1.0 CASE SUMMARY

1.1 Patient information and presenting complaints

SAR, a 54-year-old female with weight of 54kg and height of 160cm was referred to the hospital by her GP due to shortness of breath which was not relieved by taking inhaler, minimum cough with yellowish sputum, abdominal pain and mild diarrhoea. Her shortness of breath had been on and off for the past 1 week and the condition was deteriorating on the day of admission.

1.2 Relevant history

SAR is a non-smoker and a non-alcoholic housewife. She has had bronchial asthma since childhood. Her siblings and children were found to have family history of bronchial asthma as well. The patient has been taking inhaled salbutamol 200µg 1 puff when required as reliever and inhaled budesonide 200µg 2puffs bd as preventer for umpteen years. Besides that, SAR also has medical history of hypertension, diabetes mellitus and ischaemic heart disease (IHD) for 10 years. She has no relevant family history for these illnesses.

For the past few years, SAR has been taking rosuvastatin 20mg at night, fenofibrate 160mg OD and ezetimibe 10mg OD for dyslipidaemia, gliclazide 60mg BD and rosiglitazone 4mg OD for diabetes mellitus, losartan 50mg OD for hypertension, ticlopidine hydrochloride 250mg OD for prophylaxis against major ischaemic events and famotidine 20mg OD to prevent gastrointestinal ulceration due to the use of anti-platelet agent.

1.3 Clinical data

On examination upon admission, SAR’s blood pressure and pulse rate were recorded as 111/80 mmHg and 111bpm respectively. Her respiratory rate was normal (16 breaths/min). Her SpO2 measurement was 98% and it showed decreased high flow mask. Her DXT blood glucose test revealed that her random blood glucose level was abnormally high (21.6mmol/L). From the doctor’s systemic enquiry, SAR’s ankles were slightly swollen and her respiratory system showed prolonged minimal bibasal crept and rhonchi. Also, SAR’s chest X-ray showed shadowing in the lower zone of her right lung. The renal function tests gave results of high urea and elevated creatinine levels of 16.3mmol/L and 270µmol/L respectively. Creatinine clearance derived from Cockcroft and Gault formula is 17ml/min which indicates that the patient has severe renal impairment. The liver function tests revealed a mild decrease in albumin concentration and an increase in the plasma globulin. On the other hand, the haematological tests showed low red blood cell count (3.4×1012/L), low haemoglobin count (9.4g/dL), high platelet count (410×109/L), high white blood cell count (17.1×109/L), high neutrophil count (16.4×109/L) and low lymphocyte count (0.5×109/L), whereas cardiac marker tests showed abnormally high counts in creatine kinase (156IU/L) and lactate dehydrogenase (627IU/L).

1.4 Diagnosis and Management Plan

Based on the patient’s symptoms, medical history, physical examinations, and laboratory tests, SAR was diagnosed with chronic heart failure (CHF), acute exacerbation of bronchial asthma (AEBA) secondary to pneumonia and uncontrolled diabetes mellitus. Her doctor developed therapeutic plans which included anti-asthmatic drugs and antibiotics, and ordered further investigations such as SpO2 and PEFR. Besides that, her doctor also added diuretic to her ACEI therapy and restrict her fluid intake to not more than 800cc/day. Her uncontrolled diabetes mellitus was under monitoring of DXT blood glucose test 4 hourly and she was referred to dietician for diabetic diet counselling.

1.5 Ward medication

Throughout the 3days in hospital, Sarah was being prescribed with medications as listed below:

1.6 Clinical Progress and Pharmaceutical Care Issues

On the first day of admission, the patient’s past medication history was confirmed by appropriate patient interview and her family members were being advised to bring SAR’s home medication to ensure that the appropriate medications were continued and prescribed. From the interview, dust was found to be the chief precipitating factor. The patient was on appropriate drugs (nebulised ipratropium bromide 0.5mg and nebulised salbutamol 5mg in normal saline 4 hourly, IV hydrocortisone 100mg stat) for acute management of severe asthma as according to guidelines and eventually her SOB was relieved.2-3 However, she was prescribed with oral prednisolone at dose as low as 30mg od for acute asthma, it should be suggested to increase prednisolone dose to 40-50mg daily as according to evidence-based guidelines to achieve maximal effects.2-3 Another pharmaceutical care issue is regarding the patient’s poor inhaler technique. Thus, the pharmacist educated and assessed SAR on her inhaler technique since day 1.

