B- androgenic blockers are one of the most prescribed commonly as hypertension medications.[1] More than a dozen novel B-adernegenic blockers for the treatment of Hypertension have been Launched Since the availability of propranolol in 1976. Several beta-adrenergic blockers with different pharmacological qualities have been developed, which he may be grouped into three generations based on the differences in Pharmacological properties.[1] B-adrenergic blockers classification:- B-blockers differ in terms of B1/B2 – adernergic receptor Selectivity and Vasodilator activity, which has led to their classification as First, second, and third generation agents. First-generation B-blockers (propranolol, pindolol, etc.) are termed as non-selective because they exert equal blockade of B1- and B2 receptors. The second-generation beta-blockers (such as atenolol, metaprolol, bisoprolol, betaxolol, facebutolol, etc.), are referred to as selective because they have a higher. Affinity for B1-than B2-adernergic receptors. Finally, Vasodilatory properties distinguish third-generation B-blockers (labetalol, Carvedilol, nebivolol, etc.) from first – and second generation B-blockers. This class of B-blockers has varying selectivity for B1-receptors and acts as a vasodilator by blocking a1- adreno receptors and activating B3- aderenergic receptors. This class is the most effective for Lowering blood pressure.

Traditional B-blockers

The first B-blocker introduced into clinical practice was propranolol.[2]Synthesized by Sir James Black and colleagues, propranolol I was initially developed more than 50 years ago for the treatment of Angina.[2]However, its clinical utility was to some extent limited by it’s lack of B1- adernoceptor specificity; propranolol and the other traditional agents have equal affinities for blocking the B1 and B? receptors.[3] The development of Cardioselective B-blockers Such as atenolol, and metoprolol, which selectively block the B1compared with the B2 receptors[3], was therefore a significant therapeutic advance.

B-Adrenergic receptors (B-AR) and their associated Guanine nucleotide regulatory protein (G-protein/ adenylyl cyclase (AC) signal transduction pathways are central to the overall regulations of cardiac function. In particular, B-AR stimulation is a primary Control point for modulation of heart rate and myocardial contractility. However, B-AR signalling pathways undergo a number of adaptive and potential maladaptive regulatory changes as a consequence of heart failure.[4,5] This should not be surprising given that one of the best correlative makers for the degree and prognosis of chronic heart failure is plasma nor-epinephrine[6], an endogenous Ligand for adrenergic receptors.

B-adrenergic receptors and mechanism of action:-

B1 and B2 receptors are the most prevalent adrenergic receptor found in human Cardiovascular tissues.The heart and kidneys have most B1 -adrenergic receptions while the gastrointestinal tract liver, uterus ,vascular smooth muscle and skeletal muscle have B2- receptors.[7,8]The B1 and B2 receptor agonist, are individually linked to the activation of adenylyl cyclase and the production of cyclic adenosine monophosphate (c AMP) via, their interaction with the heterotrimeric G-protein Gs alpha. Adenylyl cyclase starts a c-AMP dependent pathway signalling Gs, which leads to potentiation of the receptor’s action.[9] Targeted stimulation of the B1receptor in the heart, increases heart rate and contractility (AV) nodal, and Ventricular muscle firing. The Stroke Volume and cardiac output will also increase as these two variables rise. Cardiac output is calculated as the sum of strike volume and heart rate. As stroke volume or heart rate rises as a result of targeted B1, receptor activation, Cardiac output will also increase and ultimately be responsible for the increasing perfusion to tissues throughout the body. The smooth muscle cells in the juxtaglomerular apparatus of the kidney contract and release renin due to B1 receptor activation. This effect will Ultimately raise blood volume due to the angiotensin-2 and aldosterone action.[10].

       
           
       
    Fig 1:Beta adrenergic blocking drugs stopping the binding of the epinephrine with the receptors

 SAR (Structural Activity Relationship) of B (Beta) Aderenergic blockers.

