TDM Theophylline Flashcards
What drug class is Theophylline?
Theophylline is a bronchodilator, belonging to the xanthine drug class
Describe the mechanism of action of Theophylline.
Theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels and reduces airway responsiveness to histamine, methacholine, adenosine, and allergen. Theophylline competitively inhibits type III and type IV phosphodiesterase (PDE), the enzyme responsible for breaking down cyclic AMP in smooth muscle cells, possibly resulting in bronchodilation. Theophylline also binds to the adenosine A2B receptor and blocks adenosine mediated bronchoconstriction.
What are the adverse effects of inhibiting phosphodiesterase?
Hypertension
Tachycardia
Headache
What are the therapeutic indications of Theophylline?
Chronic asthma
Severe acute asthma
Reversible airways obstruction
What is the therapeutic range for Theophylline?
55-110 umol/L or 10-20mg/L
When should Theophylline levels be taken?
For IV Aminophylline loading dose levels should be taken: 4-8 hours post dose (peak level)
For oral Theophylline/Aminophylline: pre dose trough level and 4-8 hours post dose*
What is the ongoing level monitoring for Theophylline?
Serum levels should be monitored every 5-7 days after initiating therapy and every 3 days following dose changes
What is the half life of Theophylline?
Between 8-24 hours
Are ADR of Theophylline predictable?
Yes, adverse drug reactions to Theophylline are concentration dependent and therefore certain reactions would be expected at certain serum drug levels.
What adverse effects would you expect at Theophylline serum level of less than 5mg/L?
Nausea
What adverse effects would you expect at Theophylline serum level of between 5-20mg/L?
Insomnia
Diarrhoea
What adverse effects would you expect at Theophylline serum level of between 20-35mg/L?
Persistent vomiting
GI bleed
Seizures
Cardiac arrhythmias
What adverse effects would you expect at Theophylline serum level of greater than 35mg/L?
Arrhythmias
Convulsions
What is the bioavailability and salt fractions of Theophylline?
Bioavailability is 1
Salt fractions differs between different preparations of Theophylline:
Aminophylline - 0.79
Theophylline - 1
What is an important consideration to make when switching between different preparations of Theophylline?
Whilst less of an issue nowadays as Uniphyllin is the only slow release preparation that hasn’t been discontinued, previously marketed slow release preparations of Theophylline had different absorption rate profiles (Ka hr-1) for example Uniphyllin it is 0.22 and Phyllcontin it is 0.35. If switching you would have to monitor closely.
Describe the distribution of Theophylline in vivo.
Theophylline distribution follows the two compartment model. The drug quickly distributes into the intracellular fluid with the bronchioles acting as a second compartment. For the distribution phase to occur this takes approximately 30-45 minutes.
When calculating doses of the drug for obese patients should you use ideal or actual body weight?
As Theophylline distributes poorly into adipose tissue, when calculating the dose ideal body weight should be used rather than actual as it doesn’t distribute into the excessive fat stores.
What is the volume of distribution of Theophylline?
0.5 L/kg
Describe the clearance mechanism of Theophylline.
The main route of Theophylline clearance in the body is via hepatic metabolism by the CYP450 enzymes (accounts for about 90%). Renal clearance is responsible for very little of the clearance mechanism (10% is unchanged in the urine) therefore even in CKD dose adjustments are usually unnecessary.
Describe the pharmacokinetics of Theophylline.
Most patients display 1st order linear pharmacokinetics of Theophylline, meaning that the rate of elimination is proportional to the remaining serum concentration of drug. However when higher concentrations of the drug are used there can be a mixture of first order and saturable pharmacokinetics. Usually the drug displays linear pharmacokinetics up to about 80 micromol/L and then becomes saturable when small doses result in disproportionally large serum levels but this is not predictable. Therefore intensive monitoring at small doses increases are required.
Outline which factors increase the clearance of Theophylline.
Smoking
Enzyme inducers
Age 1-16 years
Outline which factors reduce the clearance of Theophylline.
Age - premature and full term neonates, elderly
Enzyme inhibitors
Viral infections
CCF
Severe pulmonary obstruction
Cirrhosis and liver impairment
Pulmonary oedema
What is the increased rate of Theophylline clearance of a smoker compared to a non-smoker?
Up to 2x the rate of clearance of Theophylline
Why do neonates have reduced clearance of Theophylline but children between 1-16 years have increased clearance?
Neonates do not have their fully developed hepatic metabolism enzymes present however in children the rate of hepatic metabolism is increased.
