Bronchodilators methylxanthines

Examples of the xanthine derivatives (drag that stimulate the central nervous system [CNS] resulting in bronchodilation, also called methylxanthines) are theophylline and aminophylline. Additional information concerning the xanthine derivatives is found in the Summary Drag Table Bronchodilators. 

In the clinical area, the largest share of analytical methods development and publication has centered on the determination of theophylline in various body fluids, since theophylline is used as a bronchodilator in asthma. Monitoring serum theophylline levels is much more helpful than monitoring dosage levels.44 Interest in the assay of other methylxanthines and their metabolites has been on the increase, as evidenced by the citations in the literature with a focus on the analysis of various xanthines and methylxanthines. 

Methylxanthines are no longer considered first-line therapy for COPD. Inhaled bronchodilator therapy is preferred over theophylline for COPD because of theophylline s risk for drug interactions and the interpatient variability in dosage requirements. Theophylline may be considered in patients who are intolerant or unable to use an inhaled bronchodilator. A methylxanthine may also be added to the regimen of patients who have not achieved an optimal clinical response to an inhaled anticholinergic and [i2-agonist. 

As with other bronchodilators in COPD, parameters other than objective measurements such as FEVj should be monitored to assess efficacy. Subjective parameters, such as perceived improvements in dyspnea and exercise tolerance, are important in assessing the acceptability of methylxanthines for COPD patients. 

Bronchodilators. Narrowing of bronchioles raises airway resistance, e.g in bronchial or bronchitic asthma Several substances that are employed as bronchodilators are described elsewhere in more detail P2-sympathomimetics (p. 84, given by pulmonary, parenteral, or oral route), the methylxanthine theophylline (p. 326, given parenterally or orally), as well as the parasympatholytic ipratropium (pp. 104, 107, given by inhalation). 

Theophylline is frequently used as a bronchodilator in the treatment of asthma. The importance of the methylxanthines in the management of bronchial asthma is discussed more fully in Chapter 39. Caffeine as the citrate salt (Cafcit) is used for the short-term management of apnea in premature infants (28-33 weeks of gestational age). 

Smooth muscles Methylxanthines relax smooth muscles especially bronchi in asthmatic patients. Theophylline produces sustained bronchodilator action. 

In low and moderate doses, the methylxanthines—especially caffeine—cause mild cortical arousal with increased alertness and deferral of fatigue. The caffeine contained in beverages—eg, 100 mg in a cup of coffee—is sufficient to cause nervousness and insomnia in sensitive individuals and slight bronchodilation in patients with asthma. The larger doses necessary for more effective bronchodilation commonly cause nervousness and tremor in some patients. Very high doses, from accidental or suicidal overdose, cause medullary stimulation and convulsions and may lead to death. 

The bronchodilation produced by the methylxanthines is the major therapeutic action in asthma. Tolerance does not develop, but adverse effects, especially in the central nervous system, may limit the dose (see below). In addition to their effect on airway smooth muscle, these agents—in sufficient concentration—inhibit antigen-induced release of histamine from lung tissue their effect on mucociliary transport is unknown. 

Breathing rate increases in response to caffeine. The effect on respiration occurs at the level of the brain stem s respiration control center. Theophylline has the most potent action of all the methylxanthines, affecting the smooth muscle of the bronchial tree in the lungs. This is why theophylline is a treatment for asthma. Doctors may recommend weak tea for their asthmatic patients with colds this bronchodilating action of the theophylline in the tea will aid in clearing mucus. 

Theophylline, a methylxanthine, relaxes bronchial muscle, although its precise mode of action is still debated. Inhibition of phosphodiesterase (PDE), especially its type 4 isoform now seems the most likely explanation for its bronchodilator and more recently reported anti-inflammatory effects. Blockade of adenosine receptors is probably unimportant. Other actions of theophylline include chronotropic and inotropic effects on the heart and a direct effect on the rate of urine production (diuresis). 

The alkylxanthines (e.g. the methylxanthines aminophylline and theophylline) are rarely employed as diuretic agents but are commonly used as bronchodilators. Aminophylline is metabolized to its active metabolite theophylline after oral administration and increases cytosolic cyclic adenosine monophosphate (cAMP) by the inhibition of phosphodiesterase, the enzyme responsible for the degradation of cAMP. cAMP is an important intracellular messenger involved in the phosphorylation of cytosolic and membrane-bound proteins however, its effect in the kidneys remains unclear. The diuretic effect of theophylline is modest and appears to be mediated by both an increase in cardiac output, leading to increases in RBF and GFR, and a direct tubular effect, leading to... 

