Beta-blockers

Classification of $\beta$-blockers

Drugs in this group are traditionally categorized by their receptor selectivity:

• Cardioselective (selective $\beta_1$-receptor blockers): atenolol, betaxolol, bisoprolol, nebivolol, metoprolol, talinolol.
• Non-selective ($\beta_1$- and $\beta_2$-receptor blockers): the reference drug propranolol (anaprilin, obzidan, inderal), as well as nadolol (corgard), timolol (optimol, arutimol), pindolol (visken), and oxprenolol (trasicor).

Additionally, agents may differ in their mechanism of action, duration of effect, and routes of administration, but it is selectivity that determines their clinical and safety profile.

Pharmacodynamics: cardiac and renal effects

The primary therapeutic effects are mediated by the blockade of $\beta_1$-adrenergic receptors, which are localized predominantly in the heart and kidneys.

Direct action on the heart:

• Negative inotropic effect: weakening of myocardial contractility.
• Negative chronotropic effect: reduction in heart rate through suppression of sinus node automaticity.
• Negative dromotropic effect: inhibition of atrioventricular (AV) conduction.
• Reduction in the automaticity of ectopic pacemaker sites (AV node and Purkinje fibers).

The systemic consequence of these cardiac effects is a decrease in cardiac output and a significant reduction in myocardial oxygen demand, which is critically important in the treatment of coronary artery disease.

Renal effects: Blockade of receptors on renal juxtaglomerular cells leads to an approximately 60% reduction in renin secretion. This impairs angiotensin II formation, eliminating its potent vasoconstrictor action and contributing significantly to a stable hypotensive effect.

Mechanisms of antihypertensive action

Blood pressure reduction during chronic $\beta$-blocker therapy is achieved through a combination of mechanisms:

1. Cardiac component: decreased cardiac output leads primarily to a reduction in systolic pressure.
2. Renal mechanism: suppression of the renin-angiotensin-aldosterone system (RAAS) eliminates vascular spasm, reducing total peripheral vascular resistance (TPVR) and diastolic pressure.
3. Baroreflex restoration: the drugs increase the sensitivity of baroreceptors in the aortic arch and carotid sinus (depressor reflex, which is typically blunted in hypertension).
4. Presynaptic inhibition: blockade of $\beta_2$-receptors on sympathetic nerve terminals reduces norepinephrine release into the synaptic cleft.
5. Additional properties: propranolol possesses central inhibitory activity, whereas nebivolol can stimulate endothelial nitric oxide (NO) production, inducing additional vasodilation.

Vascular tone dynamics during therapy

The administration of non-selective blockers is accompanied by a biphasic change in vascular tone:

• Initial reaction (paradoxical increase in tone): at the start of treatment, the decrease in cardiac output reduces baroreceptor stimulation, which compensatorily activates the sympathetic nervous system. Since vasodilating $\beta_2$-receptors are blocked by the drug, adrenaline stimulates only $\alpha_1$-receptors, causing vasoconstriction.
• Delayed effect: after 1–2 weeks of regular administration, blood vessels dilate, total peripheral vascular resistance drops, and a sustained decrease in blood pressure is established.

Effects of $\beta_2$-receptor blockade and metabolism

Non-selective blockade of smooth muscle $\beta_2$-receptors causes a number of extracardiac effects that frequently lead to adverse reactions. Blood vessel constriction (in skeletal muscle and the coronary bed) and increased bronchial tone with the risk of bronchospasm are observed. Myometrial tone and contractile activity also increase, and gastrointestinal motility is enhanced.

Impact on metabolism:

• Carbohydrate metabolism: glycogenolysis in the liver and skeletal muscles is suppressed, and the hyperglycemic effect of adrenaline is reduced. Blood glucose levels drop, while insulin secretion by pancreatic $\beta$-cells is inhibited.
• Lipid metabolism: blockade of adipocyte receptors inhibits lipolysis, reducing the level of free fatty acids in the blood.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Metabolic component of action: effect on free fatty acid oxidation
• Mechanism of coronary blood flow redistribution (reverse "steal" phenomenon)
• The effect of propranolol on central regulation centers of vascular tone
• Antiarrhythmic effect: detailed analysis of the impact on Purkinje fibers and the AV node
• Specific properties of nebivolol and the role of nitric oxide (NO) in vasodilation

Other topics in the section "Drugs Acting on Adrenergic Synapses"

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