The patient case profile studied is Mrs X who is 70 years old female, married Indian house wife with 3 children. She was came to the accident and emergency unit in the early morning of day one with presenting complain of short of breath, cough with white sputum, chest pain, body aches and a headache. She has been having short of breath for two days and a cough with sputum with an addition of chest pain and body aches on the day of admission. Mrs X has been having a past medical history of diabetes mellitus, hypertension and bronchial asthma for the past 20 years. The patient is a housewife who is a non-smoker and a non-alcoholic with parent history of asthma from the mother's side. The patient is on a series of medications of metformin for her diabetic, ticlopidine hydrochloride and isosorbide dinitrate for prophylaxis of cardiovascular diseases, amlodipine and perindropil for her hypertension, lovastatin for her cholesterol and salbutamol and beclomethasone dipropium for her asthma. Mrs X doesn't have any penicillin allergy.
The patient is 70 years old and is in the post menstruating phase. Mrs X is 158 cm in height and has a weight of 54 kg and this accumulates to a BMI of 29.1kg/m2. The systematic enquiry on the patient showed that crepitis on the right bronchi was seen when a chest X-ray was done. As for the patient respiratory rate, she had a rate of 22 breaths per minute, slightly higher than the normal range of 12 to 20 breaths per minute. Mrs X had a blood pressure of 125/65 mmHg which is within the range of a diabetic patient of 130/80 mmHg. Besides, her pulse rate was also within the range of 70 to 90 beats per minute with a value of 84. Patient's laboratory blood results showed that patient had a high alkaline phophatase, ALP value of 146 IU/L which is higher than the range of 30 to 120 IU/L, this accounts for patient's liver not functioning at its best. The creatinine level for the patient was 108µmol/L which was higher than the normal level within 44 to 80µmol/L. This gives a creatinine clearance value of 47.19 ml/min accounting for mild renal failure in the patient. As for patient's random blood sugar, the value was 22.1mmol/L which is quite high when the cutoff point is 11.1mmol/L. This shows that the patient's blood sugar level is not controlled well. The diagnosis for Mrs X was acute exacerbation of her bronchial asthma which is secondary to upper respiratory tract infection as well as uncontrolled diabetic mellitus.
There was no further investigation required and a management plan was constructed. As patient came on Day 1, the management was based on allowing the patient to take oral medication, where all her old medications were continued as well a new regimen was introduced. Intravenous hydrocortisone was started on 200 mg stat and continued with 100 mg with a dose of four times daily. A nebulised ipratropium bromide and salbutamol, 1:2:1 of 4 mg was given, with MDI salbutamol (Ventolin) when required as well as MDI beclomethasone dipropium (Becotide) twice daily. Patient blood glucose level and blood pressure was also measured besides a dietician was contacted to monitor patient's diet. On Day 2, patient still had short of breath with white sputum with a blood pressure of 125/70 mmHg. Her pulse rate was on the high end of the normal range of 90 beats per minute with no temperature and random blood glucose of 22.1mmol/L. The impression for day two was unresolved bronchial asthma and uncontrolled diabetic mellitus. So the management plan for day 2 was to still continue intravenous hydrocortisone, addition of an anti-mucolytic bromohexine 8 mg three times daily, use of nasal prongs 3L/min and her SpO2 leves were checked as well as her MDI technique. Patient was also started on insulin therapy with a strict diabetic diet dietician referral. Patient was still continued on other medications. Besides a peak flow reading was measured.
As for Day 3, patient did not have short of breath but still had a cough. She had a blood pressure of 130/70 mmHg, random blood sugar of 21.4 mmol/L and SpO2 of 95 percentage. The impression was Mrs X still had uncontrolled diabetic mellitus with a slight high blood pressure. Hence, the management plan for day 3 was removal of intravenous hydrocortisone and nasal prongs and continuing patient's insulin treatment with addition of Biphasic Isophane Insulin (Mixtard ®) and Soluble Insulin (Actrapid®). Her other medication was continued while a dietitian has recommended for the patient to decrease salt and fat intake. The clinical progress of day 4 showed that patient had no short of breath but still coughing. She had a controlled blood pressure of 125/70 mmHg with pulse rate of 80 beats per min with random blood sugar of 7.4mmol/L. Patient gave a peak flow reading of 90, 130 and 110. Impression for day 4 was diabetic under controls with no bronchial episodes and patient was discharged.
