Theophylline

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Theophylline

Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory disease

Respiratory disease

Respiratory Disease is the term for diseases of the respiratory system. These include diseases of the lung, pleural cavity, bronchial tubes, trachea, upper respiratory tract and of the nerves and muscles of breathing....
s such as COPD

COPD

Chronic obstructive pulmonary disease is a group of diseases of the lungs in which the airways become narrowed. This leads to a limitation of the flow of air to and from the lungs causing shortness of breath....
or asthma

Asthma

Asthma is a common chronic obstructive pulmonary disease, in which the Lung constrict, become inflammation, and are lined with excessive amounts of thickened mucus, often in response to one or more triggers....
under a variety of brand names. Due to its numerous side-effects, these drugs are now rarely administered for clinical use. As a member of the xanthine

Xanthine

Xanthine , , is a purine base found in most body tissues and fluids and in other organisms. A number of mild stimulants are derived from xanthine, including caffeine and theobromine....
family, it bears structural and pharmacological similarity to caffeine

Caffeine

Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a psychoactive stimulant drug and a mild diuretic. Caffeine was discovered by a German chemist, Friedrich Ferdinand Runge, in 1819....
. It is naturally found in tea

Tea

Tea refers to the agricultural products of the leaves, leaf buds, and internodes of the Camellia sinensis plant, prepared and cured by various methods....
, although in trace quantities (~1 mg/L), significantly less than therapeutic doses.

The main actions of theophylline involve:

phylline was first extracted from tea leaves around 1888 by the German biologist Albrecht Kossel

Albrecht Kossel

Ludwig Karl Martin Leonhard Albrecht Kossel was a Germany medical doctor....
.

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Encyclopedia

Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory disease

Respiratory disease

COPD

Asthma

Xanthine

Caffeine

Tea

relaxing bronchial smooth muscle
Smooth muscle

Smooth muscle is a type of non-striated muscle, found within the tunica media layer of large and small arteries and veins, the urinary bladder, uterus, male and female reproductive tracts, gastrointestinal tract, respiratory tract, the ciliary muscle, and iris of the eye....
increasing heart muscle contractility and efficiency: positive inotropic
increasing heart rate: positive chronotropic
Chronotropic

Chronotropic effects are those that change the heart rate.Chronotropic drugs may change the heart rate by affecting the nerves controlling the heart, or by changing the rhythm produced by the sinoatrial node....
increasing blood pressure
Blood pressure

Blood pressure is the pressure exerted by circulating blood on the walls of blood vessels, and constitutes one of the principal vital signs. The pressure of the circulating blood decreases as it moves away from the heart through artery and capillary, and toward the heart through veins....
increasing renal
Kidney

The kidneys are Organ that have numerous biological roles. Their primary role is to maintain the homeostasis balance of bodily fluids by filtering and secreting Metabolomics#Metabolitess and minerals from the blood and excreting them, along with water , as urine....
blood flow
some anti-inflammatory
Inflammation

Inflammation is the complex biological response of Blood vessel tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue....
effects
central nervous system
Central nervous system

The central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of multicellular organisms....
stimulatory effect mainly on the medullary respiratory center
Respiratory center

Respiratory center is located in the medulla oblongata which is the lowermost part of the brain stem. RC receives controlling signals of neural, chemical and hormonal natures and controls the rate and depth of respiratory movements of the diaphragm and other respiratory muscles....
.

History

Theophylline was first extracted from tea leaves around 1888 by the German biologist Albrecht Kossel

Albrecht Kossel

Ludwig Karl Martin Leonhard Albrecht Kossel was a Germany medical doctor....
. The drug was chemically identified in 1896, and eventually it was synthesized by another German scientist, Wilhelm Traube

Wilhelm Traube

Wilhelm Traube was a Germany chemist....
. Theophylline's first clinical use in asthma treatment came in the 1950s.

Pharmacokinetics

Absorption

Bioavailability

In pharmacology, bioavailability is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetics properties of medication....
is 100%. However, taking the drug late in the evening may slow the absorption process, without affecting the bioavailability. Taking the drug after a meal high in fat content will also slow down the absorption process, without affecting the bioavailability.

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 suffering from obesity.

Metabolism

Theophylline is metabolized extensively in the liver (up to 70%). It undergoes N-demethylation via cytochrome

Cytochrome

Cytochromes are, in general, membrane-bound hemoproteins that contain heme groups and carry out electron transport.They are found either as subunitss or as subunits of bigger enzymatic complexes that catalyze redox reactions....
P450 1A2. It is metabolized by parallel first order and Michaelis-Menten

Michaelis-Menten kinetics

File:Michaelis-Menten.pngMichaelis?Menten kinetics approximately describes the enzyme kinetics of many enzymes. It is named after Leonor Michaelis and Maud 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

Methylation

Methylation in the chemical sciences denotes the attachment or substitution of a methyl on various Substrate . This term is commonly used in chemistry, biochemistry, soil science and the biological sciences....
in caffeine is also important in the infant population. Smokers and people with hepatic (liver) impairment metabolize it differently.

