Drugs Used in the Treatment of Asthma

Aerosol Delivery of Drugs

Topical application of drugs to the lungs can be accomplished by use of aerosols. In theory, this approach should produce a high local concentration in the lungs with a low systemic delivery, thereby significantly improving the therapeutic ratio by minimizing systemic side effects. The most commonly used drugs in the treatment of asthma, -adrenergic receptor agonists and glucocorticoids, have potentially serious side effects when delivered systemically. Since the pathophysiology of asthma appears to involve the respiratory tract alone, the theoretical advantages of aerosol treatments with limited systemic effects are substantial. Indeed, in clinical practice, probably more than 90% of asthmatic patients who are capable of manipulating inhaler devices can be managed by aerosol treatments alone. Because of the specialized nature of aerosol delivery and the substantial effects that these systems have on the therapeutic index, the principles of this delivery method are important to review.

A review of the chemistry and physics of aerosol delivery systems is available (Taburet and Schmit, 1994). A schematic diagram of the fate of therapeutic agents delivered by this route is shown in Figure 282. The critical determinant of the delivery of any particulate matter to the lungs is the size of the particles. Particles larger than 10 m will be deposited primarily in the mouth and oropharynx, while particles smaller than 0.5 m are inhaled to the alveolae and subsequently exhaled without being deposited in the lungs. Particles with a diameter of 1 to 5 m allow deposition of drugs in the small airways and are therefore the most effective. Unfortunately, no aerosol system in clinical use can produce uniform particles limited to the appropriate size range. A number of factors in addition to particle size determine effective deposition of drugs in the bronchial tree, including the rate of breathing and breath-holding after inhalation. It is recommended that a slow, deep breath be taken and held for 5 to 10 seconds when administering drugs to the lungs.

As depicted in Figure 282, even under ideal circumstances only a small fraction of the aerosolized drug is deposited in the lungs, typically 2% to 10%. Most of the remainder is swallowed. Therefore, to have minimal systemic effects, an aerosolized drug should be either poorly absorbed from the gastrointestinal system or rapidly inactivated via first-pass hepatic metabolism. Furthermore, any maneuvers that result in a higher percentage of deposition in the lungs and a lower percentage of drug reaching the gastrointestinal system should improve the therapeutic index. For example, with metered-dose inhalers, a large-volume 'spacer' can be attached to the inhaler. A spacer is a tube or expandable bellows that fits between the inhaler and the patient's mouth; the inhaler discharges into it, and the patient inhales from it. A spacer can improve markedly the ratio of inhaled to swallowed drug by limiting the amount of larger particles (>10 m) that reach the mouth and by reducing the need for the patient to coordinate accurately inhalation with inhaler activation (Bryant and Shimizu, 1988). The latter is not a trivial concern, since multiple studies have shown that more than 50% of patients using inhalers do not use proper technique (Epstein et al., 1979; Macfarlane and Lane, 1980) and thereby markedly reduce the amount of drug inhaled into the lungs while not reducing the amount deposited in the mouth.

The two types of devices used for providing aerosol therapy are metered-dose inhalers and nebulizers. Both devices provide a range of particle sizes that includes the desired 1- to 5- m range. When used appropriately, they are equally effective in delivery of drug to the lungs, even in the setting of fairly severe asthma exacerbations (Turner et al., 1988; Benton et al., 1989). Nevertheless, some clinicians and many patients prefer to use nebulizers for severe asthma exacerbations with poor inspiratory ability. Metered-dose inhalers offer the advantage of being cheaper and portable; nebulizers offer the advantages of not requiring hand/breathing coordination. In addition, nebulizer therapy can be delivered by facemask to young children or older patients who are confused. A substantial disadvantage of metered-dose inhalers is that most contain chlorofluorocarbons. Temporary exemptions have been given for these devices until alternative, safe propellants can be developed. An albuterol metered-dose inhaler using hydrofluoroalkane as a propellant (PROVENTIL HFA) is available for clinical use in the United States.

An alternative to aerosolized delivery is the use of dry-powder inhalers. These typically use lactose or glucose powders to carry the drugs. One disadvantage of these devices is that a relatively high airflow is needed to suspend properly the powder. Young children, the elderly, and those suffering from a significant asthma exacerbation may not be able to generate such air flow rates. The dry powder can be irritating when inhaled. Storage of dry-powder inhalers in areas where there are wide temperature fluctuations or high humidity can affect their performance.

-Adrenergic Receptor Agonists

The history, chemistry, pharmacological properties, and mechanisms of action of the -adrenergic agonists are discussed in Chapter 10: Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists. The discussion of these agents in this chapter is restricted to their uses in asthma.

Mechanism of Action and Use in Asthma

The -adrenergic receptor agonists available for the treatment of asthma are selective for the -receptor subtype. With few exceptions, these are delivered directly to the airways via inhalation. The agonists can be classified as short- and long-acting. This subclassification is useful from a pharmacological perspective, because short-acting agonists are used only for symptomatic relief of asthma, whereas long-acting agonists are used prophylactically in the treatment of the disease.

Short-Acting -Adrenergic Receptor Agonists

Drugs in this class include albuterol (PROVENTIL VENTOLIN), levalbuterol [XOPENEX, the (R)-enantiomer of albuterol], metaproterenol (ALUPENT), terbutaline (BRETHAIRE), and pirbuterol (MAXAIR). These drugs are used for acute inhalation treatment of bronchospasm. Terbutaline (BRETHINE BRICANYL), albuterol, and metaproterenol also are available in oral dosage form. Each of the inhaled drugs has an onset of action within 1 to 5 minutes and produces a bronchodilation that lasts for about 2 to 6 hours. When given in oral dosage forms, the duration of action is somewhat longer (oral terbutaline, for example, has a duration of action of 4 to 8 hours). Although there are slight differences in the relative -receptor potency ratios among the drugs, all of them are selective for the subtype.

The mechanism of the antiasthmatic action of short-acting -adrenergic receptor agonists is undoubtedly linked to the direct relaxation of airway smooth muscle and consequent bronchodilation. Although human bronchial smooth muscle receives little or no catecholaminergic sympathetic innervation, it nevertheless contains large numbers of -adrenergic receptors. Stimulating these receptors leads to activation of adenylyl cyclase, increases in cellular cyclic AMP, and consequent reduction of muscle tone (see Johnson and Coleman, 1995). -Adrenergic receptor agonists also have been shown to increase the conductance of potassium channels in airway muscle cells leading to membrane hyperpolarization and relaxation. This occurs, in part, by mechanisms independent of adenylyl cyclase activity and cyclic AMP production (Kume et al., 1994).

The most effective drugs in relaxing airway smooth muscle and reversing bronchoconstriction are short-acting -adrenergic receptor agonists. They are the preferred treatment for rapid symptomatic relief of dyspnea associated with asthmatic bronchoconstriction (Fanta et al., 1986; Rossing et al., 1980; Nelson, 1995). Although these drugs are prescribed on an as-needed basis, it is imperative that guidelines be given to the patient so that reliance on relief of symptoms during times of deteriorating asthma does not occur. When the asthma symptoms become persistent, the patient should be reevaluated, so that drugs aimed at controlling, in addition to reversing, the disease can be prescribed.

Long-Acting -Adrenergic Receptor Agonists

Salmeterol xinafoate SEREVENT) is a long-lasting adrenergic agonist with very high selectivity for the -receptor subtype (Cheung et al., 1992; D'Alonzo et al., 1994; Kamada et al., 1994). Inhalation of salmeterol provides persistent bronchodilation lasting over 12 hours. The mechanism underlying the therapeutic effect of salmeterol is not yet fully understood. The extended side chain on salmeterol renders it 10,000 times more lipophilic than albuterol (Brittain, 1990). The lipophilicity regulates the diffusion rate away from the receptor by determining the degree of partitioning in the lipid bilayer of the membrane. Subsequent to binding the receptor, the less lipophilic, short-acting agonists are rapidly removed from the receptor environment by diffusion in the aqueous phase. Unbound salmeterol, by contrast, persists in the membrane and only slowly dissociates from the receptor environment. Bitolterol (TORNALATE) is a highly selective -adrenergic receptor agonist that also has a relatively long duration of action, although it has a rapid onset of action and is approved in the United States for acute treatment and not prophylaxis of bronchospasm. The mechanism underlying its persistent action is related to the fact that the biological action of bitolterol is dependent on metabolism within the lung to the active metabolite colterol (Friedel and Brogden, 1988).

Long-acting -adrenergic receptor agonists relax airway smooth muscle and cause bronchodilation by the same mechanisms as do short-duration agonists. There are -adrenergic receptors on cell types in the airways other than bronchial smooth muscle. Of particular interest are the observations that stimulation of -adrenergic receptors inhibits the function of numerous inflammatory cells including mast cells, basophils, eosinophils, neutrophils, and lymphocytes. In general, stimulating -adrenergic receptors in these cell types leads to elevations in cellular cyclic AMP, causing a signaling cascade leading to inhibition of inflammatory mediator and cytokine release (Lichtenstein and Margolis, 1968; Barnes, 1999). Chronic treatment with a receptor agonist often leads to receptor desensitization and a diminution of effect. The rate and degree of -adrenergic receptor desensitization is dependent on the cell type. For example, the receptors on human bronchial smooth muscle are relatively resistant to desensitization, whereas receptors on mast cells and lymphocytes are rapidly desensitized following agonist exposure (Chong and Peachell, 1999; Johnson and Coleman, 1995). This may help to explain why there is little evidence that these drugs are effective in inhibiting airway inflammation associated with asthma.

