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Patient RR is a 58 years old female with a weight of 55kg. Patient was admitted to hospital on 9th April 2009. Her presenting complaints were cough with sputum, pain when inhaling air at chest, breathless and unable to speak in full sentence. Her past medical histories were hypercholesterolemia, bronchial asthma and she has no known drug allergy. For her social history, she works as a security guard and is living with her husband. She is a non smoker as well as non alcoholic and she has no known family history.
Patient’s drug history include metered dose inhaler (MDI) salbutamol 200mcg as required, MDI budesonide 400mcg twice daily, theophylline SR tablet 250mg once daily and lovastatin tablet 20mg once daily.
Good control: <6.5%
Adequte control: 6.5-7.9%
Poor control: >8.0%
Blood test indicated that the level of white blood cell and erythrocyte sedimentation rate is higher than normal which suggests the patient had an infection. The blood HbA1c showed adequate control of blood glucose. On the other hand, the renal test showed that the patient had low plasma potassium and the plasma creatinine level is normal.
On examination, the patient was alert with no pedal oedema. Her pulse rate was 120 beats per minute, blood pressure was 130/62 mmHg, and respiratory rate was 22 breaths per min. She was diagnosed with acute exacerbation bronchial asthma secondary to upper respiratory tract infection. The plan was to give intravenous (IV) hydrocortisone 200mg immediately then 100mg three times daily, IV Augmentin 1.2g three times daily, nebulizer atrovent: ventolin: normal saline (A:V:N) 2:1:2 every two hours and to continue SPO2 monitoring.
On day 1, the patient was given MDI Budesonide 400mcg, nebulizer AVN, IV hydrocortisone 100mg three times daily, bromhexine tablet 8mg three times daily, erythromycin tablet 400mg twice daily, prednisolone tablet 40mg once daily, oxygen 3L/min and lovastatin tablet 20mg once daily. Theophylline were stopped.
On day 3, patient’s blood pressure was 120/70 mmHg, respiratory rate was 26 breaths per minute and the SPO2 was 98%. She has cough with yellow sputum and the sputum culture showed that there are no pathogen isolated. The patient was to start on long acting beta agonist (LABA). Other medications that were given include potassium tablet 1.2g twice daily, Neb Combivent 4 hourly, IV Augmentin 1.2g three times daily, MIST expectorant 15mL three times daily. Hydrocortisone and bisolvon were stopped.
On day 4, the patient had fever, cough with yellow sputum and difficulty in breathing. No new action was taken.
On day 6, patient had no more fever but still had cough with yellow sputum. Her blood pressure was 122/80 mmHg and respiratory rate was 20 breaths per minute. The plan was to give MDI formoterol 9mcg once daily and augmentin tablet 625mg. Oxygen and prednisolone were stopped.
On day 8, patient still had cough but the sputum turned white. Patient was given theophylline SR tablet 250mg twice daily and was ready to be discharged the next day.
tds(stop at day 3)
tds (day3-day 6)
bd (stop on day 6)
tds (stop on day 7)
od (stop on day 6)
OXIS inhaler (formoterol)
Pharmaceutical Care Plan
1. Monitor K+ level
-high dose salbutamol and theophylline causes hypokalaemia
K+ level should be monitored. K+ supplement should be given if K+ level is low.
Maintain stable potassium level.
2. On day 4, patient had fever but not treated.
Paracetamol should be given.
To lower down patient’s temperature.
3. Concurrent use of oral prednisolone and IV hydrocortisone for acute treatment
-If patient can tolerate orally, oral prednisolone should be adequate.
-if cant, give IV hydrocortisone 100mg every 6 hour until conversion to oral is possible.
4. Combination inhaler can be given to patient
Symbicort inhaler (1-2 puffs bd) can be given instead of OXIS and budesonide inhaler. Besides that, Symbicort can be also given as relief to replace Combivent.
Less confusion and increases compliance.
