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Asthma pharmacotherapy--the goal is optimised control.

Asthma is one of the commonest chronic diseases in the world, with an estimated 300 million asthmatics worldwide. (1) In 2004 South Africa was estimated to have a prevalence of clinical asthma of 8.2%, and although ranked 25th in the world in terms of prevalence, South Africa was ranked 5th for asthma case fatality rates, with an estimated case fatality rate of 18.5 per 100 000. (1) It is also of concern that there is a rising prevalence in asthma symptoms in South Africa. (2)

The goal of chronic asthma management is good and sustained control of symptoms, so that the patient is symptom free, able to maintain normal activity levels (including exercise), with minimal adverse effects from medication. (3) A key component of effective asthma treatment is optimising pharmacotherapy.

Based on our current understanding of their mechanism of action, asthma drugs are classified and used as controllers and relievers.

Controller medications

Controllers are medications taken daily on a long-term basis. (4) There are 2 groups of controllers: those with anti-inflammatory action and those with a sustained bronchodilator action (Table I). These drugs are the cornerstone of effective asthma control.

Asthma is an episodic narrowing of the bronchi thought to be caused by an underlying chronic inflammatory disorder, and anti-inflammatory treatment is therefore recommended for all patients with chronic persistent asthma.

Inhaled corticosteroids

Inhaled glucocorticosteroids are currently the most effective anti-inflammatory medication for the control of persistent asthma. They reduce asthma symptoms, improve quality of life, improve lung function, decrease airway hyper-responsiveness, control airway inflammation, reduce frequency and severity of exacerbations and reduce asthma mortality. (4) However, they do not cure asthma, and when discontinued, deterioration of control follows. (4) A major advantage of inhaled corticosteroids is that the drug is targeted directly to the site of inflammation in the lungs. This substantially diminishes the number and severity of side-effects without sacrificing treatment effectiveness. A small fraction of any inhaled drug can reach the systemic circulation by direct absorption from the airways or by absorption from the gastrointestinal tract when swallowed, but current evidence suggests that in adults, systemic effects of inhaled corticosteroids do not occur at doses of 400 [micro]g or less budesonide or equivalent daily. (4) Inhaled glucocorticosteroids may cause oropharyngeal candidiasis and hoarseness, particularly at higher doses. The incidence of these local adverse effects can be reduced substantially by rinsing the mouth and throat with water after each dose and by the use of spacer devices attached to the dispenser, to improve drug delivery to the site of action and decrease drug deposition in the oral cavity. Inhaled corticosteroids differ in clinical potency (Table II). The equivalent of 200-500 [micro]g/day of beclomethasone diproprionate (BDP) would be regarded as a low dose, and the equivalent of 1 000 [micro]g or more of BDP a high dose. (3) High-dose inhaled corticosteroids give a relatively flat dose response curve, with little increase in clinical efficacy and an increased risk of systemic side-effects, such as easy bruising, adrenal suppression, osteoporosis, cataracts and glaucoma.

Long-acting [[beta].sub.2]-agonists

Two long-acting inhaled [[beta].sub.2]-agonists (LABAs) are available in South Africa: salmeterol, and formoterol. They have a similar duration of bronchodilation but formoterol has a more rapid onset of action, and can be used to relieve symptoms in acute exacerbations in addition to its role in symptom prevention. LABAs have no anti-inflammatory effect. They should never be used as monotherapy in asthma as this has been shown to increase mortality. (5) Their role is as add-on therapy to inhaled corticosteroids. When inhaled glucocorticosteroids alone fail to achieve control of asthma, a LABA should be added as a first step, before increasing the dose of inhaled corticosteroids. Inhalation corticosteroids and LABAs are available in fixed-combination inhalers that deliver both glucocorticosteroids and long-acting inhaled [[beta].sub.2]-agonists simultaneously (budesonide plus formoterol or fluticasone plus salmeterol). These formulations may be more convenient for patients and may thus improve adherence. (3) Long-acting inhaled [[beta].sub.2]-agonists may be used to prevent exercise-induced bronchospasm and are useful for control of nocturnal symptoms. LABAs may cause tremor and palpitations. The regular use of [[beta].sub.2]-agonists in both short- and long-acting forms may lead to decreased sensitivity to [[beta].sub.2]-agonists, with reduced clinical response. (4)

Leukotriene receptor antagonists

Leukotriene receptor antagonists block the bronchoconstrictor and proinflammatory activity of cysteinyl leukotrienes (metabolites of arachodonic acid produced by mast cells, basophils and eosinophils) within the asthmatic airway. (6) They have a bronchodilator effect, reduce symptoms, improve lung function and reduce airway inflammation and asthma exacerbations. When used as monotherapy, they are not as effective as low-dose inhaled corticosteroids and they should therefore not be used as a substitute for glucocorticosteroids. (4) Leukotriene receptor antagonists added to inhaled corticosteroids are less effective than LABAs added to inhaled corticosteroids in the treatment of asthma. (7) They may be useful as add-on therapy in patients with moderate to severe asthma, who are already taking inhaled corticosteroids and a LABA but remain symptomatic, in patients who do not tolerate LABA side-effects, or to allow for a reduction in the dose of inhaled corticosteroid. Not all patients respond to leukotriene receptor antagonists, and they should be withdrawn if there is no improvement in symptoms after a 4-week trial of therapy. (3) Leukotriene receptor antagonists are well tolerated with few side-effects. (4)

