Levalbuterol in Asthma
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Asthma is one of the most common pulmonary illnesses that affect more than fourteen million people in the United States (CDC, 2008). The prevalence of asthma is increasing in most countries, and estimates show that the numbers are likely to rise by 100 million by 2025 (Bateman et al., 2008). Asthma is characterized by reversible airway obstruction following exposure to environmental allergens or irritants or respiratory viral infection (CDC, 2008). Asthma is also characterized by impediment and irritation that occurs in many patients. Treatment of asthma has always been medications that are aimed at controlling the inflammation as well as the medications for general relief of the severe symptoms. However, the recommended management is the clinical assessment of the symptoms and the lung function assessment of an individual. These are viewed as the measures of the outcomes that result from this condition.
Most asthma exacerbations are dealt with in various outpatient systems. However, more severe conditions require hospitalization. These hospitalizations are responsible for the foremost healthcare expenditures by patients. In the United States, these hospitalizations lead to over 400,000 cases of asthma hospitalizations annually. This eventually leads to very high expenditures for asthma related conditions (Bharmal & Kamble, 2009). Asthma in both children and adults is associated with an increase in direct expenses, which eventually brings the expenditure to a very high level according to healthcare costs.
The main therapy in the treatment of asthma is the administration of β2-receptor agonists which reverse the acute airway obstruction as well as other conditions such as cough. According to Ameredes (2009), levalbuterol and albuterol are the most common short acting β2-receptor agonists in the treatment of asthma. Racemic albuterol is a mixture of two stereo isomers – R-albuterol and S-albuterol. Clinical studies have distinguished the two isomers in terms of their affinity. Studies upon isolation of the two isomers have revealed that R-albuterol is responsible for the bronchodilator activity. However, S-albuterol does not possess bronchodilator characteristics, but it acts in association with various pharmacological activities to neutralize the therapeutic effects of R-albuterol (Handley, 2000).
Levalbuterol, also referred to as levosalbuterol is an alternative treatment for asthma and other pulmonary illnesses such as Chronic Obstructive Pulmonary Disorder (COPD). It blocks the beta-2-receptor to prevent the constriction of the airways in these conditions, and is therefore called a bronchodilator. Cells in the airways contain receptors that are called beta-2 receptors. Levalbuterol binds and activates the beta-2 receptors and is hence referred to as a beta agonist. This initiates signaling within the cells which results to the relaxation and opening of airways. However, the safety of albuterol and Levalbuterol is generally different. The S-isomer in albuterol has been believed to be inert in nature and its presence in the drug of no consequence. But it is now thought to foreshorten the duration of R-albuterol by compressing its potency (Handley, 2000). The main purpose of this study is to provide a comparative view of asthma related therapies, as well as the outcomes of treatment after the maintenance treatment of asthma using levalbuterol and albuterol.
Studies in patient preferences on the type of medication provide crucial information on the evaluation of asthma symptoms as well as the effects of medication on the wellbeing of the patients and the levels of functional activities (Bateman et al., 2008). These studies have been insufficient in evaluating the effectiveness of albuterol in treating asthma. Albuterol has been in use for a long time but is said to be associated with various side effects such as tachycardia and jitters. The introduction of levalbuterol in 1999 has brought an opportunity to assess patient predilections between albuterol and levalbuterol.
A stepwise approach to disease management is necessary for the assessment and eventual treatment of asthma. One of the main goals of asthma treatment is to uphold the wellbeing of people as one of the main humanistic upshot measures (Reed, 1985). Today, clinicians use many other measures to manage diseases with a need to control the effects of asthma as well as the wellbeing of the patients. These measures include patient satisfaction as well as other health related measures that are centered on the quality of life. Studies have revealed that patients’ preferences have a great impact on medication side effects, as well as patients’ quality of life. Patients’ compliance with the medication is also necessary for successful control of asthma (Bharmal & Kamble, 2009). Disease control measures are also very crucial in reinforcing the positive perceptions of the treatment of asthma.
