Theophylline and other methylxanthines are often used for their performance-enhancing effects in sports, as these drugs increase alertness, bronchodilation, and increase the rate and force of heart contraction.[10] There is conflicting information about the value of theophylline and other methylxanthines as prophylaxis against exercise-induced asthma.[11]
The use of theophylline is complicated by its interaction with various drugs and by the fact that it has a narrowtherapeutic window (<20 mcg/mL).[2] Its use must be monitored by direct measurement of serum theophylline levels to avoidtoxicity. It can also cause nausea, diarrhea, increase in heart rate,abnormal heart rhythms, and CNS excitation (headaches,insomnia, irritability,dizziness, andlightheadedness).[2][12]Seizures can also occur in severe cases of toxicity, and are considered to be a neurological emergency.[2]
Its toxicity is increased byerythromycin, cimetidine, andfluoroquinolones, such asciprofloxacin. Some lipid-based formulations of theophylline can result in toxic theophylline levels when taken with fatty meals, an effect calleddose dumping, but this does not occur with most formulations of theophylline.[13] Theophylline toxicity can be treated withbeta blockers. In addition to seizures, tachyarrhythmias are a major concern.[14] Theophylline should not be used in combination with theSSRIfluvoxamine.[15][16]
Theophylline is distributed in the extracellular fluid, in the placenta, in the mother's milk and in the central nervous system. The volume of distribution is 0.5 L/kg. The protein binding is 40%.[medical citation needed]
Theophylline is metabolized extensively in the liver.[2] It undergoesN-demethylation viacytochrome P4501A2. It is metabolized by parallelfirst order andMichaelis-Menten pathways. Metabolism may become saturated (non-linear), even within the therapeutic range. Small dose increases may result in disproportionately large increases in serum concentration.Methylation to caffeine is also important in the infant population. Smokers and people with hepatic (liver) impairment metabolize it differently.[2] Cigarette and marijuana smoking induces metabolism of theophylline, increasing the drug's metabolic clearance.[22][23]
Theophylline is excreted unchanged in the urine (up to 10%). Clearance of the drug is increased in children (age 1 to 12), teenagers (12 to 16), adult smokers, elderly smokers, as well as incystic fibrosis, andhyperthyroidism. Clearance of the drug is decreased in these conditions: elderly, acute congestive heart failure, cirrhosis, hypothyroidism and febrile viral illnesses.[2]
The eliminationhalf-life varies: 30 hours for premature neonates, 24 hours for neonates, 3.5 hours for children ages 1 to 9, 8 hours for adult non-smokers, 5 hours for adult smokers, 24 hours for those withhepatic impairment, 12 hours for those with congestive heart failureNYHA class I-II, 24 hours for those with congestive heart failure NYHA class III-IV, 12 hours for the elderly.[medical citation needed]
The characteristic signals, distinguishing theophylline from related methylxanthines, are approximately 3.23δ and 3.41δ, corresponding to the unique methylation possessed by theophylline. The remaining proton signal, at 8.01δ, corresponds to the proton on the imidazole ring, not transferred between the nitrogen. The transferred proton between the nitrogen is a variable proton and only exhibits a signal under certain conditions.[25]
The unique methylation of theophylline corresponds to the following signals: 27.7δ and 29.9δ. The remaining signals correspond to carbons characteristic of the xanthine backbone.[26]
Theophylline is naturally found incocoa beans. Amounts as high as 3.7 mg/g have been reported inCriollo cocoa beans.[27]
Trace amounts of theophylline are also found in brewedtea, although brewed tea provides only about 1 mg/L,[28] which is significantly less than a therapeutic dose.
Theophylline was first extracted from tea leaves and chemically identified around 1888 by the German biologistAlbrecht Kossel.[30][31] Seven years later, achemical synthesis starting with 1,3-dimethyluric acid was described byEmil Fischer and Lorenz Ach.[32] TheTraube purine synthesis, an alternative method to synthesize theophylline, was introduced in 1900 by another German scientist,Wilhelm Traube.[33] Theophylline's first clinical use came in 1902 as adiuretic.[34] It took an additional 20 years until it was first reported as an asthma treatment.[35] The drug was prescribed in asyrup up to the 1970s as Theostat 20 and Theostat 80, and by the early 1980s in a tablet form called Quibron.
^Eldridge FL, Millhorn DE, Kiley JP (November 1985). "Antagonism by theophylline of respiratory inhibition induced by adenosine".Journal of Applied Physiology.59 (5):1428–1433.doi:10.1152/jappl.1985.59.5.1428.PMID4066573.