5. Technique to use inhaler
-Counsel patient on proper technique
-advice on oral hygiene to avoid oral candidiasis.
6. Prophylaxis of asthma
Counsel patient to avoid allergen that may trigger attack and avoid NSAIDs.
Lowers risk of asthma attack
7. Compliance issue
Advice patient on the importance to take control medication accordingly even if patient feels well.
Lowers risk of asthma attack
Disease Overview and Pharmacological Basis of Drug Therapy
Asthma affects people of all ages, but it normally starts at childhood1. Asthma affects 5-8% of the population around the world2. A study done by World Health Organization (WHO) shows that there are 15 million disability-adjusted life years lost yearly because of asthma, displaying 1% of total disease burden worldwide3. The annual worldwide mortality caused by asthma is estimated to be 250,000. In Scotland, the incidence of clinical asthma is around 18.4% of the population3.
Asthma is an inflammatory disease where there is frequent reversible airway obstruction1. The narrowing of the airway happens when people with asthma react strongly to certain substance they breathe in. These irritant stimuli are too weak to affect normal individuals1. The narrowing of airway is also caused by other factors which include mucosal swelling or inflammation caused by inflammatory mediators released by mast cell and basophil degranulation as well as mucus or phlegm production2.
The causes of asthma include genetic factor, environmental factor and history of etopic disorder5. The most common symptoms of asthma are wheezing, shortness of breath, chest tightness and sometimes cough, especially at night in younger people1, 4. The probability of asthma increased if symptoms worsen at night and early morning or in response to exercise, allergen and cold air5. Acute severe asthma may cause hypoxaemia and is not easily reversed. Therefore, the patient needs prompt treatment and hospitalization1.
Patients with asthma have continuous and excessive T-helper cell type 2 (Th2)-dominated immune response and the Th1 which is responsible for structural and defensive status of the tissue is reduced4. The activated T-cells produce cytokines in the bronchial mucosa and this attract other inflammatory granulocytes especially eosinophils which produce cysteinyl leukotrienes along with granule protein to damage epithelium. The cytokines released also promotes IgE synthesis in some asthmatic patients which cause expression of IgE receptors on mast cell and eosinophils1, 4. The important mediators associated with asthma are leukotriene B4, cysteinyl leukotrienes (C4 and D4), interleukins IL-4, IL-5, IL-13 and tissure-damaging eosinophil proteins1. In atopic asthmatic patients, inhaled allergen caused cross-linking of IgE molecules on mast cells hence activating degranulation with histamine and leukotriene B4 release. These substances are powerful bronchoconstrictors thus causing acute exacerbation of asthma1.
For diagnosis of asthma, spirometry is the preferred initial test5. It is a device to measure the functional lung volumes. Through the patient’s full force expiration into the device, the forced expiratory volume in 1 second (FEV1) and force vital capacity (FVC) are measured. Exhalation continues until there is no more breath to be exhaled. The FEV1/FVC ratio shows the severity of airflow obstruction and the normal ratio is 75-80%2. The ratio is less than 75% in asthma which indicates obstructive defect. There is normally more than 15% improvement in FEV1 after administration of B2 agonist or steroid trial in asthma patients2. Peak expiratory flow (PEF) is also another test for asthma though FEV1 uses lesser effort2. It is measured by the maximum forced expiratory through a peak flow meter and acts as an estimate of airway calibre. PEF is measured frequently to check response to treatment and disease control. PEF is used to test acute and chronic asthma with PEF decreases along with severity2.
Moderate acute asthma
Severe acute asthma
Able to talk, Respiratory rate (RR)<25/min, Pulse rate (PR)<110/min, SPO2>92%, PEF>50-75%
Incomplete sentence, RR>25/min, SPO2<92%, PR>110/min, PEF 33-50%
Silent chest, cyanosis, exhaustion, confusion, feeble respiratory effort, SPO2<92%, PEF<33%
Table 1: Classification of acute asthma6.
