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.[1, 2, 3]
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:
In 2014, the American Association of Poison Control Centers (AAPCC) reported 133 single exposures to theophylline or aminophylline, 20 of them in children or adolescents up to 19 years of age.[2] By comparison, in 2006 the AAPCC reported 413 such exposures, 73 of them in children or adolescents.[4] The decrease in the incidence of theophylline toxicity parallels the decline in the prescription of theophylline, in response to the safety and efficacy of inhaled beta2-agonists in the treatment of asthma and COPD.
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.
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.
Although theophylline toxicity can occur in people of any age, it is more severe in neonates than in children and adolescents.[5]
The prognosis of patients with theophylline toxicity depends on the amount and severity of the ingestion. Significant ingestions increase the risk of death from dysrhythmias, refractory hypotension, or status epilepticus.
Hypoxic brain injury is a risk in patients with status epilepticus, prolonged hypotension, or significant aspiration causing hypoxia.
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Patients should be advised of the potential for serious toxicity in acute and chronic overdose and of the potential for serious drug interactions.
Patients should be advised that current drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD), such as inhaled beta-agonists and inhaled steroids, offer better therapeutic effects without the risk of significant toxicity associated with theophylline.
For excellent patient education resources, visit eMedicineHealth's First Aid and Injuries Center. Also, see eMedicineHealth's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.
Acute theophylline overdose causes nausea and vomiting, abdominal pain, tachycardia, mild metabolic acidosis, hypokalemia, hypercalcemia, hypophosphatemia, hypomagnesemia, and hyperglycemia. Severe symptoms such as seizures, dysrhythmias, and hypotension usually do not occur with acute overdose until levels are 80-100 mcg/mL.
Chronic intoxication often causes milder GI symptoms and does not cause electrolyte shifts or hypotension, as observed in acute overdose. However, significant dysrhythmias and seizures are common with lower levels of the drug in chronic intoxication and in acute-on-chronic overdose.
Theophylline toxicity should be considered in patients with new-onset seizures or status epilepticus with an opportunity for exposure.
Sinus tachycardia is the most common cardiovascular finding. Supraventricular tachycardia, atrial fibrillation, atrial flutter, multifocal atrial tachycardia, and, less commonly, ventricular dysrhythmias can occur. Hypotension commonly occurs in acute overdose.
Neurologic findings commonly include tremors, restlessness, agitation, and seizures.
GI findings include nausea, vomiting, abdominal pain, and diarrhea.
Acute toxicity occurs with accidental or intentional overdose.
Chronic toxicity is caused by excessive daily dosing or interactions of drugs such as macrolide or quinolone antibiotics, allopurinol, oral contraceptives, and cimetidine, which lower the metabolism of theophylline and thereby increase its serum concentrations. Anticonvulsant medications such as phenytoin, phenobarbital, and carbamazepine enhance theophylline metabolism and increase levels of theophylline when these drugs are discontinued.[6]
Serum theophylline levels should be determined every 2 hours until levels decline and every 4 hours until 2 successive findings are below therapeutic levels.
Check the basic metabolic panel (BMP) for metabolic acidosis and hyperglycemia and determine calcium, phosphorus, and magnesium levels. In the most severe cases, all organ systems may be affected and appropriate laboratory levels, such as creatine kinase and urine myoglobin levels, should be obtained to determine if rhabdomyolysis has occurred.
A radiograph of the kidneys, ureters, and bladder (KUB) rmay reveal radiopacities from undissolved sustained-release tablets or pharmacobezoars. Bead-filled capsules may appear as radiolucencies.
Nonenhanced head CT scans may be obtained if seizures occur.
Electrocardiography and ECG monitoring may be needed to observe for the development of atrial and ventricular tachydysrhythmias.
See the list below:
Admit all patients with signs or symptoms of theophylline toxicity.
Admit patients with serial unchanged or increasing theophylline levels of more than 30 mcg/mL in acute or acute-on-chronic ingestions of sustained-release preparations.
Admit patients with cardiovascular or neurologic symptoms to the ICU, with airway management, monitoring, and supportive care as indicated.
Patients with significant cardiovascular or neurologic symptoms should receive hemodialysis. Multidose activated charcoal should be used for patients with less severe toxicity.
Patients with 2 consecutive decreasing theophylline levels of less than 30 mcg/mL, determined at least 2 hours apart, who are asymptomatic and who have no comorbid conditions may be considered for discharge. Further doses of theophylline should not be resumed until levels are within the therapeutic range (10-20 mcg/mL).
Patients with dysrhythmias, hemodynamic instability, or severe agitation, altered mental status, or seizures after ingestions of significant amounts of theophylline should be transferred to the ICU. These patients should also be transferred to facilities that can provide hemodialysis.
