Influence of Genotype on β-agonists Effectiveness 1
Running Head: Influence of Genotype on β-agonists Effectiveness
The Adverse Effects of β-agonists in Relation to the Severity and Genotype of Asthmatic
Patients
Lynn Lalley
The University of Akron
Influence of Genotype on β-agonists Effectiveness 2
Lynn Lalley
Respiratory Therapy
Ray Sibberson and Ray Reed
4 Credits
The Adverse Effects of β-agonists in Relation to the Severity and Genotype of Asthmatic
Patients
Abstract:
By studying the variability of genotypes on a patient’s β-adrenergic receptor gene, correct
medication can be prescribed to prevent exacerbations and control recurrent asthma symptoms.
The study entitled, β-Adrenergic Receptor Polymorphisms and Response to Salmeterol, supports
the concept that the integration of genotyping in patients with asthma provides significant
information pertaining to the pre-determined conclusion of the presence or absence of a
therapeutic response to β-agonist medication. Through the assessment of the usage and effects of
β-agonists in combination with an evaluation of a patient’s genotype, the findings demonstrate
why some adverse effects occur while others promote favorable outcomes. Although the clinical
study did not show a statistically significant difference, with larger patient groups and increased
patient cooperation and consistency, the limitations of this study can be overcome and the effects
of genotype on the effectiveness of asthma medication can be clearly defined and assist in the
control of asthma symptoms.
Influence of Genotype on β-agonists Effectiveness 3
Asthma is identified as a Chronic Obstructive Pulmonary Disease (COPD) that affects
over 20 million people in the United States and is one of the top five leading causes of death and
hospital admissions. COPD is recognized clinically by inflammation of the airways, excessive
mucus production, hyperinflation and bronchospasm. Unlike the other diseases classified as
COPD (cystic fibrosis, bronchiectasis, chronic bronchitis and emphysema), asthma is the only
condition that can be reversed. Since the prevalence of asthma has greatly increased in today’s
society, it is no surprise that researchers have begun to hypothesize whether there is a genetic
link to asthma. Recent studies suggest that an individual’s genetic makeup greatly influences and
affects the immune system’s response of inflammation, bronchospasm and the preventative
medications used to control exacerbations. The study entitled, β-Adrenergic Receptor
Polymorphisms and Response to Salmeterol, supports the concept that the integration of
genotyping in patients with asthma provides significant information pertaining to the predetermined conclusion of the presence or absence of a therapeutic response to medication –
specifically β-agonists. Through the assessment of the usage and effects of β-agonists, in
combination with an evaluation of a patient’s genotype, the findings demonstrate why some
adverse effects occur while others promote favorable outcomes.
Asthma is a condition that affects all age groups and ethnicities, due to chronically
inflamed and hyper-responsive airways motivated by various stimuli: allergic, non allergic and
possibly a genetic component. Allergic asthma, identifiable when a patient’s eosinophil count
exceeds 1 -3% in a sputum or blood sample, may be triggered by dander, pollen, pollution, food
or drugs, where as non allergic asthma may be triggered by exercise, air temperature changes or
emotional stress. Symptoms associated with asthma include tightness in chest, coughing,
wheezing and breathlessness with occurrence and onset dependent on the severity. If
Influence of Genotype on β-agonists Effectiveness 4
uncontrolled, an asthmatic patient may have an increase in work of breathing, secretion
production, and air trapping and become critically hypoxic, potentially resulting in an episode of
status asthmaticus. Additional clinical signs of asthma consist of: increased vital signs, tripod
and accessory muscle usage, intercostal retractions, cyanosis, expiratory prolongation, pursed-lip
breathing, increased anterior-posterior diameter, hyperresonant percussion, pulsus paradoxus and
a peak expiratory flow (PEF) measurement less than 40% of the patient’s predicted normal value
(Des Jardins, & Burton 2006). As the patient’s asthmatic episode or exacerbation increases in
severity, it is likely that multiple clinical signs will be observed upon patient assessment and
evaluation, and the patient should be monitored closely. It is essential to initiate asthma therapy
based upon the clinical classification of asthma in order to maintain control of symptoms and
minimize exacerbations or hospital admissions. Whether classified as intermittent, persistent and
either mild, moderate or severe, asthma does have a reversible expiratory airflow limitation that
can be life-threatening and remedied with numerous pharmacological solutions: adrenergics,
anti-cholinergics, steroids or xanthines.
