IJRPC 2018, 8(4), 508-529 Namratha et al. ISSN: 22312781 INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND CHEMISTRY Available online at www.ijrpc.com Review Article A STUDY ON BETA BLOCKERS - A BRIEF REVIEW TV. Namratha*, KC. Chaluvaraju and AM. Anushree Department of Pharmaceutical Chemistry, Government College of Pharmacy, Bengaluru-560 027, Karnataka, India. ABSTRACT Beta blockers are agents or drugs which competitively inhibit the action of catecholamines at the beta adrenergic receptors, which are mainly used to treat variety of clinical conditions like angina, hypertension, asthma, COPD and arrhythmias. These drugs are also useful in several other therapeutic situations including shock, premature labor and opioid withdrawal, and as adjuncts to general anesthetics. These drugs produce their effect by interacting with the beta adrenergic receptors. In the present communication, an effort has been made to compile beta adrenergic receptors and the chemistry, discovery and development, classification and therapeutic applications of beta blockers. Keywords: Beta blockers, adrenergic receptors, catecholamines and aryloxypropanolamines. 1. INTRODUCTION Beta blockers were first developed by Sir 1.1 Adrenergic receptors James Black in 1962. The structures of The ability of a molecule to selectively these receptors have been studied by x- agonize or antagonize adrenergic ray crystallography.5 In the current article receptor made great advances in beta blockers are majorly focused with pharmacotherapeutics. The discovery of respect to their location, functions adrenergic receptors lead to major mediated, discovery and development, development of newer adrenergic SAR, classification, structures and agonists as well as antagonist.1 therapeutic applications. Adrenergic receptors are 7- transmembrane spanning receptors 1.2 Locations and agonistic action of beta which mediate both central and adrenergic receptors6 peripheral actions of the adrenergic The following are the various beta neurotransmitters. Adrenergic receptors adrenergic receptors found in different are found in nearly all peripheral tissues physiological locations and their actions and on many neurons within the central mediated by their stimulation with beta nervous system.2 They play an important adrenergic agonists. (Table 1) role in the control of blood pressure, myocardial contractile rate and force, 2. DISCOVERY AND DEVELOPMENT OF airway reactivity, and a variety of BETA ADRENERGIC ANTAGONISTS metabolic and central nervous system One of the beta adrenergic agonist functions.3 drugs, Isoprenaline (Fig. 1), was In 1948, Raymond P. Ahlquist classified considered as a lead molecule. It is a the adrenergic receptors into two major beta receptor agonist but has no action types i.e. α and β, based on their on alpha receptors. This lead molecule pharmacological characteristics such as was studied in depth and suitable rank order of potency of agonists.4 structural modifications required for beta Subsequently, both α and β types were adrenergic antagonistic activity were 3 subdivided into α1, α2, β1, β2 and implemented. β3subtypes respectively. Further, based The first such modifications carried out on pharmacological and molecular included was the replacement of the evidences alpha receptor subtypes were phenolic hydroxyl groups in isoprenaline classified into α1A, α1B, α1D. with chloro substituents gave 508 IJRPC 2018, 8(4), 508-529 Namratha et al. ISSN: 22312781 dichloroisoprenaline (Fig. 2), which is a 3.2 Based on their chemical nucleus partial agonist. Beta blockers can be classified This promising molecule into: dichloroisoprenaline gave an insight in 1. Arylethanolamines next stage of development to convert the Ex: pronetalol, sotalol, labetalol, beta adrenergic agonistic activity into brefonalol, Bufuralol antagonistic activity. The general 2. Aryloxypropanolamines methodology to do so was to introduce Ex: Propranolol, esmolol, metoprolol, another aromatic ring into the existing acebutalol, atenolol molecule. This resulted in a drastic change in hydrophobic interaction of the molecule with the receptor and also 3.3 FDA classes of beta blockers for changed the induced fit between the use in pregnant women 7,8 ligand and the binding site. This new fit A. Category A resulted in binding of ligand to the Adequate and well-controlled studies receptor’s binding site but without the have failed to demonstrate a risk to activation of the same. the fetus in the first trimester of Considering the above fact, the chloro pregnancy (and there is no evidence groups were replaced with a benzene of risk in later trimesters). ring, to form a rigid naphthalene ring No β-blockers is completely safe for system. This gave pronethalol (Fig. 3), using during pregnancy. the