Overview And Pharmacological Basis Of Drug Therapy Biology Essay

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Asthma - symptoms, causes, and prevalence. Asthma, a chronic inflammatory disease of the airways, is a common but a very distressing disease; asthma patients would suffer from symptoms such as shortness of breath, wheezing, tightness in the chest, as well as coughing. Symptoms can be worse either in the morning or at night, or in response to trigger factors e.g. exercise, cold air etc. Acute exacerbation of asthma (or asthma attack) is therefore the acute worsening of the symptoms, brought on by various factors.

The exact cause of asthma is not known, however there are environmental and genetic factors that predispose a person to it.1 Atopic diseases seem to be prevalent in asthmatic patients; those who have eczema and hay fever are at a higher risk of developing asthma, and those who have a family history of asthma may also be affected by it at some point in their life. Asthmatics may find that their asthma can exacerbated by various triggers, such as environmental allergens (e.g. mold, pollen), certain medications (e.g. NSAIDs), environmental pollutants (e.g. tobacco smoke), and exercise.

Asthma prevalence in the UK was observed to be increasing in the last century, however recent reports suggest that the number of new cases of asthma has declined.2 WHO estimated that there are 300 million asthmatics and 255 000 deaths due to asthma in 2005.3

Pathophysiology

The inflammatory process in asthma is mediated by various inflammatory cells, and no single cell is completely responsible in the pathophysiology, although some cells are more important than others in causing the inflammation. While mast cells are more involved in initiating acute responses to stimuli, chronic events are mainly mediated by other cells, particularly macrophages, eosinophils, and T-lymphocytes.4

Macrophages are activated via low affinity IgE receptors, and release a number of inflammatory mediators including cytokines when activated by stimuli (i.e. allergens). They may also play a role as antigen-presenting cells, which present the allergens to T-lymphocytes after processing them. Eosinophils may be increased after allergen inhalation. Their infiltration is a feature characteristic of asthmatic inflammation, which differentiates it from other airway inflammatory conditions. T-lymphocytes release cytokines in response to allergen, resulting in inflammatory reactions in the airway.4

The inflammatory mediators released by the inflammatory cells are responsible for the chain of events that leads to symptoms of asthma. Histamine, prostaglandins, and leukotrienes are important mediators in acute inflammatory responses. They cause constriction of the airway smooth muscle, increase microvascular leakage and airway mucus secretion, and engage other inflammatory cells. Cytokines are more important in chronic inflammation. The particularly important cytokines include IL-3, which plays a role in maintaining mast cells in tissues; IL-4, which prompts B-lymphocytes to produce IgE and express VCAM-1 on endothelial cells; and IL-5, which plays a role in differentiation, durability, and priming of eosinophils.

The inflammation of the airways leads to mucus hypersecretion, which results in the formation of the mucus plugs that block the airways.

Diagnosis

Asthma is diagnosed based on some characteristic clinical features in the individual that either increase, or lower the probability of asthma. The features that increase the probability of asthma, in addition to symptoms such as wheezing, breathlessness, cough, and tightness to chest include; self and family history of asthma and atopic diseases, worsening of symptoms in response to stimuli, and unexplained low FEV1 and PEF.5

Confirmation of a diagnosis of asthma depends on the individual's peak expiratory flow. The peak expiratory flow is preferably measured with spirometry, as it provides a clearer indication of the extent of airflow obstruction, and the results also rely less on the effort exerted.5

Some differential diagnoses in asthma include COPD, bronchiectasis, large airway stenosis, and gastro-oesophageal reflux.

Asthma management and summary of drug pharmacology

The acute management of asthma depends on the severity of the asthma attack. The main drugs used in the relief of acute asthma are inhaled short-acting beta2 agonists such as salbutamol, the corticosteroid prednisolone by mouth, inhaled antimuscarinic bronchodilator ipratropium bromide, and in severe acute and life-threatening acute asthma, the bronchodilator aminophylline is given intravenously when there is failure of response. The modes of action of the drugs are summarised as below (Table 1).

Drug

Mode of Action

Salbutamol

Directly activates β2-adrenoceptor, inducing cyclic AMP and production of intracellular signalling, and subsequently airway relaxation.

Prednisolone

Inhibits release of cellular mediators e.g. interleukins, prostaglandins, leukotrienes.

Ipratropium bromide

Blocks action of acetylcholine at parasympathetic sites in airway smooth muscle, causing bronchodilation.

