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

Tradenames: Slo-Phyllin, Elixophyllin, Theolair. Slo-Bid, Slo-Phyllin, Theo-Dur, Theolair-SR & Uni-Dur taken off the US market in 2001. [7] Remaining forms of theohylline include: - Uniphyl, T-phyl, Theo-24, Theolair & generics Indications: 1) reactive airway disease (asthma & COPD*) - bronchospasm 2) used in combination with beta-2 adrenergic receptor agonists 3) neonatal apnea/bradycardia * of no benefit for preventing COPD exacerbations [10] Contraindications: 1) uncontrolled arrhythmias 2) uncontrolled peptic ulcer disease Dosage: Intravenous: 1) loading dose 6 mg/kg; infuse < 25 mg/min 2) 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: 1) heart failure 2) severe hypoxemia 3) hepatic insuffciency 4) seizures 5) hyperthyroidism 6) hypertension Pharmacokinetics: 1) onset of action is 15 minutes after an IV loading dose 2) absorption of oral formulation is variable 3) food may effect absorption (+ or -) 4) therapeutic range: 8-20 ug/mL, 5-12 ug/mL for COPD [8] 5) metabolized in the liver by cyt P450 1A2 6) elimination 1/2life: a) about 8 hours in non-smokers b) 4.4 hours in smokers c) prolonged 1/2life (> 24 hours) in patients with COPD, CHF or liver disease Conditions/disorders that alter theophylline metabolism 1) conditions that decrease theophylline levels a) cor pulmonale b) congestive heart failure c) pregnancy d) hepatic cirrhosis e) viral infection 2) conditions that increase theophylline levels a) smoking b) marijuana c) hyperthyroidism Monitor: - serum theophylline (see Laboratory: below) a) when initiating therapy b) before & after increasing dose c) when toxicity is suspected d) worsening illness predisposing to toxicity e) after smoking cessation f) after adding or stopping an interacting drug g) at least annually [9] Adverse effects: 1) not common (1-10%) - nausea/vomiting, nervousness, restlessness, tachycardia 2) uncommon (< 1%) - rash, insomnia, irritability, tremor, seizures, gastric irritation, allergic reactions 3) 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 interactions: 1) 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 2) 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 3) theophylline may decrease the effects of phenytoin 4) theophylline may have synergistic toxicity with sympathomimetics Test interactions: - chemical interferences a) theophylline may decrease 1] serum alkaline phosphate (serum ALP) 2] serum bilirubin 3] serum lactate dehydrogenase (serum LDH) b) theophylline may increase: serum uric acid Laboratory: 1) see theophylline in serum/plasma 2) specimen: serum, plasma (heparin, EDTA) 3) methods: GLC, HPLC, RIA, EIA, FPIA, color, FIA 4) 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 [2]) 1) inhibits breakdown of cAMP 2) inhibition of cGMP 3) enhanced adrenergic output to airway smooth muscle 4) antagonism of adenosine receptors 5) stimulation of endogenous catecholamines 6) decrease in [Ca+2] into bronchial smooth muscle cells or release of [Ca+2] from sarcoplasmic reticulum 7) dose-dependent increase in respiratory muscle contractility 8) relaxes smooth muscle of bronchial airways & pulmonary blood vessels 9) diuretic 10) coronary vasodilator 11) cardiac stimulant 12) CNS stimulant

Interactions

drug interactions drug adverse effects (more general classes)

Related

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

General

analeptic (CNS stimulant) antiasthmatic agent methylxanthine smooth muscle relaxant

Properties

MISC-INFO: elimination route LIVER 1/2life 8.7 +/- 2.2 HOURS 4.3 +/- 1 HOURS 3.4 +/- 1.1 HOURS 30 +/- 6.5 HOURS therapeutic-range 8-20 UG/ML toxic-range >20 UG/ML protein-binding 56% elimination by hemodialysis - hemoperfusion - peritoneal dialysis - pregnancy-category C safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 741-42
  3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  4. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  5. Clinical Diagnosis & Management by Laboratory Methods, 19th edition, J.B. Henry (ed), W.B. Saunders Co., Philadelphia, PA. 1996, pg 10
  6. Clinical Guide to Laboratory Tests, NW Tietz (ed) 3rd ed, WB Saunders, Philadelpha 1995
  7. Prescriber's Letter 8(9):51 2001
  8. Medical Knowledge Self Assessment Program (MKSAP) 14, American College of Physicians, Philadelphia 2006
  9. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com
  10. Devereux G et al. Effect of theophylline as adjunct to inhaled corticosteroids on exacerbations in patients with COPD: A randomized clinical trial. JAMA 2018 Oct 16; 320:1548. PMID: 30326124 https://jamanetwork.com/journals/jama/fullarticle/2707459 - Criner GJ, Celli BR. Failure of low-dose theophylline to prevent exacerbations in patients with COPD. JAMA 2018 Oct 16; 320:1541. PMID: 30326108 https://jamanetwork.com/journals/jama/fullarticle/2707440

Component-of

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