Patient was discharged with a drug therapy of patient's drug history mention earlier of metformin 1g twice daily, ticlodipine hydrochloride 250 mg bd, Isosorbide Dinitrate 10mg once daily, amlodipine 10mg once daily, lovastatin 20mg, perindropil 4mg, Beclomethasone Dipropium 200 µg twice daily as a nebuliser, and salbutamol 100µg 2 puffs when required. The new medication added in was oral prednisolone 30 mg once daily which will be stopped on day 9, Ipratropium bromide + Salbutamol (Combivent) a change to her early salbutamol therapy 100 µg twice daily nebuliser, Biphasic Isophane Insulin 68/46 units (Mixtard ®) subcutaneous , Soluble Insulin 20 unit (Actrapid®) subcutaneous four times daily. There was also an addition of mixture expectorant 5 ml three times daily and bromohexine 8 mg three times daily. All the medications are taken orally unless stated.
Disease Overview and Pharmacological Basis of the drug therapy
Diabetic mellitus is type II diabetes, where there is insufficient production of insulin been produced by the organ pancreas or occurs when the pancreatic cells does not react to insulin. This is known as insulin resistance and occurs at the B cells of the islet of Langerhans in the pancreas. The use of insulin hormone is to control the amount of sugar in the basic form of sugar in the blood. This pancreas which produces the insulin will released insulin as food digested, enters the bloodstream resulting in free glucose in the blood to be moved into cells resulting in the glucose to be broken down to produce energy. There far more common cases of type II diabetes compared to type I. From all of diabetic patients, 95 % percentage of them suffers from type II diabetes. The diagnosis of type II diabetes is based on uncontrolled level of glucose in the body above maximum level leading to glucose being excreted in the urine. For a patient suffering with type II diabetes, can control their symptoms by simply eating healthy diet and monitoring their blood glucose level. Only if this management does not work, then drug therapy is introduced example metformin, sulfonylurea and insulin. However, with diagnosis of type II diabetes which is a progressive condition leads to other complication such as micro vascular diseases such as retinopathy and macro vascular diseases of retinopathy as well as presence of future cardiovascular complication.
Metformin mode of action is based on increasing of both hepatic and peripheral tissue sensitivity especially in the muscle to insulin. The use of metformin also allows inhibition of hepatic gluconeogenesis as well as declining in glucose production of basal hepatic cells giving reduced fasting plasma glucose. Metformin should not cause additional weight gain and also enhances muscle insulin sensitivity and decreases fatty acid oxidation. As for insulin therapy, it is given as the disease progresses and the insulin therapy must be injected as it is a protein. The use of insulin directly lowered patient glucose level in the blood.
As for asthma, it is a condition which affects the airways, and alveoli accompanied with repeated episodes of wheezing, breathlessness, chest tightness and coughing. This patients suffering from asthma shows hyperresponsiveness when tested with methacholine or histamine challenge test. The whole pathophysiology of asthma is based on the chronic inflammation, with permeation of lymphocytes, CD4 cells, mast cells and eosinophils which expresses T helper cell type-2 cytokines which are interleukin, IL4, IL5, and IL 13, although there will be some individuals especially with severe chronic asthma will have a higher percentage of neutrophils. There is a hyperresponsive patient's response to environmental allergy as well. There were 1318 reported death from asthma in UK in the year of 2005 and over 5 million people suffer from asthma. There is also higher prevalence of asthma in women than men.
