How are beta (beta) blockers metabolized and eliminated?

From the Guidelines

Beta blockers are primarily cleared from the body through a combination of hepatic metabolism and renal excretion, with the specific clearance pathway varying between different beta blockers. Most beta blockers undergo extensive first-pass metabolism in the liver, where they are broken down by various enzymes, particularly cytochrome P450 enzymes (especially CYP2D6) 1. Some beta blockers like metoprolol, and carvedilol are highly metabolized by the liver, resulting in metabolites that are then excreted in urine. Others like atenolol, have limited hepatic metabolism and are predominantly eliminated unchanged through the kidneys, as indicated by their renal elimination half-life of 6-7 hours 1. The elimination half-life varies significantly between different beta blockers - metoprolol has a half-life of 3-4 hours, while atenolol's half-life is 6-7 hours, and bisoprolol's is 9-12 hours 1.

This variation in clearance pathways has important clinical implications, particularly for patients with liver or kidney dysfunction. For instance, in patients with hepatic impairment, dose adjustments may be necessary for highly liver-metabolized beta blockers, while in patients with renal dysfunction, dose reductions are typically needed for renally cleared agents like atenolol 1. It is essential to consider these factors when prescribing beta blockers to ensure optimal therapy and minimize potential adverse effects. The most recent guidelines support the use of beta blockers in patients with atrial fibrillation, with careful consideration of the individual patient's renal and hepatic function 1.

Key points to consider when prescribing beta blockers include:

• Hepatic metabolism: metoprolol, carvedilol
• Renal excretion: atenolol, nadolol
• Variable elimination half-life: 3-24 hours
• Dose adjustments necessary in patients with liver or kidney dysfunction
• Careful consideration of individual patient factors, such as renal and hepatic function, is crucial when prescribing beta blockers 1.

From the FDA Drug Label

Metabolism Metoprolol is primarily metabolized by CYP2D6. Elimination Elimination of metoprolol is mainly by biotransformation in the liver The mean elimination half-life of metoprolol is 3 to 4 hours; in poor CYP2D6 metabolizers the half-life may be 7 to 9 hours. Approximately 95% of the dose can be recovered in urine. In most subjects (extensive metabolizers), less than 10% of an intravenous dose are excreted as unchanged drug in the urine In poor metabolizers, up to 30% or 40% of oral or intravenous doses, respectively, may be excreted unchanged; the rest is excreted by the kidneys as metabolites that appear to have no beta blocking activity.

Beta blockers, such as metoprolol, are cleared mainly by biotransformation in the liver through the CYP2D6 enzyme. The elimination half-life of metoprolol is approximately 3 to 4 hours in extensive metabolizers, but may be longer in poor metabolizers. Most of the dose is recovered in urine, with a small percentage excreted unchanged and the rest excreted as metabolites with no beta blocking activity 2.

Metabolism and Elimination: Propranolol is extensively metabolized with most metabolites appearing in the urine. Propranolol is metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), N-dealkylation followed by further side-chain oxidation, and direct glucuronidation The four major metabolites are propranolol glucuronide, naphthyloxylactic acid and glucuronic acid, and sulfate conjugates of 4-hydroxy propranolol In-vitro studies have indicated that the aromatic hydroxylation of propranolol is catalyzed mainly by polymorphic CYP2D6.

Similarly, propranolol is also extensively metabolized, with most metabolites appearing in the urine, and is metabolized through three primary routes including aromatic hydroxylation, N-dealkylation, and direct glucuronidation 3.

From the Research

Clearance of Beta Blockers

• Beta blockers can be cleared through the liver or kidneys, depending on their lipophilicity 4, 5, 6
• Lipophilic beta blockers, such as propranolol and metoprolol, are cleared by the liver and undergo hepatic 'first-pass' metabolism 6
• Hydrophilic beta blockers, such as atenolol and sotalol, are cleared by the kidneys unchanged 4, 6
• Some beta blockers, such as bisoprolol and pindolol, are cleared partly by the liver and partly by the kidney 4, 6

Factors Affecting Clearance

• Lipid solubility is an important factor in determining the clearance of beta blockers 6
• Impaired liver or kidney function can significantly influence the rate of elimination of beta blockers 4, 5, 7
• Drug interactions with other agents that affect hepatic enzymes or renal function can also alter the clearance of beta blockers 6, 8

Clinical Implications

• The clearance of beta blockers can affect their duration of action and therapeutic efficacy 4, 5
• Dose adjustments may be necessary in patients with impaired liver or kidney function 4, 7
• Therapeutic substitution among beta blockers requires careful monitoring and retitration to assure therapeutic equivalence 8