LiverTox: Clinical and Research Information on Drug-Induced Liver Injury

The beta-adrenergic receptor antagonists (beta-blockers) are a family of agents that are widely used to treat hypertension, angina pectoris and cardiac arrhythmias. Beta-blockers are also used for migraine prophylaxis, to treat anxiety, to prevent essential tremor, and to block the side effects of hyperthyroidism. Nonspecific beta-blockers are also recommended for treatment of portal hypertension in patients with cirrhosis. The beta-blockers act by competing with beta-adrenergic agonists (such as epinephrine and norepinephrine) for beta-receptor sites. Beta-blockers are often categorized as “selective” or “non-selective” based upon whether they block both beta-1 receptors that are predominantly present in cardiac muscle and beta-2 receptors found in bronchial and smooth muscles. Beta-1 selective blockers are preferred for therapy of heart disease, whereas the nonselective beta-blockers are preferred as therapy to prevent recurrent variceal hemorrhage in patients with cirrhosis and portal hypertension. Nonselective beta-blockers (common brand name and the year of their approval for use in the United States) include propranolol (Inderal, 1967), nadolol (CorGard, 1979), pindolol (Visken, 1982), labetalol (Normodyne, Trandate, 1984), penbutolol (Levatol, 1987), sotalol (Betapace, 1992), carvedilol (Coreg, 1995), and timolol (Biocarden, 1995). Beta-1 selective blockers include metoprolol (Lopressor, Toprol, 1978), atenolol (Temormin, 1981), acebutolol (Sectral, 1984), betaxolol (Kerlone, 1985), esmolol (Brevibloc, 1986), bisoprolol (Zebeta, 1992) and nebivolol (Bystolic, 2008). Beta-blockers are some of the most frequently used medications in medicine and are usually well tolerated. Common side effects are those that are caused by the beta-adrenergic blockade and include bradycardia, fatigue, dizziness, depression, memory loss, insomnia, impotence, cold limbs and, less commonly, severe hypotension, heart failure and acute bronchospasm. Beta-blockers have been associated with a minimally increased rate of serum aminotransferase elevations and have rarely been associated with clinically apparent liver injury. Isolated case reports of idiosyncratic hepatotoxicity due to beta-blockers have been published, but there have been few case series. The case reports that have been published provide a general pattern of injury with a typical time to onset of 2 to 24 weeks and a hepatocellular pattern of serum enzyme elevations. Most cases have been mild and self-limiting, but fatal cases have been reported. Switching from one beta-blocker to another has not always resulted in recurrence of liver injury, although there have been only rare reports of such cross challenges. Most information on hepatotoxicity is available on the commonly used beta-blockers which include (and the number of prescriptions filled in 2007 for each): atenolol (42 million), metoprolol (27 million), propranolol (6.1 million), bisoprolol (4.3 million), carvedilol (2.9 million), labetalol (2.6 million), and nadolol (1.8 million). Labetalol and acebutolol have been associated with the most numbers of published cases (likelihood scores "C"), which is particularly striking in view of their relative frequency of use. Rare cases have been linked to atenolol, carvedilol and metoprolol therapy (likelihood scores "D"). The different beta-blockers are discussed separately with individual clinical cases, but references are combined and given at the end of this introductory section.