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Beta blocker use in cardiovascular disease Introduction Beta blockers have a long and well-established history of use for a variety of indications, and are one of the most widely used pharmacological agents for patients with cardiovascular disease. Most beta blockers can be used safely in adult patients and there is a sound evidence base for their efficacy in conditions such as angina, atrial fibrillation, heart failure and myocardial infarction. Due to their frequency of use, it is important that practitioners have a comprehensive understanding of the mechanism of action of beta blockers as well as their role in therapy. Although beta blockers may be used in the treatment of a range of different pathological conditions, this article will focus on their use in cardiovascular disease in particular. The pharmacology of beta blockers will be described, along with a summary of the evidence for their current place in therapy and important practical considerations for their use. Beta adrenergic receptors The primary control system associated with the regulation of heart rate, digestion, respiratory rate, pupillary response and urination is the autonomic nervous system (ANS). The sympathetic nervous system (SNS) is one of the divisions of the ANS and is mainly associated with stimulating ‘fight or flight’ responses such as increasing heart rate and slowing digestion. These responses are mediated by the release of endogenous catacholamines such as adrenaline (epinephrine) and noradrenaline (norepinephrine). Adrenaline and noradrenaline are synthesised and released in the adrenal medulla in response to sympathetic stimulation and act as neurotransmitters in the SNS, binding to adrenoreceptors in order to exert their action. Unlike adrenaline, noradrenaline is also synthesised and released in the postganglionic nerve endings and acts as the main neurotransmitter in the SNS (Figure 1).
Figure 1 : Catecholamine release and binding of adrenergic receptors in the sympathetic nervous system. Beta blockers act on beta receptors to inhibit the action of noradrenaline and adrenaline. Adrenoreceptors are present in a variety of tissues, and are divided into two main groups: α (alpha) and β (beta), with further subtypes (α1, α2, β1, β2, β 3 ) that show different affinities to binding adrenaline and noradrenaline. The physiological action of adrenaline and noradrenaline depend on the subtype and location of the adrenoreceptors that they bind to (see Table 1). Adrenoreceptors are a major target of drug action; the selective stimulation and blockade of various adrenoreceptor subtypes is responsible for a significant area of therapeutics (Rang et al. 2016). Understanding the action of adrenaline and noradrenaline on beta adrenoreceptors in the heart and vasculature can aid appreciation of the role of beta blockers in the treatment of cardiovascular disease. Beta receptors in the heart
Beta blocker properties The indiscriminate blockade of both β 1 and β 2 receptor subtypes is seen with first generation, ‘nonselective’ beta blockers (e.g. propranolol); ‘cardioselective’ beta blockers (e.g. bisoprolol, atenolol, metoprolol) are those that show greater affinity to the β 1 subtype mainly found in the heart. The cardioselectivity of these beta blockers is dose-dependant, with progressively more β 2 blockade occurring at higher doses (McDevitt 1987b). Third generation beta blockers (e.g. carvedilol, nebivolol) have additional vasodilatory activity via alpha-adrenoreceptor (α 1 ) blockade and production of endothelial nitric oxide synthesis, but with varying cardioselectivity (Bristow 2000; Kalinowski et al. 2003). Beta blockers that are lipophilic (e.g. propranolol, metoprolol) are able to penetrate the blood-brain barrier to elicit effects on the adrenergic nerves in the central nervous system. As such, central side-effects such as sleep disturbance, fatigue, hallucinations and vivid dreams are more likely to be seen with these beta blockers. Lipophilic beta blockers are well absorbed from the gut but undergo extensive first-pass metabolism in the liver (McDevitt 1987a). Hydophilic beta blockers (e.g. atenolol), by contrast, are incompletely absorbed from the gut but do not undergo hepatic metabolism, and have longer half-lives than lipophilic beta blockers. Dosing is therefore usually only needed once daily with hydrophilic beta blockers, whereas lipophilic beta blockers have shorter half-lives and may require multiple daily dosing. Beta blocker mechanism of action and role in therapeutics Beta blockers currently feature in the treatment of angina, myocardial infarction, atrial fibrillation, heart failure and hypertension. Their mechanism of action in these conditions is outlined below, along with their role in therapy.
Angina The pathophysiology of angina involves reversible myocardial ischaemia as a result of coronary artery disease, where myocardial oxygen supply cannot meet demand on exertion. Consequentially, anaerobic metabolism may result in the pain of angina pectoris, as well as shortness of breath. In order to help redress this imbalance, beta blockers may be used to both help reduce myocardial oxygen demand and improve supply (Waller and Sampson 2017). Myocardial oxygen demand is reduced by the action of beta blockers decreasing the force of cardiac contraction (negative ionotropy). By antagonising the β 1 receptor, beta blockers inhibit the stimulation of intracellular cAMP, causing a decrease in calcium loading and subsequent contractile force. A decrease in heart rate (negative chronotropy) also contributes to a reduction in myocardial oxygen demand. The spontaneous beating of the heart is controlled by the I f current in the sinoatrial node, which is regulated by the SNS via intracellular cAMP. Beta blockers inhibit this pacemaker current by inhibiting cAMP production, so that the I f channel requires a more negative intracellular voltage in order to be activated (Difrancesco 2010). The resulting slower heart rate lengthens diastole, allowing more time for coronary perfusion, thereby increasing oxygen supply. The combination of a reduced chronotopy and ionotropy also results in a decreased cardiac output and lower blood pressure, further decreasing myocardial oxygen demand and cardiac work. Beta blockers can be a useful prophylactic antianginal drug for patients with stable angina pectoris, and can reduce ischaemic events after presentation in those with unstable angina. Although evidence suggests that beta blockers do not have a significantly positive or negative impact on mortality (Huang and Fox 2012), various studies demonstrate their benefits in controlling exercise-induced angina, improving exercise capacity and limiting both symptomatic as well as asymptomatic ischaemic episodes (Gibbons et al. 2003; Montalescot et al. 2013).
