related to the central nervous system and respond to a reduction in dosage. Like other antiarrhythmic agents, flecainide may demonstrate proarrhythmic effects. It is excreted in the urine as the parent compound and inactive metabolites. The elimination half-life ranges from 12-27 hours in patients with normal renal function, allowing convenient dosing regimens of 100-200 mg twice daily in most patients. Flecainide has the potential for widespread use.

Pirmenol for control of ventricular arrhythmias: oral dose-ranging and short-term maintenance study.

The antiarrhythmic efficacy and safety of oral pirmenol hydrochloride were assessed during a controlled, dose-ranging and short-term maintenance study in 12 patients with frequent (greater than 480/8 hours) premature ventricular complexes (PVCs). Eleven patients (92%) responded favorably (greater than 70% PVC suppression) to a trial of different doses. Mean interval (8-hour) suppression of PVC frequency was 95% in these 11 and 86% in the entire group. Twenty-four-hour suppression was similar in responders (88%). Repetitive PVCs were essentially eliminated. The mean effective dose was 316 mg/day (105 mg/8 hours). The average predose (trough) plasma concentration at the end of dose ranging was 1.4 micrograms/ml and the drug elimination half-life 7.3 hours (n = 12). Of 11 responding patients, 10 completed a 2-week outpatient trial. Pirmenol continued to be effective and tolerated in 8 patients, maintaining an overall average outpatient PVC suppression of 80%. The electrocardiographic intervals were mildly prolonged after multiple dosing (PR + 7%, QRS + 12%, QTc + 8%; all p less than 0.01). Blood pressure and heart rate did not change during treatment. The echocardiographic ejection fraction was maintained. Thus, oral pirmenol appears to be effective, conveniently administered and well tolerated as an antiarrhythmic agent for control of ventricular extrasystoles.