• 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.
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.
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.
• 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.