Beta Blockers. BETA–ADRENERGIC BLOCKING DRUGS STRUCTURE-ACTIVITY RELATIONSHIPS...

Beta Blockers

BETA–ADRENERGIC BLOCKING DRUGS

•STRUCTURE-ACTIVITY RELATIONSHIPS

•MEMBRANE-STABILIZING ACTIVITY

•BETA1 SELECTIVITY

•ALPHA-ADRENERGIC ACTIVITY

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Question

According to the American Medical Association, what pattern of deaths related to high blood pressure over the past 10 years.

1. Decrease by 10%2. Decrease by 20%3. Increase by 10%4. Increase by 40%


• Beta-adrenergic blocking drugs, which constitute a major pharmacotherapeutic advance, were conceived initially for the treatment of patients with angina pectoris and arrhythmias; however, they also have therapeutic effects in many other clinical disorders including: systemic hypertension, hypertrophic cardiomyopathy, supraventricular tachycardias, mitral valve prolapse, silent myocardial ischemia, migraine, glaucoma, essential tremor, and thyrotoxicosis.


• Beta blockers have been effective in treating unstable angina and for reducing the risk of cardiovascular mortality and nonfatal re-infarction in patients who have survived an acute myocardial infarction.

• Beta blockade is also a potential treatment modality, with and without thrombolytic therapy, for reducing the extent of myocardial injury and mortality during the hyperacute phase of myocardial infarction.

The Beta-Adrenergic Receptor

•Radioligand labeling techniques have greatly aided the investigation of adrenoreceptors, and molecular pharmacologic techniques have positively delineated the beta-adrenoceptor structure as a polypeptide with a molecular weight of 67,000 daltons.


• Changes in tissue concentration of receptor sites are probably involved in mediating important fluctuations in tissue sensitivity to drug action.


• An apparent increase in the number of beta adrenoceptors, and thus a super sensitivity to agonists, may be induced by chronic exposure to antagonists.

• With prolonged adrenoceptor-blocker therapy, receptor occupancy by catecholamines can be diminished and the number of available receptors can be increased.


• When the beta blocker is withdrawn suddenly, an increased pool of sensitive receptors will be open to endogenous catecholamine stimulation.

•The resultant adrenergic stimulation could precipitate unstable angina pectoris and/or a myocardial infarction.


• Using radioligand techniques, investigators have demonstrated a decrease in beta-adrenoceptor sites in the myocardium in patients with chronic congestive heart failure.

•The concentration of beta adrenoceptors in the membrane of mononuclear cells also decreases significantly with age.


• This desensitization phenomenon or ''down- regulation'' is caused not by a change in receptor formation or degradation but rather by catecholamine-induced changes in the conformation of the receptor sites, thus rendering them ineffective.

Basic Pharmacologic Differences

among Beta-Blocking Drugs • More than 100 beta blockers have

been synthesized during the past 35 years and over 30 are available worldwide for clinical use.

•Selectivity for two subgroups of the beta-adrenergic population has also been taken advantage of :beta1 receptors in the heart and beta2 receptors in the peripheral circulation and bronchi.


among Beta-Blocking Drugs

•Fifteen beta blockers are now marketed in the United States for cardiovascular disorders



• Propranolol for angina pectoris, arrhythmias, systemic hypertension, migraine prophylaxis, essential tremor, and hypertrophic cardiomyopathy and for reducing the risk of cardiovascular mortality in survivors of an acute myocardial infarction. 1 and 2



• Atenolol and metoprolol for hypertension and angina and in intravenous and oral formulations for reducing the risk of cardiovascular mortality in survivors of myocardial infarction – specific 1



• Carvedilol both for hypertension and for reducing the rate of disease progression and mortality in patients with mild to moderate congestive heart failure.

•Alpha1 and Beta1,2 blocker

STRUCTURE-ACTIVITY

RELATIONSHIPS

• The chemical structures of most beta blockers have several features in common with the agonist isoproterenol

STRUCTURE-ACTIVITY

RELATIONSHIPS The first beta blocker developed was

dichloisoproterenol – but it has agonist activities that made it not efficacious for clinical use.

STRUCTURE-ACTIVITY

RELATIONSHIPS

•Most beta-blocking drugs exist as pairs of optical isomers and are marketed as racemic mixtures.

