Theophylline in asthma

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. 

Kips JC, Peleman RA, and Pauwels RA.The role of theophylline in asthma management. Current Opin Pulmon Med 1999 5 88-92. 

Weinberger M and Hendeles L (1996) Theophylline in asthma. New England Journal of Medicine 334 1380-1388. 

Illustrated in Figure 3 is a likely over-all mechanistic role of theophylline in asthma. Extrinsic or immediate hypersensitivity-type asthma begins with an antigen -antibody complex at mast cells and results in the release of chemical mediators which affect cells in airways. Smooth muscle cells contract, capillaries leak, and secretory cells hypersecrete to give a triad of bronchospasm, edema and Increased mucous, respectively. Shown is the two-enzyme... 

Figure 3. Likely mechanistic role of theophylline in asthma. By inhibition of phosphodiesterase and subsequent elevation of cyclic AMP in mast cells and airway smooth muscle, theophylline is shown to have an overall beneficial effect on...

Garty M, CohenE, Mazar A,IlfeldDN, SpitzerS,RosenfeldJB. Effect of nifedipine and theophylline in asthma. Clin Pharmacol 7%er(198Q 40,195-8. 

The effectiveness of theophylline in the treatment of asthma seems to result from a combination of biological properties which are not clearly understood (63). Detailed discussions of the possible role of xanthines in asthma may be found in references 64—66. 

In persistent asthma, inhaled corticosteroids provide the most comprehensive control of the inflammatory process and are the cornerstone of therapy.2 Inhaled corticosteroids are more effective than cromolyn, leukotriene modifiers, nedocromil, and theophylline in reducing markers of inflammation and AHR, improving lung function, and preventing emergency department visits and hospitalizations due to asthma exacerbations.2,25 The primary... 

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. 

Stages in severity of asthma are mentioned in Table 9. Older smdies have already shown that addition of low doses of theophylline in worsening asthma (giving serum concentrations < 10 mg/1) was more effective than doubling the dose of the inhaled corticosteroid. Similar data are now emerging with anti-leukotrienes. The reason why a combination ther-... 

Markham A, Faulds D. Theophylline. A review of its potential steroid sparing effects in asthma. Drugs 1998 56 1081-91. 

Milavetz G, Vaughan LM, Weinberger E. Evaluation of a scheme for establishing and maintaining dosage of theophylline in ambulatory patients with chronic asthma. J Pediatr 1986 109 351-356. 

Theophylline is widely used as a bronchodilator for the treatment of asthma or obstructive pulmonary disease [1]. Significant relief of bronchospasm is usually achieved with 7-20 mg/1 of theophylline in serum and toxic manifestations occur above 20-30 mg/1. The available literature... 

Theophylline improves long-term control of asthma when taken as the sole maintenance treatment or when added to inhaled corticosteroids. It is inexpensive, and it can be taken orally. Its use, however, also requires occasional measurement of plasma levels it often causes unpleasant minor side effects (especially insomnia) and accidental or intentional overdose can result in severe toxicity or death. For oral therapy with the prompt-release formulation, the typical dose is 3-4 mg/kg of theophylline every 6 hours. Changes in dosage result in a new steady-state concentration of theophylline in 1-2 days, so the dosage may be increased at intervals of 2-3 days until therapeutic plasma concentrations are achieved (10-20 mg/L) or until adverse effects develop. 

Clarke H, Cushley MJ, Persson CG, Holgate ST (1989) The protective effects of intravenous theophylline and enprofylline against histamine- and adenosine 50-monophosphate-provoked bronchoconstriction implications for the mechanisms of action of xanthine derivatives in asthma. Pulm Pharmacol 2(3) 147-154... 

Cushley MJ, Tattersfield AE, Holgate ST (1984) Adenosine-induced bronchoconstriction in asthma. Antagonism by inhaled theophylline. Am Rev Respir Dis 129(3) 380-384 De Perrot M, Liu M, Waddell TK, Keshavjee S (2003) Ischemia-reperfusion induced lung injury. Am J Respir Crit Care Med 167(4) 490-511... 

A3 receptors are present on human eosinophils and couple to signalling pathways that lead to cell activation ( Kohno et al. 1996a Reeves et al. 2000). Despite this it has not proven easy to demonstrate the functional consequences of activation of these sites (Reeves et al. 2000). Nevertheless, the chronic inflammation in asthma is characterised by extensive infiltration of the airways by activated eosinophils (Holgate 1999 Pearlman 1999) and it remains possible that the elevated adenosine concentrations associated with asthma would contribute to eosinophil activation through stimulation of A3 receptors. In addition, it has been speculated that activation of A3 receptors may protect eosinophils from apoptosis (Gao et al. 2001). Thus, blockade of A3 receptors may reduce the numbers of eosinophils and their activation thereby reducing the pro-inflammatory burden in the lung. Consistent with this, following 6 weeks treatment of mild asthmatics with theophylline there was a... 

