Background

The beta adrenergic agonists are potent bronchodilators that are widely used in the management of bronchial asthma. These agents act by engaging the beta-2 adrenergic receptors on smooth muscle of bronchial tissue, relieving bronchospasm and reducing airway resistance. They also act on smooth muscle of the vascular system, intestines and uterus. Common forms of beta adrenergic agonists include albuterol, bitolterol, fenoterol, formoterol, levalbuterol, metaproterenol, salmeterol, pirbuterol and terbutaline, which all have similar mechanisms of action, chemical structure, side effects and efficacy, but somewhat different pharmacokinetics allowing for differences in dosing regimens and duration of action. Most of these agents are administered by inhalation (alone or in combination with other bronchodilators or corticosteroids), with only albuterol and terbutaline being available in oral forms in the United States. Albuterol (also known as salbutamol) is available in generic forms and under the brand names of Proventil and Ventolin as 2 and 4 mg tablets as well as in aerosol and syrup solutions. The recommended regimen of albuterol is 2 to 4 mg orally 3 to 4 times a day. Sustained release formulations are available for twice daily dosing (4 and 8 mg). Salmeterol is available as an inhalation powder in generic forms and under the brand name of Serevent Diskus. The typical dosage is one inhalation (50 mcg) twice daily and it is recommended to be given with corticosteroids only. Systemic absorption is minimal. Terbutaline is available in generic forms and under the brand name of Brethine in tablets of 2.5 and 5 mg, the usual adult dosage being 5 mg three times daily. These oral forms of beta adrenergic agonists are approved as means of prevention and reversal of bronchospasm and are used largely in the therapy of asthma. Terbutaline is also available in parenteral formulations for use in acute bronchospasm and has also been used as therapy of premature labor. Common side effects of the beta adrenergic agonists include dizziness, headache, nervousness, tachycardia, palpitations, nausea and diaphoresis, largely due to their beta adrenergic effects on other organs. Rare, potentially severe adverse events include cardiovascular events, paradoxical worsening of asthma and acute hypersensitivity reactions.

Hepatotoxicity

Prospective studies have shown that ALT elevations occur in less than 1% of patients receiving long term oral therapy with typical beta adrenergic bronchodilators, but instances of clinically apparent liver injury have not been reported in any detail. However, several cases of acute elevations in serum aminotransferase levels have been described in pregnant women receiving high doses of beta adrenergic agents intravenously for prevention or control of premature labor (Case 1). Serum alkaline phosphatase, GGT and bilirubin levels are generally normal or within the normal range for later stages of pregnancy. The serum aminotransferase elevations are usually asymptomatic, but may be associated with nausea and right upper quadrant pain. Bilirubin elevations are minimal and cases with jaundice have not been reported. The abnormalities resolve promptly (within 1 to 3 weeks) upon stopping therapy and have not been associated with fatalities or chronic liver injury.

Likelihood score, oral beta-adrenergic agonists: E (unlikely cause of clinically apparent liver injury).

Likelihood score, intravenous terbutaline: C[H] (high doses of intravenous terbutaline are a probable cause of acute serum aminotransferase elevations that can be symptomatic and clinically apparent).

Mechanism of Hepatotoxicity

The mechanism of hepatic injury due to beta adrenergic agents is probably a direct hepatotoxicity associated with high dose, particularly intravenous, therapy.

Outcome and Management

Typically, liver enzyme abnormalities resolve rapidly after stopping beta adrenergic agents. No cases of fulminant hepatitis or chronic liver injury have been convincingly linked to use of these agents. The hepatotoxicity associated with high dose therapy is rapidly reversed and cases of recurrence upon reexposure to typical oral doses have not been reported.

Drug Class: Antiasthmatic Agents, Beta-2 Adrenergic Agonists

Key Points

Laboratory Values

* Values estimated from Figure 1, Patient 2.

Comment

The differential diagnosis of liver disease during pregnancy is challenging and includes viral hepatitis, cholestasis of pregnancy, acute fatty liver of pregnancy and drug induced liver disease. This patient was initially thought to have cholestasis of pregnancy with itching and abnormal serum enzyme elevations. However, the height of the ALT elevations with normal alkaline phosphatase levels and bilirubin were atypical of cholestasis of pregnancy and the role of terbutaline was considered. Acute fatty liver of pregnancy was excluded by the normal ultrasound. Stopping terbutaline led to a prompt decrease in ALT levels, but also triggered premature labor and delivery. The absence of bilirubin and alkaline phosphatase elevations supported the role of terbutaline induced liver injury in this patient. Asymptomatic but prominent elevations in serum aminotransferase levels have been reported with use of high doses of beta adrenergic agents in pregnant women.