Martin J. Kendall

β-Blockers and Sudden Cardiac Death

Coronary artery disease remains the major cause of death in developed countries [1], despite tremendous advances in its management. One reason for this is that the changes in treatment seen in the last decade have had little effect on the incidence of sudden cardiac death, which accounts for approximately one half of cardiac mortality [2]. Indeed, in almost one fifth of men with coronary artery disease, the first and only manifestation of their illness is sudden death [3]. Defined as unexpected death from cardiac causes occurring within 1 hour of the onset of symptoms [4], sudden cardiac death is responsible for 300 000 to 400 000 deaths each year in the United States [1]. The cause in at least 80% of patients is ventricular arrhythmia occurring as a consequence of coronary heart disease [5]. A treatment that would substantially reduce the incidence of sudden cardiac death would have a major effect on overall cardiovascular mortality rates. An Approach to Cardioprotection To reduce the incidence of sudden cardiac death, it is desirable to identify those at increased risk for this event and give them effective prophylactic treatment. The most easily identified patients at risk are those with documented coronary heart disease. However, many more persons have latent heart disease, including the 50% of patients with myocardial infarction in whom the infarction is silent [6]. A relatively small proportion of those with undeclared disease can be identified, either through known risk factors for coronary heart disease or as a result of electrocardiography or electrocardiographic stress testing. Coronary angiography yields the most information in predicting risk, but this technique is not practical for investigating large numbers of patients. Some risk factors for coronary artery disease, such as hypertension, hyperlipidemia, and cigarette smoking, are both identifiable and treatable. Although reduction of blood pressure seems to be effective in preventing death from cerebrovascular accident, its effect on coronary mortality rates is less clear [7]. Experimental results in feline left ventricular hypertrophy [8] suggest that myocardial hypertrophy contributes to the adverse electrophysiologic consequences of ischemia and reperfusion. Effective long-term treatment of hypertension may thus have an indirect beneficial effect on the ventricular arrhythmias associated with coronary artery disease. Although simvastatin was recently shown to reduce mortality in patients with established coronary artery disease [9], the use of lipid-lowering drugs does not have proven efficacy in primary prevention. As a result, the commitment of individual physicians to the treatment of hyperlipidemia varies markedly. The most effective preventive measure is cessation of cigarette smoking, which significantly reduces the likelihood of coronary death [10], but the success of programs to help persons stop smoking is frequently disappointing. Other lifestyle changes, such as weight reduction and the introduction of regular physical exercise, may also help but are equally hard to achieve in practice. After high-risk persons have been identified and their risk factors modified, subsequent aims include the treatment of myocardial ischemia, if present, and the suppression of ventricular tachyarrhythmias. The cardioprotective drug chosen should ideally achieve both of these goals, and it should have been shown in clinical trials to reduce the risk for sudden cardiac death. The agents that have most successfully met these ideal criteria are the -blockers, and they have been shown to be consistently effective in large, long-term prevention trials [11]. -Blockers and Prevention of Ventricular Fibrillation: Evidence During 30 years of surveillance, the Framingham Study investigators [12] found that the overall incidence of sudden cardiac death during each 2-year period was 6.3 cases per 1000 men and 2.0 cases per 1000 women. In persons who had no previous coronary heart disease but had definite hypertension, the risk for sudden death was more than double that in persons with normal blood pressure. Incidence rates in persons with previous coronary heart disease (31.6 cases per 1000 men and 10.0 cases per 1000 women) were six to eight times greater than those of persons without coronary heart disease (4.0 cases per 1000 men and 1.6 cases per 1000 for women). Clearly, attempts to significantly reduce overall cardiovascular mortality must address in particular the hypertensive patient and the patient with established coronary heart disease. Primary Prevention of Coronary Disease Risk stratification of patients in the Framingham Heart Study [13] indicates that hypertension is a highly significant risk factor for the development of coronary disease and for sudden cardiac death. The effect of treating hypertension has been assessed in several prospective clinical trials [14]. Although diuretics appear to reduce coronary events in