Adrenergic receptors, alpha, β-1 or β-2, are responsible for changes to the
cardiopulmonary system – the heart and lungs. By stimulating one of these receptors, a
sympathetic response is instigated which can result in increased heart rate, blood pressure,
cardiac output and bronchodilation in the pulmonary system (Gardenhire 2008). Of all the
adrenergic receptors, the β-2 receptor activities are responsible for bronchodilation and
vasodilation, which relaxes the smooth muscle in the airway. Therefore, β-agonist therapy is an
indication for asthmatic patients in hopes of reversing the narrowing of the airway. The
advantages of using β-2 medications involve considerably less cardiac side effects and the
inability to metabolize β-blockers; this could lead to bronchospasm and adverse effects such as
Influence of Genotype on β-agonists Effectiveness 5
exacerbations, increased severity of asthma, and increased airway edema – the exact symptoms
that a physician is trying to control and prevent.
An asthma exacerbation occurs due to the initial narrowing of the airway lumen, whether
due to excessive mucus, inflammation or bronchoconstriction. An exacerbation is in response to
an unequal distribution of cyclic-AMP (C-AMP) and cyclic-GMP (C-GMP) with the desired
result an excess of C-AMP. This promotes bronchial smooth muscle relaxation, stabilization of
mast cells and effective mobilization of secretions. β-2 agonists, anti-cholinergics and xanthines
are all mechanisms of bronchodilation that generate an increase in C-AMP . Anti-cholinergic
medication, such as ipratropium bromide, help promote bronchodilation by inhibiting the
breakdown of GTP to C-GMP therefore relatively more C-AMP. Xanthines, such as caffeine,
increase C-AMP by preventing the break down of C-AMP through phosodiesterase (Sibberson,
2008). The figure below illustrates the enzyme breakdown:
ATP (adenosine triphosphate)
GTP (guanine triphosphate)
adenyl cyclase
Cyclic-AMP
guanyl cyclase
Cyclic-GMP
phosphodiesterase
3,5 AMP (inactive form)
phosphodiesterase
3,5 GMP (inactive form)
Figure-1 adapted from Sibberson.
Since the medication, highlighted in the study in review, focuses on the usage of β-2 agonists,
bronchodilation is achieved by increasing the action of adenyl cyclase resulting in additional CAMP. All of these medications cause bronchodilation but only β-agonists have a direct effect on
the production of C-AMP and provide longer relief - as in the case with the long-acting β-agonist
salmeterol.
Influence of Genotype on β-agonists Effectiveness 6
The long-acting β-agonist salmeterol is utilized to try and control asthma symptoms and
prevent future exacerbations in patients who did not benefit from only the use of a short-acting βagonist medication. It is customary for many physicians to prescribe a long-acting β-agonist
when corticosteroid usage alone does not maintain control of asthma symptoms but a patient may
still need a short-acting β-agonist, such as albuterol, for immediate relief of symptoms. Shortacting medications are regularly used as a rescue medication to treat symptoms immediately
rather than as a preventative maintenance medication - the rationale for long-acting β-agonists. In
comparison to the chemical structure of short-acting agents, salmeterol’s ability to provide
therapeutic effects lasting up to 12 hours is due to the longer hydrocarbon side chain and its
ability to attach to the exosite of the cell membrane thus manipulating the release of the
medication over a longer period of time (Gardenhire 2008). Due to the extended treatment
exposure and routine medication usage, the desired result is decreased ER and hospital
admissions, less rescue medication usage, stabilization of symptoms and improved asthma care
management.
The analysis of genotyping and DNA sequencing is essential to understanding the effects
different amino acid combinations have on a patient’s ability to respond to disease and the
likelihood that a patient will suffer from a certain disease due to genetic markers. This study
obtained information regarding a patient’s genotype in hopes of discovering that adverse effects
of salmeterol are linked to the amino acid combination on the 16 th amino acid position. In order
to observe each participant’s genotype, researchers acquired a sample of epithelial cells, blood,
hair or tissue. When researching a patient’s genotype, one is specifically focusing on the
presence or absence of a particular amino acid combination at a particular reference site; by
evaluating the combinations of the amino acid sequence, specifically only arginine (Arg) and
Influence of Genotype on β-agonists Effectiveness 7
arginine or glycine (Gly) and glycine on the 16 th amino acid position, the effectiveness of long
acting β-agonists can be compared to one another and conclude that a difference in genotype
correlates with adverse pharmacological results.
