Beta blockers


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Beta blockers or better beta-receptor blockers , also beta-receptor blockers , β-blockers or beta-adrenoceptor antagonists , are a number of similarly acting drugs that combine with β-adrenoceptors in the body , block them and thus the effect of the "stress hormone" adrenaline and the Inhibit neurotransmitter norepinephrine (competitively) . The most important effects of beta blockers are the lowering of the resting heart rate and the (arterial) blood pressure, which is why they are used in the drug therapy of many diseases, in particular high blood pressure and coronary heart disease as well as cardiac insufficiency and tachycardiac arrhythmias.

Because of the well-documented effectiveness and the wide spread of diseases in which beta blockers are used, they are among the most frequently prescribed drugs: In 2017, 2.19 billion defined daily doses (DDD) beta blockers were prescribed in Germany . The best-known and most widely prescribed active ingredient is metoprolol (for 2017: 863.7 million DDD; excluding combination products).

In some sports, the use of β-blockers without medical indication is not allowed; They are on the doping list as performance-enhancing substances in disciplines that require high concentration and precise movements .

history

A hypothesis of the existence of inhibiting and stimulating receptors in the sympathetic nervous system, which developed further the side chain theory of Paul Ehrlich, was formulated by John N. Langley as early as 1905 . The correctness of this hypothesis was experimentally proven in 1906 by George Barger and Henry H. Dale . A concept developed by Raymond P. Ahlquist in 1948 to subdivide the adrenoceptors into alpha- and beta-adrenergic sympathetic receptors was not recognized for more than 10 years. But in 1958 CE Powell and Slater followed up on this thesis because they wanted to replace the then market leader isoprenaline . They tried to develop a long and specific acting bronchodilator , whereby the dichloroisoprenaline (DCI) was developed based on isoprenaline. This was the first substrate to specifically block β-receptors. However, the real potential of DCI was only recognized by James Whyte Black , who, while looking for a drug to treat angina pectoris, launched another prototype pronethalol as the first β-adrenoreceptor blocker in 1962 . Animal studies have shown that this is carcinogenic. Because of this, it was replaced by propranolol in 1964. Successors in 1966 were Alprenolol from Astra AB and Oxprenolol from Ciba AG .

In 1967, Lands devised the concept of β 1 and β 2 receptors. He divided the β-receptor population defined by Ahlquist into two separate groups with different effects: the β 1 -receptors are cardiospecific, the β 2 -receptors bronchospecific. He was able to prove this hypothesis a little later through experiments with Practolol and Salbutamol . Now the search was on for substances that did not show heart failure as an undesirable drug effect. They did not want substrates with only a β 1 -blocking effect, but rather dualistic ones (so-called partial agonists).

In the late 1960s, Sotalol and Pindolol were discovered alongside Practolol ; In 1973 timolol was launched. In Germany, esmolol (Brevibloc®, 1991), metoprolol (Beloc®, 1976), tertatolol (Prenalex®, 1991) and carvedilol (Dilatrend®, 1992) were also approved and introduced as β-blockers .

Active ingredients, chemical structure and classification

Some β 1 -selective beta blockers (without specifying the stereochemistry)
Some non-selective beta blockers (without specifying the stereochemistry)

Structurally, beta blockers are phenol ethers of vicinal diols .

The β 1 and β 2 subtypes of the β-adrenoceptor are decisive for the effectiveness of beta blockers . The various active ingredients differ in their affinity for these receptors. The first beta blocker, propranolol , was developed in the 1960s. This has approximately the same effect on both types of receptor and is therefore referred to as a non-selective beta blocker. As a result, more selective beta blockers were developed, since the blockade of the β 1 -adrenoceptor is particularly desirable. A drug that only blocks the β 1 -adrenoceptor is not available. However, active ingredients such as metoprolol or, in an even more pronounced form, bisoprolol have a stronger effect on the β 1 subtype and are therefore referred to as selective or cardioselective beta blockers.

In contrast to alpha blockers , beta blockers have a great structural similarity to β-sympathomimetics . Therefore, some of the beta blockers have a minor excitatory ( agonistic ) effect on beta receptors. This property is called intrinsic sympathomimetic activity (ISA) or partial agonistic activity (PAA) and is usually undesirable.

