Beta Blockers

Mechanism of Action

β-adrenoreceptors are a subtype of G-protein-coupled receptors (GPCRs). When endogenous catecholamines (adrenaline and noradrenaline) bind to these receptors, the  Gs-protein is de-coupled, leading to:

1. Activation of adenylyl cyclase

2. Conversion of ATP to cyclic AMP (cAMP)

3. Activation of downstream intracellular pathways

There are three β-adrenoreceptor subtypes: β1, β2, and β3. This article focuses on β1 and β2 receptors, which are most clinically relevant to cardiovascular pharmacology.

Beta-blockers exert their therapeutic effects primarily by antagonising β1 receptors in the heart, reducing heart rate, myocardial contractility, and oxygen demand.

Cardiac myocytes express both β1 and β2 receptors, with β1 receptors predominating.

Activation of β1 receptors increases intracellular cAMP, which:

• Activates protein kinase A (PKA)

• Phosphorylates L-type calcium channels

• Increases calcium influx into the cell

Calcium entry triggers calcium-induced calcium release (CICR) from the sarcoplasmic reticulum via ryanodine receptors, increasing intracellular calcium available to bind troponin C, thereby enhancing myocardial contractility (positive inotropy).

By blocking β1 receptors:

• cAMP production is reduced

• Calcium influx decreases

• Heart rate (negative chronotropy) and contractility (negative inotropy) are reduced

At the sinoatrial node, beta-blockers reduce the slope of the pacemaker potential, slowing impulse generation. This explains their role in rate control for arrhythmias, such as atrial fibrillation.

Pharmacodynamics

Beta-blockers are classified as:

• β1-selective (cardioselective)

• Non-selective (β1 and β2 blockade)

The loss of β1 selectivity increases the likelihood of β2-mediated adverse effects, such as bronchospasm and peripheral vasoconstriction.

Pharmacokinetics

• Beta-blockers are well absorbed orally, but first-pass metabolism may reduce bioavailability

• Lipophilic agents (e.g. propranolol, metoprolol, labetalol):

  • Hepatically metabolised

  • Greater CNS penetration → sleep disturbances

• Hydrophilic agents (e.g. atenolol):

  • Renally excreted

  • Lower CNS side-effect profile

Dose adjustment may be required in renal or hepatic impairment, depending on drug choice. Carvedilol is contraindicated in patients with clinically manifest hepatic impairment.

Cautions and Contraindications

Abrupt withdrawal of beta blockers may cause rebound tachycardia and hypertension due to β-receptor upregulation. Conversely beta blockers are contraindicated in symptomatic bradycardia (often withheld if HR <50 bpm, contraindicated if HR <45bpm). Specifically, in liver cirrhosis carvedilol levels increase by about 80% due to reduced first-pass metabolism; therefore, it is contraindicated in those with significant liver impairment. Other cautions and contraindications are listed below:

• Hypoglycaemia masking: β-blockers block adrenergic warning signs (e.g. tremor, tachycardia)

• Asthma/COPD: β2 blockade may precipitate bronchospasm, especially with non-selective agents

• Peripheral arterial disease: Reduced β2-mediated vasodilation may worsen claudication

• Psoriasis: beta blockers can exacerbate pre-existing psoriasis

Adverse Effects

Adverse effects reflect blockade of β receptors in non-cardiac tissues and include the following:

• Bronchospasm (β2 blockade)

• Bradycardia

• Cold extremities and Raynaud’s phenomenon

• Hypotension

• Fatigue and dizziness

• Sleep disturbance (lipophilic drugs) including nightmares

• Erectile dysfunction

Interactions

Beta-blockers have several important drug interactions that may affect respiratory and cardiovascular function. Non-selective beta-blockers can antagonise β₂-mediated bronchodilation, reducing the effectiveness of salbutamol and potentially precipitating bronchospasm.

Additive cardiovascular effects may occur when beta-blockers are used with verapamil or diltiazem, increasing the risk of severe bradycardia or atrioventricular block. Beta-blockers may also worsen rebound hypertension following clonidine withdrawal, and their antihypertensive effect can be reduced by NSAIDs such as ibuprofen and indomethacin.

Metabolic interactions are also significant. Nebivolol, carvedilol and metoprolol are metabolised by CYP2D6, and exposure may be increased by CYP2D6 inhibitors including paroxetine, fluoxetine and quinidine. In contrast, rifampicin markedly reduces carvedilol plasma concentrations via enzyme induction. Propranolol increases rizatriptan exposure by approximately 70–80% likely due to inhibition of MAO-A–mediated first-pass metabolism, therefore, when used together, a reduced rizatriptan dose of 5 mg is recommended.

References

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