the elderly [15, 16], angiotensin-converting enzyme inhibitors, calcium-channel blockers, and -blockers have not been shown to reduce the frequency of myocardial infarction, nor do they reduce the risk for sudden death. In contrast, evidence shows that -blockers have a primary preventive role in men with hypertension. In the MAPHY (Metoprolol Atherosclerosis Prevention in Hypertensives) study [17], a mean 5-year follow-up of patients treated with metoprolol or thiazide diuretics confirmed that total mortality was significantly lower in the patients treated with metoprolol. The reduction was explained primarily by the 30% reduction in the number of sudden cardiac deaths; these deaths represented 78% of total cardiovascular mortality (Figure 1). This trial has been criticized [18, 19], but the criticisms have been answered [20]. Furthermore, data from other studies [21-23] have also shown trends favoring the use of -blockers in primary prevention. Figure 1. Sudden cardiovascular deaths in hypertensive patients. Secondary Prevention After myocardial infarction, the next most frequent cause of sudden death is arrhythmia, usually ventricular fibrillation [24]. It has been clearly shown that -blockers reduce the incidence of sudden death. Recent evidence [9] also suggests that simvastatin has a beneficial effect in patients with hypercholesterolemia. Aspirin and aspirin-like drugs have been found to reduce early and late mortality after myocardial infarction [25], but no evidence shows any effects on sudden death. An average reduction in total mortality of about 20% has been shown from pooled data from 18 000 patients during long-term treatment after myocardial infarction with -blockers [26]. This translates into an absolute reduction in risk for death from about 10% to about 8%. Even more impressive is that -blocker treatment reduces sudden death among these patients by 32% to 50% [27-30]. The results of three long-term, placebo-controlled trials of -blockers administered after infarction were published in 1981 and 1982 [27-29], providing, for the first time, evidence that medical therapy could reduce mortality after myocardial infarction. The three drugs usedthe non-selective agents timolol and propranolol and the 1-selective agent metoprololreduced total mortality by 26% to 36%. In the Norwegian Multicenter Study Group trial [27], the most pronounced effects of timolol were on the sudden cardiac death rate, which was almost halved. In the -Blocker Heart Attack Trial (BHAT) [28], propranolol reduced the incidence of sudden cardiac death from 4.6% (in participants receiving placebo) to 3.3% (P < 0.05), a reduction of almost 30%. In the Goteborg metoprolol trial [29], a 40% reduction in the number of deaths occurring within 24 hours and within 1 hour of onset of symptoms was seen. An analysis of pooled data from five different trials in which long-term metoprolol therapy was used after myocardial infarction [30] suggested that the reduction in total mortality was due primarily to a 40% reduction in the incidence of sudden cardiac death, a figure that held true for both men and women (Figure 2). Figure 2. Cumulative number of sudden deaths reported in five postinfarction trials. Two large, short-term, prospective trials of -blockers administered soon after the onset of myocardial infarction have also confirmed the efficacy of these agents in reducing mortality in the acute setting [31, 32]. The First International Study of Infarct Survival (ISIS-1) [31] included approximately 16 000 patients and found that atenolol reduced early cardiovascular mortality by 14% after 7 days. The study did not specifically analyze sudden death rates. In the Metoprolol in Acute Myocardial Infarction (MIAMI) trial [32], randomly assigning 6000 patients to metoprolol or placebo produced a 13% difference in mortality at 15 days in favor of metoprolol, but the effect was not statistically significant. On the basis of pooled data from trials of early intervention with a -blocker [33], it has been calculated that -blockers reduce mortality by about 15% in the first week. It is not possible to say from these results that all -blockers will produce similar results in the treatment of myocardial infarction. Although there appears to be a class effect in lowering blood pressure, reducing ischemia, and inhibiting the development of infarction, only a few -blockers have been shown to reduce the risk for sudden cardiac death. This is true of the lipophilic (and hence central nervous system-active) -blockers timolol [27], metoprolol [30], and propranolol [28], but a long-term prophylactic effect has not been shown for the hydrophilic -blockers atenolol [31] and sotalol [34]. The clinical evidence appears to confirm experimental observations that the reduction in sudden cardiac death is, at least in part, mediated through activity in the central nervous system. Little evidence supports the efficacy of other antihypertensive or anti-ischemic agents in the secondary prevention

