AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Acute abdomen
Acute myocardial infarction
Benzodiazepine withdrawal
Hypertensive crisis
Status epilepticus
Stroke
Viral syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Theophylline levels: Check at presentation and then every 2-4 hours (to monitor treatment effects) until a return to nontoxic levels.
• Electrolytes and glucose levels: Monitor for hypokalemia, hyperglycemia, hypomagnesemia, or hypercalcemia.
• Serum creatine kinase: Measure this to assess for evidence of rhabdomyolysis.
• Arterial blood gases: Monitor these levels to assess for acid-base disturbances.
• Pregnancy test

Imaging Studies

CT scanning is indicated if seizures occur.

Other Tests

Electrocardiography

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Criteria for intensive care unit (ICU) admission
  • Patients with moderate-to-severe clinical toxicity are candidates for admission to the ICU.
  • In patients with acute overdose, a theophylline concentration greater than 50 mcg/mL warrants ICU admission.
  • ICU admission is also indicated for those with chronic overdose whose theophylline concentration is greater than 40 mcg/mL.
  • A theophylline concentration greater than 40 mcg/mL in patients younger than 6 months or older than 60 years is an indication for admission to the ICU.
  • Finally, a theophylline concentration greater than 40 mcg/mL in a patient with a chronic illness warrants ICU admission.
• Anticonvulsant treatment
  • Phenytoin is not significantly effective in these patients.
  • Initially, administer benzodiazepines in increments of 0.1-0.2 mg/kg every 1-3 minutes.
  • If continued seizure activity lasts longer than 15 minutes, administer phenobarbital intravenously at 10 mg/kg.
  • With repetitive seizure activity, load with phenobarbital intravenously at 20 mg/kg over 30-60 minutes.
  • Theophylline-induced seizures, with their risk for respiratory depression, are associated with high morbidity and mortality rates.
  • Have benzodiazepines drawn and ready at the bedside when treating patients with an acute overdose with serum concentrations greater than 100 mcg/mL or when treating patients older than 60 years with a serum concentration greater than 30 mcg/mL who may have a chronic overdose.
  • Consider prophylaxis with intravenous benzodiazepine if a delay in extracorporal removal is anticipated or the patient being treated has a previous neurologic condition that may decrease the seizure threshold.
  • If convulsions last longer than 1 hour, consider general anesthesia.
• Arrhythmia treatment
  • Most commonly, arrhythmias resolve with theophylline clearance.
  • If the patient is hemodynamically compromised, treat each arrhythmia appropriately.
  • Beta-blockers such as esmolol or metoprolol reduce the excessive beta stimulation that causes arrhythmias and hypokalemia, usually without inducing bronchospasm.
• Hypotension
  • Administer intravenous fluids at 10-20 mL/kg or titrated to a mean arterial pressure greater than 55-60 mm Hg.
  • Pressor agents such as dopamine, norepinephrine, or phenylephrine are administered and titrated to a mean arterial pressure greater than 55-60 mm Hg.
• Gastrointestinal decontamination
  • To block absorption, administer oral activated charcoal (1 mg/kg, not to exceed 20 g) every 2 hours until the serum theophylline level has fallen to less than 20-25 mcg/mL.
  • For vomiting, administer metoclopramide, droperidol, or ondansetron.
  • Avoid ipecac because it does not reduce absorption.
  • Avoid phenothiazine antiemetics (eg, prochlorperazine, perphenazine) because they lower the seizure threshold.
• Extracorporal removal
  • Consider extracorporal removal if emesis, seizure, or cardiac arrhythmia is intractable and cannot be adequately controlled.
  • Charcoal hemoperfusion for extracorporal removal is as follows:
    • Charcoal hemoperfusion directs blood from an arterial source through a charcoal cartridge and then returns it to the patient. This is better than hemodialysis for removal of highly protein–bound substances.
    • Hemoperfusion can increase clearance 6-fold (1.88-5.84 mL/kg/min).
    • The endpoint of treatment is a serum theophylline level less than 60 mcg/mL in acute overdoses and less than 40 mcg/mL in chronic overdoses, with the resolution of symptoms.
    • Adverse effects include thrombocytopenia, hypoglycemia, hemorrhage, infection, and hemolysis.
    • Charcoal hemoperfusion is indicated in patients with (1) intractable seizures with duration greater than 30 minutes or seizures at intervals of less than 20 minutes, (2) persistent hypotension unresponsive to treatment with fluids and pressure support, (3) uncontrollable arrhythmias, (4) acute intoxication with theophylline levels greater than 100 mg/dL, (5) chronic intoxication older than 60 years with theophylline levels greater than 40 mg/dL, and (6) theophylline levels greater than 60 mg/dL with impaired theophylline metabolism or an inability to tolerate oral charcoal.
  • Hemodialysis for extracorporal removal is as follows:
    • Efficiency is equivalent to that of multidose oral activated charcoal.
    • Peritoneal dialysis is ineffective.
    • Hemodialysis is indicated if (1) charcoal hemoperfusion is not available or is contraindicated and the patient has indications for extracorporal removal or (2) if multidose oral activated charcoal is not effective secondary to emesis.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity, to prevent complications, and to decrease toxic levels of theophylline.