When levalbuterol was approved in 2005, studies suggested that its use resulted in better respiratory parameters as well as fewer hospitalizations that brought about very little, if any, side effects and though it is priced much higher than albuterol since it has a higher duration of action (5-8 hours) as compared to albuterol (4-6 hours), its use led to generally lower treatment costs in terms of hospitalization and subsequent treatments (Carl, 2003). Studies comparing levalbuterol to albuterol revealed that levalbuterol yielded bronchodilation with few side effects. However, these results are not universal and some studies suggest no significant differences in clinical endpoints.
The baseline distinctiveness for the two groups of patients (those who were administered with albuterol and those who were administered with Levalbuterol) was very distinctive (Ameredes, 2009). In the medical field, albuterol has been in use for a long time, one of the factors that make it preferable. Due to the mixture of the two isomers (R)-albuterol and (S)-albuterol that are considered inert, albuterol is considered somewhat classical in the medical field. However, the single-isomer formulation that has been manufactured recently is used therapeutically when the other component is deemed to be undesirable.
Levalbuterol and albuterol are β2-receptor agonists and they reverse the acute airway obstruction as well as other conditions such as cough. The two drugs serve to reduce the resistance in the airway as they are known to enlarge the diameter of the bronchi or the air passages (Ozminkowsk et al., 2007). These drugs, therefore, help to enhance the overall flow of air both into the lungs and out. The drugs work on the beta-2 receptors resulting in the relaxation of the pulmonary smooth muscles (Perrin-Fayolle et al., 1996). Studies conducted with regard to the metabolism of levalbuterol in the human tissues indicate a 5-11 fold better sulfoconjugation within various human tissues than albuterol. A single dose of the albuterol dosage, whether taken orally or inhaled, results in a higher blood level within the body than levalbuterol (Perrin-Fayolle et al., 1996). Perhaps, this indicates a predominance of the (s)-albuterol, an inactive product, after repeated dosing of the active albuterol.
It is estimated that up to 8 % of patients who receive nebulized racemic albuterol develop paradoxical bronchospasm, a condition which is life threatening. This decline in efficacy could be attributed to the composition of racemic albuterol. Levalbuterol is the therapeutically active bronchodilator in racemic albuterol, also referred to as (R)-albuterol. Evidence indicate that (S)-albuterol does not possess any bronchodilatory activity, in fact, it increases the level of calcium in the smooth muscle cells in vitro, which favors contraction and opposes bronchodilation. This also leads to increased in vitro bronchial reactivity of human airway smooth muscles. Clinically, the isomer promoted increased hypersensitivity and increased bronchospasm that is methacholine induced in patients with moderately severe asthma. On the contrary, levalbuterol, when administered as a single isomer, eliminates all the detrimental effects of (S)-albuterol (Bateman et al., 2008)
Research has also shown that racemic albuterol and Levalbuterol are important since they produce effects that can be used as prescriptions for cancer treatment. The treatments include corticosteroid strengthening and the diminution of inflammatory mediators. However, on the other hand, (S)-albuterol produces contradictory effects. Studies indicate that the adverse effects associated with albuterol, such as jitters, tychardia and bronchospasms, are less frequent with levalbuterol (Gawchik, 2007). Symptom relief was also perceived to be higher, leading to a greater overall satisfaction with Levalbuterol treatment. However, it is important to bear in mind that while levalbuterol and albuterol help in relaxing the smooth muscles and increasing the flow of air within the airways, they do not actually reduce the speed of the progression of the primary disease (Ozminkowsk et al., 2007). They only help in minimizing the signs and symptoms of exercise and wheeze limitations along with the shortness of breath, leading to a better life for the people living with COPD.
Many investigators in their publications from studies have revealed that the use of levalbuterol yields better symptom relief and less frequency of the adverse effects as compared to albuterol. However, their pattern of outcomes cannot be applied universally because other studies propose that there is not a clear difference in clinical endpoints. Ozminkowski & Wang (2007), state that the various publications that have resulted from various studies are difficult for doctors to follow. Most of these data highlight the effects of albuterol and levalbuterol in efficiency and safety. This was done by comparing the relief of symptoms and the exhibited side effects of each form of treatment.