^Hung KC, Ho CN, Chen IW, Hung IY, Lin MC, Lin CM, et al. (August 2021). "The impact of aminophylline on incidence and severity of post-dural puncture headache: A meta-analysis of randomised controlled trials".Anaesthesia, Critical Care & Pain Medicine.40 (4) 100920.doi:10.1016/j.accpm.2021.100920.PMID34186265.S2CID235686558.
^Watson CJ, Stone GL, Overbeek DL, Chiba T, Burns MM (February 2022). "Performance-enhancing drugs and the Olympics".Journal of Internal Medicine.291 (2):181–196.doi:10.1111/joim.13431.PMID35007384.S2CID245855348.
^"Theophylline".MedlinePlus Drug Information. U.S. National Library of Medicine. Archived fromthe original on July 5, 2016.
^Hendeles L, Weinberger M, Milavetz G, Hill M, Vaughan L (June 1985). "Food-induced "dose-dumping" from a once-a-day theophylline product as a cause of theophylline toxicity".Chest.87 (6):758–765.doi:10.1378/chest.87.6.758.PMID3996063.S2CID1133968.
^Seneff M, Scott J, Friedman B, Smith M (June 1990). "Acute theophylline toxicity and the use of esmolol to reverse cardiovascular instability".Annals of Emergency Medicine.19 (6):671–673.doi:10.1016/s0196-0644(05)82474-6.PMID1971502.
^DeVane CL, Markowitz JS, Hardesty SJ, Mundy S, Gill HS (September 1997). "Fluvoxamine-induced theophylline toxicity".The American Journal of Psychiatry.154 (9):1317–1318.doi:10.1176/ajp.154.9.1317b.PMID9286199.
^Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages".American Journal of Respiratory and Critical Care Medicine.159 (2):508–511.doi:10.1164/ajrccm.159.2.9804085.PMID9927365.
^Daly JW, Jacobson KA, Ukena D (1987). "Adenosine receptors: development of selective agonists and antagonists".Progress in Clinical and Biological Research.230 (1):41–63.PMID3588607.
^Jenne JW, Nagasawa HT, Thompson RD (March 1976). "Relationship of urinary metabolites of theophylline to serum theophylline levels".Clinical Pharmacology and Therapeutics.19 (3):375–381.doi:10.1002/cpt1976193375.PMID1261172.S2CID33943915.
^Jusko WJ, Schentag JJ, Clark JH, Gardner M, Yurchak AM (October 1978). "Enhanced biotransformation of theophylline in marihuana and tobacco smokers".Clinical Pharmacology and Therapeutics.24 (4):405–410.doi:10.1002/cpt1978244406.PMID688731.S2CID44613672.
^Schack JA, Waxler SH (November 1949). "An ultraviolet spectrophotometric method for the determination of theophylline and theobromine in blood and tissues".The Journal of Pharmacology and Experimental Therapeutics.97 (3):283–291.doi:10.1016/S0022-3565(25)03717-6.PMID15392550.
^Shelke RU, Degani MS, Raju A, Ray MK, Rajan MG (August 2016). "Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors".Archiv der Pharmazie.349 (8):602–613.doi:10.1002/ardp.201600066.PMID27320965.S2CID40014874.
^Pfleiderer W (February 2008). "Pteridines. Part CXIX. A New Pteridine–Purine Transformation".Helvetica Chimica Acta.91 (2):338–353.doi:10.1002/hlca.200890039.
^Belliardo F, Martelli A, Valle MG (May 1985). "HPLC determination of caffeine and theophylline in Paullinia cupana Kunth (guarana) and Cola spp. samples".Zeitschrift für Lebensmittel-Untersuchung und -Forschung.180 (5):398–401.doi:10.1007/BF01027774.PMID4013524.S2CID40205323.
^Kossel A (1889). "Über das Theophyllin, einen neuen Bestandtheil des Thees" [On theophylline, a new component of tea].Hoppe-Seyler's Zeitschrift für Physiologische Chemie [Hoppe-Seyler's Journal of Physiological Chemistry] (in German).13:298–308.
^Fischer E, Ach L (1895). "Synthese des Caffeins" [Synthesis of caffeine].Berichte der Deutschen Chemischen Gesellschaft [Reports of the German Chemical Society] (in German).28 (3): 3139.doi:10.1002/cber.189502803156.
^Minkowski O (1902). "Über Theocin (Theophyllin) als Diureticum" [About theocine (theophylline) as a diuretic].Therapie der Gegenwart [Therapy of the Present] (in German).43:490–493.
^Schultze-Werninghaus G, Meier-Sydow J (March 1982). "The clinical and pharmacological history of theophylline: first report on the bronchospasmolytic action in man by S. R. Hirsch in Frankfurt (Main) 1922".Clinical Allergy.12 (2):211–215.doi:10.1111/j.1365-2222.1982.tb01641.x.PMID7042115.S2CID38178598.
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