Furthermore, membrane-stabilizing, non-competitive inhibitory beta blockers are distinguished, the inhibiting effect of which is called quinidine or local anesthetic-like and is shown in a delayed increase in the action potential. These include propranolol, alprenolol, and acebutolol.

Some newer beta blockers have additional vasodilating (vasodilating) properties: Carvedilol blocks the α1 adrenoceptor , nebivolol releases nitric oxide and celiprolol has an activating effect on the β 2 adrenoceptor.

without ISA with ISA
β 1 -selective beta blockers Atenolol
Bisoprolol
Metoprolol
Nebivolol
Esmolol
Betaxolol
Acebutolol
Celiprolol
Practolol
Non-selective beta blockers Propranolol
Bupranolol
Timolol
Carvedilol
Sotalol
Nadolol
Pindolol
Oxprenolol
Alprenolol
Carteolol

The importance of the enantiomeric purity of the synthetically produced active ingredients is being given increasing attention, because the two enantiomers of a chiral medicinal substance almost always show different pharmacology and pharmacokinetics . The stereospecific effects of the enantiomers of numerous beta blockers were described in an overview. Such differences were often ignored due to ignorance of the stereochemical relationships. Medicinal products often contain medicinal substances as a racemate (1: 1 mixture of enantiomers), whereby, for fundamental reasons, the use of the enantiomer which is more effective or has fewer side effects would be preferred. In the case of the β-blockers, their pharmacological activity can usually be attributed almost entirely to the ( S ) -enantiomer, which is 10 to 500 times more active than the distomer , i.e. the ( R ) -enantiomer. Timolol , penbutolol and levobunolol are marketed as enantiomerically pure ( S ) configured drugs; most other β-blockers are used as racemates. The international non-proprietary names of the individual beta blockers end with -olol .

Mechanism of action

Beta blockers inhibit the activating effects of adrenaline and noradrenaline on the β-adrenoceptors, thereby dampening the stimulating effect of the sympathetic system on the target organs, primarily the heart. The effects on other organ systems appear to be counter-directed to the effects of adrenaline .

Two types of β-adrenoceptors play a role in this: β 1 -adrenoceptors primarily stimulate cardiac output ( cardiac strength and frequency ) and, directly, blood pressure. In contrast, stimulation of the β 2 -adrenoceptors acts on the smooth muscles of the bronchi, the uterus and the blood vessels. Blocking these receptors has a contracting effect on the smooth muscles. This also increases the tone of the bronchial muscles, which can lead to cramping. In contrast to COPD, bronchial asthma is a contraindication for therapy with β 2 -effective beta blockers.

The β 1 -adrenoceptor is also found in the kidneys, where it controls the release of the blood pressure-increasing enzyme renin . This is probably the main reason the beta-blockers are effective in lowering blood pressure over the long term. COPD and bronchial asthma are no longer contraindications here, as the net benefit must always be taken into account.

Indications

high blood pressure

In drug therapy for arterial hypertension , beta blockers are usually used in combination with other antihypertensive drugs. Studies have questioned its classification as a drug of first choice. According to the guidelines for the treatment of hypertension from 2008, they are still among the drugs of first choice because they have beneficial effects, particularly in patients with coronary artery disease and heart failure. However, they have a disadvantageous effect on the risk of weight gain, lipid and glucose metabolism. "Beta blockers should therefore be avoided in patients with metabolic syndrome or its components, such as abdominal obesity, highly normal or elevated plasma glucose levels and pathological glucose tolerance" (quotation from the guideline).

The effectiveness of beta blockers in lowering blood pressure is undisputed, but how exactly this lowering is achieved is not fully understood. It is likely a combination of effects. At the beginning of the treatment, the blood pressure is lowered by reducing the cardiac output. In the long term, however, the inhibition of sympathetic activity and the reduction in renin release (mediated by the β 1 effect on the juxtaglomerular apparatus of the kidney) also play a role.

Coronary artery disease and heart attack

The beta blockers lower the heart rate and thus longer diastole, which leads to better blood flow to the coronary arteries, which are only supplied with blood during this phase. With the same physical cardiac output, this also increases efficiency and thus reduces the heart's need for oxygen. Beta blockers are therefore the most important drugs in stable angina pectoris and are also used after a heart attack with the same goal . A life-prolonging effect of beta blockers has been clearly proven for both indications.

