Management of Asthma

Posts Tagged ‘Flonase’

• describe major factors which affect breathing and review the pathology of asthma;

• explain the respiratory function tests which are useful in assessing the severity of asthma;

• review the pharmacology of agents used in treating asthma;

• appreciate the links between pathophysiology, pathology, pharmacology and the management of a common respiratory problem.

Part 1

Mandy is 13 years old and her asthma is usually quite well controlled with a ‘reliever’ and a ‘preventer’ medication. Her father and brother also have asthma. She enjoys staying with her friend Jane, who, unlike Mandy, has pet rabbits, rats and gerbils. Mandy was happy to stay for a sleepover party at Jane’s house. But, waking at midnight wheezing and coughing, she realized that she had left her inhalers at home. Jane’s mother heard her coughing and wheezing so took her to the accident and emergency department of the local hospital, by which time Mandy was distressed and very short of breath.

Which drugs are likely to be present in the ‘reliever’ and the ‘preventer’ inhaler?

Ql The most commonly used ‘reliever’ in asthma therapy is a short-acting bronchodilator, such as the beta-2-agonists salbutamol (Ventolin) or terbutaline (Brethine, Bricanyl). These are safe and effective agents for mild to moderate symptoms and are taken directly into the respiratory tract via an inhaler device. If patients need to use the reliever more than three times a week, they are usually also prescribed a ‘preventer’ inhaler containing a corticosteroid, such as beclometasone diproprionate (Qvar), budesonide (Pulmicort) or fluticasone proprionate (Flonase). Corticosteroids decrease airway inflammation, reducing airway oedema and mucus production. When used regularly they are prophylactic and reduce the frequency of asthma.

What factors could account for wheezing, coughing and shortness of breath, which occur in asthma?

Q2 Asthma involves reversible narrowing of small airways in the lung. In acute asthma the smooth muscle surrounding the bronchi and bronchioles contracts, narrowing the lumen. Concurrently, airway mucous membranes become inflamed and oedematous and mucus secretion is increased; these changes cause further narrowing and obstruct airflow. Expiration is more severely affected than inspiration since expiration is passive and involves the recoil of lung structures stretched by the active inspiratory process. Patients have difficulty in moving air through their airways, which causes breathlessness, or dyspnoea. Wheezing is caused by turbulent and restricted airflow through the airways, and coughing is triggered by irritation of lung sensory receptors.

List the risk factors for asthma and the triggers which may exist in Jane’s house.

Q3 Risk factors for asthma include a genetic susceptibility and infection, for example a viral respiratory illness. There is evidence for a strong genetic component involving a number of genes rather than a single abnormality, or an ‘asthma gene’; in this case Mandy’s father and brother are both asthmatic. Some asthma attacks can be triggered by exercise. There may be many environmental triggers in lane’s house, including allergens from the pets’ hair and skin cells and their urinary proteins, as well as cigarette smoke and house dust mites. Inhalation of such allergens in susceptible individuals leads to degranulation of pulmonary mast cells with release of mediators which cause mucosal inflammation, oedema and bronchospasm. Airway resistance is increased and wheezing, dyspnoea and coughing occur.

Part 2

On arrival at hospital, although wheezing and breathless, Mandy could describe her usual medication to staff. A blood test showed that her arterial pH was 7.25 and lung function tests produced the results indicated below.

Mandy was taken to the ward and given nebulized salbutamol. After a while her wheezing and coughing diminished and she was able to go home next morning.

Mandy’s forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) are shown below:

FVC = 2300 ml

FEV1 = 950 ml

Why are these tests useful in asthma? What is the FEV1/FVC ratio in this patient? Does this ratio indicate a restrictive or an obstructive condition?

Asthma affects expiration more than inspiration, and so tests of expiration are useful in determining the severity of the condition and the response to therapy.

Forced vital capacity (FVC) measures the maximum volume of air expelled from the lung in a single forced expiration: there is no time limit. Forced expiratory volume in one second (FEVi) measures the volume of air which can be expelled from the lung in one second. In a normal individual 80% of the vital capacity can be expired in one second, but patients with obstructive disease have difficulty in emptying the lung and this value is significantly reduced.

