Xanthines
After reading this chapter, the reader will be able to:
2. List all available xanthines used in respiratory therapy
3. Differentiate between the clinical indications of xanthines
4. Differentiate between the uses of xanthines
5. Discuss the proposed theories of activity for xanthines
Clinical indications for the use of xanthines
Use in asthma
Sustained-release theophylline is indicated as an alternative for maintenance (step 2) therapy of mild, persistent asthma and higher in patients older than 5 years of age and is listed as an alternative in step 3 and higher for patients older than 5 years of age in combination with an inhaled corticosteroid (ICS). Sustained-release theophylline is considered a less preferred alternative to low-dose ICS, cromolynlike agents, or antileukotrienes as second-line maintenance drug therapy in stable asthma. Theophylline is not recommended in the guidelines for children younger than 5 years or for any person with acute exacerbation of asthma.1
Use in chronic obstructive pulmonary disease
Current guidelines for the treatment of stable COPD state that bronchodilators are central to symptom management. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) states that inhaled bronchodilators are preferred when available. Theophylline is considered effective in COPD but, because of potential toxicity, is recommended as an alternative to inhaled bronchodilators such as β2 agonists or anticholinergic agents.2 Barr and associates3 conducted a meta-analysis on the use of xanthines for the treatment of COPD exacerbations. There findings suggest that xanthines should not be used in the treatment of COPD exacerbations. In randomized controlled trials, intravenous aminophylline has not shown any significant benefit over β2 agonists and anticholinergic therapy for COPD patients.4,5
Use in apnea of prematurity
If pharmacologic therapy is needed to stimulate breathing in apnea of prematurity, methylxanthines are considered the first-line agents of choice. Theophylline has been used most extensively, but Bhatia6 suggested that caffeine citrate may be the agent of choice. Caffeine citrate penetrates the cerebrospinal fluid better and has a higher therapeutic index with fewer side effects compared with theophylline. Caffeine citrate (Cafcit) has been approved for administration either intravenously or orally.
Specific xanthine agents
Theophylline is related chemically to the natural metabolite xanthine, which is a precursor of uric acid. Figure 8-1 shows the general xanthine structure and the structures of theophylline (1,3-dimethylxanthine) and caffeine (1,3,7-trimethylxanthine). Because of their methyl attachments, these agents are often referred to as methylxanthines. Another xanthine is theobromine. All three agents are found as alkaloids in plant species. Caffeine is found in coffee beans and kola nuts. Caffeine and theophylline are contained in tea leaves, and caffeine and theobromine are in cocoa seeds or beans. Historically, these natural plant substances have been used as brews for their stimulant effect.
There are several synthetic modifications to the naturally occurring methylxanthines, including dyphylline (7-[2,3-dihydroxypropyl]theophylline), proxyphylline (7-[2-hydroxypropyl]theophylline), and enprofylline (3-propylxanthine). Table 8-1 lists xanthine derivatives, brand names, and available formulations. Theophylline is available in a variety of formulations, including sustained-release oral forms, as aminophylline for oral or intravenous administration, and rectal suppository forms.
TABLE 8-1
| XANTHINE DERIVATIVE | BRAND NAMES | FORMULATIONS |
| Theophylline | Theochron, Elixophyllin, Theo-24 | Tablets, capsules, syrup, elixir, extended-release tablets, capsules, injection |
| Oxtriphylline | Choledyl SA | Tablets, syrup, elixir, sustained-release tablets |
| Aminophylline | Aminophylline | Tablets, oral liquid, injection, suppositories |
| Dyphylline | Lufyllin | Tablets, elixir |
General pharmacologic properties
The xanthine group has the following general physiologic effects in humans:
• Central nervous system (CNS) stimulation
• Bronchial, uterine, and vascular smooth muscle relaxation
Caffeine and theophylline differ in the intensity of the effects listed previously. These differences are summarized in Table 8-2. Caffeine has more CNS-stimulating effect than theophylline, and this includes ventilatory stimulation. In clinical use, theophylline is generally classified as a bronchodilator because of the relaxing effect on bronchial smooth muscle.
