Theophylline

Usage

• Theophylline is primarily prescribed for the treatment of respiratory diseases like asthma, chronic obstructive pulmonary disease (COPD), and bronchospasm. It helps to prevent and treat wheezing, shortness of breath, and chest tightness. It can also be used to treat apnea of prematurity in newborns.
• Pharmacological Classification: Bronchodilator, smooth muscle relaxant, phosphodiesterase inhibitor, adenosine receptor antagonist.
• Mechanism of Action: Theophylline relaxes the smooth muscles of the airways by inhibiting phosphodiesterase enzymes, which leads to increased intracellular cyclic AMP levels. It also acts as an adenosine receptor antagonist, further contributing to bronchodilation.

Alternate Names

• 1,3-Dimethylxanthine
• Elixophyllin
• Uniphyl
• Brand Names: Theo-24, Theochron, Elixophyllin, Slo-Bid, Uniphyl, Theo-Dur.

How It Works

• Pharmacodynamics: Theophylline relaxes bronchial smooth muscle, resulting in bronchodilation and improved airflow. It also has mild diuretic, cardiac stimulant, and central nervous system stimulant effects.
• Pharmacokinetics:
  • Absorption: Well-absorbed orally, with bioavailability varying depending on the formulation (immediate-release vs. extended-release).
  • Metabolism: Extensively metabolized in the liver by CYP450 enzymes, primarily CYP1A2 and CYP3A4.
  • Elimination: Primarily eliminated via hepatic metabolism, with a small amount excreted unchanged in the urine. The elimination half-life varies widely depending on age, smoking status, liver function, and co-administered medications.
• Mode of Action: Theophylline primarily inhibits phosphodiesterase enzymes, leading to increased intracellular cyclic AMP. This, in turn, relaxes bronchial smooth muscle and causes bronchodilation. It also antagonizes adenosine receptors, further contributing to bronchodilation and potentially reducing inflammation.
• Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Inhibits phosphodiesterase enzymes (PDE3, PDE4, PDE5), antagonizes adenosine receptors (A1, A2), and may modulate histone deacetylase activity.
• Elimination Pathways: Primarily hepatic metabolism by CYP1A2 and CYP3A4, with a small amount excreted unchanged in urine.

Dosage

Standard Dosage

Adults:

• Immediate-Release: 300 mg per day initially, divided every 6-8 hours, then titrated up to a maximum of 600 mg per day based on serum theophylline levels and clinical response.
• Extended-Release: 300-400 mg once daily or divided every 12 hours, then titrated up to a maximum of 600 mg per day based on serum theophylline levels and clinical response.

Children:

• Dosage is based on body weight and age.
• Refer to pediatric dosing guidelines available in standard resources like the BNF for Children or specific product information for detailed pediatric dosing recommendations.
• Close monitoring of serum theophylline levels is essential in children due to their variable metabolism and increased risk of toxicity.

Special Cases:

• Elderly Patients: Lower starting doses (25% reduction compared to younger adults) and slower titration are recommended due to age-related decline in renal and hepatic function.
• Patients with Renal Impairment: Dose reduction is necessary based on creatinine clearance.
• Patients with Hepatic Dysfunction: Dose reduction is necessary based on the severity of liver impairment.
• Patients with Comorbid Conditions: Dosage adjustments may be required for patients with congestive heart failure, sepsis, or other conditions that can alter theophylline clearance.

Clinical Use Cases

• Intubation: Theophylline is not typically used for intubation.
• Surgical Procedures: Theophylline is not routinely administered during surgical procedures.
• Mechanical Ventilation: Low-dose theophylline (e.g., 200 mg/day of aminophylline) may be used as an adjunct to improve diaphragmatic function in patients with ventilator-induced diaphragmatic dysfunction.
• Intensive Care Unit (ICU) Use: Theophylline might be administered in ICU for severe exacerbations of respiratory diseases, with dose adjusted according to patient specific factors and close monitoring of theophylline serum levels.
• Emergency Situations: Intravenous aminophylline (a theophylline salt) can be used in acute severe asthma exacerbations, though it is less effective than nebulized beta-2 agonists and systemic corticosteroids. Loading dose: 6-7 mg/kg (aminophylline) over 20-30 minutes followed by a maintenance infusion.

Dosage Adjustments

• Dose adjustments are essential based on serum theophylline levels, clinical response, and patient-specific factors, including renal/hepatic dysfunction, congestive heart failure, smoking status, interacting medications, and genetic polymorphisms affecting CYP450 enzymes.