Sustained-release theophyllines

Theophylline is a bronchodilator with very modest anti-inflammatory properties. It should not be prescribed without inhaled corticosteroids. As add-on therapy, theophylline is less effective than LABAs. (4) Theophylline has a high potential for side-effects and drug interactions due to its narrow therapeutic range. Adverse effects include gastrointestinal symptoms, cardiac arrhythmias and seizures. There is no role for oral short-acting theophyllines in chronic asthma. (3)

Oral corticosteroids

Oral glucocorticosteroids such as prednisone may be considered in patients with severe and poorly controlled asthma, but their use in chronic asthma management is limited by the risk of significant adverse effects. Patients who require long-term systemic glucocorticosteroids should receive preventive treatment for osteoporosis. Strategies include avoidance of smoking, regular exercise, calcium supplements and, in postmenopausal women, bisphosphonates or hormone replacement therapy.

Reliever medications

Relievers (Table III) quickly reverse bronchoconstriction and relieve symptoms. They are not an alternative to controller drugs. If relievers are needed more than twice a week this is an indication that control is suboptimal and that controller medication needs to be increased or improved. (3)

Short-acting [[beta].sub.2]-agonists

Short-acting [[beta].sub.2]-agonists are the drugs of choice for relief of bronchospasm during acute exacerbations. With optimal maintenance therapy they should only rarely be needed. Increased use is an indication of deterioration of asthma control. Patients should be instructed to seek medical attention if use of short-acting [[beta].sub.2]-agonists increases. If response to [[beta].sub.2]-agonist treatment during an exacerbation is not rapid and sustained, short-term treatment of the exacerbation with oral glucocorticosteroids may be needed. (4) Oral [[beta].sub.2]-agonists should not be prescribed, as onset of action is slower than inhaled therapy and incidence of systemic side-effects such as tremor, tachycardia and headache is significantly higher.

Anticholinergics

Inhaled ipratroprium bromide is a less effective reliever medication in asthma than rapid-acting inhaled [[beta].sub.2]-agonists. (3,4) It may useful as an alternative bronchodilator for patients, particularly the elderly, who cannot tolerate the [[beta].sub.2]-agonist side-effects. Inhalation of ipratroprium bromide can cause a dryness of the mouth and a bitter taste.

Selecting chronic maintenance therapy

South African treatment guidelines outline 6 therapeutic steps (Fig. 1). It is preferable to use a step-down approach, i.e. start at a higher category and decrease later once control has been achieved.

Step 1: All patients should be prescribed an inhaled short-acting [[beta].sub.2]-agonist 200 [micro]g as needed for use as symptom relief for acute asthma symptoms. If the [[beta].sub.2]-agonist is required more than twice per week, go to step 2.

[FIGURE 1 OMITTED] (8)

Step 2: Regular twice-daily low-dose inhaled corticosteroids (200-500 [micro]g/day beclomethasone or equivalent) should be added to the short-acting [[beta].sub.2]-agonist. If still uncontrolled, go to step 3.

Step 3: There are three options in addition to an inhaled short-acting [[beta].sub.2]-agonist:

* Add a long-acting [[beta].sub.2]-agonist. This is the preferred option, unless the patient does not respond to a LABA, or

* An alternative is to double the dose of inhaled corticosteroids to moderatedose (500-1000 [micro]g/day beclomethasone or equivalent), or

* Add a leukotriene receptor antagonist to the low-dose inhalation glucocorticosteroids. If still uncontrolled, go to step 4. At this point, generalists should consider specialist referral.

Step 4: Add a moderate-dose inhaled corticosteroid (500-1000 [micro]g/day beclomethasone or equivalent) to the short-acting [[beta].sub.2]-agonist plus an additional agent such as a long-acting [[beta].sub.2]-agonist, a leukotriene receptor antagonist or a sustained-release theophylline. If still uncontrolled, go to step 5.

Step 5: Add a high-dose inhaled corticosteroid (>1 000 [micro]g/day beclomethasone or equivalent) to the short-acting [[beta].sub.2]-agonist plus more than one additional agent such as a long-acting [[beta].sub.2]-agonist, a leukotriene receptor antagonist or sustained-release theophylline.

Step 6: Oral glucocorticosteroids in the lowest effective dose can be added.