Heart failure

Even with stable, chronic heart failure, studies show an improvement in prognosis through the use of beta blockers from stage NYHA- II, in hypertension and after myocardial infarction also in stage NYHA-I. The focus here is on reducing the sympathetic influence on the heart and making the work of the heart more economical , although the exact mechanism of action has not yet been clarified. When treating heart failure with beta blockers, it is important to make the treatment gradually, i.e. to start with low doses and slowly increase the dose. The beta blockers bisoprolol , carvedilol , metoprolol and nebivolol are approved for the treatment of heart failure .

Cardiac arrhythmias

Various classes of antiarrhythmic drugs are available for treating tachycardiac arrhythmias . Beta blockers are therefore also referred to as "Class II antiarrhythmics". In contrast to many other antiarrhythmic drugs, the life-prolonging effect of beta blockers has been proven, making them one of the most important drugs in antiarrhythmic therapy. For the effectiveness of beta blockers, their arousal-inhibiting effect on the heart plays a decisive role.

Further indications

Further indications for beta blockers are or can be:

Compliance

For the effectiveness of beta blockers - as with other drugs to be taken regularly - compliance is important : In an analysis of the compliance of around 31,500 patients who had survived a heart attack for at least 15 months and who were also prescribed beta blockers, among other things found that poor intake compliance reduces life expectancy. Compliance was rated as good when the patients redeemed at least 80% of the prescribed medication , and as moderate when they redeemed 40–79%. The mortality of patients with “moderate” compliance was increased by 1% (within one year) and 13% (two years), respectively, compared to those with “good” compliance.

Contraindications

Important relative and absolute contraindications that generally apply to all beta blockers are:

no contraindications

  • Beta blockers can be given for COPD; according to registry data, they reduce mortality after myocardial infarction (BMJ 2013; 347: f6650)
  • in the PAD Beta blockers are in accordance with the current guidelines ( German Society for Angiology ) no longer contraindicated

Side effects

As a rule, beta blockers are well tolerated even if they are taken for a long time. The known side effects are mostly reversible after stopping the drug or adjusting the dosage . The most important side effects, which basically apply to all beta blockers, are:

literature

  • Lutz Hein: Development of the beta blocker . In: Pharmazie in our time , 33 (6), 2004, pp. 434–437, doi: 10.1002 / pauz.200400089 .
  • Perry P. Griffin, Manfred Schubert-Zsilavecz, Holger Stark: Inhibitors of beta adrenoceptors . In: Pharmazie in our time 33 (6), 2004, pp. 442-449, doi: 10.1002 / pauz.200400091 .
  • Christoph Maack, Michael Böhm: Clinical use of beta blockers in cardiovascular indications . In: Pharmazie in our time 33 (6), 2004, pp. 466-475, doi: 10.1002 / pauz.200400094 .
  • Reinhard Larsen: Anesthesia and intensive medicine in cardiac, thoracic and vascular surgery. (1st edition 1986) 5th edition. Springer, Berlin / Heidelberg / New York a. a. 1999, ISBN 3-540-65024-5 , pp. 57-61 ( β-receptor antagonists ).