The FEV1/FVC ratio is a useful single measure of expiratory function. In a normal individual this ratio is likely to be 0.8 or more.

A ratio of <0.7 indicates some obstruction to expiratory airflow.

In Mandy’s case: FEV1/FVC ratio = 950/2300 = 0.41.

This ratio indicates obstructive disease.

Name an additional test which would be useful in assessing the severity of a patient’s asthma.

Measurement of peak expiratory flow: this is a simple measure of expiratory function. The peak flow meter measures the velocity of expired airflow and is suitable for both adults and children. The patient breathes out a short blast of air, as fast as possible, into the device. Normal individuals can achieve airflow velocity of 450-6501 min^-1. The peak flow meter is a cheap device which is used by patients at home to monitor their asthma. If a patient’s peak flow diminishes below a certain level which has been set by their nurse practitioner or family doctor, they can adjust their own treatment, within specified limits, and control their condition better.

What is the mechanism of action of beta-2-agonists, such as salbutamol, in the airways?

Salbutamol is a selective beta-2-adrenoceptor agonist which is effective in relieving mild to moderate bronchoconstriction. Inhalation of salbutamol induces bronchodilation by acting on beta-2-receptors on bronchial smooth muscle; this lasts for approximately three to five hours. It also inhibits mediator release and improves the clearance of mucus from the lung. Stimulation of beta-2-receptor increases the cellular concentration of cyclic adenosine monophosphate cAMP and activates a protein kinase. This kinase in turn inactivates myosin-light-chain kinase, an enzyme necessary for contraction in smooth muscle, and so relaxes bronchial smooth muscle.

Outline the advantages of using a nebulizer rather than a breath-activated or dry-powder inhaler. Would you expect this medication to fully reverse Mandy’s bronchoconstriction?

Nebulizers convert a solution or suspension of drug into an aerosol which is administered by inhalation. The aerosol is able to carry a higher concentration of drug deep into the lungs than the dry-powder type of inhaler used normally by asthmatic patients. Nebulizers are useful when a patient has a more severe episode of asthma than usual, which is not relieved by their normal inhaler. Good coordination is required in the use of metered dry-powder inhalers; using a nebulizer has the advantage that no coordination in drug delivery is needed by the patient. This is important if the asthmatic condition is severe and the patient is very young, or very anxious or confused. It would be expected to fully reverse Mandy’s bronchoconstriction.

Why was Mandy’s arterial pH lower than normal?

Because Mandy’s airways were constricted and obstructed, she was not able to empty her lung effectively during expiration and C0₂ was retained. Increased arterial C0₂ decreases arterial pH.

Is there any significance in the fact that Mandy could tell the staff about her asthma and her usual medication?

Yes. Her ability to tell staff about her usual medication shows that, although her asthma was moderately severe, it was not life-threatening. In very severe asthma patients cannot complete a sentence in one breath or may be too breathless to talk at all.

If salbutamol is not sufficiently effective, which other agents might be useful in treating an acute episode of asthma?

Other bronchodilator agents include nebulized ipratropium. Ipratropium is a muscarinic receptor antagonist that helps to relax bronchial smooth muscle which has contracted via parasympathetic stimulation. The xanthines theophylline and aminophylline (theophylline ethylenediamine) are alternative bronchodilator agents. These agents may act as phosphodiesterase inhibitors and, although they have been used as bronchodilators for many years, adverse CNS, GI and cardiovascular effects may limit their usefulness.

Spacer devices are often used for treating asthma when the patient is less than five years of age. Explain the function of a spacer.

When dry-powder metered-dose inhalers are used, there is some deposition of the drug dose in the mouth and pharynx. These inhaler devices need good coordination between activation of the device and the inhalation of the drug: very old, young or anxious/confused patients may not be able to coordinate well. Spacer devices both eliminate the requirement for good coordination and reduce the deposition of drug in the oropharynx. More of the drug is able to enter the lung and so the therapeutic effect of the agent is optimized. Spacers are particularly useful for very young children with asthma.

