Theophylline

Overview

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 methylxanthine drugs (e.g., theobromine and caffeine). Trace amounts of theophylline are naturally present in tea, coffee, chocolate, yerba mate, guarana, and kola nut.[1][2][3] WP

Uses, dosage and effects

Medical uses

The main actions of theophylline involve:[2] WP

• relaxing bronchial smooth muscle[2] WP
• increasing heart muscle contractility and efficiency (positive inotrope)[2] WP
• increasing heart rate (positive chronotropic)[2] WP
• increasing blood pressure[2] WP
• increasing renal blood flow[2] WP
• anti-inflammatory effects[2] WP
• central nervous system stimulatory effect, mainly on the medullary respiratory center[4][5] WP

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

• Chronic obstructive pulmonary disease (COPD)[6] WP
• Asthma[2] WP
• Infant apnea[7] WP
• Blocks the action of adenosine; an inhibitory neurotransmitter that induces sleep, contracts the smooth muscles and relaxes the cardiac muscle.[2] WP
• Treatment of post-dural puncture headache.[8][9] WP

Risks and side effects

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). Seizures can also occur in severe cases of toxicity, and are considered to be a neurological emergency.[2][10] WP

Interactions

Interactions

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. Theophylline toxicity can be treated with beta blockers. In addition to seizures, tachyarrhythmias are a major concern. Theophylline should not be used in combination with the SSRI fluvoxamine.[11–14] WP

Pharmacology

Pharmacodynamics

Like other methylated xanthine derivatives, theophylline is a competitive nonselective phosphodiesterase inhibitor which increases intracellular levels of cAMP and cGMP, activates PKA, inhibits TNF-alpha and inhibits leukotriene synthesis, and reduces inflammation and innate immunity. Theophylline also acts as a nonselective adenosine receptor antagonist, antagonizing A₁, A₂, and A₃ receptors almost equally, which explains many of its cardiac effects. Theophylline activates histone deacetylases.[2][15–19] WP

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%. WP⚠ Wikipedia itself has flagged this text: medical citation needed.

Metabolism

Theophylline is metabolized extensively in the liver. 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 marijuana smoking induces metabolism of theophylline, increasing the drug's metabolic clearance.[2][20][21] WP

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] WP

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. WP⚠ Wikipedia itself has flagged this text: medical citation needed.

History

History

Theophylline was first extracted from tea leaves and chemically identified around 1888 by the German biologist Albrecht Kossel. Seven years later, a chemical synthesis starting with 1,3-dimethyluric acid was described by Emil Fischer and Lorenz Ach. The Traube purine synthesis, an alternative method to synthesize theophylline, was introduced in 1900 by another German scientist, Wilhelm Traube. Theophylline's first clinical use came in 1902 as a diuretic. It took an additional 20 years until it was first reported as an asthma treatment. 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.[22–27] WP

Chemistry

Formula

C7H8N4O2 PC

CAS number

58-55-9 PC

Molar mass (g/mol)

180.16 PC

IUPAC name (computed by PubChem)

1,3-dimethyl-7H-purine-2,6-dione PC

SMILES

CN1C2=C(C(=O)N(C1=O)C)NC=N2 PC

InChIKey

ZFXYFBGIUFBOJW-UHFFFAOYSA-N PC

PubChem CID

2153

IUPAC name

1,3-dimethyl-7H-purine-2,6-dione WP

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

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3. Journal / agency IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 1991. PMID 2033791 · PMC7681294
4. Journal / agency Eldridge FL, Millhorn DE, Kiley JP. Antagonism by theophylline of respiratory inhibition induced by adenosine. Journal of Applied Physiology. November 1985. doi:10.1152/jappl.1985.59.5.1428 · PMID 4066573
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9. Journal / agency Barati-Boldaji R, Shojaei-Zarghani S, Mehrabi M, Amini A, Safarpour AR. Post-dural puncture headache prevention and treatment with aminophylline or theophylline: a systematic review and meta-analysis. Anesthesia and Pain Medicine. April 2023. doi:10.17085/apm.22247 · PMID 37183286 · PMC10183611
10. Journal / agency Theophylline
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