There are relatively few studies evaluating the antiinflammatory effect of adding long-acting -adrenergic receptor agonist therapy to inhaled glucocorticoid treatment. In one such study, symptomatic asthmatic subjects taking inhaled glucocorticoid therapy were given either salmeterol or fluticasone. In the salmeterol group, there was a significant reduction of eosinophils in the airway wall, suggesting an antiinflammatory effect (Li et al., 1999).

Chronic treatment with long-acting -adrenergic receptor agonists has been shown to improve lung function, decrease asthma symptoms, decrease use of short-acting inhaled -adrenergic agonists, and decrease nocturnal asthma. This was not associated with a marked decrease in airway inflammation. Therefore, in a report issued by the National Heart, Lung, and Blood Institute (Publication # 95-3659, 1996), it is suggested that treatment of chronic, persistent asthma with a long-acting -adrenergic receptor agonist should be accompanied by antiinflammatory medications. For patients with chronic asthma who are not controlled adequately by inhaled glucocorticoid therapy, the physician either can increase the dose of steroid or add another class of drug to the regimen. Clinical studies have provided evidence in favor of adding a long-acting -adrenergic agonist over doubling the dose of steroid in these patients (Greening et al., 1994; Woolcock et al., 1996). A fixed-dosage combination of salmeterol and the steroid fluticasone (ADVAIR) has been approved for treatment of asthma in Europe and is pending approval in the United States.

Salmeterol should not be used to reverse acute symptoms of asthma. Rather, physicians prescribing salmeterol also should prescribe a short-acting -adrenergic receptor agonist for symptomatic relief. Use of short-acting agonists as 'rescue' medication should be monitored. If the patient requires four or more inhalations a day for two or more consecutive days of a rescue medication, then the patient should be advised to see a physician for a reevaluation.

Toxicity

Owing to their -receptor selectivity and topical delivery, inhaled -adrenergic receptor agonists, at recommended doses, have relatively few side effects. A portion of inhaled drug is inevitably absorbed into the systemic circulation. At higher doses, therefore, these drugs may lead to increased heart rate, cardiac arrhythmias, and central nervous system effects associated with -adrenergic receptor activation as described in Chapter 10: Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists. This can become of particular concern in poorly controlled asthma, where there may be excessive and inappropriate reliance on symptomatic treatment with short-acting -receptor agonists.

Oral Therapy with -Adrenergic Receptor Agonists

The use of orally administered adrenergic agonists for bronchodilation has not gained wide acceptance, largely because of the greater risk of producing side effects, especially tremulousness, muscle cramps, cardiac tachyarrhythmias, and metabolic disturbances (see Chapter 10: Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists). There are two situations in which oral -adrenergic agonists are used frequently. First, in young children (<5 years old) who cannot manipulate metered-dose inhalers yet have occasional wheezing with viral upper respiratory infections, brief courses of oral therapy (albuterol or metaproterenol syrups) are well tolerated and effective. Second, in some patients with severe asthma exacerbations, any aerosol, whether delivered via a metered-dose inhaler or a nebulizer, can be irritating and cause a worsening of cough and bronchospasm. In this circumstance, oral therapy with -adrenergic agonists (albuterol, metaproterenol, or terbutaline tablets) can be effective. However, the frequency of adverse systemic side effects with orally administered agents is higher in adults than in children.

Even though stimulation of -adrenergic receptors has been shown to inhibit the release of inflammatory mediators from mast cells, long-term administration of -adrenergic agonists, either orally or by inhalation, does not reduce bronchial hyperresponsiveness. Thus, other approaches for the treatment of chronic symptoms are preferred.

Glucocorticoids

The history, chemistry, pharmacological properties, and mechanisms of action of glucocorticoids are discussed in Chapter 60: Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones. Here, the discussion is restricted to their uses in asthma. Barnes and Pedersen (1993) have provided a thorough review of this subject.

Systemic glucocorticoid administration long has been employed to treat severe chronic asthma or severe, acute exacerbations of asthma (McFadden, 1993; Greenberger, 1992). The development of aerosol formulations significantly improved the safety of glucocorticoid treatment, allowing it to be used for moderate asthma (Busse, 1993). Asthmatic subjects who require inhaled -adrenergic agonists four or more times weekly are viewed as candidates for inhaled glucocorticoids (Anonymous, 1991; Israel and Drazen, 1994; Barnes, 1995).

Mechanism of Action in Asthma

Asthma is a disease associated with airway inflammation, airway hyperreactivity, and acute bronchoconstriction. Glucocorticoids do not relax airway smooth muscle and thus have little effect on acute bronchoconstriction. By contrast, these agents are singularly effective in inhibiting airway inflammation. Very few mechanisms that lead to the inflammatory reaction escape the inhibitory effects of these drugs (Schleimer, 1998). The mechanisms that contribute to the antiinflammatory effect of glucocorticoid therapy in asthma include modulation of cytokine and chemokine production, inhibition of eicosanoid synthesis, marked inhibition of accumulation of basophils, eosinophils, and other leukocytes in lung tissue, and decreased vascular permeability (Schleimer, 1998). The profound and generalized antiinflammatory action of this class of drugs explains why they are the most effective drugs used in the treatment of asthma at present.

Inhaled Glucocorticoids

Glucocorticoids have long been known to be effective in controlling asthma, but treatment with systemic glucocorticoids comes with the cost of considerable unwanted side effects. A major advance in asthma therapy was the development of glucocorticoids that could be delivered to the lungs via inhalation. This allowed for the targeting of the drug directly to the relevant site of inflammation. In so doing, the therapeutic index of the drugs has been greatly enhanced by substantially diminishing the number and degree of side effects, without sacrificing clinical efficacy. There are currently five glucocorticoids available in the United States for inhalation therapy: beclomethasone dipropionate (BECLOVENT VANCERIL), triamacinolone acetonide (AZMACORT), flunisolide (AEROBID), budesonide (PULMICORT), and fluticasone propionate (FLOVENT). A sixth drug, mometasone (ASMANEX), is pending approval by the United States Food and Drug Administration for use in asthma. These drugs differ markedly in their affinity for the glucocorticoid receptor, with fluticasone and budesonide having much higher affinity than beclomethasone. Mechanistically, however, there are no differences among the available choices, and, with the appropriate dose, they all are effective in controlling asthma. Few studies have directly assessed the relative therapeutic index of the various formulations of inhaled steroids in the treatment of asthma, but available data indicate that one does not clearly stand out with a far superior therapeutic index (O'Byrne and Pedersen, 1998).

Inhaled glucocorticoids are used prophylactically to control asthma, rather than to acutely reverse asthma symptoms. As with all prophylactic therapies, compliance is a significant concern. Issues relating to drug compliance, therefore, become relevant when choosing among the various steroid formulations. Having highly potent glucocorticoid action, the newer drugs can be effective with as little as one or two puffs administered twice or even once daily. This more convenient dosage regimen may be preferred by patients, which in turn translates to better compliance and therefore better asthma control. The appropriate dose of steroid must be determined empirically. Important variables that influence the effective dose include the severity of disease, the particular steroid used, and the device used for drug delivery, as it determines the actual quantity of drug delivered to the lungs (Smaldone, 1997). When determining the optimal dose, it should be kept in mind that maximal improvement in lung function may not occur until after several weeks of treatment.

Asthmatic patients maintained on inhaled glucocorticoids show improvement in symptoms and lowered requirements for 'rescue' with -adrenergic agonists (Laitinen et al., 1992; Haahtela et al., 1994). Beneficial effects may be seen within 1 week; however, improvement, in terms of reduced bronchial hyperreactivity, may continue for several months (Juniper et al., 1990). When directly compared to regular use of inhaled -adrenergic agonists, inhaled glucocorticoids provide better symptom control (Laitinen et al., 1992). One study showed that, during treatment with inhaled budesonide (600 g twice daily) for 2 years, bronchial hyperreactivity remained improved throughout the study (Haahtela et al., 1994). After 2 years, most patients were able to reduce their dose of budesonide to 200 g twice daily without loss of control of their asthma. Upon complete discontinuation of budesonide, bronchial hyperreactivity returned, and symptoms usually worsened, although one-third of patients were able to discontinue completely their budesonide inhalers without symptomatic worsening after prolonged treatment. Based on these findings, periodic attempts to discontinue inhaled glucocorticoids should be considered in patients who are extremely well controlled.

