Classification of beta-blockers
The division into generations is based on $\beta_1$-receptor selectivity and the presence of additional vasodilating properties.
- 1st generation (non-selective). Block both $\beta_1$- and $\beta_2$-receptors. A typical representative is propranolol, which has high lipophilicity and membrane-stabilizing activity (MSA). This group also includes nadolol (hydrophilic, without MSA) and pindolol (amphiphilic, with intrinsic sympathomimetic activity — ISA).
- 2nd generation (cardioselective). Selectively act on $\beta_1$-receptors. These include metoprolol (lipophilic, weak MSA), atenolol (hydrophilic, no additional properties), bisoprolol (amphiphilic, high selectivity), and betaxolol.
- 3rd generation (with vasodilating properties). Possess the ability to dilate blood vessels. Nebivolol stimulates nitric oxide (NO) production. Carvedilol blocks $\alpha_1$-adrenergic receptors. Celiprolol has a complex mechanism: $\alpha_2$-receptor blockade, $\beta_2$-receptor stimulation, and NO release.
Lipophilicity and hydrophilicity
Physicochemical properties determine the pharmacokinetics of drugs.
- Lipophilic (e.g., propranolol, metoprolol, carvedilol). Well absorbed, but have low bioavailability due to a pronounced first-pass hepatic effect. Protein-bound, metabolized in the liver. Easily cross the blood-brain barrier (BBB), which can cause central nervous system side effects (depression, sleep disturbances).
- Hydrophilic (atenolol, nadolol). Incompletely absorbed, hardly metabolized in the liver, excreted by the kidneys. Do not cross the BBB.
- Amphiphilic (bisoprolol, pindolol, celiprolol). Soluble in both water and lipids. Have a balanced elimination pathway (liver + kidneys).
Dosing and metabolism features
When prescribing beta-blockers, the condition of excretory organs must be considered:
- In liver disease or reduced hepatic blood flow, the dose of lipophilic drugs must be adjusted.
- In renal impairment (and in elderly patients), a dose reduction of hydrophilic agents is required as they can accumulate (cumulate).
- Pharmacogenetics is important: the metabolism of certain lipophilic drugs (metoprolol, carvedilol, nebivolol) depends on the CYP2D6 enzyme. Polymorphism of this gene can lead to slowed metabolism, increased bioavailability, and an increased risk of side effects. In such cases, the dose should be reduced.
The duration of action depends on the half-life ($T_{1/2}$). Long-acting drugs (bisoprolol, atenolol, carvedilol, nadolol, betaxolol) are taken 1–2 times a day, while short- and intermediate-acting ones (propranolol, metoprolol) are taken more frequently. Esmolol has a $T_{1/2}$ of about 10 minutes and is used to manage acute conditions.
Briefly: answers to topical questions
Which drugs belong to the 1st generation of beta-blockers?
The 1st generation of non-selective beta-blockers includes propranolol, nadolol, and pindolol.
- Propranolol is the reference drug of the group, possessing membrane-stabilizing activity and high lipophilicity.
- Nadolol is a hydrophilic drug that lacks membrane-stabilizing and intrinsic sympathomimetic activity.
- Pindolol is an amphiphilic drug combining lipophilicity and hydrophilicity, with intrinsic sympathomimetic activity.
Which beta-blockers possess intrinsic sympathomimetic activity (ISA)?
Intrinsic sympathomimetic activity (ISA) is possessed by the following beta-blockers: pindolol and celiprolol.
- Pindolol is a 1st-generation non-selective beta-blocker characterized by amphiphilic properties (combining lipophilicity and hydrophilicity) and marked ISA.
- Celiprolol is a 3rd-generation beta-blocker with vasodilating properties, in which ISA is manifested through beta2-receptor stimulation combined with alpha2-receptor blockade and nitric oxide release.
What central nervous system side effects are caused by lipophilic beta-blockers?
Lipophilic beta-blockers can cause central side effects because lipophilicity is associated with penetration across the blood-brain barrier.
CNS side effects include:
- Lethargy and drowsiness.
- Sleep disturbances, including nightmares.
- Depressive states.
- Confusion.
- Central dyspeptic disorders — nausea and vomiting.
Which cardioselective beta-blockers belong to the 2nd generation?
The 2nd generation of cardioselective beta1-blockers includes the following drugs:
- Metoprolol is a lipophilic drug whose membrane-stabilizing activity is manifested only at high doses.
- Atenolol is a hydrophilic drug with low lipophilicity, completely devoid of additional properties (no MSA or ISA).
- Bisoprolol is an amphiphilic drug distinguished by high cardioselectivity.
- Betaxolol is a lipophilic drug that possesses weak membrane-stabilizing activity.
What are the indications for the use of beta-blockers?
Sources indicate the following areas of application for beta-blockers:
- Arterial hypertension.
- Chronic heart failure; for nebivolol, use is indicated in mild to moderate CHF as part of complex therapy.
- Stable angina; for nebivolol, an advantage is noted due to coronary vasodilation via NO.
- Tachyarrhythmias — ventricular and supraventricular.
- Psychostimulant poisoning — in severe tachycardia, beta-blockers are used, with esmolol being preferred over propranolol; use only in combination with nitrates.
- After cessation of massive stimulant and cocaine intake — propranolol is used to reduce anxiety, tachycardia, normalize blood pressure, and improve sleep.
Class and exam questions
What is the difference between the 1st and 2nd generations of beta-blockers?
The first generation (e.g., propranolol) are non-selective, blocking both β1- and β2-receptors. The second generation (metoprolol, bisoprolol) are cardioselective, predominantly blocking β1-receptors.
Why should the dose of atenolol be reduced in renal failure?
Atenolol is a hydrophilic drug; it is eliminated from the body primarily by the kidneys in unchanged form. With reduced renal function, it can accumulate, causing overdose.
How do 3rd-generation drugs affect blood vessels?
They dilate blood vessels (vasodilation). Mechanisms vary: nebivolol stimulates nitric oxide release, while carvedilol blocks α1-adrenergic receptors.
What is the «first-pass» effect?
This is intensive drug metabolism in the liver immediately after absorption from the intestine, before reaching the systemic circulation. Because of this, lipophilic drugs have low bioavailability.
What else to study on this topic
- Intrinsic sympathomimetic activity (ISA)
- Membrane-stabilizing action
- Genetic polymorphism of enzymes (CYP2D6)
- Effects of beta-blockers on hemodynamics and hepatic blood flow during course treatment
- Metabolic effects (impact on insulin resistance and lipid profile)
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