Appropriate antibiotics indicated for pneumonia which included IV ceftriaxone 2g stat and oral azitromycin 500mg od were initiated upon admission. Oral cefuroxime 250mg bd was added to the drug regimen on day 2 after stopping IV ceftriaxone 2g on the first day. Therefore, signs of recovery and WBC count were monitored regularly and completion of antibiotic course was ensured. In addition to that, vaccinations against pneumococcal infection and influenza should be strongly recommended in this asthmatic patient.2-3,5-8

Co-administration of high dose IV furosemide (40mg bd) and corticosteroids can increase the risk of hypokalaemia, therefore SAR should be started on potassium chloride 600mg bd which is an appropriate dose for renal insufficiency patient to avoid the potential risk.1 Besides that, potassium level of SAR should also be closely monitored during the administration of potassium chloride.

The doctor added lovastatin 20mg at night to her existing triple therapy of dyslipidaemia (rosuvastatin, ezetimibe, fenofibrate). Rosuvastatin should be avoided if patient’s creatinine clearance is less than 30ml/min.1 Due to its same mechanism of action as lovastatin and its contraindication in patient with severe renal impairment, rosuvastatin should be withdrawn from the drug regimen. Practically, a comprehensive lipid profile of SAR should be established and monitored in order to choose the best combination of lipid lowering agents to improve the individual components of lipid profile. Combination therapy of ezetimibe and lovastatin is considered more appropriate as concurrent use of fenofibrate and statin may potentiate myopathy. Therefore, fenofibrate and rosuvastatin should not be continued. Liver function should be monitored to avoid the risk of hepatotoxicity.

SAR was diagnosed with uncontrolled diabetes mellitus which means her blood glucose level was not adequately controlled with concurrent therapy of gliclazide and rosiglitazone. Her random blood glucose level was fluctuating throughout day 1 (24.9mmol/L, 14.2mmol/L, 7.3mmol/L and 14.7mmol/L). Targets for blood glucose levels should be ideally maintained between 4 and 7mmol/L pre-meal and <9mmol/L post-meal provided there is no significant hypoglycaemia, and HbA1c of ≤7% is a more practical target compared to HbA1c of 6.5%.1,4 SAR was started on insulin injections to lower and control her blood glucose level during hospital admission. Type 2 diabetes mellitus management guideline recommends the addition of insulin to the two oral hypoglycaemic agents after the dual oral therapy fails.4 However, rosiglitazone is contraindicated in patient with CHF and not recommended in patient with history of IHD; therefore the use of rosiglitazone should be reviewed.1,5-6 The most appropriate action is to withdraw rosiglitazone from the drug regimen and close monitoring of patient’s random blood glucose and glycosylated haemoglobin (HbA1c) should be carried out to confirm the effectiveness of the combination therapy (gliclazide and insulin) in controlling the blood glucose level. Although metformin is the first line treatment of Type 2 diabetes mellitus, it is contraindicated in Type 2 diabetic patients undergoing treatment with CHF and there is increased risk of lactic acidosis in severe renal impairment patient, therefore addition of metformin should be avoided in this case.1,4 During the hospital admission, SAR was educated on the proper technique of insulin injection. In this case, the decreased plasma levels of haemoglobin and red blood cells in the heart failure patient were most likely exacerbated by the administration of rosiglitazone.1 If the anaemia problem is not improved upon the withdrawal of rosiglitazone, erythropoietin and iron therapy can be considered.9

