Current role of b-blockers in treatemet of hypertension

prof. dr. Hossam kandil
Prof. of Cardiology cairo University
Current role of b-blockers in treatemet of hypertension
Beta blockers are in wide spread use for the treatment of a variety of cardiovascular diseases : These include stable and unstable angina pectoris, hypertension, acute myocardial infarction,congestive heart failure due to systolic or diastolic dysfunction, and the therapy and prevention of some arrhythmias.
There are many beta blockers available and although they all have the same mechanism of action, ie, blockade of the beta adrenoreceptor, there are various characteristics that differ among these agents; these characteristics primarily impact upon drug metabolism and the side effect profile but not efficacy.
The initiation of antihypertensive therapy has been largely empiric, since the major classes of antihypertensive drugs have roughly equal efficacy.
However, each of the major classes of antihypertensive drugs has both advantages and disadvantages that vary with underlying diseases that may be present.
These relationships may be helpful in deciding which agent to use.
There are at least three distinct types of beta receptors:
ß1,which are found primarily in heart muscle. Activation of these receptors results in an increase in heart rate, contractility, atrioventricular (AV) conduction, and a decrease in AV node refractoriness.
ß2, which are present in heart muscle but are more prominent in bronchial and peripheral vascular smooth muscle. Activation of these receptors result in vasodilatation and bronchodilatation.
ß3, which are found in adipose tissue and the heart. Activation of these receptors may mediate catech0lamine induced therrnogenesis and may reduce cardiac contractility.
beta blockers act by competitively inhibiting catecholamines from bindig to these receptors.
the different ß-blockers are listed in table-1 arranged alphabetically.
table -1: list of different ß-blockers arranged alphabetically:
acebutalol
atenolol
betaxolol
bisoprolol
bucindolol
carteolol
carvedilol
celiprolol
Esmolol
Epanolol
Labetalol
Metoprolol
Nadolol
Oxprenolol
Penbutolol
Pindolol
Practolol
Propranolol
Sotalol
Timolol
BIOCHEMICAL
CHARACTERISTICS
Beta blockers are competitive inhibitors of catecholamines at beta-adrenoreceptor sites. They act to reduce the effect of the catecholamine agonist on sensitive tissues.
Most beta blockers exist as pairs of optical isomers and are marketed as racemic mixtures. Almost all of the beta blocking activity is found in the negative levorotatory (1) stereoisomer. which can be up to 100 times more active than the positive dextrorotatory (d) isomer.
The d-isomers of beta blocking drugs have no apparent clinical value except for d-sotalol, which has type ııı antiarrhythmic properties, ie, it blocks the potassium channel and prolongs membrane repolarization, thereby increasing the QT interval. d-propranolol has type I (quinidine-like) membrane stabilizing activity that is manifested only when very high doses of racemic propranolol are administered.
Selectivity - Beta blockers are also classified as nonselective or selective. Selectivity (or cardioselectivity) refers to the ability of a drug to preferentially block the beta-1 receptors. Propranolol, the prototypic beta blocker, has an equal affinity for the beta-1 and beta-2 receptors and is considered a nonselective agent.
On the other hand, relatively cardioselective agents, such as atenolol or metoprolol, will at inhibit the beta-1 receptors while producing less inhibition of the beta-2 receptors that mediate bronchodilatation or peripheral vasodilatation.
Cardioselectivity is a relative property; substantial beta-2 blockade can also occur at the higher doses such as those often required to treat angina.
Ventricular muscle also appears to contain functional beta-2 receptors which may be important in certain pathologic conditions such as congestive heart failure or myocardial ischemia.
In an animal study, for example, isoproterenol infusion produced an increased intracellular influx of calcium in myocytes from animals susceptible to ischemia-mediated ventricular fibrillation compared to myocytes from resistant animals.
These changes were prevented by selective blockade of the beta-2 receptor, but not by blockade of the beta-1 receptor. Beta-2 receptor blockade also prevented ischemiamediated ventricular fibrillation.
These data suggest that activation of the beta-2 receptor and the resulting increase in cytosolic calcium can produce after potentials that may ultimately trigger ventricular fibrillation.
intrinsic sympathomimetic activity Certain beta blockers (such as pindolol and acebutolol) possess partial agonist activity (also called intrinsic sympathomimetic activity or ISA).
These drugs cause a slight to moderate activation of the beta receptor even as they prevent access of natural and synthetic catecholamines to the receptor sites.
The result is a weak stimulation of the receptor. Mild to moderate ISA in a beta blocker does not interfere with efficacy.
