Theophylline

Mechanism of Action

Theophylline is a methylxanthine and a bronchodilator. Although its mechanism of action is not fully known, the relaxant effect on smooth muscle is thought to be a result of phosphodiesterase (PDE) isoenzyme inhibition, leading to an increase in cAMP and/or cGMP. Type IV PDE is implicated in inflammatory cells and theophylline may have some anti-inflammatory effect.

Competitive antagonism of adenosine at A1 and A2 receptors may also have a role to play in the mechanism of theophylline. Furthermore, theophylline enhances suppressor T-cell activity and reduces eosinophil and neutrophil function.

Created in BioRender. Boucher, M. (2026) https://BioRender.com/fj8d3in

Fig 1: Mechanism of Action of Bronchodilators such as β2 agonists, theophylline and muscarinic antagonists

Pharmacokinetics

When given intravenously, theophylline ethylenediamine is administered (also known as aminophylline) to increase its solubility in water. Aminophylline contains 80% theophylline, therefore when converting from IV to oral dosing, a conversion factor of 0.8 should be applied. This assumes that the patient is stable on IV aminophylline for at least 48 hours. When given orally, theophylline is administered in a prolonged-release formulation. 

Absorption

Theophylline is either administered orally with a prolonged-release preparation or intravenously as aminophylline. When given orally, it is well absorbed with bioavailability (F)=100% and Tmax occurs at approximately 5 hours. 

Distribution

Theophylline is approximately 60% bound to plasma proteins. It crosses into the placenta and is present in breastmilk. In pregnancy, protein binding decreases, leading to a higher proportion of free drug, therefore aiming for a lower therapeutic range may be indicated. 

Theophylline distributes poorly into fat, therefore mg/kg doses (when using in children/using aminophylline) are usually calculated based on ideal body weight (IBW). 

[clinical-start]How to calculate Ideal Body Weight

IBW (kg) for males = 50 + 2.3(inches over 5ft)

IBW (kg) for females = 45.5 + 2.3(inches over 5ft)[clinical-end

Metabolism

Metabolised primarily by CYP450 enzymes (mainly CYP1A2) to 1, 3-dimethyl uric acid and 3- methylxanthine.

Excretion

Excreted mainly via the kidneys; approximately 10% is excreted unchanged. Liver dysfunction and viral infection increase exposure and prolong half-life, while smoking reduces half-life via enzyme induction 

Half life = 8hours in healthy adults

Monitoring

Baseline monitoring is recommended prior to theophylline initiation, including liver function tests (LFTs), urea and electrolytes and smoking status.

Theophylline has a narrow therapeutic window therefore monitoring of plasma concentrations is required to ensure levels are within range. For theophylline, therapeutic plasma concentration is 5-20mg/L. Adverse effects can occur between 10-20mg/L, with severity and frequency increased at levels >20mg/L.

Oral theophylline (prolonged-release)

Plasma levels should be taken 5 days after treatment commences and 3 days after a dose change. The level should be taken 4-6 hours post dose. Generally levels are taken every 6 – 12 months, but may be indicated more frequently in the presence of taking interacting medications (check level 2-3 days post initiation), change of smoking status and adverse effects that may indicate toxicity. 

Aminophylline IV

Plasma level should be taken 1-2 days after treatment commences for smokers, and 2 days for smokers due to enhanced clearance. The level should be taken as a trough level, at least 14 hours after the initial maintenance infusion. 

Contraindications

Both theophylline and aminophylline are contraindicated in children <6 months of age and in patients with porphyria.

Theophylline is contraindicated with ephedrine in patients <6 years old due to the risk of theophylline toxicity.

Cautions and Adverse Effects

Theophylline has a narrow therapeutic window and at levels >20mg/L can cause cardiac dysrhythmias, seizures and gastrointestinal disturbances such as nausea, vomiting and epigastric pain. 

Metabolic effects such as hypokalaemia, hyperglycaemia, hypomagnesaemia, hypophosphataemia (aminophylline), hyponatraemia (aminophylline) and metabolic acidosis may occur. Toxicity can occur as long as 12 hours post dosing when prolonged-release formulations are taken.

Due to the narrow therapeutic window, caution should be undertaken when prescribing theophylline to elderly patients with conditions where theophylline clearance may be reduced. 

