3D Mol Similar

Theophylline

: Iupac Name：1,3-dimethyl-7H-purine-2,6-dione; CAS No.: 58-55-9; Molecular Weight：180.16400; Modify Date.: 2022-11-10 22:00; Introduction: Dosing requires the determination of plasma levels with 10 to 20 μg/mL being associated with the least incidence of side effects. Overdose of theophylline can result in a quick onset of ventricular arrhythmias, convulsions, or even death without any previous warning. Many drugs increase the plasma concentration of theophylline, including quinolone and macrolide antibiotics, nonselective β-blockers, ephedrine, calcium channel blockers, cimetidine, and oral contraceptives. Theophylline is available in tablet, capsule, liquid, and parenteral dosage preparations. There also are combination products with guaifenesin and ephedrine available as tablet and liquid dosage forms. There are two products that are theophylline salts. Aminophylline is theophylline ethylenediamine, which contains 70% theophylline and is available in tablets, liquid, parenteral, and suppository dosage forms. Oxytriphylline is the choline salt of theophylline, and it contains 64% theophylline in tablets and liquid dosage forms. Care must be taken to correctly calculate the equivalent dose when switching a patient from theophylline to one of its salts. View more+

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1. Names and Identifiers

: 1.1 Name; Theophylline; 1.2 Synonyms; [13C]-Theophyllin [14C]-Theophyllin [3H]-Theophyllin 1,3-Dimethyl-3,7-dihydro-1H-purine-2,6-dione 1,3-Dimethylpurine-2,6(1H,3H)-dione 1,3-dimethyl-xanthin 1,3-Dimethylxanthine 1H-Purine-2,6-dione, 3,7-dihydro-1,3-dimethyl- 3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione 3,7-dihydro-1,3-dimethyl-1h-purine-6-dione 3h)-dione,1,3-dimethyl-purine-6(1h 6-dione,3,7-dihydro-1,3-dimethyl-1H-Purine-2 accurb accurbron Acet-theocin Adisne Aerolate Afonilum asmax austyn Bilordyl Bronchoretard Cetraphylline Diffumal Diphyllin (VAN) duraphy Duraphyllin Egifilin EINECS 200-385-7 Elixex Elixophyllin Etheophyl Euphylline Euphylong LABID LASMA MFCD00079619 Nuelin Physpan Pulmidur Pulmo-Timelets Slo-Phyllin Slo-PhyllinTM Solosin Talotren Teonova Teosona Theal Theobid Theoclear Theodel Theodrip Theolair Theon Theona P Theoplus Theotard unidur Unifyl Uniphyl UNIPHYLLIN Xanthium; View all

1.3 CAS No.: 58-55-9

1.4 CID: 2153

1.5 EINECS(EC#): 200-385-7

1.6 Molecular Formula: C7H8N4O2 (isomer)

1.7 Inchi: InChI=1S/C7H8N4O2/c1-10-5-4(8-3-9-5)6(12)11(2)7(10)13/h3H,1-2H3,(H,8,9)

1.8 InChIkey: ZFXYFBGIUFBOJW-UHFFFAOYSA-N

1.9 Canonical Smiles: CN1C2=C(C(=O)N(C1=O)C)NC=N2

1.10 Isomers Smiles: CN1C2=C(C(=O)N(C1=O)C)NC=N2

2. Properties

2.1 Density: 1.465 g/cm3

2.1 Melting point: 271-273°C

2.1 Boiling point: 454.1ºC at 760 mmHg

2.1 Refractive index: 1.737

2.1 Flash Point: 11°C

2.1 Precise Quality: 180.06500

2.1 PSA: 72.68000

2.1 logP: -1.03970

2.1 Solubility: 0.1 M HCl: soluble

2.2 Appearance: white to off-white crystalline powder

2.3 Storage: Ambient temperatures.

2.4 Chemical Properties: white to light yellow crystal powder

2.5 Color/Form: Powder

2.6 Decomposition: When heated to decomposition it emits toxic fumes of /nitrogen oxides/.

2.7 Odor: Odorless

2.8 PH: A saturated solution in water is faintly acid.

2.9 pKa: 8.77(at 25℃)

2.10 Water Solubility: 8.3 g/L (20 oC)

2.11 Stability: Stable. Incompatible with strong oxidizing agents.

2.12 StorageTemp: 2-8°C

3. Use and Manufacturing

3.1 Definition: ChEBI: A dimethylxanthine having the two methyl groups located at positions 1 and 3. It is structurally similar to caffeine and is found in green and black tea.

