Class II; Beta Blockers (BBL)

BBL are a heterogeneous group. What they have in common is competitive antagonistic action on beta-adrenoreceptors.

• As a basic principle, BBL antagonize adrenergic stimulation of beta-adrenoreceptors (B-AR) in a competitive way through their structural similarities to catecholamines.

• The heart contains B1-AR (beta1-adrenoreceptors) in excess to B2-AR in a 70/30 ratio. Due to excess B1-AR compared to B2-AR in the heart, B1-selectivity is often referred to as "cardio"-selectivity.

• Adrenoreceptors on smooth muscle cells in arterial walls mediate vasoconstriction (A2-AR) and vasodilation (B2-AR).

• Beta-blocker therapy in coronary artery disease also leads to uncontested survival benefit, the cardioprotective mechanism largely due to rate reduction.

• ß2-Agonists favor the development of VF by promoting calcium transients or hypokalemia. (see the picture.) BBL prevent this mechanism. → Primary and secondary prevention of SCD → Prevention of SCD in patients with CHF & post MI

• Beta-blockage resulted in an approximately 30% increased risk of NOD "new onset diabetes" compared to placebo. (Pepine CJ, Cooper-DeHoff RM. Cardiovascular therapies and risk for development of diabetes. J Am Coll Cardiol 2004; 44: 509-12.) Receptor selectivity is important, with decreasing negative metabolic impact with increasing B1-selectivtiy. (Cooper-DeHoff RM, Pacanowski MA, Pepine CJ. Cardiovascular therapies and associated glucose homeostasis. J Am Coll Card 2009; 53: S28-34.)

(Chapter 24 ANTIARRHYTHMIC DRUGS Geoffrey W. Abbott and Roberto Levi)

Famous Effects

Beta-blockage decreases spontaneous depolarization of pacemakers, causes prolongation of sinus node cycle length, atrioventricular conduction times and atrioventricular refractory period, a class II anti-arrhythmic activity. Other antiarrhythmic mechanisms are reduction of myocardial ischaemia and catecholamine-induced hypokalaemia.

• When you treat a HF patient in CCU, remember that BBL decrease cardiac output. So in severe systolic dysfunction, start BBL with caution and very small dosage (Bisoprolol 1.25mg), and then raise it gradually.

Heterogeneity of Betablockers

First-generation beta-blockers are non-selective agents. Second-generation agents bind more to B1- compared to B2-AR, a selectivity that is different for the different agents available. Third-generation or vasodilating beta-blockers are structurally different from classic BBL, leading to A1-blocking, B2-stimulating, NO-generating, anti-oxidant and/or anti-inflammatory properties. (Triposkiadis F, ... , Butler J. The Sympathetic nervous system in heart failure. J Am Coll Cardiol 2009; 54: 1747-62.)

(Table from; Beta-blockers: focus on mechanism of action; Which beta-blocker, when and why? Frauke GORRE1 MD; Hans VANDEKERCKHOVE2 MD, Acta cardiologica October 2010)

Intrinsic sympathomimetic activity (ISA); BBL with ISA are agents having partial agonist (thus catecholamine) activity on certain B-AR2. B1-ISA on the heart is most evident at rest with absent negative chronotropic effects in the resting state. A partial B2-ISA (e.g. nebivolol) induces vasodilation by acting on smooth muscle cells of the peripheral vessels. Electrically, BBL with ISA lower the threshold for ventricular fibrillation. Agents with ISA can lower blood pressure at rest while preserving cardiac output.

Metabolism ; Lipophylic agents undergo hepatic clearance, have long half-lives and penetrate the blood brain barrier, causing more central neurologic side effects. Hydrophilic products undergo renal clearance, have shorter half-lives resulting in multiple-day dosage and only penetrate the blood brain barrier when doses are high.

Antihypertensive effect

• Antihypertensive mechanisms and effect differ according to receptor-specificity and ISA, where differences in duration of action also have to be considered.

• As a basic mechanism, a cardioinhibitory effect reduces cardiac output. This in turn is followed by a baroreflex-mediated proportional increase in peripheral vascular tone to maintain blood pressure. This "vascular resistance" is described in B1- selective as well as non-selective agents, thus not depending on B2-blocking action. (Cruickshank JM. Beta-blockers in clinical practice, Chapter 2-7. Churchill Livingstone, New York, 1988.)

• Antihypertensive activity is dependent on ISA, with reduced lowering of blood pressure at rest but not during exercise-induced sympathetic activation. (Leonetti G, ... , Zanchetti A. Does beta 1-selective agonistic activity interfere with the antihypertensive efficacy of beta1-selective blocking agents? J Hypertension 1985; 3(3): S243-5.)

• The vasodilatory activity leads to improvement of endothelial function and antihypertensive action with little effect on cardiac output.

Which beta-blocker, in what type of heart failure?

• In heart failure with reduced ejection fraction, three molecules proved a reduction of about 30% in mortality and/or hospitalization: long-acting metoprolol succinate (MERIT-HF Study), bisoprolol (CIBIS II Investigators) and carvedilol (COPERNICUS Study). The beneficial effect is due to B1-blocking and/or vasodilating actions.

• Agents with B1-ISA and non-selective molecules have a less favourable profile. B2-blockage leads to peripheral vasoconstriction with increased afterload due to unopposed alfa-action. The beneficial results of carvedilol, although being a non-selective molecule, can be explained by its alfa lytic activity.

• In this heart failure population there is a possible role for Nebivolol (selective and vasodilating).

Carvedilol

• A nonselective - and a1-adrenergic antagonist that also is targeting Intracellular Calcium Handling.

• Blocks IKur, IKr, ICaL, Ito1, IKs ion channels & exerts antioxidant & has antiproliferative effects.

• Suppresses sarcoplasmic reticulum Ca2+ release → antiarrhythmic effects in HF patients

• Prevent catecholaminergic polymorphic ventricular tachycardia (CPVT) without causing significant bradycardia.

BBL in AF

• Efficacy to prevent AF is moderate, specially if AF develops during exercise or stress.

• In paroxysmal AF, do not start a BBL for vagally mediated AF. When there is sinus bradycardia and AF begin at rest, it could be vagally mediated AF.

• In slow persistent AF, when you don't want to decrease ventricular rate at rest, I recommend you try a BBL with ISA feature.

• In paroxysmal AF, after starting a BBL the patient could be unaware of recurrent AF due to reduce ventricular rate. If there is anticoagulation indications (Chadsvasc>1), do not stop warfarin even though the patient is asymptomatic.

 

 

Compilation by Dr. Samad Ali Moradi, According to heart journals, finnish cardiology reference book & author work experience.