madman
Super Moderator
ABSTRACT
b-blockers are a heterogeneous class, with individual agents distinguished by selectivity for b1- vs. b2-and a-adrenoceptors, presence or absence of partial agonist activity at one of more b-receptor subtype, presence or absence of additional vasodilatory properties, and lipophilicity, which determines the ease of entry the drug into the central nervous system. Cardioselectivity (b1-adrenoceptor selectivity) helps to reduce the potential for adverse effects mediated by blockade of b2-adrenoceptors outside the myocardium, such as cold extremities, erectile dysfunction, or exacerbation of asthma or chronic obstructive pulmonary disease. According to recently updated guidelines from the European Society of Hypertension, b-blockers are included within the five major drug classes recommended as the basis of antihypertensive treatment strategies. Adding a b-blocker to another agent with a complementary mechanism may provide a rational antihypertensive combination that minimizes the adverse impact of induced sympathetic overactivity for optimal blood pressure-lowering efficacy and clinical outcomes benefit.
Introduction
The clinical use of b-adrenergic receptor antagonists (b-blockers) began nearly 60 years ago with the invention of propranolol by Black et al.1 The initial therapeutic use was for angina pectoris, but soon extended to managing hypertension and other cardiovascular disorders 2. Propranolol is a non-selective b-blocker that blocks b-adrenoceptors indiscriminately. Following its introduction, different subtypes of b-adrenergic receptors were discovered in the heart, vasculature and elsewhere; and research to develop specific receptor subtype blockers grew a pace, along with elucidation of variations in their molecular pharmacology and the clinical applications 2.
Currently available b-blockers are a heterogeneous class of therapeutic agents and significant intra-class differences in individual drug selectivity, lipophilicity, and potential for partial agonism can inform the choice of b-blocker for a patient with one or more of a range of comorbid conditions 3. This article reviews the clinical pharmacology of b-blockers, with an emphasis on the difference between members of this heterogeneous class. With regard to hypertension treatment, the use of guideline-recommended combinations of two or more antihypertensive agents has been reviewed in an accompanying article and we will also consider the relevance of variations in b-blocker pharmacology for their use within combination regimens. Other accompanying articles in this series explore the implications of the properties of individual b-blockers for tolerability and safety 4, and the management of hypertension5, coronary heart disease 6, and heart failure 7.
*b-adrenergic receptors: where they are and what they do
Pharmacologic properties of individual b-blockers
*Administration and pharmacokinetics
-Posology, administration and elimination
-Inter-individual variation in pharmacokinetics
-Drug-drug interactions
*Properties influencing interactions with adrenoceptors
-Receptor selectivity
-Lipophilicity
-Inverse agonism
-Biased signal transduction
-Other sympathoinhibitory mechanisms
-Dialyzability
*b-blockers and peripheral vasodilatation
-Intrinsic sympathomimetic activity (ISA) at the b1-adrenoceptor
-Additional vasodilatory mechanisms of action
*Implications for b-blocker-based combination therapy
Conclusions
The updated ESH guidelines have restored b-blockade as one of the five main classes of antihypertensive therapy suitable for initiating pharmacologic antihypertensive therapy, especially in patients with cardiovascular comorbidities such as CHD or heart failure. In this review, we have set out to reinterpret the properties of this diverse therapeutic class inthe light of the new evidence that has prompted this change in guidance. Recent management guidelines in this area have also emphasized the need to prescribe combination antihypertensive therapies for most people with hypertension. The mechanism of b-blockade is complementary to most other antihypertensive agents and adding a b-blocker to another agent with a complementary mechanism may provide a rational antihypertensive combination that reduces the adverse impact of the activated RAAS on the cardiovascular system. Cardioselective b1-adrenoceptor b-blockers are as effective as other subclasses of b-blockers for BP management; and bisoprolol is one three cardioselective b-blockers (along with carvedilol) that are recommended for improving clinical outcomes in patients with HFrEF in current European guidance 90. Moreover, b1-selectivity helps to reduce the potential for adverse effects associated with the contraction of smooth muscle cells due to the blockade of b2-adrenoceptors, leading to cold extremities, erectile dysfunction, or exacerbation of asthma or chronic obstructive pulmonary disease31. At the same time, these agents remain strongly recommended for patients with defined cardiovascular comorbidities such as coronary heart disease or heart failure.