If the patient is poorly controlled the following should be considered and excluded or addressed: (3)

* poor adherence

* concomitant medications that may aggravate asthma such as aspirin, nonsteroidal anti-inflammatory drugs and [beta]-blockers

* other medical conditions such as heart failure which may mimic bronchospasm clinically

* poor metered-dose inhaler technique: this may be addressed by use of a spacer device, or by use of an alternative formulation (dry powder inhaler or autohaler)

* patient confusion about when to use controller and reliever drugs

* exposure to trigger factors at home and work

* presence of gastro-oesophageal acid reflux disease

* inadequately treated rhinitis and/or sinusitis.

Asthma is common in South Africa, and case fatality rates are alarmingly high. This suggests that many patients receive suboptimal therapy and are poorly controlled, despite the availability of a range of drugs, formulations and delivery mechanisms, as well as local, evidence-based, treatment guidelines. The appropriate use of controller medications, particularly inhaled corticosteroids and LABAs, is critical in optimising symptom control.

References

(1.) Masoli M, Fabian D, Holt S, Beasley R. Global Burden of Asthma, 2004. Availabe at http:// www.ginasthma.org (accessed 13 March 2008).

(2.) Zar HJ, Ehrlich RI, Workman L, Weinberg EG. The changing prevalence of asthma, allergic rhinitis and atopic eczema in African adolescents from 1995 to 2002. Pediatr Allergy Immunol 2007: 18: 560-565.

(3.) Lalloo U, Ainslie G, Wong M, et al. Guidelines for the management of chronic asthma in adolescents and adults. SA Fam Pract 2007; 49(5): 19-31. Available at www.pulmonology. co.za/guidelines/asthma%20adult.htm

(4.) O'Byrne P, Bateman ED, Brousquet J, et al. Global Initiative for Asthma: Global Strategy For Asthma Management and Prevention. 2006. Available at http:// www.ginasthma.org (accessed 13 March 2008).

(5.) Salpeter RS, Buckley NS, Ormiston TM, Salpeter EE. Meta-analysis: Long-acting [beta]-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med 2006;144: 904-912.

(6.) Sampson A, Holgate S. Leukotriene modifiers in the treatment of asthma. BMJ 1998; 316: 1257-1258.

(7.) Scow DT, Luttermoser GK, Dickerson KS. Leukotriene inhibitors in the treatment of allergy and asthma. Am Fam Physician 2007; 75(1): 65-70.

(8.) Gibbon CJ, Blockman M, Barnes KI, et al. South African Medicines Formulary, 8th ed. Cape Town: Health and Medical Publishing Group, 2007.

ERIC DECLOEDT, MB ChB, BSc Pharm Hons

KAREN COHEN, MB ChB, FCFP (SA), MSc (Epid), Dip HIV Man, Dip Obst

Division of Clinical Pharmacology, University of Cape Town
Table I. Classification of drugs used in the maintenance
treatment of asthma (3)

CONTROLLERS
Anti-inflammatory action Sustained bronchodilator action but
 weak or unproven anti-inflammatory
 effect
Inhaled corticosteroids Long-acting [[beta].sub.2]-agonists
* Beclomethasone * Salmeterol
* Budesonide * Formoterol
* Ciclesonide
* Fluticasone

Leukotriene receptor antagonists Sustained-release theophylline
* Montelukast preparations
* Zafirlukast

Oral corticosteroids
* Prednisone
* Prednisolone
* Methylprednisone
* Methylprednisolone

RELIEVERS

For quick relief of symptoms and use in acute attacks as when
required (PRN)
dosage only

Short-acting [[beta].sub.2]-agonists
* Salbutamol
* Fenoterol
* Terbutaline
Anticholinergics
* Ipratropium bromide

Table II. Equivalent doses of inhaled glucocorticosteroids (3)

Drug Equivalent metered dose in asthma

Beclomethasone 200-250 [micro]g
Budesonide 200 [micro]g
Ciclesonide 80 [micro]g
Fluticasone 100 [micro]g

Table III. Levels of asthma control (8)

Characteristic Controlled Partly Uncontrolled
 (all of the controlled
 following) (any measure
 present in
 any week)

Daytime symptoms [less than > 2/week
 or equal to]
 2/week

Limitations of None Any
activities 3 or more
 features
Nocturnal None Any of partly
symptoms/awakening controlled
 asthma in
Need for reliever/ [less than > 2/week any week
rescue treatment or equal to]
 2/week

Lung function Normal < 80%
(PEF/[FEV.sub.1]) predicted or
 personal
 best (if
 known)

Exacerbations None 1 or more/ 1 in any
 year * week
 ([dagger])

* Any exacerbation should prompt review of maintenance treatment
to ensure that it is adequate.

([dagger]) By definition, an exacerbation in any week makes that
an uncontrolled asthma week.

Adapted from the South African Medicines Formulary, reproduced
with permission.
COPYRIGHT 2008 South African Medical Association
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2008 Gale, Cengage Learning. All rights reserved.

Article Details
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Title Annotation:Clinical pharmacology
Author:Decloedt, Eric; Cohen, Karen
Publication:CME: Your SA Journal of CPD
Article Type:Report
Geographic Code:6SOUT
Date:Apr 1, 2008
Words:2198
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