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.

Figure 8-1 Chemical structure of xanthine and its methylated derivatives theophylline and caffeine.

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 Derivatives Used as Bronchodilators in Obstructive Airways Diseases, with Selected Brand Names and Available Formulations

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

! KEY POINT

Xanthines generally have stimulant properties, exemplified by the xanthine caffeine. Other effects of this class of drug include diuresis and smooth muscle relaxation (e.g., bronchodilation).

The xanthine group has the following general physiologic effects in humans:

• Central nervous system (CNS) stimulation

• Cardiac muscle stimulation

• Diuresis

• Bronchial, uterine, and vascular smooth muscle relaxation

• Peripheral and coronary vasodilation

• Cerebral vasoconstriction

Some of the effects seen with xanthines are well known to individuals who drink caffeinated beverages (e.g., coffee, colas, and tea). Coffee in particular can be used for the CNS stimulatory effect to remain awake. The diuretic effect after drinking coffee or cola is also well known. Caffeine or theophylline can also cause tachycardia, and the cerebral vasoconstricting effect has been used to treat migraine headaches. A special agent intended for this use is Cafergot, each tablet of which contains 100 mg of caffeine and 1 mg of ergotamine tartrate.

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.

Figure 8-2 Effect of attachments at various sites on the xanthine molecule and comparative illustration of the structures of theophylline, dyphylline, and enprofylline. BD, Bronchodilation.

! KEY POINT

The exact mode of action of xanthines is unclear; antagonism of adenosine receptors may occur, perhaps as a partial mechanism for the effects of drugs such as theophylline.

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.

Figure 8-3 Two proposed mechanisms of action by which theophylline and xanthines reverse airway obstruction. A, Inhibition of phosphodiesterase. B, Blockade of adenosine receptors. *AMP,* Adenosine monophosphate; *ATP,* adenosine triphosphate.

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.

Catecholamine release

A third explanation of xanthine action is that these agents cause the production and release of endogenous catecholamines, which could cause muscle tremor, tachycardia, and bronchial relaxation. Studies on plasma levels of catecholamines such as epinephrine have reported conflicting results, with both an increase and no change reported.¹⁰

Titrating theophylline doses

In the past, clinical use of the xanthine theophylline, in its many forms, was questioned because of wide variability in its therapeutic effect. It was subsequently found that individuals metabolize theophylline at differing rates, which makes it difficult to determine therapeutic doses. This situation is complicated further by the fact that different forms of the drug are not always equivalent.

Equivalent doses of theophylline salts

The standard with which salts of theophylline are compared is anhydrous theophylline. Anhydrous theophylline is 100% theophylline. By contrast, salts of theophylline such as oxtriphylline (Choledyl SA) are not pure theophylline by weight. A 400-mg dose of Choledyl SA contains approximately 256 mg of theophylline, whereas Theo-24 (a brand of theophylline) is 100% anhydrous theophylline. A 200-mg dose of Choledyl SA does not give the same amount of theophylline as a 200-mg dose of Theo-24. Table 8-3 lists the equivalent dose of pure theophylline provided by the salts, such as oxtriphylline and aminophylline.

TABLE 8-3

Theophylline Content of Salts of Theophylline, with Amount Needed for Equivalence to 100% Anhydrous Theophylline

THEOPHYLLINE SALT	THEOPHYLLINE (%)	EQUIVALENT DOSE (mg)
Theophylline anhydrous	100	100
Theophylline monohydrate	91	110
Aminophylline anhydrous	86	116
Aminophylline dihydrate	79	127
Oxtriphylline	64	156

Because oxtriphylline is 64% theophylline, a dose equivalent to 100 mg of theophylline anhydrous would be 156 mg of oxtriphylline (100 mg/0.64 = 156 mg). Similarly, 127 mg of aminophylline dihydrate (theophylline ethylenediamine) would be required for equivalency to 100 mg of theophylline anhydrous. Dyphylline is not a theophylline but a derivative of theophylline. It does not form theophylline in the body and is about one-tenth as potent as theophylline; this is consistent with its structure-activity relationship, described previously.

Serum levels of theophylline

In 1972, Jenne and colleagues¹¹ indicated that the optimal serum theophylline level for maximal bronchodilation in adults was 10 to 20 μg/mL. The effects associated with a range of serum levels are as follows:

• No effects seen: Less than 5 μg/mL

• Therapeutic range: 10 to 20 μg/mL

• Nausea: greater than 20 μg/mL

• Cardiac arrhythmias: Greater than 30 μg/mL

• Seizures: 40 to 45 μg/mL

! KEY POINT

Because individuals vary in the rate at which theophylline is metabolized, dosage must be titrated to clinical effectiveness, avoidance of side effects, and, most precisely, a therapeutic serum level of 5 to 10 μg/mL in COPD management and 5 to 15 μg/mL in asthma management.

Since the originally proposed serum levels of 10 to 20 μg/mL, the recommended range has been changed to a more conservative 5 to 15 μg/mL for the management of asthma.¹² GOLD recommendations for the use of theophylline in COPD suggest a target serum level of 5 to 10 μg/mL.² Both of these ranges seek maximal therapeutic effect with minimal toxicity and side effects. It is stressed that the ranges listed for toxic effects are general. It is possible for an individual to bypass the nauseous phase of toxicity and immediately enter the seizure phase.