b-blockers are a heterogeneous class, with individual agents distinguished by selectivity for b1- vs. b2-and a-adrenoceptors, presence or absence of partial agonist activity at one of more b-receptor subtype, presence or absence of additional vasodilatory properties, and lipophilicity, which determines the ease of entry the drug into the central nervous system. Cardioselectivity (b1-adrenoceptor selectivity) helps to reduce the potential for adverse effects mediated by blockade of b2-adrenoceptors outside the myocardium, such as cold extremities, erectile dysfunction, or exacerbation of asthma or chronic obstructive pulmonary disease. According to recently updated guidelines from the European Society of Hypertension, b-blockers are included within the five major drug classes recommended as the basis of antihypertensive treatment strategies. Adding a b-blocker to another agent with a complementary mechanism may provide a rational antihypertensive combination that minimizes the adverse impact of induced sympathetic overactivity for optimal blood pressure-lowering efficacy and clinical outcomes benefit.
Introduction
The clinical use of b-adrenergic receptor antagonists (b-blockers) began nearly 60 years ago with the invention of propranolol by Black et al.1 The initial therapeutic use was for angina pectoris, but soon extended to managing hypertension and other cardiovascular disorders 2. Propranolol is a non-selective b-blocker that blocks b-adrenoceptors indiscriminately. Following its introduction, different subtypes of b-adrenergic receptors were discovered in the heart, vasculature and elsewhere; and research to develop specific receptor subtype blockers grew a pace, along with elucidation of variations in their molecular pharmacology and the clinical applications 2.
Currently available b-blockers are a heterogeneous class of therapeutic agents and significant intra-class differences in individual drug selectivity, lipophilicity, and potential for partial agonism can inform the choice of b-blocker for a patient with one or more of a range of comorbid conditions 3. This article reviews the clinical pharmacology of b-blockers, with an emphasis on the difference between members of this heterogeneous class. With regard to hypertension treatment, the use of guideline-recommended combinations of two or more antihypertensive agents has been reviewed in an accompanying article and we will also consider the relevance of variations in b-blocker pharmacology for their use within combination regimens. Other accompanying articles in this series explore the implications of the properties of individual b-blockers for tolerability and safety 4, and the management of hypertension5, coronary heart disease 6, and heart failure 7.
*b-adrenergic receptors: where they are and what they do
Pharmacologic properties of individual b-blockers
*Administration and pharmacokinetics
-Posology, administration and elimination
-Inter-individual variation in pharmacokinetics
-Drug-drug interactions
*Properties influencing interactions with adrenoceptors
-Receptor selectivity
-Lipophilicity
-Inverse agonism
-Biased signal transduction
-Other sympathoinhibitory mechanisms
-Dialyzability
*b-blockers and peripheral vasodilatation
-Intrinsic sympathomimetic activity (ISA) at the b1-adrenoceptor
-Additional vasodilatory mechanisms of action
*Implications for b-blocker-based combination therapy
Conclusions
The updated ESH guidelines have restored b-blockade as one of the five main classes of antihypertensive therapy suitable for initiating pharmacologic antihypertensive therapy, especially in patients with cardiovascular comorbidities such as CHD or heart failure. In this review, we have set out to reinterpret the properties of this diverse therapeutic class inthe light of the new evidence that has prompted this change in guidance. Recent management guidelines in this area have also emphasized the need to prescribe combination antihypertensive therapies for most people with hypertension. The mechanism of b-blockade is complementary to most other antihypertensive agents and adding a b-blocker to another agent with a complementary mechanism may provide a rational antihypertensive combination that reduces the adverse impact of the activated RAAS on the cardiovascular system. Cardioselective b1-adrenoceptor b-blockers are as effective as other subclasses of b-blockers for BP management; and bisoprolol is one three cardioselective b-blockers (along with carvedilol) that are recommended for improving clinical outcomes in patients with HFrEF in current European guidance 90. Moreover, b1-selectivity helps to reduce the potential for adverse effects associated with the contraction of smooth muscle cells due to the blockade of b2-adrenoceptors, leading to cold extremities, erectile dysfunction, or exacerbation of asthma or chronic obstructive pulmonary disease31. At the same time, these agents remain strongly recommended for patients with defined cardiovascular comorbidities such as coronary heart disease or heart failure.