first beta blocker to be used clinically to treat angina, arrhythmia and B. Category B hypertension.5 Though, it exhibited great Animal reproduction studies have therapeutic activity, it was soon failed to demonstrate a risk to the withdrawn due to its carcinogenic effects. fetus and there are no adequate and 6 well-controlled studies in pregnant The further development was a result of women. the introduction of side chains between Eg. Pindalol, acebutalol, sotalol the naphthalene ring and the ethanolamine. The discovery of C. Category C propranolol (Fig. 4) was in fact a result of Animal reproduction studies have an accident during the synthesis for shown an adverse effect on the fetus which α-naphthol was used in the and there are no adequate and well reaction mixture instead of the β- controlled studies in humans, but naphthol and a drug having structure potential benefits may warrant use of with side chain at C1 of the naphthalene the drug in pregnant women despite ring rather than the C2 was obtained. potential risks. Propranolol is a pure antagonist and this Eg. Labetalol, Bisoprolol, Timolol, molecule is considered to be a bench Metoprolol mark in evaluation of all other beta blockers. D. Category D There is positive evidence of human 3. CLASSIFICATION OF BETA fetal risk based on adverse reaction BLOCKERS data from investigational or marketing 3.1 Beta blocking agents are classified experience or studies in humans, but into 3 classes based on selectivity and potential benefits may warrant use of action: the drug in pregnant women despite 1 First generation-Non selective in potential risks. nature and cause no vasodilation Eg. Atenolol Ex: Propranolol, Nadolol, Pindolol 2 Second generation - cardioselective 4. STRUCTURE ACTIVITY in nature RELATIONSHIP OF Ex: Acebutolol, atenolol ARYLOXYPROPANOLAMINES 3 Third generation–Non selective Presently, aryloxypropanolamines are agents which cause vasodilation the most commonly used beta Ex: Primidolol, Epanolol adrenergic blockers. Though the beta blockers are marketed in the racemic form, typically the activity lies only in one of its isomeric form. In arylethanolamines, the activity was 509 IJRPC 2018, 8(4), 508-529 Namratha et al. ISSN: 22312781 found to reside in the (R) form, while receptors by the neurotransmitters, in case of aryloxypropanolamines, it results in the production of cAMP by resides in the (S) form.9 adenyl cyclase. cAMP is a secondary Following are the necessary structural messenger molecule which activates requirements for their optimum activity: 4 the Protein Kinase A (PKA). The Presence of branched N-alkyl action of PKA is to increase the functional moieties. This fits into the calcium release which is responsible hydrophobic pockets, both branching for the physiological action. Beta and extension of this alkyl side chain blockers act by binding to the beta is essential. adrenergic receptors and blocking the Presence of hydroxyl group on the action of neurotransmitters. (Fig. 5) side chain is essential for the hydrogen bonding with receptors. 6. BETA ADRENERGIC Presence of amino group is essential BLOCKERS10-25 and it should be secondary in nature, Various beta adrenergic blockers, and it is required for the ionic bonding their structures, molecular formula, interaction. molar mass and therapeutic uses are Presence of oxymethylene bridge is discussed here. also essential for the drug to bind to The following are the most widely the receptor. used beta adrenergic blockers: (Table 2). However, the following changes are feasible: The aromatic ring system can be 7. CONCLUSION heterocyclic in nature. Beta blockers constitute an important Aryloxy substitution can be at C2 class of drugs in the clinical treatment which gives more potent compounds of various disorders like hypertension, than those substituted at C1 angina pectoris, asthma, glaucoma Variation in lipophilicity can be and arrhythmias. Various physical achieved by introducing suitable and chemical parameters of beta substituents. adrenergic antagonists such as the specificity, solubility, permeability and The following modifications were found to be distribution of the molecule can be detrimental and lead to loss of activity: modified in order to obtain a drug with Introduction of substituent on the preferred characteristics. Study of the propyl side chain. nature and type of receptor at the Replacement of the ethereal oxygen target tissue, and also by analyzing with S, CH2 or N-CH3. the structure activity relationship helps in obtaining molecules with 5. MECHANISM OF ACTION OF BETA optimum biological and BLOCKERS 6 physiochemical properties. Beta receptors are G protein coupled receptors. Activation of these 510 IJRPC 2018, 8(4), 508-529 Namratha et al. ISSN: 22312781 TABLES Table