Systemic Glucocorticoids

Systemic glucocorticoids are used for acute asthma exacerbations and chronic, severe asthma. Substantial doses of glucocorticoids (e.g., 40 to 60 mg of prednisone daily for 5 days; 1 to 2 mg/kg per day for children) often are used to treat acute exacerbations of asthma (Weinberger, 1987). Although an additional week of therapy at somewhat reduced dosage may be required, the steroids can be withdrawn abruptly once control of the symptoms by other medications has been restored; any suppression of adrenal function appears to dissipate within 1 to 2 weeks. More protracted bouts of severe asthma may require longer treatment and a slow tapering of the dose to avoid exacerbating asthma symptoms and suppressing pituitary/adrenal function. In persistent asthma, alternate-day therapy with oral prednisone was common in the past. Now, most patients considered for this regimen likely can be treated better with high-dose inhaled glucocorticoids.

Toxicity

Inhaled Glucocorticoids

While there is a great deal of enthusiasm for inhaled glucocorticoids in asthma, local and systemic adverse effects remain a concern (Table 283). Some portion of any inhaled drug is swallowed. Therefore, inhaled drugs can reach the circulation by direct absorption from the lung or by absorption from the gastrointestinal tract. The newer glucocorticoids have extremely low oral bioavailability due to extensive first-pass metabolism by the liver. These reach the circulation almost exclusively by absorption from the lung (Brattsand and Axelsson, 1997). In contrast to the beneficial effects on asthma, which reach a plateau at about 1600 g/day, the probability of adverse effects continues to increase at higher doses. Oropharyngeal candidiasis and, more frequently, dysphonia can be encountered. The incidence of candidiasis can be reduced substantially by rinsing the mouth and throat with water after each use and by employing spacer or reservoir devices attached to the dispenser to decrease the deposition of drug in the oral cavity (Johnson, 1987). Appreciable suppression of the hypothalamic-pituitary-adrenal axis is difficult to document at doses below 800 g/day and probably is rarely of physiologic importance even at doses up to 1600 g/day. Modest but statistically significant decreases in bone mineral density do occur in female asthmatics receiving inhaled steroids, possibly even when doses as low as 500 g/day are employed (Ip et al., 1994). Others have shown increases in markers for bone mineral turnover (serum osteocalin and urine hydroxyproline levels) during treatment with inhaled glucocorticoids (Pavord and Knox, 1993; Israel and Drazen, 1994). The clinical relevance of these bone metabolism findings remains to be determined, but they do argue that inhaled glucocorticoid treatment should be reserved for moderate and severe asthma, since such treatment is likely to last for many years (Israel and Drazen, 1994). Nonetheless, it has been suggested that the small risk of adverse effects at high doses of inhaled glucocorticoids is outweighed by the risks of not controlling severe asthma adequately (Barnes, 1995).

Systemic Glucocorticoids

The adverse effects of systemic administration of adrenocortical steroids are well known (see Chapter 60: Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones), but treatment for brief periods (5 to 10 days) causes relatively little dose-related toxicity. The most common adverse effects during a brief course are mood disturbances, increased appetite, loss of glucose control in diabetics, and candidiasis.

Leukotriene-Receptor Antagonists and Leukotriene-Synthesis Inhibitors

Zafirlukast ACCOLATE) and montelukast (SINGULAIR) are leukotriene-receptor antagonists. Zileuton (ZYFLO) is an inhibitor of 5-lipoxygenase, which catalyzes the formation of leukotrienes from arachidonic acid.

History

The history of leukotrienes can be traced back to the classical pharmacological studies in the late 1930s by Kellaway and Trethewie (1940). Upon investigating antigen-induced responses in guinea pigs sensitized to egg albumin, they discovered a slow-reacting, smooth-muscle-stimulating substance. They named the substance SRS based on its pharmacological activity and concluded that it was a unique substance found only in immunologically sensitized tissues subsequently challenged with antigen. Decades later, Brocklehurst (1960) renamed SRS as slow-reacting substance of anaphylaxis, or SRS-A.

Two pivotal discoveries were required before the importance of SRS-A in allergic responses was proven. First was the discovery in 1973 by scientists at Fisons pharmaceutical company of an SRS-A antagonist called FPL 55712 (Augstein et al., 1973), and second was the elucidation by Samuelsson and colleagues of the structure of SRS-A as a 5-lipoxygenease product of arachidonic acid, which they termed cysteinyl leukotriene (Murphy et al., 1979; see Chapter 26: Lipid-Derived Autacoids: Eicosanoids and Platelet-Activating Factor). Soon thereafter, an enormous effort was undertaken by the pharmaceutical industry to discover novel inhibitors of leukotrienes as potential therapeutic agents for asthma. The strategies taken were either to reduce the synthesis of leukotrienes by inhibiting the 5-lipoxygenase enzyme, or to antagonize the effects of leukotrienes at their receptors. This effort bore fruit in the 1990s with the development of three new drugs now available for the treatment of asthma in the United States. These drugs are the leukotriene-receptor antagonists zafirlukast (Krell et al., 1990), and montelukast (Jones et al., 1995), and the leukotriene-synthesis inhibitor zileuton (Carter et al., 1991).

Chemistry

The chemical structures of zafirlukast, montelukast, and zileuton are shown below.

Pharmacokinetics and Metabolism

Each of the three leukotriene-modifying drugs is available for oral administration in tablet form. Zafirlukast is rapidly absorbed, with greater than 90% bioavailability. At therapeutic plasma concentrations, it is over 99% protein bound. Zafirlukast is extensively metabolized by the liver cytochrome P450 isozyme CYP2C9. The parent drug is responsible for the drug action with metabolites being less than 10% effective. The half-life of zafirlukast is approximately 10 hours.

Montelukast is rapidly absorbed, with about 60% to 70% bioavailability. At therapeutic concentrations, it is highly protein bound (99%). It is extensively metabolized by cytochrome P450 isozymes CYP3A4 and CYP2C9. The half-life of montelukast is between 3 and 6 hours.

Zileuton is rapidly absorbed upon oral administration and is extensively metabolized by cytochrome P450 isozymes and by UDP-glucuronosyltransferases. The parent molecule is responsible for the therapeutic action. Zileuton is a short-acting drug, with a half-life of approximately 2.5 hours. Like montelukast, zileuton is highly protein bound (93%).

Mechanism of Action in Asthma

Leukotriene-modifying drugs act either as competitive antagonists of leukotriene receptors or by inhibiting the synthesis of leukotrienes. The pharmacological properties of leukotrienes are discussed in detail in Chapter 26: Lipid-Derived Autacoids: Eicosanoids and Platelet-Activating Factor.

Leukotriene-Receptor Antagonists

Cysteinyl leukotrienes (cys-LTs) include LTC4, LTD4, and LTE4. All of the cys-LTs are potent constrictors of bronchial smooth muscle. On a molar basis, LTD4 is approximately 1000 times more potent than is histamine as a bronchoconstrictor (Dahlen et al., 1980). The receptor responsible for the bronchoconstrictor effect of leukotrienes is the cys-LT1 receptor (Buckner et al., 1986; Lynch et al., 1999). Although each of the cys-LTs are agonists at the cys-LT1 receptor, LTE4 is less potent than either LTC4 or LTD4. Zafirlukast and montelukast are selective, high-affinity, competitive antagonists of the cys-LT1 receptor (Krell et al., 1990, Jones et al., 1995). Pranlukast is another cys-LT1receptor antagonist used in some countries in the treatment of asthma, but it is not approved for use in the United States. Inhibition of cys-LTinduced bronchial smooth muscle contraction likely is involved in the therapeutic effects of these agents to relieve the symptoms of asthma.

The effects of cys-LTs that are potentially relevant to bronchial asthma are not limited to bronchial smooth muscle contraction. Cys-LTs can increase microvascular leakage, increase mucus production, and enhance eosinophil and basophil influx into the airways (Hay et al., 1995). The extent to which inhibiting these non-smooth-muscle effects of leukotrienes contribute to the therapeutic effects of the drugs is not known. It may be noteworthy, however, that zafirlukast significantly inhibits the influx of basophils and lymphocytes entering the airways following experimental allergen challenge in asthmatic subjects (Calhoun et al., 1998).

Leukotriene-Synthesis Inhibitors

The formation of leukotrienes depends on lipoxygenation of arachidonic acid by the enzyme 5-lipoxygenase. Zileuton is a potent and selective inhibitor of 5-lipoxygenase activity and thus inhibits the formation of all 5-lipoxygenase products. This means that, in addition to inhibiting the formation of the cys-LTs, zileuton inhibits the formation of leukotriene B4 (LTB4), a potent chemotactic autacoid, and other eicosanoids that depend on LTA4 synthesis (see Chapter 26: Lipid-Derived Autacoids: Eicosanoids and Platelet-Activating Factor). In theory, the therapeutic effects of a 5-lipoxygenase inhibitor would include all of those observed with the cys-LT1receptor antagonists, as well as other effects that may result from inhibiting the formation of LTB4 and other 5-lipoxygenase products.

