<h2>British Guideline on the Management of Asthma</h2>
Aim of oxygen therapy is to maintain SpO2>=92%.
SpO2 = the saturation level of oxygen in hemoglobin; can be determined by noninvasive method of pulse oximetry. ABGs should be taken for patients with SpO2 <92%
ABGs as marker of severity – Normal or raised PaCO2 >4.6kPa 35mmHg, Severe hypoxia PaO2 <8kPa, 60mmHg; Low pH (raised PaCO2 indicates near fatal asthma exacerbation)
<h2>Management of Asthma</h2>
Treatment of asthma has two aims: relief of symptoms and reduction of airways inflammation.
First aim of therapy is to reduce the chronic inflammation and airway hyperresponsiveness with anti-inflammatory drugs, particularly inhaled glucocorticoids and leukotrine inhibitors. The second aim is to overcome acute excessive airway smooth muscle contraction with bronchodilator drugs. These relax airway smooth muscle or block the actions of bronchoconstrictors. For example, one class of bronchodilator drugs mimics the normal action of epinephrine on beta-adrenergic (beta 2) receptors. Another class of bronchodilator drugs block muscarinic cholinergic receptors, which have been implicated in bronchoconstriction.
Severe asthma attack:
Inability to complete a sentence, pulse >=110bpm, PEFR <=50% of expected or previous best. Treat by ensuring adequate hydration, 40-60% oxygen by facemask, nebulised beta2-adrenoceptor such as salbutamol, preferably using oxygen. IV hydrocortisone and/or high-dose oral prednisolone
Life-threatening asthma attack:
Silent chest, bradycardia or hypotension, PEFR <=33% of expected or previous best, exhaustion, confusion or coma. Treat as above, plus nebulised ipratropium, IV aminophylline or beta2-adrenoceptor agonist such as salbutamol, IV magnesium sulphate, consider assisted ventilation if there is not rapid clinical improvement.
After recovery from a severe asthma attack, oral corticosteroids should be continued until there are no residual symptoms, especially at night, and the PEFR is at least 80% of the person’s previous best. High doses of these drugs can be stopped abruptly if used for 3 weeks or less, or tapered off if they have been used for a longer period.
Prophylaxis of recurrent attacks
First try to identify and avoid triggers. After initially gaining control of asthma symptoms, long-term treatment is guided by a stepwise treatment plan recommended by the British Thoracic Society / Scottish Intercollegiate Guidelines Network:
Step 1 – mild intermittent ashma – inhaled short acting beta2-adrenoreceptor agonist such as salbutamol, taken as required. For those who are intolerant to this treatment, inhaled ipratropium and oral theophylline are alternative options, but with a higher risk of unwanted effects with the latter.
Step 2 – regular preventer therapy – for adults, a corticosteroid such as beclomethasone is most often used. For children and some adults, an initial trial of cromoglicate or nedocromil can be undertaken, but these agents are generally less effective than inhaled corticosteroid. A leukotriene receptor antagonist could also be tried at this stage.
Step 3 – add-on therapy – in people taking moderately high doses of inhaled corticosteroid, a suitable add-on therapy would be a long-acting beta2-adrenoceptor agonist such as salmeterol. If there is no beneficial response to the beta2-receptor agonist, it should be stopped and the corticosteroid further increased. If control still remains poor, the increased corticosteroid dose together with a long-acting beta2-adrenoceptor agonist should be given. For persistent poor control, sequential add-on therapy with either a leukotriene receptor agonist, a modified-release theophylline formulation or a modified-release oral beta2-adrenoceptor agonist should be tried.
Step 4 – Addition of fourth drug. High-dose inhaled corticosteroid with a short-acting beta2-adrenoceptor agonist as required, and usually an inhaled long-acting beta2-adrenoceptor agonist plus a sequential trial of one or more of the following:
- leukotriene receptor antagonist
- oral modified-release thophylline formulation
- oral modified-release beta2-adrenoceptor agonist
Step 5 – continuous or frequent use of oral prednisolone. This is undertaken in addition to other measures outlined above
For people with resistant disease, especially those requiring oral corticosteroids, the use of immunosuppresive drugs such as ciclosporin or methotrexate has been advocated.
