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CURRICULUM IN CARDIOLOGY - HISTORY OF MEDICINE
Year : 2018  |  Volume : 4  |  Issue : 1  |  Page : 49-51

The discovery of beta-blockers


Department of Pharmacology, AIIMS, New Delhi, India

Date of Web Publication4-May-2018

Correspondence Address:
Prof. Subir Kumar Maulik
AIIMS, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpcs.jpcs_11_18

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  Abstract 

The introduction of β-adrenergic-blocking drugs in the early 1960s represented a major advance in therapeutics. Their use highlighted the importance of the sympathetic nervous system. This article briefly highlights some of the steps in their development.

Keywords: Bacteriologist, Carvedilol Prospective Randomized Cumulative Survival Study, immunologist, Metoprolol Randomized Intervention Trial in Congestive Heart Failure


How to cite this article:
Maulik SK. The discovery of beta-blockers. J Pract Cardiovasc Sci 2018;4:49-51

How to cite this URL:
Maulik SK. The discovery of beta-blockers. J Pract Cardiovasc Sci [serial online] 2018 [cited 2022 Aug 8];4:49-51. Available from: https://www.j-pcs.org/text.asp?2018/4/1/49/231925

The story of beta-blocker is interesting as it spans a whole century of discovery from receptors to drug development to clinical trial.


  The First Step in the Discovery of Beta-Blockers was the Description of Receptors Top


Ehrlich and Langley proposed the receptor theory in the 1900s.

John N Langley (Physiologist) gave origin to the concept of the receptive substance, postulated the receptor theory after his experiments with nicotine and curare analogs [Figure 1].
Figure 1: John N Langley.

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Paul Ehrlich (Immunologist and Bacteriologist) designated the term receptor, introduced the concept of cell receptors [Figure 2].
Figure 2: Paul Ehrlich.

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  The Description of Alpha- and Beta-Receptors Top


Raymond P. Ahlquist (1914–1983) [Figure 3] made his distinction, in 1948, between α- and β-adrenoceptors. He divided adrenoceptors into α- and β-adrenoceptor subtypes.
Figure 3: Raymond P Ahlquist.

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In his experiments, he chose six agonists and ranked them according to their action on blood vessels and the heart. He found that they had different potencies in their action on the blood vessels and the heart, and he named the receptors on the blood vessels as alpha-receptors and the ones on the heart as the beta-receptors.[1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14]


  The First Beta-Blockers Top


The first beta-blocker developed was dichloroisoproterenol (1950s) which was modified to a clinical molecule pronethalol in 1962. This was launched as “Alderlin” and was found useful in angina and certain arrhythmias though found to cause thymic tumors in mice. Dr James Black created another beta-blocker propranolol which was nonselective, as effective and without the side effect. This was marketed as Inderal. James Black also discovered cimetidine and won the Nobel prize in 1988 [Figure 4].[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30]
Figure 4: James Black.

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After this, practolol was developed but was withdrawn due to side effects. Next came atenolol (1976, name of Tenormin) which was a selective beta-1 receptor antagonist. Later came other drugs such as carvedilol (additional alpha blocking), nebivolol (additional direct vasodilator), and metoprolol (beta-1 receptor selective).


  The Current Status Top


They are used extensively in heart failure,[31],[32],[33] hypertension, angina, aortic diseases including dissection, arrhythmias, cardiomyopathies, pregnancy, and endocrine disorders. The data on heart failure came from major trials, some of which are Beta-blocker Evaluation of Survival Trial, Cardiac Insufficiency Bisoprolol Trial II (CIBIS-II), Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS), and Metoprolol Randomized Intervention Trial in Congestive Heart Failure. In CIBIS I, bisoprolol was compared with placebo, and no significant difference was seen. In CIBIS II trial, 2647 patients were randomized, and a significant reduction in all-cause mortality was observed. The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure showed a favorable effect on all-cause mortality. The results from the US Carvedilol Heart Failure Study were found in favor of carvedilol. The COPERNICUS trial in patients with severe heart failure also showed benefit. In the Carvedilol Or Metoprolol European Trial, two generations of beta-blockers were compared. A significant reduction in mortality was observed in favor of the group treated with carvedilol, but here, the metoprolol was immediate release and not sustained release.

In angina, there are at least 26 trials with more than 6000 patients showing decrease in rates of death and unstable angina. In hypertension, beta-blockers are no longer the first-line therapy though they are used if there is an additional compelling indication, like coronary artery disease.

Beta-blockers have now established their role in a number of cardiac conditions and other indications such as migraine and essential tremor, and their indications are evolving and refining with time.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Ahlquist RP. A study of the adrenotropic receptors. Am J Physiol 1948;153:586-600.  Back to cited text no. 1
    
2.
Sutherland JH, Carrier GO, Greenbaum LM. Dr. Raymond P. Ahlquist. Pharmacologist 1983;25:73.  Back to cited text no. 2
    
3.
Wenger NK, Greenbaum LM. From adrenoceptor mechanisms to clinical therapeutics: Raymond Ahlquist, Ph.D 1914-1983. J Am Coll Cardiol 1984;3:419-21.  Back to cited text no. 3
    
4.
Little RC. Raymond P. Ahlquist (1914-1983). Clin Cardiol 1988;11:583-4.  Back to cited text no. 4
    
5.
Rubin RP. A brief history of great discoveries in pharmacology: In celebration of the centennial anniversary of the founding of the American Society of Pharmacology and Experimental Therapeutics. Pharmacol Rev 2007;59:289-359.  Back to cited text no. 5
    