The pharmacological actions of cys-LTs are not fully accounted for by activation of the cys-LT1 receptor. For example, cys-LTinduced contraction of vascular smooth muscle (Gorenne et al., 1995) and stimulation of expression of P-selectin by endothelial cells occur via noncys-LT1 receptor subtypes (Pedersen et al., 1997). This provides another theoretical advantage of zileuton over zafirlukast and montelukast, because 5-lipoxygenase inhibitors would inhibit cys-LT effects regardless of the receptor subtypes involved. These theoretical advantages notwithstanding, studies thus far do not support the hypothesis that zileuton is significantly more efficacious than the cys-LT1receptor antagonists in the treatment of asthma.

Toxicity

There are few adverse effects directly associated with inhibition of leukotriene synthesis or function. This is likely due to the fact that the production of leukotrienes is predominantly limited to sites of inflammation.

Zafirlukast and Montelukast

In large clinical studies, the adverse effect profile of these drugs was similar to that observed with placebo treatment. In very rare instances, patients taking these drugs developed a systemic eosinophilia and a vasculitis with features similar to Churg-Strauss syndrome. This problem was often associated with the reduction in oral glucocorticoid therapy, and may represent the uncovering of a preexisting disease. Zafirlukast, but not montelukast, may interact with warfarin and increase prothrombin-times, so prothrombin-times should be monitored in those patients subject to this interaction.

Zileuton

The adverse effect profile in patients taking zileuton is similar to that in patients taking placebo. In about 4% to 5% of patients taking zileuton, however, there is an elevation in liver enzymes. In the majority of patients, this occurs during the first two months of therapy. Zileuton decreases the steady-state clearance of theophylline, resulting in substantive increases in theophylline plasma concentrations. Zileuton also decreases warfarin clearance.

Use in Asthma

Although leukotriene inhibitors have been proven to be effective prophylactic treatment for mild asthma, their position in the guidelines for asthma therapy have not yet been clearly stated. Most clinical studies with these drugs have been conducted in patients with mild asthma who were not taking glucocorticoids. In general, the studies show a modest but significant improvement in lung function and a decrease in symptoms and asthma exacerbations. In a meta-analysis of clinical trials with zafirlukast, all studies showed some decrease in the rate of asthma exacerbations, with an average effect of 50% reduction (Barnes and Miller, 2000). When zafirlukast (Laitinen et al., 1997) or montelukast (Malmstrom et al., 1999) were compared with low-dose, inhaled glucocorticoid therapy, the improvement in lung function and decreased dependence on short-acting -adrenergic receptor agonist therapy was found to be greater in the glucocorticoid-treated subjects. There was little difference, however, between the steroid- and montelukast-treated subjects in the reduction in rate of asthma exacerbations. Clinical trials with antileukotriene drugs have revealed considerable intersubject heterogeneity in response to therapy, with patients falling into 'responder' and 'nonresponder' groups. For those who respond to antileukotriene therapy, the National Heart, Lung, and Blood Institute recognizes these drugs as alternatives to low-dose, inhaled steroids for control of mild chronic asthma.

More studies are required before the role of these drugs in moderate and more severe asthma can be adequately assessed. Some clinical trials have demonstrated an ability of leukotriene antagonists to allow a reduction in the dose of inhaled steroid needed to control asthma exacerbations (Lofdahl et al., 1999; Jarvis and Markham, 2000). If this is the case, it may be particularly relevant in children with more severe asthma. This class of drugs is not indicated for rapid bronchodilator therapy; thus, patients are instructed to have appropriate rescue medications available, i.e, short-acting -adrenergic receptor agonists. Montelukast and zafirlukast are effective with once- or twice-daily treatment, respectively. In contrast, zileuton is recommended to be taken four times a day, and liver enzymes should be monitored in patients beginning zileuton therapy to guard against the potential of liver toxicity. These pharmacokinetic and safety issues have dampened enthusiasm for the use of zileuton in asthma therapy, leaving montelukast and zafirlukast as the antileukotriene drugs most commonly prescribed today.

Cromolyn Sodium and Nedocromil Sodium

History and Chemistry

Cromolyn was synthesized in 1965 as part of an attempt to improve on the bronchodilator activity of khellin, a chromone (benzopyrone) derived from the plant Ammi visnaga, which had been used by the ancient Egyptians for its spasmolytic properties (see Shapiro and Knig, 1985). Although devoid of the bronchodilating capability of the parent compound, cromolyn was found to inhibit antigen-induced bronchospasm as well as the release of histamine and other autacoids from sensitized rat mast cells. Cromolyn has been used in the United States for the treatment of asthma since 1973. The initial clinical results were disappointing, in retrospect largely due to a misplaced emphasis on the hope that cromolyn would reduce or eliminate the need for systemic glucocorticoids in the treatment of patients with relatively severe asthma. However, its therapeutic role has been reevaluated in recent years, and cromolyn has emerged as one of the first-line agents in the treatment of mild to moderate asthma. Nedocromil, a compound with similar chemical and biological properties, became available in 1992 (Wasserman, 1993; Brogden and Sorkin, 1993). Cromolyn sodium (disodium cromoglycate) and nedocromil sodium have the following structures:

Mechanism of Action

Cromolyn and nedocromil have been reported to have a variety of activities that may relate to their therapeutic effect in asthma. These include: inhibiting mediator release from bronchial mast cells (Pearce et al., 1989); an ability to reverse increased functional activation in leukocytes obtained from the blood of asthmatic patients (Murphy and Kelly, 1987); suppression of the activating effects of chemotactic peptides on human neutrophils, eosinophils, and monocytes (Kay et al., 1987; Moqbel et al., 1988); inhibition of parasympathetic and cough reflexes (Hargreaves and Benson, 1995; Fuller et al., 1987); and inhibition of leukocyte trafficking in asthmatic airways (Hoshino and Nakamura, 1997). Suffice it to say that the mechanism of action of cromolyn and nedocromil in asthma is not known.

Pharmacokinetics

For asthma, cromolyn is given by inhalation, using either solutions (delivered by aerosol spray or nebulizer) or, in some countries but not in the United States, powdered drug (mixed with lactose and delivered by a special turbo-inhaler). The pharmacological effects are from the topical deposition of the drug in the lung. Only about 1% of an oral dose of cromolyn is absorbed. Once absorbed, the drug is excreted unchanged in the urine and bile in about equal proportions. Peak concentrations in plasma occur within 15 minutes of inhalation, and excretion begins after some delay, such that the biological half-life ranges from 45 to 100 minutes. The terminal half-time of elimination following intravenous administration is about 20 minutes. The pharmacokinetic properties of cromolyn have been reviewed by Shapiro and Knig (1985) and by Murphy and Kelly (1987).

Toxicity

Cromolyn and nedocromil generally are well tolerated by patients. Adverse reactions are infrequent and minor; these include bronchospasm, cough or wheezing, laryngeal edema, joint swelling and pain, angioedema, headache, rash, and nausea. Such reactions have been reported at a frequency of less than 1 in 10,000 patients (see Murphy and Kelly, 1987). Very rare instances of anaphylaxis also have been documented. Nedocromil and cromolyn can cause a bad taste.

Use in Asthma

The main use of cromolyn (INTAL) and nedocromil (TILADE) is in the treatment of mild to moderate bronchial asthma to prevent asthmatic attacks. These agents are ineffective in treating ongoing bronchoconstriction. When inhaled several times daily, cromolyn will inhibit both the immediate and the late asthmatic responses to antigenic challenge or to exercise. With regular use for more than 2 to 3 months, there is evidence of reduced bronchial hyperreactivity, as measured by response to challenge with histamine or methacholine (see Murphy and Kelly, 1987; Hoag and McFadden, 1991). Nedocromil generally is more effective than cromolyn in animal models and human studies (Brogden and Sorkin, 1993). Nedocromil is approved for use in asthmatic patients 12 years old and older; cromolyn is approved for all ages.

Compared to inhaled glucocorticoids, cromolyn and nedocromil are less potent in controlling asthma. Cromolyn, 2 mg inhaled four times daily, was not as effective as beclomethasone, 200 g twice daily (Svendsen et al., 1987), and was less effective than nedocromil, 4 mg four times daily (Brogden and Sorkin, 1993). In terms of lung function measurements, 4 mg of nedocromil inhaled twice daily was approximately as effective as 200 g of beclomethasone inhaled twice daily, but nedocromil was not as effective in controlling symptoms, reducing bronchodilator use, or improving bronchial hyperreactivity (Svendsen et al., 1989). In a second study, 4 mg of nedocromil four times daily was as effective as 100 g of beclomethasone four times daily (Bel et al., 1990). In a thorough review, Brogden and Sorkin (1993) concluded that nedocromil is useful in patients with mild to moderate asthma as added therapy, as an alternative to regularly administered oral and inhaled -adrenergic agonists and oral methylxanthines, and possibly as an alternative to low-dose, inhaled glucocorticoids.

The use of cromolyn or nedocromil in addition to inhaled glucocorticoids in moderately severe asthma has been investigated. Several studies have shown that the addition of cromolyn to inhaled glucocorticoid therapy yields no additional benefit (Toogood et al., 1981). Nedocromil may allow a reduction of steroids in patients receiving high doses of inhaled steroids (Brogden and Sorkin, 1993). These studies were short term; whether or not long-term reduction in steroid doses is possible remains to be determined. In one study, the addition of nedocromil, 4 mg four times daily, to high-dose, inhaled glucocorticoid treatment resulted in modest improvements when administered for 8 weeks to patients with moderately severe asthma (Svendsen and Jorgensen, 1991). Because of its limited potency, the use of cromolyn is decreasing.