•Almost all the beta-blocking activity is found in the negative (-) levorotatory stereoisomer.

STRUCTURE-ACTIVITY

RELATIONSHIPS • The two stereoisomers of beta blockers

are useful for differentiating between the pharmacologic effects of beta blockade vs membrane-stabilizing activity (possessed by both optical forms).

•The positive (+) dextrorotatory stereoisomers of beta-blocking agents have no apparent clinical value, except for d-sotalol, which appears to have type III antiarrhythmic properties.

MEMBRANE-STABILIZING

ACTIVITY

•At concentrations well above therapeutic levels, certain beta blockers have a quinidine-like or local anesthetic membrane-stabilizing effect on the cardiac action potential.

•This issue is highly important in the interpretation of research reports!

MEMBRANE-STABILIZING

ACTIVITY • This property is exhibited equally by the two

stereoisomers of the drug and is unrelated to beta-adrenergic blockade and major therapeutic antiarrhythmic actions.

• There is no evidence that membrane-stabilizing activity is responsible for any direct negative inotropic effect of the beta blockers, since drugs with and without this property may equally depress left ventricular function.

BETA1 SELECTIVITY • Beta-adrenergic blockers may be classified

as selective or nonselective, according to their relative abilities to antagonize the actions of sympathomimetic amines in some tissues at lower doses than those required in other tissues.

• When used in low doses, beta1-selective blocking agents such as acebutolol, betaxolol, bisoprolol, esmolol, atenolol, and metoprolol inhibit cardiac beta1 receptors but have less influence on bronchial and vascular beta adrenoceptors (beta2).

INTRINSIC SYMPATHOMIMETIC ACTIVITY (PARTIAL AGONIST ACTIVITY)

• Certain beta blockers possess intrinsic sympathomimetic activity (ISA, or partial agonist activity) at beta1-adrenoceptor receptor sites, beta2-adrenoceptor receptor sites, or both.

INTRINSIC SYMPATHOMIMETIC ACTIVITY (PARTIAL AGONIST ACTIVITY)

• It is still debated whether the presence of partial agonist activity in a beta blocker constitutes an overall advantage or disadvantage incardiac therapy.

• In general, beta blockers can cause a 20 percent reduction in cardiac output both at rest and with maximal exercise.

• Drugs with partial agonist activity cause less slowing of the heart rate at rest than do propranolol and metoprolol, although the increments in heart rate with exercise are similarly blunted.

ALPHA-ADRENERGIC ACTIVITY

•Labetalol is a beta blocker with antagonistic properties at both alpha and beta adrenoceptors, and has direct vasodilator activity.


• Whether or not concomitant alpha-adrenergic blocking activity is actually advantageous in a beta blocker remains to be determined.

•Carvedilol is another beta blocker having additional alpha-blocking activity. This is a very important therapy in heart failure.


•Carvedilol has antioxidant and antiproliferative activities.

•Carvedilol has been used for the treatment of hypertension and angina pectoris, and it was recently approved as a treatment for patients having symptomatic heart failure.

Epidemiology of Heart Failure in the US

• More deaths from heart failure than from all forms of cancer combined

• 4.7 million symptomatic patients; estimated 10 million in 2037

• Incidence: About 550,000 new cases/year

• Prevalence is 1% between the ages of 50 and 59, progressively increasing to >10% over age 80

*Rich M. J Am Geriatric Soc. 1997;45:968–974.American Heart Association. 2001 Heart and Stroke Statistical Update. 2000.

3.5

4.7

10

0

2

4

6

8

10

12

1991 2000 2037*

Hea

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Etiology and Clinical Characteristics of Heart

Failure

• Coronary artery disease is the most common etiology of heart failure1

• 75% of CHF cases have antecedent hypertension

• Signs of congestion (eg, rales, dyspnea, etc) are not common in most HF patients

• Most patients will die suddenly and unexpectedly despite apparent clinical compensation

