Introduction
Background
Theophylline is classified structurally as a methylxanthine and, in its common form, is a white, odorless powder. Theophylline is indicated for the treatment of symptoms of reversible airflow obstruction associated with asthma, emphysema, and chronic obstructive pulmonary disease.
Pathophysiology
With oral dosing, theophylline is rapidly and completely absorbed. It is 50-60% plasma protein–bound (primarily to albumin) and enters the cerebrospinal fluid and breast milk and crosses the placenta. The volume of distribution is 0.4-0.6 L/kg.
Theophylline undergoes hepatic metabolism through the P-450 system. It is a CYP1A2 inhibitor, thereby affecting drugs metabolized by this enzyme. It is then excreted in the urine, with 90% having undergone metabolism and 10% remaining unchanged (50% unchanged in neonates). The pharmacokinetics can be highly variable and are not predictable by demographic characteristics (eg, sex, race, weight, age). However, conditions such as age (>60 y), hypothyroidism, body temperature (>38.8°C [102°F]), liver disease, smoking, congestive heart failure, acute illness, sepsis, and shock may alter clearance.
In healthy adults, the serum half-life is usually 4-10 hours. The elapsed time before peak serum levels varies by the formulation. It occurs within 2 hours after liquid ingestion, 4 hours after non–sustained-release tablet or capsule ingestion, and 4-12 hours after sustained-release tablet or capsule ingestion.
Theophylline has 2 key mechanisms of action. First, theophylline acts to induce smooth muscle relaxation, resulting in bronchodilation. The exact means by which this occurs remain uncertain. The bronchodilatory effects are believed to be secondary to theophylline's inhibition of 2 isoenzymes of phosphodiesterase (ie, PDE III and PDE IV). Second, theophylline acts to suppress the airway response to irritant stimuli. Other actions induced or promoted by theophylline include diaphragmatic contractility, mucociliary clearance, and lowered pulmonary artery pressure.
The serum therapeutic range of theophylline is 10-20 mcg/mL (the unbound theophylline range is 6-12 mcg/mL). A level greater than 20 mcg/mL is considered toxic. However, any adverse effect (including toxic effects) can occur at levels less than 20 mcg/mL.
For effects of various drugs on theophylline plasma levels, see Medication.
Age
In chronic overdose, the severity of the overdose is more strongly correlated with a patient's age than with the theophylline concentration; patients older than 60 years have the greatest risk for mortality. These patients are more likely to have seizures, and these neurologic events often occur at lower theophylline concentrations than those in acute overdose (>30 mcg/mL).
Clinical
History
- Differentiation between acute and chronic overdose
- Distinguishing between these 2 types of overdose is important because it affects management and treatment choices.
- An acute overdose occurs with the ingestion of a single large dose. These patients usually present with gastrointestinal symptoms and cardiovascular manifestations. Seizure risk is not as great as in a chronic overdose unless the theophylline serum concentration is greater than 100 mcg/mL.
- A chronic overdose occurs in people who have ingested repeated doses over time that are greater than their ability to clear the medication. This can be due to patient error in taking the medication, an excessive prescribed dose, or some mitigating factor that has altered the patient's clearance rate. In chronic overdose, the severity of theophylline overdose is more strongly correlated with a patient's age than with the theophylline concentration; patients older than 60 years have the greatest risk for mortality. These patients are more likely to have seizures, especially as a presenting event, and these neurologic events often occur at lower theophylline concentrations than those in acute overdose (>30 mcg/mL).
- Adverse effects
- Cardiovascular effects include hypotension and arrhythmias (eg, sinus tachycardia, premature ventricular complexes, atrial fibrillation, atrial flutter, supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation).
- Gastrointestinal effects include nausea, vomiting, diarrhea, and abdominal pain or cramping.
- Metabolic effects include hypokalemia, hyperglycemia, hypercalcemia, rhabdomyolysis, and acidosis.
- Neurologic effects include headaches, restlessness, tremors, disorientation, hallucinations, insomnia, and seizures.
- Alternative or complementary herbal supplements may increase the risk of theophylline toxicity or adverse effects.
- Ingestion of caffeinated agents (eg, any tea, coffee, cocoa, cola, guarana, mate) should be minimized.
- Ingestion of any ephedra or ephedralike agents (eg, country mallow, ephedra) should be completely avoided.
- Ingestion of the following agents may increase the risk of seizure and should be avoided: ginkgo, thuja.
- Ingestion of ipriflavone can increase theophylline levels, increasing the risk of toxicity.
Physical
- Cardiovascular - Tachycardia, hypotension, or arrhythmias
- Gastrointestinal - Abdominal tenderness
- Neurologic - Confusion, agitation, tremors, or seizure activity
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
Hu Z, Yang X, Ho PC. Herb-drug interactions: a literature review. Drugs. 2005;65(9):1239-82. [Medline].
Ayres SM, Grenvik A, Holbrook PR, Shoemaker WC, eds. Textbook of Critical Care. 3rd ed. Philadelphia, Pa: WB Saunders; 1995.
Civetta JM, Taylor RW, Kirby RR, eds. Critical Care. 3rd ed. Philadelphia, Pa: Lippincott-Raven; 1997.
Dawson AH, Whyte IM. The assessment and treatment of theophylline poisoning. Med J Aust. Dec 4-18 1989;151(11-12):689-93. [Medline].
Ellenhorn MJ. Ellenhorn's Medical Toxicology, Diagnosis, and Treatment of Human Poisoning. 2nd ed. Baltimore, Md: Williams & Wilkins; 1997.
Ismail N, Hakim R. Management of theophylline intoxication. UpToDate [serial online]; 2004.
Natural Medicines Comprehensive Database. Naturaldatabase.com.
PDR. Physicians' Desk Reference. 54th ed. Montvale, NJ: Medical Economics Company; 2000.
Shechter P, Berkenstat H, Segal E, Rapoport J. Theophylline intoxication: clinical features and pharmacokinetics during treatment with charcoal hemoperfusion. Isr J Med Sci. Sep 1996;32(9):766-70. [Medline].
Further Reading
Keywords
theophylline toxicity, theophylline overdose, Elixophyllin, Slo-bid, Slo-Phyllin, Theo-24, Theo-Dur, Uni-Dur, Uniphyl, methylxanthine, asthma, emphysema, chronic obstructive pulmonary disease, COPD, reversible airflow obstruction, drug overdose, drug toxicity, theophylline poisoning, theophylline overdose, chronic theophylline overdose, acute theophylline overdose, prescription error