However, this clinical research provides no superiority of levalbuterol over albuterol. The effects of levalbuterol may be greatest to patients with moderate to severe asthma, especially in cases of racemic albuterol overuse (Ameredes, 2009). When a patient inhales racemic albuterol, he or she has a persistent effect that is caused by (S)-albuterol. This is in comparison to levalbuterol. This suggests potential contradictory outcomes from clinical experiments.
One study carried out on children under the age of twelve years evaluated the treatment of asthma in children by caregivers who used either albuterol or levalbuterol. Various interviews were scheduled for caregivers, and the main questions were the satisfaction level of their children with bronchospasms. The caregivers were supposed to report contentment or discontent. The patients were administered with albuterol and levalbuterol for four consecutive weeks. After the first dose, levalbuterol created a greater relief of symptoms compared to doses of albuterol in nearly all patients including those with relentless asthma (Carl, 2003).
Ameredes (2009), carried out a research study to find out the distinctive difference between albuterol and Levalbuterol. The objective of this study was to find out whether levalbuterol reduced the costs of treating asthma as compared to albuterol and to find out the various ways that levalbuterol and albuterol were different. He used a correlational research design that brought forward thirty seven patients who were diagnosed with acute asthma. The patients in his sample were children between the ages of 6-18. The results of this study indicate that Levalbuterol’s potency is 2-fold than racemic albuterol and 90 to 100 fold more than S- albuterol.
Ameredes (2009) suggests that there have been highly heterogenous results from various studies that compare the clear differences between albuterol and levalbuterol. In one study, levalbuterol was more effective in suppressing bronchospasm than (R) albuterol and (S) albuterol. However, subsequent research studies revealed that there are equivalences between albuterol and levalbuterol. Some indicated that the effect of 1.25 mg levalbuterol was similar to that of 2.5 mg racemic albuterol, with (S) albuterol showing little measurable effect. The above studies were shot-term, and thus a short-time approach would be used to evaluate the two drugs. This approach, however, did not measure the difference that existed between albuterol and its isomers, if used chronically.
Nelson (1998), conducted a clinical trial that would compare albuterol to levalbuterol. The study was based on both children and adults that were diagnosed with acute asthma in the United States. In his study, the patients were selected randomly and assigned levalbuterol or racemic albuterol. This trial was aimed at checking the equivalences of equal amounts of the two drugs. The study was correlational and involved fifteen patients from a local hospital. The study resulted in greater improvements in force expiratory volume in one second in the levalbuterol group as compared to the dose-equivalent of racemic albuterol group. This implied that an equimolar dose of levalbuterol produced better results than albuterol. The dose that produced numerically equivalent bronchodilation as recemic albuterol, 2.5 mg, was 0.63 mg levalbuterol, not 1.25 mg which is the mass equivalent dose. The interpretation of this data shows a particularly damaging effect of S-albuterol (Nelson, 1998).
Clinical studies have been carried out in pediatric patients with asthma. According to Gawchik (2007), a randomized placebo-controlled trial was necessary to compare the two drugs. In his study, he discovered that no differences existed in bronchodilation with levalbuterol and albuterol. This was because there was no dose-related correlation in children with moderate asthma. However, the dose-related correlation was found in children with severe asthma. In another study of acutely asthmatic patients between the ages of 6-18 years, there was a conclusion that the more expensive levalbuterol did not reduce the amount of return visits to the hospital for further asthma management as compared to racemic albuterol (PerrinFayolle, 1996).
The treatment also did not shorten the length of stay at the emergency department, improve expiratory flow (PEF), neither did it reduce the number of nebulized treatments when compared to racemic albuterol.
On the other hand, contrary to this, Gawchik (2007), writes about the new form of albuterol inhalers that are in use in the market since 2009 in a bid to compare albuterol to levalbuterol. He notes that due to the recent changes, the new form is adjusted and better in terms of the security of use due to the fact that they are both human and environmentally friendly. The chloroflouroalkane found in rescue inhalers both in levalbuterol and albuterol have been found to harm the environment. Therefore, the inclusion of hydroflouroalkane has been important as a propellant. This is actually a positive step in the study of the effects of the two types of drugs.
