Pharmacology

and Therapeutics
of Asthma and
COPD
β2 Agonists
 ISI
• Introduction
• Clinical Classification of β Agonists
• SABAs
• LABAs
• Ultra-LABAs
• Mechanisms of Action
• Adverse Effects
• Pharmacogenetics and the β2AR
• Future Perspectives and Summary
 INTRODUCTION
• β agonists are the frontline treatment for asthma and
COPD
• Bronchodilatory effects via β2 adrenoceptors (β2ARs)
located on airway smooth muscle (ASM) cells
• Activation of these receptors results in ASM, and
airway relaxation
• β2 ARs are also found in epithelial cells, submucosal
glands, vascular endothelium, vascular smooth muscle,
and inflammatory cells mincluding mast cells,
macrophages, and eosinophils (Barnes 2004).
• The β2AR is a member of the G-protein coupled
receptor (GPCR)
• It is composed of seven transmembrane spanning
domains and has an intracellular C-terminus and an
extracellular N-terminus
• GPCRs as targets for drug therapy, estimated 30–50%
of medicines directly or indirectly
• Selectivity of beneficial over unwanted effects
• Major side effects are: anxiety, tachycardia, tremor, and
sweating
Fig. 1 The classic β2AR signalling pathway Barnes Page .
 History
• β agonist aw relaxation was first used 5,000 years ago in Chinese
medicine when ma huang was used to alleviate respiratory conditions
• Ephedrine activates the β2AR pathway indirectly via activity of
noradrenaline at βARs
• In western medicine it was not until the early 20th century that
ephedrine-mediated bronchodilatory effects were described
• The first pure (but nonselective between β1AR and β2ARs) β agonist,
isoprenaline (isoproterenol in the USA), in the 1940s
• Next 20 years Isoprenaline became the most commonly used inhaled
treatment for asthma
• 1956 intoduce as a metered dose inhaler in 1956
 History
• 1960s an epidemic of deaths in 6 countries, likely due to usage
of a higher of isoprenaline
• The first β2AR-selective agonist, salbutamol, was synthesized
in 1968
• It still remains relatively short acting (SABA)
• Glaxo modify salbutamol producing salmeterol,
bronchodilatory
• effect for up to 12 h LABAs
• The subsequently developed LABA formoterol
• More recently the discovery of even longer acting such as
indacaterol, for once daily dosing, called ultra-LABAs
• LABAs is the cornerstone of treatment for
asthma and COPD
• In 2011 the US FDA warned, when treating
asthma, LABAs must only be used in combination
with ICS
• For COPD, LABA monotherapy is a frontline
treatment
• Indacaterol (ultra LABA) is indicated for COPD
and not asthma
 Clinical Classification of β Agonists
• BA are grouped into three classes : SABAs, LABAs, Ultra LABAs
• Table 1 lists the β agonists used clinically
• SABAs have short half-lives and are used as rapid relievers
• LABAs and ultra-LABAs provide sustained symptomatic relief
• LABA monotherapy for asthma is contraindicated due to safety
• The prolonged duration of action of the
• LABAs currently used in clinical practice is not thought to be due
to a difference in
• receptor kinetics but rather retention within the cell membrane
and hence a
• continued presence of the drug near to the receptor.
 SABAs
• SABAs delivered via MDI or DPI
• Provide instant symptomatic relief and are the frontline
therapy in asthma
• Combat bronchoconstriction and acute exacerbations
• Their bronchoprotective effect in minutes and remains
for 4–6 h
• Also available for oral administration and more prone to
systemic side effects
• SABAs are recommended to be used only on an “as
required” basis
 SABAs
• For COPD SABAs are recommended as the
initial treatment for the relief of
breathlessness and exercise
• Efficacy in COPD is less than in asthma
 LABAs
• For asthma, Inhaled LABA as the initial add-on
therapy in patients already taking a regular ICS
but inadequate control
• LABA Monotherapy in asthma is contraindicated.