On day 2, SAR was feeling much more comfortable and had not complaint of SOB. However, SAR’s maintenance management of asthma was found to be not conformed to the asthma guidelines.2-3 She was prescribed with unacceptable high dose of corticosteroids (MDI beclomethasone 200µg 2 puffs tds) in addition to her current steroid regimen (MDI budesonide 200µg 2 puffs bd and oral prednisolone 30mg od). SAR was at potential high risk of experiencing considerable side effects such as diabetes, oesteoporosis, Cushing syndrome with moon face, striae, acne, abdominal distension and other profound effects on musculoskeletal, neuropsychiatric and ophthalmic systems as a result of overdosage of corticosteroids.1 Oropharyngeal side effects such as candidiasis are also more common at high dose of inhaled steroids, but can be minimized if the patient rinse the mouth with water after inhalation. It should be recommended to add the long acting beta agonist (LABA) to the inhaled corticosteroids (ICS) treatment instead of initiating SAR on high dose steroid (2000µg). Combination inhaler of formoterol and budesonide (Symbicort 200/6 Turbohaler® 2 puffs bd) should be given and control of asthma need to be continuing assessed.2-3 If LABA is proved to be not effective, addition of 4th agent (leukotriene receptor antagonist, theophylline or oral beta agonist) can be considered.2 When SAR showed recovery of leg swelling, furosemide was given orally instead of intravenously with reduced frequency and total daily dose.

On day 3, SAR was arranged to be discharged. The pharmacist should review the appropriateness of discharged medication by checking discharged prescriptions against ward medication chart and ensure all information relevant to primary care referrals are included. In addition to that, the pharmacist should also reiterate and reinforce the importance of patient compliance and follow-up reviews, counsel on indications, doses and possible adverse effects of each discharged medication, and rechecked SAR’s inhaler and insulin injection techniques prior discharged. Asthma education includes advice to avoid trigger factors, including caution with NSAIDs and avoidance of dust exposure. Greater attention should be paid to inhaler technique as poor technique leading to failure of treatment. SAR should be educated on the use of peak flow meters and advised to monitor and record her own PEFR at home. A written personalised asthma action plans should be designed for SAR prior discharged. Diabetic counselling should emphasize on proper insulin injection techniques and healthy lifestyle modifications. SAR needs to be made aware of the signs of hypoglycaemia and hyperglycaemia and how to response to them. Polypharmacy may adversely affect compliance with prescribed drug therapy, therefore SAR should be taught not to mix up her medicines by using daily pill box and her family member should also be advised to supervise her on medicine taking.

2.0 PHARMACOLOGICAL BASIS OF DRUG THERAPY

2.1 Disease background

2.1.1 Asthma

Asthma is a common chronic inflammatory condition of the lung airways affecting 5-10% of the population and appears to be on the increase.5 It is especially prevalent in children, but also has a high incidence in more elderly patient. Asthma mortality is approximately 1500 per annum in the UK and costs in the region of £2000 million per year in health and other costs.2-3,6 Symptoms of asthma are recurrent episodes of dyspnoea, chest tightness, cough and wheeze (particularly at night or early in the morning) caused by reversible airway obstruction. Three factors contribute to airway narrowing: bronchoconstriction triggered by airway hyperresponsiveness to a wide range of stimuli; mucosal swelling/inflammation caused by mast cell, activated T lymphocytes, macrophages, eosinophils degranulation resulting in the release of inflammatory mediators; smooth muscle hypertrophy, excessive mucus production and airway plugging.7 There is no single satisfactory diagnostic test for all asthmatic patients. The useful tests for airway function abnormalities include the force expiratory volume (FEV1), force vital capacity (FVC) and peak expiratory flow rate (PEFR). The diagnosis is based on demonstration of a greater than 15% improvement in FEV1 or PEFR following the inhalation of a bronchodilator.2,3,6 Repeated pre and post-bronchodilator readings taken at various times of the day is necessary. The FEV1 is usually expressed as the percentage of total volume of air exhaled and is reported as the FEV1/FVC ratio. The ratio is a useful and highly reproducible measure of lungs capabilities. Normal individuals can exhale at least 75% of their total capacity in 1 second. A decrease in FEV1/FVC indicates airway obstruction.