Structure activity relationship of B-blockers is based on Adrenergic agonists because B-blockers have structural similarities as adrenergic agonists .The basic modifications in structure of adrenergic agonists to exert B-antagonist activity as follows:-

Fig 2 :Basic model of beta blockers

1. Replacement of – OH’ group at R4 by – So? NH? or -CH?OH or other groups produce,     antagonist, activity.
2. Removal of -OH’ group at R3 also give antagonist activity
3. The 2-Carbon chain is important for activity
4. Addition of – OCH2 between side chain & aromatic ring also produce, better antagonist properties.
5. The larger Aryl group at N-Shows, B-antagonist activity.
6. Aromatic ring may be phenyl or heteroaromatic.
7. Replacement of phenyl by naphthyl or substituted naphthyl produces non- selective B-blockers.
8. Asymmetric (Chiral) Carbon is essential
1. R-isopropyl, t-butyl, Aryl, alkyl increases polarity.
10. X=H Called “Aryl ethanol amines, produces non- Selective blockers with ‘R’ configuration.
11. X=-OCH Called ‘Aryl oxypropanolamines. Active in “s-configuration.

B-blockers are of two types of structure:-

Arylethanol amines:-

The first B-blocker was produced after changing groups of 3,4 hydroxy groups of Isoproterenol to dichloro groups, Dichloroisoproterenol. It is not true antagonist, so not used clinically now. Since DCI (Dichloroisoproterenol), a classic Bblocking agent, it also a partial B-agonist and it cannot be used as a hypotensive agent. DCI turned out to be Carcinogenic. Replacement of the electron rich hydroxyl grouped with an electron rich phenyl at 3,4 positions gives pronethalol, which it even better B-blocker than dichloroisoproterenol.

Aryloxypropanolamines :-

 Pronethalol, an arylethanolamine, was withdrawn from clinical testing because of reports that it caused thymic tumors in mice. However, within two years of this report, Black and Co-workersdiscovered, a potent B-blocker propranolol, a close structural relative of pronethalol.

First generation

Second generation

Administration

Beta-blockers are given orally, intravenously, or ophthalmically; it can also be injected intramuscularly.Dosages come in a variety of ranges depending on the medication involved. Outpatient prescriptions include once-a-day dosing, like some of the longer-acting beta-blockers such as metoprolol succinate. However, most beta blockers are typically dosed at least twice per day. Some beta-blockers have a half-life of approximately 4 hours, like propranolol, which is dosed up to 3 or 4 times a day depending on the indication and dose.[22]

Absorption-

Passive diffusion is typically used to absorb ?-blockers from the gastrointestinal tract. Their absorption is therefore not regarded as stereoselective.Nonetheless, certain ?-blockers that travel through intestinal secretion, such tanilolol, might be somewhat streoselective. However, the majority of ?-blockers do not have a stereoselective secretion mechanism.[18,19]

Distribution-

Since they are basic medications, ?-blockers can bind to plasma albumin and ?1-glycoprotein.Because the proteins are chiral, ?-blockers may bind to them in a stereoselective manner. If there is a higher free fraction of some ?-blockers in plasma, such as acebutolol, pindolol, and sotalol21–23, then the binding of these blockers to plasma proteins doesn't seem to be selective.The majority of the time, neither the tissue uptake itself nor the ?-blockers' binding to it is stereoselective. (R)-propranolol was shown to be more concentrated in the heart, muscles, and rat lungs as opposed to (S)-propranolol.24 One possible explanation for this apparent stereoselectivity could be a greater drug-free fraction of (S)-propranolol in the plasma. Similar to this, the main factor causing the stereoselective binding of propranolol enantiomers to plasma is an apparent stereo selective in the drug's RBC distribution. It has been observed that hydrophilicity and hydrophobicity demonstrate stereoselectivity during both release and storage from adrenergic nerve terminals. 25The effect of this stereoselectivity on the concentration of active enantiomers at the binding sites could have significant ramifications.[19].

