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PubMed2002

Hypertrophic cardiomyopathy: a systematic review.

CONTEXT: Throughout the past 40 years, a vast and sometimes contradictory literature has accumulated regarding hypertrophic cardiomyopathy (HCM), a genetic cardiac disease caused by a variety of mutations in genes encoding sarcomeric proteins and characterized by a broad and expanding clinical spectrum. OBJECTIVES: To clarify and summarize the relevant clinical issues and to profile rapidly evolving concepts regarding HCM. DATA SOURCES: Systematic analysis of the relevant HCM literature, accessed through MEDLINE (1966-2000), bibliographies, and interactions with investigators. STUDY SELECTION AND DATA EXTRACTION: Diverse information was assimilated into a rigorous and objective contemporary description of HCM, affording greatest weight to prospective, controlled, and evidence-based studies. DATA SYNTHESIS: Hypertrophic cardiomyopathy is a relatively common genetic cardiac disease (1:500 in the general population) that is heterogeneous with respect to disease-causing mutations, presentation, prognosis, and treatment strategies. Visibility attached to HCM relates largely to its recognition as the most common cause of sudden death in the young (including competitive athletes). Clinical diagnosis is by 2-dimensional echocardiographic identification of otherwise unexplained left ventricular wall thickening in the presence of a nondilated cavity. Overall, HCM confers an annual mortality rate of about 1% and in most patients is compatible with little or no disability and normal life expectancy. Subsets with higher mortality or morbidity are linked to the complications of sudden death, progressive heart failure, and atrial fibrillation with embolic stroke. Treatment strategies depend on appropriate patient selection, including drug treatment for exertional dyspnea (beta-blockers, verapamil, disopyramide) and the septal myotomy-myectomy operation, which is the standard of care for severe refractory symptoms associated with marked outflow obstruction; alcohol septal ablation and pacing are alternatives to surgery for selected patients. High-risk patients may be treated effectively for sudden death prevention with the implantable cardioverter-defibrillator. CONCLUSIONS: Substantial understanding has evolved regarding the epidemiology and clinical course of HCM, as well as novel treatment strategies that may alter its natural history. An appreciation that HCM, although an important cause of death and disability at all ages, does not invariably convey ominous prognosis and is compatible with normal longevity should dictate a large measure of reassurance for many patients.

Cardiomyopathy, Hypertrophic↗
PubMed1992

Effect of basic drugs on the hepatic uptake of ouabain by sinusoidal plasma membrane vesicles isolated from rat liver.

Although antiarrhythmic drugs are used to treat digitalis-induced cardiac disorders, some of these drugs have been reported to increase the serum digoxin concentration in patients, causing the severe side-effects. We have previously shown that many basic drugs including antiarrhythmic drugs inhibited the hepatic uptake of cardiac glycosides into isolated rat hepatocytes, which could be a cause for the increased serum digoxin concentration. The present study was designed to examine the mechanism of this inhibition using isolated rat sinusoidal plasma membrane vesicles. The effect of nine basic drugs (dipyridamole, nifedipine, verapamil, chlorpromazine, lidocaine, quinidine, ajmaline, disopyramide, and propranolol) on the uptake of ouabain was studied. Quinidine reduced the initial uptake rate of ouabain (30 s) while it did not change the uptake of ouabain in an equilibrium condition (30 min). Other basic drugs, such as verapamil, dipyridamole, and nifedipine also significantly reduced the initial uptake rate of ouabain. These basic drugs had no effect on the membrane fluidity. The inhibitory effects on the vesicular uptake were significantly correlated with the inhibitory effects on ouabain uptake by the isolated rat hepatocytes. These findings may suggest that the mechanism of the inhibition involves the inhibition of the transport process via the sinusoidal plasma membrane.

Animals↗
PubMed1989

The FDA perspective on the development of stereoisomers.

