Dosage for Maintenance Therapy of Chronic Asthma

The interpatient variability in clearance, combined with the narrow therapeutic index of theophylline, results in an overlap of therapeutic and potentially toxic doses, i.e., doses optimal for some patients may be excessive for patients with slower clearance. Furthermore, initiation of therapy with theophylline may be associated with mild, transient caffeine-like side effects such as nausea, headache, nervousness, and insomnia even at low serum concentrations (96). These symptoms can generally...

What Is the Role of Leukotriene Modifiers in the Treatment of Asthma

On the basis of their relative effectiveness in mediating asthma symptoms and maintaining lung function, their comparative efficacy with respect to other asthma treatment modalities, their excellent safety profile, and most important their ease of administration, each of the leukotriene modifiers has earned an important place in the treatment of asthma. But where do these medications fit in the complex treatment paradigms that physicians use in treating this disease In addition to their clear...

Frequency of Administration

When ICS were first introduced it was recommended they should be taken four times daily. Subsequently it was shown that similar efficacy could be achieved in most patients with a twice-daily regimen (77), although there may be a small benefit with a four-times-daily regimen in those with severe or unstable asthma (78). The twice-daily regimen has major advantages in terms of compliance, and as a result has become the preferred regimen. However, even with a twice-daily regime, less than half of...

Future Prospects of Asthma Pharmacotherapy

Although drug therapy is crucial in the management of patients with asthma, there is a huge variation in drug responses between individual patients. In asthmatics, this variation may be due to differences in disease severity, drug adherence, environmental exposures, or age, but genetic factors may account for 60 to 80 of the heterogeneity in treatment responsiveness. Pharmacogenetics is the study of the contribution of these genetic differences among individuals to the variability in the...

Dosage for Acute Bronchodilatation

When theophylline is used as an acute bronchodilator, the goal of obtaining a therapeutic serum concentration is best accomplished with an intravenous loading dose (118,313). Because of rapid distribution into body fluids, the serum concentration obtained from an initial loading dose is related primarily to the volume of distribution, the apparent space into which the drug diffuses. If a mean volume of distribution of about 0.5L kg is assumed (actual range is 0.3-0.7 L kg), each mg kg (ideal...

Noninvasive Ventilation

Marked increase in inspiratory and expiratory airflow obstruction leads to dynamic hyperinflation in severe AA (137) (Fig. 2). The cumulative cost of this is respiratory muscle fatigue that, along with the associated increase in dead space, may lead to hypercarbic respiratory failure. Noninvasive positive pressure ventilation (NIPPV) has been extensively reported to be beneficial in other forms of hypercapnic respiratory failure (138-142). While only a minority of patients with AA requires...

Cromolyn for Allergic Rhinitis

In recent years, the one airway hypothesis linking disease and therapy in the lung and nose simultaneously suggests a need to briefly review the effect of the chromones on nasal allergy. Intranasal cromolyn is available over the counter as an aqueous preparation topical spray. Several studies have reported that intranasal cromolyn is superior to placebo in the treatment of seasonal allergic rhinitis (SAR) (5). In particular, a decrease in mouth breathing, nasal congestion, rhinorrhea, postnasal...

Biologic Effects of Leukotrienes Rationale for a Role in Asthma

Since elucidating the structure and biosynthetic pathway of leukotrienes, researchers have further demonstrated their potency in smooth muscle constriction in both human and animal models, in vitro and in vivo, and have shown that 5-LO products stimulate smooth muscle proliferation (37-39). For example, inhaled LTC4 and LTD4 resulted in potent airway obstruction as manifest by decreased specific airway conductance (SGaw) (40), and Bisgaard et al. (41) demonstrated that asthmatic subjects were...

Acute Severe Asthma Status Asthmaticus in Adults

Clinical studies suggest that b2-adrenergic agonists are more effective bronchodilators in the setting of acute severe asthma, and that an anticholinergic agent should not be used as the sole initial bronchodilator. The question arises whether an anticholinergic agent can add to the bronchodilatation achieved by the adrenergic agent. Rebuck et al. (33) found that the combination of 500 mg nebulized ipratropium with 1.25 mg nebulized fenoterol (a p2-adrenergic agent available outside the United...

Clinical Effects

Bronchodilation and Bronchoprotection Formoterol is a more potent bronchodilator than salmeterol in vitro (19). This difference is also evident in vivo (57), as formoterol causes similar bronchodila-tion compared to salmeterol but at lower doses. Another important difference between these two drugs is the onset of action formoterol has a faster onset Figure 5 Time course of bronchodilation with short- and long-acting b-agonists. Increase in FEV1 over 12 hours after inhalation of salbutamol 200...