Are there any therapeutic agents which might be particularly useful in the prophylaxis of asthma in children?

Children who need more than occasional relief of bronchoconstriction are usually prescribed a standard corticosteroid inhaler as prophylaxis. There is some evidence that children under five years of age obtain benefit from use of nedocromil sodium or sodium cromoglicate. These agents are used only in prophylaxis: cromoglicate is not a bronchodilator and cannot be used to treat acute episodes of asthma. Its action is not well understood but the prophylactic effect appears to be partly due to stabilization of mast cells, which reduces release of histamine and other mediators so that hyperactive bronchial muscle is less responsive to environmental triggers. Other, recent additions to prophylaxis in asthma therapy include the leukotriene receptor antagonist montelukast. This drug is taken as a tablet and blocks the actions of cysteinyl leukotrienes in the airways. The latter are products of the lipoxygenase pathway which cause bronchoconstriction and inflammation. It is no more effective than standard corticosteroids in the prophylaxis of asthma, but there is some evidence that when given together with a steroid there maybe a beneficial additive effect.

Key Points

• Asthma involves reversible bronchoconstriction, which particularly affects expiration.

• Patients with asthma are usually treated with a ‘reliever’, usually a short-acting P2-agonist, and a ‘preventer’ inhaler containing a corticosteroid.

• Children may benefit from asthma prophylaxis using sodium cromoglicate or nedocromil sodium.

• Risk factors for asthma include genetic susceptibility, infection and exposure to triggers such as cold air, animal products and house dust mites.

• Respiratory function tests of particular use in asthma include peak expiratory flow and FEV1.

• Nebulizers are useful in treating severe asthma as they administer bron-chodilator drugs as an aerosol and, unlike dry-powder inhalers, require no coordination by the patient in their use.

• Spacer devices are useful to deliver drugs into the respiratory tract of young children with asthma. They reduce the deposition of bronchodilator drugs in the pharynx and require little coordination by the patient to deliver the required dose.

(British Approved Name, rINN)

Drug Nomenclature

Fluticasona; Fluticasonum

S-(Fluoromethyl) 6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate

Флутиказон

Fluticasone Furoate

(British Approved Name Modified, US Adopted Name, rINNM)

Drug Nomenclature

Fluticasonum Furoas; Furoate de Fluticasone; Furoato de Fluticasona; GW-685698X

6α,9-Difluoro-17-{[(fluoromethyl)sulfa-nyl]carbonyl}-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-dien-17α-yl furan-2-carboxylate

Флутиказон Фуроат

Fluticasone Propionate

Drug Approvals

(BANM, US Adopted Name, rINNM)

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (Fluticasone Propionate). A white or almost white powder. Practically insoluble in water slightly soluble in alcohol sparingly soluble in dichloromethane. Protect from light.

The United States Pharmacopeia 31, 2008 (Fluticasone Propionate). Micronised fluticasone propionate is a fine white powder. Store in airtight containers at a temperature not exceeding 30°. Protect from light.

Adverse Effects, Treatment, Withdrawal, and Precautions

As for corticosteroids in general. Hypersensitivity reactions have occurred. Eosinophilic conditions, including Churg-Strauss syndrome, have been reported rarely, in most cases after a transfer from oral corticosteroid therapy.

When applied topically, particularly to large areas, when the skin is broken, or under occlusive dressings, corticosteroids may be absorbed in sufficient amounts to cause systemic effects. Inhalation or nasal use of large amounts of fluticasone may produce systemic effects also (see below).

Adrenal suppression. Despite the fact that inhaled fluticasone is generally thought to lack systemic effects at therapeutic doses, a study in 25 healthy subjects indicated that fluticasone propionate as single inhaled doses of 250, 500, and 1000 micrograms did produce a reduction in plasma cortisol, indicating suppression of the hypothalamic -pituitary-adrenal axis to some degree. Others have also found evidence of adrenal suppression with fluticasone, particularly at high doses and in children, and the effect may be more marked with repeated than with single doses. A number of cases of adrenal crisis have been associated with high-dose inhaled fluticasone, including at least one fatality. It has been recommended that children using inhaled fluticasone at doses above 400 micrograms daily should have adrenal function monitoring and a written plan for emergency corticosteroid replacement therapy.