The similarities in the adverse effects of long-acting β-agonists to those of short-acting βagonists in patients with asthma homozygous genotypes on the 16th amino acid position of βadrenergic receptors gene were analyzed and examined by Wechsler et al (2005). The study
analyzes the effects of salmeterol on asthmatic patients with continuous, decreasing or
discontinued inhaled corticosteroid usage (Wechsler et al. 2005). Arg/Arg and Gly/Gly are
genotypes located on the β-adrenergic receptor gene. The usage of a long-acting β-agonist, such
as salmeterol and formoterol, is considered maintenance therapy as it is rapidly absorbed by the
cell membrane and then slowly and repeatedly released to the receptor, therefore constantly
providing relief from symptoms and controlling inflammation and bronchospasm. Short-acting
β-agonists act as quick relief for acute attacks and sudden dyspnea, wheezing and coughing.
Previous studies have suggested that short-acting β-agonists have adverse effects on Arg/Arg in
comparison to Gly/Gly thus the authors sought to discover if the same was true of long-acting βagonists (Wechsler et al. 2005). The result presented a significant difference between the uses of
salmeterol in the different homozygous genotypes on a.m. PEF as Arg/Arg had considerable
adverse effects in comparison to Gly/Gly patients (Wechsler et al. 2005).
Many researchers agree that using a long term β-agonist regularly can have adverse
effects on a patient dependent on the duration of treatment and the severity of asthma. A.E.
Tattersfield found that “β-agonists may alter airway caliber including inhibition of mediator
release from inflammatory cells in the lungs, reduction of parasympathetic discharge from
cholinergic ganglia, and an increase in the volume or viscosity of mucus or through a reduction
Influence of Genotype on β-agonists Effectiveness 8
in vascular permeability and edema in the airways (1992).” Without the confirmation of a
genetic-link, it is still evident that the regular use of a β-agonist increases bronchial reactivity
even though the cause may vary. Prophylactic use of β-agonists is also suggested to improve
compliance with anti-inflammatory therapy as well as to reduce the severity of obstruction once
regular β-agonist treatment is withdrawn as proven in a series of studies by M.R. Sears (1992).
The article by Beasley et al supports the conclusion that β-agonists have adverse affects
on asthmatic patients due to the fact that “in several countries a close correlation has been
observed between increasing mortality and morbidity from asthma and sales of β-agonist drugs
(1992).” However, the relationship between β-agonist usage and mortality is difficult to confirm
due to non-pharmacological factors, such as certain allergic reactions. Since the airway response
to β-agonists varies by patient, some experienced reduced symptoms while others merely
worsened. An evaluation and testing of a patient’s genotype may support why in some patients
adverse affects occur while in others favorable outcomes occur.
If genotype-specific asthma exists, Wechsler et al proposed that a patient can receive
modifications to pharmacological treatment to correctly control asthma symptoms by removing
or adding β-agonists. In order to maintain this hypothesis, the study emphasizes the adverse
effects of β-agonists on Arg/Arg and Gly/Gly subjects by observing PEF, bronchospasms,
exacerbations, inflammation and specifically, a.m. PEF (Wechsler et al. 2005). Two trials were
conducted: Salmeterol or Corticosteroid (SOCS) and Salmeterol with or without Inhaled
Corticosteroid (SLIC).
The SOCS trial divided stabilized asthmatic patients into three groups of subjects who:
continued inhaled corticosteroid (ICS) usage, discontinued ICS and replaced with salmeterol,
Influence of Genotype on β-agonists Effectiveness 9
and placebo – eventually all subjects experienced placebo substitution (Wechsler et al. 2005). A
statistically significant difference was not observed in the a.m. PEF between ICS and salmeterol
as it was concluded that patients undergoing ICS therapy could not be switched to salmeterol
without risk of loss of asthma control (Wechsler et al. 2005). Subsequently, once salmeterol was
removed from regular usage and no longer inhibiting the response of bronchodilation, a.m. PEF
increased – a clear sign that an alternative therapy is necessary as the combination of ICS and
salmeterol did not provide airway stability. In relation to genotype comparison, it was
acknowledged that a.m. PEF in Gly/Gly patients increased in those patients treated, 21.5LPM (p
= 0.050) with salmeterol and decreased in Arg/Arg patients to 29.9 LPM (p = 0.040) also treated
with salmeterol (Wechsler et al. 2005).
The SLIC trial, on the other hand, took uncontrolled asthmatic patients and placed them
in three random groups who received: salmeterol in addition to ICS, salmeterol with diminishing
usage of ICS and salmeterol with a placebo (Wechsler et al. 2005). Similar to the SOCS trial, the
comparison between a.m. PEF illustrated that Gly/Gly patients benefited from salmeterol and
ICS without treatment failure, and an increased number of adverse effects were found in Arg/Arg
subjects – genotype-specific difference of 36.8LPM (p = 0.048) (Wechsler et al. 2005).