3.2 General Description: Odorless white crystalline powder. Odorless. Bitter taste.

3.3 Purification Methods: It crystallises from H2O as the monohydrate which becomes anhydrous above 100o. It is freely soluble in hot H2O, but its solubility at 15o is 0.44%. It complexes with heavy metals. It is a diuretic, vasodilator and a cardiac stimulant. [Lister Purines Part II, Fused Pyrimidines Brown Ed, Wiley-Interscience pp253-254 1971, ISBN 0-471-38205-1, Beilstein 26 H 455, 26 I 134, 26 II 263, 26 III/IV 2331.]

3.4 Usage: Xanthine derivative with diuretic, cardiac stimulant and smooth muscle relaxant activities; isomeric with theobromine. Small amounts occur in tea. Bronchodilator.

4. Safety and Handling

4.1 Symbol: GHS06

4.1 Hazard Codes: Xn

4.1 Signal Word: Danger

4.1 Risk Statements: R22

4.1 Safety Statements: S7-S16-S36/37-S45

4.1 Packing Group: III

4.1 Fire Hazard: Flash point data for Theophylline are not available, however Theophylline is probably combustible.

4.2 Hazard Class: 6.1(b)

4.2 Hazard Declaration: H301

4.2 RIDADR: UN 2811 6.1/PG 3

4.2 Safety Profile: Human poison byingestion, parenteral, intravenous, and rectalroutes. Experimental poison by multipleroutes. An experimental teratogen. Humansystemic effects: coma, convulsions or effecton seizure threshold, cyanosis, EKGchanges, fever and other metabolic effects,heart arrhythmias, heart rate change,hyperglycemia, metabolic acidosis, nausea orvomiting, potassium-level changes,respiratory stimulation, salivary glandchanges, somnolence, tremor. Experimentalreproductive effects. Human mutation datareported. Used as a dturetic, cardtacstimulant, smooth muscle relaxant, and totreat asthma. When heated todecomposition it emits toxic fumes of NOx.

4.3 Caution Statement: P301 + P310

4.3 WGK Germany: 1

4.3 RTECS: XH3850000

4.3 Report: Reported in EPA TSCA Inventory. EPA Genetic Toxicology Program.

4.4 Safety: Human poison by ingestion, parenteral, intravenous, and rectal routes. Experimental poison by multiple routes. An experimental teratogen. Human systemic effects: coma, convulsions or effect on seizure threshold, cyanosis, EKG changes, fever and other metabolic effects, heart arrhythmias, heart rate change, hyperglycemia, metabolic acidosis, nausea or vomiting, potassium-level changes, respiratory stimulation, salivary gland changes, somnolence, tremor. Experimental reproductive effects. Human mutation data reported. Used as a diuretic, cardiac stimulant, smooth muscle relaxant, and to treat asthma. When heated to decomposition it emits toxic fumes of NO_x.
Hazard Codes:?Xn,T,F,Xi
Risk Statements: 22-39/23/24/25-23/24/25-11-36/37/38?
R22:Harmful if swallowed.
R39:Danger of very serious irreversible effects.?
R23/24/25:Toxic by inhalation, in contact with skin and if swallowed.?
R11:Highly flammable.?
R36/37/38:Irritating to eyes, respiratory system and skin.
Safety Statements: 7-16-36/37-45-36-26?
S7:Keep container tightly closed.?
S16:Keep away from sources of ignition.?
S36/37:Wear suitable protective clothing and gloves.?
S45:In case of accident or if you feel unwell, seek medical advice immediately (show the label whenever possible.)?
S36:Wear suitable protective clothing.?
S26: In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.
RIDADR: UN 2811 6.1/PG 3
WGK Germany: 1
RTECS of Theophylline (CAS NO.58-55-9): XH3850000; View all

4.5 Specification: ?Theophylline (CAS NO.58-55-9), its Synonyms are Theophylline anhydrous ; 1,3-Dimethylxanthine ; 3,7-Dihydro-1,3-dimethyl-1H-purine-2,6-dione ; Acet-theocin ; Aerolate ; Aerolate III ; Armophylline ; Lanophyllin ; Liquophylline ; Maphylline ; Medaphyllin ; Pseudotheophylline ; Purine-2,6(1H,3H)-dione, 1,3-dimethyl- . It is odorless white crystalline powder and bitter taste.