Aspergillosis. The fungal infection aspergillosis has been reported in patients receiving inhaled’ and intranasal fluticasone.

Effects on the bones. For studies of the effects on bone of inhaled fluticasone, compared with beclometasone.

Effects on the muscles. Proximal myopathy has been reported in children receiving high-dose inhaled fluticasone the patients recovered after replacement of fluticasone with alternative corticosteroid therapy.

Interactions

The interactions of corticosteroids in general are described.

Pharmacokinetics

For a brief outline of the pharmacokinetics of corticosteroids.

Fluticasone propionate is poorly absorbed from the gastrointestinal tract and undergoes extensive first-pass metabolism oral bioavailability is reported to be only about 1%.

Uses and Administration

Fluticasone is a corticosteroid with mainly glucocorticoid activity.

Fluticasone propionate is stated to exert a topical effect on the lungs without significant systemic effects at usual doses, due to its low systemic bioavailability (but see Adrenal Suppression, above). It is used by powder or aerosol inhalation for the prophylaxis of asthma. Typical initial doses in the UK range from 100 to 250 micrograms twice daily in mild asthma up to 1 mg twice daily in severe asthma, adjusted according to response. Children over 4 years of age may be given initial doses of 50 to 100 micrograms twice daily, increased to 200 micrograms twice daily if necessary.

The drug may also be given via a nebuliser in severe chronic asthma. Usual adult doses are 0.5 to 2mg twice daily. Children aged 4 to 16 years may be given 1 mg twice daily. In the USA, doses by powder inhalation are similar to that in the UK. The aerosol inhalation formulations contain 50, 125, or 250 micrograms of fluticasone propionate in each metered spray, which delivers 44,110, or 220 micrograms, respectively from the actuator. Doses are therefore expressed in these units dosage ranges from 88 micrograms twice daily to 880 micrograms twice daily, depending on previous therapy. Children aged 4 to 11 years are given 88 micrograms twice daily.

Fluticasone propionate is also available in some countries as a powder or aerosol inhalation for the treatment of chronic obstructive pulmonary disease, when it is given in doses of 500 micrograms twice daily.

Fluticasone is administered by nasal spray in the prophylaxis and treatment of allergic rhinitis. The

usual dose of fluticasone propionate is 100 micrograms into each nostril once daily, increased if necessary to 100 micrograms into each nostril twice daily. Children over 4 years of age may be given half these doses. Fluticasone furoate is also used in the management of allergic rhinitis. This salt has enhanced affinity for the glucocorticoid receptor, and is given in a starting dose of 55 micrograms into each nostril once daily. When the maximum benefit has been achieved and symptoms controlled, the dose should be gradually reduced to the minimum effective dose 27.5 micrograms into each nostril once daily may be sufficient to maintain control of symptoms. Children aged 2 years and over may be started on 27.5 micrograms into each nostril once daily, which may be increased to 55 micrograms into each nostril once daily if necessary to control symptoms.

Fluticasone propionate drops are used in the treatment of nasal polyps, 200 micrograms should be instilled into each nostril once or twice daily for at least 4 to 6 weeks.

Fluticasone propionate is applied topically in the treatment of various skin disorders. Creams and ointments containing 0.05% and 0.005%, respectively are available. For recommendations concerning the correct use of corticosteroids on the skin.

Asthma. Corticosteroids and beta₂-adrenoceptor agonists form the cornerstone of the management of asthma. Patients requiring only occasional relief from symptoms may be managed with an inhaled short-acting beta₂ agonist, and an inhaled corticosteroid such as fluticasone is added if symptomatic relief is needed more than once daily. In more severe asthma other drugs may be added (combination with a long-acting beta₂ agonist may have synergistic benefits), or the dose of inhaled corticosteroid may be increased.

Some references to the use of fluticasone propionate for asthma are given below, including one to a study indicating that increasing the dose of inhaled fluticasone did not produce increased benefit.