Additional outcomes that support an improvement in Gly/Gly over Arg/Arg: p.m. PEF rates,
FEV1 and PEF rates, and the number of rescue puffs needed. For those subjects that used ICS to
control their asthma and saw an improvement by including salmeterol into their medication
regimen, a reduction in ICS would not cause a loss of control in asthma; nevertheless, removing
ICS completely would cause significant deterioration in asthma control (Wechsler et al. 2005).
One would assume that combining a long-acting β-agonist with an inhaled corticosteroid
would enhance the effectiveness of the therapy, yet it does not reduce the severity of airway
Influence of Genotype on β-agonists Effectiveness 10
responsiveness but actually worsens the symptoms of asthma in some patients. Inhaled
corticosteroids, considered the first-line therapy for asthma, are used for anti-inflammatory
effects and long-term maintenance; in most cases, it restores β-adrenergic stimulation at the
receptors allowing bronchodilators to work effectively. It seems possible that the combination of
an inhaled corticosteroid and β-agonist may stimulate the receptor sites to a large enough extent
that it actually causes desensitization at the site. In a study conducted by M.R. Sears, asthmatic
patients who used an inhaled corticosteroid and β-agonist regularly had more exacerbations and
“improved when the β-agonist was used only as required for control of symptoms (1992).”
Naturally, when treating asthma that has become more severe, a physician prescribes more βagonist or inhaled corticosteroid treatment which, according to the research, would then only
begin a vicious cycle of constantly increasing dosage that causes the severity of asthma to move
farther from the norm. Therefore, once the dosage of a β-agonist in increased, it is imperative
that assessment and monitoring are increased as well in case of intensified airway reactivity.
While both trials were placebo-based and double-blind, measures needed to be taken in
order for patient safety; differing severities and the possibility of a life-threatening asthmatic
attack upon being taken off all treatment and placed on a placebo is a medically dangerous
(Wechsler et al. 2005). As a result, albuterol was available as a rescue medication. Albuterol
usage would compromise the validity of the study as a rescue medication could affect the
outcome since an even greater increase in β-agonists in subjects who already demonstrate
adverse effects to them only increases the difference between Arg/Arg and Gly/Gly genotypes.
Increased albuterol usage could also be due to the adverse effects caused by using a long-acting
β-agonist regularly instead of as a prophylactic drug, or by confirming that Arg/Arg patients are
unable to yield the therapeutic results of a long-acting β-agonist as Gly/Gly patients. Wechsler et
Influence of Genotype on β-agonists Effectiveness 11
al prepared for this criticism by declaring that once rescue medications were used, the last value
observed before failure was documented as patient safety was the overall main concern (2005).
In addition, there was some variability with the subjects of the study as age, baseline function
and severity were not consistent between the three groupings of the SOCS and SLIC trials
(Wechsler et al. 2005). For example, a younger a patient may not have as severe exacerbations as
an elderly patient with a history of respiratory conditions. To prevent error, genotyped subjects
should also be more specifically classified by age and asthma severity.
Additional studies and testing must be done in order to show a statistically significant
difference between Gly/Gly and Arg/Arg as the evidence is still not strong enough due to patient
inconsistency and limitations within the study. It would be fascinating to repeat the study with
another LABA, such as formoterol, and see if the same results are yielded for each genotype.
Formoterol is similar to salmeterol in its desired patient response and chemical structure but
greatly differs in its binding capacity; formoterol is amphipathic in its ability to bind to both the
lipid bilayer membrane and the β-receptor. Salmeterol is only able to bind specifically to the
lipid membrane. Since formoterol can bind to both sites, it has a longer duration and faster onset
- quick relief and then continuous response (Anderson 1994). It would be interesting to observe
how the Arg/Arg patients and Gly/Gly patients respond to formoterol therapy in comparison to
salmeterol; if differences are present, perhaps the cause is due to the fast onset and bind capacity.
It is important that in all types of asthma the airway obstruction, bronchoconstriction or
inflammation be treated effectively and in a timely manner to reduce the chances of
exacerbations or relapse. The usage of a β-agonist in the treatment of asthma does have many
positive effects, such as bronchodilation and symptom relief. For those patients who are
adversely affected by regular β-agonist usage though, a simple increase in severity may lead to
Influence of Genotype on β-agonists Effectiveness 12
fatal results. By studying the variability of genotypes on a patient’s β-adrenergic receptor gene,
correct medication can be prescribed to prevent exacerbations and control recurrent asthma
symptoms.
Influence of Genotype on β-agonists Effectiveness 13
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