Unresolved Issues and Future Directions

Despite the widespread publicity surrounding the GINA and NAEPP reports within the medical community, their impact in improving asthma treatment has been relatively modest. As already mentioned, published surveys of asthmatic patients in developed countries seem to suggest that asthma pharmacotherapy is suboptimal in many patients, and is not in compliance with evidence-based guidelines. Studies performed by Suissa et al. (34,36) in Canada would suggest that there has been some impact as...

Safety

Overall, both oral inhaled cromolyn and nedocromil are well tolerated with minimal side effects. The side effects reported with cromolyn include throat irritation, cough, nasal congestion, mild bronchospasm, urticaria, angioedema, anaphylaxis, anaphylactoid reaction, and pulmonary infiltration with eosinophilia (PIE), cardiac tamponade and eosinophilia, dysuria, dermatitis, and myositis (155). One patient experienced a near-death exacerbation as he tried to use DSCG during an asthma attack...

Molecular Interactions Between LABA and Corticosteroids

ICS are commonly prescribed for asthmatics with persistent symptoms in order to control inflammation. These drugs bind to the cytoplasmic corti-costeroid receptor (GR), which exerts its effects either through (i) interactions with transcription factors, e.g., binding to and hence inactivating NFkB or (ii) translocation to the nucleus and binding to corticosteroid response elements (GREs) in the promotor regions of specific genes, thus increasing mRNA synthesis (47). As LABA are often prescribed...

References

Johansson SGO, O'B Hourihane J, Bousquet J, Bruijnzeel-Koomen C, Dreborg S, Haatela T, Kowalski ML, Mygind N, Ring J, van Cauwenberge P, et al. A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy 2001 56 813-824. 2. Johansson SGO, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, Motala C, Ortega Martell JA, Platts-Mills TA, Ring J, et al. HC. Revised nomenclature for allergy for global use Report from the Nomenclature Review...

Receptor Activation and Signaling

Gumg Transmembrane

The p2-adrenoreceptor is a G-protein coupled receptor, with seven transmembrane domains that are connected by intra- and extracellular connecting loops (Fig. 1). It has an extracellular amino terminus and an intracellular carboxyl terminus. The binding sites for ligands lie within the lipophilic transmembrane domains of the receptor. Amino acid residues that are directly involved in binding have been identified, e.g., asp 113, serine 204, and serine 207 (4). It is likely that ligands with...

Cromolyn and Nedocromil Comparison Trials

A few studies have compared cromolyn to nedocromil, whereas others have compared cromolyn, nedocromil, and ICS. No differences in PFT could be found in 195 children treated with cromolyn, nedocromil, or ICS (131). Similarly, there were no differences found in efficacy when comparing cromolyn to nedocromil in another paper (132). Review of the Cochrane database also could find no difference in efficacy between DSCG and nedo-cromil during the post-exercise pulmonary functions in either the...

Spacers Inhaler Devices

A proportion of patients fail to coordinate actuation with inhalation when using a standard metered dose inhaler (MDI) and greater deposition in the airways can be achieved through the use of a spacer device (139). For this reason spacers are recommended for most asthmatics receiving corticosteroid therapy delivered by MDI, and certainly those on high doses. Technique is still important with spacers. For example, multiple actuations before inhalation and a delay between actuation and inhalation...

Future Directions

IgE plays a central role in the initiation and propagation of the inflammatory cascade and therefore in the allergic response. The concept of attenuating allergic disease by specifically inhibiting IgE and the development of omalizumab, the first agent capable of achieving this, were major breakthroughs in the management of allergic asthma. Specific binding of IgE by omalizumab has been shown in clinical trials to diminish both early and late asthmatic responses, and reduce symptoms of...

Pharmacological Activities Potentially Relevant for Asthma

Although traditionally classified as a bronchodilator and initially used primarily for acute bronchodilatation, the ability of theophylline as maintenance therapy to control chronic asthma has always appeared disproportionately greater than was explainable by its modest degree of bronchodilator activity alone (14-22). In addition to bronchodilatation, theophylline has broncho-protective (23-26), anti-inflammatory (27-30), and immunomodulatory (22) effects that potentially contribute to its...

Heliox

Heliox is a mixture of oxygen with the inert gas helium. Commonly used concentrations of this agent utilize 60 to 80 helium (128). Its therapeutic benefit in asthma is attributed to lower turbulent flow in high-resistance airways secondary to its lower density compared with air-oxygen mixtures. More importantly, a low-density gas such as heliox decreases the pressure gradient required to achieve a given flow rate through turbulent airways. This effect could lead to partial attenuation of the...

