Theophylline Aminophylline

Chemical

A methylxanthine derivative

Use

Tx bronchoconstriction

Presentation

Tablet, syrup, solution for IV injection

Route/Dose

Loading Dose 7mg/kg calculated by IB and given over 30 minutes

Maintenance 0.6mg/kg/hr (IV) or 7mg/kg (PO)

MoA

PHOSPHODIESTERASE INHIBITOR

  • ∴↑cAMP
  • ↑Protein kinase A
  • Inhibits phosphorylation of myosin + ↓Ca2+ = smooth m. relaxation + bronchodilation

ADENOSINE RECEPTOR BLOCKER

  • Blocks adenosine mediated bronchoconstriction

PD

Resp

  • Bronchodilation
  • ↑respiratory centre sensitivity to CO2
  • Disturbs HPVC

CVS

  • +ve chonotropy & inotropy
  • *** arrhythmogenic at high doses

GU

  • ↓RBF & GFR
  • ↓Na+ reabsorption → diuresis

PK

A

  • Rapidly + completely absorbed PO route

D

  • 0.3 – 0.7L/kg, PPB 40%

M

  • 90% of the dose is metabolised in the liver
  • Hepatic Demethylation occurs and then further hydroxylation to metabolites
  • Caffeine & 3-methylxanthine are the only active metabolites
  • Both these pathways are capacity-limited and there is wide intersubject variability in the rate of metabolism
  • The relationship is non linear and any increase/decrease in dose should be monitored with levels
  • Clearance is reduced in patients with hepatic impairment

E

  • Renally excreted
  • 10% unchanged
  • t ½ 8hrs

Therapeutic Index & Drug Monitoring

  • Bronchodilation occurs over a concentration of 5-20mcg/ml

  • As concentrations >20mcg/ml so do the frequency & severity of adverse events

Adverse Effects

Metabolic

  • Hypokalaemia 2° diuresis
  • Abnormal LFTs
  • Inappropriate ADH secretion

CNS

  • Convulsions → if administered rapidly

CVS

  • Arrhythmias → including VF at high doses

MSK

  • Antagonises non-depol NMB @ high doses

P50 interactions

↑[Theophylline]

  • Cimetidine
  • Propanolol
  • Erythromycin

↓[Theophylline]

  • Barbiturates
  • Alcohol
  • Phenytoin