Labetalol is an antihypertensive agent with both alpha- and beta-adrenergic receptor blocking activity. Labetalol has been linked to several cases of clinically apparent drug induced liver disease, some of which have been severe and even fatal.
Labetalol (la bayt' a lol) is a unique antihypertensive agent that has both alpha- and beta-adrenergic receptor blocking activity. The beta-blockade is nonselective, acting on both beta-1 and beta-2 adrenergic receptors. Beta-1 adrenergic blockade reduces the heart rate and myocardial contractility by slowing the AV conduction and suppressing automaticity. Beta-2 blockade affects peripheral vascular resistance and can cause bronchospasm and hypoglycemia. The alpha blockade is largely directed at the alpha-1 receptors and leads to relaxation of arterial smooth muscle and vasodilation. Labetalol was approved for use in the United States in 1984 and currently more than 2 million prescriptions are filled yearly. Current indications for labetalol are in the therapy of hypertension alone or in combination with other agents. Parenteral forms of labetalol are indicated for therapy of hypertensive emergencies, severe hypertension and pheochromocytoma. Labetalol is available in tablets of 100, 200 and 300 mg in generic formulations and under the trade name Trandate. Parenteral formulations for intravenous administration are also available. The typical oral dose of labetalol in adults is 100 mg twice daily initially with subsequent dose adjustments based upon clinical response and tolerance to a range of 200 to 1200 mg daily. Common side effects include bradycardia, hypotension, fatigue, dizziness, orthostatic hypotension, depression, memory loss, impotence, weight gain and diarrhea. As with all beta-blockers, sudden withdrawal can trigger rebound hypertension.
Labetalol therapy has been associated with mild-to-moderate elevations of serum aminotransferase levels in up to 8% of patients, a rate far higher than with other beta-blockers. These elevations, however, are usually transient, not associated with symptoms, and can resolve even with continuation of therapy. Idiosyncratic, clinically apparent liver injury from labetalol is rare, but several instances have been reported as isolated case reports as well as in case series. The liver injury typically arises after 4 to 16 weeks of therapy and the pattern of serum enzyme elevations is usually hepatocellular with an acute hepatitis-like onset and course. Immunoallergic features (rash, fever, eosinophilia) are uncommon as is autoantibody formation. While most cases resolve rapidly once labetalol is stopped, there have been several instances of acute liver failure and death or need for emergency liver transplantation associated with labetalol use, particularly if there is a delay in its discontinuation. Labetalol is the beta-blocker with the highest apparent risk for causing clinically apparent liver injury.
Mechanism of Injury
The mechanism of labetalol hepatic injury is unknown, but it believed to be due to metabolic idiosyncratic disposition of the agent, which is known to be extensively metabolized in the liver. There is little evidence for hypersensitivity as the cause of injury.
Outcome and Management
Severity ranges from minimal and transient ALT elevations to clinically apparent acute hepatitis with jaundice to acute liver failure and death or need for liver transplantation. No instances of chronic hepatic injury or vanishing bile duct syndrome attributable to labetalol have been reported. Rechallenge is usually followed by recurrence of liver injury and should be avoided. There is little information on whether there is cross reactivity of the liver injury with other beta-blockers and patients who are switched to other agents should be carefully monitored.
|Medication:||Labetalol (200 mg daily)|
|Severity:||2+ (initially); 5+ (upon reexposure); fatal|
|Recovery:||1 month after initial episode|
|Weeks After Starting||Weeks After Stopping||AST* (U/L)||Alk P* (U/L)||Bilirubin* (mg/dL)||Other|
|Patient was lost to follow up for 6 months|
|19||6||225||266||16.8||Death from liver failure|
|DRUG||CAS REGISTRY NUMBER||MOLECULAR FORMULA||STRUCTURE|
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