The central management of asthma is to prevent exacerbation of asthma, and is revolved around certain drugs such as inhaled corticosteroids, long-acting B2 agonist and anti-muscarinic nebulisers. The use of both B2 agonist and anti-muscarinic nebulisers is based on dilating the airways and airways. As for B2 agonist, example salbutamol mimics noradrenaline but have a lower affinity for cardiac β1 receptors hence only affecting the receptor at the lungs and not the heart. This allows increased intracellular cyclic AMP resulting in relaxation of the bronchial smooth muscle. While an anti-muscarinic example ipratropium hydrochloride which is also known as anticholinergic drug inhibits muscarinic receptor on the bronchial smooth muscle by reducing intracellular cyclic GMP release resulting in reduction in bronchoconstriction. As for inhaled corticosteroid example beclomethasone, its mode of action is its interaction with glucocorticosteroid receptor and nuclear DNA. This steroid alters the synthesis of inflammatory cytokines and leukotrienes on B2 receptors, as well as reducing the activation of macrophages, T-lymphocytes, and eosinophil in epithelial cells airways. This not only reduces hyperresponsive response causing bronchial and alveoli cell constriction but also reduces mucosal oedema
Evidence for treatment of the conditions
As for patient's diabetic therapy, a measure of lifestyle change of diet and exercise is first managed before an Hb1Ac level of higher than 6.5 percentages allows an oral agent is added into a therapy. Ideally a biguanide, metformin is the first line of drug choice according to patient according to NICE guidelines. Mrs X was given metformin 1g twice daily for her diabetic. Well documented clinical trials done for metformin therapy have shown consistently decrease in the plasma glucose level of fasting individuals by 3.3 to 3.9mmol/L and in poorly controlled diabetic patient reduction of HbA1c value by 1.5 to 2.0 percentage points. In another large double blinded study which involved 289 diet-treated patients with type II diabetes with values of fasting glucose level of 13.3mmol/L, metformin caused a decreased by 2.9mmol/L for its fasting glucose levels and also showing Hb1Ac values reduction of 1.4 percentage point from the baseline. This decrease seen in patients with metformin were independent of their age, ethnicity, duration of diabetes, the body weight or fasting and glucose stimulated plasma insulin or C-peptide levels. A similar result was also seen in large dose-ranging study and was later confirmed in a meta-analysis. In that study of patient with type II therapy given a monotherapy of metformin, approximately 25 percent of the patient achieved a fasting plasma glucose concentration of lower than 7.8mmol/L with 11.1mmol/L its threshold level. This confirms the use of effectiveness of metformin as the first line for diabetic. It also showed the same effectiveness of reducing fasting plasma glucose and HbA1c values of type II diabetes when compared to another class of diabetic agent, sulfonylurea.
Metformin mode of action of inhibiting hepatic glucose production and the decrease in amount of fasting glucose makes its pharmacodynamic action to the body more predictable. The hypoglycaemic action of metformin is based on a linearity increase, even at values of high fasting plasma glucose levels of 16.7mmol/L. It is observed that at a fasting plasma glucose levels as high as 16.7mmol/L, the mean decrease observed for diabetic patient type II of metformin is about 6.7mmol/L. Besides, hyperglycaemic effect, metformin given as monotherapy or given together with a sulfonylurea, decreases plasma triglyceride including low-density lipoprotein (LDL) cholesterol levels by approximately 10-15 percent. Besides it also reduces plasma concentration and oxidation of free fatty acid levels. Fasting triglyceride levels account for the magnitude of decrease in plasma triglyceride levels and also is not affected by variation of glucose level in the plasma. This result is consistent with the effects of metformin when view in patient who are non dieabetic with hypertriglyceridemia. There are no changes or slight increase in patient's high-density lipoprotein level (HDL) after metformin therapy but shows an reduction in elevated plasminogen activator inhibitor-1 levels in patients with or without diabetic complication. There is also no observation of weight gain seen in patients with type II diabetes receiving metformin as a monotherapy or with combination with other oral agent such as sulfonylurea or insulin. This is proved in a 1-year randomized, double-blind trial of 457 non diabetic patient with android which is male type or abnormal obesity, showing a significant weight loss with metformin.
There is complication of metformin causing lactic acidosis in patients with renal problems as in case of Mrs X she is seen to have mild renal failure. The data collected on this side effect from time to time has been unclear and are mainly based on isolated case reports. Hence, a study was conducted witht the aim of evaluating the safety of continued use of metformin in patients contraindicated with this agent. A total number of 393 patients with a serum creatinine concentration of 130-220 mmol/L also with type II diabetes mellitus were studied. From the total amount 266 also had coronary heart disease (CHD), 94 with congestive heart failure (CHF), and 91 with chronic obstructive pulmonary disease. All of the patients had been treated with metformin and these patients were placed randomly in groups of either continuing or stopping metformin and the time span of this study was 4 years. The mean age of the separated group was 64 and 65, with body mass index of 28.4 and 28.7kg/m2. The groups also had a mean serum creatinine of 161 and 163µmol/L, respectively. The results obtained showed that patients in the group which had stopped metformin gave a result of weight gain, worsening glucose control and haemoglobinA1c showed significantly greater value than those who continued the use of the drug but there were no cases of lactic acidosis. Moreover, both groups did not differ in values of lactic acid and only showed changes in serum creatinine and body mass index. Besides, the complications of microvascular diabetic, complication of cardiovascular disease and total mortality was identical in both groups. So from the study it can be concluded that the use of metformin can be given and continued in diabetic patients even when patient is having mild renal complication, with possibly maximum serum creatinine concentration of 220µmol/L.