The current regulatory position of the Food and Drug Administration is discussed with regard to the approval of racemates and pure stereoisomers. Circumstances in which stereochemically sensitive analytical methods are necessary to ensure the safety and efficacy of a drug are described. Regulatory guidelines are interpreted for applications for the approval of a pure enantiomer in which the racemate is marketed, for the approval of either a racemate or a pure enantiomer in which neither is marketed, and for clinical investigations to compare the safety and efficacy of a racemate and its enantiomers. Examples of the basis for such regulation are drawn from historical situations (thalidomide, benoxaprofen) as well as currently marketed drugs (arylpropionic acids, disopyramide, indacrinone).

Legislation, Drug↗
PubMed1990

Mexiletine: pharmacology and therapeutic use.

Mexiletine is a Class IB antiarrhythmic which has basic and clinical electrophysiologic properties similar to lidocaine. Like other Class I antiarrhythmic agents, mexiletine blocks the rapid inward sodium current responsible for phase 0 of the action potential. It has been noted in the clinical electrophysiology laboratory to have minimal effect on sinus node function and AV nodal and His-Purkinje system conduction. Pharmacokinetic studies have shown that oral absorption is rapid with bioavailability of 80-90%. Mexiletine is predominantly metabolized by the liver with elimination half-life of 9 to 12 hours. The antiarrhythmic effects of the primary drug's metabolites remain to be defined. Hemodynamic studies have shown mexiletine to have a lesser negative inotropic effect than procainamide or disopyramide. Although mexiletine as a single agent successfully suppresses 60 to 80% of spontaneous ventricular arrhythmias, it has lower efficacy in suppression of induced ventricular arrhythmias. Multiple studies have shown that as monotherapy mexiletine is effective in preventing the induction of ventricular tachycardia in approximately 20% of patients. When used in combination with a Class IA antiarrhythmic drug for suppression of induced ventricular arrhythmias, multiple investigators have reported greater efficacy. Neurological side effects (tremor, dizziness, memory loss) occur in approximately 10% of patients while gastrointestinal side effects (nausea, anorexia, gastric irritation) occur in up to 40% of patients. Proarrhythmia or other serious toxicity from the drug is uncommon.

Anti-Arrhythmia Agents↗
PubMed1991

Coronary vasospasm as a potential cause of myocardial infarction and paroxysmal atrial fibrillation in a relatively young woman.

Vasospasm-related myocardial infarction in young women with normal coronary arteries has infrequently been reported and vasospasm-related paroxysmal atrial fibrillation (PAF) has rarely been described. We present a 33-year-old woman with old inferior myocardial infarction and postinfarction angina at rest; the angina was accompanied by PAF and electrocardiographic ST-segment elevation in the inferior leads. Coronary angiography revealed normal coronary arteries and intracoronary acetylcholine provoked an intense and diffuse spasm of the right and left coronary artery. The spasm of the right coronary artery was associated with PAF and ST-segment elevation in the inferior leads. Frequently documented PAF, accompanied by chest discomfort and ST-segment elevation in the inferior leads, was more effectively removed with isosorbide dinitrate than with disopyramide. These data suggest that coronary vasospasm is a likely cause of myocardial infarction and even PAF, although the precise mechanism leading to PAF remains unknown.

Acetylcholine↗
PubMed1997

Atrial fibrillation: a review of mechanism, etiology, and therapy.

