FRCA Notes

Theophylline & Aminophylline

  • Theophylline and aminophylline are methylxanthine derivatives and non-selective phosphodiesterase inhibitors

Theophylline

  • Presents as modified-release tablets for oral use in the treatment of (chronic) asthma or other reversible airways obstruction

Aminophylline

  • Is formulated as a complex of 80% theophylline and 20% ethylenediamine (which improves solubility, but has no therapeutic effect)
  • Presents as a 25mg/ml solution for intravenous use as a treatment for severe acute exacerbations of asthma or COPD, as either:
    • A loading dose of max. 5mg/kg followed by an infusion of 300-700μg/kg/hr (if not already taking oral theophylline); or
    • An infusion alone (if already taking oral theophylline)

  • Can be used to reduce frequency of episodes of central apnoea in preterm neonates
  • In theory may work in heart failure but the advent of specific PDE-inhibitors has superseded this

  • Non-selective inhibitor of all 5 phosphodiesterase isoenzymes → increases the levels of cAMP and possibly cGMP too
  • Within bronchial smooth muscle, inhibition of PDE-3 causes bronchodilation

  • Acts as an antagonist of adenosine, which is a pro-spasmodic inflammatory mediator
  • May directly release noradrenaline from sympathetic neurones; appears to be synergistic with catecholamines
  • Interferes with translocation of Ca2+ into smooth muscle
  • Inhibits the translocation of the proinflammatory transcription factor nuclear factor-κB
  • Inhibits mast cell degranulation by blocking their adenosine receptors
  • Potentiates prostaglandin synthetase activity
  • Activates histone deacetylase 2, thereby reversing steroid resistance in treatment-refractory asthma and COPD

Absorption

  • Theophylline demonstrates 90-100% oral bioavailability
  • Dose dumping: can be absorbed alongside fatty meals due to the effect of posprandial pancreatic secretions and bile salts on its absorption, which is otherwise very slow

Distribution

  • 50-56% plasma protein bound

Metabolism

  • Metabolism is via CYP450 enzymes to inactive metabolites
  • Has a low hepatic extraction ratio so its metabolism is independent of hepatic blood flow
  • Above 35μg/ml hepatic enzymes become saturated and kinetics change from first-order to zero-order (non-linear, saturation) kinetics

Excretion

  • 10% unchanged in the urine
  • Cigarette smoking increases clearance due to CYP2E1 activation by nicotine

Respiratory

  • Bronchodilation
  • Improves diaphragmatic contractility
  • Increases sensitivity of the respiratory centre to CO2

Cardiovascular

  • Mild positive inotropic and chronotropic effect
  • Some coronary and peripheral vasodilation
  • Lowers (ventricular) arrhythmia threshold, especially in the presence of halothane

Neurological

  • Alkyl group at position 1 causes CNS stimulation; this reduces seizure threshold

Renal

  • Alkyl group also causes weak diuretic effect by inhibiting tubular Na+ reabsorption
  • May precipitate hypokalaemia

Endocrine

  • Stimulates insulin secretion and may cause hypoglycaemia

Drug interactions

  • Elimination is reduced (enzyme inhibitors) or increased (enzyme inducers) by other drugs acting on the CYP450 system

  • Therapeutic plasma concentration is 10-20μg/ml
  • However, adverse effects can occur within the therapeutic range and both the frequency and severity increase at concentrations above 20 mg/litre
  • Cardiac toxicity manifests as tachyarrhythmias (inc. VF)
  • CNS toxicity includes tremor, insomnia and seizures
  • Other toxic effects include nausea, vomiting and rhabdomyolysis

  • Therefore, plasma theophylline levels should be measured:
    • 5 days after starting oral theophylline
    • 3 days after any dose adjustment
    • Before starting an aminophylline infusion in a patient already taking oral theophylline
    • 4-6hrs after starting an aminophylline infusion