Caution should also be applied in the following conditions: 

• Cardiac arrhythmias/cardiac disease (can exacerbate)
• Reduced theophylline clearance can be seen in hepatic disease, hypothyroidism and viral infections 
• Exacerbations of lung disease
• Fever (inhibition of CYP enzymes can lead to increased theophylline levels)

In contrast, hyperthyroidism and cystic fibrosis can increase theophylline clearance; therefore, dose increases may be required.

Theophylline should also be used with caution in patients with a history of seizures, as theophylline may exacerbate frequency and duration of seizures, especially when given alongside ketamine. Furthermore, when given orally theophylline can act as an irritant to the gastrointestinal tract, so caution should be applied to patients with peptic ulcers.

Interactions

Theophylline is associated with numerous clinically significant drug interactions due to its metabolism primarily via the hepatic cytochrome P450 enzyme system, particularly CYP1A2. Drugs that alter the activity of these enzymes may significantly affect plasma concentrations of theophylline and therefore increase the risk of therapeutic failure or toxicity.

Enzyme Inducers

Drugs that induce hepatic enzyme activity can increase the metabolism of theophylline, leading to reduced plasma concentrations and decreased therapeutic effect. Important enzyme inducers include:

• Rifampicin
• Phenytoin
• Carbamazepine
• St John’s Wort
• Ritonavir

These agents may increase the clearance of theophylline and reduce its plasma concentrations, potentially necessitating dose adjustment and therapeutic drug monitoring. Additionally, theophylline may reduce plasma concentrations of phenytoin.

Enzyme Inhibitors

Several drugs inhibit hepatic metabolism of theophylline and may therefore increase plasma concentrations and the risk of toxicity. Examples include:

• Erythromycin
• Clarithromycin
• Ciprofloxacin
• Diltiazem
• Fluconazole
• Cimetidine

When these drugs are initiated or discontinued during theophylline therapy, plasma theophylline concentrations should be monitored and dose adjustments may be required; the dose is generally halved during treatment with potent CYP2E1, CYP2A1 or CYP3A3 inhibitors. 

By TeachMeSeries Ltd (2026)

Fig 2: CYP1A2 inducers and inhibitors

Drugs Affecting Theophylline Clearance

Some medications reduce the clearance of theophylline and may increase systemic exposure. These include:

• Methotrexate
• Verapamil
• Propranolol
• Isoniazid
• Oral contraceptives

Fluvoxamine is a particularly potent inhibitor of theophylline metabolism and should generally be avoided. If concurrent use is unavoidable, theophylline dosage should be reduced and plasma concentrations monitored closely.

Lifestyle Factors

Lifestyle factors can also significantly influence the pharmacokinetics of theophylline. Cigarette smoking induces hepatic enzymes (particularly CYP1A2), increasing the clearance of theophylline and potentially reducing therapeutic efficacy. Conversely, smoking cessation may reduce clearance and increase the risk of toxicity, therefore dose adjustment may be required.

Furthermore, high alcohol intake can reduce exposure of theophylline due to CYP enzyme induction. 

Pharmacodynamic Interactions

Certain drugs may increase the risk of adverse effects when administered with theophylline due to pharmacodynamic interactions:

• Increased risk of convulsions when administered with quinolone antibiotics or ketamine.
• Increased risk of hypokalaemia when used concurrently with β2 agonists, diuretics or corticosteroids.

Effects on Other Drugs

Theophylline may increase the urinary clearance of lithium, potentially reducing lithium plasma concentrations and therapeutic efficacy.

References

1. Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019. 
2. Switching between aminophylline and theophylline in adults – NHS SPS – Specialist Pharmacy Service – The first stop for professional medicines advice Accessed 9/3/26
3. UNIPHYLLIN 200mg prolonged release tablets – Summary of Product Characteristics (SmPC) – (emc) | 100850 Accessed 14/03/26
4. Aminophylline 25 mg/ml solution for injection/infusion – Summary of Product Characteristics (SmPC) – (emc) | 6299 Accessed 14/03/26
5. Theophylline monitoring – NHS SPS – Specialist Pharmacy Service – The first stop for professional medicines advice Accessed 16/03/2026
6. Pokrajac M, Simić D, Varagić VM. Pharmacokinetics of theophylline in hyperthyroid and hypothyroid patients with chronic obstructive pulmonary disease. Eur J Clin Pharmacol. 1987;33(5):483-6. doi: 10.1007/BF00544240. PMID: 3428340.