Chapter 191 β-BLOCKERS
INTRODUCTION
For a long time, β-adrenergic receptor blockers have been important treatment options in both human and veterinary medicine, although they have only been used to manage mild to moderate congestive heart failure (CHF) in humans for the last 10 years. The use of β-blockers for heart failure represented a dramatic theoretic change because physicians previously believed that β-blockers were contraindicated in any kind of CHF.1 Although frequently used for certain cardiomyopathies and arrhythmias in veterinary medicine, β-blockers may be underutilized in dogs and cats with CHF.
On the other hand, they have immense value in the critical care setting because of their usefulness in diverse situations. For example, using the ultra–short-acting drug esmolol for an arrhythmia can test the efficacy of β-blockers without overtly compromising the patient. Once β-blockers have proven beneficial, longer acting agents or a constant rate infusion (CRI) of esmolol may be prescribed.
PATHOPHYSIOLOGY OF β-ADRENERGIC RECEPTORS
Classically, β-receptors are divided into β1-receptors, found in the heart muscle, and β2-receptors, located primarily in bronchial and vascular smooth muscle but also found in cardiac muscle. β3-Receptors also exist, but because their existence and function in the critical care setting are not well known, they will not be discussed here. β-Receptors are coupled to adenylcyclase by a stimulatory G protein; this coupling causes the formation of cyclic adenyl monophosphate (cAMP). cAMP is a second messenger with two primary effects in the heart muscle: (1) a positive inotropic effect (an increase in the rate and force of myocardial contraction) and (2) a relaxing or lusitropic effect (by facilitating reuptake of calcium into the sarcoplasmic reticulum). In the sinus node there are both chronotropic (increased rate of firing) and dromotropic (accelerated rate of conduction) effects that combine to increase the heart rate.2 Beta stimulation can also stimulate growth of cardiomyocytes and cause the particularly deleterious effects of myocyte toxicity and apoptosis.1
The failing human heart has an increased adrenergic drive, which supports the heart in early, acute stages, but it ultimately causes damage to the myocardium in the chronic state.1,3 In normal human ventricles the number of β1-receptors is much greater than β2-receptors, but the ratio is reversed in failing ventricles because of selective downregulation of β1-receptors.1 The altered ratio of β1 and β2 receptors has also been shown in a canine model of induced heart failure.4
MECHANISMS OF ACTION
Generations of β-Blockers
Although β-blockers are only one class of drugs, their effects are extremely varied and are determined by their pharmacologic properties: selective versus nonselective, presence or absence of intrinsic sympathomimetic activity, and additional actions (e.g., carvedilol is a nonselective β-blocker with α-adrenergic vasodilatory properties). Division of the various β-blockers is by generations.2
First-generation β-blockers are nonselective, blocking both β1-adrenergic and β2-adrenergic receptors.1,2 Propranolol is the prototypical first-generation agent and has been used the longest in veterinary medicine.
Second-generation β-blockers are known as selective β-blockers because at normal dosages they are more cardioselective, acting predominantly on β1-receptors rather than β2-receptors. Atenolol and metoprolol are selective β-blockers and have the advantage of generating less bronchospasm or any other side effect that might arise from β2-blockade.
Third-generation β-blockers such as carvedilol are nonselective and have the additional property of being vasodilators through α1-blockade.1,2,5
β-Blockers are also recognized as class II antiarrhythmic drugs in the Vaughan-Williams classification.
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