Theophylline and Aminophylline

Mechanism

Mechanism of action

Theophylline acts through multiple cellular pathways dependent on the serum concentration reached:

1. Non-selective inhibition of Phosphodiesterases (PDE): Inhibits the isoenzymes PDE3 (bronchial and cardiac smooth muscles) and PDE4 (inflammatory cells). This prevents the degradation of cAMP, increasing its intracellular levels and inducing moderate muscle relaxation. A high plasma concentration is required (> 10 µg/mL).
2. Adenosine receptor antagonism (A₁ and A₂): Adenosine acts as an endogenous bronconstrictor in asthmatic patients and promotes mast cell degranulation. Theophylline competitively blocks this action.
3. Activation of Histone Deacetylase 2 (HDAC2): *Low-dose mechanism.* Oxidative stress in COPD activates the cellular receptor for inflammatory cytokines and deactivates the HDAC2 enzyme (essential for the glucocorticoid receptor to silence inflammatory genes). Theophylline at low therapeutic doses (5 - 10 µg/mL) selectively recruits and activates HDAC2, effectively restoring cellular sensitivity to corticosteroids.

Pharmacokinetics

Pharmacokinetics

• Absorption: Excellent oral absorption of sustained release formulations (> 95%).
• Distribution: Volume of distribution of 0.5 L/kg. Plasma protein binding of approximately 40%.
• Metabolism: Extensive liver by the cytochrome P450 system, mainly by the isoenzyme CYP1A2 (90%) and to a lesser extent by CYP3A4. It suffers metabolic saturation at high doses (non-linear kinetics).
• Excretion: Renal (only 10% is eliminated unchanged).
• Half-life: Highly variable. 6 to 8 hours in healthy non-smoking adults; decreases to 4-5 hours in smokers (due to induction of CYP1A2 by hydrocarbons); increases to > 24 hours in patients with decompensated liver cirrhosis or heart failure.

Indicators and dose

Dosage and Clinical Adjustment

Adults (sustained release theophylline):

• Standard dose: 200 mg to 300 mg orally every 12 hours. It is recommended to adjust the dose individually to maintain serum plasma levels between 5 and 12 µg/mL.
• Intravenous aminophylline (Emergency): Reserved for severe crises refractory to inhalation therapy. Loading bolus of 5 - 6 mg/kg slow intravenous over 30 minutes, followed by a maintenance infusion of 0.5 mg/kg/hour. *Mandatory:* Measure plasma levels of theophylline after 12-24 hours of infusion.

Adjustment in Renal and Hepatic Failure: Contraindicated in Child-Pugh C liver failure unless daily serum level control is performed. Reduce the dose by half in patients with severe congestive heart failure.

Security

Risk of Intoxication and Narrow Therapeutic Margin

The classic therapeutic range of theophylline for bronchodilation is 10 to 20 µg/mL, and serious adverse effects appear at concentrations above 20 µg/mL. However, at low doses of 5 - 10 µg/mL the anti-inflammatory benefit is preserved and ADRs are minimized. Manifestations of severe intoxication include refractory ventricular arrhythmias (ventricular tachycardia, torsade de pointes) and generalized seizures that are difficult to control medically due to antagonism of the brain GABA receptor.

Adverse effects (ADRs)

• Common with plasma levels >15 µg/mL: Persistent nausea and vomiting (due to stimulation of the chemoreceptor trigger zone), throbbing headache, sleep insomnia and nervousness (due to central adenosine blockade).
• Serious (>25 µg/mL): Supraventricular tachycardia (SVT), rapid ventricular response atrial fibrillation, severe hypokalemia, epileptiform seizures that are difficult to control.

Drug interactions

• CYP1A2 inhibitors (increase theophylline levels): Coadministration with Ciprofloxacin, Fluvoxamine or Erythromycin can rapidly double or triple the plasma concentration of theophylline, inducing potentially fatal arrhythmias. It is necessary to reduce the theophylline dose by half prophylactically.
• CYP1A2 inducers (Decrease theophylline levels): Tobacco, Rifampicin, Carbamazepine and Phenytoin. They require significant dose increases.