Although there is a dose-related response to higher serum levels of theophylline, there is evidence that the response does not continue at the same rate of increase as levels increase. The improvement in forced expiratory volume in 1 second (FEV₁) tends to flatten above a serum level of 10 to 12 μg/mL, whereas the toxic effects of theophylline (discussed subsequently) tend to increase even within the therapeutic range of 10 to 20 μg/mL.¹³

Dosage schedules

Because of the variability in the rate at which individuals metabolize theophylline and the other factors that affect theophylline metabolism and clearance rates, dosage schedules are used to titrate the drug. These schedules are found in the product literature, references such as Drug Facts and Comparisons and Physicians’ Desk Reference, and general pharmacology texts.

For rapid theophyllinization, the patient may be given an oral loading dose of 5 mg/kg, provided that the patient was not previously receiving theophylline. This dose is based on anhydrous theophylline. Lean body weight should be used in calculating theophylline doses because theophylline does not distribute into fatty tissue. In titrating the dose, each 0.5-mg/kg dose of theophylline given as a loading dose results in a serum level of approximately 1 μg/mL. If theophylline was taken previously by the patient, a serum theophylline level should be measured if possible.

For long-term therapy, a slow titration is helpful, with an initial dose of 16 mg/kg/24 hr or 400 mg/24 hr, whichever is less. These dosages may need to be modified in the presence of factors such as age (younger children versus the elderly), congestive heart disease, or liver disease. The effects of these factors on serum theophylline levels and on dosage are discussed subsequently. The dosage guidelines given have been obtained from theophylline product information.

Dosage of theophylline can be guided by the clinical reaction of the patient or, better, by measurement of serum drug levels. Without a serum drug level, the dose of theophylline should be based on the benefit provided and should be reduced if the patient experiences toxic side effects. When monitoring serum theophylline levels, the sample should be taken at the time of peak absorption of the drug—1 to 2 hours after administration for immediate-release forms and 5 to 9 hours after the morning dose for sustained-release forms.

The previous examples of dosage schedules are not complete for all situations; they are intended only as an example of such schedules and of the complexity involved in treating patients with theophylline. Complete tables for different ages and clinical applications should be consulted when administering theophylline.

Theophylline toxicity and side effects

! KEY POINT

Theophylline has a narrow therapeutic margin, and side effects such as gastric upset, headache, insomnia, nervousness, palpitations, and diuresis occur frequently, even within the therapeutic range of dosing. Blood levels of theophylline are affected by many factors, which can either increase or decrease the amount of drug in the body.

An important problem with the use of theophylline is its narrow therapeutic margin; there is very little difference between the dose and serum level that give therapeutic benefit and that cause toxic side effects. Even within the therapeutic serum levels of 10 to 20 μg/mL, distressing side effects can be experienced. To reduce side effects, inhaled theophylline is being studied.¹⁴ The most common adverse reactions usually seen with theophylline are listed in Box 8-1.

Gastric upset, headache, anxiety, and nervousness are not unusual as less toxic side effects of theophylline and can result in loss of school time or workdays. The diuretic effect should be noted in patients with excess airway secretions (e.g., patients with bronchitis or cystic fibrosis), with adequate fluid replacement when necessary to prevent dehydration and thickening of secretions.

Reactions to levels of theophylline also can be unpredictable from patient to patient. Studies are cited in which reported serum levels of 78.5 μg/mL and 104.8 μg/mL caused only gastrointestinal symptoms, whereas mean levels of 35 μg/mL caused cardiac arrhythmias or seizures.¹³ Also, minor side effects may provide little warning before serious toxic effects such as arrhythmias or seizures occur.

Factors affecting theophylline activity

Theophylline is metabolized in the liver and eliminated by the kidneys. Any condition that affects these organs can affect theophylline levels in the body. Interactions between other drugs and theophylline can affect serum levels of the drug. Some common drugs and conditions that increase or decrease theophylline levels are listed in Box 8-2.

BOX 8-2 Factors That Can Increase or Decrease Blood Levels of Theophylline and Affect Dosage Requirements

Increase

• Alcohol (0.9 g/kg)

• β-blocking agents

• Calcium channel blockers

• Cimetidine, ranitidine

• Corticosteroids

• Disulfiram

• Influenza virus vaccine

• Interferon

• Ephedrine

• Estrogen

• Macrolide antibiotics (e.g., clarithromycin)

• Mexiletine

• Methotrexate

• Pentoxifylline

• Quinolones, oral contraceptives

• Congestive heart failure

• Isoniazid (+ or −)*

• Isoproterenol (IV)

• Ketoconazole

• Loop diuretics (+ or −)*

^*+, Increase in theophylline level; −, decrease in theophylline level.

Data from Weinberger M, Hendeles L: Theophylline in asthma, N Engl J Med 334:1380, 1996; American Thoracic Society: Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease, Am J Respir Crit Care Med 152:S77, 1995.