Individual evidence

  1. Martin Wehling: Clinical Pharmacology . 1st edition. Georg Thieme Verlag, Stuttgart 2005, ISBN 978-3-13-126821-1 , p. 52, 76 .
  2. U. Schwabe, D. Paffrath, W.-D. Ludwig, J. Klauber (Ed.): Drug Ordinance Report 2018 . 1st edition. Springer Medizin Verlag, Heidelberg 2018, ISBN 978-3-662-57385-3 , p. 8 .
  3. U. Schwabe, D. Paffrath, W.-D. Ludwig, J. Klauber (Ed.): Drug Ordinance Report 2018 . 1st edition. Springer Medizin Verlag, Heidelberg 2018, ISBN 978-3-662-57385-3 , p. 448 .
  4. ^ The 2015 Prohibited List . WADA; accessed on November 23, 2015.
  5. Axel W. Bauer : Beta receptor blockers. In: Werner E. Gerabek , Bernhard D. Haage, Gundolf Keil , Wolfgang Wegner (eds.): Enzyklopädie Medizingeschichte. De Gruyter, Berlin / New York 2005, ISBN 3-11-015714-4 , p. 173.
  6. ^ Wolf-Dieter Müller-Jahncke , Christoph Friedrich , Ulrich Meyer: Medicinal history . 2., revised. and exp. Edition. Knowledge Verl.-Ges., Stuttgart 2005, ISBN 978-3-8047-2113-5 , pp. 169 f .
  7. a b c d Thomas Herdegen: Short textbook pharmacology and toxicology . 1st edition. Georg Thieme Verlag, Stuttgart 2008, ISBN 978-3-13-142291-0 , p. 79 ff .
  8. Martin Wehling: Clinical Pharmacology . 1st edition. Georg Thieme Verlag, Stuttgart 2005, ISBN 978-3-13-126821-1 , p. 53 .
  9. Reinhard Larsen (1999), p. 57 f.
  10. Reza Mehvar, Dion R. Brocks: Stereo Specific Pharmacokinetics and Pharmacodynamics of Beta-Adrenergic Blockers in Humans . In: J. Pharm. Pharmaceut. Sci. , 4, 2001, pp. 185-200.
  11. ^ EJ Ariëns: Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology . In: European Journal of Clinical Pharmacology , 26, 1984, pp. 663-668, doi: 10.1007 / BF00541922
  12. Joni Agustiana, Azlina Harun Kamaruddina, Subhash Bhatiaa: Single enantiomeric β-blockers - The existing technologies . In: Process Biochemistry , 45, 2010, pp. 1587-1604.
  13. ^ RA Sheldon: The Industrial Synthesis of Optically Active Compounds . In: Miklós Simonyi (Ed.): Problems and Wonders if Chiral Molecules . Akadémiai Kiadó, Budapest 1990, ISBN 963-05-5881-5 , pp. 349-386.
  14. Overview of the most frequently prescribed preparations / active ingredients and their allocation to active ingredient groups according to the documentation data set, taking into account the AOK discount agreements and the active ingredient agreement. (PDF) General local health insurance funds , October 1, 2018
  15. A balanced view can be found u. a. at the German Heart Foundation : Thomas Eschenhagen: Beta blockers - how good are they? 2006.
  16. Guidelines for the Management of Arterial Hypertension. Working Group of Scientific Medical Societies (AWMF), June 1, 2008, accessed on July 1, 2012 .
  17. Klaus Aktories, Ulrich Förstermann, Franz Bernhard Hofmann, Klaus Starke (eds.): General and special pharmacology and toxicology . 10th edition. Elsevier, Munich 2009, ISBN 978-3-437-42522-6 , pp. 4.7.2 .
  18. Thomas Herdegen: Short textbook pharmacology and toxicology . 1st edition. Georg Thieme Verlag, Stuttgart 2008, ISBN 978-3-13-142291-0 , p. 91 .
  19. a b Martin Wehling: Clinical Pharmacology . 1st edition. Georg Thieme Verlag, Stuttgart 2005, ISBN 978-3-13-126821-1 , p. 76 .
  20. Thomas Herdegen: Short textbook pharmacology and toxicology . 1st edition. Georg Thieme Verlag, Stuttgart 2008, ISBN 978-3-13-142291-0 , p. 96 .
  21. Thomas Herdegen: Short textbook pharmacology and toxicology . 1st edition. Georg Thieme Verlag, Stuttgart 2008, ISBN 978-3-13-142291-0 , p. 105 .
  22. Quoted after Poor compliance is fatal . In: MMW update. Med. , No. 5, 2007 (149th year), p. 22, quoted from JN Rasmussen et al. In: JAMA , 297, 2007, pp. 177-186.
  23. Diagnosis and therapy of peripheral arterial occlusive disease (PAD). awmf.org, accessed June 17, 2012 .
  24. Berthold Jany, Tobias Welte: Pleural effusion in adults - causes, diagnosis and therapy. In: Deutsches Ärzteblatt. Volume 116, No. 21, (May) 2019, pp. 377-385, here: p. 380.