2.1.2 Community-acquired pneumonia

Pneumonia is defined as inflammation of the alveoli as opposed to the bronchi and of infective origin. It presents as an acute illness clinically characterized by the presence of cough, purulent sputum, breathlessness, fever and pleuritic chest pains together with physical signs or radiological changes compatible with consolidation of the lung, a pathological process in which the alveoli are filled with bacteria, white blood cells and inflammatory exudates. The incidence of community acquired pneumonia (CAP) reported annum in UK is 5-11 per 1000 adult population, with mortality rate varies between 5.7% and 14% (patients hospitalised with CAP).8 Streptococcus pneumonia is the commonest cause, followed by Haemophilus influenzae and Mycoplasma penumoniae.7

2.1.3 Congestive cardiac failure

Congestive cardiac failure occurs when the heart fails to pump an adequate cardiac output to meet the metabolic demands of the body. It is a common condition with poor prognosis (82% of patients dying within 6 years of diagnosis) and affects quality of life in the form of breathlessness, fatigue and oedema.6,7 The common underlying causes of cardiac failure are coronary artery disease and hypertension. Defects in left ventricular filling and/or emptying causes inadequate perfusion, venous congestion and disturbed water and electrolyte balance. In chronic cardiac failure, the maladaptive body compensatory mechanism secondary physiological effects contribute to the progressive nature of the disease.6

2.1.4 Diabetes mellitus

Diabetes mellitus is a heterogenous group of disorders characterised by chronic hyperglycaemia due to relative insulin deficiency and/or resistance. It can be classified as either Type 1 or Type 2. In Type 1, there is an inability to produce insulin and is generally associated with early age onset. Decreased insulin production and/or reduced insulin sensitivity, maturity onset and strong correlation with obesity are characteristics of Type 2 diabetes. Diabetes affects 1.4 million people in the UK, over 75% of them have Type 2 diabetes.6 It is usually irreversible and if not adequately managed, its late complications can result in reduced life expectancy and considerable uptake of health resources.

2.2 Drug pharmacology

2.2.1 Treatment for asthma

2.2.1.1Beta-adrenoceptor agonists (e.g. salbutamol, terbutaline)

These short-acting selective β2 agonists (SABA) are the first line agents in the management of asthma and are also known as relievers. The selective β2 agonists act on β2 aderenoceptors on the bronchial smooth muscle to increase cyclic adenosine monophosphate (cAMP) leading to rapid bronchodilation and reversal of the bronchospasm associated with the early phase of asthmatic attack.5 Such treatment is very effective in relieving symptoms but does little for the underlying inflammatory nature of the disease. β2 agonists should be initiated ‘when required’ as prolonged use may lead to receptor down regulation renders them less effective.5-6 Compared to SABA, long-acting beta-adrenoceptor agonists (e.g. salmeterol, formoterol) have slower rate of onset and their intrinsic lipophilic properties render them to be retained near the receptor for a prolonged period (12hours), which means that they cause prolonged bronchodilation.

2.2.1.2 Muscarinic receptor antagonists (e.g. ipratropium)

Ipratropium blocks parasympathetic-mediated bronchoconstriction by competitively inhibiting muscarinic M3 receptors in bronchial smooth muscle.1,5-6 It has slower onset of action than β2 agonists but last longer.

2.2.1.3 Inhaled corticosteroids (ICS; e.g. beclomethasone, budesonide) and oral

prednisolone

These agents are used to prevent asthmatic attacks by reducing airway inflmmation. They exert their anti-inflammatory actions via activation of intracellular receptors, leading to altered gene transcription. This results in decreased cytokine production and the synthesis of lipocortin leading to phospholipase A2 inhibition, and the inhibition of leukotriene and prostaglandins.5 Candidiasis occurs as common side effects with inhalation and systemic steroid effects such as adrenal suppression and osteoporosis, occur with high dose inhalation or oral dosing.

2.2.2 Treatment for pneumonia

Antiobiotic treatment is appropriate with amoxicillin being used as first choice agent for mild, community-acquired infections. Depending on response and the strain of bacteria, other antibiotic agents can be used. Two groups of antibiotics which were given to the patient in this case scenario will be discussed here.

2.2.2.1 Cephalosporins (e.g. cefuroxime, ceftriaxone)

Both ceftriaxone and cefuroxime are broad spectrum bactericidal antibiotics belong to cephalosporins group. They inhibit the synthesis of bacterial cell wall by binding to specific penicillin-binding proteins and ultimately leading to cell lysis. Second generation cefuroxime is beta-lactamase resistant and active against Gram-negative bacteria such as Haemophilus influenzae and Klebsiella pneumoniae. Being third generation cephalosporin, ceftriaxone display high beta–lactamase resistance and enhanced activity against Gram-negative pathogens (including Pseudomonas Aeruginosa), but it has relatively poor activity against Gram-positive organisms and anaerobes.1,5-6

2.2.2.2 Maclolides (e.g. azithromycin, erythromycin, clarithromycin)

Maclolides prevent protein synthesis by inhibiting the translocation movement of the bacterial ribosome along the mRNA, resulting in bacteriostatic actions. Azithromycin has slightly less activity than erythromycin against Gram-positive organisms but possesses enhanced activity against Gram-negative bacteria including Haemophilus influenza.

