Theophylline Toxicity


Article Author:
Jonathan Journey


Article Editor:
Thomas Bentley


Editors In Chief:
Melissa Max
Danyae Lee
Manouchkathe Cassagnol


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
12/6/2018 6:35:18 PM

Introduction

Around the world, theophylline (1,3-dimethylxanthine) is primarily used as a bronchodilator for patients with asthma and chronic obstructive pulmonary disease (COPD). However, in the United States, asthma and COPD are mainly treated with other agents, and theophylline is largely used to treat bradycardia and apnea in premature newborns. Theophylline causes endogenous release catecholamines through indirect stimulation of beta-1 and beta-2 receptors, which at therapeutic levels cause desired bronchodilation. Unfortunately, theophylline has a narrow therapeutic window, and even levels slightly above this therapeutic window can have many adverse effects in the setting of acute and chronic toxicity. The excess circulating catecholamines cause the serious clinical effects that are associated with theophylline toxicity. Depending on the dose and route of administration, theophylline can have a wide range of cardiovascular, neurologic, metabolic, musculoskeletal and gastrointestinal manifestations. Emergency department providers should become familiar with how to manage patients with theophylline toxicity since arrhythmias, seizures, hyperglycemia, and rhabdomyolysis are several of the complications that can arise.[1][2][3]

Etiology

Theophylline has an extremely narrow therapeutic window. Theophylline toxicity occurs when serum theophylline levels surpass the levels in the therapeutic range. This can occur by intentional overdose or unintentionally when metabolism and/or clearance of theophylline is altered due to certain physiological stressors.

Epidemiology

Toxic exposures to theophylline have decreased significantly since its management for asthma and COPD has declined. From 1985 to 1995 in the United States, theophylline poisoning requiring hemodialysis or hemoperfusion accounted for 49 cases per one million poison center calls, compared to the 6 cases per one million poison center calls from 1996 to 2005. According to the American Association of Poison Control Centers, there were 133 exposures to theophylline in 2014. Of these, 14 were in children younger than 6 years old, and 107 were in patients older than 19 years old. There were 2 deaths out of 81 patients treated for theophylline exposure treated at healthcare facilities.

Pathophysiology

Theophylline has 2 primary mechanisms. One mechanism is that theophylline blocks adenosine receptors, which has both therapeutic and toxic effects such as bronchodilation, tachycardia, cardiac arrhythmias, seizures, and cerebral vasoconstriction. At larger doses, theophylline inhibits phosphodiesterase causing increased cyclic adenosine monophosphate resulting in increased levels of adrenergic activation and catecholamine release. In theophylline toxicity, epinephrine levels can be 4- to 8-times higher than normal, and norepinephrine concentrations can be 4- to 10-times higher than normal. Increased catecholamine concentrations have a variety of adverse effects such as cardiac arrhythmias, metabolic acidosis, hyperglycemia, and hypokalemia. Chronic theophylline toxicity can occur when there is an accumulation of the drug due to metabolism being overwhelmed or inhibited. It can also occur when clearance is decreased.[1][4]

Toxicokinetics

Toxic doses of theophylline can be as low as 7.5 mg/kg. When taken orally, 80% to 100% of theophylline is absorbed in the gastrointestinal tract. Peak serum levels can occur from 30 to 120 minutes for immediate release formulations. Sustained release formulations have peak levels between 6 and 10 hours. Intravenously, theophylline takes 30 minutes to reach peak levels. Therapeutic serum levels range from 10 to 20 mcg/mL. Toxic levels are considered to be 20 mcg/mL or higher. However, toxic effects can be seen within therapeutic levels as well.   Cardiac dysrhythmias, seizures, and death can be seen with levels of 80 to 100 mcg/mL. Chronic toxicity can be seen at levels of 40 to 60 mcg/mL. Fifty percent to 65% of theophylline is protein-bound in the circulation. Volume distribution is small, at 0.45 L/kg.  The half-life varies with age. A half-life of 4 to 8 hours is seen in young adults. A shorter half-life is seen in newborns. Theophylline is metabolized in the liver by the cytochrome P450 system and excreted by the kidneys. Therefore, any agents or pathology that alters the cytochrome P450 system or renal function can have a substantial effect on theophylline levels.[1][5]

History and Physical

Depending on the dose, route of administration, and coingestants, there is a wide spectrum of clinical effects of theophylline toxicity, ranging from abdominal pain to cardiac arrhythmias to seizures. Many times, patients cannot give a clear history, so it is imperative to obtain a history from EMS personnel, family, friends, and witnesses.