Chronic obstructive pulmonary disease. For discussion of the value of inhaled corticosteroids in chronic obstructive pulmonary disease, including reference to the use of fluticasone.

Cough. A small study in children with persistent nocturnal cough compared fluticasone propionate 1 mg twice daily for 3 nights, followed by 500 micrograms twice daily for 11 nights, given by metered-dose inhaler, with placebo. Coughs reduced significantly by nights 15 and 16 in the children given the corticosteroid. However, both groups improved significantly compared to baseline, leading the authors to conclude that inhaled corticosteroids should not be given at the time of presentation of persistent nocturnal cough. If they are given, then a 2-week course of high dose corticosteroids may benefit some children. In a controlled crossover study in adult patients with chronic cough, inhaled fluticasone 500 micrograms twice daily for 14 days significantly improved certain measurements of cough, although overall reduction in cough severity was modest. In adults with a cough lasting more than 2 weeks, fluticasone 500 micrograms twice daily for 2 weeks decreased cough scores from day 5 onwards in non-smokers.

Eczema. In a study in patients with moderate to severe eczema, fluticasone propionate 0.05% cream or 0.005% ointment was applied once or twice daily for 4 weeks if eczema stabilised, either the cream, the ointment, or an emollient placebo was then applied on 2 days per week, for up to 16 weeks. Fluticasone cream reduced the risk of relapse to about one-sixth of that of placebo, whereas the ointment formulation reduced the risk to about half median times to relapse were similar for both fluticasone formulations. The formulations were originally expected to be of similar potency. Others have commented that caution should be exercised in generalising these results to primary care settings where most cases of eczema are likely to be mild, and relapses infrequent.

Inflammatory bowel disease. Fluticasone propionate, given orally, has produced variable results in the treatment of Crohn’s disease and ulcerative colitis ‘ some benefit was also reported in coeliac disease The dose was 5 mg four times daily but some consider higher doses necessary.

For a review of the management of inflammatory bowel disease, including the role of corticosteroids.

Nasal polyps. For discussion of the value of corticosteroids in the treatment of nasal polyps, including reference to the use of fluticasone.

Rhinitis. For a discussion of the management of rhinitis, including the use of corticosteroids. Some further references to the use of fluticasone in rhinitis are given below.

Preparations

British Pharmacopeia 2008: Fluticasone Cream; Fluticasone Nasal Spray; Fluticasone Ointment

The United States Pharmacopeia 31, 2008: Fluticasone Propionate Nasal Spray.

Proprietary Preparations

Argentina: Cutivate Flixonase Flixotide Fluti-K Fluticort Lidil Cort Proair Rinisona

Australia: Avamys Beconase Allergy Flixonase Flixotide

Austria: Cutivate Flixonase Flixotide

Belgium: Cutivate Flixonase Flixotide

Brazil: Flixonase Flixotide Fluticaps Flutivate Plurair

Canada: Cutivate Flonase Flovent

Chile: Albeoler Brexonase Brexovent Flixonase Flixotide Flusona Flutivate Nebulex Raffonin

Czech Republic: Alergonase Avamys Cutivate Flixonase Flixotide Nasofan

Denmark: Cutivat Flixonase Flixotide

Finland: Flixonase Flixotide

France: Flixonase Flixotide Flixovate

Germany: Atemur Flutide Flutivate

Greece: Alerxem Cortixide Dermocort Flicazen Flihaler Flixocort Flixoderm Flixonase † Flixotide Flucortis Flutinasal Flutizal Ybecor

Hong Kong: Cutivate Flixonase Flixotide

Hungary: Cutivate Flixonase Flixotide Flutirin

India: Flohale Flomist Zoflut

Indonesia: Cutivate Flixonase Flixotide Nedicort

Ireland: Flixonase Flixotide Nasofan

Israel: Allegro Cutivatef Flixonase Flixotide

Italy: Flixoderm Flixonase Flixotide Fluspiral Ticavent

Japan: Flonase

Malaysia: Cutivate Flixonase Flixotide

Mexico: Cutivate Flixonase Flixotide

The Netherlands: Cutivate Flixonase Flixotide Flutide

Norway: Flutide Flutivate

New Zealand: Flixonase Flixotide Nasaclear

Philippines: Cutivate Flixotide

Poland: Cutivate Flixonase Flixotide

Portugal: Asmatil Asmo-Lavi Brisovent Cutivate Eustidil Flixotaide Flutaide Rontilona Ubizol

