Theophylline Toxicity

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 most commonly is used orally in sustained-release preparations.

narrow therapeutic index, rarely used for asthma/Chronic obstructive pulmonary disease (COPD) management
both acute and chronic overdose is potentially life-threatening

Pathophysiology

unknown exact mechanism of toxicity
- adenosine antagonism
- PDE inhibition at high levels
- endogenous catecholamine release (at therapeutic levels)
pharmacokinetics
- 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
toxic dose
- 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.

Clinical Presentation

Hypotension, tachycardia, and ventricular arrhythmias are caused primarily by excessive beta-adrenergic stimulation.

Acute single overdose

Vomiting, tremor, anxiety, tachycardia. Hypokalemia (due to shift), hypophosphatemia, hyperglycemia, and metabolic acidosis
With serum levels above 90–100 mg/L, hypotension, ventricular arrhythmias, and seizures are common; status epilepticus is frequently resistant to anticonvulsant drugs.
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.

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.

vomiting is rarer. Tachycardia is common, hypotension is rare. Metabolic effects such as hypokalemia and hyperglycemia do not occur.
Seizures may occur with lower serum levels (eg, 40–60 mg/L) and have been reported with levels as low as 20 mg/L.

Diagnosis

Based on ingestion history + presence of tremor, tachycardia, and other manifestations in patients known to be on theophylline.

Hypokalemia strongly suggests acute overdose > chronic ingestion
Serum theophylline levels. 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.
- with chronic intoxication, severe toxicity may occur with levels of 40–60 mg/L.
- Levels of less than 80–100 mg/L after acute overdose usually are not associated with severe symptoms, such as seizures and ventricular arrhythmias.

Treatment

Initial Measures

Airway
Seizures, arrythmia, hypotension management. Best approach with beta-adrenergic agents if required.
Hypokalemia is due to shifting.
Monitor vital signs, ECG, and serial theophylline levels for at least 16–18 hours after a significant oral overdose

Specific Measures

Hypotension, tachycardia, and ventricular arrhythmias are caused primarily by excessive beta-adrenergic stimulation. Treat with low dose propanolol 01–0.03 mg/kg IV, or esmolol 0.025/0.05 mg/kg/min.
Decontamination - consider AOC +/- lavage +/- WBI
Enhanced elimination - efficiently removed by HD, or repeat-dose activated charcoal.
- Hemodialysis or hemoperfusion should be performed if the patient is in status epilepticus or if the serum theophylline concentration is greater than 100 mg/L.
- Repeat-dose activated charcoal is not as effective but may be used for stable patients with levels below 100 mg/L.