4.6 Toxicity

Organism	Test Type	Route	Reported Dose (Normalized Dose)	Effect	Source
child	TDLo	intramuscular	50mg/kg (50mg/kg)	BEHAVIORAL: EXCITEMENT CARDIAC: CHANGE IN RATE LUNGS, THORAX, OR RESPIRATION: RESPIRATORY STIMULATION	Journal of Pediatrics. Vol. 90, Pg. 827, 1977.
child	TDLo	oral	10mg/kg (10mg/kg)	BEHAVIORAL: HEADACHE CARDIAC: PULSE RATE INCREASE WITHOUT FALL IN BP GASTROINTESTINAL: NAUSEA OR VOMITING	Southern Medical Journal. Vol. 78, Pg. 1000, 1985.
guinea pig	LD50	oral	183mg/kg (183mg/kg)	?	United States Patent Document. Vol. #4089959,
guinea pig	LDLo	subcutaneous	170mg/kg (170mg/kg)	?	"Handbook of Toxicology," 4 vols., Philadelphia, W.B. Saunders Co., 1956-59Vol. 5, Pg. 168, 1959.
human	TDLo	intravenous	10mg/kg/D (10mg/kg)	BEHAVIORAL: TREMOR CARDIAC: ARRHYTHMIAS (INCLUDING CHANGES IN CONDUCTION) GASTROINTESTINAL: NAUSEA OR VOMITING	JAMA, Journal of the American Medical Association. Vol. 235, Pg. 1983, 1976.
human	TDLo	oral	5mg/kg (5mg/kg)	BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD GASTROINTESTINAL: NAUSEA OR VOMITING	"Toxicology of Drugs and Chemicals," Deichmann, W.B., New York, Academic Press, Inc., 1969Vol. -, Pg. 92, 1969.
human	TDLo	rectal	6mg/kg (6mg/kg)	BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD GASTROINTESTINAL: NAUSEA OR VOMITING	"Toxicology of Drugs and Chemicals," Deichmann, W.B., New York, Academic Press, Inc., 1969Vol. -, Pg. 92, 1969.
human	TDLo	subcutaneous	3500ug/kg (3.5mg/kg)	BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD GASTROINTESTINAL: NAUSEA OR VOMITING	"Toxicology of Drugs and Chemicals," Deichmann, W.B., New York, Academic Press, Inc., 1969Vol. -, Pg. 92, 1969.
infant	TDLo	oral	348mg/kg/4D-I (348mg/kg)	BEHAVIORAL: ANOREXIA (HUMAN BEHAVIORAL: IRRITABILITY LUNGS, THORAX, OR RESPIRATION: RESPIRATORY STIMULATION	Pediatric Pharmacology. Vol. 5, Pg. 209, 1985.
man	LDLo	intravenous	3429ug/kg (3.429mg/kg)	BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD LUNGS, THORAX, OR RESPIRATION: CYANOSIS GASTROINTESTINAL: CHANGES IN STRUCTURE OR FUNCTION OF SALIVARY GLANDS	JAMA, Journal of the American Medical Association. Vol. 136, Pg. 397, 1948.
man	LDLo	parenteral	12mg/kg (12mg/kg)	?	Deutsches Archiv fuer Klinische Medizin. Vol. 80, Pg. 510, 1904.
man	TDLo	oral	66mg/kg (66mg/kg)	CARDIAC: CHANGE IN RATE VASCULAR: BP LOWERING NOT CHARACTERIZED IN AUTONOMIC SECTION GASTROINTESTINAL: NAUSEA OR VOMITING	American Journal of Emergency Medicine. Vol. 11, Pg. 609, 1993.
man	TDLo	oral	66mg/kg (66mg/kg)	BEHAVIORAL: MUSCLE CONTRACTION OR SPASTICITY) GASTROINTESTINAL: CONTRACTION (ISOLATED TISSUE) GASTROINTESTINAL: NAUSEA OR VOMITING	Medical Journal of Australia. Vol. 156, Pg. 512, 1992.