Williams classification of antiarrythmic drugs, and reduce the rate of spontaneous depolarisation of nodal tissue in both the sinoatrial and AV nodes, slowing down AV conduction (via adrenoreceptor-sensitive f-channels) and reducing ventricular rate, both at rest and during exercise (DiFrancesco 2010). In AF, rate control has been shown to be as effective as rhythm control with respect to mortality, and is associated with a lower risk of adverse drug effects, greater cost-effectiveness and a decreased incidence of hospitalisations (Van Gelder et al. 2002; Hagens et al. 2004). Beta blockers were found to achieve rate control in 70% patients when used alone or with digoxin in the AFFIRM trial, which was greater than the success associated with calcium channel blockers (Olshansky et al. 2004). In the RATAF study, however, calcium channel blockers were shown to be more effective than beta blockers for rate control (Ulimoen et al. 2013). Current guidance therefore stipulates that either class of drug can be used first-line for AF depending on patient-specific factors (such as comorbidities and contraindications) (Kirchhof et al. 2016). Heart failure The mechanism of action of beta blockers in heart failure is poorly understood, but in addition to their ability to reduce the workload of ischaemic myocardium and inhibit arrhythmia (see above), it has been shown that they can reduce the cardiac remodelling process responsible for disease progression in heart failure (Bhatt 2017). Carvediolol, for example, may reverse the remodelling process by reducing left ventricular volumes and improving systolic function (Khattar 2003). It also has antiproliferative, antioxidant properties and blocks the expression of several genes involved in myocardial damage (Yue et al. 1995). Historically, beta blockers were considered to be contraindicated in heart failure due to their negative ionotropic properties causing a reduction in cardiac output. There is now clear evidence for their use in all stages of heart failure to confer substantial mortality benefits as well as symptomatic relief in patients with heart
failure. As such, beta blockers are recommended in all patients with heart failure (or LVSD) without contraindications (Packer et al. 1996; The CIBIS-II Investigators 1999; The MERIT-HF Investigators 1999; Packer et al. 2001; Ponikowski et al. 2016). Although negative ionotropic effects can still be problematic, they may be limited by using small starting doses, uptitrating slowly (e.g. over a number of weeks), and monitoring heart rate, blood pressure and clinical status after each dose increase. Initiation should also follow stabilisation with ACE inhibitor and diuretic therapy in order to limit adverse negative ionotropic effects (NICE 2017). Hypertension The reduction in force of myocardial contraction and heart rate results in a decreased cardiac output and therefore a reduction in arterial blood pressure. Beta blockers alter baroreceptor reflex sensitivity, and reduce β 1 mediated renin release from the kidneys (Mann 2017). Reduced renin leads to a reduction in angiotension II and aldosterone, which in turn enhances renal sodium and water loss and lowers blood pressure. The initial treatment for hypertension no longer includes beta blockers due to their inferior effects on reducing cardiovascular mortality, stroke and myocardial infarction compared to other antihypertensive drugs (Wiysonge et al. 2017). They may, however, still form an important part of antihypertensive treatment in patients who are unable to take first line agents, or who are already established on combination therapy. A summary of recommendations for the use of beta blockers in cardiovascular disease is shown in Table 2.
pharmacokinetic interactions via the CYP450 enzyme group (Flockhart and Tanus- Santos 2002). All beta blockers may be subject to pharmacodynamic interactions, for example additive effects on lowering blood pressure when used concomitantly with other antihypertensive drugs (e.g. ACE inhibitors), or hypoglycaemia with antidiabetic drugs. Other common drug interactions with beta blockers are included in Table 3. Conclusion Beta blockers are an important class of medication that are widely used for a number of cardiovascular indications. Their benefits range from the effective control of heart rate in AF to the significant reduction in mortality in patients with heart failure. Adverse effects of beta blockers should be considered when prescribing them to patients with concomitant conditions (e.g. asthma, diabetes) but should not necessarily exclude their use when their benefit may outweigh the risks. Practitioners have an important role in educating patients with respect to the role of beta blockers in order to optimise their use in the therapy of cardiovascular disease. Key points Adrenaline and noradrenaline are catacholamines that act in the sympathetic nervous system by binding alfa and beta adrenoreceptors. Beta blockers act on β 1 receptors in the heart to a decrease in contractility, conduction velocity, heart rate and relaxation rate. Beta blockers confer mortality benefits when used post-myocardial infarction and in heart failure. Symptomatic benefits are seen with beta blocker use in angina and heart failure. When prescribing and administering beta blockers, potential interactions with other medication should be considered, alongside common adverse effects.
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