Theophylline, also known as 1,3-dimethylxanthine, is a drug that inhibits phosphodiesterase and blocks adenosine receptors.[1] It is used to treat chronic obstructive pulmonary disease (COPD) and asthma.[2] Its pharmacology is similar to other methylxanthine drugs (e.g., theobromine and caffeine).[1] Trace amounts of theophylline are naturally present in tea, coffee, chocolate, yerba maté, guarana, and kola nut.[1][3]

Theophylline
Clinical data
Trade namesTheolair, Slo-Bid
AHFS/Drugs.comMonograph
MedlinePlusa681006
Pregnancy
category
Routes of
administration
oral, IV, rectal
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability100% (oral)
Protein binding40% (primarily to albumin)
MetabolismHepatic to 1-methyluric acid
Elimination half-life5–8 hours
Identifiers
  • 1,3-dimethyl-7H-purine-2,6-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.350 Edit this at Wikidata
Chemical and physical data
FormulaC7H8N4O2
Molar mass180.167 g·mol−1
3D model (JSmol)
  • Cn1c2c(c(=O)n(c1=O)C)[nH]cn2
  • InChI=1S/C7H8N4O2/c1-10-5-4(8-3-9-5)6(12)11(2)7(10)13/h3H,1-2H3,(H,8,9) checkY
  • Key:ZFXYFBGIUFBOJW-UHFFFAOYSA-N checkY
  (verify)
Theophylline extended-release tablets in Japan

The name 'theophylline' derives from "Thea"—the former genus name for tea + Legacy Greek φύλλον (phúllon, “leaf”) + -ine.

Medical uses edit

The main actions of theophylline involve:[2]

The main therapeutic uses of theophylline are for treating:[2]

Performance enhancement in sports edit

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.[9] There is conflicting information about the value of theophylline and other methylxanthines as prophylaxis against exercise-induced asthma.[10]

Adverse effects edit

The use of theophylline is complicated by its interaction with various drugs and by the fact that it has a narrow therapeutic window (<20 mcg/mL).[2] Its use must be monitored by direct measurement of serum theophylline levels to avoid toxicity. It can also cause nausea, diarrhea, increase in heart rate, abnormal heart rhythms, and CNS excitation (headaches, insomnia, irritability, dizziness and lightheadedness).[2][11] Seizures can also occur in severe cases of toxicity, and are considered to be a neurological emergency.[2]

Its toxicity is increased by erythromycin, cimetidine, and fluoroquinolones, such as ciprofloxacin. Some lipid-based formulations of theophylline can result in toxic theophylline levels when taken with fatty meals, an effect called dose dumping, but this does not occur with most formulations of theophylline.[12] Theophylline toxicity can be treated with beta blockers. In addition to seizures, tachyarrhythmias are a major concern.[13] Theophylline should not be used in combination with the SSRI fluvoxamine.[14][15]

Spectroscopy edit

UV-visible spectroscopy edit

Theophylline is soluble in 0.1N NaOH and absorbs maximally at 277 nm with an extinction coefficient of 10,200 (cm−1 M−1).[16]

Proton nuclear magnetic resonance spectroscopy (1H-NMR) edit

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.[17]

Carbon nuclear magnetic resonance spectroscopy (13C-NMR) edit

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.[18]

Natural occurrences edit

Theophylline is naturally found in cocoa beans. Amounts as high as 3.7 mg/g have been reported in Criollo cocoa beans.[19]

Trace amounts of theophylline are also found in brewed tea, although brewed tea provides only about 1 mg/L,[20] which is significantly less than a therapeutic dose.

