A. Pathogenesis

1. Normal Actions
   1. May block adenosine receptors at pharmacologic doses
   2. Higher (toxic) doses are required for cAMP phosphodiesterase (cAMPase) inhibition
   3. Direct bronchodilation is weak relative to ß-adrenergic agonists
   4. Doses below therapeutic range have synergistic efficacy with inhaled glucocorticoids
   5. Chronic use may have immunomodulatory effects
2. Toxic Actions
   1. Main toxic effects are believed to be due to inhibition of cAMP phosphodiesterase
   2. This leads to increased levels of cAMP in affected cells
   3. Tachycardia
   4. Hypokalemia - due to increased Na+/K+ ATPase activity from increased cAMP [2]
   5. Coronary vasoconstriction (may be related to adenosine receptor effects

B. Symptoms and Signs

1. Mild
   1. Tachycardia
   2. Nausea, Vomiting
   3. Abdominal Pain
   4. Tremors
2. Severe
   1. Hypotension
   2. Hypokalemia
   3. Cardiac Arrhythmias
   4. Seizures
   5. Death
3. Cardiac Arrhythmias
   1. Regular Supraventricular Tachycardia - often ectopic atrial focus
   2. Irregular SVT: Multifocal Atrial Tachycardia (MAT), Atrial Fibrillation

B. Predictors of Poor Outcome [1]

1. Level >100mg/L after acute intoxication
2. Age >60
3. Chronic overmedication carries greater risk than acute intoxication
4. Agents that increase theophylline concentration: ciprofloxacin

C. Treatment

1. Cardiorespiratory Support
2. Correction of electrolyte disturbances
3. Multiple dose charcoal administration
4. Charcoal hemoperfusion
   1. Most effective before major toxicity develops
   2. Poor efficacy after seizures or cardiac arrhythmias develop
5. Atrial Fibrillation, MAT Therapy
   1. Intravenous diltiazem
   2. Consider procainamide rapid iv load (20-40mg/min)

References

1. Shannon M. 1993. Ann Intern Med. 119(12):1161
2. Gennari FJ. 1998. NEJM. 339(7):451