man	TDLo	oral	86mg/kg (86mg/kg)	CARDIAC: CHANGE IN RATE VASCULAR: BP LOWERING NOT CHARACTERIZED IN AUTONOMIC SECTION LUNGS, THORAX, OR RESPIRATION: RESPIRATORY STIMULATION	Annals of Emergency Medicine. Vol. 20, Pg. 1143, 1991.
man	TDLo	oral	129mg/kg (129mg/kg)	ENDOCRINE: HYPERGLYCEMIA	Annals of Internal Medicine. Vol. 104, Pg. 284, 1986.
mouse	LD50	intramuscular	271mg/kg (271mg/kg)	?	Drugs in Japan Vol. 6, Pg. 34, 1982.
mouse	LD50	intraperitoneal	70mg/kg (70mg/kg)	BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD	British Journal of Pharmacology. Vol. 73, Pg. 887, 1981.
mouse	LD50	intravenous	136mg/kg (136mg/kg)	?	Pharmaceutica Acta Helvetiae. Vol. 48, Pg. 133, 1973.
mouse	LD50	oral	235mg/kg (235mg/kg)	?	Arzneimittel-Forschung. Drug Research. Vol. 45, Pg. 569, 1995.
mouse	LD50	rectal	166mg/kg (166mg/kg)	BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD BEHAVIORAL: MUSCLE CONTRACTION OR SPASTICITY) LUNGS, THORAX, OR RESPIRATION: OTHER CHANGES	Pediatric Research. Vol. 11, Pg. 783, 1977.
mouse	LD50	subcutaneous	138mg/kg (138mg/kg)	?	Arzneimittel-Forschung. Drug Research. Vol. 3, Pg. 328, 1953.
mouse	LD50	unreported	400mg/kg (400mg/kg)	?	United States Patent Document. Vol. #4767763,
rabbit	LD50	intravenous	150mg/kg (150mg/kg)	?	Drugs in Japan Vol. 6, Pg. 34, 1982.
rabbit	LD50	oral	350mg/kg (350mg/kg)	?	"Prehled Prumyslove Toxikologie; Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986Vol. -, Pg. 865, 1986.
rat	LD50	intraperitoneal	150mg/kg (150mg/kg)	?	United States Patent Document. Vol. #4120947,
rat	LD50	oral	225mg/kg (225mg/kg)	?	United States Patent Document. Vol. #4089959,
rat	LD50	unreported	300mg/kg (300mg/kg)	?	United States Patent Document. Vol. #4767763,
rat	LDLo	intravenous	240mg/kg (240mg/kg)	?	"Drug Dosages in Laboratory Animals - A Handbook," Rev. ed., Barnes, C.D., and L.G. Eltherington, Berkeley, Univ. of California Press, 1973Vol. -, Pg. 259, 1973.
rat	LDLo	subcutaneous	325mg/kg (325mg/kg)	?	European Patent Application. Vol. #0134762,
women	LDLo	oral	130mg/kg (130mg/kg)	?	Annals of Internal Medicine. Vol. 101, Pg. 457, 1984.
women	TDLo	intravenous	120mg/kg/3D-C (120mg/kg)	CARDIAC: EKG CHANGES NOT DIAGNOSTIC OF ABOVE	Drug Intelligence and Clinical Pharmacy. Vol. 16, Pg. 877, 1982.
women	TDLo	oral	5mg/kg (5mg/kg)	BEHAVIORAL: COMA CARDIAC: ARRHYTHMIAS (INCLUDING CHANGES IN CONDUCTION) GASTROINTESTINAL: NAUSEA OR VOMITING	British Medical Journal. Vol. 288, Pg. 1497, 1984.
women	TDLo	oral	108mg/kg (108mg/kg)	ENDOCRINE: HYPERGLYCEMIA	American Journal of Emergency Medicine. Vol. 3, Pg. 408, 1985.
women	TDLo	oral	281mg/kg/4W (281mg/kg)	BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY)	British Medical Journal. Vol. 281, Pg. 1322, 1980.
women	TDLo	oral	388mg/kg (388mg/kg)	BEHAVIORAL: COMA CARDIAC: CHANGE IN RATE	Annals of Emergency Medicine. Vol. 20, Pg. 1135, 1991.