Russia: Cutivate Flixonase Flixotide Seretide

South Africa: Cutivate Flixonase Flixotide Flohale DP Flomist

Singapore: Cutivate Flixonase Flixotide

Spain: Drolasona † Flixonase Flixotide Fluinol Flusonal Inalacor Rinosone Rontilona Trialona

Sweden: Flutide Flutivate

Switzerland: Axotide Cutivate Flutinase

Thailand: Flixonase Flixotide

Turkey: Brethal Cutivate Flixonase Flixotide

UAE: Potencort

UK: Cutivate Flixonase Flixotide Nasofan

USA: Cutivate Flonase Flovent Veramyst

Venezuela: Cutivate Flixonase Flixotide Fluticort

Multi-ingredient

Argentina: Flutivent Neumotide Seretide

Australia: Seretide

Austria: Seretide Viani

Belgium: Seretide

Brazil: Seretide

Canada: Advair

Chile: Aerometrol Plus Aurituss Brexotide Seretide

Czech Republic: Duaspir Seretide

Denmark: Seretide

Finland: Seretide

France: Seretide

Germany: Atmadisc Viani

Greece: Seretide Vianif

Hong Kong: Seretide

Hungary: Seretide Thoreus

India: Duonase Forair Seretide Seroflo

Indonesia: Seretide

Ireland: Seretide

Israel: Seretide

Italy: Aliflus Seretide

Mexico: Seretide

The Netherlands: Seretide Viani

Norway: Seretide

New Zealand: Seretide

Philippines: Seretide

Poland: Seretide

Portugal: Brisomax Naizar Seretaide Veraspir

South Africa: Seretide

Singapore: Seretide

Spain: Anasma Brisair Inaladuo Plusvent Seretide

Sweden: Seretide

Switzerland: Seretide

Thailand: Seretide

Turkey: Seretide

UK: Seretide

USA: Advair

Venezuela: Seretide

Traditionally, asthma has been treated with oral and inhaled bronchodilators, which help control the symptoms of asthma but do nothing for the inflammation. Now, the focus is on prevention, which involves treating the underlying inflammation as well as the bronchoconstriction, and constantly monitoring breathing efficacy.

It is essential that asthmatic patients understand how to manage drug therapy and side effects, monitor breathing efficiency, and deal with environmental factors that contribute to bronchoconstriction (irritants, allergens, exercise, cold air inhalation, and infection). Unfortunately, despite the fact that much is known about asthma and its cause and care, the disease is seriously undertreated. One study of 94 adult asthmatics found that nearly 75% were not receiving the appropriate therapy, or were not using medications properly. The newly issued Guidelines of the National Asthma Education and Prevention Program advocate a stepwise approach to asthma therapy, starting with short-acting inhaled beta2-agonists as needed for mild intermittent asthma; these are followed, depending on disease severity, by the addition of an inhaled corticosteroid and/or cromolyn or nedocromil sodium, a long-acting inhaled beta2-agonist, an oral beta-agonist or theophylline, or a leukotriene inhibitor. For very severe disease, an oral corticosteroid may be added (see Table).

