How does theophylline work and what is its typical dosage and administration?

From the Guidelines

Theophylline works as a bronchodilator by inhibiting phosphodiesterase enzymes, which increases cyclic AMP levels in bronchial smooth muscle cells, causing relaxation and airway dilation, and it also has anti-inflammatory effects and improves diaphragmatic contractility. The mechanism of action is primarily through the inhibition of phosphodiesterase 3 at higher serum levels, which contributes to its bronchodilator effects, and at lower doses, it likely has anti-inflammatory effects mediated through phosphodiesterase 4 inhibition and activation of histone deacetylase 2 1.

Key Points About Theophylline

• The typical adult dosage ranges from 300-600 mg daily, divided into 2-3 doses for immediate-release formulations or once daily for extended-release preparations, with initial dosing often starting at 300 mg daily and titrated based on serum levels 1.
• The therapeutic range is 10-20 mcg/mL, and monitoring of serum levels is essential due to its narrow therapeutic window, with toxicity occurring above 20 mcg/mL.
• Dose adjustments are necessary for patients with liver disease, heart failure, or those taking medications that interact with theophylline's metabolism, such as certain antibiotics and seizure medications.
• Common side effects include nausea, headache, insomnia, and at higher levels, cardiac arrhythmias and seizures.
• Theophylline should be taken consistently with respect to meals, as food can affect absorption.

Administration and Monitoring

• For stable patients with COPD, treatment with oral slow-release theophylline twice daily is suggested to prevent acute exacerbations of COPD 1.
• Patients should be advised that changes in tobacco use habits will affect serum theophylline levels and that they should inform their physicians if they stop smoking while taking theophylline.
• Physicians should use the lowest effective dose in prescribing theophylline in order to avoid adverse effects and should be vigilant to avoid serious drug interactions that lead to changes in serum theophylline levels 1.

From the FDA Drug Label

Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects) While the mechanisms of action of theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.

Theophylline works by relaxing smooth muscles in the airways, which leads to bronchodilation, and by suppressing the response of the airways to stimuli. The exact mechanisms of action are not fully understood, but it is thought to involve the inhibition of phosphodiesterase isozymes. Additionally, theophylline increases the force of contraction of diaphragmatic muscles. The typical dosage and administration of theophylline should be guided by monitoring serum theophylline concentrations and the patient's clinical response. The dose should be low initially and increased slowly over a period of a week or longer. Serum theophylline concentrations should be measured regularly to ensure the dose is appropriate. 2 Key points to consider when administering theophylline include:

• Monitoring serum theophylline concentrations regularly
• Adjusting the dose based on the patient's clinical response and serum concentrations
• Being aware of potential interactions with other drugs and physiologic conditions that can alter theophylline clearance. 2 It is also important to note that saliva concentrations of theophylline cannot be used reliably to adjust dosage without special techniques. 2

From the Research

Mechanism of Action

• Theophylline works by inhibiting phosphodiesterase (PDE)3, which leads to bronchodilatation 3
• It also has anti-inflammatory effects by inhibiting PDE4 and activating histone deacetylase-2, resulting in the switching off of activated inflammatory genes 3
• Theophylline can reverse corticosteroid resistance, which may be of particular value in severe asthma and COPD 3

Typical Dosage and Administration

• Theophylline is given systemically, either orally as slow-release preparations for chronic treatment or intravenously for acute exacerbations of asthma 3
• The efficacy of theophylline is related to blood concentrations, which are determined mainly by hepatic metabolism 3
• The typical dosage of theophylline is not specified, but it is usually used as an add-on therapy in patients with asthma not well controlled on inhaled corticosteroids with or without long-acting β2-agonists and in patients with COPD with severe disease not controlled by bronchodilator therapy 3

Side Effects

• Side effects of theophylline are related to plasma concentrations and include nausea, vomiting, and headaches due to PDE inhibition 3
• At higher concentrations, theophylline can cause cardiac arrhythmias and seizures due to adenosine A1-receptor antagonism 3

Therapeutic Uses

• Theophylline is used to treat airway diseases, including asthma and chronic obstructive pulmonary disease (COPD) 3, 4, 5
• It may be useful in reversing corticosteroid resistance in COPD and severe asthma 3
• Theophylline is not generally recommended for the treatment of other respiratory disorders such as obstructive sleep apnea (OSA) or hypoxia 6