Drug delivery by aerosol spray allows the use of smaller doses and therefore reduces the risk of unwanted side effects. Particles >5micrometres will impact on upper airways and be swallowed. Particles <0.5um will not deposit in the lower respiratory tract and will be exhaled. Optimal size is 1-3um.
About 1/3 users find pressurised metered dose inhalers difficult. Even with optimal coordination, ~70-90% of aerosol is deposited in the oropharynx, then swallowed. Spacers – 750ml, 350ml for young children. Breath activated devices, delivering either aerosol or dry powder, require high airflow and are therefore less efficient than metered-dose inhalers, especially in those with severe airflow limitation. Nebulisers distribute drug from reservoir solution. Jet nebulisers pass air or oxygen through a narrow orifice to such drug solution from a reservoir into a feed tube with fine ligaments. The impact of the solution on these ligaments generates droplets. Ultrasonic jet nebulisers use a piezoelectric crystal vibrating at high frequency – vibrations transmitted through a buffer to the drug solution form a fountain of liquid in the nebulisation chamber. Ultrasonic nebulisers produce a more uniform particle size than do jet nebulisers. Up to 10x the amount of drug is required in a nebuliser to produce the same degree of bronchodilation achieved by a metered dose inhaler. Delivery is more efficient via a mouthpiece than via a mask.
<h2>Symptom-relieving dugs of airflow obstruction.</h2>
Beta2-adrenoceptor agonists, e.g. salbutamol, terbutaline, salmeterol, formoterol
The airways are rich in beta2-adrenoceptors, which are found on bronchial smooth muscle but also on several other cell types. Effects of receptor stimulation include:
- Bronchodilation via generation of intracellular cyclic adenosine monophosphate (cAMP)
- inhibition of mediator release from mast cells
- enhanced mucociliary clearance
Selectivity of an agonist for the beta2-adrenoceptors avoids systemic unwanted effects from stimulation of beta1-adrenoceptors. The selectivity of beta2-adrenoceptors is dose dependent. Inhalation of the drug aids selectivity since it delivers small but effective doses to the airways and minimises systemic exposure. The dose-response relationship for bronchodilation is log-linear, therefore, and tenfold increase in dose is required to double the effect. A metered-dose aerosol inhaler is the most frequently used delivery mechanism, but breath-activated devices and nebuliser solutions are available.
After inhalation, the onset of drug action is rapid, often within 5 minutes, Agents such as salbutamol have an intermediate duration of action (producing bronchodilation for up to about 6h), far longer than the natural adrenoceptor agonists. Their chemical structure prevents neuronal uptake and reduces their affinity for catechol-O-methyl transferase, which metabolises catecholamines.
The long-acting agent salmeterol bronchodilates for up to 12h by virtue of a long lipophilic side-chain on the molecule, which binds to an area adjacent to the active site of the receptor, producing prolonged receptor activation. Formoterol has a prolonged duration of action by entering the lipid bilayer of the cell membrane, from which it is gradually released to stimulate the receptor.
Salbutamol and terbutaline can also be given orally (as conventional or modified-release formulations), or by subcutaneous or intramuscular injections or by IV infusion. However, larger doses are required to deliver and adequate amount to the lungs by any of these routes. This reduces selectivity for beta2-adrenoceptors, and systemic unwanted effects can be troublesome.
Tolerance to pharmacological bronchodilation can occur with beta2-adrenoceptor agonists but not with inhaled antimuscarinic drugs. The Committee on Safety of Medicines has advised that salmeterol and formoterol should not be used for relief of acute asthma and should only be used along with a concurrently administered corticosteroid.
- Fine skeletal muscle tremor from beta2-adrenoceptor stimulation
- Tachycardia and arrhythmias result from both beta1 and beta2-adrenoceptor stimulation when high doses of inhaled drug are used, or after oral or parenteral administration.
- Acute metabolic responses to high-dose beta2-adrenoceptor stimulation include hypokalaemia, hypomagnesaemia and hyperglycemia. They do not persist during long term use.
- Paradoxical bronchospasm has been reported with inhalation, usually when given for the first time or with a new canister.
Concern has been expressed that regular use of high doses of inhaled beta2-adrenoceptor agonsits may be linked with asthma deaths by precipitation of serious arrhythmias. An alternative possibility is that high doses might allow people to tolerate initial exposure to larger doses of allergens or irritants, which then produce an enhanced late asthmatic response. However it is more likely that the use of high doses is really a reflection of the severity of the underlying asthma.