Initial stabilization: Initial treatment of theophylline poisoning involves assessment of the ABCs, cardiac monitoring, administration of isotonic fluids for rehydration, and determination of glucose level. Perform endotracheal intubation as indicated for airway protection and ventilatory assistance.
Treatment of cardiovascular effects: Observe for hypotensive effects. Administer isotonic fluids for hypotension. Refractory hypotension may require administration of a pure alpha-agonist vasopressor agent (eg, phenylephrine). Most patients tolerate theophylline-induced tachycardia without difficulty. Beta-blockers should be used with extreme caution, as mixed results following administration have been reported in the literature. Theophylline toxicity is refractory to adenosine. Ventricular dysrhythmias should be treated in the usual manner.
CNS hyperstimulation treatment: Patients who are preseizurogenic (ie, manifesting signs of hyperreflexia, clonus, and marked tremor) should be treated with either benzodiazepines or phenobarbital. If seizures develop, prompt therapy with benzodiazepines and phenobarbital should be initiated. Phenytoin may worsen theophylline-induced seizures and should be avoided.
Administer activated charcoal (1-2 g/kg). Consider whole-bowel irrigation for massive ingestion of sustained-release preparations. Multidose activated charcoal has been beneficial in the treatment of theophylline toxicity because it binds theophylline that diffuses through the small intestine ("gut dialysis"). Recurrent vomiting may be treated with metoclopramide or ondansetron.
Treat hypokalemia cautiously in patients with acute ingestions. Hypokalemia is secondary to an intracellular shift, rather than total-body depletion. Potassium replacement may cause hyperkalemia as theophylline levels decrease. Most electrolyte disturbances are asymptomatic and do not require treatment.
Hemodialysis is as efficacious as hemoperfusion and is the preferred method of extracorporeal elimination. Hemodialysis should be considered if the theophylline level is more than 100 mcg/mL in acute ingestions and more than 60 mcg/mL in chronic. In patients who develop seizures, refractory hypotension that is unresponsive to fluids, and unstable dysrhythmias, hemodialysis should be considered, regardless of the theophylline level. The molecular adsorbent recirculating system (MARS) has been cited in case reports as being efficacious in the removal of protein-bound drugs such as theophylline. However, the literature is quite limited in the use of MARS in the pediatric population, especially for the treatment of drug toxicity.[7, 8]
Consult a toxicologist. A nephrologist may be consulted in cases of severe toxicity requiring charcoal hemoperfusion or hemodialysis.
Drug levels should be periodically monitored in patients who are being treated with theophylline.
Particular attention should be paid to potential drug interactions.
Macrolide and quinolone antibiotics should be avoided. If they are administered, theophylline levels should be carefully monitored.
Patients should be counseled about the potential for serious toxicity in acute and chronic overdose and about the potential for drug interactions.
Clinical Context: Dopamine antagonist that stimulates acetylcholine release in myenteric plexus. Centrally acts on chemoreceptor triggers in floor of fourth ventricle, which provides important antiemetic activity.
Clinical Context: Selective 5-HT3-receptor antagonist that blocks serotonin peripherally and centrally. Prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and complete-body radiation therapy.
These agents may be used to control vomiting. Phenothiazine antiemetics should be avoided to prevent potentiation of theophylline toxicity.
Clinical Context: Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal absorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water. For maximum effect, administer within 30 min after poison ingestion.
Activated charcoal is used to decrease drug absorption and may be all that is required in mild-to-moderate toxicity. It is not absorbed and is excreted entirely through the GI tract.
Clinical Context: Laxative with strong electrolyte and osmotic effects that has cathartic actions in GI tract.
Polyethylene glycol is used to increase GI transit time, decreasing absorption of theophylline. It may be used in older children or adults who have ingested significant amounts of products with delayed absorption. It is not absorbed and is entirely excreted through the GI tract.
Clinical Context: Depresses all levels of CNS (eg, limbic system, reticular formation), possibly by increasing activity of GABA. Individualize dose and increase doses cautiously to avoid adverse effects.
Clinical Context: Sedative hypnotic with short onset of effects and relatively long half-life. May depress all levels of CNS, including limbic system and reticular formation, by increasing action of GABA, a major inhibitory neurotransmitter in the brain. Excellent when sedation longer than 24 hours is needed.
Clinical Context: Strong postsynaptic alpha-receptor stimulant with little beta-adrenergic activity that produces vasoconstriction of arterioles in the body. Increases peripheral venous return.
Clinical Context: Excellent in patients at risk for complications from beta-blockade, particularly those with reactive airway disease, mild-to-moderate LV dysfunction, and/or peripheral vascular disease. Short half-life of 8 min allows for titration to desired effect and quick discontinuation if needed.
These agents are used to treat severe tachycardia with ischemia or severe hypertension. Short-acting agents should be used because of the potential for significant hypotension in theophylline toxicity.