In this case, β2 adrenoceptor agonists are used which include salbutamol and formoterol. Salbutamol is a short acting bronchodilator and is normally used as needed to control symptoms while formoterol is a long acting agent and given twice daily as adjunctive treatment when the asthma is not well controlled by glucocorticoids4. The airways and bronchial smooth muscles are full of β2-adrenoceptors. Administration of β2 adrenoceptor agonists results in stimulation of receptors thus causing bronchodilation through production of intracellular cyclic adenosine monophosphate (cAMP), suppression of mediator release from mast cell as well as tumour necrosis factor (TNF)-α release from monocytes and increased mucociliary clearance by cilia action1, 4.
Corticosteroids are used as anti-inflammatory for example budesonide and prednisolone. Steroids activate glucocorticoid receptors thus decrease cytokines formation that activates eosinophils especially Th2 cytokines1. It also reduces IgE synthesis, up-regulate β2 adrenoceptors and also inhibits phospholpase A2 which is responsible for inflammatory prostaglandins and leukotrienes production4.
Antimuscarinic agent is also used in the case for example ipratropium bromide which is used as bronchodilator. Ipratropium is non selective which bind to all three types of muscarinic receptors in the lung (M1, M2 and M3)4. There is possibility that the blockage of M2 receptors on the cholinergic nerve enhances acetylcholine release and decrease the antagonism of the smooth muscle’s M3 receptors1. It also suppresses mucus secretion and increase mucociliary clearance of bronchial secretions1.
Xanthine drug for example theophylline is used. It has vasodilator, anti-inflammatory and immunomodulatory effects1. It inhibits phosphodiesterase isoenzymes thus causing smooth muscle relaxation due to increase in cAMP4. Theophylline also inhibits adenosine A1 and A2 receptors that release histamine and leukotrienes therefore reduce bronchoconstriction4.
Evidence for Treatment of the Condition(s)
Acute asthma management
Salbutamol and ipratropium
According to the SIGN guideline of acute asthma management, inhaled short acting β2 agonist is given by 4-10 puffs of 100mcg salbutamol or nebulised salbutamol 5mg while ipratropium bromide 500mcg is given via oxygen driven nebulizer. In this case, the patient was given nebulizer AVN 2:1:2 where the atrovent (ipratropium) is 2 units with a total of 500mcg while ventolin (salbutamol) is 1 unit which is 5mg. This complies with the guideline.
In a meta-analysis from 10 randomized, double-blind, placebo-controlled studies involving 1377 asthmatic patients, the use of ipratropium as adjunctive therapy to β2 agonist was compared with placebo. The results showed that there is 7.3% improvement in FEV1 for the usage of ipratropium and a complete improvement in FEV1 for the ipratropium and β2 agonist combination group. There is statistically significant improvement in obstruction of airway when ipratropium is used together with β2 agonist for acute asthma management7.
Another double-blind, two-center, randomized, single-dose study was done on 338 patients to determine the clinical benefits of combination nebulizer of salbutamol with ipratropium over nebulised salbutamol alone in acute asthma. It is found that combination of salbutamol and ipratropium has more benefits in acute asthma than salbutamol alone with a p-value of less than 0.05 8.
A systematic review of 32 randomized studies with 3611 patients was done and the result showed that there is a statistically significant reduction in hospitalizations in adults using inhaled antimuscarinic for asthma (p-value=0.002). There is also significant improvement in spirometry measures after therapy for combination treatment in adults (p-value=0.0001). Therefore, the use of ipratropium with salbutamol is useful in the management of severe exacerbation of acute asthma9.
The patient was given prednisolone 40mg orally for 5 days in this case. According to SIGN guideline, prednisolone 40-50mg oral for at least 5 days or IV hydrocortisone 100mg every 6 hours is given for severe acute asthma. Thus, the treatment given to the patient complies with the guideline.
