eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Toxicology

Toxicity, Theophylline

Author: Tracey H Reilly, MD, Attending Physician, Department of Emergency Medicine, United Health Services Hospitals
Coauthor(s): Christopher P Holstege, MD, Associate Professor of Emergency Medicine and Pediatrics, University of Virginia; Director, Division of Medical Toxicology, Center of Clinical Toxicology; Medical Director, Blue Ridge Poison Ctr, Associate Medical Toxicology Fellowship Director, VA Dept of Health; Chandra D Aubin, MD, Associate Residency Director, Division of Emergency Medicine, Assistant Professor, Washington University School of Medicine; Michael E Mullins, MD, Assistant Professor, Department of Emergency Medicine, Washington University School of Medicine
Contributor Information and Disclosures

Updated: Dec 9, 2008

Introduction

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.

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.

Clinical

History

  • 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.

Physical

  • Cardiovascular findings: Sinus tachycardia is the most common 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: Tremors, restlessness, agitation, and seizures are common.
  • GI findings: Nausea, vomiting, abdominal pain, and diarrhea can occur.

Causes

  • 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.

More on Toxicity, Theophylline

Overview: Toxicity, Theophylline
Differential Diagnoses & Workup: Toxicity, Theophylline
Treatment & Medication: Toxicity, Theophylline
Follow-up: Toxicity, Theophylline
References
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References

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  2. Novelli G, Rossi M, Morabito V, et al. Pediatric acute liver failure with molecular adsorbent recirculating system treatment. Transplant Proc. Jul-Aug 2008;40(6):1921-4. [Medline].

  3. Charytan D, Jansen K. Severe metabolic complications from theophylline intoxication. Nephrology (Carlton). Oct 2003;8(5):239-242. [Medline].

  4. de Pont AC. Extracorporeal treatment of intoxications. Curr Opin Crit Care. Dec 2007;13(6):668-73. [Medline].

  5. Holstege CP, Dobmeier S. Cardiovascular challenges in toxicology. Emerg Med Clin North Am. Nov 2005;23(4):1195-217. [Medline].

  6. Holstege CP, Hunter Y, Baer AB, et al. Massive caffeine overdose requiring vasopressin infusion and hemodialysis. J Toxicol Clin Toxicol. 2003;41(7):1003-7. [Medline].

  7. Lheureux P, Penaloza A, Gris M. Pyridoxine in clinical toxicology: a review. Eur J Emerg Med. Apr 2005;12(2):78-85. [Medline].

  8. Minton NA, Henry JA. Acute and chronic human toxicity of theophylline. Hum Exp Toxicol. Jun 1996;15(6):471-81. [Medline].

  9. Minton NA, Henry JA. Treatment of theophylline overdose. Am J Emerg Med. Oct 1996;14(6):606-12. [Medline].

  10. Rutten J, van den Berg B, van Gelder T, van Saase J. Severe theophylline intoxication: a delay in charcoal haemoperfusion solved by oral activated charcoal. Nephrol Dial Transplant. Dec 2005;20(12):2868-9. [Medline].

  11. Shannon MW. Comparative efficacy of hemodialysis and hemoperfusion in severe theophylline intoxication. Acad Emerg Med. Jul 1997;4(7):674-8. [Medline].

  12. Stork CM, Howland MA, Goldfrank LR. Concepts and controversies of bronchodilator overdose. Emerg Med Clin North Am. May 1994;12(2):415-36. [Medline].

  13. Watson WA, Litovitz TL, Rodgers GC, et al. 2004 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 2005;23(5):589-666. [Medline].

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Further Reading

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Keywords

theophylline toxicity, theophylline overdose, acute theophylline overdose, chronic theophylline intoxication, methylxanthine, asthma treatment, chronic obstructive pulmonary disease treatment, COPD treatment, theophylline adverse affects, theophylline prescription, methylxanthine derivative, 1, 3-dimethylxanthine, smooth muscle relaxant, diuretic, cardiac stimulant, vasodilator, angina pectoris treatment, peripheral vascular disease treatment, bronchial asthma treatment, hypokalemia, hyperglycemia, hypercalcemia, hypophosphatemia, hypomagnesemia, and metabolic acidosis,  atrial fibrillation, atrial flutter, multifocal atrial tachycardia

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Contributor Information and Disclosures

Author

Tracey H Reilly, MD, Attending Physician, Department of Emergency Medicine, United Health Services Hospitals
Tracey H Reilly, MD is a member of the following medical societies: American College of Emergency Physicians, American College of Medical Toxicology, and American Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Christopher P Holstege, MD, Associate Professor of Emergency Medicine and Pediatrics, University of Virginia; Director, Division of Medical Toxicology, Center of Clinical Toxicology; Medical Director, Blue Ridge Poison Ctr, Associate Medical Toxicology Fellowship Director, VA Dept of Health
Christopher P Holstege, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American Association for the Advancement of Science, American College of Emergency Physicians, American College of Medical Toxicology, American Medical Association, Medical Society of Virginia, Society for Academic Emergency Medicine, Society of Toxicology, and Wilderness Medical Society
Disclosure: Nothing to disclose.

Chandra D Aubin, MD, Associate Residency Director, Division of Emergency Medicine, Assistant Professor, Washington University School of Medicine
Disclosure: Nothing to disclose.

Michael E Mullins, MD, Assistant Professor, Department of Emergency Medicine, Washington University School of Medicine
Michael E Mullins, MD is a member of the following medical societies: American Academy of Clinical Toxicology and American College of Emergency Physicians
Disclosure: Johnson & Johnson stock ownership None; Savient Pharmaceuticals stock ownership None

Medical Editor

Halim Hennes, MD, MS, Pediatric Emergency Medicine Research Director, Professor, Departments of Pediatrics and Emergency Medicine, Medical College of Wisconsin
Halim Hennes, MD is a member of the following medical societies: American Academy of Pediatrics
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Jeffrey R Tucker, MD, Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center
Jeffrey R Tucker, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Pediatrics, and Massachusetts Medical Society
Disclosure: Merck Salary Employment

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Timothy E Corden, MD, Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin
Timothy E Corden, MD is a member of the following medical societies: American Academy of Pediatrics, Phi Beta Kappa, Society of Critical Care Medicine, and Wisconsin Medical Society
Disclosure: Nothing to disclose.

 
 
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