Secretory immunoglobulin A and cardiovascular reactions to mental arithmetic, cold pressor, and exercise: Effects of beta‐adrenergic blockade

We investigated the influence of sympathetic nervous system processes on mucosal immunity by comparing the effects of beta-adrenoceptor blockade with 40 mg propranolol and placebo on secretory immunoglobulin A (sIgA) at rest and during paced serial arithmetic, cold pressor, and submaximal cycling. These tasks produced patterns of cardiovascular activity indicative of combined alpha- and beta-adrenergic, alpha-adrenergic, and beta-adrenergic activation, respectively. The effectiveness of the beta blockade was confirmed by the attenuation under propranolol of the shortening of the cardiac preejection period and the tachycardia elicited by mental arithmetic and exercise. The cold pressor test did not affect sIgA under either the placebo or the propranolol. Mental arithmetic increased sIgA concentration, and this increase was not blocked by propranolol. Exercise elicited increases in both sIgA concentration and sIgA secretion rate, which were not diminished by beta blockade. These data suggest that sIgA is not regulated by beta-adrenergic mechanisms.

Clinical relevance of pharmacokinetic differences between beta blockers.

Fundamental differences in the pharmacodynamic and pharmacokinetic profiles of beta-adrenergic blocking agents must be considered in optimizing their efficacy and determining the appropriate selection of these drugs in different patients. Beta blockers are contraindicated in patients with asthma and should be used cautiously in heart failure. Clinically important distinctions are related to whether a beta blocker is beta1-selective or nonselective. Most adverse effects of beta-blocker use are related to interference with beta2-mediated functions including bronchodilation, vasodilation, and mobilization of free fatty acids. To achieve the potential benefits of beta1 blockade (decreased heart rate, blood pressure, cardiac workload, and excitability), a low plasma concentration of a beta1-selective drug is required. Adverse effects of beta blockers can be further decreased by selecting a sustained-release beta1-selective drug. Beta blockers are further differentiated on the basis of lipophilicity or hydrophilicity. Lipophilic beta blockers cross the blood-brain barrier, whereas hydrophilic agents do not enter the central nervous system. Some lipophilic agents (metroprolol, timolol, and propanolol) have been shown to decrease mortality in coronary heart disease, particularly sudden cardiac death.

The impact of therapeutic doses of paracetamol on serum total antioxidant capacity

Introduction:  A link between regular paracetamol intake and asthma in adults has recently been postulated. Detoxification of paracetamol may deplete stores of glutathione, which is one of the major antioxidants present in the lung. A reduced source of glutathione in the lung may lead to increased oxidative damage to the epithelium and hence increased frequency and severity of asthma attacks in susceptible individuals.

A study of the effect of aspirin on the pharmacokinetics of oral and intravenous diclofenac sodium

SummaryPrevious studies have shown that aspirin interacts with orally administered diclofenac sodium, causing reduced peak concentrations, lower levels and decreased areas under curves. In this study, diclofenac sodium was administered orally and intravenously with and without aspirin, to 6 healthy female volunteers. After intravenous dosing both plasma levels and areas under curves were significantly reduced although none of the rate constants was affected. The volume of distribution of diclofenac was increased as was the plasma clearance. Oral administration with aspirin also resulted in lower plasma levels, particularly peak levels, and areas under curves. Comparison of AUCs for both modes of administration with and without aspirin suggested that lower levels after oral administration were not due to impaired absorption. These observations are best explained by decreased protein binding and increased biliary excretion of diclofenac in the presence of salicylate.

The pharmacokinetics of diclofenac sodium in patients with active rheumatoid disease

SummaryPharmacokinetic data for diclofenac sodium has been well established in healthy volunteers, whereas in patients with rheumatoid arthritis very little information is available in the literature. A single oral dose of enteric-coated diclofenac sodium was given to 10 patients with active rheumatoid disease, adopting the same procedures used for a group of 10 healthy volunteers in whom pharmacokinetic data was already available. Plasma specimens were collected over a period of 8h following administration and concentrations of diclofenac determined by GLC. Resulting plasma concentration curves were similar to those obtained in the healthy subjects in that areas under curves and terminal half-lives were comparable. However, peak concentrations of diclofenac were significantly reduced in the rheumatoid patients. The lower peak concentrations were correlated with the lower serum albumin levels in the patients which are associated with active rheumatoid disease.

Insulin resistance - the new goal!