The addition of insulin to a monotherapy of metformin helps improve patient's glycemic control in patients with type II diabetes. Seen here in a study by Giuliano and colleagues, in a 50 patient with poor control type II diabetes which had been randomly divided to receiving metformin or placebo for half a year. The group that had a combination of both metformin and insulin showed an Hb1Ac values decreased by 1.9 percentage points where the plasma glucose levels was seen to have decreased by 5.1 mmol/L and the use of insulin was also lowered by 24 percent. In another recent double-blinded, placebo-controlled study in insulin treated patients with poorly controlled type II diabetes. It was shown that there were significant improvements in glucose levels control and also a reduction in insulin doses with patients with both metformin and insulin therapy. In these studies conducted, there was no increase or only a small decrease in body weight as well as LDL levels but there was an overall decrease of total cholesterol levels.
According to SIGN/BTS 2008 guidelines for long term asthma control this patient is on step 2 which is the use of a beta agonist salbutamol 100µg 2 puffs when required together with a regular inhaled steroid of 400µg per day. There have been questions that doubting the effect of a beta agonist inhaler leading to a deteriorating effect on progress of asthma. A study done in US using regular salbutamol given as a monotherapy for patients with mild asthma, showed a very small but non-significant outcome towards poorer control and no increase in airway responsiveness towards use of beta agonist inhaler. Another study which was done by Taylor and his friends, showed a similar outcome when comparing group of patients on salbutamol and a placebo group. There was no significant difference recorded in frequency and duration of exacerbation in both group.
Then there was TRUST (The Regular Use of Salbutamol Trial) which conducted a study on the effects of using inhaled salbutamol, the most used beta agonist in asthma management in the UK. In this trial a randomised, double-blind, placebo-controlled trial was done using 983 patients with asthma where this particular patients are either been treated with short-acting beta 2 agonist alone or in combination of an inhaled steroids of (2mg or less daily). These patients were then randomised to receive 400µg of salbutamol as for the other matching placebo group was a Diskhaler four times per day for 12 months. The result of the study showed that there was no difference in annual rate, timing, or duration of exacerbation between the two groups. This was supported by the use of peak expiratory flow, where the morning reading showed similar reading between both the groups. In addition the mean evening peak expiratory also showed (p less than 0.001) and the use of rescue bronchodilator was less (p less than 0.001) in the group which received regular salbutamol. TRUST came to a conclusion that there was no evidence that support the increase rate of exacerbation on rate of asthma of population studied with regular used of salbutamol inhaler 400 µg when required daily.
Besides, a study was also conducted based on the effectiveness of combine therapy of an inhaled corticosteroids and beta2 agonist in asthma. The study was conducted in a patient group of 16 to 44 years old who were on a starting combination or a concurrent therapy. The study concluded as the was a observed difference in combination treatment than a concurrent therapy of inhaled steroids as the combination therapy is associated with a reduction in rate of moderate to severe asthma exacerbation among combination users. This outcome was based on persistence fall of 10 percent and 5 percent in combination and concurrent users, respectively. The combine therapy showed a 17 percent less likely to have moderate to severe asthma exacerbation compared to group on inhaled steroid only. It also shows that in clinical scenario combination treatment is preferred to the concurrent therapy when treating patients with asthma.
Mrs X was managed well on her diabetic ailment, as the used combination of metformin and insulin for her diabetic management has shown good improvement based on the random blood sugar sample been reduce and within the range for the 4 days stay in the hospital. But management of her asthma, patient showed an asthma exacerbation and after patient was control in the hospital with oral and intravenous steroid together with her regular asthma medication. Patient was sent home on her previous drug dosing. In her asthma management, to prevent any future episodes of trigger factor for asthma, her asthma management should be stepped up to step 3 with the introduction of long acting beta 2 agonist salmeterol as well as increasing patients inhaled steroid dosage to 800µg per day together with patients salbutamol inhaler used when required. The use of salmeterol is associated with a greater improved in lung function and better asthma control.