Download Theophylline Revisited

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Introduction
Theophylline dosage regimen
Guideline recommendation
Pharmacology
Toxicity
Theophylline enteral feeding
Practice point
Theophylline
• Albercht Kossel:
• Tea leaves extraction (1888)
• Discover of theophylline structure (1896)
• Wilhelm Träube
• Research and development (1926)
• Clinical use in asthma (1950)
Case study
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Male 65 yr, 50 kg, 165 cm
CC: mild dyspnea
Diagnosis: COPD
SH: 20 pack-year
• Med Hx:
– Seretide® MDI (25/125) 2 puff bid
– Berodual® MDI 1 puff q 4-6 hr
Case study
• Physician ask you to recommend theophylline
dosage regimen.
• How do you recommend?
– Brand?
– Formulation?
– Dosage regimen?
Theophylline dosage regimens
Formulation
Recommendation
ImmediateInitial loading dose for acute bronchodilation,
release tablets 5 mg/kg of lean (ideal) body weight ORALLY to
and elixir
peak serum concentration of 5 to 15 mcg/mL
Initial, 300 mg/day ORALLY in divided doses over
6 to 8 hours; after 3 days (if tolerated), increase
to 400 mg/day ORALLY in divided doses over 6 to
8 hours; after 3 more days (if tolerated and
needed), increase to 600 mg/day ORALLY in
divided doses over 6 to 8 hours
Aminophylline (100)
Theophylline dosage regimens
Formulation
extendedrelease 12
hour
formulation
Recommendation
Initial, 300 mg/day ORALLY divided every 12
hours; after 3 days if tolerated, 400 mg/day
ORALLY divided every 12 hours; after 3 more days
if tolerated, 600 mg/day ORALLY divided every 12
hours
Theophylline dosage regimens
Formulation
extendedrelease 24
hour
formulation
Recommendation
12 years and older (previously stable on oral
formulation), 400 or 600 mg ORALLY once daily
with meals; dose should be same mg as previous
immediate- or controlled-release dosing
Initial, 300 to 400 mg ORALLY once daily; after 3
days if tolerated, 400 to 600 mg ORALLY once
daily; after 3 more days if tolerated, if dose is
greater than 600 mg, titrate according to blood
levels
ATS/ERS Guideline Recommendations
Celli BR, MacNee W. Eur Respir J. 2004;23:932-946
GOLD Guideline Recommendations
GOLD 2011 Update
Stable COPD: Pharmacologic Therapy
Case study
• The physician decided to start Theo-dur® 200
mg 1 tab bid add on previous medicine.
• What is the potential benefit from Theo-dur ® ?
Pharmacology
• MOA not completely understood
§ Traditional theory
§ Inhibition of PDE which converts cAMP to AMP
§ Other theories include alterations in
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Binding of cAMP, cGMP PDE inhibition
Prostaglandin antagonism
Intercellular calcium, or
Catecholamine release
Pharmacology
B2 agonist
AMP
E
D
P
ATP
Adenylyl Cyclase
cAMP
Theophylline
Bronchodilation
Martin M, et al. American Journal of Pharmaceutical Education 2007; 71 (5)
Barnes PJ. Chest 2006:129;151-5.
Theophylline improved corticosteroid resistant
Proposed MOA of theophylline
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Phosphodiesterase inhibition (non-selective)
Adenosine receptor antagonism (A1-, A2A-, A2B-receptors)
Inhibition of nuclear factor-kB (↓ nuclear translocation)
Inhibition of phosphoinositide 3 kinase-δ
↑ Interleukin-10 secretion
↑ Apoptosis of inflammatory cells
↓ poly(ADP-ribose)polymerase-1 (inhibits cell death)
↑ Histone deacetylase activity (↑ efficacy of steroids)
Multiple cellular effects of theophylline
Theophylline
Barnes PJ. Pharmaceuticals 2010;3:725-47.