The prevalence of elderly individuals in the populations of developed countries is increasing rapidly, and atrial fibrillation (AF) is quite common in these elderly patients: currently, 11% of the U.S. population is between the ages of 65 and 85 years; 70% of people with AF are between the ages of 65 and 85 years. AF causes symptoms secondary to hemodynamic derangements that are the result of increased ventricular response and loss of atrial booster function. AF can lead to reversible impairment of left ventricular function, cardiac chamber dilatation, clinical heart failure, and thromboembolic events. AF requires treatment in order to prevent these potential complications. Type Ia, Ic, and III antiarrhythmics are capable of converting AF to normal sinus rhythm (NSR). Amiodarone has the greatest efficacy and safety for converting AF and maintaining NSR while digoxin and verapamil are ineffective in restoring NSR. Quinidine, flecainide, disopyramide, and sotalol have also been shown to maintain NSR after conversion of AF. Proarrhythmia is a definite concern with the latter four agents. Alternative therapy for AF includes anticoagulation with warfarin or aspirin for the prevention of thromboembolic events, and a variety of agents to control the ventricular response. All medications used to treat AF carry significant risks in the elderly, whether from proarrhythmia, overdosing because of compliance errors, or hemorrhage secondary to anticoagulation. Treatment of AF must be based on a careful risk-benefit evaluation. The physician must know the capability of the particular patient as well as drug mechanisms and effects in the elderly. The decision to convert patients from AF to NSR or to leave the patient in AF and control the ventricular response represents a complex intellectual challenge. Factors favoring one or the other of these two clinical strategies are discussed. Multicenter clinical trials, for example, the Atrial Fibrillation Follow-up Investigation Rhythm Management (AFFIRM) trial, are currently underway to assess various clinical strategies for maintenance of NSR following conversion from AF. Amiodarone is one of the drugs under investigation.

Aged↗
PubMedDate not supplied

Plasma protein binding of bepridil.

The binding of the calcium-channel blocking agent, bepridil HCl (Vascor), to plasma proteins was investigated using radiolabeled bepridil and equilibrium dialysis. Greater than 99.7% of added bepridil-14C was found to freshly collected human plasma. The binding was characterized by a saturable high-affinity site (KD = 32 ng/mL = 87 nM) on alpha1-acid glycoprotein (AAG) or on an AAG-human serum albumin complex and lower affinity binding sites on albumin and other plasma macromolecules. Bepridil that is not bound to plasma proteins is extensively distributed into erythrocytes as evidenced by a red blood cell to free drug distribution coefficient of 71 +/- 7. Despite this high value, the blood to plasma ratio of bepridil averaged only 0.67 in humans, indicating that most of the circulating drug is bound to plasma proteins. Bepridil protein binding was not affected by additions of nonesterified fatty acids. Free fractions of bepridil were enhanced by addition of verapamil, nifedipine, diltiazem, disopyramide, and warfarin but only at concentrations above those achieved clinically. Bepridil was also displaced by the plasticizer, tris-(2-butoxyethyl)phosphate. Plasma obtained from a small number of angina patients prior to bepridil administration showed no differences in ability to bind bepridil compared with plasma obtained from healthy subjects.

Angina Pectoris↗
PubMedDate not supplied

Pharmacology and clinical use of mexiletine.

Mexiletine is an antiarrhythmic agent with structural and electrophysiologic properties similar to those of lidocaine. Mexiletine decreases ventricular automaticity while shortening both action potential duration and effective refractory period. The drug may be administered orally or intravenously. Hepatic metabolism is the major route of elimination. The elimination half-life is approximately 10 hours, but longer in patients with acute myocardial infarction, chronic congestive heart failure or hepatic insufficiency. Mexiletine suppresses ventricular ectopy in the acute phase of myocardial infarction. The drug is effective for some patients in whom lidocaine has failed. It suppresses chronic ventricular ectopy and is well tolerated in approximately two-thirds of stable outpatients treated with this agent. In that population, mexiletine is comparable in efficacy to quinidine, procainamide and disopyramide. It is effective in 30-50% of patients with ventricular arrhythmias refractory to other antiarrhythmic drugs. In patients with refractory arrhythmias, the efficacy of mexiletine may be enhanced by combination with propranolol, quinidine or amiodarone. Adverse reactions limit use of mexiletine in approximately 20% of patients. Gastrointestinal and central nervous system side effects are the most common. Mexiletine does not depress myocardial function. Aggravation of arrhythmias is uncommonly observed. The usual intravenous dose of mexiletine is 150-250 mg over at least 10 minutes. Long-term oral dosages are usually 200-300 mg 3 or 4 times daily.