They may, however, cause less reduction in heart rate, less depression of atrioventricular (AV) conduction, and less negative inotropy than beta blockers without this property.
Alpha-adrenergic blocking activity - Caredilol blocks both beta and alpha receptors with a potency ratio of 4:1. It is a nonselective beta blocker without ISA.
It reduces the heart rate and cardiac contractility (as with other beta blockers) and, because of its alpha blocking effects, reduces peripheral and coronary vascular resistance.
Carvedilol has a long duration of action (elimination t1/2 7-10 hrs) with no Lipid solubility (no CNS side effects).
The interpatient variations in plasma levels is Minimal. It has important Ancillary properties that are present in other beta blockers, i.e anti-oxidant and anti-proliferative activites.
Labetalol is another nonselective beta blocker which blocks the alpha receptor.
Pharmacokinetics - Although the beta blockers have similar pharmacotherapeutic effects, their pharmacokinetic properties differ significantly in ways that may influence their clinical usefulness and side effects.
Among individual drugs, there are differences in completeness of gastrointestinal absorption, amount of first-pass hepatic metabolism, lipid solubility, protein binding, extent of distribution in the body, penetration into the brain, concentration in the heart, rate of hepatic biotransformation, pharmacologic activity of metabolites, and renal clearance of the drug and its metabolites.
On the basis of their pharmacokinetic properties, the betablockers can be classified into two broad categories:
● Those eliminated by hepatic metabolism
● Those excreted unchanged by the kidney
Drugs in the first group (such as propranolol and metoprolol) are lipid-soluble, almost completely absorbed by the small intestine, and largely metabolized by the liver.
They enter the central nervous system (CNS) in high concentrations, possibly resulting in an increased incidence of CNS side effects. They tend to have highly variable bioavailability and relatively short plasma half-lives.
In contrast, drugs in the second category (such as Caredilol, atenolol and sotalol) are more water soluble, incompletely absorbed through the gut, eliminated unchanged by the kidney, and do not as readily enter the central nervous system.
They show less variance in bioavailability and have longer plasma half-lives.
Ultra-short-acting beta blockers (such as esmolol) with a half-life of no more than 10 minutes offer advantages in some patients.
They can be given for the treatment of supraventricular arrhythrnias and, as a test dose, to a patient who has a questionable history congestive heart failure. The short half.-life of esmolol is due to its rapid metabolism by blood tissue and hepatic esterases.
ADVERSE EFFECTS
Beta blockers are generally well tolerated but have a well recognized set of potential side effects that can limit their use. Summarized briefly, the following are the major concerns with beta blocker therapy:
● Decreases in heart rate, contractility and AV node conduction can lead to severe sinus bradycardia, sinus arrest, heart failure, and AV block.
● Bronchoconstriction, due to ß2 receptor blockade, can be induced by nonselective agents and high doses of cardioselective agents. Nonselective agents are generally contraindicated in patients with asthma and most patients with chronic obstructive lung disease; cardioselective agents or those with ISA must be used very cautiously in these settings.
● Nonselective beta blockers can cause worsening of symptoms of severe peripheral vascular disease or Raynaud's phenomenon but usually not milder disease with mild to moderate intermittent claudication. Cardioselective beta blockers are probably preferable in such patients.
● Fatigue may be due to the reduction in cardiac output or to direct effects on the central nervous system. Other central side effects that can occur include depression, nightmares, insomnia, and hallucinations. Impotence can also be a problem.
● Nonselective beta blockers (including labetalol) can mask the early, sympathetically-mediated symptoms of hypoglycemia in patients with insulin-dependent diabetes mellitus; they can also delay the rate of recovery of the blood glucose concentration.
In addition, patients with ischemic heart disease must be warned not to rapidly discontinue treatment, since this can lead to a withdrawal syndrome characterized by accelerated angina, myocardial infarction, and even death.
These findings, which can occur even in patients without previously known coronary disease, probably result from upregulation of the beta receptors following chronic beta blockade.
MECHANISMS OF ACTION
Although the primary activity of beta blockers is adrenoreceptor blockade, the mechanisms of their action in various cardiovascular disease states is related to different tissue effects.
Hypertension - The mechanism of beta blocker action in hypertension has not been completely established. It is likely that one or more of the following factors con-tribute in individual patients:
● A decline in cardiac output due to the reductions in heart rate and contractility; however, this is not sufficient in many patients because of a reflexinduced increase in systemic vascular resistance.
● Inhibition of renal renin release by the kidneys.