  • General: Agitation, irritability, restlessness
  • Cardiovascular: Sinus tachycardia, ventricular tachycardia atrial fibrillation, supraventricular tachycardia, hypotension, cardiac arrest
  • Respiratory: Tachypnea, acute lung injury, respiratory alkalosis
  • Gastrointestinal (GI): Nausea, vomiting, abdominal pain
  • Neurological: Tremors, hallucinations, seizures[1][3]

Evaluation

 Workup should include the following:

  • Serum theophylline level
  • Serum glucose: Hyperglycemia is common theophylline toxicity
  • Complete metabolic panel: Hypokalemia and metabolic acidosis are common with theophylline toxicity
  • Complete blood count (CBC): White blood cells can be elevated due to increase catecholamine release
  • Serum calcium: Hypercalcemia is seen in theophylline toxicity
  • Serum acetaminophen level, serum salicylate level, urine drug screen: Evaluate for co-ingestion or unknown ingestion
  • Serum iron level: Iron toxicity can have a similar presentation to theophylline toxicity
  • Creatine kinase: Evaluation for rhabdomyolysis
  • Liver function tests: Evaluation of liver dysfunction as the liver metabolizes theophylline
  • ECG to evaluate arrhythmias, ischemia or other toxic ingestions
  • Consider CT Head: Evaluation of other potential causes of altered mental status or seizures[1][3]

Treatment / Management

Most patients with theophylline toxicity are successfully managed with supportive care. Airway, breathing, circulation, and hemodynamic monitoring are essential to the care of patients with theophylline toxicity. Intubation with ventilator support may be required for airway protection.

GI decontamination: Activated charcoal (1 g/kg) by mouth or nasogastric tube is recommended in patients that present to the emergency department within if there are no contraindications to activated charcoal. Gastric lavage or induced emesis is not recommended in theophylline toxicity. Whole bowel irrigation is controversial as animal models do not demonstrate that it is a beneficial therapy. Multiple-dose activated charcoal is recommended for acute theophylline toxicity if there are no contraindications.

Hypotension-isotonic saline (20 mL/kg): Hypotension refractory to IV fluid administration, an alpha agonist such as phenylephrine is recommended. Primarily alpha agonists such as norepinephrine can be used as well. Treatment of hypotension with a beta antagonist should only be used in consultation with a toxicologist.

Nausea and vomiting: Ondansetron is recommended. Metoclopramide can be used in cases that are refractory to ondansetron.

Cardiac arrhythmias: Treatment of cardiac arrhythmias should be managed according to advanced cardiac life support and pediatric advanced life support protocols.

Seizures: In adults benzodiazepines (lorazepam, midazolam, diazepam) are the first-line treatment for theophylline-induced seizures.  Phenobarbital and continuous infusion of propofol or midazolam can be used for seizures refractory to benzodiazepines. In pediatrics, benzodiazepines are the first-line treatment for seizures. Phenobarbital or continuous infusion of midazolam or pentobarbital or propofol can be used refractory seizures.

Hemodialysis: In acute overdose, hemodialysis is indicated for life-threatening arrhythmias and seizures, theophylline levels greater than 100 mcg/mL, clinical instability, or increased theophylline levels despite appropriate care. In chronic theophylline toxicity, hemodialysis is indicated with severe symptoms, such as life-threatening arrhythmias, seizures, and theophylline levels greater than 60 mcg/mL in patients between the ages of 6 months to 60 years, or levels greater than 50 mcg/mL in patients of age less than 6 months or greater than 60 years. Hemodialysis is preferred as opposed to hemoperfusion. However, if hemodialysis is not available, hemoperfusion may be used instead. Decisions to initiate hemodialysis or hemoperfusion should always be made in consultation with a medical toxicologist.

Hypokalemia: Potassium supplementation Is recommended for patients with ventricular arrhythmias or potassium levels less than 3 mEq/L.[1][3][5]

Differential Diagnosis

  • Alcoholic ketosis
  • Amphetamine intoxication
  • Anticholinergic poisoning
  • Atrial fibrillation
  • Atrial flutter
  • Bipolar disorder
  • Cocaine intoxication
  • Carbon monoxide toxicity
  • Diphenhydramine toxicity
  • Delirium tremors
  • Diabetic ketoacidosis
  • Encephalitis
  • Hypercalcemia
  • Hyperthyroidism
  • Hyponatremia
  • Hypoxia
  • Iron toxicity
  • Monoamine oxidase inhibitor toxicity
  • Salicylates toxicity
  • Sepsis
  • Status epilepticus
  • Ventricular tachycardia

Complications

  • Arrhythmias
  • Cardiac arrest
  • Acute lung injury
  • Agitation, hallucinations
  • Seizures
  • Heart failure
  • Liver dysfunction