TABLE 8-2
Differences in Intensity of Effects for Caffeine and Theophylline
| EFFECT | CAFFEINE | THEOPHYLLINE |
| Central nervous system stimulation | +++ | ++ |
| Cardiac stimulation | + | +++ |
| Smooth muscle relaxation | + | +++ |
| Skeletal muscle stimulation | +++ | ++ |
| Diuresis | + | +++ |
Structure-activity relationships
Figure 8-2 illustrates the general xanthine structure and the effect of attachments at various sites on the molecule. Also, the chemical structure of theophylline is shown in comparison with the theophylline derivatives dyphylline and enprofylline. The methyl attachments at the nitrogen-1 and nitrogen-3 positions for theophylline enhance its bronchodilating effect and its toxic side effects, which are discussed later in this chapter. In contrast, the structure of caffeine (see Figure 8-1) has an additional methyl group at the nitrogen-7 position, decreasing its bronchodilator effect in relation to theophylline. Dyphylline has the same methyl attachments at the nitrogen-1 and nitrogen-3 positions as theophylline but also has a large attachment at the nitrogen-7 position that decreases its bronchodilator potential. Enprofylline, which is not clinically available in the United States at this time, has potent bronchodilating effects, probably because of the large substitution at the nitrogen-3 position.
Proposed theories of activity
The exact mechanism of action of xanthines, and theophylline in particular, is unknown.7 It was originally thought that xanthines caused smooth muscle relaxation by inhibition of phosphodiesterase (PDE), leading to an increase in intracellular cyclic adenosine 3′,5′-monophosphate (cAMP). An increase in cAMP causes relaxation of bronchial smooth muscle. The effect of increased cAMP is described in Chapter 6 in the discussion of β-adrenergic agents. Use of this explanation to account for therapeutic xanthine actions has been questioned, however. Several alternative theories concerning the action of xanthines have been proposed in addition to PDE inhibition. Each of the proposed theories of activity for xanthines is briefly described and commented on in the following sections.
Inhibition of phosphodiesterase
Theophylline is a weak and nonselective inhibitor of cAMP-specific PDE. The pathway by which this inhibition can lead to an increase in intracellular cAMP, with consequent bronchial relaxation or antiinflammatory effects, is illustrated in Figure 8-3, A. However, at the dosage levels used clinically in humans, theophylline is a poor inhibitor of the enzyme.8 As a result, this may not be the best theory on how xanthines exert a therapeutic effect. PDE is a generic term referring to at least 11 distinct families that have been identified as hydrolyzing cAMP or cyclic guanosine 3′,5′-monophosphate (cGMP) and that have unique tissue and subcellular distributions. The various PDE families differ in substrate specificity, inhibitor sensitivity, and cofactor requirements.7 There are two cAMP-hydrolyzing PDEs, referred to as PDE3 and PDE4, that may play a role in asthma. PDE4 is expressed in airway smooth muscle, pulmonary nerves, and many proinflammatory and immune cells. PDE4 inhibitors suppress processes thought to contribute to asthma inflammation by blocking the degradation of cAMP in target cells and tissue. The antiinflammatory effect of theophylline and xanthines is reviewed in the discussion of the clinical application of these drugs in COPD and asthma.
Antagonism of adenosine
An alternative explanation of bronchodilation is that theophylline acts by blocking the action of adenosine. This mechanism is illustrated in Figure 8-3, B. Adenosine is a purine nucleoside that can stimulate A1 and A2 receptors. A1-receptor stimulation inhibits cAMP, whereas A2-receptor stimulation increases cAMP. Inhaled adenosine has produced bronchoconstriction in asthmatic patients. Theophylline is a potent inhibitor of both A1 and A2 receptors and could block smooth muscle contraction mediated by A1 receptors.
This explanation is contradicted by the action of enprofylline, which is about five times more potent than theophylline for relaxing smooth muscle yet lacks a sufficient attachment at the nitrogen-1 position to provide adenosine antagonism.9 This can be seen in Figure 8-2 by comparing the structures of theophylline and enprofylline. In addition, A1 receptors are sparse in smooth muscle, and isolated animal tissue preparations have shown smooth muscle relaxation through adenosine stimulation of the A2 receptors.