A review was done from 6 randomized controlled trials with total of 374 patients comparing the use of corticosteroids with placebo in acute asthma management. This study showed that there is significantly lesser relapse to acquire extra care in steroid patient group (Relative risk [RR] 0.38; 95% confidence interval [CI] 0.2 to 0.74). Using corticosteroids for a short duration also reduce hospitalizations without addition in adverse effects. Both intramuscular and oral steroids are effective10.
Another study was done on 53 patients to compare the use of 2 different corticosteroids administration route used for acute asthma treatment which is the oral and intravenous route. It is found that there is no significant difference in the two groups of patients and both demonstrates same results11. This showed that oral corticosteroids can be used in this case.
A randomized clinical trial was also done to compare the non-tapering and tapering dose of prednisolone in acute asthma. 13 patients were administered with non-tapering dose of prednisolone (40mg daily for 8 days) and another 13 patients were administered with tapering dose of prednisolone (40mg daily reduced by 5mg per day) for 8 days. It is found that there is no significant difference between the two groups in terms of FEV1, adrenal suppression and relapse rate12. Thus, it is appropriate to give at least 5 days of oral prednisolone 40mg in this case.
Chronic asthma management
A short acting inhaled β2 agonist is given and used as required in chronic asthma management from SIGN guideline. The patient was given salbutamol 200mcg as required for symptom relief of asthma.
A study was done to compare the effects of inhaled salbutamol on FEV1 in 20 normal people and 19 patients with asthma. The sensitivity to salbutamol in patients with asthma was greater compared to normal subjects with the p-value less than 0.001 and there is 20% improvement in FEV1. The maximum and overall responses to inhaled β2 agonist are greater in asthma patients with significant bronchodilation and airway stabilization13. Hence, the use of salbutamol is justified.
Another trial was done to compare the effects of salbutamol and placebo on resting metabolic rate in subjects with airway problem who are receiving treatment for bronchodilation. After 5 minutes of salbutamol or placebo administration, there is highest improvement in the oxygen consumption and carbon dioxide generation. In summary, when compared to placebo, inhaled β2 agonist causes statistically significant improvement in metabolic rate during rest and it is dependent on the dose14.
The comparison of efficacy of regular short-acting β2 agonist, long-acting β2 agonist and placebo in asthma control was conducted by a randomized study. Results from 157 subjects show that short-acting β2 agonist only causes improvement in daytime symptoms. Besides that, the minor and major exacerbation ratio of short-acting β2 agonist is not much difference compared to placebo. Hence, salbutamol can only be used in an ‘as required’ basis for symptom relief and not to be administered regularly for symptom control15.
As mentioned in the SIGN guideline for asthma control, step 2 was to add an inhaled steroid of 200-800mcg daily. 400mcg of steroid per day as starting dose is suitable for most patients. In this case, the patient was prescribed MDI budesonide 400mcg two times daily thus the therapy complies with the guideline.
Evidence showed that inhaled corticosteroids for four weeks improve the non-invasive markers for inflammation in asthma patients. These markers include histamine induced airway hyperresponsiveness, eosinophil sputum and degree of nitric oxide exhalation. When compared to placebo, steroids raised the FEV1 in subjects. Therefore, steroids may be used in treatment of asthma to control symptoms16.
A review was conducted to examine the response of asthmatic patients to budesonide when compared with placebo. In the 43 trials which had a total of 2801 patients, the results showed that there is significant improvement in FEV1 and morning PEF in patient administered with budesonide compared to placebo. There was also lesser risk of acute exacerbation of asthma in budesonide group17. Hence, budesonide can be used to as asthma control in asthmatic patients as shown in this case.
Another study with 1435 asthma patients was done to compare the relationship of budesonide administration dose and response rate. The result showed that the benefit of 200-400mcg daily was 80% similar to the dose of 1600mcg daily while administration of 300-600mcg daily had 90% similarity in benefit. Thus, the dose with most significant therapeutic value for MDI budesonide is 400-1000mcg daily18. In this case, 800mcg of budesonide daily was prescribed to patient and this dose is justified.