Table 2. Drugs Used for Asthma

Generic Name	Trade Name(s)
Bronchodilators: Beta2-Agonists
albuterol terbutaline bitolterol pirbuterol salmeterol fenoterol * formoterol *	Proventil, Ventolin Brethaire, Brethine, Bricanyl Tornalate Maxair Serevent – –
Bronchodilators: Other
theophylline	Various
Mast Cell Inhibitors
cromolyn sodium nedocromil sodium	Intal Tilade
Corticosteroids: Metered-Dose Inhaler
flunisolide triamcinolone acetonide beclomethasone dipropionate budesonide fluticasone propionate	AeroBid Azmacort Beclovent, Vanceril, Vanceril DS Pulmicort Flonase
Corticosteroids: Oral
methylprednisolone prednisone prednisolone	Various Various Various
Leukotriene Inhibitors or Antagonists
zafirlukast zileuton pranlukast * montelukast * pobilukast * tomelukast * verlukast *	Accolate Zyflo Ultair Singulair – – –
Anticholinergics
ipratropium bromide	Atrovent

*Investigational

Bronchodilators: Beta₂-Agonists, Theophylline

The introduction three decades ago of bronchodilating beta₂-agonists – adrenergic agonists selective for the beta₂ receptor – revolutionized the treatment of asthma. These agents proved to be more potent and longer acting (4-6 hours) than the nonselective adrenergic receptor agonists such as isoproterenol, which stimulate both alpha- and beta-adrenergic receptors. Beta₂-agonists give rapid symptomatic relief and also protect against acute bronchoconstriction caused by stimuli such as exercise or the inhalation of frigid air. Frequency of use can also serve as an indicator of asthma control. Recently, an extra long- acting beta₂-agonist-salmeterol (duration up to 12 hours)-was introduced in the United States. Salmeterol is so potent that it may mask inflammatory signs; therefore, it should be used with an anti-inflammatory.

Theophylline is a relatively weak bronchodilator with a narrow therapeutic margin (blood level monitoring is recommended to avoid toxicity) and a propensity for drug interactions (competition for hepatic cytochrome P450 drug-metabolizing enzymes alters plasma levels of several important drugs metabolized by that same system). On the plus side, theophylline has some anti-inflammatory activity, can be taken orally, and is available in long-acting formulations; patient compliance is good with once- or twice-daily oral formulations.

About 60% to 70% of asthmatics have mild disease that can be managed with inhaled beta₂-agonists alone, when pretreatment is provided before allergen exposure or exercise (cromolyn or nedocromil sodium can be substituted). Asthmatics with more severe disease are generally treated with inhaled beta₂-agonists as needed, along with other antiasthma medications, in particular, inhaled corticosteroids (regular use of inhaled corticosteroids, but not beta-agonists, has been shown to reduce the number of exacerbations of asthma, even in patients with mild disease). Theophylline is generally reserved for use in conjunction with other antiasthma agents for patients with moderate to severe disease.

Before 1990, beta₂-agonists were often administered on a regular schedule, which was thought to provide better asthma control. However, recent studies have shown that scheduled use is associated with poorer control and possibly with increasing asthma mortality worldwide. This association was first noted in the late 1960s with the use of a potent formulation of the nonselective isoproterenol. A second dramatic increase in asthma mortality was associated with the introduction in the late 1970s of a high-dose formulation of fenoterol. Later, frequent use of fenoterol or albuterol (primarily via nebulizer, and not metered-dose inhaler) was found to increase the risk of death in patients with severe asthma.

It is possible that the overuse of inhaled beta₂-agonists is simply a marker for severe uncontrolled asthma, and may not be the cause of death. However, it is also possible that the transient deterioration of airway responsiveness observed when the medication is stopped contributes to the risk. Also, beta-agonists have been associated with a rebound increase in bronchoconstrictor response to allergens, and with a partial loss of protection against exercise-induced bronchoconstriction. Several studies have shown that as-needed administration is at least as effective as regularly scheduled administration; therefore, using beta₂-agonists on demand is preferred. One recent trial involved 255 patients with mild asthma who received albuterol inhalation therapy either on a regular schedule (126 patients) or as needed (129 patients). The follow-up period lasted 18 weeks, and outcomes measured included peak expiratory flow, forced expiratory volume in one second, asthma symptoms, asthma exacerbations, quality of life, need for additional albuterol, and airway responsiveness to methacholine.