Side Effects

Common Side Effects:

• Nausea, vomiting
• Headache
• Insomnia
• Irritability
• Tachycardia
• Diuresis

Rare but Serious Side Effects:

• Seizures
• Cardiac arrhythmias
• Respiratory arrest

Long-Term Effects:

• Chronic insomnia
• Growth retardation in children (with high doses)

Adverse Drug Reactions (ADR):

• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Angioedema

Contraindications

• Hypersensitivity to theophylline or other xanthine derivatives.
• Active peptic ulcer disease
• Uncontrolled seizure disorders

Drug Interactions

• CYP450 Interactions:
  • Inducers (e.g., rifampicin, phenobarbital, smoking): Decrease theophylline levels.
  • Inhibitors (e.g., cimetidine, ciprofloxacin, erythromycin, fluconazole): Increase theophylline levels.
• Other Interactions:
  • Caffeine: Additive stimulant effects.
  • Beta-blockers: May antagonize bronchodilator effects.
  • Lithium: May decrease lithium levels.
• Food and Lifestyle Factors:
  • High-protein/low-carbohydrate diets: Increase theophylline clearance.
  • High-carbohydrate/low-protein diets: Decrease theophylline clearance.
  • Charbroiled foods: Increase theophylline clearance.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C (US FDA)
• Fetal Risks: Potential for fetal toxicity, including low birth weight and premature birth.
• Breastfeeding: Theophylline is excreted in breast milk. Monitor infants for irritability and feeding difficulties.

Drug Profile Summary

• Mechanism of Action: Bronchodilation by inhibiting phosphodiesterase enzymes and antagonizing adenosine receptors.
• Side Effects: Nausea, vomiting, headache, insomnia, seizures, cardiac arrhythmias.
• Contraindications: Hypersensitivity, active peptic ulcer, uncontrolled seizures.
• Drug Interactions: CYP450 inducers/inhibitors, caffeine, beta-blockers.
• Pregnancy & Breastfeeding: Category C; use with caution. Excreted in breast milk.
• Dosage: Adult: 300-600 mg/day; pediatric: weight-based dosing. Adjust based on serum levels.
• Monitoring Parameters: Serum theophylline levels, ECG, renal and liver function tests.

Popular Combinations

• Theophylline is often combined with inhaled corticosteroids and long-acting beta-agonists in the management of persistent asthma and COPD.

Precautions

• General Precautions: Monitor serum theophylline levels, renal and hepatic function, and cardiac status.
• Specific Populations:
  • Pregnant Women: Use only if clearly needed and under close monitoring.
  • Breastfeeding Mothers: Monitor infants for side effects.
  • Children & Elderly: Adjust dosage based on age and weight.
• Lifestyle Considerations: Smoking and diet can affect theophylline clearance. Advise patients to avoid excessive caffeine intake.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Theophylline?

A: The recommended dosage varies depending on the patient’s age, weight, medical condition, and formulation used (immediate-release or extended-release). Adults typically start with 300-400 mg/day, which can be adjusted based on serum theophylline levels and clinical response, up to a maximum of 600 mg/day for most adults. Pediatric dosing is weight-based and should be carefully calculated and monitored.

Q2: How should theophylline levels be monitored?

A: Serum theophylline levels should be measured after 4-6 hours post-dose for immediate-release formulations and at steady-state (usually after 2-3 days) for extended-release formulations. The therapeutic range is generally considered to be 10-20 mcg/mL, although some patients may benefit from lower levels (5-15 mcg/mL), especially in outpatient settings to minimize side effects.

Q3: What are the signs of theophylline toxicity?

A: Signs of theophylline toxicity include nausea, vomiting, headache, insomnia, irritability, seizures, cardiac arrhythmias, and tachycardia. Severe toxicity can lead to respiratory arrest and death.

Q4: How is theophylline toxicity managed?

A: Management includes supportive care, activated charcoal, and multiple-dose activated charcoal for severe cases. Consider hemodialysis or hemoperfusion in life-threatening situations with very high serum levels or refractory seizures.

Q5: What are the drug interactions to be aware of with theophylline?

A: Theophylline interacts with numerous medications, including CYP450 enzyme inducers (e.g., rifampin, phenobarbital) and inhibitors (e.g., cimetidine, ciprofloxacin, erythromycin). It also interacts with caffeine, beta-blockers, lithium, and other medications.

Q6: Can theophylline be used during pregnancy?

A: Theophylline is classified as Pregnancy Category C, meaning that animal studies have shown some adverse effects on the fetus, but there are no adequate and well-controlled studies in humans. It should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

Q7: Can theophylline be used in children?

A: Yes, theophylline can be used in children, but the dosage must be carefully calculated based on their weight and age. Close monitoring of serum levels is crucial in pediatric patients due to variable clearance and higher risk of toxicity.

Q8: What is the role of theophylline in mechanically ventilated patients?

A: Low-dose theophylline (e.g., 200 mg/day of aminophylline) may be considered in patients with ventilator-induced diaphragmatic dysfunction (VIDD) to improve diaphragmatic contractility and facilitate weaning from mechanical ventilation.

Q9: Is theophylline still considered first-line therapy for asthma and COPD?

A: No, theophylline is no longer considered first-line therapy for asthma and COPD. Inhaled corticosteroids and long-acting beta-agonists are preferred due to their better efficacy and safety profile. Theophylline may be used as an add-on therapy in patients who are not adequately controlled on other medications.