Long acting β2 agonist (LABA)
In the step 3 of asthma management, an add-on therapy, LABA is given and the control of asthma is monitored. In this case, the patient was given OXIS inhaler which is formoterol 9mcg once daily.
A trial was done on 239 patients to compare the use of formoterol in asthma control compared to placebo. The results showed that formoterol significantly reduce the asthma symptoms compared to placebo with a p-value of 0.04. Besides that, formoterol improves morning PEF (p-value of 0.0001) and also reduce the frequency of short acting β2 agonist usage in asthma patients (p-value=0.0001)19. Thus, the use of formoterol is justified in this case.
Another study was conducted to compare benefits of OXIS formoterol with terbutaline and placebo. This study was done on 397 patients and it was found that low dose formoterol is statistically significant in improving PEF and decreasing symptoms of asthma compared to four times daily dosing of terbutaline as well as placebo20. Thus, OXIS formoterol is suitable in this case.
Combination inhaler of formoterol and budesonide
It is recommended that a combination inhaler should be given to replace the two different inhalers of formoterol and budesonide to cause less confusion to patient, increase compliance and also convenience. Single inhaler simplifies therapy while supplying anti-inflammation and bronchodilation.
A study was done to compare the efficacy of using single combination inhaler with the usage of formoterol and budesonide alone as well as placebo. This randomized trial which include 480 subjects showed that there is significant improvement in FEV1 in the group of subjects using combination inhaler when compared to other groups with a p-value of less than 0.005. There is also fewer cases of condition worsening in the combination group (p-value less than 0.001). In the end, combination of budesonide and formeterol in a single inhaler with a twice daily dosing schedule significantly improve asthma symptoms when compared to the usage of these 2 drugs alone21.
Besides that, combination of formoterol and budesonide can also be given as relief therapy other than the normal control therapy. This is because formoterol can provide both short and long acting activities on bronchodilation. A study with 2780 subjects showed that the administration of this combination as maintenance (twice daily dosing schedule) and relief (as required dosing schedule) therapy causes reduction of 45-47% of asthma exacerbation risk when compared to the traditional treatment of budesonide/formoterol as control and a short acting β2 agonist as relief medication. This result is statistically significant with a p-value of less than 0.001 22. Thus, combination of formoterol and budesonide may be used as control and relief therapy of asthma.
In the step 4 of asthma management, a regular high-dose inhaled steroid and an addition of a fourth drug may be considered. In this case, theophylline 500mg twice daily was given but the dose of steroid remained low.
A randomized, double-blind study was conducted comparing the use of theophylline and a low dose budesonide with the use of high dose budesonide. It is found that the FEV1 and FVC were significantly improved in the low dose steroid and theophylline therapy with a p-value of 0.03. The PEF variability and usage of β2 agonist were also significantly reduced. However, the level of cortisol in blood was significantly decreased in the high dose steroid group. Thus, high dose budesonide and low dose budesonide with theophylline have the same benefits. The low dose steroid is more preferable due to the cost23. In this case, the decision of theophylline and a low dose of inhaled budesonide are justified.
The patient’s condition in this case is well managed according to guidelines of disease and various evidence based studies. For acute asthma management, the patient was given salbutamol, which is a short-acting β2 agonist; ipratropium, which is an anti-muscarinic and also an oral steroid which is prednisolone. The usage of these drugs are justified and proven to be significantly improving asthma symptoms in acute asthma compared to placebo. In the case of steroid used, oral and IV steroid has no significant difference between each other and the same goes to tapering and non-tapering dose of prednisolone. For chronic asthma management, salbutamol, theophylline and the combination of LABA and steroid were given. The usages of these drugs are also justified. Salbutamol may cause significant improvement in asthma symptoms in asthma patients while combination of LABA and steroids is significantly better compared to LABA or steroids alone. On the other hand, the choice to given theophylline with low dose steroid compared to high dose steroid alone is also justified because both groups had been proven to have same benefits and the former had a lower cost.
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