Beta-receptor blockers

Group of similarly acting drugs that (competitively) inhibit the sympathomimetically active neutrotransmitters adrenalin and noradrenalin at the cellular beta-receptors of the respective successful organ. Beta blockers are among the most frequently prescribed drugs. The most frequently prescribed drug is metoprolol.

The subtypes β1 and β2 of the β adrenoceptor are crucial for the clinical efficacy of beta blockers. The different drugs differ in their affinity for these receptor types.

Propranolol has about the same effect on both receptor types: "non-selective beta-receptor blocker".

Atenolol, metoprolol and bisoprolol act mainly on the β1 adrenoceptor: "beta-1-selective or also cardioselective beta-receptor blockers".

Carvedilolol, celiprolol and nebivolol are also called "intrinsic sympathomimetic beta-receptor blockers", ISA. This effect is explained by their structural similarity to β sympathomimetic drugs.

Some newer beta-blockers have additional vasodilatory effects: carvedilol blocks the α1 adrenoreceptor, nebivololol releases nitric oxide. Celiprolol has an activating effect on the β2 adrenoceptor.

Heart: In the heart (mainly ß1-receptors), beta-receptor blockers have a negative inotropic effect (reduction of contractility), lead to a reduction in the resting frequency of the heart (inhibition of excitatory regression, negative chronotropy), to a slowing of the sinus node rhythm and the rate of conduction (negative dromotropy), as well as to a reduction in the excitability of the myocardium (negative bathmotropy) and to a reduction in blood pressure. They are used in the drug therapy of numerous diseases, especially arterial hypertension and coronary heart disease. Their main and clinically preferred effects are the reduction of resting heart rate and blood pressure.

Kidney: At the kidney (ß1-receptors), beta-receptor blockers lead to a reduced release of renin from the juxtaglomerular apparatus.

Smooth muscles (mainly ß2-receptors): Here beta-receptor blockers lead to an increase in muscle tone. This causes a constriction of the bronchial muscles, the peripheral vessels and the uterus muscles.

Fatty tissue: Inhibition of catecholamine-dependent lipolysis.

Eye: Reduction of the production of aqueous humor.

Pharmacokinetics: The hydrophilic beta-blockers (Nadolol, Atenolol) are mainly excreted renally. The lipophilic beta-blockers (carvedilolol, propanololol, timolol) are mainly metabolized, the remaining beta-blockers such as pindolol and bisoprolol both renal and metabolic. All metabolically eliminated substances are substrates of CYP2D6. It is important to note that about 7% of the European population are slow metabolisers of substrates of this enzyme. At current dosages, plasma levels of these beta-blockers (e.g. metoprolol) are 3-5 times higher than those of "fast metabolisers".

Arterial hypertension: In the drug therapy of arterial hypertension (I10.90) beta-blockers are preferably used in combination with other antihypertensives. Their antihypertensive efficacy is significantly lower than that of thiazide diuretics, ACE inhibitors and Ca channel blockers (Wright JM et al. 2018). They belong to the first-line antihypertensives.

All beta-blockers are equivalent with regard to their antihypertensive efficacy. How this effect comes about is not known with absolute certainty. There is probably a summation effect (initially a reduction in cardiac output becomes effective). In the long term, an inhibition of the sympathetic nervous system activity and a reduction in the release of renin play a role.

However, they have a negative effect on the risk of weight gain, lipid and glucose metabolism. Beta-blockers increase the likelihood of developing diabetes in patients with high blood pressure by about 25%. "Beta-blockers should therefore be avoided in patients with metabolic syndrome or its components, such as abdominal obesity, high normal or elevated plasma glucose levels and pathological glucose tolerance". Beta-blockers with intrinsic sympathomimetic activity (ISA) do not have an adverse effect on serum pipids.

Coronary artery disease and heart attack: Beta-blockers reduce the oxygen demand of the heart by decreasing the cardiac output. In addition, by lowering the heart rate, a better blood supply to the coronary arteries is achieved, as these are only supplied with blood in diastole. Beta-blockers without ISA and without alpha-blocking properties are important drugs in stable angina pectoris and in myocardial infarction. A life-prolonging effect of this group of drugs has been proven for both indications.