Aminophylline

Inhibits phosphodiesterase enzyme thus increasing intracellular cAMP; antagonist at adenosine receptor; inhibits action of prostaglandin.

Table 1: Modes of action of drugs used in acute management of asthma.

Chronic management of asthma involves a stepwise approach, as outlined in the British Thoracic Society (BTS)/ Scottish Intercollegiate Guidelines Network (SIGN) guideline for the management of asthma.5

Evidence for the treatment of the condition

Treatment of acute exacerbation of asthma depends on the extent of severity of symptoms the patient presents with, i.e. ability of speech, respiratory rate, pulse rate, arterial oxygen saturation, and peak flow. However, patients with severe or life-threatening acute asthma may not have all of the abnormalities that usually accompany these types of asthma exacerbation. Thus, unless shown otherwise, it is advised that all emergency cases should be treated as severe acute asthma.

The BTS/SIGN guideline recommends the use of short-acting beta2 agonists as first line agents in acute asthma. The beta2 agonists commonly used are salbutamol and terbutaline, but other beta2 agonists such as adrenaline have also been used to treat acute asthma. The guideline recommends either inhaled or nebulised salbutamol or terbutaline to be given for the quick relief of bronchospasm, and should be given as early as possible, but there is no evidence comparing the efficacy between the two drugs.

Salbutamol has been shown to be just as effective as adrenaline in the treatment of acute asthma.6 In a study by Garrett et al, 22 patients with acute severe asthma were randomised to either nebulised salbutamol or nebulised adrenaline. The peak expiratory flow (PEF) increased significantly for both groups on evaluation at 20 and 40 minutes. The PEF in the salbutamol group was slightly better than in the adrenaline, however the difference did not reach statistical significance. No side effects were recorded with either drug.

Beta2 agonist may be given as a metered-dose inhalation, or as nebulisation. Rodrigo et al studied the difference in efficacy between salbutamol delivered by metered-dose inhaler plus spacer (MDI-spacer) and by wet nebulisation.7 22 patients treated at the ED for acute exacerbation of asthma were randomly assigned to receive salbutamol either by an MDI-spacer or a nebuliser. Both groups showed significant increase in PEF and FEV1 from baseline values, however there was no significant difference in the increase between the two groups. It was also found that2.5 mg of salbutamol by nebulisation was needed to achieve the same therapeutic effect produced by 1 mg of salbutamol by MDI-spacer. Nebuliser delivery also produced more side effects, as more salbutamol were absorbed, which resulted in a higher plasma level.

Inhaled beta2 agonists have also been compared to intravenous (IV) administration, and studies have shown that the IV route is not superior to the inhaled route in acute severe asthma.8,9 IV beta2 agonists should only be administered in those not eligible for inhaled therapy.

In this case the patient, Ms. J, was appropriately given inhaled salbutamol in the ED, as well as in the ward. She had also been on inhaled salbutamol for the management of her chronic asthma previously.

Steroids are known to have some benefits in the treatment of acute asthma. Early administration of steroids can prevent relapses and subsequent hospitalisation, as well as improving pulmonary function.10 The BTS/SIGN guideline recommends that steroids be given in all cases of acute asthma, either orally or intravenously. An evidence-based evaluation of the use of corticosteroids in the acute treatment of asthma exacerbation in the ED suggests that IV administration corticosteroids does not reduce hospitalisation rates, nor does it improve obstruction of airflow.11 The paper also suggests that IV corticosteroids may take 6 to 24 hours to produce an effect. Effects of both IV and oral corticosteroids appear to be equal.

A meta-analysis of nine different trials comparing the efficacy of low, medium, and high doses of corticosteroids suggests that the outcomes concerning pulmonary function in the treatment of acute severe asthma are similar, although the doses vary.12 High dose corticosteroids do not appear to be therapeutically superior to low or medium doses in acute severe asthma.

Ms. J was given prednisolone orally, and at a low dose of 30 mg, which, based on the evidence above, was appropriate for her.

The guideline also states that the steroid doses do not need to be tapered down after a course of acute administration, provided that the patient receives inhaled steroids. O'Driscoll et al studied 35 patients presented at the hospital with acute asthma.13 The patients were all treated for 10 days with 40 mg enteric coated prednisolone, before being randomised to receive either a lower dose of 5 mg prednisolone or a placebo for the next 8 days. The dose was tapered down from seven tablets at day 11 to no tablets at the end of the course. It was found that tapering down of dose did not produce a better response than abruptly stopping the steroid course in acute asthma.

