Drug treatment of respiratory disorders

Chapter 13 Drug treatment of respiratory disorders

ANATOMY AND PHYSIOLOGY

The organs of the respiratory system comprise the nose, pharynx, larynx, trachea, bronchi, bronchioles, alveoli and lungs (Fig. 13.1).

Fig. 13.1 The organs of the respiratory system: the lungs and an alveolus.

The main functions of respiration are to take in oxygen and to give off carbon dioxide. In health, the respiratory epithelium is protected by a mucous blanket of secretions, and ciliary activity ensures that the airways remain clear to allow the transport of gases between the alveoli and the atmosphere. The commonest disorders of the respiratory system are the result of:

• upper respiratory tract infection

• inhaled irritants

• intrinsic causes.

Changes to mucus production and cilia lead to cough, while narrowing of the airways produces dyspnoea and, in some cases, wheezing. Depending on the body’s capacity to compensate for diminished oxygen intake, the patient may or may not become cyanosed. Drug treatment is directed primarily towards getting the airways to function normally. A variety of pulmonary function tests assists the doctor in both making a diagnosis and selecting the appropriate drug therapy.

ASTHMA

OVERVIEW

Asthma is a common condition placing a heavy burden on healthcare resources. It has been estimated that 5.1 million people in the UK (1.4 million children and 3.7 million adults) currently receive treatment for asthma (National Asthma Campaign 2001). Most asthma care is provided in primary care. Estimates place the current annual cost of treating asthma within the NHS at £850 million.

People with asthma may suffer from a variety of symptoms, none of which is specific for asthma (British Thoracic Society and Scottish Intercollegiate Guidelines Network 2005). The hallmark of asthma is that these symptoms tend to be:

• shortness of breath

• chest tightness

• intermittent

• worse at night

• provoked by triggers, including exercise.

Asthma can be divided into two broad types.

• Early onset, which occurs in childhood or adolescence, is allergy-related and occurs in patients who develop allergic disorders such as eczema or hay fever; there is a strong familial tendency.

• Late onset, which affects older people, has no allergic cause and is often referred to as intrinsic asthma.

Various factors can aggravate both types, and these include dust, tobacco smoke, environmental pollution, rapid changes in humidity or temperature, respiratory tract infection, exercise and stress.

While allergic asthma often resolves after a few years, intrinsic asthma rarely does. Severe acute asthma is a medical emergency clinically recognised by severe wheeze, inability to speak sentences without pausing for breath and a pulse rate over 110 per minute in the adult.

ALLERGIC CONDITIONS

Allergic conditions vary from mild forms of hay fever, skin rashes and eczema to more severe forms such as asthma and anaphylactic shock. Allergens that provoke this response in certain individuals include pollen, animal hair, dust, components of various foods (such as fish and eggs), some food dyes (notably tartrazine), drugs and feathers.

Initial exposure to an allergen inhaled or ingested into the body stimulates the production and release of immunoglobulin E from lymph nodes in atopic individuals. The immunoglobulin E becomes fixed to mast cells (sensitised mast cells), which, on a second exposure to the allergen, causes release of inflam-matory mediators including histamine, the cysteinyl-leukotrienes and prostaglandin D₂.

In allergic asthma, the initial response to allergen provocation occurs abruptly and is due to spasm of the bronchial smooth muscle and results in inflammation with oedema of the bronchial mucosa.

PHARMACOLOGICAL MANAGEMENT

The aims of pharmacological management of asthma are the control of symptoms, including nocturnal symptoms and exercise-induced asthma, prevention of exacerbations and the achievement of best pulmonary function with minimal side-effects. Individual patients will have different goals and may also wish to balance these against the potential side-effects or inconvenience of taking the medication necessary to achieve ideal control. In general, control of asthma is assessed against the following:

• minimal symptoms during day and night

• minimal need for reliever medication

• no exacerbation

• no limitation of physical activity

• normal lung function, in practical terms forced expiratory volume in 1 s (FEV₁) and/or peak expiratory flow > 80% predicted or best.