Pharmacology
• Orally absorbed
– peak levels in 60 - 120 minutes
– Enteric or SR peak in 6 - 8 hours
– Daily preparations have erratic peaks
• IV
– Peak within 30 minutes
– Not useful for acute exacerbations in adults
Pharmacokinetic Parameters
• Bioavailability fraction
• Salt factor
– Theophylline
– Aminophylline
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Volume of Distribution
Percent excreted renally
Time to steady-state
Effect of dialysis
1.0
1.0
0.8
0.5 L/kg
10%
40 hr
dialyzable
Pharmacology
• 40% protein bound
• Metabolism
– 85-90% hepatic P450 system:CYP1A2 (M), 2E1 (m)
– 10-15% urinary excretion
• First order elimination kinetics
• T1/2 is 4-8 hours
• Bronchodilation effect at 10-20 µg/ml
Factors affecting clearance of theophylline
Increased Clearance
Decreased Clearance
o Enzyme induction (rifampicin,
phenobarbitone, ethanol)
o Smoking (tobacco, marijuana)
o High protein, low
carbohydrate diet
o Barbecued meat
o Childhood
o Enzyme inhibition (cimetidine,
erythromycin, ciprofloxacin,
allopurinol, zileuton)
o Congestive heart failure
o Liver disease
o Pneumonia
o Viral infection
o Vaccination (immunization)
o High carbohydrate diet
o Old age
Mean Frequency of Symptoms
The dose of theophylline was
individualized to achieve a serum
concentration of 10-20 mg/l
Placebo (P) and Theophylline (T)
Nocturnal symptoms of coughing,
wheezing, or dyspnea that
disturbed sleep were recorded
each morning, and symptoms
that interfered with normal
activity and any episodes of
coughing or wheezing during the
day were recorded each evening.
Symptoms were
graded as absent, transient,
repeated, or continuous.
Nassif EG, et al. N Engl J Med 1981;304:71-5.
Case study
• The physician decided to start Theo-dur® 200
mg 1 tab bid add on previous medicine.
• What is the theophylline concentration at
steady state?
PK parameter calculation
• Factor affecting Cl:
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Smoking: 1.6
Acute CHF: 0.6
Liver failure: 0.6
Age > 60 yr: 0.7
interacting drug: ciprofloxacin 0.7
PK parameter calculation
• Factor affecting Cl:
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Smoking: 1.6
Age > 60 yr: 0.7
Loading dose calculation
LD
= Vd x Cdesired / (S x F)
LD
Vd
Cdesired
S
F
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=
loading dose (mg)
volume of distribution (L)
desired target Theophylline concentration (mg/L)
salt equivalent
bioavailability
Case study
• Plasma concentration at steady state?
• Caverage =
[SFD/τ] / Cl
=
[1*1*200 mg/12 hr] / 2.24 L/hr
=
7.44 mg/L
• What should pharmacist do?
a) Increase dose
b) Nothing
c) Decrease dose
Theophylline Therapeutic Level
• Narrow therapeutic window:
Toxicity: >20 µg/ml
Bronchodilator effect: 10-20 µg/ml
Non bronchodilator effect: <10 µg/ml
Toxic effects
• Toxicity:
§ Cardiovascular
§ Neurologic
§ Metabolic
§ GI toxic effects
• Symptoms do not always correlate to serum-level
• Life threatening effects may occur with out warning
Prevention
• Toxicity only rarely intentional
• Patients being started on cimetidine,
macrolides, or fluoroquinolones should
reduce the theophylline dose by 25%
• Loading doses based on the initial
theophylline level
Case study
• 1 month later he come back to OPD
• CC: tremor and occasional N/V
• PI: muscle pain last two week on herbal
extract solution 1 tsp bid
• Lab: ALT 120
• Dx: herbal induced hepatitis
• What should we do?
Simulation in worse case
• Patient with AECOPD need intubation.
• How can we manage oral medicine in this
case?
– Crush/break Theo-dur®
– Change to new formulation
– Change drug
– Nothing
Theophylline Enteral Feeding
• Problem issue
– Decrease in absorption
• Management
– Separate administration time before and after
dietary feed at least 2 hr
– Flush feeding tube with 30 ml of NSS or water
before and after drug administration
– Set interval more frequently: q 6 hr or q 8 hr
• Beware fluctuation effect
Aminophylline
• 200 mg/tab, 250 mg/10 ml injection
• Loading dose
– No aminophylline use within previous 24 hr:
• Load 4 - 6 mg/kg
– Aminophylline use within previous 24 hr:
• Load 2 - 3 mg/kg
• Maintenance dose: base on PK calculation
– Bioavailability equivalent as 80% of theophylline
Mean Compliance with the Prescribed Regimen
Kelloway JS, et al. Arch Intern Med 1994;
154:1349-52.
Practice Point
• Treatment consideration base on EBM
• Proper selecting on
– Brand
– Formulation
– Dosage regimen
• Set therapeutic level and predict
• Closely monitoring efficacy and safety
• Medical reconciliation
Thank you for your attention