Heart failure: In stable, chronic heart failure, the use of beta-blockers improves the prognosis from stage NYHA-II, in hypertension and after myocardial infarction also in stage NYHA-I (Verbrugge FH et al. 2015). For example, bisoprolol, metoprolol and carvedilol improve the prognosis of heart failure patients by about 35%. In larger meta-analytic studies it was shown that discontinuing beta-blockers in "Acute Decompensated Heart Failure", ADHF, led to an increase in mortality (Prins KW et al. 2015). For the ADHF, the reduction of the sympathetic nervous system influence on the heart and the economisation of heart work is the main focus. Initially, the treatment of heart failure must be "creeping in". Approved preparations: bisoprolol, carvedilol, metoprolol and nebivololol.

Cardiac arrhythmias: Beta-blockers have been shown to play an important role in the treatment of tachycardic arrhythmias as class II (propranolol, metoprolol) and class III (sotalol, D-sotalol) antiarrhythmics. Their life-prolonging effect is well documented. For the effectiveness of the antiarrhythmic beta-blockers, their anti-stimulation effect on the heart plays a decisive role.

Chronic off-angle glaucoma (as a local therapeutic agent). Beta-blockers (e.g. Timolol, Betaxolol) lower the intraocular pressure when applied topically, because these preparations reduce the production of aqueous humor. The systemic effectiveness of these preparations should not be underestimated.

Further indications: Further indications for beta-blockers are or may be: hyperthyroidism, tremor, migraine, pheochromocytoma, anxiety disorders, portal hypertension, prevention of esophageal varices bleeding, dumping syndrome, Ehlers-Danlos syndrome, infant hemangioma (Propranolol: systemic and local; Hagen R et al. 2018). In cosmetics, beta-blockers are used to lengthen the eyelashes.

Beta-blockers are well tolerated even after prolonged use (Gu J et al. 2016). The known side effects are usually reversible after discontinuation of the drug or adjustment of the dosage. The most important side effects are:

• Relatively high incidence of central nervous disorders (fatigue, fatigue, sleep disorders, depressive moods), bradycardia, worsening of heart failure, asthma attacks, obstruction of the airways, cardiac conduction disorders, erectile dysfunction, increase in peripheral circulatory disorders(intermittent claudication), triggering or worsening of psoriasis and seborrheic dermatitis. Allergic reactions are rare.
• Triggers of lichenoid drug exanthema: Acebutal, Atenolol, Labetalol, Levubatanol, Metoprolol, Nebivolol, Oxprenalol, Timolol, Sotalol

Simultaneous intake of Ca-channel blockers of the verapamil or diltiazem type (amplification of cardiodepression). Phenothiazines (sympatholytic interaction), beta-sympathomimetics (attenuation of all effects).

Important relative and absolute contraindications for (all) beta blockers are:

bronchial asthma (in COPD beta-blockers may be given), pre-existing bradycardia with a heart rate below 50/min, AV conduction disorders, AV block >1st degree, sick sinus syndrome, acute heart failure, in PAVK beta-blockers are no longer contraindicated according to the current guideline (German Society of Angiology).

Hyposensitization should not be performed in patients whose heart failure is treated with beta-blockers, as the risk of anaphylactic reactions is increased.

Depending on the selectivity towards the different β receptors, different groups of beta blockers are distinguished:

Non-selective β blockers (blocking of β1 and β2 adrenoceptors):

• Propranolol
• Pindolol
• Carvedilol
• Sotalol
• Timolol

β1-selective beta blockers:

• Atenolol
• Bisoprolol
• Metoprolol
• Nebivololol
• Esmolol
• Betaxolol
• Acebutolol
• Celiprolol
• Practolol

β-Blocker with additional effects:

• Carvedilol: additional blockade of α1 receptors
• Sotalol: additional use as class III antiarrhythmic agent
• Celiprolol: additional β2 agonism
• Nebivolol: additional stimulation of NO release in endothelial cells

In some sports, the use of beta-blockers is not permitted because they are on the doping list as performance-enhancing substances.

1. Gu J et al (2016) Long-term prescription of beta-blocker delays the progression of heart failurewith preserved ejection fraction in patients with hypertension: A retrospective observational cohort study. Eur J Prev Cardiol 23:1421-1428.
2. Hagen R et al (2018) Infantile hemangiomas: what have we learned from propranolol? Curr Opin Pediatr 30:499-504.
3. Prins KW et al (2015) Effects of beta-blocker Withdrawal in Acute Decompensated Heart Failure: A Systematic Review and Meta-Analysis. JACC Heart Fail 3:647-653.
4. Verbrugge FH et al (2015) Heart rate reduction and exercise performance in recent onset heart failure with reduced ejection fraction: arguments for beta-blocker hypo-response. Acta Cardiol 70:565-572 Wright JM et al. (2018) First-line drugs for hypertension. Cochrane Database Syst Rev 4: CD001841.