A stepwise approach aims to abolish symptoms as soon as possible and to optimise peak flow by starting treatment at the level most likely to achieve this. Patients should start treatment at the step most appropriate to the initial severity of their asthma. The aim is to achieve early control and to maintain control by stepping up treatment as necessary and stepping down when control is good. Before initiating a new drug therapy, practitioners should check compliance with existing therapies and inhaler technique, and eliminate trigger factors.

Drugs used in the management of asthma include:

• β₂ agonists

• antimuscarinic bronchodilators

• theophylline

• corticosteroids

• leukotriene receptor antagonists.

ADMINISTRATION OF DRUGS FOR ASTHMA

Inhalation delivers the drug directly to the airways, requiring a smaller dose than with the oral route, resulting in reduced side effects. Various devices are available for delivering a measured dose (see p. 235). The use of a spacer device may improve drug delivery. Solutions for nebulisation are available for use in acute severe asthma. They are administered over a period of 5–10 min from a nebuliser (see p. 237).

Oral preparations are taken when administration by inhalation is not possible. Systemic side effects occur more frequently when a drug is given orally rather than by inhalation, because of the higher dose required orally. Drugs given by mouth for the treatment of asthma include β₂ agonists, cortico-steroids, theophylline and leukotriene receptor antagonists.

In acute severe asthma, drugs such as β₂ agonists, corticosteroids and aminophylline may be given by injection when administration by nebulisation is inadequate or inappropriate.

SELECTIVE β₂ AGONISTS

Mild to moderate symptoms of asthma respond rapidly to the inhalation of a selective short-acting β₂ agonist such as salbutamol. These drugs have a rapid onset of action – about 15 min – and their effects last between 4 and 6 h. They are indicated in step 1 of the advice on the management of acute asthma based on the recommendations of British Thoracic Society and Scottish Intercollegiate Guidelines Network (2005; see p. 232). If β₂-agonist inhalation is required three or more times a week, there should be a move to step 2.

Salmeterol and formoterol are longer-acting β₂ agonists that are administered by inhalation. They are not suitable for relief of an acute asthma attack and are administered as a preventive. β₂ agonists are highly effective at preventing bronchoconstriction when used shortly before exercise or exposure to known allergens. The longer-acting β₂ agonists are included in step 3 (see p. 232) for regular, twice-daily use as second-line controlling treatment in conjunction with a standard dose of inhaled corticosteroid. Dosages of β₂ agonists are shown in Table 13.1.

Table 13.1 β₂ agonists

Drug	Dose
Formoterol	Dry powder for inhalation:
	12–24 micrograms twice daily
	By turbohaler: 6–24 micrograms twice daily
Salbutamol	Aerosol inhalation for persistent symptoms: 100–200 micrograms three or four times daily; for prophylaxis in exercise-induced bronchospasm, 200 micrograms (one or two puffs) Inhalation of powder: 200–400 micrograms for persistent attacks three to four times daily; for prophylaxis of exercise-induced bronchospasm 400 micrograms
	Inhalation of nebulised solutions:
	2.5–5 mg up to four times daily
	Oral: 2–8 mg three to four times daily
Salmeterol	By inhalation: 50–100 micrograms twice daily
Terbutaline	Inhalation of powder: 500 micrograms up to four times daily
	Inhalation of nebulised solution:
	5–10 mg two to four times daily
	Oral: 2.5–5 mg three times daily

Mode of action.

β₂ agonists act by directly stimu-lating β₂ receptors in the smooth muscle of the airways, producing bronchodilation. They also stabilise mast cells, preventing release of inflammatory mediators and histamine on exposure to allergens.

Side-effects.

Only small doses of β₂ agonists are required by the inhalation route. In this way, side-effects are minimised. Side-effects may occur with the much higher doses required by the oral route and include fine tremor in the hands or headaches.

CORTICOSTEROIDS

Inhaled corticosteroids

Inhaled corticosteroids are the mainstay of preventive therapy in asthma. Inhaled steroids are best started at high dose and reduced as control is achieved. High-dose steroids via metered dose inhalers should be taken through spacers (see p. 236).

Mode of action.

Inhaled corticosteroids act by inhibiting a variety of inflammatory agents, reducing inflammatory aspects of asthma and decreasing bronchospasm.

