Theophylline

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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: CYP1A2, CYP2E1, CYP3A4
Metabolites• 1,3-Dimethyluric acid
• 1-Methyixanthine
• 3-Methylxanthine
Elimination half-life5–8 hours
Identifiers
  • 1,3-dimethyl-7H-purine-2,6-dione
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

Theophylline, also known as 1,3-dimethylxanthine, is a drug that inhibits

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]

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

Medical uses

The main actions of theophylline involve:[2]

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

Performance enhancement in sports

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

The use of theophylline is complicated by its interaction with various drugs and by the fact that it has a narrow

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

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

UV-visible spectroscopy

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)

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)

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

Theophylline is naturally found 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

Pharmacodynamics

Like other methylated xanthine derivatives, theophylline is both a

  1. competitive nonselective
    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

Absorption

When theophylline is administered

intravenously, bioavailability is 100%.[27]

Distribution

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

Theophylline is metabolized extensively in the liver.

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 marijuana smoking induces metabolism of theophylline, increasing the drug's metabolic clearance.[28][29]

Excretion

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

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

Theophylline was first extracted from tea leaves and chemically identified around 1888 by the German biologist

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

  1. ^ a b c "Theophylline". PubChem, US National Library of Medicine. 26 August 2023. Retrieved 2 September 2023.
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  11. ^ "Theophylline". MedlinePlus Drug Information. U.S. National Library of Medicine. Archived from the original on July 5, 2016.
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  19. ISBN 978-0-8493-2647-9
    . Retrieved 2013-11-10.
  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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  30. doi:10.1002/cber.188802101422
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  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. doi:10.1002/cber.189502803156
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  33. doi:10.1002/cber.19000330352
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  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. S2CID 38178598
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