6.
Starke K. The history of the α-adrenoceptor agonists. Pharm Unserer Zeit 2011;40:456-61.  Back to cited text no. 6
    
7.
Ahlquist RP, Huggins RA, Woodbury RA. The pharmacology of benzyl-imidazoline (Priscol). J Pharmacol Exp Ther 1947;89:271-88.  Back to cited text no. 7
    
8.
Ahlquist RP, Levy B. Andrenergic receptive mechanism of canine ileum. J Pharmacol Exp Ther 1959;127:146-9.  Back to cited text no. 8
    
9.
Ahlquist RP. Historical perspective. Classification of adrenoreceptors. J Auton Pharmacol 1980;1:101-6.  Back to cited text no. 9
    
10.
Wenger NK, Lowell M. Greenbaum, From adrenoceptor mechanisms to clinical therapeutics: Raymond Ahlquist, Journal of the American College of Cardiology 1984;3:419-21.  Back to cited text no. 10
    
11.
Available from: https://en.wikipedia.org/wiki/Raymond_P._Ahlquist. [Last accessed on 2018 Mar 24].  Back to cited text no. 11
    
12.
Goodman LS, Hardman JG, Limbird LE, Gilman AG. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill International Editions; 2001. p. 249-68.  Back to cited text no. 12
    
13.
Lemke TL, Williams DA, Roche VF, Zito SW. Foye's Principles of Medicinal Chemistry. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2008. p. 410-1.  Back to cited text no. 13
    
14.
Frishman WH. Fifty years of beta-adrenergic blockade: A golden era in clinical medicine and molecular pharmacology (commentary). Am J Med. 2008;121:933-4.  Back to cited text no. 14
    
15.
Quirke V. Putting theory into practice: James black, receptor theory and the development of the beta-blockers at ICI, 1958-1978. Med Hist 2006;50:69-92.  Back to cited text no. 15
    
16.
Gringauz A. Introduction to Medicinal Chemistry: How Drugs Act and Why. New York: Wiley-VCH; 1997. p. 428-38.  Back to cited text no. 16
    
17.
Hara T. Innovation in the Pharmaceutical Industry: The Process of Drug Discovery and Development. Great Britain: MPG Books; 2003. p. 38-51.  Back to cited text no. 17
    
18.
Frishman WH. B-adrenergic blockade in cardiovascular disease. J Cardiovasc Pharmacol Ther 2013;18:310-9.  Back to cited text no. 18
    
19.
Poirier L, Lacourcière Y. The evolving role of β-adrenergic receptor blockers in managing hypertension. Can J Cardiol 2012;28:334-40.  Back to cited text no. 19
    
20.
de Peuter OR, Souverein PC, Klungel OH, Büller HR, de Boer A, Kamphuisen PW, et al. Non-selective vs. selective beta-blocker treatment and the risk of thrombo-embolic events in patients with heart failure. Eur J Heart Fail 2011;13:220-6.  Back to cited text no. 20
    
21.
Lednicer D. Strategies for Organic Drug Synthesis and Design. Canada: John Wiley & Sons; 1998. p. 37-41.  Back to cited text no. 21
    
22.
Panchgalle SP, Gore RG, Chavan SP, Kalkote UR. Organocatalytic enantioselective synthesis of β-blockers: (S)-propranolol and (S)-naftodipil. Tetrahedron Asymmetry 2009;20:1767-70.  Back to cited text no. 22
    
23.
Agustian J, Kamaruddin AH, Bhatia S. Single enantiomeric β-blockers – The existing technologie. Process Biochem 2010;45:1587-604.  Back to cited text no. 23
    
24.
Lechat P. Clinical pharmacology of beta-blockers in cardiology: Trial results and clinical applications. Hot Top Cardiol 2008;10:7-44.  Back to cited text no. 24
    
25.
Frishman WH. Alpha- and beta-adrenergic blocking drugs. In: FrishmanWH, Sonnenblick EH, Sica DA, editors. Cardiovascular Pharmacotherapeutics. 2nd ed. New York: McGraw Hill; 2003. p. 67-97.  Back to cited text no. 25
    
26.
Hoffman BB, Taylor P. Neurotransmission: The autonomic and somatic motor nervous systems. In: Hardman JG, Limbird LE, editors. Goodman & Gilman's the Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw Hill; 2001.  Back to cited text no. 26
    
27.
Brodde OE, Bruck H, Leineweber K. Cardiac adrenoceptors: Physiological and pathophysiological relevance. J Pharmacol Sci 2006;100:323-37.  Back to cited text no. 27
    
28.
Black JW, Stephenson JS. Pharmacology of a new adrenergic beta-receptor-blocking compound (Nethalide). Lancet 1962;2:311-4.  Back to cited text no. 28
    
29.
Powell CE, Slater IH. Blocking of inhibitory adrenergic receptors by a dichloro analog of isoproterenol. J Pharmacol Exp Ther 1958;122:480-8.  Back to cited text no. 29
    
30.
Black JW, Crowther AF, Shanks RG, Smith LH, Dornhorst AC. A new adrenergic betareceptor antagonist. Lancet 1964;1:1080-1.  Back to cited text no. 30
    
31.
Alcock SJ, Bond PA. Observations of the toxicity of alderlin (pronethalol) in laboratory animals. Proc Eur Soc Study Drug Toxic 1964;4:30-9.  Back to cited text no. 31
    
32.
Stephen SA. Unwanted effects of propranolol. Am J Cardiol 1966;18:463-72.  Back to cited text no. 32
    
33.
Frishman WH. Clinical Pharmacology of the Beta- Adrenoreceptor Blocking Drugs. 2nd ed. Norwalk, CT: Appleton-Century-Crofts; 1984.  Back to cited text no. 33
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

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