Introduction
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.
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.
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.
Frequency
United States
The 2007 annual report of the American Association of Poison Control Centers' National Poison Data System documented 230 exposures to theophylline, with 39 in children younger than 6 years and 163 in persons older than 19 years.1 Of the 118 theophylline exposures treated in health care facilities, 8 were reported to have major adverse outcomes and no fatalities were noted. The documented toxic exposures have decreased markedly over the past decade as the utilization of theophylline for the management of asthma has diminished.
Race
No scientific data have demonstrated that outcomes of theophylline toxicity are dependent on race.
Sex
No scientific data have demonstrated that outcomes of theophylline toxicity are dependent on sex.
Clinical
History
- Symptomology correlates better with single acute ingestions than with chronic overexposures. Symptoms of acute theophylline overdose are as follows:
- Nausea
- Vomiting
- Severe and protracted
- Acute overdose >>> Chronic overdose
- Sustained-release preparations >>> Immediate-release preparation
- Abdominal pain
- Mild metabolic acidosis
- Hypokalemia
- Hypophosphatemia
- Hypomagnesemia
- Hypocalcemia/hypercalcemia
- Hyperglycemia
- Tachycardia
- Chronic theophylline overdose has minimal GI signs or symptoms.
- Seizures, hypotension, and significant dysrhythmias usually are observed when serum levels approach 80 mcg/mL.
- Seizures are more common with acute overdose than with chronic overdose. In chronic exposures, seizures may develop at lower serum concentrations (40-60 mcg/mL).
- Cardiac dysrhythmias are more common following a chronic overdose rather than acute overdose and with lower serum concentrations.
Physical
- Cardiovascular
- Sinus tachycardia (most common)
- Atrial fibrillation
- Atrial flutter
- Supraventricular tachycardia (SVT)
- Multifocal atrial tachycardia
- Ventricular tachycardia
- Hypotension (severe overdoses) - Due to β2 effect/agonsim
- Ventricular fibrillation
- Pulseless electrical activity (PEA)
- Cardiac arrest
- Pulmonary
- Increased respiratory rate leads to respiratory alkalosis
- Acute lung injury (ALI)
- Respiratory failure leads to arrest
- Neurological
- Tremors (most common)
- Restlessness
- Agitation
- Hallucinations
- Headaches
- Irritability
- Seizures (Persistent seizures may occur with serum levels >25 mcg/mL.)
- Gastrointestinal
- Nausea
- Vomiting
- Abdominal cramps
- Diarrhea
Causes
- Chronic theophylline toxicity
- Drug interactions (eg, ethanol [ETOH], cimetidine, oral contraceptives, allopurinol, macrolide, quinolone antibiotics)
- Liver disease
- Congestive heart failure
- Febrile viral upper respiratory illness
- Acute theophylline toxicity
- Nonintentional overdose
- Intentional overdose
More on Toxicity, Theophylline |
 Overview: Toxicity, Theophylline |
| Differential Diagnoses & Workup: Toxicity, Theophylline |
| Treatment & Medication: Toxicity, Theophylline |
| Follow-up: Toxicity, Theophylline |
| References |
| Next Page » |
References
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Seneff M, Scott J, Friedman B, Smith M. Acute theophylline toxicity and the use of esmolol to reverse cardiovascular instability. Ann Emerg Med. Jun 1990;19(6):671-3. [Medline].
Kearney TE, Manoguerra AS, Curtis GP, Ziegler MG. Theophylline toxicity and the beta-adrenergic system. Ann Intern Med. Jun 1985;102(6):766-9. [Medline].
Brashear RE, Aronoff GR, Brier RA. Activated charcoal in theophylline intoxication. J Lab Clin Med. Sep 1985;106(3):242-5. [Medline].
Charytan D, Jansen K. Severe metabolic complications from theophylline intoxication. Nephrology (Carlton). Oct 2003;8(5):239-42. [Medline].
Cooling DS. Theophylline toxicity. J Emerg Med. Jul-Aug 1993;11(4):415-25. [Medline].
Gaudreault P, Harwood-Nuss. Methylxanthines, Toxicology. In: Clinical Practice of Emergency Medicine. 4th ed. 2005:1649-1652.
Henderson A, Wright DM, Pond SM. Management of theophylline overdose patients in the intensive care unit. Anaesth Intensive Care. Feb 1992;20(1):56-62. [Medline].
Kallstrom TJ. Evidence-based asthma management. Respir Care. Jul 2004;49(7):783-92. [Medline].
Marshall H, Emerman CL, Tintinalli J. Theophylline, Toxicology and Pharmacology. In: Emergency Medicine, A Comprehensive Study Guide. 6th ed. 2004:1098-1101.
Medical Economics Staff. Drugs. In: Physician's Desk Reference. Medical Economics Co; 1997.
Micromedex. Theophylline. In: Micromedex. 1974-2008:36.
Further Reading
Keywords
theophylline overdose, theophylline poisoning, theophylline exposure, acute theophylline overdose, chronic theophylline intoxication, methylxanthine, asthma treatment, chronic obstructive pulmonary disease treatment, COPD treatment, theophylline adverse affects, methylxanthine derivative, 1,3-dimethylxanthine, angina pectoris treatment, peripheral vascular disease treatment, bronchial asthma treatment