2.2.3 Treatment for chronic cardiac failure

2.2.3.1 Loop diuretics (e.g. furosemide)

Diuretics are the mainstay of the management of heart failure and provide rapid symptomatic relief of pulmonary and peripheral oedemia.5,6,9 Loop diuretics are indicated in majority of symptomatic patients and they work by inhibiting Na+/K+/2Cl- transporter in the ascending limb of the loop of Henle, inhibiting the establishment of a hyperosmotic interstitium and thus reducing the production of concentrated urine in kidney, leading to profuse dieresis.5-6

2.2.3.2 Angiotensin II receptor antagonists (e.g. losartan, candesartan, valsartan)

These agents block the action of angiotensin II at the AT1 receptor, which will also reduce the stimulation of aldosterone release. Therefore AT1 receptor antagonists can be used as an alternative in patients suffering from a cough secondary to ACE inhibitors.

2.2.4 Treatment for Type II diabetes mellitus

2.2.4.1 Sulphonylureas (e.g. Gliclazide, glibenclamide, glipizide)

The sulphonylureas have two main actions: increase basal and stimulated insulin secretion and reduce peripheral resistance to insulin action. They bind to receptors associated with voltage dependent KATP channels on the surface of pancreatic beta cell, causing channel closure which facilitates calcium entry into the cell and leads to insulin release. Sulphonylureas are considered in Type II diabetes patients who are intolerant to metformin, not contraindicated and not overweight.

2.2.4.2 Thiazolidinediones (e.g. rosiglitazone, pioglitazone)

These new agents are ‘insulin sensitisers’ which act as nuclear peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist. They work by enhancing insulin action and promoting glucose utilization in peripheral tissue, and so reduce insulin resistance. Thiazolidinediones is known to be associated with oedema and increased cardiovascular risks, therefore these agents should be avoided in patients with heart failure.1,4,6

3.0 EVIDENCE FORTREATMENT OF CONDITIONS

3.1 Asthma

3.1.1 Evidence for the use of oral prednisolone and IV hydrocortisone in the

management of AEBA

There are mounting evidences suggesting that systemic corticosteroids effectively influence the airway oedema and mucus plugging associated with acute asthma by suppressing the components of inflammation, including the release of adhesion molecules, airway permeability and production of cytokines.10-12 A randomised trial involving 88 patients (aged 15-70years) with AEBA reported the significant efficacy of oral prednisolone (40mg daily for 7 days) in improving FEV1 and FVC at values of 68±45.3% and 53.4±46.5% respectively (P=0.04) in prednisolone-treated group.13 A Cochrane meta-analysis involving six trials recruiting 374 acute asthmatic exacerbation patients determined the early use of systemic corticosteroids significantly reduced the number of relapses to additional care, hospitalisation and use of short-acting β2-agonist without increasing side effects, regardless of the routes of administration studied (oral/intramuscular/intravenous) and choice of agents.14

3.1.2 Evidence for the use of inhaled ipratropium bromide in the management of

AEBA

A double-blind, randomised controlled trials recruiting 180 patients with AEBA admitted to emergency department showed that ipratropium had beneficial effects in improving pulmonary function, with a 20.5% increment in PEF (p=0.02) and a 48.1% greater improvements in FEV1 (p=0.0001) compared to those given β2-agonists alone. Ipratropium also demonstrated a 49% reduction in the risk of hospital admission.15 A more recent meta-analysis incorporating thirty-two double-blind, randomised controlled trials including 3611 patients with moderate to severe exacerbations of asthma also showed the benefits of combination treatment of nebuliser β2-agonists and anti-muscarinic in reducing hospital admissions (relative risk 0.68,p=0.002) and in producing a significant increase in lung function parameters in AEBA patients (standard mean difference -0.36, p=0.00001).16 Another pooled analysis of three multicenter, double-blind, randomised controlled studies also showed that combination therapy of ipratropium bromide and salbutamol for the treatment of AEBA had decreased risk of the need for additional treatment (relative risk=0.92), asthma exacerbation (relative risk=0.84) and hospitalisation (relative risk=0.80).17

