theophylline (Slo-Phyllin, Elixophyllin, Uniphyl, Theo-24, Theo-Dur, Slo-bid, Theolair)

Introduction

Tradenames: Slo-Phyllin, Elixophyllin, Theolair.

Slo-Bid, Slo-Phyllin, Theo-Dur, Theolair-SR & Uni-Dur taken off the US market in 2001.

Remaining forms of theohylline include:

• Uniphyl, T-phyl, Theo-24, Theolair & generics

Indications

• reactive airway disease (asthma & COPD*)
  • bronchospasm
• used in combination with beta-2 adrenergic receptor agonists
• neonatal apnea/bradycardia

* of no benefit for preventing COPD exacerbations

Contraindications

• uncontrolled arrhythmias
• uncontrolled peptic ulcer disease

pregnancy category = c

safety in lactation = ?

Dosage

Intravenous:

• loading dose 6 mg/kg; infuse < 25 mg/min
• infusion 0.5 mg/kg/hr

Oral:

• 100-300 mg PO TID/QID.

Tabs: 60, 100, 200, 300 mg.

Liquid: (Theolair) 80 mg/15 mL (15 mL, 19 mL, 30 mL, 480 mL).

Sustained release (once daily):

• Tradenames: Uniphyl, Theo-24.

Tabs: 100, 200, 300, 400 mg. Sustained release (twice daily):

• Tradenames: Theo-Dur, Slo-bid.
• 100-300 mg PO BID.

Tabs: 100, 200, 300, 450 mg.

Pediatrics: sprinkles?: Tradename: Theo-Dur.

• 10 mg/kg PO BID.

Tabs: 50, 75, 125, 200 mg.

Caution: dosage should be decreased by 50% in patients with:

• heart failure
• severe hypoxemia
• hepatic insuffciency
• seizures
• hyperthyroidism
• hypertension

Pharmacokinetics

• onset of action is 15 minutes after an IV loading dose
• absorption of oral formulation is variable
• food may effect absorption (+ or -)
• therapeutic range: 8-20 ug/mL, 5-12 ug/mL for COPD
• metabolized in the liver by cyt P450 1A2
• elimination 1/2life:
  • about 8 hours in non-smokers
  • 4.4 hours in smokers
  • prolonged 1/2life (> 24 hours) in patients with COPD, CHF or liver disease

Conditions/disorders that alter theophylline metabolism

• conditions that decrease theophylline levels
  • cor pulmonale
  • congestive heart failure
  • pregnancy
  • hepatic cirrhosis
  • viral infection
• conditions that increase theophylline levels
  • smoking
  • marijuana
  • hyperthyroidism

elimination via liver

protein binding = 56 %

elimination by hemodialysis = -

elimination by hemoperfusion = -

elimination by peritoneal dialysis = -

Monitor

• serum theophylline (see Laboratory: below)
  • when initiating therapy
  • before & after increasing dose
  • when toxicity is suspected
  • worsening illness predisposing to toxicity
  • after smoking cessation
  • after adding or stopping an interacting drug
  • at least annually

Adverse effects

• not common (1-10%)
  • nausea/vomiting, nervousness, restlessness, tachycardia
• uncommon (< 1%)
  • rash, insomnia, irritability, tremor, seizures, gastric irritation, allergic reactions
• other
  • arrhythmias & convulsions have occurred with serum levels > 35 ug/mL
  • rapid IV administration may be associated with hypotension, syncope & cardiac arrest
  • adverse effects umcommon at serum theophylline concentrations < 20 ug/mL

* Toxicity: best treated by charcoal & hemoperfusion.

• drug adverse effects of analeptics
• drug adverse effects of psychotropic agents

Drug interactions

• drugs that decrease theophylline levels
  • phenytoin (Dilantin)
  • carbamazepine (Tegretol)
  • furosemide (Lasix)
  • rifampin
  • beta-adrenergic receptor agonists
  • ketoconazole
  • phenobarbital
  • aminoglutethimide
  • any drug that induces cyt P450 1A2
• drugs that increase theophylline levels
  • antibiotics
    • macrolides
    • quinolones
      • ciprofloxacin
      • norfloxacin
      • enoxacin
    • isoniazid
    • troleandomycin
    • lincomycin
  • allopurinol
  • propranolol
  • caffeine
  • cimetidine & possibly ranitidine
  • mexiletine
  • amiodarone
  • oral contraceptives
  • fluvoxamine
  • any drug that inhibits cyt P450 1A2
• theophylline may decrease the effects of phenytoin
• theophylline may have synergistic toxicity with sympathomimetics

• drug interaction(s) of theophylline with fluvoxamine
• drug interaction(s) of theophylline with macrolide
• drug interaction(s) of theophylline with fluoroquinolone
• drug interaction(s) of lithium carbonate with xanthine

Test interactions

• chemical interferences
  • theophylline may decrease
    • serum alkaline phosphate (serum ALP)
    • serum bilirubin
    • serum lactate dehydrogenase (serum LDH)
  • theophylline may increase: serum uric acid

Laboratory

• see theophylline in serum/plasma
• specimen: serum, plasma (heparin, EDTA)
• methods: GLC, HPLC, RIA, EIA, FPIA, color, FIA
• labs with Loincs
  • theophylline in body fluid
    • theophylline in blood
    • theophylline in serum/plasma
      • theophylline free in serum/plasma
    • theophylline in CSF
    • theophylline in gastric fluid
    • theophylline in saliva
    • theophylline in urine

Mechanism of action

(proposed)

• inhibits breakdown of cAMP
• inhibition of cGMP
• enhanced adrenergic output to airway smooth muscle
• antagonism of adenosine receptors
• stimulation of endogenous catecholamines
• decrease in [Ca+2] into bronchial smooth muscle cells or release of [Ca+2] from sarcoplasmic reticulum
• dose-dependent increase in respiratory muscle contractility
• relaxes smooth muscle of bronchial airways & pulmonary blood vessels
• diuretic
• coronary vasodilator
• cardiac stimulant
• CNS stimulant

More general terms

• methylxanthine
• antiasthmatic agent
• analeptic (CNS stimulant)
• smooth muscle relaxant

Additional terms

• cytochrome p450 1A2 (cytochrome P3-450, phenacetin deethylase, cytochrome p450-4, CYP1A2)
• theophylline in serum/plasma

Component of

• potassium iodide/theophylline
• guaifenesin/pseudoephedrine/theophylline
• ephedrine/phenobarbital/potassium iodide/theophylline
• ephedrine/hydroxyzine/theophylline
• guaifenesin/theophylline
• aminophylline (ethylene diamine/theophylline, Somophyllin-DF)
• oxtriphylline [choline theophyllinate] (Choledyl)

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=2153
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=77034