The metabolic process

The majority of ?-blockers are eliminated either renal excretion of unaffected substances or hepatic metabolism. While more hydrophilic ?-blockers, such sotalol and atenolol, are removed without affecting urine quality, lipophilic ?-blockers, like propranolol, are mostly eliminated by metabolism. Stereoselectivity in the ?-blocker metabolism process is possible. The active enantiomer is rapidly eliminated while the inactive enantiomer accumulates and vice versa. Cytochrome P-450 complex can be inhibited or activated by ?-blocker enantiomers.Carvalho et al. reported that the concentrations of labetalol's (RR) and (SR) enantiomers in blood plasma were lower. Research conducted on individuals in good health revealed that metoprolol administration led to a greater concentration of the (R)-enantiomer than its antipode.[19,20]

Renal excretion

Changes in renal function can lead to the accumulation of both enantiomers of ?-blockers in the plasma, which are largely removed in their unaltered state. Renal excretion exhibits a marked stereoselectivity that favours (R)-metoprolol. Due to stereospecific clearance of the (S)-enantiomer in the urine, atenolol and pindolol showed a greater concentration of the less active (R)-enantiomer. Specifically, when compared to the (S)-enantiomer, the plasma concentration of (R)-pindolol is higher. In general, beta-blockers have variable pharmacokinetic properties. Absorption from the gastrointestinal tract leads to peak plasma concentration within 1-3 h. Propranolol is most extensively protein-bound, 93%, compared with timolol, 10%; metoprolol, 12%; nadolol, 25%; and atenolol, 3%. 13 This difference in its protein-binding property makes propranolol more likely to displace other protein-bound drugs effectively compared with other beta-blockers. In plasma, beta-blockers bind albumin and a?-acid glycoprotein. These two chemical forms of the drugs have bioavailabilities of 30% for propranolol, 50-75% for timolol, 50% for metoprolol, 20%-30% for nadolol, and 50% for atenolol.13 The reason for the low. 14 Beta-blockers' large volume of distribution ranges from 0.7 to 5.6 L/kg, suggesting physiochemical properties; that is, lipophilicity or hydrophilicity of drugs, which may influence the duration of ?-receptor blockade and, subsequently, tissue concentration because of extravascular penetration and diffusion across biologic barriers like the blood–brain barrier. 13 Discussion More specifically, the great distribution volume of beta-blockers is an indication of their lipophilic nature, which is the reason for their ability to penetrate tissues more readily, thus having a longer duration compared to those molecules with a lower volume of distribution, depending on the target. Beta-blockers can be found in the brain tissue despite potentially low cerebrospinal fluid concentration, thus an indication that beta-blockers cross the blood–brain barrier. Atenolol, metoprolol and propranolol are all present in very small amounts in breast milk. Nadolol is present to a greater extent and its use is therefore contraindicated during lactation.[19,21]

Pharmacological characteristics:-

The physlochemical properties of molecules are of significant importance for Therapeutic and side effects. Although beta blockers have similar Pharmacotherapeutics effects, they may have different pharmacokinetic properties gastrointestinal absorption rate, first pass effect, lipid solubility hepatic biotransformation sate, the pharmacological activity of metabolites and clearance sate. According to thean properties, beta blockers are divided into two major groups-agents eliminated from the body by hepatic metabolism and those excreted unchanged by the kidneys. First class beta blackens, such as propransit Or metoprolol, are almost completely absorbed in the small intestine, metabolized by the liver, and have a high solubility in lipids. In Contrast, beta-blockers in the other category, such as atenolol Or sotalol, are less or all soluble in lipiis, incompletely absorbed and excreated unchanged by the kidney.Schematic representation of the difference between lipophilic and hydrophic beta-blockers: chemical formula, partition coefficient (log P), physical properties, and permeability through a biological membrane.