Inhaled corticosteroids are also recommended for prophylactic treatment of asthma when patients are using a β₂ agonist more than once daily. Corticosteroid inhalers must be used regularly to obtain maximum benefit; alleviation of symptoms usually occurs 3–7 days after initiation. Beclometasone dipropionate, budesonide and fluticasone propionate appear to be equally effective. If a patient is using a β₂ agonist inhaler and a corticosteroid inhaler concurrently, the β₂ agonist should be inhaled first, as the resulting bronchorelaxation will result in a more effective dose of corticosteroid.

Patients who have been taking long-term oral corticosteroids can often be transferred to an inhaled corticosteroid, but the transfer must be slow, with gradual reduction in the dose of oral corticosteroid and at a time when the asthma is well controlled. High-dose inhalers are available for patients who respond only partially to standard dose inhalers.

Systemic therapy may be necessary during episodes of infection or if asthma is worsening, when higher doses are needed and access of inhaled drug to small airways may be reduced.

Side-effects of corticosteroids.

Because of the much smaller dose administered, inhaled corticosteroids have considerably fewer systemic effects than oral corticosteroids, but adverse effects have been reported, including a small increased risk of glaucoma with prolonged high doses of inhaled corticosteroids; cataracts have also been reported with inhaled cortico-steroids. Higher doses of inhaled corticosteroids may induce adrenal suppression, and patients on high doses should be given a steroid card (see Ch. 16).

Bone mineral density is reduced following long-term inhalation of higher doses of corticosteroids, and this may predispose patients to osteoporosis (see Ch. 16).

Patients on inhaled steroids should wash out the mouth and teeth after treatment to reduce the occurrence of fungal infection. Use of a large-volume spacer device may be helpful for those experiencing side effects.

Oral corticosteroids

Acute attacks of asthma should be treated with short courses of oral corticosteroids starting with a high dose, for example prednisolone 40–50 mg daily for at least 5 days. Patients whose asthma has deteriorated rapidly usually respond quickly to corticosteroids. The dose can usually be stopped abruptly in a mild exacerbation of asthma. When patients take long-term steroids (greater than 7.5 mg daily for more than 3 months), side effects may be experienced: indigestion, water retention, muscle weakness, signs of diabetes, hypertension, depression and cataracts.

ANTIMUSCARINIC BRONCHODILATORS

Ipratropium can provide short-term relief in chronic asthma, but short-acting β₂ agonists act more quickly and are preferred. Ipratropium by nebulisation may be added to other standard treatment in life-threatening asthma or when acute asthma fails to improve with standard therapy.

Antimuscarinic bronchodilators are regarded as being more effective in relieving bronchoconstriction associated with chronic obstructive pulmonary disease (COPD, see pp. 231-234) than in relieving asthma.

THEOPHYLLINE

Theophylline is a bronchodilator used for reversible airways obstruction. It may have an additive effect when used in conjunction with small doses of β₂ agonists. The bronchodilatory effect of theophylline has been used for many years in the treatment of patients with persistent symptoms. Theophylline is indicated in step 3 of the British Thoracic Society and Scottish Intercollegiate Guidelines Network (2005) guideline as an addition in patients taking high-dose (800 micrograms daily) inhaled corticosteroids whose asthma is still uncontrolled following a trial of a long-acting β₂ agonist. Patients who suffer from nocturnal asthma may benefit from slow-release preparations of theophylline, as these can provide therapeutic plasma concentrations overnight.

Theophylline acts by inhibiting the enzyme phosphodiesterase in bronchial muscle, causing it to relax and thus relieve bronchospasm. Theophylline may also have an anti-inflammatory effect and may therefore be of benefit when used in combination with inhaled corticosteroids, providing an alternative to increasing the dosage of corticosteroids in suitable patients.

Theophylline has a narrow margin between the therapeutic and the toxic dose. In most patients, a plasma theophylline concentration of 10–20 mg/L is usually required for satisfactory bronchodilation. A dose of theophylline of 125–250 mg three or four times daily is given after food. However, theophylline modified-release preparations are usually able to produce adequate plasma concentrations for up to 12 h. When given as a single dose at night, they have a useful role in controlling nocturnal asthma and early morning wheezing.