View all

5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

Acute toxicity - Oral, Category 3

2.2 GHS label elements, including precautionary statements

Pictogram(s)
Signal word	Danger
Hazard statement(s)	H301 Toxic if swallowed
Precautionary statement(s)
Prevention	P264 Wash ... thoroughly after handling. P270 Do not eat, drink or smoke when using this product.
Response	P301+P310 IF SWALLOWED: Immediately call a POISON CENTER/doctor/\u2026 P321 Specific treatment (see ... on this label). P330 Rinse mouth.
Storage	P405 Store locked up.
Disposal	P501 Dispose of contents/container to ...

2.3 Other hazards which do not result in classification

none

View all

6. NMR Spectrum

13C NMR : in DMSO-d6

13C NMR : Predict

1H NMR : 90 MHz in DMSO-d6

Mass spectrum (electron ionization)

UV/Visible spectrum

7. Synthesis Route

58-55-9Total: 56 Synthesis Route

85-18-7 66 Suppliers

58-55-9 338 Suppliers

Literatures:
US2142935 , ;
Yield: ~%

74-88-4

58-55-9 338 Suppliers

Literatures:
Chemische Berichte, , vol. 33, p. 3665
Yield: ~%

58-08-2

58-55-9 338 Suppliers

83-67-0 177 Suppliers

Literatures:
Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, , vol. 28, # 1-11 p. 311 - 312
Yield: ~20%

View all

8. Other Information

8.0 Usage: Theophylline has been used to study its effects on rat gene expression in the ubiquitin-proteasome pathway that regulates spermatogenesis and epididymal sperm quality. Theophylline has also been used as an internal standard for the measurement of plasma paracetamol levels in humans.

8.1 Merck: 14,9285

8.2 BRN: 13463

8.3 Description: Theophylline is a methylxanthine that acts as a weak bronchodilator. It is useful for chronic therapy and is not helpful in acute exacerbations.
Theophylline is a methylxanthine alkaloid that is a competitive inhibitor of phosphodiesterase (PDE; Ki = 100 μM). It is also a non-selective antagonist of adenosine A receptors (Ki = 14 μM for A1 and A2). Theophylline induces relaxation of feline bronchiole smooth muscle precontracted with acetylcholine (EC40 = 117 μM; EC80 = 208 μM). Formulations containing theophylline have been used in the treatment of asthma and chronic obstructive pulmonary disease (COPD).

8.4 Chemical Properties: white to light yellow crystal powder

8.5 Physical properties: Appearance: white, crystalline powder, odorless, with a bitter taste. Solubility: freely soluble in solutions of alkali hydroxides and in ammonia; sparingly soluble in alcohol, in chloroform, and in ether; slightly soluble in water. Water solubility, 7.36?g/L (20?°C); density, 1.62?g/cm3 ; melting point, 270–274?°C; boiling point, 390.1?°C (760? mmHg); flash point, 189.7?°C; vapor pressure, 2.72E-06? mmHg (25?°C).

8.6 History: Theophylline was firstly extracted from tea leaves and chemically identified by the German biologist Albrecht Kossel. A cup of tea contains about 1?mg/mL theophylline. In 1895, a chemical synthesis of theophylline starting with 1,3-dimethyluric acid was described by Emil Fischer and Lorenz Ach. Theophylline was synthesized by Wilhelm Traube in 1900. Aminophylline, a derivative of theophylline ethylenediamine, is widely used due to its greater aqueous solubility.
Theophylline was firstly used clinically as a diuretic in 1902. Twenty years later it was firstly reported by D.I.?Macht and G.C.?Ting for asthma treatment in pig bronchial smooth muscle. The first successful clinical use of theophylline in bronchial asthma was reported in 1922 by S.? Hirsch, who described that four patients responded well to the rectal administration of a mixture of 66.7% theophylline and 33.3% theobromine. He also tested the combination of theophylline with theobromine on bovine bronchial smooth muscle strips and noted smooth muscle relaxation. Thus he concluded that dimethylxanthines act by producing relaxation of bronchial smooth muscle. In 1937, two concurrent but independent clinical trials reported that methylxanthines were efficacious in asthma. The Food and Drug Administration approved the use of theophylline for asthma in the USA in 1940.
There are more than 300 derivatives of theophylline. The main derivatives include aminophylline, dihydroxypropyl theophylline, and oxtriphylline.
2. Doxofylline: 7-(1,3-dioxalan-2-ylmethyl) theophylline. It has antitussive and bronchodilator effects. In animal and human studies, it has shown similar efficacy to theophylline but with fewer side effects. Related research has showed that the effect of doxofylline on airway relaxation is 10–15 times that of aminophylline.
3. Diprophylline: 7-(2,3-dihydroxypropyl)-1,3-dimethyl-3,7-dihydro-1H-purine- 2,6-dione. Diprophylline is the neutral preparation of theophylline. It causes less of nausea and gastric irritation.
4. Oxtriphylline: choline theophyllinate; administered orally. Oxtriphylline is five times more soluble than aminophylline.; View all

