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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 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

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

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

Medical uses

The main actions of theophylline involve:

The main therapeutic uses of theophylline are for treatment of:

Adverse effects

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). 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).[7][8] Seizures can also occur in severe cases of toxicity, and are considered to be a neurological emergency.[9] 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.[10] Theophylline toxicity can be treated with beta blockers. In addition to seizures, tachyarrhythmias are a major concern.[11] Theophylline should not be used in combination with the SSRI fluvoxamine.[12][13][14]

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).[15]

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.[16]

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.[17]

Natural occurrences

Theophylline is naturally found in cocoa beans. Amounts as high as 3.7 mg/g have been reported in Criollo cocoa beans.[18]

Trace amounts of theophylline are also found in brewed tea, although brewed tea provides only about 1 mg/L,[19] which is significantly less than a therapeutic dose.

Trace amounts of theophylline are also found in guarana (Paullinia cupana) and in kola nuts.[20]

Pharmacology

Pharmacodynamics

Like other methylated xanthine derivatives, theophylline is both a

  1. competitive nonselective phosphodiesterase inhibitor which increases intracellular levels of cAMP and cGMP,[21][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,[26] antagonizing A1, A2, and A3 receptors almost equally, which explains many of its cardiac effects.

Theophylline has been shown to inhibit TGF-beta-mediated conversion of pulmonary fibroblasts into myofibroblasts in COPD and asthma via cAMP-PKA pathway and suppresses COL1 mRNA, which codes for the protein collagen.[27]

It has been shown that theophylline may reverse the clinical observations of steroid insensitivity in patients with COPD and asthmatics who are active smokers (a condition resulting in oxidative stress) via a distinctly separate mechanism. Theophylline in vitro can restore the reduced HDAC (histone deacetylase) activity that is induced by oxidative stress (i.e., in smokers), returning steroid responsiveness toward normal.[28] Furthermore, theophylline has been shown to directly activate HDAC2.[28] (Corticosteroids switch off the inflammatory response by blocking the expression of inflammatory mediators through deacetylation of histones, an effect mediated via histone deacetylase-2 (HDAC2). Once deacetylated, DNA is repackaged so that the promoter regions of inflammatory genes are unavailable for binding of transcription factors such as NF-κB that act to turn on inflammatory activity. It has recently been shown that the oxidative stress associated with cigarette smoke can inhibit the activity of HDAC2, thereby blocking the anti-inflammatory effects of corticosteroids.)[citation needed]

Pharmacokinetics

Absorption

When theophylline is administered intravenously, bioavailability is 100%.[29]

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%. The volume of distribution may increase in neonates and those suffering from cirrhosis or malnutrition, whereas the volume of distribution may decrease in those who are obese.[citation needed]

Metabolism

Theophylline is metabolized extensively in the liver (up to 70%). 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. Cigarette and marihuana smoking induces metabolism of theophylline, increasing the drug's metabolic clearance.[30][31]

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.[citation needed]

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.[citation needed]

Caffeine metabolism by the liver produces small amount of theophylline.[32]

