Role of anticholinergic
therapy in COPD
Adil Al Sulami
Medical Resident
KAUH
• Both anticholinergic agents and beta
adrenergic agonists are effective in reversing
the reversible part of airway obstruction.
• Inhaled ipratropium bromide is preferred
over beta-2 agonists by many as the
bronchodilator of choice in COPD for the
following reasons:
– Its minimal cardiac stimulatory effects compared
to those of beta agonists.
– Its greater effectiveness than beta agonist or in
most studies of patients with COPD.
• active anticholinergic alkaloids exist in the
roots, seeds, and leaves of a variety of
belladonna plants.
• The most important of these naturally
occurring alkaloids are atropine and
scopolamine.
PHYSIOLOGY AND
PHARMACOLOGY
• The parasympathetic nervous system plays a
major role in regulating bronchomotor tone
through branches of vagus nerve, which cause
bronchoconstriction through muscarinic
cholinergic receptors.
Muscarinic receptors
• M1 receptors are present on peribronchial
ganglion cells where the preganglionic nerves
transmit to the postganglionic nerves.
• M2 receptors are present on the postganglionic
nerves.
• M3 receptors are present on smooth muscle.
• The activation of M1 and M3 receptors by ACh and its
analogs stimulates secretion by tracheobronchial
glands and causes bronchoconstriction.
• On the other hand, activation of M2 receptors limits
further production of ACh and protects against
parasympathetic-mediated bronchoconstriction.
• Based upon this information, an ideal anticholinergic
agent would inhibit only the M1 and M3 receptors and
spare the M2 receptors.
TERTIARY VERSUS
QUATERNARY AGENTS
• Quaternary ammonium drugs (such as
ipratropium) are synthetic derivatives of the
naturally occurring tertiary ammonium
compounds (such as atropine).
• Ipratropium bromide is derived by the
introduction of an isopropyl group to the N
atom of atropine.
• The structure of the quaternary ammonium
compounds renders them freely soluble in
water but insoluble in lipids, it is therefore
difficult for these compounds to cross biologic
barriers that can be easily crossed by the
tertiary ammonium compounds like atropine.
• The tertiary ammonium compounds are lipid-soluble,
easily absorbed, and can cause significant side
effects, including tachycardia, dry mouth, flushing of
the skin, blurred vision, and mood changes.
• Since compounds with a quaternary ammonium
structure are poorly absorbed after oral
administration, they cause fewer side effects.
• Ipratropium bromide is the most widely studied and
used quaternary anticholinergic medication in the
treatment of COPD.
• Ipratropium bromide produces effects similar to
atropine when each agent is administered
parenterally.
• These include bronchodilation, tachycardia, and
inhibition of salivary secretion.
• Unlike atropine, ipratropium lacks effect on
the CNS, is poorly absorbed from the lungs or
the gastrointestinal tract, and does not inhibit
mucociliary clearance .
• Even when ipratropium bromide is administered in
amounts many times the recommended dosage, little
or no change occurs in heart rate, blood pressure,
bladder function, intraocular pressure, or pupillary
diameter .
• This selectivity results from the very inefficient
absorption of the drug from airway or gastrointestinal
mucosa.
IPRATROPIUM VERSUS
BETA-AGONISTS
• In COPD, ipratropium has been shown to be
superior to the beta-adrenergic agonists in both shortand long-term studies.
• In a randomized, double-blind, multicenter study of
260 patients with COPD but no asthma or atopy,
ipratropium was more potent at its peak effect and
was longer acting than metaproterenol.
• beta-2 agonist use in patients with COPD may be
accompanied by pulmonary vasodilation, which may
worsen ventilation-perfusion matching and result in a
slight fall in arterial PaO2.
• The beneficial effects of ipratropium bromide
combined with its minimal side effects make this
agent the preferred bronchodilator for COPD in the
ambulatory setting.
COMBINATION
THERAPY
• Several physiologic reasons exist for the potential
benefit of combination therapy with ipratropium
and beta agonists:
– Anticholinergics act predominantly on the proximal large airways,
while sympathomimetics act on the more distal small airways.
– The two classes of medications cause bronchodilation via different
mechanisms: beta agonists are thought to cause bronchodilation by
directly acting on muscle, and ipratropium causes bronchodilation by
reducing cholinergic tone.
– Coadministration of adrenergic and anticholinergic agents provides the
rapid onset of action of the former and the sustained activity of the
latter; the potency of their combined action is utilized at intermediate
times.
Tiotropium bromide (Spiriva)
• is a long-acting anticholinergic agent with M1 and
M3 selectivity.
• Tiotropium may therefore have a theoretical
advantage over ipratropium bromide, since the M2
receptor mediates bronchodilation.
• In January 2004, the FDA approved tiotropium for
long-term once-daily treatment of bronchospasm in
patients with COPD.
One study randomized 288 patients with severe COPD
to receive either tiotropium once per day or
ipratropium four times per day:
• Significantly greater bronchodilation was achieved and
significantly less albuterol was used in the tiotropium group.
• Continuous therapy appears to be well tolerated, and is
associated with decreased dyspnea, fewer acute exacerbations
and hospitalizations, a reduction in hyperinflation, and
improved overnight arterial oxygen saturation compared to
placebo.
• Tiotropium, like ipratropium, appears to provide superior
bronchodilation and improvements in dyspnea when compared
with long-acting beta-agonists in patients with stable disease .
• This was demonstrated in a large three-armed study comparing
tiotropium with the long-acting beta-agonist salmeterol and
placebo in over 1200 patients with COPD.
• Therapy with tiotropium resulted in a significant delay in the
time until first exacerbation, and fewer exacerbations per year,
than treatment with salmeterol or placebo .
Over the long-term, tiotropium
• Improves lung function .
• Quality of life.
• Decreases the risk of exacerbations and
hospitalizations.
but does not reduce the rate of decline in (FEV1).
Thank you