Carvedilol

-Blockade

-Blockade

Carbazol

NH

O–CH2–CH–CH2–NH–CH2–CH2O

CH3O

OH

Effects of Sympathetic Activationin Heart Failure

receptors

receptors

receptorsActivation

of RAS

CNS sympathetic outflow

Cardiac sympathetic activity Sympatheticactivity to kidneys+ blood vessels

Myocyte deathIncreased arrhythmias

VasoconstrictionSodium retention

Disease progression

Effect of Carvedilol on Left VentricularEjection Fraction

40

30

20

10

0

RestingLVEF

P=.0001

Carvedilol(n=546)

Placebo(n=293)

Baseline End point Baseline

End point

22%

31%

23%25%

%

Effect of Carvedilol on Progressionin Mild or Moderate Heart Failure

1.0

0.8

0.6

00 50 100 150 200 250 300 350 400 0 50 100 150 200 400

MILD MODERATE

Carvedilol(n=232)

Carvedilol(n=133)

Placebo(n=134)

Placebo(n=145)

P=.008 P=.019Risk reduction48%

Risk reduction39%

Days Days

1.0

0.8

0.6

Eve

nt-

free

su

rviv

al

0

New York Heart AssociationFunctional Classification

I. No limitations of physical activity, no symptoms with ordinary activities

II. Mild/slight limitation, symptoms with ordinary activities

III. Moderate/marked limitation, symptoms with less than ordinary activities

IV. Severe limitation, symptoms of heart failure at rest Symptoms: Dyspnea or fatigue

Improvement in NYHA Classwith Carvedilol in Heart Failure

% o

f P

atie

nts

P=.014

Placebon=130

Carvediloln=124

Pre Post Pre Post

58%

42%

51%

49% 64%

36%

41%

59%

Class III-IV

Class I-II

0

25

50

75

100

Esmolol

• Ultrashort-acting beta blockers may be useful where a short duration of action is desired, as in patients with congestive heart failure. One of these compounds, esmolol, a beta1-selective drug

THERAPEUTIC USES IN CARDIAC

ARRHYTHMIAS • Beta-adrenergic blocking drugs have

become an important treatment modality for various cardiac arrhythmias.

• Although it has long been believed that beta blockers are more effective in treating supraventricular arrhythmias than ventricular arrhythmias, it has only recently been appreciated that this may not be the case.

THERAPEUTIC USES IN CARDIAC

ARRHYTHMIAS One mechanism that may have profound effects on cardiac arrhythmias is the report by your instructor who demonstrated that beta-blockers reduce the sympathetic outflow and discharge mediated by central –CNS activity.

REGRESSION OF LEFT

VENTRICULAR HYPERTROPHY • Left ventricular hypertrophy induced by systemic

arterial hypertension is an independent risk factor for cardiovascular mortality and morbidity.

• Regression of left ventricular hypertrophy with drug therapy is feasible and may improve patient outcome.

• Beta blockers can cause regression of left ventricular hypertrophy, as determined by echocardiography, with or without an associated reduction in blood pressure.

BETA-BLOCKER WITHDRAWAL • After abrupt cessation of chronic

beta-blocker therapy, exacerbation of angina pectoris and, in some cases, acute myocardial infarction and death have been reported.

•Observations made in multiple double-blind randomized trials have confirmed the reality of a propranolol withdrawal reaction.

BETA-BLOCKER WITHDRAWAL

• When the beta blocker is then withdrawn, the increased beta-receptor population readily results in an excessive beta-receptor stimulation that is clinically important when the delivery and use of oxygen are finely balanced, as occurs in ischemic heart disease.

BETA-BLOCKER WITHDRAWAL

• Other suggested mechanisms for the withdrawal reaction include heightened platelet aggregation, an elevation in thyroid hormone activity, and an increase in circulating catecholamines.

HYPOGLYCEMIA AND

HYPERGLYCEMIA

• Severe hypoglycemic reactions have been described during therapy with beta-blocking drugs.

•Some of the patients affected were insulin-dependent diabetics, while others were non-diabetic.

HYPOGLYCEMIA AND

HYPERGLYCEMIA • The enhancement of insulin-induced

hypoglycemia and its hemodynamic consequences may be less with beta1-selective agents, where there is no blocking effect on 2 receptors, or agents with intrinsic sympathomimetic activity that may stimulate beta2 receptors.

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Beta Blockers. BETA–ADRENERGIC BLOCKING DRUGS STRUCTURE-ACTIVITY RELATIONSHIPS...

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