● Diminution of tonic sympathetic outflow from the vasomotor centers in the brain, an effect that may be most prominent at higher doses.
Congestive heart failure - Alhough beta blockers have negative inotropic activity, an increasing number of studies suggest that they lead to symptomatic improvement
and even improved survival in some patients with CHF.
Several explanations have been proposed to explain this apparently beneficial effect.
● Long-term exposure to catecholamines is deleterious to cardiac function in both animals and humans. There is a reduction inresponsiveness to beta-adrenergic agonists due to desensitization of the betareceptor.
In addition, some patients with dilated cardiomyopathy have circulating autoantibodies directed against the beta-1- adrenergic receptor, which may contribute to functional impairment of the receptor. All of these responses may be counteracted by beta blockers.
There is evidence that catecholamines can directly decrease myocardial contractility in CHF.
Studies of human ventricular endomyocardial biopsy specimens have shown that activation of myocardial beta-3-receptors has a negative inotropic effect [38] that is mediated by activation of nitric oxide synthesis.
Thus, in patients with heart failure, the combination of activation of these receptors plus downregulation of beta-1- receptors could result in a catecholamine-induction reduction in myocardial contractility.
● Nonselective beta blockers can attenuate cardiac sympathetic activation by blockade of prejunctional beta-1 and beta-2 receptors in both the heart and adrenal medulla.
● Ventricular myocardium contains both beta-1 and beta-2 adrenergic receptors; in CHF there is a selective reduction in the density of the beta-1, but not beta -2,receptors.
As a consequence, the failing heart is more dependent upon beta-2 adrenergic receptors for inotropic support. In addition, beta-2 receptor stimulation may increase the propensity for ventricular fibrillation which can be prevented by beta-2-receptor blockade.
Beta blockade upregulates myocardial beta-1-receptor density in patients with CHF, partially reve rersing the usual reduction in beta-1-receptor density seen in this setting.
This effect could increase the inotropic sensitivity to circulating catecholamines with a subsequent improvement in systolic contractile function and enhanced exercise tolerance.
However, selective beta -1 receptor blockade and the increased sympathetic effect might also be detrimental by promoting the development of ventricular arrhythmias.
● Beta blockers appear to reduce the circulating level of vasoconstrictors, including renin, norepinephrine, and endothelin. Thus, beta blockers may diminish sympathetic nerve traffic as well as inducing antagonism at the receptor level.
● Beta blockers may improve diastolic function.
● Beta blockers have a beneficial effect on left ventricular remodeling, reducing left ventricular volumes, increasing left ventricular ejection fraction, and preventing left ventricular dilatation. The improvement in left ventricular geometry, defined by the length/ diameter ratio, reduces mitral regurgitation.
● Beta blockers restore cyclic AMP-dependent positive inotropic effects independent of beta-adrenoceptors. This effect most likely involves modulation at the level of the inhibitory G-proteins.
ß-blockers are widely used in the initial therapy of essential hypertension.
Although it has been suggested that these drugs may have a specific cardioprotective effect in patients with hypertension (as they do following a myocardial infarction), most studies have failed to document this hypothesis.
Furthermore, the nonselective and ß-1 selective agents have adverse metabolic effects - moderate elevation in plasma glucose concentration, increased insulin resistance, reduced HDL-cholesterol, and elevated triglycerides.
It has also been proposed that inhibition of sympathetic activity may lead to a reduction in the patient's quality of life (due, for example, to fatigue, depression, or decreased exercise capacity) when compared to therapy with an angiotensin converting enzyme inhibitor; however, a quality of life disadvantage with ß-blockers has not been confirmed in other studies.
There are also settings in which ß-adrenergic tone is beneficial and therefore in which ß-blockersare relatively or, depending upon disease severity, absolutely contraindicated.
Included in this group are patients with asthma or chronic obstructive pulmonary disease, severe peripheral vascular disease (but usually not milder disease with intermittent claudication), Raynaud's phenomenon, depression, bradycardia, second or third degree heart block, and hypoglycemia-prone diabetics in whom the early warning symptoms of hypoglycemia may be masked.
SUMMARY
Hypertension is a highly prevalent disease in adults and constitutes a major public health problem.
Beta-blockers diuretics therapy remain the recommended first line therapy for uncomplicated hypertension.
Due to low rates of compliance in most of hypertension surveys, drugs with better tolerability and with benefits beyond BP control should have priority in prescriptions.
Carvedilol is a novel, balanced beta-blocker with vasodilator properties.
It is well tolerated by most patients and it has both antioxidant and anti-proliferative effects.
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