Anticuscarinic agents, e.g. ipratropium, tiotropium
The antimuscarinic drugs used for bronchodilation are non-selective and bind to all three types of muscarinic receptors in the lung. It remains uncertain whether they also have specific anti-inflammatory effects in addition to their actions on bronchial smooth muscle and mucus secretion. Main use is in COPD, where they are effective. Little use in mild to moderate asthma, but may have a place when added to beta2-adrenoceptor agonists in severe exacerbations of asthma.
Methylxanthines: theophyline, aminophyline
Methylxanthines are a group of naturally occuring substances found in tea, coffee, chocolate and related foodstuffs. Theophylline and its ester derivative aminophylline are the only compounts in clinical use, chemically similar to caffeine. Vasodilator, anti-inflammatory and immunomodulatory actions.
<h2>Anti-inflammatory drugs for airways obstruction</h2>
Corticosteroids e.g. beclamethasone, dipropionate, budesonide, hydrocortisone, fluticasone, propionate, mometasone, prednisolone
Glucocorticoids are the most effective class of drug in the treatment of chronic asthma but are relatively ineffective in COPD. The are recommended as preventer when inhaled beta2-androceptor agonists are used more than once daily. They act to suppress inflammation and the immune response. Powerful glucocorticoids, devoid of significant mineralcorticoid activity, are usually used. (see Steroids)
Intracellular events involved in the anti-inflammatory action
A major event in asthma is probably activation of glucocorticoid receptors that inhibit transcription of genes coding for the cytokines involved in inflammation. Glucocorticoid receptors recruit histone deacetylases to the transcription complex of activated inflammatory genes. The deacetylation of core histones at the transcription complex silence genes that have been activated by inflammatory stimuli. Used long term, corticosteroids reduce airway responsiveness to several bronchoconstrictor mediators and block both the early and late reactions to allergen. Following a delay of 6-12h, several anti-inflammatory actions occur which may be important in ashtma.
Short term anti-inflammatory effects include:
- Reduced inflammatory cell activation (including macrophages, T-lymphocytes, eosinophils and airway epithelial cells)
- Decreased IgE synthesis
- Reduced mucosal oedema and decreased local generation of inflammatory prostaglandins and leukotrienes by inhibition of phospholipase A2
- Beta-adrenoceptor upregulation, which restores responisveness to beta2-adrenoceptor agonists.
Longterm anti-inflammatory effects include:
- Reduced T-cell cytokine production and reduced dentritic cell signalling to T-cells
- Reduced eosinophil deposition in bronchial mucosa (by removing cytokine stimulation, reducing expression or epithelial adhesion molecules and enhancing apoptosis)
- Reduced mast cell deposition in bronchial mucosa (although the release of mediators from these cells is unaffected)
- Reversal of the excess epithelial cell shedding and goblet cell hyperplasia found in the bronchial epithelium in asthma.
Inhaled corticosteroids produce some improvement in asthmatic symptoms after 24h and a maximum response after 1-2weeks. Reduction in airway responsiveness to allergens and irritants occurs gradually over several months. Corticosteroids block the late-phase reaction to allergens in asthma. However, many of the chronic structural changes in the airways in asthma are unaffected by corticosteroids.
Pharmacokinetics: Corticosteroids can be used intravenously or orally in severe asthma. However, wherever possible they are given by inhalation of an aerosol or dry powder to minimise systemic unwanted effects. Desirable properties of the inhaled corticosteroid include low rates of absorption across mucosal surfaces (such as the lung, but also including the gut for swallowed drug) and rapid inactivation once absorbed. Beclomethasone dipropionate fulfils the former criterion but is only slowly inactivated once it reaches the systemic circulation. Mudesonide (which is inactivated by extensive first-pass metabolism in the liver if systemically absorbed) and fluticasone (which is very poorly absorbed from the gut) are not given orally and may be prefered if high doses of inhaled drug are needed, or for the treatment of children.
Unwanted effects: amount of swallowed drug can be minimised using a large-volume spacer. Hoarseness and oral candidiasis can occur with inhaled corticosteroids.