Enhancing Healthcare Team Outcomes

Theophylline toxicity is best managed in a multidisciplinary fashion. The drug can affect many organ systems including the heart, lung, central nervous system (CNS), and GI tract. The key to theophylline toxicity is prevention. First, healthcare providers should avoid prescribing this agent for asthma when other safer drugs are available. All patients should be educated about the dangers of theophylline. Parents should be told to store theophylline in a safe place away from the reach of children. For those who intentionally overdose on the drug, a mental health consult is recommended before discharge.[6] (Level V)

Outcomes

Only anecdotal reports and small case series exist on short-term outcomes after theophylline toxicity. However, despite the few cases being reported, the drug is associated with high morbidity and mortality. Several deaths have been reported both in the United States and abroad following theophylline toxicity. But overall, the number of cases of theophylline toxicity are subsiding as healthcare providers are no longer prescribing this agent for asthma.[7][8] (Level V)


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Theophylline Toxicity - Questions

Take a quiz of the questions on this article.

Take Quiz
A 58-year-old man with chronic obstructive pulmonary disease is brought to the emergency department for disorientation. He has been taking theophylline for six months, and the bottle is empty. His theophylline level is 51 mcg/mL. Which action should be taken first?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which electrolyte disturbance is most commonly found with theophylline overdose?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What anti-asthmatic drug can cause convulsions and arrhythmias?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is most appropriate for the early treatment of theophylline overdose?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A patient with chronic obstructive pulmonary disease (COPD) is being treated with a steroid inhaler, theophylline by mouth, and oral steroids daily. Thiabendazole is to be administered for the treatment of roundworms. For which of the following should the patient be monitored?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is the most appropriate test to order in the case of a elderly male with chronic obstructive pulmonary disease and hypertension who takes enalapril, aspirin, hydrochlorothiazide, theophylline, and an over the counter medication for heartburn who is found on exam to have a normal blood pressure, tachycardia, a tremor, and an otherwise normal cardiac exam?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which would be indicated in severe theophylline toxicity causing supraventricular tachycardia and hypotension?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
An asthmatic patient that has developed low potassium should be evaluated for:



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 17 year old is administered theophylline for his asthma. He inadvertently takes 4 pills at one time and then presents to the emergency department with tachycardia, diaphoresis, palpitations, and anxiety. Blood levels reveal very high levels of theophylline. The patient is hypotensive and unresponsive to fluids. Which treatment would be best?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
If a patient were to take excessive amounts of theophylline, which of the following toxic responses might be expected?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 54-year-old male with past medical history of chronic obstructive pulmonary disease and depression presents to the emergency department by emergency medical services after a suicide attempt. The patient's wife states she saw the patient take "half a bottle" of theophylline pills approximately 90 minutes ago. The patient is agitated and tremulous. His heart rate is 130 beat per minute, and his blood pressure is 160/90 mmHg. The patient then begins to have a generalized seizure. What medication should be given to treat his seizure?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is not a complication of theophylline toxicity?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Theophylline Toxicity - References

References

Greene SC,Halmer T,Carey JM,Rissmiller BJ,Musick MA, Theophylline toxicity: An old poisoning for a new generation of physicians. Turkish journal of emergency medicine. 2018 Mar     [PubMed]
Sharma S,Chakraborty RK, Asthma Medications null. 2018 Jan     [PubMed]
Aggelopoulou E,Tzortzis S,Tsiourantani F,Agrios I,Lazaridis K, Atrial Fibrillation and Shock: Unmasking Theophylline Toxicity. Medical principles and practice : international journal of the Kuwait University, Health Science Centre. 2018     [PubMed]
Khan Z,Khan MS, Rare Case of Theophylline Toxicity due to Influenza A Infection in an Adult With Asthma. American journal of therapeutics. 2018 Jul 10     [PubMed]
Monteiro J,Alves MG,Oliveira PF,Silva BM, Pharmacological potential of methylxanthines: Retrospective analysis and future expectations. Critical reviews in food science and nutrition. 2018 Apr 6     [PubMed]
Blix HS,Viktil KK,Moger TA,Reikvam A, Drugs with narrow therapeutic index as indicators in the risk management of hospitalised patients. Pharmacy practice. 2010 Jan     [PubMed]
Mohamad N,Abd Halim NN,Ahmad R,Baharuddin KA, Theophylline toxicity: A case report of the survival of an undiagnosed patient who presented to the emergency department. The Malaysian journal of medical sciences : MJMS. 2009 Apr     [PubMed]
Shannon MW, Comparative efficacy of hemodialysis and hemoperfusion in severe theophylline intoxication. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 1997 Jul     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Pharmacy-Pharmacotherapy. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Pharmacy-Pharmacotherapy, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Pharmacy-Pharmacotherapy, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Pharmacy-Pharmacotherapy. When it is time for the Pharmacy-Pharmacotherapy board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Pharmacy-Pharmacotherapy.