Arrhythmias, Cardiac↗
PubMed1985

Drug distribution within human milk phases.

Phase distribution and protein binding of drugs in human milk have been measured. The analytical method is reproducible, rapid, and requires only small sample volumes. Five drugs were studied: diazepam, phenobarbital, warfarin, phenytoin, and disopyramide. Experiments were carried out at 37 degrees C on milk samples with variable fat and protein contents. Results for the distribution of drugs between the skimmed-milk phase and fat-rich phase are presented, as well as the results of the dialysis of drugs in skimmed milk. It is shown that, among the physicochemical properties of a drug, the lipid solubility seems to be the most important property for predicting variations in drug concentrations in milk. The potential significance of the findings with respect to in vivo distribution of drugs into human milk is discussed.

Chemical Phenomena↗
PubMed1986

The contribution of Na channel block to the negative inotropic effect of antiarrhythmic drugs.

The specific Na channel blocker tetrodotoxin (TTX) produces a direct negative inotropic effect on the isolated guinea-pig papillary muscle stimulated at 1 Hz. The toxin is significantly more potent in reducing maximal upstroke velocity of the transmembrane action potential (Vmax, an index of the available Na conductance) than in reducing force of contraction (Fc), the IC50 for Vmax divided by the IC50 for Fc being 0.23 (95% confidence interval, 0.16-0.43). This IC50 ratio defines the negative inotropic influence of Na channel blockade per se, because TTX has no known action other than blocking Na channels. Vmax-reducing to negative inotropic concentration ratios were also obtained for 5 widely used and 2 experimental antiarrhythmic agents belonging to the Na channel-blocking class (class 1). Five of these drugs (aprindine, CCI 22277, disopyramide, mexiletine, and quinidine) differed significantly from TTX in that the Na channel block was associated with a stronger negative inotropic effect. It is concluded that one or more mechanisms in addition to Na channel blockade are involved in the negative inotropic effect of these antiarrhythmic drugs. If the antiarrhythmic activity of class 1 agents depended solely on Na channel block, more selective agents with less negative inotropic action could conceivably be developed.

Animals↗
PubMed1988

Calcium channel antagonists. Part IV: Side effects and contraindications drug interactions and combinations.

With the correct selection of drug and patient, the calcium antagonists as a group can be remarkably effective at relatively low cost of serious side effects. Almost all side effects are dose related. Minor side effects include those caused by vasodilation (flushing and headaches), constipation (verapamil), and ankle edema. Serious side effects are rare and result from improper use of these agents, as when intravenous verapamil (or diltiazem) is given to patients with sinus or atrioventricular nodal depression from drugs or disease, or nifedipine to patients with aortic stenosis. The potential of a marked negative inotropic effect is usually offset by afterload reduction, especially in the case of nifedipine which actually has the most marked negative inotropic effect. Yet caution is required when even calcium antagonists, especially verapamil, are given to patients with myocardial failure unless caused by hypertensive heart disease. Drug interactions of calcium antagonists occur with other cardiovascular agents such as alpha-adrenergic blockers, beta-adrenergic blockers, digoxin, quinidine, and disopyramide. The most marked interaction with digoxin is that with verapamil, which may raise digoxin levels by over 50%. Combination therapy of calcium antagonists with beta-blockers is increasingly common, and is probably safest in the case of dihydropyridines. Other combinations being explored are those with angiotensin-converting enzyme inhibitors and diuretics.

Calcium Channel Blockers↗
PubMed1994

Lidocaine increases the number of beta-adrenoceptors in neonatal rat cardiocytes in culture.

