F11ii / 23B11: Describe the mechanism of action, dose and pharmacokinetics and pharmacodynamics of aminophylline

23B11: Exam Report

Describe the mechanism of action, dose and pharmacokinetics and pharmacodynamics of aminophylline

21% of candidates passed this question.

This question required a detailed description of the many mechanisms of action of aminophylline. This included PDE inhibition and the down stream pathway and its adenosine antagonist and anti- inflammatory actions.

Important pharmacokinetic concepts included hepatic metabolism with saturable kinetics and thus a narrow therapeutic window/index requiring need for drug monitoring and the risk of metabolic interactions with accelerated or reduced metabolism from inducers or inhibitors of the main enzyme (CYP1A2).

Detailed pharacodynamic consequences on the respiratory and cardiovascular systems were prioritised as well as highlighting the neurological, cardiovascular and musculoskeletal consequences of toxicity.

F1ii / 23B11: Describe the mechanism of action, dose and pharmacokinetics and pharmacodynamics of aminophylline

Theophylline Aminophylline

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

Author: Krisoula Zahariou