Ozminkowski & Wang (2007), conducted another age-stratified randomized study with hospital admission rate of the patients presented to the emergency department as the outcome. The study was aimed at finding out the frequency of admission of patients to the emergency section and the return rate after discharge. The objectives of this study were to find out the patient-return rate after treatment in the emergency section and find out the role played by levalbuterol in assisting the quick recovery of patients in the emergency section. The admission rate was lower in the levalbuterol group as compared to the albuterol group (Ozminkowski & Wang, 2007). The risk of the admitted group was greater in the albutrerol groups than the levalbuterol group.
However, the length of hospital stay in the levalbuterol group was not significantly shorter than the albuterol group and there were no adverse effects in both groups. In this study, the conclusion was that substituting the administration of albuterol with levalbuterol would reduce the number of hospitalizations (Carl et al., 2003). This was supported by another study by Nowark et. al. that showed that levalbutereol was preferrable to albuterol in the treatment of acute asthma. Administration of the same dose showed that improvement was greater in levalbuterol as compared to racemic albuterol. The study also indicated that patients with higher plasma levels of (S) albuterol show slower improvement and have a higher likelihood of hospital admission
In the same research, the investigator notes several factors. First and foremost, he acknowlegdes the fact that abuterol is the most commonly prescribed inhaler with beta-2 agonist. In addition, he notes that it is also considered the best drug when it comes to reversal of acute bronchospasm. Due to the equal mixture of (S) and (R)-albuterols, there is little effect of broncholdilating activities. On the contrary, the (R)- albuterol has a better binding effect to beta-2 receptors as compared to the (S)-albuterol (Tripp, 2008). According to the investigator, the creation of levalbuterol was needed for several reasons including fewer incidences of transcient tachycardia; the chance of better tolerability as compared to albuterol; and a higher efficacy than albuterol. A further examination of the research, showed that patients benefit more from levalbuterol.
Additionally, the outcomes of the study revealed that levalbuterol was better than albuterol in a sense that patients treated with levalbuterol required less medication after recovery and that they had shorter lengths of hospital stay. A regression analysis revealed that levalbuterol was allied with duration of stay savings. Another study conducted by Truitt, Witko, & Halpern (2003), showed similar improvements in FEV and mean heart rate decreased with levalbuterol. This study that was carried out in comparison to albuterol. However, the researchers note that the magnitude of the difference is minute. Therefore, it is important to study these differences together in order to detrmine the most reliable results.
Nonetheless, the investigators note that results may be helpful to patients who are affected with arrhythmias, cardiac conditions and structural heart diseases. This is because if the differences are not considered, it may worsen the heart condition. Therefore, the investigators note that the transcient tachycardia that is evident in cardiac patients may be a key indicator of the dose dependancy that is formed with time by patients who use levalbuterol and albuterol (Truit, Witko & Halpern, 2003).
In another study, Nowak (2008) and his colleagues compared the effects that are brought forth by nebulized levalbuterol. This was in comparison to the ones that are brought forth by racemic albuterol. The subjects were 627 adults who suffered from acute asthma. The subjects were radnomly given the opportunity to use either 1.25 mg of levalbuterol or 2.5 mg of albuterol. This was after twenty minutes of emergency admission and 40 minutes later all the patients received 40 mg of prednisone. The level of expiratory volume was forcefully increased by 40 percent when the patients were administered with levalbuterol, this is in comparison to racemic albuterol. The investigators also discovered that this coresponded to a fourty percent reduction in the subjects who required hospitalization (Nowak, 2008). The effects of levalbuterol were evident in patients who had severe asthma. The high levels of (S)-albuterol in the circulating plasma are thought to be the main cause of overuse of racemic albuterol. The number of relapses in the two groups after a period of thirty days, however, did not differ.
In another randomized clinical trial, Carl et al. compared the use levalbuterol with racemic albuterol in over 500 pediatric patients reporting to a hospital’s ED. Hospital admission rates were reduced among those receiving levalbuterol in comparison with those receiving racemic albuterol treatments. The study was also seeking to establish the hospital conversion where levalbuterol racemic albuterol was replaced with levalbuterol 1.25 mg every 8 hours or levalbuterol 0.63 mg every 6 hours. Despite that the frequency of levalbuterol was less, the patients required fewer rescue treatments to reduce the symptoms than did those treated with racemic albuterol. This means that the less frequently scheduled treatments with levalbuterol will lead to reduced workload and reduced number of missed treatments because of unavailability of therapists.