In patients with systemic mastocytosis who have gastrointestinal symptoms due to an excessive number of mast cells in the gastrointestinal mucosa, an oral preparation of cromolyn (GASTROCROM) is effective in reducing symptoms (Horan et al., 1990). The benefits are derived from the topical application rather than systemic absorption; cromolyn is poorly absorbed, and only the gastrointestinal symptoms are improved in the treated patients.

Theophylline

Theophylline, a methylxanthine, is among the least expensive drugs used to treat asthma, and consequently it remains a commonly used drug for this indication in many countries. In industrialized countries, the advent of inhaled glucocorticoids, -adrenergic receptor agonists, and leukotriene-modifying drugs have significantly diminished the extent to which theophylline is used. In the United States, theophylline for the most part has been relegated to a third-line treatment, used in patients whose asthma is otherwise difficult to control.

Source and History

Theophylline, caffeine, and theobromine are three closely related alkaloids that occur in plants widely distributed geographically. At least half the population of the world consumes tea (containing caffeine and small amounts of theophylline and theobromine), prepared from the leaves of Thea sinensis, a bush native to southern China and now extensively cultivated in other countries. Cocoa and chocolate, from the seeds of Theobroma cacao, contain theobromine and some caffeine. Coffee, the most important source of caffeine in the American diet, is extracted from the fruit of Coffea arabica and related species. Cola-flavored drinks usually contain considerable amounts of caffeine, in part because of their content of extracts of the nuts of Cola acuminata (the guru nuts chewed by the natives of the Sudan) and in part because of the addition of caffeine as such in their production (see Graham, 1978).

The basis for the popularity of all the caffeine-containing beverages is the ancient belief that they have stimulant and antisoporific actions that elevate mood, decrease fatigue, and increase capacity for work. For example, legend credits the discovery of coffee to a prior of an Arabian convent. Shepherds reported that goats that had eaten the berries of the coffee plant gamboled and frisked about all through the night instead of sleeping. The prior, mindful of the long nights of prayer that he had to endure, instructed the shepherds to pick the berries so that he might make a beverage from them.

Classical pharmacological studies, principally of caffeine, during the first half of this century confirmed these experiences and revealed that methylxanthines possess other important pharmacological properties as well. These properties were exploited for a number of years in a variety of therapeutic applications, in many of which caffeine has now been replaced by more effective agents. However, in recent years there has been a resurgence of interest in the natural methylxanthines and their synthetic derivatives, principally as a result of increased knowledge of their cellular basis of action.

Chemistry

Theophylline, caffeine, and theobromine are methylated xanthines. Xanthine itself is a dioxypurine and is structurally related to uric acid. Caffeine is 1,3,7-trimethylxanthine; theophylline, 1,3-dimethylxanthine; and theobromine, 3,7-dimethylxanthine. The structural formulas of xanthine and the three naturally occurring xanthine derivatives are as follows:

The solubility of the methylxanthines is low and is much enhanced by the formation of complexes (usually 1:1) with a wide variety of compounds. The most notable of these complexes is that between theophylline and ethylenediamine (to form aminophylline). The formation of complex double salts (e.g., caffeine and sodium benzoate) or true salts [e.g., choline theophyllinate (oxtriphylline)] also enhances aqueous solubility. These salts or complexes dissociate to yield the parent methylxanthines when dissolved in aqueous solution and should not be confused with covalently modified derivatives such as dyphylline [1,3-dimethyl-7-(2, 3-dihydroxypropyl)xanthine].

A large number of derivatives of the methylxanthines have been prepared and examined for their ability to inhibit cyclic nucleotide phosphodiesterases (Beavo and Reifsnyder, 1990) and to antagonize receptor-mediated actions of adenosine (Daly, 1982; Linden, 1991), the two best-characterized cellular actions of the methylxanthines. In general, both activities are reduced in derivatives that lack substituents at position 1 or contain substituents at position 7, as compared with the corresponding 1,3-dialkylxanthine. For example, the order of potency for the naturally occurring methylxanthines is theophylline > caffeine > theobromine. Congeners of theophylline with larger nonpolar substituents at positions 1 and 3 usually display enhancement of both activities (Choi et al., 1988). Addition of aromatic, cyclohexyl, or cyclopentyl groups at position 8 usually markedly increases affinity for adenosine receptors but reduces inhibition of cyclic nucleotide phosphodiesterases (Martinson et al., 1987). Although neither caffeine nor theophylline discriminates among the subtypes of adenosine receptors (see below), certain 8-substituted derivatives of 1, 3-dipropylxanthine display marked selectivity for A₁ receptors, while some analogs of caffeine display appreciable selectivity for A₂ receptors. In addition, certain tricyclic nonxanthine compounds are potent antagonists at adenosine receptors (Linden, 1991).

Mechanism of Action

Theophylline inhibits cyclic nucleotide phosphodiesterase enzymes (PDEs). PDEs catalyze the breakdown of cyclic AMP and cyclic GMP to 5^'-AMP and 5^'-GMP, respectively. Inhibition of PDEs will lead to an accumulation of cyclic AMP and cyclic GMP, thereby increasing the signal transduction through these pathways. It is now recognized that cyclic nucleotide PDEs are members of a superfamily of at least eleven families of genetically distinct enzymes (Soderling and Beavo, 2000). Theophylline and related methylxanthines are relatively nonselective in the PDE subtypes they inhibit.

The potency and efficacy of PDE inhibitors in affecting cell function is dependent on the basal level of cyclic nucleotide production. Cyclic AMP and cyclic GMP production in cells is regulated by endogenous receptor-ligand interactions leading to activation of adenylyl cyclase and guanylyl cyclase, respectively (see Chapter 2: Pharmacodynamics: Mechanisms of Drug Action and the Relationship Between Drug Concentration and Effect). Diffusable mediators such as nitric oxide and related molecules also may lead to increases in cyclic GMP by direct interaction with guanylyl cyclase. Inhibitors of PDEs therefore can be thought of as drugs that enhance the activity of endogenous autacoids, hormones, and neurotransmitters that signal via cyclic nucleotide messengers. This may explain why the in vivo potency often is increased relative to that observed in vitro.

Theophylline also is a competitive antagonist at adenosine receptors (Fredholm and Persson, 1982). Adenosine can act as an autacoid and transmitter with myriad biological actions. Of particular relevance to asthma are the observations that adenosine can cause bronchoconstriction in asthmatics and potentiate immunologically induced mediator release from human lung mast cells (Cushley et al., 1984; Peachell et al., 1988). Inhibition of the actions of adenosine must therefore also be considered when attempting to explain the mechanism of action of theophylline (Feoktistov et al., 1998).

Pulmonary System

Theophylline effectively relaxes airway smooth muscle and thus can be classified as a bronchodilator. This likely contributes to the acute therapeutic efficacy in asthma. Evidence supports a role for both adenosine receptor antagonism and PDE inhibition in the bronchodilating effect of theophylline. Adenosine does not directly contract human isolated bronchial smooth muscle, but when inhaled acts as a potent bronchoconstrictor in asthmatic subjects (Cushley et al., 1984). Therefore, inhibition of this function of adenosine may contribute to theophylline-induced bronchodilation in some asthmatic subjects. Inhibition of PDE isozymes type III and IV effectively relaxes human isolated bronchial smooth muscle (Torphy et al., 1993). It thus seems likely that inhibition of PDEs also contributes to the bronchodilating effect of theophylline. Also seeming to support a role for PDE inhibition in the mechanism of bronchodilator action of theophylline have been studies with a related methylxanthine drug, enprofylline (3-propylxanthine), which has been extensively studied in Europe for use in the treatment of asthma. Enprofylline is more potent than theophylline as a bronchodilator, but is much less potent than theophylline as an antagonist at most types of adenosine receptors (Pauwels et al., 1985). The latter point, however, needs to be interpreted cautiously. Activation of the A_2B subtype of adenosine receptor causes several proinflammatory effects, and both theophylline and enprofylline are potent competitive antagonists of A_2B adenosine receptors (Feoktistov et al., 1998).

Theophylline also inhibits synthesis and secretion of inflammatory mediators from numerous cell types including mast cells and basophils (Page, 1999). This effect of theophylline likely is due to PDE inhibition and can be mimicked in large part with drugs that selectively inhibit the PDE IV isozymes (Torphy and Undem, 1991). It has been argued that, at therapeutic concentrations, the antiinflammatory effect of theophylline may be more relevant to the drug's therapeutic actions than is direct bronchodilation, but this remains unproven (Page, 1999).

A discussion of pharmacological properties of theophylline and other methylxanthines involving other organ systems can be found in previous editions of this book.

