METHYLXANTHINES

  • Theophylline, aminophylline and caffeine are examples.
  • Understand PD and toxicity.
Structure/Class
Pharmacodynamics
  1. Methylxanthines act by inhibition of phosphodiesterase (several different isoforms). This leads to increased cAMP, and therefore relaxation of smooth muscle, stimulation of cardiac cells and decreased activity of inflammatory cells.
  2. Methylxanthines may also inhibit adenosine receptors (explains why adenosine is less effective in the presence of theophylline)
  3. Of all the methylxanthines, theophylline is the most selective in its smooth muscle effects.
  4. Organ system effects
    • Smooth muscle
      1. Bronchodilation (used in severe asthma). No tolerance will develop.
      2. May also limit histamine release from lung tissue.
      3. The dose used for smooth muscle relaxation is limited by adverse effects in CNS.
    • CNS effects
      1. Increased arousal
      2. High doses à seizures and death
    • CVS
      1. Positive inotropy and chronotropy (due to increased cAMP)
    • Other effects
      1. May improve skeletal muscle contractility (improved diaphragm strength in COPD)
      2. Weak diuretic effect (not significant clinically)
      3. Stimulates gastric acid production
Absorption/administration
Distribution
  1. 600microg of theophylline/kg of body weight will increase serum theophylline by 1 microg/ml. Serum concentration of 10-20microg/ml is needed for smooth muscle relaxation.
Metabolism
  1. Hepatic
    • Enzyme inhibitors (e.g. cimetidine and amiodarone) will dramatically increase its level.
    • Enzyme inducers (e.g. smoking, barbiturates) will dramatically decrease its level.

 
Excretion
  1. Urine
Indications
  1. Bronchospasm
Contraindications
Special precautions
Interactions
  1. Enzyme inhibitors (e.g. erythromycin, cimetidine and propranolol) may increase theophylline levels.
  2. Enzyme inducers (e.g. phenytoin, barbiturates and smoking) may decrease levels.
Adverse events
  1. Theophylline has a very small therapeutic window.
    • Bronchodilation occurs at 5-20mg/L.
    • At 15mg/L, nausea, vomiting, anorexia and nervousness occurs.
    • Higher levels (>40mg/L) may precipitate seizures and arrhythmias. Importantly, note that seizures and arrhythmias may occur without any warning signs.
Dosing/administration
Toxicology
  1. Acute toxicity will cause symptoms as described above.
  2. Theophylline toxicity also has increased β2-stimulation – hypokalemia, hyperglycaemia and mild metabolic acidosis may occur.
  3. Chronic toxicity will cause milder GIT symptoms, but dysrhythmias and seizures can occur at lower levels of drug than in acute OD.
  4. Treatment is as follows:
    • Good supportive care – attention to A, B, C and D.
    • Specific antidotes as follows:
      1. Β-Blockers (e.g. esmolol) for dysrhythmias
      2. Hypotension (due to over β2-stimulation) requires α-agonist agents (e.g. noradrenaline)
      3. BZDs/barbiturates for seizures (note that phenytoin may worsen seizures, and other anti-convulsants usually do not work)
    • Enhanced elimination
      1. Gastric lavage if significant quantities of sustained release preparations have been taken.
      2. Whole bowel irrigation can be considered.
      3. Multidose activated charcoal may help bind theophylline.
      4. Haemodialysis is an option.
Withdrawal syndrome
Special notes