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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 • • • • 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 § § § § 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 § § § § § § § § 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 • • • • 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: § § § § § 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: • • Smoking: 1.6 Age > 60 yr: 0.7 Loading dose calculation LD = Vd x Cdesired / (S x F) LD Vd Cdesired S F = = = = = 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