Trace amounts of theophylline are also found in guarana (Paullinia cupana) and in kola nuts.[21]

Pharmacology edit

Pharmacodynamics edit

Like other methylated xanthine derivatives, theophylline is both a

  1. competitive nonselective phosphodiesterase inhibitor which increases intracellular levels of cAMP and cGMP,[2][22] activates PKA, inhibits TNF-alpha[23][24] and inhibits leukotriene[25] synthesis, and reduces inflammation and innate immunity[25]
  2. nonselective adenosine receptor antagonist, antagonizing A1, A2, and A3 receptors almost equally, which explains many of its cardiac effects.[2][26] Theophylline activates histone deacetylases.[2]

Pharmacokinetics edit

Absorption edit

When theophylline is administered intravenously, bioavailability is 100%.[27]

Distribution edit

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]

Metabolism edit

Theophylline is metabolized extensively in the liver.[2] It undergoes N-demethylation via cytochrome P450 1A2. It is metabolized by parallel first order and Michaelis-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 marihuana smoking induces metabolism of theophylline, increasing the drug's metabolic clearance.[28][29]

Excretion edit

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 in cystic fibrosis, and hyperthyroidism. Clearance of the drug is decreased in these conditions: elderly, acute congestive heart failure, cirrhosis, hypothyroidism and febrile viral illnesses.[2]

The elimination half-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 with hepatic impairment, 12 hours for those with congestive heart failure NYHA class I-II, 24 hours for those with congestive heart failure NYHA class III-IV, 12 hours for the elderly.[medical citation needed]

History edit

Theophylline was first extracted from tea leaves and chemically identified around 1888 by the German biologist Albrecht Kossel.[30][31] Seven years later, a chemical synthesis starting with 1,3-dimethyluric acid was described by Emil Fischer and Lorenz Ach.[32] The Traube 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 a diuretic.[34] It took an additional 20 years until it was first reported as an asthma treatment.[35] The drug was prescribed in a syrup up to the 1970s as Theostat 20 and Theostat 80, and by the early 1980s in a tablet form called Quibron.

References edit

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  3. ^ IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (1991). "Coffee, Tea, Mate, Methylxanthines and Methylglyoxal". IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. International Agency for Research on Cancer. 51: 391–419. PMC 7681294. PMID 2033791.
  4. ^ 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. PMID 4066573.
  5. ^ Mahemuti G, Zhang H, Li J, Tieliwaerdi N, Ren L (10 January 2018). "Efficacy and side effects of intravenous theophylline in acute asthma: a systematic review and meta-analysis". Drug Design, Development and Therapy. 12: 99–120. doi:10.2147/DDDT.S156509. PMC 5768195. PMID 29391776.
  6. ^ Miao Y, Zhou Y, Zhao S, et al. (19 September 2022). "Comparative efficacy and safety of caffeine citrate and aminophylline in treating apnea of prematurity: A systematic review and meta-analysis". PLOS ONE. 17 (9): e0274882. Bibcode:2022PLoSO..1774882M. doi:10.1371/journal.pone.0274882. PMC 9484669. PMID 36121807.
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  13. ^ 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. PMID 1971502.
  14. ^ 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. PMID 9286199.
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  16. ^ 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. PMID 15392550.
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  20. ^ "TABLE 2a: Concentrations of caffeine, theobromine and theophylline in tea products". Food Surveillance Information Sheet Number 103. MAFF, Department of Health and the Scottish Executive. Archived from the original on 2006-09-27.
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  24. ^ 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. PMID 9927365.
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  30. ^ Kossel A (1888). "Über eine neue Base aus dem Pflanzenreich" [About a new base from the plant kingdom]. Berichte der Deutschen Chemischen Gesellschaft [Reports of the German Chemical Society] (in German). 21: 2164–2167. doi:10.1002/cber.188802101422.
  31. ^ 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.
  32. ^ 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.
  33. ^ Traube W (1900). "Der synthetische Aufbau der Harnsäure, des Xanthins, Theobromins, Theophyllins und Caffeïns aus der Cyanessigsäure" [The synthetic structure of uric acid, xanthine, theobromine, theophylline and caffeine from cyanoacetic acid]. Berichte der Deutschen Chemischen Gesellschaft [Reports of the German Chemical Society] (in German). 33 (3): 3035–3056. doi:10.1002/cber.19000330352.
  34. ^ 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.
  35. ^ 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. PMID 7042115. S2CID 38178598.