COPD - Training Manual - Module 1

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MODULE 1









Role of LAMA in COPD Management

Role of LAMAs in COPD Management:

Focus on Tiotropium











1.1 GOLD recommendations: Place in therapy for LAMAs in the

COPD armamentarium

Bronchodilators are central to the management of chronic obstructive pulmonary
disease (COPD). The 2021 update of the Global Initiative for Chronic Obstructive
Lung Disease (GOLD) Strategy Report continues to include a model for initiation
of pharmacological treatment, which is based on the assessment of symptoms
and exacerbation risk according to the GOLD ABCD assessment tool. Long-acting
muscarinic antagonist (LAMA) monotherapy is recommended as the initial
treatment in the majority of COPD patients, i.e. for GOLD groups B, C, and D
(Figure 1).



Figure 1: Initial pharmacological management algorithm as per the GOLD 2021
guidelines

























LAMA: long-acting muscarinic antagonist; LABA: long-acting beta2-agonist; ICS: inhaled corticosteroid;
CAT: COPD Assessment Test; eos: eosinophils ; mMRC: modified Medical Research Council score

1.2 Mechanism of action of LAMAs

LAMAs inhibit the bronchoconstrictor e ect of acetylcholine (Figure 2) by
prolonged binding to the M3 muscarinic receptors present on airway smooth
muscle cells (SMCs) and rapid dissociation from the M2 receptors.

Figure 2: Mechanism of action of LAMAs


























SMC: Smooth Muscle Cells

COPD is characterised by chronic inflammation and structural changes to the
airways. Inflammation is, therefore, an important therapeutic target for managing
the disease, and therapy that provides anti-inflammatory benefits in addition to
bronchodilation is desired. Various studies have suggested that tiotropium, an
anticholinergic agent, may exert both direct and indirect anti-inflammatory
e ects that reduce the inflammation in the airways.


Further, mucus hypersecretion may contribute to airflow limitation in COPD and is
a risk factor for accelerated loss of lung function and an increase in exacerbations.
Animal studies have suggested that tiotropium might improve airflow limitation
by reducing airway mucus; in a study of patients with COPD, tiotropium was
associated with a reduction in sputum volume.



1.3 Evidence regarding tiotropium use in COPD management

Tiotropium, an anticholinergic agent that is used for once-daily inhalation, has
consistently shown significant beneficial e ects with respect to the parameters
mentioned below:

Symptoms: Reduction in COPD symptoms such as wheezing and shortness of
breath have been proven with the use of tiotropium. vii


Exercise tolerance: a) Increase in the constant work-rate cycle ergometry
endurance time (a measure of exercise capacity); and, b) Increase in the mean
distance walked during the shuttle walk test.


Rescue medication use: Reduced use of short-acting bronchodilators for
symptomatic relief, which is an indication of a better degree of control of
dyspnoea with tiotropium.

Exacerbations: Delayed the time to first exacerbation and reduced the number
of exacerbations. The reduction in exacerbations with tiotropium maintenance
treatment may be partially explained by the sustained bronchodilation and
consequent reduction in lung hyperinflation a orded by maintenance
tiotropium treatment.


QoL: Improvement in the QoL and patient-reported outcomes are an
important goal of COPD management. Numerous studies have demonstrated
the beneficial e ects of tiotropium versus placebo on symptom reduction,
health status and the QoL, as measured by the St. George’s Respiratory
Questionnaire (SGRQ) score in patients across the GOLD groups.


A few studies have compared the long-term e cacy and safety of tiotropium
versus the short-acting anticholinergic agent, ipratropium. Compared with
ipratropium, tiotropium significantly reduced dyspnoea, the use of rescue
medication and the number of exacerbations, and improved health-related QoL
(HRQoL).



1.4 Tiotropium versus other LAMAs


Many other LAMAs have been developed after the introduction of tiotropium.
However, tiotropium has some pharmacological and clinical characteristics that,
when considered as a whole, sets it apart from other long-acting bronchodilators
for the maintenance treatment of COPD.


Tiotropium is structurally similar to ipratropium but with significantly higher
a nity for the muscarinic receptors within the lungs (M3 receptors). Binding
studies show that tiotropium dissociates slowly from the M3 receptors versus the
M2 receptors, resulting in a long half-life (allowing once-daily administration) and
limits the cardiac side e ects (Table 1).


Table 1: Pharmacokinetic properties of tiotropium versus other LAMAs

Table 2: Summary of clinical trials comparing tiotropium versus other LAMAs

Key Takeaways:




LAMAs are recommended as the initial pharmacological approach for
managing COPD patients (GOLD groups B, C and D).


In addition to bronchodilation, tiotropium also has anti-inflammatory
e ects and reduces mucus hypersecretion.


Results of clinical trials indicate that tiotropium extends benefits with
respect to improvement in lung function, reduction in exacerbations,
improvement in symptoms and overall QoL, and reduction in the use
of rescue inhalers.


Despite the availability of newer LAMAs, tiotropium has some
pharmacological properties that set it apart from the other recent
additions.


Tiotropium binds to M3 receptors with greater a nity as compared
with other LAMAs, and reduces cough and mucus hypersecretion.
There are also multiple studies that show that when compared with
other LAMAs, tiotropium demonstrates similar benefits in improving
lung function and COPD disease outcomes.