8.7 Uses: Xanthine derivative with diuretic, cardiac stimulant and smooth muscle relaxant activities; isomeric with theobromine. Small amounts occur in tea. Bronchodilator.

8.8 Uses: theophylline is tonic and skin conditioning. Its cosmetic activity is not clearly or definitively established. It is most often found in anti-cellulite products. Theophylline is in the same family of bio chemicals as caffeine. It is naturally occurring in tea.

8.9 Definition: ChEBI: Theophylline is a dimethylxanthine having the two methyl groups located at positions 1 and 3. It is structurally similar to caffeine and is found in green and black tea. It has a role as a vasodilator agent, a bronchodilator agent, a muscle relaxant, an EC 3.1.4.* (phosphoric diester hydrolase) inhibitor, an anti-asthmatic drug, an anti-inflammatory agent, an immunomodulator, an adenosine receptor antagonist, a drug metabolite, a fungal metabolite and a human blood serum metabolite.

8.10 Indications: Twenty years ago theophylline (Theo-Dur, Slo-bid, Uniphyl, Theo-24) and its more soluble ethylenediamine salt, aminophylline, were the bronchodilators of choice in the United States. Although the β2-adrenoceptor agonists now fill this primary role, theophylline continues to have an important place in the therapy of asthma because it appears to have antiinflammatory as well as bronchodilator activity.

8.11 General Description: Odorless white crystalline powder. Odorless. Bitter taste.

8.12 Air & Water Reactions: Slightly soluble in water.

8.13 Reactivity Profile: Theophylline neutralizes acids in exothermic reactions to form salts plus water. May be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen may be generated in combination with strong reducing agents, such as hydrides.

8.14 Hazard: Questionable carcinogen.

8.15 Fire Hazard: Flash point data for Theophylline are not available, however Theophylline is probably combustible.

8.16 Biological Activity: Bronchodilator, anti-inflammatory and immunomodulator. Antagonizes adenosine receptors and is a weak non-selective inhibitor of phosphodiesterases (PDEs).

8.17 Biochem/physiol Actions: Phosphodiesterase inhibitor; diuretic; cardiac stimulant; muscle relaxant; asthma medication.

8.18 Mechanism of action: In spite of a great deal of investigation, just how theophylline causes bronchodilation is not clearly understood. Inhibition of the enzyme PDE, which is responsible for the hydrolysis of cAMP and cyclic guanosine monophosphate (cGMP), generally is put forth as the mechanism of action; however, theophylline also is an adenosine antagonist and has been implicated in stimulation of the release of catecholamines. It has been clearly shown that theophylline does inhibit PDEs in vitro, and x-ray crystallographic studies have identified the binding residues that interact with the methylxanthines. Theophylline binds to a subpocket of the active site and appears to be sandwiched between a phenylalanine and a valine via hydrophobic bonds. Its binding affinity is reinforced by hydrogenbonding between a tyrosine and N-7 and a glutamine and O-6 of the xanthine ring system. There are more than 11 families of PDEs, and studies have shown that theophylline binds in a similar manner to both the PDE4 and PDE5 family isoforms.; View all

8.19 Pharmacology: Smooth muscle relaxation, central nervous system (CNS) excitation, and cardiac stimulation are the principal pharmacological effects observed in patients treated with theophylline.The action of theophylline on the respiratory system is easily seen in the asthmatic by the resolution of obstruction and improvement in pulmonary function. Other mechanisms that may contribute to the action of theophylline in asthma include antagonism of adenosine, inhibition of mediator release, increased sympathetic activity, alteration in immune cell function, and reduction in respiratory muscle fatigue. Theophylline also may exert an antiinflammatory effect through its ability to modulate inflammatory mediator release and immune cell function.
Inhibition of cyclic nucleotide phosphodiesterases is widely accepted as the predominant mechanism by which theophylline produces bronchodilation. Phosphodiesterases are enzymes that inactivate cAMP and cyclic guanosine monophosphate (GMP), second messengers that mediate bronchial smooth muscle relaxation.; View all

8.20 Clinical Use: The principal use of theophylline is in the management of asthma. It is also used to treat the reversible component of airway obstruction associated with chronic obstructive pulmonary disease and to relieve dyspnea associated with pulmonary edema that develops from congestive heart failure.

