Theophylline Poisoning

Basics

Theophylline is a methylxanthine, related to caffeine and theobromine
Clinical uses of theophylline include:
- Treatment of airway diseases including:
  - Bronchospasm/asthma
  - COPD
- Neonatal apnea
Theophylline mechanism of action:
- Stimulates the release of endogenous catecholamines resulting in stimulation of β₁- and β₂-receptors
- Antagonist of adenosine receptor
- Inhibition of phosphodiesterase (at supratherapeutic levels)
  - Increases intracellular cAMP
  - cAMP augments β-adrenergic stimulation
Available in immediate- and sustained-release formulations
Peak absorption is 60–90 min with immediate-release and 6–10 hr with sustained-release formulations
Half-life is highly variable
- In a healthy, nonsmoker adult half-life is typically 4.5 hr
Therapeutic serum concentration 5–15 mcg/mL
Acute overdose:
- Ingestion within an 8-hr interval in a patient with no prior theophylline use
Acute-on-chronic overdose:
- Single excessive dose in a patient previously receiving usual therapeutic doses for ≥24 hr
Chronic intoxication:
- Accumulation of theophylline >20 mcg/mL associated with prior therapeutic use for ≥24 hr secondary to:
  - Drug–drug, drug–diet, or drug–disease interactions
- Use of serial excessive doses

Acute ingestions require larger concentrations to achieve specific toxic effects compared with acute-on-chronic or chronic overdoses
Drug–drug interactions:
- Inhibiting theophylline metabolism (leads to toxicity when started):
  - H₂-receptor antagonists
  - Macrolide antibiotics
  - Fluoroquinolones
  - Allopurinol
  - Influenza vaccine
  - Oral contraceptives
  - Interferons
- Enhances theophylline metabolism (leads to toxicity when discontinued):
  - Carbamazepine
  - Barbiturates
  - Smoking
  - Rifampin
Chronic theophylline accumulation:
- Uncontrolled CHF
- Liver disease (cirrhosis or severe hepatitis)
- Acute viral infections

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