The average total use of albuterol in the scheduled group was 9.3 puffs per day, and in the as-needed group, 1.6 puffs per day. Basically, there were no clinically important differences between the two groups, although bronchodilator response to albuterol was increased in the scheduled-treatment group at the end of the trial. The investigators concluded, “In patients with mild asthma, neither deleterious nor beneficial effects derived from the regular use of inhaled albuterol beyond those derived from use of the drug as needed. Inhaled albuterol should be prescribed for patients with mild asthma on an as- needed basis.”

Anti-inflammatory Agents: Corticosteroids, Mast Cell Inhibitors, Antileukotrienes

Moderate asthma is treated with a daily inhaled anti-inflammatory-corticosteroid or mast cell inhibitor (cromolyn or nedocromil sodium)-plus an inhaled beta₂-agonist as needed (3 – 4 times per day) to relieve breakthrough symptoms or allergen- or exercise-induced asthma. Cromolyn and nedocromil sodium block bronchospasm and inflammation, but are usually effective only for asthma that is associated with allergens or exercise. Inhaled corticosteroids improve inflammation, airways hyperreactivity, and obstruction, and reduce the number of acute exacerbations. They may entirely eliminate symptoms, although noncompliance is often a problem because relief is not immediate (it takes a month before effects are apparent and up to a year for marked improvement to occur). The most frequent side effects are hoarseness and oral candidiasis. More serious side effects have been reported – partial adrenal suppression, growth inhibition, and reduced bone formation – but only with the use of higher doses. Beclomethasone, triamcinolone, and flunisolide probably have a similar mg-for-mg potency; the newer approvals budesonide and fluticasone are more potent and reportedly have fewer systemic side effects. This is caused, in part, by negligible oral bioavailability (a small portion of each dose is swallowed). Spacer devices are recommended for all inhaled corticosteroids; they reduce systemic effects by increasing drug delivery to the lungs and reducing residue on the pharynx and tongue.

For severe asthma, the dosage of the inhaled corticosteroid can be increased or a long- acting bronchodilator (including an oral beta₂-agonist or theophylline) added, especially for nocturnal symptoms. Oral corticosteroids are used for severe flare-ups and should be administered early (when bronchodilators fail to reverse an episode) because they take 12 to 24 hours to act. When long-term oral corticosteroids are needed, alternate-day therapy with the lowest effective dose should be used to help prevent long-term side effects (cataracts, osteoporosis, weight gain, skin fragility, fluid retention, growth suppression, exacerbation of diabetes, and hypothalamic-pituitary-adrenal suppression).

Despite optimal use of bronchodilators and anti-inflammatory agents, many patients continue to suffer from uncontrolled asthma. These patients may benefit from therapy with one of the new antileukotrienes. These drugs are members of a heterogeneous class of antiasthma agents with the potential to interfere with the initial steps in the inflammatory cascade. Leukotrienes are inflammatory substances related to prostaglandins; both are generated from arachidonic acid in cell membranes. When arachidonic acid in mast cells, macrophages, monocytes, eosinophils, and basophils is released from membrane phospholipids by phospholipase A2, it is metabolized via two major pathways: the cyclooxygenase pathway (which produces prostaglandins and thromboxanes) and the 5- lipoxygenase pathway (which produces leukotrienes). Leukotrienes play an important role in bronchial inflammation. They induce migration, aggregation, and adhesion of various white blood cells (neutrophils, eosinophils, monocytes), increase capillary permeability, and cause bronchial smooth muscle contraction. The results include edema, leukocyte chemotaxis, enhanced production of mucus, reduced mucociliary transport, and bronchospasm. Certain classes of leukotrienes – for example, the cysteinyl leukotrienes – are particularly potent bronchoconstrictors, being approximately 100 to 1,000 times more active than histamine.

In recent months, the FDA has approved two antileukotrienes: zafirlukast and zileuton. Zafirlukast blocks receptors for cysteinyl leukotrienes C4, D4, and E4, and zileuton specifically inhibits 5-lipoxygenase, thus preventing the synthesis of leukotrienes B4, C4, D4, and E4. With long-term use, these new drugs significantly relieve the wheezing, coughing, and dyspneic symptoms of asthma. They are not bronchodilators and should not be used to reverse bronchospasm, although therapy can be continued during acute attacks.