8.21 Side effects: Theophylline has a narrow therapeutic index and produces side effects that can be severe, even life threatening. Importantly, the plasma concentration of theophylline cannot be predicted reliably from the dose. In one study, the oral dosage of theophylline required to produce therapeutic plasma levels (i.e., between 10 and 20 μg/mL) varied between 400 and 3,200 mg/day. Heterogeneity among individuals in the rate at which they metabolize theophylline appears to be the principal factor responsible for the variability in plasma levels. Such conditions as heart failure, liver disease, and severe respiratory obstruction will slow the metabolism of theophylline.

8.22 Safety Profile: Human poison by ingestion, parenteral, intravenous, and rectal routes. Experimental poison by multiple routes. An experimental teratogen. Human systemic effects: coma, convulsions or effect on seizure threshold, cyanosis, EKG changes, fever and other metabolic effects, heart arrhythmias, heart rate change, hyperglycemia, metabolic acidosis, nausea or vomiting, potassium-level changes, respiratory stimulation, salivary gland changes, somnolence, tremor. Experimental reproductive effects. Human mutation data reported. Used as a dturetic, cardtac stimulant, smooth muscle relaxant, and to treat asthma. When heated to decomposition it emits toxic fumes of NOx.

8.23 Chemical Synthesis: Theophylline, 1,3-dimethylxanthine (23.3.5), is present in small quantities in tea leaves. It is synthesized synthetically by the Traube method, a general method suggested for making purine bases. In the given example, reacting N,N-dimethylurea with cyanoacetic ether in the presence of acetic anhydride gives cyanoacetylmethylurea (23.3.1), which cyclizes into 6-amino-1,3-dimethyluracil (23.3.2). The resulting compound transforms into 5-nitroso-6-amino-1,3-dimethyluracil (23.3.3) upon reaction with nitric acid. Reduction of the nitroso group gives 5,6-diamino-1,3-dimethyluracil (23.3.4), the subsequent reaction of which with formamide gives the desired theophylline (23.3.5).

8.24 Environmental Fate: Theophylline is readily broken down in the environment. It may undergo photolytic degradation in the air or when exposed to light. In moist soil, or aqueous environments, it undergoes rapid biodegradation.

8.25 Metabolism: Chemically, theophylline is 1,3-dimethylxanthine and contains both an acidic and a basic nitrogen (N-7 and N-9, respectively). Physiologically, it behaves as an acid (pKa = 8.6), and its poor aqueous solubility can be enhanced by salt formation with organic bases. Theophylline is metabolized by a combination of C-8 oxidation and N-demethylation to yield methyluric acid metabolites. The major urinary metabolite is 1,3-dimethyl uric acid, which is the product of the action of xanthine oxidase. Because none of the metabolites is uric acid itself, theophylline can be safely given to patients who suffer from gout.

8.26 Purification Methods: It crystallises from H2O as the monohydrate which becomes anhydrous above 100o. It is freely soluble in hot H2O, but its solubility at 15o is 0.44%. It complexes with heavy metals. It is a diuretic, vasodilator and a cardiac stimulant. [Lister Purines Part II, Fused Pyrimidines Brown Ed, Wiley-Interscience pp253-254 1971, ISBN 0-471-38205-1, Beilstein 26 H 455, 26 I 134, 26 II 263, 26 III/IV 2331.]

