Methylxanthines, Leukotriene Modifiers, and Mast Cell Stabilizers
Theophylline pharmacokinetics, leukotriene pathway targets, and aspirin-exacerbated respiratory disease
Theophylline: Mechanism and Toxicity
- PDE3/PDE4 inhibition → cyclic AMP ↑ → bronchodilation
- Adenosine A1/A2B antagonism → bronchodilation + mast cell inhibition
- Therapeutic window: 10–20 mcg/mL
- Non-linear kinetics — small dose Δ = large level Δ
Toxicity
Organ System Effects
- GI: nausea, vomiting (earliest sign)
- CNS: seizures (refractory to anticonvulsants)
- Cardiac: tachycardia, arrhythmias
- Smoking cessation → levels rise (CYP1A2 loss)
Leukotriene Pathway: Drug Targets
|
Zileuton |
Montelukast |
Zafirlukast |
Cromolyn |
| Target | 5-Lipoxygenase | CysLT1 receptor | CysLT1 receptor | Mast cell |
| Dosing | 4× daily | Once daily | Twice daily | 4× daily |
| Key concern | CYP1A2 inhibitor; hepatotoxicity | Neuropsychiatric black box | Drug interactions | Less effective than ICS |
| Use in AERD | Yes | Yes — preferred | Yes | No |
Aspirin-Exacerbated Respiratory Disease
Triad
Clinical Presentation
- Asthma
- Nasal polyps / chronic rhinosinusitis
- Aspirin / NSAID hypersensitivity
- Reaction within 30–180 min of ingestion
Mechanism and Management
COX-1 Inhibition → LT Surge
- COX-1 blocked → PGE2 falls → 5-LOX unopposed
- Cysteinyl leukotriene surge → bronchoconstriction
- Safe: acetaminophen <1g; celecoxib
- Treat with LTRAs; avoid NSAIDs