Diabetes mellitus is a well‐recognized risk‐factor for coronary artery disease (CAD). Epidemiological studies have shown that the risk of CAD increases two to sixfold in patients with type 2 diabetes compared with those without the disease. Furthermore the prevalence of diabetes in the UK has increased by 30% since 1991 and the world population of people with diabetes in 2010 is expected to be twice that of 1990. In addition whilst the mortality from CAD in patients without diabetes has declined over the past 20 years the mortality in men with type 2 diabetes has not changed and in women may have increased. UKPDS and other studies have shown a significant improvement in the onset and course of microvascular complications with good diabetic control. However the same is not true for macrovascular complications for which there is no good evidence of improvement with better diabetic control. This apparent lack of benefit from improved care of diabetic patients has led to many different approaches. These include attempts to achieve even better glycaemic control, greater emphasis on other risk factors particularly hypertension and interestingly attention to the prediabetic state characterized by insulin resistance (IR). The latter is associated with a number of abnormalities which could play a causative role in the development of cardiovascular disease. This article will review the concept of IR and the possible interventions available to tackle it.

Pharmacokinetics and pharmacodynamics of isradipine (PN 200-110) in young and elderly patients

Abstract Isradipine (PN 200-110) was given to eight young and nine elderly mildly hypertensive patients. Pharmacokinetic and pharmacodynamic studies were carried out after a single 5 mg dose and after three weeks dosing with 5 mg twice daily. Isradipine lowered blood pressure and was well tolerated. Plasma concentration time profiles were not significantly different in young and elderly patients. Changes in blood pressure were similar in both groups. Unlike other dihydropyridines, short-term administration of isradipine did not cause tachycardia.

β-Blockers in the Management of Hypertension in Patients with Type 2 Diabetes Mellitus

It has been conclusively established that treatment of hypertension in patients with type 2 (non-insulin-dependent) diabetes mellitus will significantly reduce the incidence of stroke, heart failure and progression of diabetic complications. β-Blockers are effective antihypertensive agents which, in long term studies, have proven beneficial in reducing important clinical end-points. However nonselective β-blockers may have a negative effect on lipid profiles and contribute to hypoglycaemic unawareness, thus preventing their use in some patients with diabetes mellitus. The development of newer and more selective β-blockers has overcome many of these problems. In addition, some of the newer agents have novel properties such as release of nitric oxide, which theoretically would make them more attractive in patients with diabetes mellitus. Overall, the adverse metabolic effects of β-blockers do not appear to be important in clinical practice and these agents should no longer be contraindicated in patients with type 2 diabetes mellitus. Their proven cardiovascular benefits would seem to easily tip the balance in favour of their use.

Causality assessment of adverse effects: When is re-challenge ethically acceptable?

One of the most difficult tasks in the evaluation of a medicine is whether it causes a particular rare and unusual (idiosyncratic) adverse effect. Such causality assessments are sometimes done by drug de-challenge and re-challenge. When the adverse effect is potentially serious, there is clearly an important decision to be made as to whether the re-challenge is justifiable and hence ethical. The recent controversy about the potential cardiotoxicity of fexofenadine, the fatalities associated with penicillin re-challenge and the fatalities associated with abacavir re-challenge highlight some of the potential serious risks of drug re-challenge. The associated important ethical issues are discussed. In particular, there is the need to ensure respect for the patient and to consider the scientific and social value of the re-challenge. A framework for evaluating and assessing the appropriateness of a particular drug re-challenge is proposed in the light of recent as well as long-standing discussions of drug re-challenge, patient informed consent and the ethics of human experimentation, in general. It is suggested that a drug re-challenge should be approached with the same rigour and standards of documentation as are currently required of clinical trials. Given the potential conflicts of interest inherent with any drug study, it is argued that the safeguards, as may be provided by scrutiny by an ethics committee, are necessary for a drug re-challenge. For the investigator contemplating the conduct of a drug re-challenge we would recommend the following: (i) a careful risk-benefit assessment as part of the decision-making process; (ii) careful scientific preparation, including appropriate expert support and emergency back-up facilities, if re-challenge is deemed necessary; (iii) the writing of a detailed protocol for independent approval and for safeguarding all concerned; and (iv) meticulous record keeping.