Some physiological functions of the heart are modulated through cardiac beta-adrenoceptors. In acute myocardial infarction, ventricular arrhythmias occur frequently and class I antiarrhythmic drugs such as lidocaine are often administered continuously over long period. The aim of this study was to investigate the effects of long-term treatment with lidocaine on cardiac beta-adrenoceptors. Ventricular cardiocytes from 2-day-old Wistar rat were cultured in the presence or absence of lidocaine, and beta-adrenoceptors of the membrane fraction of the cells were measured with a binding assay using [125I]-iodocyanopindolol ([125I]CYP) as a radioligand. When the cells were cultured in the presence of lidocaine at clinical or toxic concentrations, the binding of [125I]CYP to the cells increased in a concentration (10(-5) mol/l-10(-3) mol/l)--and time (12-72 h)--dependent manner. The effect was due to an increase in maximum binding and was not due to a change in the dissociation constant for the ligand. The stimulation of adenylyl cyclase activity in the cell membrane by 1 mumol/l isoproterenol increased in lidocaine-treated cells. The increased number of receptors returned to the control level when the cells were cultured without lidocaine for a further 24 h. These results indicate that lidocaine up-regulates cardiac beta-adrenoceptors at both clinical or toxic doses during the period of treatment. Other antiarrhythmic drugs such as disopyramide (Ia), mexiletine (Ib) and flecainide (Ic) also increased the number of beta-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1990

New concepts affecting the use of antiarrhythmic agents.

Three underappreciated concepts having an important impact on the use of antiarrhythmic agents having Class I activity are discussed. These are stereochemical influences on antiarrhythmic action, the modulated receptor theory, and pharmacogenetics. The stereoisomers of some antiarrhythmic agents behave differently in terms of their potency, disposition, and antiarrhythmic action. For example, the enantiomers of both tocainide and mexiletine are cleared at different rates, and those of disopyramide have opposite effects on repolarization. The modulated receptor theory suggests that the affinity of antiarrhythmic drugs to bind to a specific receptor on or near the sodium channel depends on whether the sodium channel is open, resting, or inactivated. Study of the interaction between the state of the sodium channel and the differing actions of the antiarrhythmic agents have provided evidence for synergistic drug combinations. Pharmacogenetics relates to the differences observed in drug metabolism among individuals, which can result in variations of two- to fourfold in clearance and plasma concentration in some cases. There is still much to learn about Class I antiarrhythmic agents. These concepts should lead to a better understanding of their actions and increase their utility.

Anti-Arrhythmia Agents↗
PubMed1981

Intracardiac electric stimulation in conscious rabbits. A new model for screening membrane-stabilizing antiarrhythmics.

Cardiac arrhythmics were induced in conscious rabbits by intracardiac electric stimulation. The arrhythmic threshold remained constant for a period of more than 6 months. The antiarrhythmic drugs ajmaline, prajmalium, disopyramide, quinidine, lidocaine, propranolol and verapamil, given i.v. or orally, were screened for their threshold-raising potency. Particularly the membrane-stabilizing antiarrhythmics showed significant effects. The model may constitute a useful screen for such drugs in the conscious animal.

Administration, Oral↗
PubMed1993

Use-dependent block of the delayed K+ current in rabbit ventricular myocytes.

Block of the delayed K+ current, iK, and the concomitant increase in refractoriness is considered an alternative to a decrease of conduction in the treatment of reentry arrhythmias. Ideally an agent should selectively prolong the action potential at high frequencies. A minimum requirement is use-dependent block. A number of drugs were tested for the existence of use dependence by applying a train of depolarizing clamps to single cardiac myocytes of the rabbit ventricle. Development of block during a long depolarizing clamp and recovery from block were also measured. Five of the nine drugs tested, i.e., disopyramide, encainide, quinidine, sotalol, and tedisamil, did not show use dependence. When a train of depolarizing clamps was applied, block was already present for the first depolarization and did not increase with repetition of the pulse. This result suggests block of the channel in the rested state or a very fast block of the open channel. Almokalant and amiodarone, and to a lesser extent dofetilide and E4031, showed use-dependent block, i.e., block increased during the train of depolarizing clamps. The time constant for the open channel block was 1.07 seconds for almokalant and 0.67 seconds for amiodarone. Recovery from block for almokalant and amiodarone was very slow: time constants measured at -50 mV were 13.9 and 12.7 seconds, respectively. For dofetilide it was in the order of minutes. The existence of this slow recovery explains why frequency-dependent changes in block were negligible or absent for frequencies above 0.5 Hz. Future research should be aimed to select drugs with a slower onset of active state block and faster recovery from block.