The metabolic problem

Effects on glucose metabolism-

In this respect, the diabetogenic effect of non-selective beta-blockage results from a decrease in pancreatic insulin secretion and decreased insulin sensitivity secondary to a reduced peripheral blood supply, increased body weight, and increased gluconeogenesis through glycogenolysis secondary to unopposed alfa 2 activity. The term “new onset diabetes” is vaguely defined and, in many cases, not defined at all by the authors. A large meta-analysis investigated the prevalence of NOD in a hypertensive population treated with BBL and found that the investigated BBL was either not or only moderately selective. Beta-block- age resulted in an approximately 30% increased risk of NOD compared to placebo and a 20% increased risk compared to CCB and RAAS-i. When comparing BBL to thiazide diuretics, data are less uniform, reporting neutral17.18 to less diabetogenic effects 16 of BBL, Data concerning diabetogenic effects of non-thiazide diuretics are lacking. The diabetogenic profile of BBL does not represent a class effect. Receptor selectivity is important with decreasing negative metabolic impact with increasing Bl-selectivtiy20. BBL with vasodilating activity also show little or no metabolic side effects. There is no concordance regarding the implications of antihypertensive therapy-induced diabetes on major endpoints. The negative effect of hyper-glycaemia on cardiovascular end points could be balanced at least in part by the antihypertensive action of the treatment, also assuming general negative prognostic significance of new diabetes in patients with hypertension under treatment .[16]

Lipid metabolism

First- and second-generation BBL are considered “atherogenic” because they exert an unfavourable effect on the distribution of the different subgroups. Of lipids (reducing HDL, increasing LDL and triglyceride). The lipase responsible for degraded triglycerides is inhibited by unopposed A-AR stimulation in beta-blockade. HDL-lowering possibly is ISA-dependent 13, Third-generation BBL exert a neutral or positive effect on the lipid profile. Data concerning impact on outcome are lacking.[16,17]

Contraindications-

Traditionally, beta-blockers have been absolutely contraindicated in asthmatic patients. More recently, societies have come into agreement that cardio-selective beta-blockers, also referred to as beta-1 selective, are permissible in asthmatics but non-selective betablockers are not. Non-selective beta-blockers should not be used in patients with asthma.Those patients who have either acute or chronic bradycardia and/or hypotension have relative contraindications to beta-blocker usage.Certain beta-blockers are contraindicated in patients with a history of specific medical conditions. The drug sotalol should not be used in patients with a diagnosis of long QT syndrome or who have had torsades de pointes in the past. Beta-blockers are relatively contraindicated in patients with Raynaud’s phenomenon since the medication will exacerbate this condition.[22]

Toxicity

The antidote overdose for beta-blockers is glucagon. It is particularly useful for cardiotoxicity that is induced by beta-blockers. Cardiac pacing is a second line when glucagon may fail, and this may comprise of either transcutaneous or transvenous pacing.[22].

CNS– Related Side Effects with beta blockers (Metoprolol ,Atenolol, Propranolol).

Central nervous system (CNS) side effects of beta blockers include Vivid and bizarre dreams, hallucinations, Disturbance of sleep and mood, and paranoid psychosis (Fraser and Carr 1976;Fleminger 1978).CNS side –Effects depend on several factors, notably the degree of lipophilicity and protein binding. Highly lipophilic Drugs such as propranolol and pindolol readily penetrate brain tissue, whereas water -soluble agents such as Atenolol do not (cruick-Shank 1980).No Significant CNS side effects were reported with atenolol, but Of metoprolol caused a significant increase in the incidence of Sleep disturbance (p<0>

Lipophillic property

The lipophilic property of some beta-blockers is the ability of the drug to diffuse through the blood-brain. barrier. First, the agent must cross it and attach directly to the beta-adrenergic receptors, the suppression of which it medates, flecond, the drug must also interact with non-adrenergic receptors, blocking their signals or destabilizing the call membrane. Highly lipophilic beta blockers such as propranolol, diffuse rapidly through the brain tissues compared to hydrophilic beta blockers, such as atenolol, which lacks the property.