History

Theophylline was first extracted from tea leaves and chemically identified around 1888 by the German biologist Albrecht Kossel.[33][34] Seven years later, a chemical synthesis starting with 1,3-dimethyluric acid was described by Emil Fischer and Lorenz Ach.[35] The Traube purine synthesis, an alternative method to synthesize theophylline, was introduced in 1900 by another German scientist, Wilhelm Traube.[36] Theophylline's first clinical use came in 1902 as a diuretic.[37] It took an additional 20 years until it was first reported as an asthma treatment.[38] 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. ^ Humans, IARC Working Group on the Evaluation of Carcinogenic Risks to (1991). "Theophylline". Coffee, Tea, Mate, Methylxanthines and Methylglyoxal. International Agency for Research on Cancer.
  2. ^ Alboni P, Menozzi C, Brignole M, Paparella N, Gaggioli G, Lolli G, Cappato R (July 1997). "Effects of permanent pacemaker and oral theophylline in sick sinus syndrome the THEOPACE study: a randomized controlled trial". Circulation. 96 (1): 260–6. doi:10.1161/01.cir.96.1.260. PMID 9236443.
  3. ^ 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. PMID 29391776.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  4. ^ Miao Y, Zhou Y, Zhao S, Liu W, Wang A, Zhang Y, 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. doi:10.1371/journal.pone.0274882. PMID 36121807.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ 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. PMID 34186265. S2CID 235686558.
  6. ^ Shaat AM, Abdalgaleil MM (January 2021). "Is theophylline more effective than sumatriptan in the treatment of post-dural puncture headache? A randomized clinical trial". Egyptian Journal of Anaesthesia. 37 (1): 310–316. doi:10.1080/11101849.2021.1949195. ISSN 1110-1849.
  7. ^ "Theophylline". MedlinePlus Drug Information. U.S. National Library of Medicine. Archived from the original on July 5, 2016.
  8. ^ "Theophylline (Theo-24, Theolair) Uses, Side Effects & Dosage". Archived from the original on May 9, 2008.
  9. ^ Yoshikawa H (April 2007). "First-line therapy for theophylline-associated seizures". Acta Neurologica Scandinavica. 115 (4 Suppl): 57–61. doi:10.1111/j.1600-0404.2007.00810.x. PMID 17362277. S2CID 11347304.
  10. ^ 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): 758–65. doi:10.1378/chest.87.6.758. PMID 3996063. S2CID 1133968.
  11. ^ 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): 671–3. doi:10.1016/s0196-0644(05)82474-6. PMID 1971502.
  12. ^ DeVane CL, Markowitz JS, Hardesty SJ, Mundy S, Gill HS (September 1997). "Fluvoxamine-induced theophylline toxicity". The American Journal of Psychiatry. 154 (9): 1317–8. doi:10.1176/ajp.154.9.1317b. PMID 9286199.
  13. ^ Sperber AD (November 1991). "Toxic interaction between fluvoxamine and sustained release theophylline in an 11-year-old boy". Drug Safety. 6 (6): 460–2. doi:10.2165/00002018-199106060-00006. PMID 1793525. S2CID 21875026.
  14. ^ Brøsen K (September 1998). "Differences in interactions of SSRIs". International Clinical Psychopharmacology. 13 (Suppl 5): S45-7. doi:10.1097/00004850-199809005-00009. PMID 9817620. S2CID 38403377.
  15. ^ 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): 283–91. PMID 15392550.
  16. ^ 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): 602–13. doi:10.1002/ardp.201600066. PMID 27320965. S2CID 40014874.
  17. ^ Pfleiderer W (February 2008). "Pteridines. Part CXIX. A New Pteridine–Purine Transformation". Helvetica Chimica Acta. 91 (2): 338–353. doi:10.1002/hlca.200890039.
  18. ^ Apgar JL, Tarka Jr SM (1998). "Methylxanthine composition and consumption patterns of cocoa and chocolate products and their uses". In Spiller GA (ed.). Caffeine. CRC Press. p. 171. ISBN 978-0-8493-2647-9. Retrieved 2013-11-10.
  19. ^ "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.
  20. ^ 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. PMID 4013524. S2CID 40205323.
  21. ^ Barnes PJ (October 2013). "Theophylline". American Journal of Respiratory and Critical Care Medicine. 188 (8): 901–906. doi:10.1164/rccm.201302-0388PP. PMID 23672674.
  22. ^ Essayan DM (November 2001). "Cyclic nucleotide phosphodiesterases". The Journal of Allergy and Clinical Immunology. 108 (5): 671–680. doi:10.1067/mai.2001.119555. PMID 11692087.
  23. ^ Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R (June 2008). "Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition". Clinics. 63 (3): 321–8. doi:10.1590/S1807-59322008000300006. PMC 2664230. PMID 18568240.
  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): 508–11. doi:10.1164/ajrccm.159.2.9804085. PMID 9927365.
  25. ^ a b Peters-Golden M, Canetti C, Mancuso P, Coffey MJ (January 2005). "Leukotrienes: underappreciated mediators of innate immune responses". Journal of Immunology. 174 (2): 589–94. doi:10.4049/jimmunol.174.2.589. PMID 15634873.
  26. ^ 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. PMID 3588607.
  27. ^ Yano Y, Yoshida M, Hoshino S, Inoue K, Kida H, Yanagita M, et al. (March 2006). "Anti-fibrotic effects of theophylline on lung fibroblasts". Biochemical and Biophysical Research Communications. 341 (3): 684–90. doi:10.1016/j.bbrc.2006.01.018. PMID 16430859.
  28. ^ a b Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ (June 2002). "A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression". Proceedings of the National Academy of Sciences of the United States of America. 99 (13): 8921–6. Bibcode:2002PNAS...99.8921I. doi:10.1073/pnas.132556899. PMC 124399. PMID 12070353.
  29. ^ Griffin, J. P. The Textbook of Pharmaceutical Medicine (6th ed.). New Jersey: BMJ Books. ISBN 978-1-4051-8035-1
  30. ^ 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. PMID 1261172.
  31. ^ Enhanced biotransformation of theophylline in marihuana and tobacco smokers Clinical pharmacology and therapeutics 1978 Oct;24(4):405-10.
  32. ^ Mandal A (28 February 2010). "Caffeine Pharmacology". Website Medical News. Archived from the original on 2016-05-31.
  33. ^ Kossel A (1888). "Über eine neue Base aus dem Pflanzenreich". Ber. Dtsch. Chem. Ges. 21: 2164–2167. doi:10.1002/cber.188802101422.
  34. ^ Kossel A (1889). "Über das Theophyllin, einen neuen Bestandtheil des Thees". Hoppe-Seyler's Z. Physiol. Chem. 13: 298–308.
  35. ^ Fischer E, Ach L (1895). "Synthese des Caffeins". Ber. Dtsch. Chem. Ges. 28 (3): 3139. doi:10.1002/cber.189502803156.
  36. ^ Traube W (1900). "Der synthetische Aufbau der Harnsäure, des Xanthins, Theobromins, Theophyllins und Caffeïns aus der Cyanessigsäure]". Chem. Ber. 33 (3): 3035–3056. doi:10.1002/cber.19000330352.
  37. ^ Minkowski O (1902). "Über Theocin (Theophyllin) als Diureticum". Ther. Gegenwart. 43: 490–493.
  38. ^ 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): 211–5. doi:10.1111/j.1365-2222.1982.tb01641.x. PMID 7042115. S2CID 38178598.
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