Metabolism

Theophylline is eliminated from the body by hepatic biotransformation into relatively inactive metabolites that are rapidly excreted in the urine (209). About 85 to 90 of a dose is metabolized (210) primarily by cytochrome P450 1A2 and to a lesser extent by 3A3 and 2E1 (211). This occurs over multiple parallel pathways by both first-order and capacity-limited kinetic processes (163,210,212). The major metabolite, 1,3-dimethyluric acid, is formed by hydroxylation in the C-8 position, whereas...

Back Titration

One of the recommendations of asthma management guidelines is that an attempt is made to reduce the dose of ICS once asthma control has been achieved, a regime referred to as ''back titration.'' This recommendation applies particularly to patients receiving well in excess of the established therapeutic range. This is an important issue as in western countries, many adult patients with asthma are prescribed ICS doses well beyond the top of the dose-response curve (96,97). Many doctors and...

Diagnosis of Asthma

The schema presented for asthma classification and diagnosis is particularly relevant. The GINA document emphasizes the importance of utilizing lung-function measurements in the diagnosis of asthma. The GINA guideline highlights questions that can be used in a clinical setting, which are from the International Union Against Tuberculosis and Lung Disease questionnaire, a validated instrument that has been employed in epidemiologic studies (6). Traditionally, a diagnosis of asthma is confirmed by...

Leukotriene Modifiers Safety Considerations

Standard asthma treatments may be complicated by several adverse effects. For instance, p-agonists may cause tachycardia, palpitations, and headaches. Theophylline has a very narrow toxic-therapeutic window, interacts with many medications, and may cause tremors, nausea, and several other ill effects. While systemic corticosteroids have a myriad of adverse effects, including hyperglycemia, growth retardation, hypertension, insomnia, and edema, even inhaled corticosteroids pose risks, including...

Historical Background

Khellin Structure

Cromolyn and nedocromil are members of the chromone group of chemical compounds. The chemical formula for chromone is 5 6 benz-1 4 pyrone (2) (Fig. 1). In 1968, disodium cromoglycate (DSCG) or CS combined with isoproterenol was introduced in the United Kingdom as the first antiinflammatory medication used in asthma (3-5). The addition of the bronchodilator was done to prevent bronchoconstriction that can occur with inhalation of a sodium salt (4). By 1973, cromolyn was approved by the Food and...

Leukotriene Biosynthesis

Leukotrienes are fatty acids and members of a larger group of biomolecules known as eicosanoids, which also encompasses cyclooxygenase products such as prostaglandins, thromboxanes, and prostacyclin and the products of 12- or 15-lipoxygenase (the lipoxins) and 5- and 15-lipoxygenase (5,6). Leu-kotrienes are synthesized in mast cells, eosinophils, and alveolar macrophages (7-9), all of which have been implicated as critical effector cells in the pathobiology of asthma. Airway epithelial cells...

Cromolyn for Asthma

Several studies have shown that ICS are more effective than cromolyn in patients with severe asthma (88-90). However, some studies in mild to moderate asthmatics have shown either comparable efficacy (91-93) or an even better response to ICS (94,95). On the other hand, the addition of cromolyn to ICS failed to show any beneficial effect (96). A more recent review of 24 placebo-controlled trials of cromolyn concluded, ''there is insufficient evidence for a beneficial effect of CS as maintenance...

Clinical Use of SABA

Albuterol was the first b2-specific bronchodilator to be used for the treatment of asthma. There was initial evidence that regular treatment with this drug over one week improved symptoms and lung function (38). This encouraged clinicians to prescribe albuterol as a regular long-term treatment in order to maximize bronchodilation, and when fenoterol and terbu-taline were introduced they were also used in this manner. Fenoterol became widely used in certain countries such as New Zealand....

Neurogenic Mechanisms of Chromones

The bronchoconstriction induced by sulfur dioxide and bradykinin is inhibited by both cromolyn and nedocromil (Table 2) (60). Inhaled sodium metabisulfate generates sulfur dioxide in the airways with both of these agents causing bronchoconstriction in asthma subjects. The mechanism of action of sulfur dioxide may be through stimulation of laryngeal afferent nerve fibers in experimental animals (61). Nedocromil has been shown to prevent the bronchial hyper-responsiveness in dogs exposed to...

Nedocromil

Nedocromil belongs to the structural class of pyranoquinolines (3). As noted above nedocromil is water soluble, rapidly absorbed from the lung, has negligible fat accumulation, and has minimal absorption from the GI tract. Similar to CS, adverse drug reactions occur infrequently due to the low to moderate protein binding capacity of nedocromil. Drugs that do bind proteins readily are not displaced by nedocromil, resulting in no changes in half-life or clearance of these other compounds....