Effects of various drugs on theophylline plasma levels are as follows:

• Cimetidine clearance is decreased, and the theophylline level is increased.
• St. John's wort clearance is increased, and the theophylline level is decreased.
• Oral contraceptive clearance is decreased, and the theophylline level is increased.
• Rifampin clearance is increased, and the theophylline level is decreased.
• Isoniazid clearance is decreased, and the theophylline level is increased.
• Class I antiarrhythmic clearance is decreased, and the theophylline level is decreased.

Drug Category: Antiemetics

Useful in the treatment of symptomatic nausea.

Drug Category: Anticonvulsants

Prevent seizure recurrence and terminate clinical and electrical seizure activity.

Drug Category: Benzodiazepines

By binding to specific receptor sites, appear to potentiate the effects of GABA and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.

Drug Category: Antidotes

Reduce toxicity of drugs by inhibiting absorption in the lower GI tract.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Review the patient's home medication list for the following medications or for others that may affect cytochrome P-450 metabolism:
• • Erythromycin
  • Cimetidine
  • Ciprofloxacin
  • Oral contraceptives
  • Allopurinol
  • Beta-blockers
  • Calcium channel blockers
  • Loop diuretics
  • Ephedrine
  • Corticosteroids

Further Outpatient Care

• Review diet restrictions with patients, including restriction of caffeine-containing products and ingestion of slow-release theophylline 1 hour before or 2 hours after meals to avoid sudden "dumping" of the dose.
• Review any herbal or supplemental nutraceuticals, as many affect theophylline metabolism.¹

Transfer

• Transfer patients to another facility under the following circumstances:
• • Hemoperfusion is indicated clinically but not available at present institution: Indications include theophylline level greater than 40 mcg/mL, intolerance to repeated oral or intragastric charcoal doses, or severe toxic symptoms.
  • ICU care is indicated but not available at present institution: Indications include hemodynamic instability, life-threatening arrhythmias, seizures, mechanical ventilation, severe acidosis, kidney or other organ failure, or coma.
  • Patient condition for transfer: Secure the airway and stabilize the vital signs.

Deterrence/Prevention

• Careful patient education and vigilance by health care professionals should reduce the risk of accidental toxicity.

Complications

• Complications result from the seizures and gastrointestinal and cardiovascular instability that occur with toxicity. These complications may include hypoxic organ injury and multiple organ dysfunction, severe electrolyte disorders, and rhabdomyolysis.

Patient Education

• Inform patients that overdose can be caused by patient error in taking the medication, an excessive prescribed dose, or some mitigating factor that has altered the patient's clearance rate.
• Patients also must be educated about which drugs, alternatives, or complementary substances may adversely interact with theophylline and the early signs and symptoms of toxicity so that they may seek help. The following is a list of substances with at least a moderate chance of increasing theophylline effect or level:
• • Black/white pepper
  • Any tea or caffeine-containing substance
  • Capsicum
  • Country mallow
  • Any ephedra-containing substance
  • Dandelion
  • Echinacea
  • Eucalyptus
  • Feverfew
  • Fo-ti
  • Chamomille
  • Gingko
  • Ginseng
  • Grapefruit
  • Guarana
  • Mate
  • Peppermint
  • Red clover
  • Sulforaphane
• Patients should be made aware that thuja, used for respiratory tract or skin infections, osteoarthritis, flavoring agent and fragrance, contains a neurotoxin with potential for a major adverse interaction with theophylline, increasing risk of seizures. Those on theophylline should not take thuja.
• For excellent patient education resources, visit eMedicine's Drug Overdose Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

Any health care professional who prescribes a pharmacologic agent without recognizing that agent's effect on the patient's theophylline level is at risk for legal action if the patient has an adverse event. The classic example is a patient with chronic obstructive pulmonary disease who is prescribed cimetidine and who presents 2 days later with intractable seizures and a toxic theophylline level. This is an avoidable event, and this mistake is indefensible.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Hu Z, Yang X, Ho PC. Herb-drug interactions: a literature review. Drugs. 2005;65(9):1239-82. [Medline].
2. Ayres SM, Grenvik A, Holbrook PR, Shoemaker WC, eds. Textbook of Critical Care. 3rd ed. Philadelphia, Pa: WB Saunders; 1995.
3. Civetta JM, Taylor RW, Kirby RR, eds. Critical Care. 3rd ed. Philadelphia, Pa: Lippincott-Raven; 1997.
4. Dawson AH, Whyte IM. The assessment and treatment of theophylline poisoning. Med J Aust. Dec 4-18 1989;151(11-12):689-93. [Medline].
5. Ellenhorn MJ. Ellenhorn's Medical Toxicology, Diagnosis, and Treatment of Human Poisoning. 2nd ed. Baltimore, Md: Williams & Wilkins; 1997.
6. Ismail N, Hakim R. Management of theophylline intoxication. UpToDate [serial online]; 2004.
7. Natural Medicines Comprehensive Database. Naturaldatabase.com.
8. PDR. Physicians' Desk Reference. 54th ed. Montvale, NJ: Medical Economics Company; 2000.
9. 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].

Article Last Updated: May 29, 2008