Pediatric Theophylline Toxicity
- Author: Tracey H Reilly, MD; Chief Editor: Timothy E Corden, MD more...
Background
The frequency of theophylline overdose has greatly decreased as the use of theophylline for the treatment of asthma and chronic obstructive pulmonary disease (COPD) has declined because of its narrow therapeutic window and the effectiveness of inhaled beta-agonists. The occurrence of adverse effects with theophylline, even at levels in the therapeutic range, and the severity of its effects in acute and chronic overdose are notable; however, theophylline continues to be prescribed for some patients.
Pathophysiology
Theophylline is a methylxanthine derivative that works by inhibiting phosphodiesterase and potentiating intracellular levels of cyclic adenosine monophosphate (cAMP). It is also an antagonist at adenosine receptors in the bronchial smooth muscle, peripheral vasculature, CNS, and myocardium. Peak serum levels occur 90-120 minutes after oral administration, and sustained-release preparations are common; these preparations cause delayed absorption and potential bezoar formation.
Theophylline is 56% protein bound and has a volume of distribution of 0.5 L/kg. Approximately 90% of it is metabolized by the CYP1A2 isozyme of the hepatic cytochrome P450 system to form inactive substances, and 10% is excreted unchanged in the urine. The elimination half-life is significantly longer in neonates than in children and adolescents and is increased in patients with viral illness, congestive heart failure, and hepatic disease. Theophylline metabolism is inhibited by drugs that affect the cytochrome P450 system such as cimetidine, macrolides, and fluoroquinolones. Drugs such as phenytoin, barbiturates, carbamazepine, and tobacco can increase the metabolism of theophylline and lead to toxicity when they are discontinued.
Theophylline affects various body systems, as follows:
- Cardiovascular system: Theophylline stimulates beta1-receptors and can cause atrial tachydysrhythmias such as sinus and supraventricular tachycardia, even at therapeutic levels. Higher levels can also cause atrial fibrillation, multifocal atrial tachycardia in patients with COPD, and, occasionally, ventricular tachycardia or fibrillation. Hypotension may occur in severe overdoses secondary to beta2-receptor–stimulated vasodilatation. It may be refractory to fluids and conventional vasopressors.
- CNS: Neurologic adverse effects, including tremor, restlessness, and agitation, can also occur at therapeutic levels. Seizure is the most severe neurologic effect, occurring at levels higher than 90 mcg/mL in acute overdose, higher than 30 mcg/mL in acute-on-chronic ingestion, and as low as 20 mcg/mL in chronic toxicity.
- GI system: Nausea and vomiting are common in acute overdose. Abdominal pain and diarrhea can occur, and drug bezoars may occur with ingestion of sustained-release products.
- Metabolic system: Hypokalemia, hyperglycemia, hypercalcemia, hypophosphatemia, hypomagnesemia, and metabolic acidosis can occur secondary to beta-adrenergic stimulation.
Epidemiology
Frequency
United States
In 2006, the American Association of Poison Control Centers (AAPCC) reported 413 exposures to theophylline or aminophylline; 73 of those exposures were in children younger than 19 years.[1] The incidence of theophylline toxicity has greatly decreased over the past decade. This decline in the prescription of theophylline is secondary to the safety and efficacy of the inhaled beta2-agonists in the treatment of asthma and COPD.
International
No current statistics on the international use of theophylline are available, although the drug continues to be available. It is potentially available without prescription in some countries.
Mortality/Morbidity
The most significant morbidity and mortality of theophylline toxicity in acute overdose are secondary to the cardiovascular and CNS effects. Life-threatening tachydysrhythmias and hypotension, as well as refractory seizures, can occur.
Age
Although theophylline toxicity can occur in people of any age, it is more severe in neonates than in children and adolescents.[2]
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