Absorption, Fate, and Excretion

The methylxanthines are absorbed readily after oral, rectal, or parenteral administration. Absorption from rectal suppositories is slow and unreliable. Theophylline administered in liquids or uncoated tablets is rapidly and completely absorbed. Absorption also is complete from some, but not all, sustained-release formulations (see Hendeles and Weinberger, 1982). In the absence of food, solutions or uncoated tablets of theophylline produce maximal concentrations in plasma within 2 hours; caffeine is more rapidly absorbed, and maximal plasma concentrations are achieved within 1 hour. Numerous sustained-release preparations of theophylline are available, designed for dosing intervals of 8, 12, or 24 hours. These preparations cause marked interpatient variability with regard to the rate and extent of absorption and especially the effect of food and time of administration on these parameters (see Symposium, 1986a). Thus, it has become necessary to calibrate a given preparation in a given patient and to avoid substituting one apparently similar product for another.

Food ordinarily slows the rate of absorption of theophylline but does not limit its extent. With sustained-release preparations, food may decrease the bioavailability of theophylline within some products but may increase it with others. High-carbohydrate, low-protein diets decrease theophylline elimination, whereas low-carbohydrate, high-protein diets and consumption of 'char-broiled' meat increase elimination. Recumbency or sleep also may reduce the rate or extent of absorption to an important degree. These factors make it difficult to maintain relatively constant concentrations of theophylline in plasma throughout the day. Fortunately, it also has become apparent that the concentrations required to alleviate asthmatic symptoms do not remain constant, and the emphasis has shifted toward designing dosing regimens that ensure peak concentrations in the early morning hours, when symptoms frequently worsen (see Symposium, 1988a).

Methylxanthines are distributed into all body compartments; they cross the placenta and pass into breast milk. The apparent volumes of distribution for caffeine and theophylline are similar and usually are between 0.4 and 0.6 liter/kg. These values are considerably higher in premature infants. Theophylline is bound to plasma proteins to a greater extent than is caffeine, and the fraction bound declines as the concentration of methylxanthine increases. At therapeutic concentrations, the protein binding of theophylline averages about 60%, but it is decreased to about 40% in newborn infants and in adults with hepatic cirrhosis (see Hendeles and Weinberger, 1982).

Methylxanthines are eliminated primarily by metabolism in the liver. Less than 15% and 5% of administered theophylline and caffeine, respectively, are recovered in the urine unchanged. Caffeine has a half-life in plasma of 3 to 7 hours; this increases by about twofold in women during the later stages of pregnancy or with long-term use of oral contraceptive steroids. In premature infants, the rate of elimination of both methylxanthines is quite slow. The average half-life for caffeine is more than 50 hours, while the mean values for theophylline obtained in various studies range between 20 and 36 hours. However, the latter values include the extensive conversion of theophylline to caffeine in these infants (see Symposium, 1981; Roberts, 1984).

There is marked interindividual variation in the rate of elimination of theophylline, due to both genetic and environmental factors; fourfold differences are not uncommon (see Lesko, in Symposium, 1986a). The half-life averages about 3.5 hours in young children, while values of 8 or 9 hours are more typical of adults. In most patients the drug obeys first-order elimination kinetics within the therapeutic range. However, at higher concentrations zero-order kinetics becomes evident because of saturation of metabolic enzymes. This prolongs the decline of theophylline concentrations to nontoxic levels.

The disposition of methylxanthines also is influenced by the presence of other agents or of disease (see Jonkman, in Symposium, 1986a). For example, the clearance of theophylline is increased nearly twofold during the administration of phenytoin or barbiturates; cigarette smoking or the administration of rifampin or oral contraceptives produces smaller but appreciable increases in theophylline clearance. By contrast, the administration of cimetidine or certain macrolide antibiotics (e.g., erythromycin) reduces the clearance of theophylline. Although there have been reports to the contrary, neither glucocorticoids nor immunization with purified subvirion influenza vaccine appear to have a significant effect, although acute viral infections and interferon can reduce theophylline clearance. The half-life of theophylline can be quite prolonged in patients with hepatic cirrhosis, congestive heart failure, or acute pulmonary congestion, and values of more than 60 hours have been observed.

Although scarcely detectable in adults, the conversion of theophylline to caffeine is an important metabolic pathway in preterm infants (see Symposium, 1981; Roberts, 1984). Caffeine accumulates in plasma to a concentration approximately 25% that of theophylline and is one of the urinary products. About 50% of the theophylline administered to such infants appears in the urine unchanged; the excretion of 1,3-dimethyluric acid, 1-methyluric acid, and caffeine accounts for nearly all of the remainder.

Toxicology

Fatal intoxications with theophylline have been much more frequent than with caffeine. Rapid intravenous administration of therapeutic doses of aminophylline (500 mg) sometimes results in sudden death that is probably due to cardiac arrhythmias, and the drug should be injected slowly over 20 to 40 minutes to avoid severe toxic symptoms. These include headache, palpitation, dizziness, nausea, hypotension, and precordial pain. Additional symptoms of toxicity are tachycardia, severe restlessness, agitation, and emesis; these effects are associated with plasma concentrations of more than 20 g/ml. Focal and generalized seizures also can occur, sometimes without prior signs of toxicity.

Most toxicity is the result of repeated administration of theophylline by either oral or parenteral routes. Although convulsions and death have occurred at plasma concentrations as low as 25 g/ml, seizures are relatively rare at concentrations below 40 g/ml (see Goldberg et al., in Symposium, 1986a). Patients with long-term theophylline intoxication appear to be much more prone to seizures than those who experience short-term overdoses. Such a dependence upon the history of exposure to theophylline may contribute to the difficulty in establishing a relationship between the severity of toxic symptoms and the concentration of the drug in plasma (Aitken and Martin, 1987; Bertino and Walker, 1987), and greater caution is advised in treating intoxicated patients who have been ingesting theophylline regularly (see Paloucek and Rodvold, 1988). Treatment may include prophylactic administration of diazepam, perhaps together with phenytoin or phenobarbital; phenytoin also may be a useful alternative to lidocaine in the treatment of serious ventricular arrhythmias. Once seizures appear, they may be refractory to anticonvulsant therapy, and it may be necessary to resort to general anesthesia and other measures used in the treatment of status epilepticus (see Goldberg et al., in Symposium, 1986a).

The widespread use of sustained-release preparations of theophylline has renewed emphasis on measures to prevent continued absorption, particularly the use of oral activated charcoal and of sorbitol as a cathartic (Goldberg et al., 1987); multiple doses of oral charcoal also will accelerate clearance of theophylline. However, when plasma concentrations exceed 100 g/ml, invasive measures usually are required, especially hemoperfusion through charcoal cartridges (see Paloucek and Rodvold, 1988).

Behavioral Toxicity

As noted above, moderate doses of caffeine can provoke intense feelings of anxiety, fear, or panic in some individuals. Even subjects with a history of light-to-moderate use of caffeine experience tension, anxiety, and dysphoria after ingesting 400 mg or more of the drug (see Griffiths and Woodson, in Symposium, 1988b). In infants who have received treatment for apnea of prematurity, theophylline may produce persistent changes in sleep-wake patterns (Thoman et al., 1985), but long-term effects on behavior or cognitive development have yet to be identified (see Aranda et al., in Symposium, 1986a). There has been mounting concern that the treatment of asthmatic children with theophylline might produce depression, hyperactivity, or other behavioral toxicity. However, a study of academic performance of asthmatic children treated or not with theophylline showed equal academic performance in asthmatic and nonasthmatic children (Lindgren et al., 1992). Even though it is difficult to factor out specific effects of theophylline from those caused by the illness or by other features of the treatment regimen, many investigators believe that most children will benefit from the use of alternative means of controlling their symptoms.

Use in Asthma

Theophylline has proven efficacy as a bronchodilator in asthma and formerly was considered first-line therapy. It now has been relegated to a far less prominent role, primarily because of the modest benefits it affords, its narrow therapeutic window, and the required monitoring of drug levels (Stoloff, 1994; Nasser and Rees, 1993). Nocturnal asthma can be improved with slow-release theophylline preparations (Self et al., 1992), but other interventions such as inhaled glucocorticoids or salmeterol are probably more effective (Meltzer et al., 1992). Some pediatricians favor theophylline over inhaled glucocorticoids because of the theoretic potential for growth suppression. However, in most circumstances, mild or moderate asthma that can be controlled with theophylline likely can be controlled with cromolyn or nedocromil, thus avoiding potential glucocorticoid side effects. There are few data to support the routine use of theophylline in the treatment of acute, severe bronchospasm (Fanta et al., 1986; Rossing et al., 1980). Some chronic asthmatic patients benefit from control of nocturnal symptoms with slow-release theophylline preparations.