Theophylline is given by injection as aminophylline: a mixture of theophylline with ethylenediamine, which is 20 times more soluble than theophylline alone. Aminophylline must be given by very slow intravenous injection (over at least 20 min); it is too irritant for intramuscular use.

Intravenous aminophylline has a role in the treat-ment of severe attacks of asthma that do not respond rapidly to a nebulised β₂ agonist. Measurement of plasma theophylline concentration may be helpful and is essential if aminophylline is to be given to patients who have been taking oral theophylline preparations, because serious side effects such as convulsions and arrhythmias can occasionally precede other symptoms of toxicity.

Side-effects.

Side-effects can occur within the 10–20 mg/L plasma theophylline concentration, but their frequency and severity increase at concentrations above 20 mg/L. These include nausea, insomnia and palpitations. These may be the initial signs of toxicity, and the patient should be referred to the doctor as soon as possible.

Metabolism/drug interactions.

Theophylline is metabolised in the liver; there is considerable variation in its half-life, particularly in smokers, in patients with hepatic impairment or heart failure, or if certain drugs are taken concurrently. The half-life is increased in heart failure, cirrhosis, viral infections and in the elderly, and by drugs such as cimetidine, ciprofloxacin, furosemide, calcium-channel blockers, erythromycin, fluvoxamine and oral contraceptives. The half-life is decreased in smokers and in chronic alcoholism, and by drugs such as phenytoin, carbamazepine, rifampicin and barbiturates.

These differences in half-life are important be-cause theophylline has a narrow margin between the therapeutic and toxic dose, and will necessitate a reduction or an increase in dosage in order to maintain the plasma level between 10 and 20 mg/L. Conversely, if a smoker decides to quit, the effect of the theophylline dose may be increased.

LEUKOTRIENE RECEPTOR ANTAGONISTS

Cysteinyl leukotrienes cause potent stimulation of bronchial smooth muscle, release of eosinophils and production of secretions in the airways. Leukotriene receptor antagonists block these effects, relieving smooth muscle bronchoconstriction and preventing inflammation.

Montelukast and zafirlukast are indicated for the prophylaxis of asthma. They are also useful in preventing exercise-induced asthma and aspirin-sensitive asthma.

The dose for montelukast is 10 mg daily at bedtime and for zafirlukast is 20 mg twice daily.

Side-effects appear to be mild but include gastrointestinal disturbances.

CROMONES

The cromones consist of sodium cromoglicate and nedocromil sodium. The cromones improve symptom control in mild to moderate asthma but are less effective than corticosteroids and have therefore been superseded by inhaled steroids, and their use in practice has declined.

Cromones inhibit the release of substances from mast cells responsible for bronchospasm by causing mast cell stabilisation, and are therefore referred to as mast cell stabilisers. Both cromoglicate and nedocromil reduce allergen-induced early- and late-phase responses to immunological stimuli, and they inhibit bronchospasm during and after exercise and exposure to cold or dry air. They tend to be more effective in patients with mild atopic asthma, in particular children with exercise- or allergen-induced asthma.

Because of their short duration of action and four times daily dosing, compliance with therapy can be a problem. However, cromones are well tolerated and rarely cause adverse effects.

STEPWISE MANAGEMENT

The steps involved in the management of asthma in adults are illustrated in Figure 13-2.

Fig. 13.2 Stepwise management of asthma in adults.

STEPPING DOWN

Stepping down treatment once asthma is controlled is recommended but often not implemented, leaving some patients overtreated. Regular review of patients as treatment is stepped down is important. When deciding which drug to step down first and at what rate the severity of asthma, the side-effects of the treatment, the beneficial effect achieved and the patient’s preference should all be taken into account.

Patients should be maintained at the lowest possible dose of inhaled steroid. Reduction in inhaled steroid dose should be slow, as patients deteriorate at different rates. Reductions should be considered every 3 months, decreasing the dose by approximately 25–50% each time.

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May 13, 2017 | Posted by admin in NURSING | Comments Off

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