Aminophylline / Theophylline
Aminophylline and theophylline are **methylxanthine derivatives** primarily utilized in veterinary medicine for their potent bronchodilatory effects. They are frequently employed in the management of lower airway diseases (such as feline asthma, equine recurrent airway obstruction, and canine bronchitis), collapsing trachea, and as adjunctive therapy for cardiogenic pulmonary edema. > **Clinical Pearl:** Aminophylline is essentially a water-soluble salt of theophylline, created by adding ethylenediamine. **100 mg of hydrous aminophylline contains approximately 79 mg of anhydrous theophylline.** Dosage conversions must be carefully calculated when switching between the two forms. While highly effective, these drugs possess a **narrow therapeutic index**. Toxicity is dose-dependent, though dogs and cats generally tolerate higher serum concentrations than humans. Due to significant interpatient variability in metabolism, therapeutic drug monitoring is strongly recommended, especially in patients with concurrent hepatic or cardiac disease.
Mecanismo: The primary mechanism of action involves the competitive inhibition of **phosphodiesterase (PDE)** enzymes. * **PDE Inhibition** → Decreased breakdown of **cyclic AMP (cAMP)** → Elevated intracellular cAMP levels. * Increased cAMP → Enhanced release of endogenous **epinephrine** → Relaxation of bronchial and pulmonary vascular smooth muscle. * Elevated cAMP also inhibits the release of inflammatory mediators like **histamine** and slow-reacting substance of anaphylaxis (SRS-A) from mast cells. * **Intracellular Calcium Translocation:** Methylxanthines alter intracellular ionized calcium dynamics, contributing to increased diaphragmatic contractility (reducing respiratory fatigue) and weak positive inotropic/chronotropic effects on the heart. * **Additional Effects:** Induces mild diuresis, stimulates the central nervous system (CNS) and respiratory centers, and increases gastric acid secretion.
Dosificación por especie
- Bronchodilation (Extended-Release) · 20 mg/kg PO once daily in the PM; using Slo-Bid: 25 mg/kg PO once daily in the PM · PO · q24h · Products Theo-Dur and Slo-Bid are no longer available in the USA. Cautious use of dog dose/products is a reasonable alternative.
- Bronchodilation · 6.6. mg/kg PO twice daily; using sustained release tablets (Theo-Dur): 25-50 mg (total dose) per cat PO in the evening · PO · q12h or q24h · Using aminophylline tablets or sustained release tablets
- Tracheal collapse (mild clinical signs, <50% collapse) · aminophylline: 5 mg/kg PO, two times daily. · PO · q12h
- Bronchoconstriction associated with fulminant CHF · Aminophylline 4-8 mg/kg SC, IM, IV q8-12h. · SC/IM/IV · q8-12h
- Cough · Aminophylline: 5 mg/kg PO twice daily · PO · q12h
- Bronchodilation · 4.25 mg/kg PO 2-3 times a day · PO · q8-12h
- Pulmonary edema · Aminophylline 2-7 mg/kg IV q6-12h; Theophylline 5-15 mg/kg PO q12h · IV/PO · q6-12h · IV aminophylline should be diluted in at least 100 mL of D5W or normal saline and administered slowly (not >25 mg/min).
- Pulmonary edema · 11 mg/kg PO or IV q8-12h. · PO/IV · q8-12h · To 'load' may either double the initial dose or give both oral and IV dose at the same time. IV infusion in ~1L fluids over 20-60 mins.
Vías de administración
Contraindicaciones
- Hypersensitivity to any xanthines (including theobromine or caffeine)
- Hypersensitivity to ethylenediamine (specific to aminophylline)
Efectos adversos
- Nausea and vomiting
- Diarrhea
- Insomnia / Restlessness
- Polyphagia (increased appetite)
- Polydipsia and polyuria (increased thirst and urination)
- Tachycardia (rapid heart rate)
- Nervousness, excitability, and tremors (especially in horses)
- Diaphoresis (sweating in horses)
- Ataxia
- Seizures (in severe toxicity)
- Cardiac dysrhythmias (in severe toxicity)
Interacciones farmacológicas
- Phenobarbital · May decrease theophylline levels via hepatic enzyme induction.
- Fluoroquinolones (e.g., enrofloxacin, ciprofloxacin) · Can significantly increase theophylline levels. Consider reducing theophylline dose by 30% and monitor for toxicity.
- Macrolides (e.g., erythromycin, clindamycin, lincomycin) · Can increase theophylline levels.
- Cimetidine · Can increase theophylline levels by inhibiting hepatic metabolism.
- Ketamine · Concurrent use can cause an increased incidence of seizures.
- Halothane · Concurrent use may cause an increased incidence of cardiac dysrhythmias.
- Sympathomimetics (e.g., ephedrine, isoproterenol) · Toxic synergism; can lead to severe cardiac arrhythmias.
- Beta-blockers (non-selective, e.g., propranolol) · Can increase theophylline levels and antagonize bronchodilatory effects.
- Corticosteroids · Can increase theophylline levels.
Monitorización
- Therapeutic efficacy (improvement in breathing/cough)
- Clinical signs of toxicity (GI upset, CNS stimulation, tachycardia)
- Serum trough levels at steady state (Target: >8-10 mcg/mL in small animals; do not exceed 15 mcg/mL in horses. Human therapeutic range is 10-20 mcg/mL)
Sobredosis
Clinical signs of toxicity are usually associated with serum levels **greater than 20 mcg/mL** in humans, though dogs appear to tolerate higher levels. **Life-threatening signs:** * Tachycardia and severe cardiac arrhythmias * CNS effects including seizures and hyperthermia **Treatment is supportive:** * **Decontamination:** Empty the gut, administer activated charcoal and a cathartic if oral ingestion was recent. * **Seizures:** Maintain an adequate airway and treat with IV **diazepam**. * **Monitoring:** Continuous ECG monitoring for arrhythmias. Monitor and correct fluid/electrolyte imbalances. * **Symptomatic Care:** Hyperthermia may be treated with phenothiazines; severe tachycardia may be treated with **propranolol** if life-threatening.
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