• LABA monotherapy proving less clinically
effective than treatment with ICS and mainly due
to the safety issues in the “adverse effects”
 LABAs
• If asthma is still poorly controlled even
• following increased doses of ICS, further add-
on drugs are advised to be trialled including
leukotriene receptor antagonists, slow release
theophylline, or antimuscarinic agents
including the new long acting muscarinic
antagonists (LAMAs) such as tiotropium
 LABAs
• LABAs are a frontline treatment for COPD
• Recommended as maintenance therapy either alone
(if FEV150% predicted) or combination with an ICS (if
FEV1<50% predicted)
• In people with stable COPD and an FEV1 50% who
remain breathless or have exacerbations despite
maintenance therapy with a LABA a combination
inhaler LABA/ ICS is also recommended
• LAMAs can be used interchangeably with LABAs
depending on the patients’ symptomatic response
 Ultra-LABAs
• The ultra-LABA indacaterol was given for the
maintenance treatment of patients with COPD
• Indacaterol is delivered by inhalation as a dry
powder and has a fast onset of action
• In December 2014 a combination ultra-
LABA/LAMA (indacaterol/glycopyrronium
bromide) was launched for COPD
• Indacaterol has not yet been approved for asthma
 Mechanisms of Action
• Characteristic of transmembrane signalling involving
GPCR (β2AR), heterotrimeric G protein (Gs for the
β2AR) and an effector (adenylyl cyclase (AC)
downstream of β2AR-Gs)
• AC mediates the hydrolysis of ATP into cAMP, which in
turn activates the cAMP-PKA (Protein kinase A)
• PKA is the first discovered cAMP effector, and has
been shown to phosphorylate numerous intracellular
substrates to effect various functions in a cell type-
dependent manner
Fig. 2 The pros and cons of β2AR activation. As shown in Fig. 1, activation of the β2AR
induces bronchorelaxation (i.e., a beneficial effect) via its activation of the adenylyl
cyclase-cAMP-PKA\ pathway.
 Adverse Effects
• The majority of adverse effects can be
attributed to either: (1) a lack of selectivity for
the β2AR, resulting in “off-target” effects
mediated by either α or β1 ARs; or (2) ill-
defined β2AR-mediated effects that appear to
involve either β2AR desensitization or
exacerbation of airway inflammation and its
consequences.
 Adverse Effects
• β1AR Agonism Promotes Several Adverse Effects of
Therapeutic Relevance including tachycardia, arrhythmia,
tremor, and headache
• β agonists such as adrenaline (activating both α and β ARs)
and isoprenaline (activating both β1 and β2ARs)
• β2AR-selective such as salbutamol and terbutaline
• The degree of selectivity (see table 1)
• The sensitivity of patients to experience cardiovascular side
effects depend on individual characteristics including the
presence or absence of significant co-morbidities such as
ischemic heart disease.
 Adverse Effects
• Safety Concerns over β Agonist Use in Asthma Prompted
by Mortality and Morbidity Data Are Controversial
• Mechanistic Basis for Increased Mortality/Morbidity Is
Poorly Understoom
• Use of the SABA isoprenaline in is associated with
increased AE and mortality
• Asthma-related mortality increased after the release of
the SABA fenoterol in New Zealand in 1976, yet
subsequently waned after the drug was removed from
the market in 1989
 Adverse Effects
• The safety of LABAs was also questioned
shortly after their introduction
• The Nationwide Surveillance (SNS) Study, a
prospective study which suggested a trend
towards asthma-related deaths associated
with the use of salmeterol
 FDA recommendation
• Use of a LABA alone for asthma, without use
of ICS, is contraindicated (absolutely advised
against)
• LABAs should not be used in patients whose
asthma is adequately controlled on low or
medium dose ICS
• LABAs should only be used as additional
therapy for asthma who are currently taking but
are not adequately controlled with ICS
 FDA recommendation
• Once asthma control is achieved and
maintained, patients should be assessed at
regular intervals and step down therapy
should begin (e.g., discontinue LABA)
• If possible without loss of asthma control, and
the patient should continue to be treated with
ICS
 Mechanism
• Possible explanations have been offered, the loss of
drug effectiveness due to desensitization of β2AR on
ASM
• β2AR desensitization as evidenced by diminished β
agonist stimulated intracellular signalling and function
has been seen to occur with chronic β2 agonist
• The loss of asthma control associated with chronic
• β2 agonist use causing β2AR desensitization represents
one attractive explanation for poorer control of disease
 Future Perspectives and Summary
• β2 agonists continue to have a major role in the
treatment of airflow obstruction
• Using in combination with ICS they have proven
effective and have a good overall safety record
• Improvements offers potential to further refine the
use of this class of drugs
• The development of more selective agents with
longer durations of action will likely continue,
although safety concerns will still need to be assessed
TERIMA KASIH