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Theophylline Toxicity

  • Author: Greg Hymel, MD; Chief Editor: Asim Tarabar, MD  more...
 
Updated: Jan 07, 2016
 

Background

Theophylline (1,3-dimethylxanthins) can indirectly stimulate both β1 and β2 receptors through release of endogenous catecholamines. It is used for the treatment of pulmonary conditions, including asthma and chronic obstructive pulmonary disease (COPD). In neonates, theophylline can be used for the treatment of apnea.

Medication, diet, and underlying diseases can alter its narrow therapeutic window. Adverse effects can be evident at therapeutic serum levels. The use of theophylline for the treatment of asthma and chronic obstructive pulmonary disease has decreased significantly in recent years.[1] This has greatly decreased the incidence of theophylline overdose.[2]

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Pathophysiology

Major mechanisms of theophylline therapeutic efficacy and its toxicity are through the excess of catecholamines and adenosine antagonism. Adenosine blockade can theoretically reduce histamine release and indirectly reverse bronchospasm. In addition, high levels of theophylline inhibit phosphodiesterase, resulting in elevation of cyclic adenosine monophosphate (cAMP) and consequent adrenergic stimulation.

Theophylline is absorbed rapidly and completely after oral administration. Peak serum levels for immediate release preparations are relatively rapid and can range from 30-120 minutes. Fasting or large volumes of fluid enhance absorption. Enteric-coated and sustained-release tablets have a delayed absorption with peak between 6 and 10 hours. It is important to recognize that these time intervals are much longer in the setting of overdose. The intravenous form of theophylline (aminophylline) reaches peak serum levels in 30 minutes.[3]

Theophylline is around 60% protein bound and has a distribution volume of 0.5 L/kg. Therapeutic serum levels range from 10-20 mcg/mL. Toxic levels are considered to be higher than 20 mcg/mL; however, adverse effects may be evident within the normal therapeutic range. Severe complications including cardiac dysrhythmias, seizures, and death can be observed with the levels of 80-100 mcg/mL. In chronic exposure, those levels could be lower (40-60 mcg/mL).

Theophylline is eliminated by the hepatic cytochrome P-450 system (85-90%) and by urinary excretion (10-15%). The half-life is 4-8 hours in young adults and is shorter in children and smokers. Diet, cardiac or liver disease, tobacco use, and medications (cimetidine, erythromycin, oral contraceptives) affecting the cytochrome P-450 system (CYP1A2) can affect the half-life.

Theophylline affects the cardiovascular (CV), central nervous (CN), gastrointestinal (GI), pulmonary, musculoskeletal, and metabolic systems. Hypokalemia, hyperglycemia, hypercalcemia, hypophosphatemia, and acidosis commonly occur after an acute overdose.

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Epidemiology

Frequency

United States

The 2014 annual report of the American Association of Poison Control Centers' National Poison Data System documented 133 exposures to theophylline, with 14 in children younger than 6 years and 107 in persons older than 19 years.[2] Of the 81 theophylline exposures treated in health care facilities, eight were reported to have major adverse outcomes and two deaths were noted. Documented toxic exposures have decreased markedly over the past decade as the use of theophylline for the management of asthma has diminished.[4]

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Contributor Information and Disclosures
Author

Greg Hymel, MD Assistant Medical Director, Associate Chairman, Department of Emergency Medicine, Mercy St Vincent Medical Center

Greg Hymel, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians

Disclosure: Nothing to disclose.

Specialty Editor Board

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Fred Harchelroad, MD, FACMT, FAAEM, FACEP Attending Physician in Emergency Medicine, Excela Health System

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Additional Contributors

Lance W Kreplick, MD, FAAEM, MMM Medical Director of Hyperbaric Medicine, Fawcett Wound Management and Hyperbaric Medicine; Consulting Staff in Occupational Health and Rehabilitation, Company Care Occupational Health Services; President and Chief Executive Officer, QED Medical Solutions, LLC

Lance W Kreplick, MD, FAAEM, MMM is a member of the following medical societies: American Academy of Emergency Medicine, American Association for Physician Leadership

Disclosure: Nothing to disclose.

References
  1. Horita N, Miyazawa N, Kojima R, Inoue M, Ishigatsubo Y, Kaneko T. Chronic Use of Theophylline and Mortality in Chronic Obstructive Pulmonary Disease: A Meta-analysis. Arch Bronconeumol. 2015 Nov 20. [Medline].

  2. Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 32nd Annual Report. Clin Toxicol (Phila). 2015 Dec. 53 (10):962-1147. [Medline]. [Full Text].

  3. Fisher J, Graudins A. Intermittent haemodialysis and sustained low-efficiency dialysis (SLED) for acute theophylline toxicity. J Med Toxicol. 2015 Sep. 11 (3):359-63. [Medline].

  4. Hocaoğlu N, Yıldıztepe E, Bayram B, Aydın B, Tunçok Y, Kalkan Ş. Demographic and Clinical Characteristics of Theophylline Exposures between 1993 and 2011. Balkan Med J. 2014 Dec. 31 (4):322-7. [Medline].

  5. Seneff M, Scott J, Friedman B, Smith M. Acute theophylline toxicity and the use of esmolol to reverse cardiovascular instability. Ann Emerg Med. 1990 Jun. 19(6):671-3. [Medline].

  6. Kearney TE, Manoguerra AS, Curtis GP, Ziegler MG. Theophylline toxicity and the beta-adrenergic system. Ann Intern Med. 1985 Jun. 102(6):766-9. [Medline].

  7. Brashear RE, Aronoff GR, Brier RA. Activated charcoal in theophylline intoxication. J Lab Clin Med. 1985 Sep. 106(3):242-5. [Medline].

  8. Charytan D, Jansen K. Severe metabolic complications from theophylline intoxication. Nephrology (Carlton). 2003 Oct. 8(5):239-42. [Medline].

  9. Cooling DS. Theophylline toxicity. J Emerg Med. 1993 Jul-Aug. 11(4):415-25. [Medline].

  10. Gaudreault P, Harwood-Nuss. Methylxanthines, Toxicology. Clinical Practice of Emergency Medicine. 4th ed. 2005. 1649-1652.

  11. Henderson A, Wright DM, Pond SM. Management of theophylline overdose patients in the intensive care unit. Anaesth Intensive Care. 1992 Feb. 20(1):56-62. [Medline].

  12. Kallstrom TJ. Evidence-based asthma management. Respir Care. 2004 Jul. 49(7):783-92. [Medline].

  13. Marshall H, Emerman CL, Tintinalli J. Theophylline, Toxicology and Pharmacology. Emergency Medicine, A Comprehensive Study Guide. 6th ed. 2004. 1098-1101.

  14. Medical Economics Staff. Drugs. Physician's Desk Reference. Medical Economics Co; 1997.

  15. Micromedex. Theophylline. Micromedex. 1974-2008. 36.

 
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