8.27 Toxicity evaluation: In acute overdoses, theophylline often causes severe emesis (75% in acute vs 30% in chronic). The emesis is often difficult to control with antiemetics. It is thought that theophylline causes increased gastric acid secretion and smooth muscle relaxation. Theophylline causes a release of endogenous catecholamines, and therefore is a cardiac stimulant. There is a positive inotropic and dose-dependent chronotropic response. Tachydysrhythmias, especially supraventricular tachycardia, are common due to adenosine receptor antagonism. Ventricular tachydysrhythmias can occur as well in acute overdose; however, they are rare at therapeutic concentrations. Rapid administration of aminophylline has resulted in sudden cardiac death. Hypokalemia, hypercalcemia, and hyperglycemia may contribute to arrhythmias as well. In cases of chronic toxicity, dysrhythmias occur at lower serum concentrations (40–80 mg ml-1) compared to acute overdose. Theophylline will stimulate the CNS respiratory center causing increased respiratory rate and can lead to respiratory alkalosis. Theophylline will cause CNS stimulation and vasoconstriction, similar to caffeine, and may lead to headache, anxiety, agitation, insomnia, tremor, irritability, hallucinations, and seizures. Methylxanthines exhibit weak diuretic effects by increasing cardiac output and renal vasodilation. Theophylline has a narrow therapeutic index, with 12–25% of overdose patients developing serious or life-threatening symptoms including arrhythmias and seizure. Toxicity can develop at lower serum concentrations for those treated chronically or older patients. Age greater than 60 years and chronic use are risk factors for increased morbidity and mortality.; View all

8.28 Precautions: Theophylline should be used with caution in patientswith myocardial disease, liver disease, and acutemyocardial infarction. The half-life of theophylline isprolonged in patients with congestive heart failure.Because of its narrow margin of safety, extreme cautionis warranted when coadministering drugs, such as cimetidineor zileuton, that may interfere with the metabolismof theophylline. Indeed, coadministration of zileutonwith theophylline is contraindicated. It is alsoprudent to be careful when using theophylline in patientswith a history of seizures.

8.29 References: Fischer., Ber., 30, 553 (1897)
Schwabe., Arch. Pharm., 245, 312 (1907)
Biltz, Strufe.,Annalen, 404, 137, 170(1914)
Yoshitomi., Chem. Abstr., 19,2303 (1925)
Mossini., Boll. chim. farm., 75, 557 (1936)
Deichmeister., Farm. Zhur., 13, 18 (1940)
Deichmeister., Chem. Zentr., 1, 1280 (1942)
Deniges., Bull. trav. soc. ph arm. Bordeaux, 79, 141 (1941)
Lesser., Drug & Cosmetic Ind., 66, 276,340 (1950)

9. Computational chemical data

Molecular Weight: 180.16400g/mol
Molecular Formula: C₇H₈N₄O₂
Compound Is Canonicalized: True
XLogP3-AA: null
Exact Mass: 180.06472551
Monoisotopic Mass: 180.06472551
Complexity: 267
Rotatable Bond Count: 0
Hydrogen Bond Donor Count: 1
Hydrogen Bond Acceptor Count: 3
Topological Polar Surface Area: 69.3
Heavy Atom Count: 13
Defined Atom Stereocenter Count: 0
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Isotope Atom Count: 0
Covalently-Bonded Unit Count: 1
CACTVS Substructure Key Fingerprint: AAADccBjsAAAAAAAAAAAAAAAAAAAAWAAAAAsAAAAAAAAAFgBgAAAHgAQAAAACAgBlgQHsBfJkACoAQdxdACAgC2XEKABUYGoVECASAhASCAUAIgIByJAAGAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA==

10. Question & Answer

What are the Research Progress and Medical Applications of Theophylline? Jun 12 2024
Introduction Theophylline, a widely existing organic compound in tea, has garnered significant attention for its unique pharmacological effects. With a chemical formula of C7H8N4O2, it is an alkaloid ..
What are the uses, side effects, and advantages/disadvantages of Theophylline? May 28 2024
Uses Theophylline is utilized in combination with other medications to manage asthma, bronchitis, emphysema, and other respiratory conditions. It falls under the category of bronchodilators, which are..
What are the Different Caffeine EP Impurities and Their Uses in Pharmaceutical Research? Jul 26 2023
Caffeine EP impurity A, also known as theophylline or 1,3-Dimethyl-3,7-dihydro-1H-purine-2,6-dione, is a chemical compound used in the treatment of asthma and chronic obstructive pulmonary disease. Wh..
What is Theophylline and How is it Used in Respiratory Diseases? Jun 29 2022
Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under ..