Some other drugs that appear to owe part of their action to phosphodiesterase inhibition include a number of naturally occurring methylxanthine drugs and their derivatives (e.g. aminophylline. caffeine, theobromine, theophylline), but they also have ADENOSINE RECEPTOR ANTAGONIST properties see BRONCHODILATORS CENTRAL STIMULANTS. 

Methylxanthine (xanthine) Methylxanthine is a bronchodilator that stimulates the central nervous system to increase respirations, dilate coronary and pulmonary vessels, and increase urination (diuresis). 

The methylxanthines may produce bronchodilation through numerous mechanisms, including (1) inhibition of phosphodiesterase, thereby increasing cAMP levels, (2) inhibition of calcium ion influx into smooth muscle, (3) prostaglandin antagonism, (4) stimulation of... 

The methylxanthines consist of aminophylline, dyphyl-line, enprofylline, and pentoxifylline. Aminophylline (theophylline ethylenediamine) is the most widely used of the soluble theophyllines. Its main therapeutic effect is bronchodilation. In addition, it causes CNS stimulation, cardiac acceleration, diuresis, and gastric secretion. Aminophylline is available in an oral, rectal (pediatric), or intravenous solution, which is used in the treatment of status asthmaticus. Although it is a less effective bronchodilator than beta-adrenergic agonists, it is particularly useful in preventing nocturnal asthma (see also Figure 94). 

Theophylline effectively relaxes airway smooth muscle this bronchodilation likely contributes to its acute therapeutic efficacy in asthma. Both adenosine receptor antagonism and PDE inhibition are likely involved in the bronchodilating effect of theophylline. Inhibition of PDE4 and PDE5 effectively relaxes human isolated bronchial smooth muscle, and inhibition of these PDEs likely contributes to the bronchodilating effect of theophylline. Studies with the related methylxanthine enprofylline (3-propylxanthine), which has been investigated extensively for treatment of asthma in Europe, also support a mechanistic role for PDE inhibition in the bronchodilator actions of theophylline. 

Bronchodilators include sympathomimetics, especially selective agonists, muscarinic antagonists, methylxanthines, and leukotriene receptor blockers. 

B. Mechanism of Action The methylxanthines inhibit phosphodiesterase (PDE), the enzyme that degrades cAMP to AMP (Figure 20-3), and thus increase cAMP. This anti-PDF effect, however, requires high concentrations of the drug. Methylxanthines also block adenosine receptors in the CNS and elsewhere, but a relationship between this action and the bronchodilat-ing effect has not been clearly established. It is possible that bronchodilation is caused by a third tis yet unrecognized action. 

Methylxanthine (xanthine) derivatives are a second group of bronchodilators used to treat asthma. They include aminophylhne, theophylMne, and caffeine. 

Treatment--Bronchodilators. The methylxanthine theophylline and its analogues are widely used in the treatment of CB. 

There are three major groups of bronchodilators two of these, the methylxanthines and the sympathomimetic amines are available, while the third, anticholinergics, is still experimental. Available routes of administration include oral, inhalation, rectal, subcutaneous, and intravenous. The choice of types of agent and routes of administration depends on individual patient need and tolerance. Long-term maintenance is usually achieved with oral bronchodilators with occasional supplementation with rectal or inhalation agents. Rectal, subcutaneous and intravenous therapy is indicated in acute... 

As with CB, anticholinergic agents are also rational bronchodilators for use in asthma. Their use would be expected to contribute additional bronchodilation to that provided by methylxanthines and sympathomimetic amines since the mechanism of action is directed at the effects of the non-specific stimuli. The concomitant use of all three types could also permit a more precise assessment of the non-reversible component of the patient s airways obstruction. Since many antihistamines have anticholinergic activity, it is possible that patients who take such therapy for other reasons may already have some benefit of this kind of bronchodilation. 

Phosphodiesterase Inhibitors - Catecholamines increase the concentration of cyclic AMP by stimulating the enzyme adenyl cyclase. Methylxanthines Increase the concentration of cyclic AMP by Interfering with its inactivation by phosphodiesterase and this is thought to be the biochemical basis for the bronchodilator action of theophylline. 

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