Xanthine derivatives are a group of chemically similar compounds that exert a variety of pharmacologic effects. Common xanthine derivatives include theophylline, caffeine, and theobromine (Fig. 26-2) these compounds are frequently found in various foods and beverages (tea, coffee, soft drinks). Theophylline and several theophylline derivatives are also administered therapeutically to produce bronchodilation in asthma and other forms of reversible airway obstruction (bronchitis, emphysema).65,79 Theophylline and caffeine are also potent CNS stimulants, and some of the more common side effects of these drugs are related to this CNS excitation (see Adverse Side Effects, later in this chapter). 

Hansel TT, Tennant RC, Tan AJ, et al. Theophylline mechanism of action and use in asthma and chronic obstructive pulmonary disease. Drugs Today. 2004 40 55-69. 

Suessmuth S, Freihorst J, Gappa M. Low-dose theophylline in childhood asthma a placebo-controlled, double-blind study. Pediatr Allergy Immunol. 2003 14 394-400. 

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, an asthma controller, has a very low safety/therapeutic ratio. One of the first clinical application for HPLC was to titrate theophylline levels in patient blood to avoid toxic overdoses. Blood levels can be controlled by assay at UV, 270 nm, on a C18 column in 7% An/water at pH 4.0 with phosphate buffer. 

When the hormonal stimulus stops, the intracellular actions of cAMP are terminated by an elaborate series of enzymes. cAMP-stimulated phosphorylation of enzyme substrates is rapidly reversed by a diverse group of specific and nonspecific phosphatases. cAMP itself is degraded to 5 -AMP by several cyclic nucleotide phosphodiesterases (PDE, Figure 2-13). Competitive inhibition of cAMP degradation is one way caffeine, theophylline, and other methylxanthines produce their effects (see Chapter 20 Drugs Used in Asthma). 

The major bases found in nucleic acids are adenine and guanine (purines) and uracil, cytosine, and thymine (pyrimidines). Thymine is found primarily in DNA, uracil in RNA, and the others in both DNA and RNA. Their structures, along with their chemical parent compounds, purine and pyrimidine, are shown in Figure 10.1, which also indicates other biologically important purines that are not components of nucleic acids. Hypoxanthine, orotic acid, and xanthine are biosynthetic and/or degradation intermediates of purine and pyrimidine bases, whereas xanthine derivatives—caffeine, theophylline, and theobromine—are alkaloids from plant sources. Caffeine is a component of coffee beans and tea, and its effects on metabolism are mentioned in Chapter 16. Theophylline is found in tea and is used therapeutically in asthma, because it is a smooth muscle relaxant. Theobromine is found in chocolate. It is a diuretic, heart stimulant, and vasodilator. 

Theophylline has several effects which have been described, especially in asthma ... 

Ellis EF, Koysooko R, Levy G (1976) Pharmacokinetics of theophylline in children with asthma. Pediatrics 58 542-547. 

Mode of action. Caffeine and theophylline have complex and incompletely elucidated actions, which include inhibition of phosphodiesterase (the enzyme that breaks down cyclic AMP, see p. 191), effects on intracellular calcium distribution, and noradrenergic function. When theophylline (as aminophylline) is used alongside salbutamol in asthma its action adds up to increased benefit to the bronchi, but increased risk to the heart. 

Interactions. An important footnote to the use of nitrates (and NO-dilators generally) has been the marked potentiation of their vasodilator effects observed in patients taking the phosphodiesterase (PDE) inhibitor sildenafil (Viagra). This agent targets an isoform of PDE (PDE-5) expressed in the blood vessel wall. Other methylaxanthine PDE inhibitors, such as theophylline, do not cause a similar interaction because they are rather weak inhibitors of PDE-5, even at the doses effective in asthma. A... 

Theophylline is relatively insoluble and it is formulated either as a salt with choline (choline theophyllinate) or complexed with EDTA (amino-phylline). Aminophylline is sufficiently soluble to permit i.v. use of theophylline in status asthmaticus. There are numerous sustained-release oral forms for use in chronic asthma. These are not bioequivalent and patients should not switch between them once they are stabilised on a particular preparation. It has also been used in the past for the emergency treatment of left ventricular failure (see p. 518). At high therapeutic doses some patients... 

Hendeles, L. Weinberger, M. Szefler, S. Safety and efficacy of theophylline in children with asthma. J. Pediatr. 1992, 120, 177-183. 

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