Viral hepatitis or left ventricular failure can cause elevated serum levels of theophylline for a given dose because of decreased liver metabolism of the drug. An opposite effect—decreased serum levels—is caused by cigarette smoking, which stimulates the production of liver enzymes that inactivate methylxanthines ¹⁵; this necessitates higher theophylline doses. Some drugs used for the treatment of tuberculosis, such as isoniazid, and the loop diuretics, such as furosemide (Lasix) or bumetanide (Bumex), are unpredictable in their effect and may either increase or decrease theophylline levels. Measurement of serum levels is extremely important when using these agents with theophylline.

β agonists and theophylline have an additive effect and are often combined when treating patients with asthma or COPD. Theophylline may antagonize the sedative effect of benzodiazepines (e.g., Valium). Theophylline can also reverse the paralyzing effect of nondepolarizing neuromuscular blocking agents (pancuronium and atracurium) in a dose-dependent manner. This is important to realize when paralyzing patients with severe asthma to facilitate ventilatory support and when intravenous administration of aminophylline is used.

Clinical uses of theophylline

More recent guidelines for the pharmacologic management of asthma and COPD do not indicate theophylline as first-line therapy.¹^,² The disadvantages of theophylline are its narrow therapeutic margin, toxic effects, unpredictable blood levels and need for individual dosing, and numerous drug-drug and drug-condition interactions. The use of theophylline in asthma and COPD is described in the following sections.

Use in asthma

! KEY POINT

Theophylline has been relegated to the level of a second-line or third-line drug in treating asthma and is considered only if β agonists and antiinflammatory therapy fail to control symptoms.

The role of theophylline preparations in the management of acute and stable asthma and COPD has been debated.¹⁶^,¹⁷ In the treatment of asthma, theophylline is suggested for use after reliever agents, such as a β₂ agonist, and other controller agents, such as ICS, or mediator antagonists (cromolyn-like drugs) targeting the underlying inflammation.¹^,²

Adachi and colleagues ¹⁸ compared a combination of salmeterol and fluticasone propionate with a combination of fluticasone and sustained-release theophylline. Results favored the salmeterol/fluticasone combination in the treatment of moderate asthmatics.

Use in chronic obstructive pulmonary disease

! KEY POINT

In COPD, the nonbronchodilating effects of theophylline, such as ventilatory drive stimulation, and enhanced respiratory muscle function are of value, although use of theophylline in COPD is debated.

Use as a maintenance agent in COPD is indicated if anticholinergics and β₂ agonist fail to provide adequate control. Development of long-acting β₂ agonists, such as salmeterol, formoterol, and arformoterol, offers an additional drug choice to preserve lung function in COPD before using theophylline, especially if theophylline was used to prevent nocturnal symptoms. The increased FEV₁ with salmeterol gives more consistent improvement in lung function on a 12-hour basis and maintains a higher baseline of lung function.¹⁹ Theophylline and its salt, aminophylline, are listed as bronchoactive agents for managing an acute exacerbation of COPD in the GOLD guidelines; however, use of other bronchodilators is preferred.²

! KEY POINT

COPD guidelines suggest the use of inhaled β agonists (e.g., albuterol) and anticholinergics (e.g., ipratropium) over the use of theophylline because of its side effects.

Because of side effects in the gastrointestinal system, xanthines are contraindicated in subjects with active peptic ulcer or acute gastritis. Suppositories should not be used if the rectum or lower colon is irritated. If stomach upset occurs with theophylline, the drug may be taken with food. Ingestion of large amounts of caffeine from other sources such as tea or coffee may precipitate side effects when taking theophylline.

Antiinflammatory effects

Theophylline also has some antiinflammatory effects, which may explain its efficacy despite the fact that the drug is a relatively weak bronchodilator.¹⁶^,²⁴ Evidence indicates that theophylline can produce some degree of immunomodulation and an antiinflammatory and bronchoprotective effect through inhibition of cAMP-specific PDE enzymes, particularly PDE3 and PDE4, in proinflammatory cells and tissues. Theophylline has been shown to cause the following (see references for detailed antiinflammatory effects of theophylline^16,24-28):

• Decreased migration of activated eosinophils into bronchial mucosa with allergen stimuli and reduced eosinophil survival

• Reduced T-cell proliferation and accumulation in atopic asthma with corresponding improvement in pulmonary function

• Inhibition of proinflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor-α, and interferon-γ, and increased production of the antiinflammatory cytokine IL-10

• Attenuation of the late phase response to histamine in patients with allergic asthma

• Reduced airway responsiveness to stimuli such as histamine, methacholine, allergen, sulfur dioxide, distilled water, cyanates, and adenosine

• Increased activation of a group of enzymes, histone deacetylase, also known as lysine deacetylase, which are used by corticosteroids to reduce inflammatory response.

The antiinflammatory and immunomodulating effects of theophylline occur at lower plasma concentrations such as 9 to 10 μg/mL, in contrast to the concentrations usually recommended for bronchodilation, and may result in a steroid-sparing effect.²⁵ Inhibitors of PDE4, with more selectivity than theophylline and reduced toxic effect profile, may offer a new class of antiinflammatory agents.⁷