Elimination

Theophylline is excreted unchanged in the urine (up to 10%). Clearance of the drug is increased in these conditions: children 1 to 12, teenagers 12 to 16, adult smokers, elderly smokers, cystic fibrosis

Cystic fibrosis

Cystic Fibrosis is a Genetic disorder affecting the exocrine glands of the lungs, liver, pancreas, and intestines, causing progressive disability due to multisystem failure....
, hyperthyroidism

Hyperthyroidism

Hyperthyroidism is the term for overactive tissue within the thyroid gland,resulting in overproduction and thus an excess of circulating free thyroid hormones: thyroxine , triiodothyronine , or both....
. Clearance of the drug is decreased in these conditions: elderly, acute congestive heart failure, cirrhosis, hypothyroidism and febrile viral illness.

The elimination half-life

Half-life

The half-life of a quantity whose value decreases with time is the interval required for the quantity to decay to half of its initial value. The concept originated in describing how long it takes atoms to undergo radioactive decay but also applies in a wide variety of other situations....
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.

Indications

The main therapeutic uses of theophylline are aimed at:

chronic obstructive diseases of the airways
chronic obstructive pulmonary disease (COPD
COPD

Chronic obstructive pulmonary disease is a group of diseases of the lungs in which the airways become narrowed. This leads to a limitation of the flow of air to and from the lungs causing shortness of breath....
)
bronchial asthma
infant apnea
Apnea of prematurity

Apnea of prematurity is defined as cessation of breathing by a premature birth infant that lasts for more than 15 seconds and/or is accompanied by hypoxia or bradycardia....

Mechanisms of action

The main mechanism of action

Mechanism of action

In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a Medication substance produces its pharmacological effect....
of theophylline is that of adenosine receptor

Adenosine receptor

The adenosine receptors are a class of purinergic receptors, G-protein coupled receptors with adenosine as endogenous ligand.In humans, there are four adenosine receptors....
antagonism

Receptor antagonist

A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a Receptor , but blocks or dampens agonist-mediated responses....
. Theophylline is a non-specific adenosine antagonist, antagonizing A1, A2, and A3 receptors almost equally, which explains many of its cardiac effects and some of its anti-asthmatic effects.

Another proposed mechanism of action includes a non-specific inhibition of phosphodiesterase

Phosphodiesterase

A phosphodiesterase is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below....
enzyme

Enzyme

Enzymes are biomolecules that catalysis chemical reactions. Almost all enzymes are proteins. In enzymatic reactions, the molecules at the beginning of the process are called Substrate , and the enzyme converts them into different molecules, the products....
s, producing an increase in intracellular cyclic AMP; however, this is not known with certainty.

Theophylline has been shown to inhibit TGF-beta-mediated conversion of pulmonary fibroblasts into myofibroblasts in COPD

COPD

Asthma

Asthma is a common chronic obstructive pulmonary disease, in which the Lung constrict, become inflammation, and are lined with excessive amounts of thickened mucus, often in response to one or more triggers....
via cAMP-PKA pathway and suppresses COL1 mRNA, which codes for the protein collagen

Collagen

Collagen is the main protein of connective tissue in animals and the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content....
.

It has been shown that theophylline may reverse the clinical observations of steroid insensitivity in patients with COPD and asthmatics that are active smokers (a condition resulting in oxidative stress

Oxidative stress

Oxidative stress is caused by an imbalance between the production of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or easily repair the resulting damage....
) 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. Furthermore, theophylline has been shown to directly activate HDAC2. (Corticosteroid

Corticosteroid

Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiology systems such as stress , immune system and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior....
s 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?B 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.) Thus theophylline could prove to be a novel form of adjunct therapy in improving the clinical response to steroids in smoking asthmatics.

Side-effects

The use of theophylline is complicated by the fact that it interacts with various drugs, chiefly cimetidine

Cimetidine

Cimetidine is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers....
and phenytoin

Phenytoin

Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to dampen the unwanted, runaway brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage gated sodium channels....
, and that it has a narrow therapeutic index

Therapeutic index

The therapeutic index , is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxic effects....
, so its use must be monitored to avoid toxicity

Toxicity

Toxicity is the degree to which a substance is able to damage an exposed organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver ....
. It can also cause nausea, diarrhea, increase in heart rate, arrhythmias, and CNS excitation (headaches, insomnia

Insomnia

Insomnia is a symptom of a sleep disorder characterized by persistent difficulty falling sleep or staying asleep despite the opportunity. Insomnia is a symptom, not a stand-alone diagnosis or a disease....
, irritability, dizziness

Dizziness

Dizziness describes a number of subjective symptoms, which the patient may describe as feelings of lightheadedness, floating, wooziness, giddiness, confusion, disorientation or loss of balance....
and lightheadedness

Lightheadedness

Light-headedness is a common and often unpleasant sensation of dizziness and/or feeling that one may be about to fainting , which may be transient, recurrent, or occasionally chronic ....
) . Its toxicity is increased by erythromycin

Erythromycin

Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins....
, cimetidine

Cimetidine

Cimetidine is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers....
, and fluoroquinolones, such as "cipro" (ciprofloxacin). It can reach toxic levels when taken with fatty meals, an effect called dose dumping

Dose dumping

Dose dumping is a phenomenon of drug metabolism in which environmental factors can cause the premature and exaggerated release of a medication. This can greatly increase the concentration of a drug in the body and thereby produce Adverse effect or even drug-induced toxicity....
.

Synthesis

Theophylline can be prepared synthetically starting from dimethylurea

Dimethylurea

Dimethylurea is a urea derivative and used as an intermediate in organic synthesis. It is a colorless crystalline powder with little toxicity....
and ethyl 2-cyanoacetate.