Therapy is usually initiated by the administration of 12 to 16 mg/kg per day of theophylline (calculated as the free base) up to a maximum of 400 mg per day for at least 3 days (Weinberger, 1987). Children <1 year old require considerably less; the dose in mg/kg per day may be calculated as 0.2 X (age in weeks) + 5.0. Starting with these low doses minimizes the early side effects of nausea, vomiting, nervousness, and insomnia, which often subside with continued therapy, and virtually eliminates the possibility of exceeding concentrations of 20 g/ml in the plasma of patients over the age of 1 year who do not have compromised hepatic or cardiac function. Thereafter, the dosage is increased in two successive stages to between 16 to 20 and, subsequently, 18 to 22 mg/kg per day (up to a maximum of 800 mg per day), depending on the age and clinical response of the patient, allowing at least 3 days between adjustments. The plasma concentration of theophylline is determined before a further adjustment in dosage is made. Although extended-release preparations of theophylline usually allow twice-daily dosing, variations in the rate and extent of absorption of such preparations require individualized calibration of dosing regimens for each patient and preparation.

Apnea of Preterm Infants

Episodes of prolonged apnea, lasting more than 15 seconds and accompanied by bradycardia, are not infrequent occurrences in premature infants. They pose the threat of recurrent hypoxemia and neurologic damage. Although they often are associated with serious systemic illness, no specific cause is found in many instances. Beginning with the work of Kuzemko and Paala (1973), methylxanthines have undergone numerous clinical trials for the treatment of apnea of undetermined origin. The oral or intravenous administration of methylxanthines can eliminate episodes of apnea that last more than 20 seconds, and markedly reduces the number of episodes of shorter duration (see Symposium, 1981; Roberts, 1984; Aranda et al., in Symposium, 1986a). Satisfactory responses may occur with plasma concentrations of theophylline of 4 to 8 g/ml, but concentrations of nearly 13 g/ml are more frequently required (Muttitt et al., 1988). Still higher concentrations may produce a more regular pattern of respiration without further reduction in the frequency of episodes of apnea and bradycardia, and these usually are associated with a definite tachycardia. Therapeutic concentrations are achieved with loading doses of about 5 mg/kg of theophylline (calculated as the free base) and can be maintained with 2 mg/kg given every 12 or 24 hours (see Roberts, 1984). Although caffeine initially was used less frequently than theophylline, some physicians now prefer it because the dosing regimens are simpler and more predictable. Moreover, the administration of theophylline leads to the accumulation of substantial amounts of caffeine in these infants (see above). Somewhat higher concentrations are required, but the available data indicate that caffeine is equally effective. The recommended loading dose is 10 mg/kg of caffeine, with maintenance doses of 2.5 mg/kg per day (see Roberts, 1984).

Although effects on the growth or development of infants following treatment with methylxanthines have not been detected, the evidence is far from definitive. Therapy is thus continued for as brief a period as possible, usually only a few weeks.

Anticholinergic Agents

There is a long history of the use of anticholinergic agents in the treatment of asthma. These agents are discussed in detail in Chapter 7: Muscarinic Receptor Agonists and Antagonists. With the advent of inhaled -adrenergic agonists, use of anticholinergic agents declined. However, renewed interest in anticholinergic agents has paralleled both the more recent realization that parasympathetic pathways are important in bronchospasm in some asthmatics and the availability of ipratropium bromide (ATROVENT), a quaternary anticholinergic agent, which has better pharmacological properties than prior drugs. A particularly good response to ipratropium may be seen in the subgroup of asthmatic patients who experience psychogenic exacerbations (Neild and Cameron, 1985; Rebuck and Marcus, 1979).

The bronchodilation produced by ipratropium in asthmatic subjects develops more slowly and is usually less intense than that produced by adrenergic agonists. Some asthmatic patients may experience a useful response lasting up to 6 hours. The variability in the response of asthmatic subjects to ipratropium presumably reflects differences in the strength of parasympathetic tone and in the degree to which reflex activation of cholinergic pathways participates in generating symptoms in individual patients. Hence, the utility of ipratropium must be assessed on an individual basis by a therapeutic trial. The pharmacological properties and therapeutic uses of ipratropium have been reviewed by Gross (1988) (see also Symposium, 1986b).

Combined treatment with ipratropium and -adrenergic agonists results in slightly greater and more prolonged bronchodilation than with either agent alone in baseline asthma (Bryant and Rogers, 1992). In acute bronchoconstriction, the combination of a -adrenergic agonist and ipratropium is more effective than either agent alone and more effective than simply giving more -adrenergic agonist (Bryant, 1985; Bryant and Rogers, 1992). A large multicenter study confirmed these findings and showed that the asthmatic subjects with the worst initial lung function benefited most from this combination of agents (Rebuck et al., 1987). Thus, the combination of a selective -adrenergic agonist and ipratropium should be considered in acute treatment of severe asthma exacerbations. Ipratropium is available in metered-dose inhalers and as a nebulizer solution. A metered-dose inhaler containing a mixture of ipratropium and albuterol (COMBIVENT) also is available in the United States. In Europe, metered-dose inhalers containing a mixture of ipratropium and fenoterol are available (DUOVENT BERODUAL

Drug Therapy of Asthma in Special Circumstances

Pediatric Asthma

The pathophysiology of asthma in children appears similar to that in adults (Hill et al., 1992). International guidelines (Rachelefsky and Warner, 1993) and thorough reviews (Van Bever and Stevens, 1992; Moffitt et al., 1994) dealing with the treatment of asthma in children have been published. In general, treatment strategies for children do not differ substantively from those for adults, except that more emphasis is placed on a trial of antileukotriene therapy, nedocromil (age 12 and greater), or cromolyn (Van Bever and Stevens, 1992) to avoid possible complications from glucocorticoids. Although inhaled glucocorticoids may impair growth velocity, a large meta-analysis found that final adult height appears to be unaffected by use of these agents (Allen et al., 1994). Indeed, good control of asthma probably is important in allowing good growth, since poorly controlled asthma itself inhibits growth. Use of oral prednisone in asthma is associated with slightly diminished growth, in terms of attaining final predicted height (Allen et al., 1994). Metered dose inhalers require substantial dexterity and cannot be used by children younger than 5 years of age. This limitation dictates use of either nebulized solutions or parenteral therapy in this patient population.

Emergency-Room Patients

-Adrenergic agonists are the only drugs that have been proven to be effective in the immediate treatment of severe asthma exacerbations. Several studies (Fanta et al., 1986; Fanta et al., 1982; Rossing et al., 1980) compared the use of -adrenergic agonists and aminophylline for emergency treatment of asthma. Patients responded better to inhaled -adrenergic agonists alone than to aminophylline alone. Addition of aminophylline infusions to inhaled -adrenergic agonists did not improve patients' lung function or symptoms. Another study found that emergency-department patients treated for wheezing with aminophylline infusions did not differ from control subjects in terms of spirometry, symptoms, or global physician assessment, but the treated patients were less likely to be admitted to the hospital than those receiving placebo (Wrenn et al., 1991). Before theophylline therapy can be considered standard emergency treatment, further studies confirming lower hospitalization rates will be required (McFadden, 1991). When glucocorticoids were administered systemically during emergency-room visits for asthma, the rate of hospitalization both during the visit and after discharge were reduced (Chapman et al., 1991). Glucocorticoids take a minimum of 6 to 12 hours to be effective. Oral dosing is as rapid in onset as parenteral administration. For most adult and many pediatric asthmatic patients whose exacerbations require emergency-room visits, a short course of glucocorticoids, for example, 40 to 60 mg/day of prednisone orally (1 mg/kg per day for 5 days), is indicated.

Hospitalized Patients

In addition to regular use of inhaled -adrenergic agonists for bronchodilator therapy, hospitalized asthmatic patients should be treated with substantial doses of systemic glucocorticoids (McFadden, 1993). Most physicians recommend 30 to 120 mg of methylprednisolone intravenously every 6 hours. If the patient is able to take medications orally, prednisone and other glucocorticoid preparations are well absorbed and are as effective as intravenous preparations (Ratto et al., 1988; McFadden, 1993). The optimal dose and frequency of administration of glucocorticoids have not been well established. A synopsis of 20 different studies has been published (McFadden, 1993). Reasonable investigations have shown that 30 mg of methylprednisolone every 6 hours is probably as effective as higher doses. While the beneficial effects of glucocorticoids may reach a plateau at 30 to 45 mg of methylprednisolone intravenously every 6 hours (equivalent to 40 to 60 mg prednisone every 6 hours), the adverse effects continue to escalate at higher dose levels. Most authors would agree with erring toward the higher doses for treatment of seriously ill asthmatic patients, but doses higher than 120 mg of methylprednisolone every 6 hours are not recommended. Prophylaxis for gastric and duodenal ulcerations using H₂-histamine receptor antagonists is recommended when using high-dose systemic glucocorticoids for asthma exacerbations.

Asthma exacerbations requiring hospitalization are handled essentially no differently in children than in adults; treatment with systemic glucocorticoids is required. The dose recommended is 1 to 2 mg/kg per day, divided into four doses. The once-common practice of instituting continuous isoproterenol infusions in children with asthma exacerbations has not been proven to be effective. Maguire et al. (1986) showed that such infusions in children are associated with detectable levels of cardiac-specific creatinine kinase in serum. These infusions also can be associated with tachyarrythmias. At present there is little to recommend such infusions.

