|
 
 |
| CURRICULUM IN CARDIOLOGY - HISTORY OF MEDICINE |
|
| Year : 2018 | Volume
: 4
| Issue : 1 | Page : 49-51 |
|
The discovery of beta-blockers
Subir Kumar Maulik
Department of Pharmacology, AIIMS, New Delhi, India
| Date of Web Publication | 4-May-2018 |
Correspondence Address:
Prof. Subir Kumar Maulik
AIIMS, New Delhi
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jpcs.jpcs_11_18
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 |
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 | |  |
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].
Paul Ehrlich (Immunologist and Bacteriologist) designated the term receptor, introduced the concept of cell receptors [Figure 2].
| The Description of Alpha- and Beta-Receptors | | |
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.
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 | | |
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]
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 | | |
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 | | |
| 1. | Ahlquist RP. A study of the adrenotropic receptors. Am J Physiol 1948;153:586-600.  |
| 2. | Sutherland JH, Carrier GO, Greenbaum LM. Dr. Raymond P. Ahlquist. Pharmacologist 1983;25:73. |
| 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. |
| 4. | Little RC. Raymond P. Ahlquist (1914-1983). Clin Cardiol 1988;11:583-4. |
| 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. |
| 6. | Starke K. The history of the α-adrenoceptor agonists. Pharm Unserer Zeit 2011;40:456-61. |
| 7. | Ahlquist RP, Huggins RA, Woodbury RA. The pharmacology of benzyl-imidazoline (Priscol). J Pharmacol Exp Ther 1947;89:271-88. |
| 8. | Ahlquist RP, Levy B. Andrenergic receptive mechanism of canine ileum. J Pharmacol Exp Ther 1959;127:146-9. |
| 9. | Ahlquist RP. Historical perspective. Classification of adrenoreceptors. J Auton Pharmacol 1980;1:101-6. |
| 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. |
| 11. | |
| 12. | Goodman LS, Hardman JG, Limbird LE, Gilman AG. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 10 th ed. New York: McGraw-Hill International Editions; 2001. p. 249-68. |
| 13. | Lemke TL, Williams DA, Roche VF, Zito SW. Foye's Principles of Medicinal Chemistry. 6 th ed. Philadelphia: Lippincott Williams & Wilkins; 2008. p. 410-1. |
| 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. |
| 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. |
| 16. | Gringauz A. Introduction to Medicinal Chemistry: How Drugs Act and Why. New York: Wiley-VCH; 1997. p. 428-38. |
| 17. | Hara T. Innovation in the Pharmaceutical Industry: The Process of Drug Discovery and Development. Great Britain: MPG Books; 2003. p. 38-51. |
| 18. | Frishman WH. B-adrenergic blockade in cardiovascular disease. J Cardiovasc Pharmacol Ther 2013;18:310-9. |
| 19. | Poirier L, Lacourcière Y. The evolving role of β-adrenergic receptor blockers in managing hypertension. Can J Cardiol 2012;28:334-40. |
| 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. |
| 21. | Lednicer D. Strategies for Organic Drug Synthesis and Design. Canada: John Wiley & Sons; 1998. p. 37-41. |
| 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. |
| 23. | Agustian J, Kamaruddin AH, Bhatia S. Single enantiomeric β-blockers – The existing technologie. Process Biochem 2010;45:1587-604. |
| 24. | Lechat P. Clinical pharmacology of beta-blockers in cardiology: Trial results and clinical applications. Hot Top Cardiol 2008;10:7-44. |
| 25. | Frishman WH. Alpha- and beta-adrenergic blocking drugs. In: FrishmanWH, Sonnenblick EH, Sica DA, editors. Cardiovascular Pharmacotherapeutics. 2 nd ed. New York: McGraw Hill; 2003. p. 67-97. |
| 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. 10 th ed. New York: McGraw Hill; 2001. |
| 27. | Brodde OE, Bruck H, Leineweber K. Cardiac adrenoceptors: Physiological and pathophysiological relevance. J Pharmacol Sci 2006;100:323-37. |
| 28. | Black JW, Stephenson JS. Pharmacology of a new adrenergic beta-receptor-blocking compound (Nethalide). Lancet 1962;2:311-4. |
| 29. | Powell CE, Slater IH. Blocking of inhibitory adrenergic receptors by a dichloro analog of isoproterenol. J Pharmacol Exp Ther 1958;122:480-8. |
| 30. | Black JW, Crowther AF, Shanks RG, Smith LH, Dornhorst AC. A new adrenergic betareceptor antagonist. Lancet 1964;1:1080-1. |
| 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. |
| 32. | Stephen SA. Unwanted effects of propranolol. Am J Cardiol 1966;18:463-72. |
| 33. | Frishman WH. Clinical Pharmacology of the Beta- Adrenoreceptor Blocking Drugs. 2 nd ed. Norwalk, CT: Appleton-Century-Crofts; 1984. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
|
Search Pubmed for