This is also supported by Truit et al, who reported that treatment with levalbuterol required one day less of admission, significantly fewer treatments and a 67 % decrease in readmissions within 30 days of discharge after treatment with the β2-agonist compared with racemic albuterol. Other studies reported similar results, indicating that treatment with levalbuterol reported decreased numbers of daily treatments, reductions of staffing and fewer as-needed treatments when compared to racemic albuterol as the acting β2-agonist.
Nowak (2008) conducted another study of patients who suffered from acute asthma and another group suffering from chronic obstructive pulmonary disease (COPD). There was a comparison of treatment of levalbuterol and albuterol that were administred in a period of 6 to 8 hours in 1.25 and 2.5 miligrams repectively. There were fewer nebulizations that were requiredwhen it came to the case of levalbuterol. On the other hand, there was an increased need for rescue aerosols in the period of 14 days hospitalization. However, most of the other outcomes were similar in the two groups. This is including the costs and study of the pulmonary functions. In the study by Truitt et. al. (2003), the retrospective chart review on hospitalized patients who had asthma and COPD showed that the results were more or less the same. This therefore led to the conclusion that the benefit of levalbuterol over albuterol is usually greatest in patients who have moderate as compared to severe asthma, particularly those with an overuse of albuterol.
Vitro and animal studies have shown significant outcomes that can be used as a basis of comparison. Many research studies reveal that albuterol is associated with severe effects that raise concerns, such as chest pain and high blood pressure. This could be because of the fact that inhalation of racemic albuterol leads to pushiness in circulating S-albuterol twelve times more than levalbuterol (Ameredes, 2009). Levalbuterol has been acclaimed to be a safer form of albuterol but it comes at increased costs. It costs five times more than racemic albuterol.
According to Gawchick (2007), albuterol is purely used for the treatment of symptoms that are occasional but an overdose of the drug can be fatal. One of the precautionary measures that should be taken when using albuterol is that the use should be discontinued in cases of adverse side effects, including hypersensitivity; abnormal heart rhythms; diabetes; epilepsy this is coupled with seizure disorder; and heart diseases. The researcher also notes wheezing, pounding heart, tight chest, nervousness, blood pressure, and chest pains side effect may be a sign of hypersensitvity.
Evidence from preclinical and clinical studies suggest that the worsening of asthma symptoms in some patients with continued use of albuterol or its overuse could be contributed by the racemic mixtures of albuterol isomers, which may result from the presence of the (S)-albuterol. The slow phamarcokinetic profile is one significant characteristic of (S)-albuterol. It is metabolized 12 times slower than levalbuterol. This is because it does not have sulfation and elimination enzymes preferrentially specific to levalbuterol. This leads to the differences in circulating levels of the isomers after administration of racemic albuterol. After administering a dose of inhalable racemic albuterol, it has been shown that the circulating levels of levalbuterol are undetectable wheras the levels of (S)-albuterol persisit for as long as 12 hours and may be preferentially retained in the lungs (PerrinFayolle, 1996). Therefore, it is important to consider the physiologic and pharmacologic effects of each isomer within the racemate mixture separately.
