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methylxanthines

methylxanthines

introduction

  • methylxanthines are a group of structurally similar, stimulant xanthine alkaloid chemicals which primarily act as competitive antagonists of adenosine at purine P1 receptors, and in higher doses, effects from their additional competitive antagonism of phosphodiesterase enzyme results in increased intracellular cAMP levels (see also phosphodiesterase inhibitors (PDE inhibitors))
  • theophylline introduced as a Rx for asthma in the 1950's.

caffeine

theophylline

mechanisms of actions:

normal dose:

  • ⇒ antagonist of adenosine at all P1 receptors - ?its main action:
    • ⇒ bronchodilatation
    • ⇒ inhibit mast cell degranulation
    • ⇒ pre-synaptic P1 antagonist → increased NA release
    • ⇒ +ve chronotropic & +ve inotropic effects
    • ⇒ mild rise in total peripheral resistance & BP
    • ⇒ decreased blood viscosity ? mechanism
    • ⇒ secretion of gastric & digestive enzymes
    • ⇒ weak diuretic effect not clinically useful
    • ⇒ strengthen skeletal muscle contraction eg. diaphragm
    • ⇒ CNS effects - cortical arousal, nervousness, insomnia, tremor

high dose (>10uM):

  • ⇒ inhibits phosphodiesterase → increased cAMP
    • ⇒ cardiac Ca influx → +ve chronotrope/inotrope
    • ⇒ bronchodilatation
    • ⇒ vasodilatation except in cerebral vessels which are constricted

v.high dose (>100uM):

  • ⇒ impaired Ca uptake by sarcoplasmic reticulum
  • ⇒ medullary stimulation & convulsions
  • ⇒ hypokalaemia

rapid IV dose

  • ⇒ convulsions, arrhythmias

other actions and uses:

  • Rx of apnoea of preterm infants
  • low [] specif. antag. opioid-induced resp.depn.
  • Whilst bronchodilator effect ??[] over 5-20mg/L, it also inhibits the late response phase to PAF, etc. esp. at 10mg/L when inhib of late response > inhibition of early response & optimal is 10-20mg/L.
  • ⇒ decr. PAF-induced eosinophils;
  • ⇒ decr. activity of: basophils, macrophages, mast cells, platelets, PMNL's;
  • ⇒ incr. suppressor T cell activity;
  • ⇒ decr. plasma leakage into airways;

P/K of theophylline:

  • bioavailability = 96%
  • 5mg theophylline = 6mg aminophylline (actually 86% theophylline by weight)
  • aminophylline doses:
  • Vd = 0.5L/kg lean body mass
  • metabolised by liver thus metabolism impaired by:
    • decreased hepatic function (eg. cirrhosis)
    • decreased hepatic blood flow (eg. CCF)
    • drugs (erythromycin, cimetidine)
  • Clearance = 0.041 L/kg/h in normal adults but variable → monitor serum levels
  • Clearance higher in children = 0.06-0.9 L/kg/h
    • BUT neonates & infants have the SLOWEST CLEARANCE
  • target serum level is usually 10-20mg/L
  • steady state is achieved in 1-2 days → alter dose at intervals of 2-3 days prn

enprofylline:

  • Devoid of adenosine antagonist effects yet 5x theophylline bronchodilator potency !!;
  • less effects on CNS, renal fn, cerebrovasc.resistance but same GIT disturbances & more tachycardia than theophylline;

pentoxifylline (Trental):

  • no bronchodilator activ. & no vasodil. activity
  • used in PVD as ? decr. blood viscosity, ? TNF-alpha effect, etc;
  • suppresses TNF-alpha production via affect on RNA transcription:
    • may have benefit in Rx of idiopathic dilated cardiomyopathy
  • Sliwa et al. Lancet April 11 1998 351:1091-1093:
    • 6mths Rx with 400mg tds in placebo-controlled trial of 28pts
    • ⇒ >20% increase in ejection fraction
    • ⇒ decreased LV end-systolic diameter but no decrease in afterload
    • ⇒ thus implies increased contractility ? via Pdiesterase inhibition
methylxanthines.txt · Last modified: 2014/02/22 13:40 (external edit)