Ms. J was given oral prednisolone for 5 days only, and the course was stopped after the recovery of her acute asthma. The decision to not taper down her prednisolone dose is therefore an appropriate and safe decision.

There is some evidence that ipratropium bromide is just as effective as an initial bronchodilator as beta agonists, as shown by Leahy et al.14 Patients with acute exacerbation of asthma were randomised to either one of two groups; one group received ipratropium first before being given salbutamol 1 hour later, the other group received the drugs in the reversed order. It was found that there were no significant differences in the PEFR, arterial PO2, respiratory frequency, and heart rate between the two groups in the first hour. However, a higher increase n PEFR was observed in the second hour in the group treated with ipratropium first followed by salbutamol. Similar outcomes were also observed in other trials.15,16

The BTS/SIGN guideline suggests the addition of ipratropium bromide to beta2 agonist treatment to achieve better bronchodilation in acute asthma. A meta-analysis of 10 studies comparing the outcomes between treatment with salbutamol alone (placebo) and treatment with salbutamol combined with ipratropium bromide supports the guideline recommendation.17 The combined treatment proves to have better outcomes compared to the placebo as ipratropium bromide was found to have a higher pooled improvement from baseline in FEV1 and PEFR (7.3% and 22.1% respectively). A pooled analysis of three trials conducted in three different countries also shows consistent, albeit small, benefits in favour of the combined treatment.18 The need for additional treatment, risk of exacerbation of asthma, and subsequent hospitalisation, were all reduced by 8%, 16%, and 20% respectively with combined treatment, compared to treatment with salbutamol alone.

Ms. J was given Combivent (ipratropium bromide + salbutamol) nebuliser in the ED, and based on the evidence presented, the combined treatment was an appropriate choice in the treatment of her acute asthma.

Whyte et al investigated the maximum effective dose of ipratropium bromide in acute exacerbation of asthma.19 32 patients with acute severe asthma were randomly assigned to receive either 0.5 mg or 1.0 mg ipratropium bromide. There was 51% increase in the PEFR with 0.5 mg dose and 37% increase with 1.0 mg dose at one hour after administration, however the difference was not statistically significant. The difference in the other parameters measured- the heart rate and ear oxygen saturation- between the two groups also did not reach statistical significance. The study concluded that both 0.5 mg and 1.0 mg ipratropium bromide were equally effective.

The dose of ipratropium bromide that Ms. J was given in the Combivent nebuliser was 0.5 mg, and was therefore a safe and effective dose.

Antibiotics are not recommended by the guideline when the exacerbation of asthma is due to an infection, as it is more likely to be a viral infection rather than bacterial. A study investigated the benefits of antibiotics in the treatment of asthma attack.20 60 patients presented with acute asthma attacks were randomised to receive either amoxicillin or placebo. It was found that there was no significant difference in the response (measured as period of hospitalisation, length of time taken for 50% symptom improvement, respiratory function of patient, and presence of symptoms upon discharge) between the two groups. It was thus concluded that antibiotics should not routinely be prescribed for patients presenting with acute exacerbation of asthma.

Ms. J's exacerbation of asthma was secondary to an upper respiratory tract infection, and she was not given any antibiotics, as is recommended by the guideline and the evidence from the trial.

Conclusion

Ms. J's acute exacerbation of asthma was managed as severe acute asthma, and it was appropriate to the symptoms she presented with: inability to complete full sentences in one breath; respiratory rate of ≥25 breaths per minute; pulse of ≥110; arterial oxygen saturation of ≥92%; and peak flow of 33-50% of predicted or best. She was treated with a beta2 agonist, oral prednisolone, and ipratropium bromide, and each of these drugs are proven to have benefits in the treatment of asthma in the acute settings.

Beta2 agonists have been shown to be useful in the quick relief of bronchospasm. Adequate treatment with inhaled or oral steroids and proper monitoring of patient is important in prevention of mortality in cases of acute exacerbation. Evidence have also showed that adding ipratropium bromide to beta agonist therapy is beneficial and has been proven to have a better bronchodilation effect compared to treatment with beta agonists alone. Antibiotics therapy is not recommended by the BTS/SIGN guideline for treatment of acute asthma, and studies have also shown that antibiotics do not improve the symptoms nor do they reduce the length of hospitalisation.

Thus, in light of the evidence presented, it can be concluded that the management of the acute severe asthma of this patient is evidence based, appropriate and safe.

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