According to Truit, Witko & Halpern (2003), the issue of tolerance is still a bit controversial. There are some researchers that have noted that the overuse of racemic albuterol may lead to some factors that include hypokalemia and even increased mortality. Therefore, due to the lack of bronchodilator activities in (S)-albuterol, there may arise the situation of worsening air activity or rather pro-inflammatory effects. This is because it is metabolized 10-fold slower than levalbuterol (Truit, Witko & Halpern, 2003). This could additionally result in the accumulation of (S)-isomer over (R)-albuterol leading to paradoxic bronchospasm. In addition, patients who suffer from asthma or COPD and other cardiac diseases have a likelihood of worsening the situation when they experience tachycardia and this therefore means that they are safer when using levalbuterol as compared to albuterol (Lovtall, Palmqvist, Maloney, Vantresca and Ward 2004). Studies have also discovered poor adherence to medication by patients who suffer from tachycardia
The other main factor that was noted when comparing the two agents is cost. Before the year 2009, the metered-dose inhaler (MDI) that had generic formulations was widely available. There were also versions of albuterol that were much cheaper. They included proventil and ventolin. This fact also applied to levalbuterol. On the contrary, many of the MDI formulations contained a lot of chloroflourocarbon and therefore, this meant that they had to be banned by the FDA (Food and Drug Administration). This was particularly due to environmental reasons. Therefore, the unavailabilty of the MDI has led to the leveling in price of the two agents (Truitt et. al., 2003). However, there are variations in the cost of levalbuterol nebulization as compared to albuterol nebulization. The use of levalbuterol faces various limitations including higher costs, small sample size in terms of testing, inadequate manpower and lack of support by many researchers
This however, does not mean that albuterol should be preffered over levalbuterol since there are instances when levalbuteral tends to be widely accepted. First and foremost, there is a need by patients who have severe chronic asthma to get the doses of beta-2 agonist. This happens in spite of the use of controller therapies. A study by Tripp (2008) showed that levalbuterol resulted in Forced Expiratory Values (FEV) that were equivalent to or better than those that were observable in albuterol. The β-mediated effects were lower for a single dose of levalbuterol as compared to racemic albuterol. In this studies, treatment of asthma using levalbuterol was cheaper due to the little numbers of hospital admissions (Tripp, 2008). In this particular study, levalbuterol treatment in the emergency department was cost effective because it led to a situation of patients recovering faster and thus reducing the cost of healthcare.
Although the (R) -albuterol and (S) –albuterol isomers are similar in their molecular weight and their physiochemical properties, their 3-dimensional structure makes them super imposable. This conformational stereochemistry makes their properties distinct and for each isomer which results to them being considered different compounds (Nelson, 1998) As a result, regulatory authorities have demanded that the potential risks associated with the mixtures that make up racemic albuterol be quantified. Levalbuterol was developed to minimize the side effects associated with (S)-albuterol and maximize therapeutic effects. The findings of this study demonstrate that the use of levalbuterol significantly reduces hospital admission rates in patients presenting to the ED with acute asthma when compared to racemic albuterol. The study suggests that levalbuterol has clinical benefits over racemic albuterol in critical care settings, and these benefits are evident in both pediatric and adult patients administered with levalbuterol.
The above studies were conducted in geographically distinct ED settings, with varying patient populations, physicians, and socioeconomic conditions demonstrating that substituting racemic albuterol with levalbuterol improves patient outcomes by reducing hospital admissions. Different studies have suggested that levalbuterol produces greater bronchodilation than racemic albuterol and improves discharge rates and health resource use (Ozminkowski & Wang 2007). A post-hoc analysis on the patients found that their (S)-albuterol plasma levels negatively impacted their baseline forced expiratory volume in 1 second as well as pulmonary function an hour after ED treatment was commenced.
Despite the higher cost of levalbuterol in the treatment of asthma, when the total costs are considered, the differences in the costs are insignificant. The overall costs were similar in the levalbuterol group and the racemic albuterol group. The cost reductions were reported with increasing severity of asthma. This results from reduced hospital admissions and less frequent dosing, making the treatment more cost effective despite its high cost (Nowak, 2006)
The clinical and preclinical benefits of levalbuterol observed in the literature cited in this investigation occur due to the difference between the two agents which is the presence of (S)-isomer in the racemic mixture. Despite previous studies suggesting that it is inert, the (S) isomer may instead have some proinflammatory effects. The bronchoprotective efficacy of racemic albuterol progressively declines with regular use, leading to reduced interval between dose and decreased bronchodilation (Nelson, 1998).
The above findings indicate that levalbuterol, when used in place of albuterol reduces the number of hospital admissions, and is cost effective in the treatment of acute asthma in the ED setting. This makes the observations provocative and interesting since the only difference between the two agents is the presence of the (S)-isomer in the racemic mixture. The mainstay of therapy for reactive airway diseases has been rapid-onset β2-agonist agents such as racemic albuterol. However, the recent isolation of (R)-isomer levalbuterol has provided a new option for the treatment of asthma and COPD. The use of levalbuterol therapy produces both clinical and economical advantages when compared to albuterol therapy.
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