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Theophylline

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Theophylline Basic information

Product Name:
Theophylline
Synonyms:
  • 1,3-Dimethyl-3,7-dihydro-1H-purine-2,6-dione
  • 1,3-dimethyl-xanthin
  • 1H-Purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-
  • 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
  • accurbron
  • Acet-theocin
CAS:
58-55-9
MF:
C7H8N4O2
MW:
180.16
EINECS:
200-385-7
Product Categories:
  • AlkaloidsForensic and Veterinary Standards
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Mol File:
58-55-9.mol
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Theophylline Chemical Properties

Melting point:
271-273 °C
Boiling point:
312.97°C (rough estimate)
Density 
1.3640 (rough estimate)
refractive index 
1.6700 (estimate)
Flash point:
11 °C
storage temp. 
2-8°C
solubility 
0.1 M HCl: soluble
pka
8.77(at 25℃)
form 
powder
color 
white
Water Solubility 
8.3 g/L (20 ºC)
Merck 
14,9285
BRN 
13463
Stability:
Stable. Incompatible with strong oxidizing agents.
InChIKey
ZFXYFBGIUFBOJW-UHFFFAOYSA-N
CAS DataBase Reference
58-55-9(CAS DataBase Reference)
IARC
3 (Vol. 51) 1991
NIST Chemistry Reference
1,3-Dimethylxanthine(58-55-9)
EPA Substance Registry System
Theophylline (58-55-9)
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Safety Information

Hazard Codes 
Xn,T,F,Xi
Risk Statements 
22-39/23/24/25-23/24/25-11-36/37/38
Safety Statements 
7-16-36/37-45-36-26-24/25
RIDADR 
UN 2811 6.1/PG 3
WGK Germany 
1
RTECS 
XH3850000
10-23
TSCA 
Yes
HazardClass 
6.1(b)
PackingGroup 
III
HS Code 
29395900
Hazardous Substances Data
58-55-9(Hazardous Substances Data)
Toxicity
LD50 oral in rabbit: 350mg/kg

MSDS

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Theophylline Usage And Synthesis

Description

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.

Description

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).

Chemical Properties

white to light yellow crystal powder

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).

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.

Uses

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

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.

Uses

Action on the CNS depends directly on the dose of administered drug, and can be manifested as fatigue, anxiety, tremors, and even convulsions in relatively high doses. Theophylline acts on the cardiovascular system by displaying positive ionotropic and chronotropic effects on the heart, which, can likely be linked to the elevated influx of calcium ions by modulated cyclic adenosine monophosphate and its action on specific cardiac phosphodiesterases. In the gastrointestinal system, methylxanthines simultaneously stimulate secretion of both gastric juice and digestive enzymes. Theophylline reduces contractile activity of smooth musculature, widens bronchi and blood vessels, reduces pulmonary vascular resistance, stimulates the respiratory center, and increases the frequency and power of cardiac contractions. It is used for bronchial asthma, preventing attacks, and systematic treatment. Theophylline is also used for symptomatic treatment of bronchospastic syndrome of a different etiology (chronic obstructive pulmonary disease, chronic bronchitis, and pulmonary emphysema). A large number of combined drugs are based on theophylline. Synonyms of theophylline are adophyllin, asthmophyllin, theocin, and many others.

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.

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.

General Description

Odorless white crystalline powder. Odorless. Bitter taste.

Air & Water Reactions

Slightly soluble in water.

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.

Hazard

Questionable carcinogen.

Fire Hazard

Flash point data for Theophylline are not available, however Theophylline is probably combustible.

Biological Activity

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

Biochem/physiol Actions

Phosphodiesterase inhibitor; diuretic; cardiac stimulant; muscle relaxant; asthma medication.

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.

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.

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.

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.

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.

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).

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.

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.

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.]

Toxicity evaluation

The mechanism of action is multifactorial. Suggested theories of action include increased cellular cyclic adenosine monophosphate levels via inhibition of phosphodiesterase, increased turnover of monoamines in the central nervous system (CNS),inhibition of prostaglandins, and antagonism of adenosine receptors. Overall, these mechanisms contribute to an increase in catecholamine release. 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.

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.

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)

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