3.1.3 Evidence for addition of LABA to ICS in the management of asthma

Symbicort Maintenance and Reliever Therapy (SMART) studies demonstrated the combined use of formoterol/budesonide contributes to a greater reduction in risks of exacerbations, improved lungs performance and better control of asthma than high dose of ICS with SABA.18-22 These studies also reported the advantage of this approach in terms of patient compliance as it allows the use of single inhaler for both rescue and controller therapy, and reductions in healthcare costs.18-22 A large double-blind, randomised trial reported that there was a significant 21-39% reduction of severe exacerbations in asthmatic patients treated with SMART therapy compared with high dose budesonide plus SABA.23 A meta-analysis involving 30 trials with 9509 patients showed that the use of combination inhaler (formoterol/beclomethasone 400mcg) resulted in greater improvement in FEV1, in the use of rescue SABA and in the symptom-free days compared to a higher dose of ICS (800-1000mcg/day).24 Another double-blind randomised trial investigating the effect of combination budesonide and formoterol as reliever therapy for 3394 patients who were assigned budesonide plus formoterol for maintenance therapy showed that the time to first severe exacerbation was significantly longer in as needed budesonide/formoterol group compared to as needed terbutaline group (p=0.0051). The other finding of the study is the significant lower rate of severe exacerbation for as needed budesonide/formoterol versus as needed terbutaline group (0.19 vs 0.37, p<0.0001).25 Chung et al. (2009) reported that addition of LABA may potentiate the anti-inflammatory properties of ICS as addition of formoterol to budesonide resulted in 63% reduction in severe exacerbation rates.26 Other findings of the study are local and systemic side effects of ICS become more frequent when used alone at doses above 800mcg/day, and the increased efficacy of combination with formoterol was achieved with lower dose of budesonide than was required in the budesonide group..26

3.2 Community-acquired pneumonia

3.2.1 Evidence use of combination therapy of second and/or third generation

cephalosporins and macrolide in the management of pneumonia

A multicenter, randomised trial investigated the efficacy of IV ceftriaxone 2g for 1 day followed by oral cefuroxime 500mg bd in the adult pneumonia treatment. The sequential therapy in combination with a macrolide achieved 90% of clinical success, 85% of overall bacteriologic clearance with 100% eradication of S.pneumoniae after 5-7days of treatment.27 An open label, prospective study involving 603 patients demonstrated that adding azithromycin (500mg od for 3days) to IV ceftriaxone 1g/day in the treatment of community-acquired pneumonia resulted in shorter hospital stay (7.3days vs 9.4days) and a significant lower mortality rate (3.7% vs 7.3%) than adding clarithromycin.28 Lack of randomisation and no blinding of evaluators may become the major limitations of this study; however the effectiveness of macrolide in addition to cephalosporins empirical therapy in treating pneumonia is unquestionable.

3.3 Chronic heart failure

3.3.1 Evidence use of loop diuretic in the management of chronic heart failure (CHF)

A meta-analysis of 18 randomised controlled trials concluded that diuretics significantly lowered the mortality rate (odds ratio (OR) 0.25, P=0.03) and reduced hospital admissions for worsening heart failure (OR 0.31, P=0.001) in patients with CHF compared to placebo.29 Compared to active control, diuretics significantly improved exercise capacity in CHF patients. (OR 0.37, P=0.007).29 A recent review reappraisaled the role of loop diuretics as first line treatment for CHF concluded that existing evidence of association of loop diuretics with rapid symptomatic relief and decreased mortality supporting the essential role of diuretics in the management of CHF.30

3.3.2 Evidence use of angiotensin II receptor antagonists in the management of CHF

The Losartan Heart Failure Survival Study ELITE II, a double-blind, randomised controlled trial involved 3152 patients with NYHA class II-IV heart failure and ejection fraction ≤40% reported that there were no significant differences between losartan and enalapril groups in all cause mortality (11.7 vs 10.4% mean mortality rate). However, losartan