Why is theophylline no longer used?

Should We Still Be Using Theophylline to Treat Asthma?

Theophylline is a medication primarily used to treat asthma and chronic obstructive pulmonary disease (COPD) as a second-line drug. It functions as a bronchodilator. This article reviews the indications, actions, and contraindications for using theophylline as a potential agent in managing asthma and COPD, highlighting its mechanism of action, adverse event profile, pharmacokinetics, and drug interactions.

Objectives:

• Describe the mechanism of action of theophylline.
• Review the therapeutic uses of theophylline.
• Explain the side effects of theophylline.
• Outline the importance of interprofessional team collaboration when dosing and monitoring theophylline therapy.

Indications

Theophylline, derived from methylxanthine, has smooth muscle relaxant, bronchial dilation, diuretic, cardiac, and central nervous system (CNS) stimulant activities. Initially synthesized in 1895, it was clinically utilized for asthma in 1922 due to its bronchodilator effects. It treats various respiratory conditions like asthma and COPD.

Medical Uses

• Chronic obstructive pulmonary disease
• Asthma
• Infant Apnea
• Anosmia (under investigation, a 2008 study suggested potential benefits)

Asthma Exacerbations

The current clinical guidelines do not recommend theophylline for asthma exacerbations (2018 GINA Report; NAEPP 2007).

COPD Management

According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) in 2018, IV theophylline is not recommended for acute COPD due to significant side effects.

Mechanism of Action

Theophylline relaxes the smooth muscles in the bronchial airways and pulmonary blood vessels and reduces airway responsiveness to histamine, adenosine, methacholine, and allergens. It functions through two mechanisms:

• Competitive nonselective phosphodiesterase inhibition (mainly types III and IV), increasing intracellular cAMP concentration, activating protein kinase A, and inhibiting TNF-alpha and leukotriene synthesis.
• Nonselective adenosine receptor antagonism on A1, A2, and A3 receptors, affecting cardiac functions and enhancing diaphragmatic muscle contraction.
• Other mechanisms include inhibiting nuclear factor-kappaB, increasing interleukin-10 secretion, inhibiting phosphoinositide 3-kinase-delta, and increasing apoptosis of inflammatory cells.

Administration

Theophylline can be administered orally (tablets, solution, syrup, capsule) or intravenously in its more soluble form, aminophylline. Careful administration is required for patients consuming high-caffeine foods or drinks.

Intravenous (IV)

For acute bronchospasm, a loading dose followed by a maintenance dose keeps serum concentrations at 10-15 mg/L. IV aminophylline is less commonly used now, with recommended dosages adjusted based on the patient's condition and theophylline use history.

Oral

Oral theophylline tablets offer rapid absorption but are not recommended due to plasma concentration fluctuations. Sustained-release preparations provide steadier plasma concentrations over 12-24 hours. Consistent administration with or without food maintains stable serum drug concentrations.

Other Routes

Inhalation and intramuscular administration are ineffective and painful, respectively.

Dosing Considerations

• Aminophylline doses should increase by 25% (aminophylline is 79%-86% theophylline).
• Calculations should use ideal body weight.
• Immediate-release theophylline is recommended for loading.

Adverse Effects

Theophylline has a narrow therapeutic window, and interaction with other drugs limits its use. Monitoring serum concentrations can prevent toxicity. Common side effects include nausea, vomiting, headache, increased stomach acid secretion, gastroesophageal reflux, CNS symptoms, and, in severe cases, seizures and cardiac arrhythmias.

Contraindications

• Hypersensitivity to theophylline or its components (e.g., corn-related products in injections).
• Hypersensitivity to xanthine derivatives.
• Coronary artery disease, where cardiac stimulation might be harmful.

Precautions

• Cardiovascular disease: Use cautiously in patients with arrhythmias.
• Cystic fibrosis: Increased theophylline clearance in these patients necessitates caution.
• Hepatic impairment: Clearance decreases in these patients, requiring frequent monitoring and dose adjustment.
• Hyperthyroidism: Use cautiously due to increased clearance.
• Peptic ulcer disease: Theophylline may exacerbate ulcers.
• Seizure disorders: Theophylline may worsen the condition.

Special Populations

• Elderly: Increased risk of serious theophylline toxicity.
• Pediatric: Regular monitoring of concentrations is necessary, especially for children under one year.

Pregnancy

Theophylline is category C and should only be used if the potential benefit outweighs the risk to the fetus.

Monitoring

Monitoring includes the patient’s heart rate, CNS effects, respiratory rate, electrolyte concentrations, fluid balance, and acid-base balance during prolonged IV therapy. Serum theophylline concentrations should be checked regularly, especially after therapy initiation, dose adjustments, and any occurrence of toxicity symptoms.

Oral Theophylline

For oral treatment, serum concentrations should be monitored at six-month intervals for rapidly developing children and annually for other patients with well-controlled symptoms.

IV Theophylline

Following a loading dose, serum concentrations should be checked 30 minutes post-administration and regularly during the continuous infusion to adjust dosing as needed.

Therapeutic Concentrations for Theophylline

• Children: 5-15 mcg/mL
• Adults: 10-20 mcg/mL
• Toxic concentration: >20 mcg/mL

Toxicity

Theophylline toxicity can cause gastrointestinal distress, insomnia, tremor, severe nausea, vomiting, cardiac arrhythmias, hypotension, and convulsions. Overdoses could be lethal due to arrhythmias and convulsions.

Enhancing Healthcare Team Outcomes

Theophylline is prescribed by various healthcare professionals, including nurse practitioners, pulmonologists, and emergency department physicians. Awareness of its adverse effect profile is crucial due to the low therapeutic index and potential side effects. Regular drug concentration monitoring and close patient observation are essential. With safer bronchodilators available, theophylline should not be routine unless necessary, with the healthcare team being alert for potential adverse effects. An interprofessional approach can improve patient outcomes when using this medication. For more information, please visit theophylline synthetic raw material manufacturer. For thoughtful service on theophylline and other chemical needs, Guangxing offers efficient solutions. Click here to learn more.