β-blockers bind ADRB1,2,3

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R-HSA-9609310
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Reaction [binding]
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Homo sapiens
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β-adrenergic receptor antagonists ("β-blockers") are widely used drugs in cardiovascular medicine in the management of hypertension, heart failure, anxiety, migraine and glaucoma. β-adrenergic receptors bind the endogenous catecholamines adrenaline (epinephrine) and noradrenaline (norpeinephrine) that mediate the fight-or-flight response. β-blockers competitively block the receptor sites on β-adrenergic receptors so these catecholamines cannot bind to them. The three known types of β-adrenergic receptors, β1, β2 and β3 receptors are located in the heart and kidneys (β1), lungs, GI tract, liver, vascular smooth muscle and skeletal muscle (β2) and fat cells (β3). In cardiovascular disease treatment, the goal of β-blockers is to improve symptoms and reduce mortality by selectively blocking β1 receptors in the heart whilst as the same time not affecting β2 receptors in the lung (and thus reducing life-threatening bronchospasm) (Baker et al. 2017). In reality, most β-blockers are non-selective for β1 receptors (Baker 2005) so they are contraindicated for patients with both heart disease and asthma or COPD (Feary et al. 2010). Newer β-blockers that are highly cardioselective (block β1 receptors only) would increase the safety of their use in patients with asthma or COPD. The β-blockers described here are used in the treatment of cardiovascular diseases and glaucoma.

Propranolol (brand name Inderal) was the first clinically significant β-blocker to be synthesised in 1964 for the treatment of angina pectoris (Black et al. 1964). It is a lipid-soluble compound that is used to treat hypertension, arrythmias, anxiety, migraine and angina. Metoprolol (trade name Lopressor), first created in 1969, is used to treat heart failure (MERIT-HF Study Group 1999), tachycardia and migraines. Carvedilol (brand name Coreg), created in 1995, is a 3rd generation β-blocker used to treat severe congestive heart failure, left ventricular disfunction and hypertension (Stroe & Gheorghiade 2004, Baker 2005). Carvedilol is both a non-selective beta adrenergic receptor blocker (β1, β2) and an alpha adrenergic receptor blocker (α1). Introduced in 1976, atenolol was developed as a replacement for propranolol in the treatment of hypertension and specifically labeled for myocardial infarction (Nuttall et al. 2003). Unlike propranolol, atenolol does not readily pass through the blood–brain barrier, thus decreasing the incidence of central nervous system side effects. Atenolol was widely used in the UK but since 2006 has been downgraded to a 4th line of treatment as recent studies indicate that it does not reduce the morbidity or mortality caused by hypertension. Although marketed as a selective β1 receptor antagonist, it has equal if not greater affinity for B2 receptors.

Nebivolol is a 3rd generation cardioselective β1 adrenergic receptor antagonist used in the treatment of hypertension, and in Europe, also for left ventricular failure (Pauwels et al. 1991, Nuttall et al. 2003, Zanchetti 2004). It also has additional nitric oxide-mediated vasodilating and antioxidant properties. It is highly cardioselective in uncomplicated hypertension (de Boer et al. 2007). Sotalol is a non-selective β-adrenergic receptor antagonist, discovered in the 1960s, widely used in the 1980s, only used for serious arrhythmias (Anderson & Prystowsky 1999). Its prolongation of the QT interval carries a small risk of life-threatening polymorphic ventricular tachycardia known as torsade de pointes (Dessertenne 1966). It also exhibits Class III antiarrhythmic properties, protecting against ventricular and atrial fibrillation (Bertrix et al. 1986). Acebutolol is a cardioselective β1-adrenergic receptor antagonist used for the treatment of hypertension and arrhythmias (Davidov 1985, Chandraratna 1985). It also has ISA (intrinsic sympathomimetic activity) therefore more suitable than non-cardioselective β-blockers for patients with asthma or chronic obstructive pulmonary disease (COPD). Nadolol (Corgard) is a non-selective β-blocker used in the treatment of hypertension (Metelitsa & Filatova 1990) and chest pain (angina pectoris) (Nikolenko et al. 1984). Esmolol (Brevibloc) is a cardioselective β1-adrenergic receptor blocker with rapid onset of action. It is a class II anti arrhythmic agent, decreasing the force and rate of heart contractions (Jaillon & Drici 1989).

Bupranolol is a non-selective β-blocker without intrinsic sympathomimetic activity (ISA), but with strong membrane stabilizing activity (Weisser et al. 1989). Its potency is similar to propranolol and can be used to treat hypertension and tachycardia. Labetalol is a non-selective β-adrenergic receptor antagonist, and a post-synaptic α-adrenergic receptor antagonist. It is used in the treatment of essential hypertension. Its use is limited by its main side effect, postural hypotension, where the individual experiences a substantial drop in blood pressure when standing up (MacCarthy & Bloomfield 1983, Fahed et al. 2008). Pindolol is a non-selective β-adrenergic receptor antagonist with partial agonist activity and also possesses intrinsic sympathomimetic activity (Golightly 1982). Levobunolol (AK-Beta, Liquifilm, Betegan) is a non-selective β-blocker. It is used topically to manage glaucoma (Leung & Grunwald 1997, Ogasawara et al. 1999). Betaxolol (Betoptic, Betoptic S, Lokren, Kerlone) is a selective β1-adrenergic receptor blocker used in the treatment of hypertension and glaucoma (Buckley et al. 1990). Levobetaxolol (Betaxon) is marketed as an ophthalmic solution used to lower the pressure in the eye to treat conditions such as glaucoma (Quaranta et al. 2007). Practolol is a selective β1-blocker that has been used in the emergency treatment of cardiac arrhythmias. However, practolol is highly toxic and chronic administration causes serious oculocutaneous and peritoneal reactions (No authors listed 1975). Cicloprolol is a β-adrenoceptor antagonist used in the treatment of congestive heart failure (CHF) (Cocco et al. 1992).

Literature References
PubMed ID Title Journal Year
15655528 The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors

Baker, JG

Br. J. Pharmacol. 2005
28400472 Novel selective β1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease

Baker, JG, Gardiner, SM, Woolard, J, Fromont, C, Jadhav, GP, Mistry, SN, Thompson, KSJ, Kellam, B, Hill, SJ, Fischer, PM

FASEB J. 2017
20871122 Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke: a comprehensive analysis using data from primary care

Feary, JR, Rodrigues, LC, Smith, CJ, Hubbard, RB, Gibson, JE

Thorax 2010
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