Theophylline is a methylxanthine that once was used widely for the treatment of asthma. Intravenous infusions of aminophylline, the ethylenediamine salt of theophylline, are sometimes used to treat bronchospasm, congestive heart failure, and neonatal apnea. Theophylline is commonly prescribed orally in sustained-release preparations.

1. The exact mechanism of toxicity is not known. Theophylline is an antagonist of adenosine receptors, and it inhibits phosphodiesterase at high levels, increasing intracellular cyclic adenosine monophosphate (cAMP). It also is known to release endogenous catecholamines at therapeutic concentrations.
2. Pharmacokinetics. Absorption may be delayed with sustained-release preparations. The volume of distribution is approximately 0.5 L/kg. The normal elimination half-life is 4-6 hours; this may be doubled by illnesses (eg, liver disease, congestive heart failure, influenza) or interacting drugs (eg, erythromycin, cimetidine) that slow hepatic metabolism and may increase to as much as 20 hours after overdose.

An acute single dose of 8-10 mg/kg can raise the serum level by up to 15-20 mg/L, depending on the rate of absorption. Acute oral overdose of more than 50 mg/kg may potentially result in a level above 100 mg/L and severe toxicity.

Two distinct syndromes of intoxication may occur, depending on whether the exposure is acute or chronic.

1. Acute single overdose is usually a result of a suicide attempt or accidental childhood ingestion but also may be caused by accidental or iatrogenic misuse (therapeutic overdose).
   1. Usual manifestations include vomiting (sometimes hematemesis), tremor, anxiety, and tachycardia. Metabolic effects include pronounced hypokalemia, hypophosphatemia, hyperglycemia, and metabolic acidosis.
   2. With serum levels above 90-100 mg/L, hypotension, ventricular arrhythmias, and seizures are common; status epilepticus is frequently resistant to anticonvulsant drugs.
   3. Seizures and other manifestations of severe toxicity may be delayed 12-16 hours or more after ingestion, in part owing to delayed absorption of drug from sustained-release preparations.
2. Chronic intoxication occurs when excessive doses are administered repeatedly over 24 hours or longer or when intercurrent illness or an interacting drug interferes with the hepatic metabolism of theophylline. The usual victims are very young infants and elderly patients, especially those with chronic obstructive lung disease.
   1. Vomiting may occur but is not as common as in acute overdose. Tachycardia is common, but hypotension is rare. Metabolic effects such as hypokalemia and hyperglycemia do not occur.
   2. Seizures may occur with lower serum levels (eg, 40-60 mg/L) and have been reported with levels as low as 20 mg/L.

Is based on a history of ingestion or the presence of tremor, tachycardia, and other manifestations in a patient known to be on theophylline. Hypokalemia strongly suggests an acute overdose rather than chronic intoxication.

1. Specific levels. Serum theophylline levels are essential for diagnosis and determination of emergency treatment. After acute oral overdose, obtain repeated levels every 2-4 hours; single determinations are not sufficient because continued absorption from sustained-release preparations may result in peak levels 12-16 hours or longer after ingestion.
   1. Levels of less than 80-100 mg/L after acute overdose usually are not associated with severe symptoms, such as seizures and ventricular arrhythmias.
   2. However, with chronic intoxication, severe toxicity may occur with levels of 40-60 mg/L. Note: Acute caffeine overdose will cause a similar clinical picture and produce falsely elevated theophylline concentrations with some older commercial immunoassays (check with the clinical laboratory).
   3. Many hospital laboratories no longer offer theophylline testing due to reduced demand.
2. Other useful laboratory studies include electrolytes, glucose, BUN, creatinine, hepatic function tests, and ECG monitoring.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary.
   2. Treat seizures, arrhythmias and hypotension if they occur. Tachyarrhythmias and hypotension are best treated with a beta-adrenergic agent (see Item B below).
   3. Hypokalemia is caused by intracellular movement of potassium and does not reflect a significant total body deficit; it usually resolves spontaneously without aggressive treatment.
   4. Monitor vital signs, ECG, and serial theophylline levels for at least 16-18 hours after a significant oral overdose.
2. Specific drugs and antidotes. Hypotension, tachycardia, and ventricular arrhythmias are caused primarily by excessive beta-adrenergic stimulation. Treat with low-dose propranolol, 0.01-0.03 mg/kg IV, or esmolol, 0.025-0.05 mg/kg/min. Use beta blockers cautiously in patients with a prior history of asthma or wheezing.
3. Decontamination . Administer activated charcoal orally if conditions are appropriate (see Table I-37,). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly. Consider the use of repeated doses of activated charcoal and whole-bowel irrigation after a large ingestion of a sustained-release formulation.
4. Enhanced elimination. Theophylline has a small volume of distribution (0.5 L/kg) and is efficiently removed by hemodialysis or repeat-dose activated charcoal. Although it is protein bound at therapeutic concentrations, the free fraction dominates at higher levels.
   1. Hemodialysis should be performed in patients with status epilepticus, life-threatening dysrhythmias, shock, or if the serum theophylline concentration is greater than 100 mg/L after acute overdose or 50-60 mg/L after chronic intoxication.
   2. Repeat-dose activated charcoal is not as effective but may be used for stable patients with levels below 100 mg/L.