Action Potentials↗
PubMed1983

Displacement of lidocaine from serum alpha 1-acid glycoprotein binding sites by basic drugs.

Since little is known of the number and types of binding sites on alpha 1-acid glycoprotein (AAG) and because drug-drug protein binding interactions often fail to fit a simple model, a study of the effect of 9 known AAG binding drugs on lidocaine free fraction (LFF) was performed. Serum was obtained from 10 healthy males, pooled and various concentrations (from 0.15 to 1000 micrograms/ml) of amitriptyline, bupivacaine, chlorpromazine, disopyramide, imipramine, meperidine, nortriptyline, propranolol and quinidine were added. LFF was determined by equilibrium dialysis at an initial lidocaine concentration of 2.0 micrograms/ml. LFF increased from 0.30 +/- 0.019 (mean +/- SD) in the absence of displacing agents to maximum values ranging from 0.59 (nortriptyline) to 0.73 (bupivacaine). Plots of LFF vs. the logarithm of displacing drug concentration yielded simple sigmoidal curves in all cases. LFF was increased 50% by an initial bupivacaine concentration of 6.0 micrograms/ml with all other drugs requiring more than 10 micrograms/ml to increase LFF to that extent. Lidocaine binding in a 4.5 g/dl albumin solution was unaffected by concentrations of quinidine, meperidine, nortriptyline and bupivacaine up to 200 micrograms/ml. Addition of AAG to serum reduced LFF as expected. A plot of the reciprocal of bound drug concentration vs. the reciprocal of free drug concentration in the presence and absence of quinidine suggested a competitive binding interaction. These data indicate that the binding interactions between lidocaine and the various displacing compounds are not significantly complicated by cooperative effects and that, with the possible exception of bupivacaine, displacement of lidocaine by any of these drugs is likely to be of clinical significance.

Binding Sites↗
PubMed1984

Prediction of the volumes of distribution of basic drugs in humans based on data from animals.

The apparent volume of distribution-after distribution equilibrium and the ratio of distributive tissue volume to the unbound fraction in the tissue (VT/fuT) of 10 weak basic drugs, i.e., chlorpromazine, imipramine, propranolol, disopyramide, lidocaine, quinidine, meperidine, pentazocine, chlorpheniramine, and methacyclin were compared in animal species and humans. In these two parameters, a statistically significant correlation between animals and humans was obtained, when the parameters were plotted on a log-log scale. The correlation coefficient between VT/fuT was significantly higher than that between the apparent volumes of distribution (p less than 0.05). In general, there was little difference between VT/fuT of various basic drugs in animals and that in humans. Prediction of the apparent volume of distribution in humans using animal data of VT/fuT, plasma unbound fraction, blood volume, and blood-to-plasma concentration ratio in humans was successful for most of drugs studied.

Animals↗
PubMed1995

Observations on midodrine in a case of vasodepressor neurogenic syncope.

A 43-year-old man presented with recurrent syncope and dizziness after he had a dual chamber pacemaker fitted for presumed sino-atrial disease. Head-up tilt produced vasodepressor neurocardiogenic syncope, despite appropriate heart rate support during pacing, and reproduced symptoms. Symptoms were not improved by disopyramide. A double-blind cross-over trial of midodrine, an alpha-receptor agonist, was effective in reducing symptoms: it abolished syncope and reduced frequency and severity of dizziness, coupled with improved haemodynamic responses to head-up tilt.

Adrenergic alpha-Agonists↗