Asthma during Pregnancy and Lactation

Poorly controlled asthma can adversely affect the outcome of pregnancy and even cause maternal or fetal death. Asthma affects up to 5% of pregnant women. In the past, asthma frequently caused significant difficulty during pregnancies. With the recognition by patient and physician of the need for excellent preventive control of asthma during pregnancy, complications of pregnancy by asthma should be rare. A consensus conference published its recommendations concerning the treatment of asthma during pregnancy (NIH, 1993). In general, essentially the same guidelines should be used for treating pregnant asthmatic patients as for treating nonpregnant asthmatic patients. Although most drugs used to treat asthma are FDA category C (not proven to be safe for use during pregnancy), some are in category B (cromolyn, nedocromil, terbutaline, leukotriene modifiers), and there is a large clinical experience with inhaled -adrenergic agonists and inhaled glucocorticoids in pregnant women. In general, the known adverse effects of poorly controlled asthma are thought to outweigh the theoretical possibility of drug-induced fetal abnormalities.

Except for a few studies in animals in which high systemic drug doses were used, there is no evidence that -adrenergic agonists produce fetal abnormalities. Not all animal studies revealed adverse effects, even at high doses, and clinical experience does not suggest any fetal developmental abnormalities associated with use of -adrenergic agonists. During acute bronchospasm, inhaled -adrenergic agonists are indicated to improve maternal respiratory function and prevent fetal distress. Maternal and fetal adverse effects are rare when inhaled -adrenergic agonists are used at the recommended doses. Systemic -adrenergic agonists can cause fetal tachycardia and neonatal tachycardia, hypoglycemia, and tremor. There has been concern that nonselective agonists, such as epinephrine, may cause uterine vasoconstriction due to an -adrenergic effect. In practice, the use of epinephrine for severe asthma exacerbation appears unlikely to cause significant fetal or maternal injury. However, inhaled -adrenergic agonists appear to be more effective and do not carry the risk of uterine vasoconstriction. There is no contraindication to the use of inhaled -adrenergic agonists during lactation.

Antiinflammatory treatment to prevent asthma exacerbations is indicated whenever pregnant asthmatic patients require daily inhaled -adrenergic agonists for control of symptoms. Inhaled cromolyn is considered particularly safe in pregnancy, because it is extremely poorly absorbed from the gastrointestinal tract. There is little experience with the use of nedocromil in pregnancy. Inhaled glucocorticoids also are considered relatively safe in pregnancy. The largest and longest experience with inhaled glucocorticoids in pregnancy is with beclomethasone, and some authors favor its use for those reasons (NIH, 1993). Although high doses of systemic glucocorticoids given to pregnant rats consistently have been associated with palate defects in the pups, the doses used have far exceeded those typically prescribed for human asthma. Chronic maternal administration of systemic corticosteroids has been associated with a mild decrease in birth weight in human beings. Neither systemic nor inhaled corticosteroids are a contraindication to breast feeding (NIH, 1993).

Despite a long history of successful use of theophylline preparations in pregnancy, this drug is now infrequently used, in part because of its limited effectiveness and narrow therapeutic window. Theophylline elimination is affected by pregnancy, but to a variable degree. The increased glomerular filtration rate associated with pregnancy increases the rate of elimination of theophylline; conversely, metabolic elimination of theophylline by the liver is decreased. In the last trimester of pregnancy, the overall effect is an approximately 30% diminished rate of elimination of theophylline. Because of marked interindividual variability and the changes associated with progression of pregnancy, frequent drug level monitoring is required. When maternal levels exceed 20 g/ml, fetal tachycardia can occur. Neonatal levels greater than 10 g/ml are associated with jitteriness, vomiting, and tachycardia and are most often seen when maternal plasma drug levels are greater than 12 g/ml at delivery. In practice, theophylline should be limited to third-line therapy after inhaled antiinflammatory agents and -adrenergic agonists, because of the above difficulties in its administration and the potential for serious adverse effects. Theophylline is not contraindicated during lactation.

Use of Asthma Drugs in Rhinitis

Seasonal allergic rhinitishay feveris caused by deposition of allergens on the nasal mucosa, resulting in an immediate hypersensitivity reaction. This reaction usually is not accompanied by asthma, because the allergens usually are contained in particles too large to be inhaled into the lower airways (e.g., pollens). Treatment for allergic rhinitis is similar to that for asthma. Topical glucocorticoids (beclomethasone, mometasone, budesonide, flunisolide, fluticasone, triamcinolone acetonide) or cromolyn can be highly effective with minimal side effects, particularly if treatment is instituted immediately prior to the allergy season. Topical glucocorticoids can be administered twice daily (beclomethasone, flunisolide) or even once daily (budesonide, mometasone, fluticasone, triamcinolone). Cromolyn usually requires dosing three to six times daily for full effects. Rare instances of local candidiasis have been reported with glucocorticoids and probably can be avoided by rinsing the mouth after use. Unlike in asthma, antihistamines (Chapter 25: Histamine, Bradykinin, and Their Antagonists) afford considerable, though incomplete, symptom relief in allergic rhinitis. Nasal decongestants rely on -adrenergic agonists (pseudoephedrine, phenylephrine) as vasoconstrictors and are discussed in Chapter 10: Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists.

Perennial allergic rhinitis, caused by exposure to allergens present year-round, such as dust mites or animal dander, can be treated similarly. However, since this situation requires continuous exposure to medicines such as topical glucocorticoids, alternatives such as modifying the patient's environment and using immunotherapy (allergen desensitization) should be considered.

Use of Asthma Drugs in Chronic Obstructive Pulmonary Disease

Emphysema can be prevented or its progression slowed by the patient's ceasing to smoke (Ferguson and Cherniack, 1993). Pharmacological interventions can help patients to stop smoking. Nicotine gum and transdermal patches are moderately useful when combined with other interventions such as support groups and physician encouragement. Clonidine may be helpful in reducing the craving for cigarettes. Treatment of nicotine addiction is discussed in Chapter 24: Drug Addiction and Drug Abuse.

The pharmacological treatment of established emphysema resembles that of asthma largely because the inflammatory/bronchospastic component of a patient's disease is the aspect amenable to therapy (Ferguson and Cherniack, 1993). For patients with emphysema who have a significant degree of active inflammation with bronchospasm and excessive mucus production, symptomatic use of inhaled ipratropium or a -adrenergic agonist may be helpful. Ipratropium usually produces about the same modest degree of bronchodilation in patients with chronic obstructive pulmonary disease (COPD) as do maximal doses of -adrenergic agonists. As in asthmatic patients, continuous use of bronchodilators is controversial, with some studies suggesting that it is associated with an unfavorable course of COPD (van Schayck et al., 1991). A subgroup of patients may respond favorably to short courses of oral glucocorticoids. It is not possible to predict whether or not a particular patient will respond to glucocorticoids without a treatment trial. Response to oral glucocorticoids may predict those patients who will respond to inhaled glucocorticoids. However, except for the treatment of acute bronchospastic episodes, glucocorticoids have given mixed results in the treatment of COPD (American Thoracic Society, 1987; Dompeling et al., 1993). In some patients, theophylline may be effective (Murciano et al., 1989); in others who have a profound response to -adrenergic agonists, theophylline fails to produce additional bronchodilation beyond that achieved by maximal doses of the inhaled drug.

In fact, there are many patients who have nearly pure emphysema, without a significant degree of reversible inflammation or bronchoconstriction. Nevertheless, these patients often receive prolonged courses of ipratropium, -adrenergic agonists, glucocorticoids, and/or theophyl-line, with little likelihood for benefit and all of the usual possibilities for adverse effects.

-Antiproteinase Deficiency

In a minority of patients, emphysema results from a genetic deficiency of the plasma proteinase inhibitor -antiproteinase (also called -antitrypsin) (Crystal, 1990). Lung tissue destruction is caused by the unopposed action of neutrophil elastase and other proteinases. Purified -antiproteinase (PROLASTIN) from human plasma has become available for intravenous replacement. Clinical efficacy studies have not been performed except to show that intravenous administration of -antiproteinase does lead to serum levels thought to be protective against development of emphysema in nonsmokers. The recommended dose is 60 mg/kg administered intravenously once weekly. This dosage regimen should maintain -antitrypsin concentrations above the threshold serum concentration of 80 mg/dl to provide adequate antielastase activity in the lung epithelial lining fluid. Transgenic sheep secreting human -antiproteinase in their milk have been created and may be a safer and less expensive source for -antiproteinase in the future. No trials have been conducted using -antiproteinase in cigarette-induced emphysema.

Recombinant DNAse (dornase alfa, PULMOZYME) is available as a nebulizer solution for treatment of cystic fibrosis. In cystic fibrosis, inspissated secretions containing large numbers of inflammatory cells lodge in the smaller airways, causing obstruction. A substantial portion of the viscosity of the purulent material is due to the DNA from the nuclei of lysed cells. Inhaled DNAse has been shown to aid in clearing these secretions and improving pulmonary function in patients with cystic fibrosis (Harris and Wilmott, 1994; Wilmott and Fiedler, 1994). Efficacy trials are currently underway to assess DNAse treatment in adult COPD exacerbations, where purulent bronchial secretions also contribute to airway obstruction.