Pharmacodynamics

P-Agonists can only exert their pharmacological effects while bound to the p2-AR. The duration of action of a p-agonist is therefore related to its ability to remain at the receptor-binding site. This is determined predominantly by the lipophilicity of the molecule. SABA are hydrophilic in nature, and so approach the b2-AR extracellularly, allowing a rapid onset of action (14). However, diffusion of the ligand into the extracellular compartment occurs easily and results in a relatively short...

AntiIgE Therapy for Asthma

Department of Medicine, Unit of Clinical Immunology and Allergy, Karolinska University Hospital Stockholm, Sweden Pulmonary Department, Mainz University Allergic diseases, such as allergic asthma, are hypersensitivity reactions initiated by immunological mechanisms (1,2). They are usually mediated by IgE antibodies, triggering an inflammation characterized by an increase in production of Th2-type cytokines at a mucosal surface, the interface between the external and the internal environments....

Physiologic Factors Associated with Alteration in Theophylline Disposition

Theophylline Dose Serum Level

Total body clearance, the product of volume of distribution and elimination rate constant, quantifies theophylline removal from the body. While intrapatient variability in clearance is small (223,229), interpatient variability is large and appears to be from differences in the rate of hepatic biotransformation, which changes with age, concurrent illness, smoking, pregnancy, aberrations in diet, and intake of other drugs. The volume of distribution is a somewhat larger fraction of body weight in...

Drugs That Alter Theophylline Disposition

Most commonly used drugs do not interact adversely with theophylline. Amoxicillin (262,263), ampicillin with (264) or without sulbactam (265), cefaclor (266,267), metronidazole (268), co-trimoxazole (269), tetracycline (270), azithromycin (271), terfenadine (272), and montelukast (data on file, Merck Pharmaceuticals) have been specifically studied and have no effect on theophylline clearance, nor is there evidence that other related medications have drug interactions with theophylline. On the...

Toxicity

The therapeutic benefit from theophylline has required consideration for its use in a manner that minimizes its potential for adverse effects (90). Drug interactions or alterations in clearance for other reasons have the potential to cause toxicity. However, toxicity has occurred most commonly from errors in dosage (91,92). Fortunately, most cases of toxicity are mild and readily reversible without residual effects. In virtually every case where there has been serious toxicity such as seizures...

Adrenal Effects

The interpretation of studies of the effects of ICS on adrenal function have proven difficult due to small numbers and insufficient periods to determine effects of clinical relevance, and the use of single doses or lack of a placebo-group, thereby preventing the accurate assessment of the dose-response relationship. In addition, most studies have reported single morning plasma Cortisol measurements, which is an insensitive and variable measure for detecting adrenal suppression. A preferable...

A 52Agonists

The mainstays of initial therapy for AA are the inhaled p2-agonists. These agents treat bronchial smooth muscle constriction and thus produce bronchodilation. This salutary effect is more pronounced with p2-agonists than other classes of bronchodilators (53,54). Among the intermediate-acting p2-agonists, the most commonly used agent is albuterol (or salbutamol). Other short-onset, intermediate-acting agents include pirbuterol, terbutaline, metaproteronol, and fenoterol (not used in the United...

Cromone Mechanism of Action

The exact mechanism of action of cromolyn and nedocromil has not been determined. Multiple mechanisms involving ion channel blockade, blockade of signaling of heat shock protein or G-protein, or even blockade of capsaicin receptor have been identified. However, the final common mechanism appears to be an inhibition of mast cell activation. Studies have reported that the phosphorylation of a 78-kDa-molecular-weight protein prevents mediator release in mast cells (17). More specifically in rat...

Pharmacotherapy for Asthma Stepwise Approach

The NAEPP report emphasizes that the stepwise approach should be used to guide but not replace physician decisions regarding treatment of individual patients (2). In rating severity, a patient should be assigned to the most severe step if any one feature of the higher severity category is present. Physicians should follow the strategy of achieving control as quickly as possible (e.g., treating with a burst of oral prednisone, if indicated) and then stepping down to the least medication needed...

Justification for Recommendation of Specific Agents

Both the GINA document of 2002 and the NHLBI-NAEPP report of 1997 present evidence-based rationale for selection of specific agents in both children and adults. Long-term controller medications as defined by GINA include inhaled corticosteroids, LABA, systemic corticosteroids, long-acting oral p-agonists, sustained-release theophylline, cromolyn sodium, nedocromil, leukotriene-blocking agents, and steroid-sparing agents. These are widely recognized as the most effective controller medications...

Conclusion

While overall mortality remains low, asthma cases are prevalent and contribute substantially to national health expenditures. The disproportionate majority of this cost occurs in a minority of asthmatics that suffer from episodes of AA requiring ED attention or hospitalization. Recent trends in mortality and hospitalization seem to have reached a plateau in the United States. Complete assessment of severity, full understanding of therapeutic options, and adequate transition to outpatient...