Anticholinergic (Parasympatholytic) Bronchodilators
History and Development
The prototype anticholinergic agent is atropine, which is found naturally in
the plants Atropa belladonna and the Datura species.
Scopalamine is also extracted from the belladonna plant, and both atropine
and scopolamine are called belladonna alkaloids.
Agent
Belladonna alkaloids
Date
Thousands of Years
Datura species of plants
India – 17th century
Great Britain – 1802
United States – c1850
Aerosols of Datura
19th century
Atropine
1833
Anticholinergic
(parasympatholytic)
agents
19th century
Anticholinergic
19th and early 20th
Event
There is evidence that
atropine and
scopolamine have been
ingested in one form or
another for thousands
of years for their effects
on the central nervous
system.
Fumes from burning the
Datura species of plants
were inhaled as a
treatment for
respiratory disorders
Aerosols of liquid with
Datura were noted and
the respiratory route for
delivery of medications
began to be
appreciated.
The alkaloid daturine
was identified as
Atropine by Geiger and
Hesse
Many physicians in
Great Britain and
America considered the
use of inhaled
parasympatholytic
agents as “quackery”
Physician disagreement
(parasympatholytic)
agents
century
on the use of Datura
probably rested on
several issues:
(1) Difficulty in accurate
dosage with smoking or
aerosol therapy
(2) The irritant effects
of smoke
(3) Confusion over
diagnosing and clinically
differentiating
obstructive and
occupational lung
diseases led to
inappropriate use of
Datura alkaloids
Adrenaline and
ephedrine
1930s
By the 1930s,
adrenaline and
ephedrine had largely
replaced stramonium
and belladonna extracts
for treatment of
asthma.
Anticholinergic
(parasympatholytic)
agents
1980s
Interest in the
anticholinergic agents
was renewed, based on
two factors:
(1) A new
understanding of the
role of the
parasympathetic system
in airway obstruction
(2) The introduction of
atropine derivatives
with fewer side effects
Ipratropium bromide
1987
Ipratropium bromide
was released in the US
as the aerosol Atrovent.
Clinical Indication for Use
I.
Indication for Anticholinergic Bronchodilator
a. Ipratropium or other anticholinergic agents are indicated as a
bronchodilator for maintenance treatment in COPD, including
chronic bronchitis and emphysema
II.
Indications for Combined Anticholinergic and β-Agonist Bronchodilators
a. A combination anticholinergic and β-agonist, such as ipratropium
and albuterol (Combivent), is indicated for use in patients with
COPD on regular treatment who require additional bronchodilation
for relief of airflow obstruction
b. Ipratropium is also commonly used in severe asthma in addition to
β-agonists, especially in acute bronchoconstriction that does not
respond well to β-agonist therapy
III. Anticholinergic Nasal Spray
a. A nasal spray formulation is indicated for symptomatic relief of
allergic and non-allergic perennial rhinitis and the common cold
Specific Anticholinergic (Parasympatholytic) Agents
Drug
Ipratropium
bromide
Brand Name
Atrovent
Ipratropium
bromide and
albuterol
Combivent
Ipratropium
bromide and
albuterol
Oxitropium
bromide*
DuoNeb
Tiotropium
bromide
Spiriva
Oxivent
Adult Dosage
MDI: 18 mcg/puff
2 puffs qid
SVN: 0.02% sol.
500 mcg tid, qid
MDI: ipratropium 18
mcg/puff and albuterol
90 mcg/puff
2 puffs qid
SVN: ipratropium 0.5 mg
and albuterol 3.0 mg
Unit dose qid
MDI: 100 mcg/puff
2 puffs bid, tid
DPI: 18 mcg/inhalation
1 inhalation daily
*Available outside the United States
Clinical Pharmacology
I.
Tertiary Ammonium Compounds
a. Agents
i. Atropine sulfate
Time Course
Onset: 15 min.
Peak: 1-2 hr
Duration: 4-6 hr
Onset: 15 min.
Peak: 1-2 hr
Duration: 4-6 hr
Onset: 15 min.
Peak: 1-2 hr
Duration: 4-6 hr
Onset: 15 min.
Peak: 1-2 hr
Duration: 8 hr
Onset: 30 min.
Peak: 3 hr
Duration: 24 hr
II.
ii. Scopolamine
b. Clinical Pharmacodynamics
i. Easily absorbed into the bloodstream
1. cause systemic effects
ii. Cross the blood-brain barrier
1. cause CNS effects
Quaternary Ammonium Compounds
a. Agents
i. Ipratropium bromide
ii. Oxitropium bromide
iii. Tiotropium bromide
b. Clinical Pharmacodynamics
i. Poorly absorbed into the bloodstream
1. no/minimal systemic effects
ii. Does not cross the blood-brain barrier
1. no CNS effects
Pharmacologic Effects of Anticholinergic (Antimuscarinic) Agents
Table 7-2
Comparison of cholinergic antagonism to cholinergic effects
Cholinergic Effect
Decreased heart rate
Miosis (contraction of iris, eye)
Salivation
Lacrimation
Urination
Defecation
Secretion of mucus
Bronchoconstriction
Anticholinergic Effect
Increased heart rate
Mitosis (pupil dilatation)
Drying of the upper airway
Inhibition of tear formation
Urinary retention
Antidiarrheal or constipation
Mucociliary slowing
Inhibition of constriction
Table 7-3
Pharmacologic Effects of Tertiary versus Quaternary Anticholinergic Agents
Given by Inhalation
Organ System
Respiratory Tract
Tertiary
Bronchodilation
Decreased mucociliary
clearance
Blocks hypersecretion
Central Nervous System
Altered CNS function
Quaternary
Bronchodilation
Little or no change in
mucociliary clearance
Blocks nasal
hypersecretion
No effect
Eye
Cardiac
Gastrointestinal
Genitourinary
Mydriasis
Cycloplegia
Increased intraocular
pressure
Minor slowing of heart
rate (smaller doses)
Increased heart rate
(larger doses)
Dry mouth, dysphagia,
dysphonia
Urinary retention
Usually no effect*
No effect
Dry mouth
Usually no effect**
*Assumes aerosol is not sprayed into eye; use with caution in glaucoma
**Use with caution in prostatic enlargement or urinary retention
Mode of Action
I.
II.
Anticholinergic Agents
a. Cholinergic stimulation of muscarinic receptors on airway smooth
muscle and submucosal glands cause bronchoconstriction and
increased mucus production
b. Anticholinergic agents block the action of acetylcholine at
parasympathetic postganglionic effector cell receptors
c. Anticholinergic agents act as antagonists at parasympathetic
receptor sites and block cholinergic-induced bronchoconstriction
d. The effect seen will depend on the degree of tone present that can
be blocked
i. Individuals with normal lungs will have minimal airway
dilation – only a resting level of tone to be blocked
ii. Individuals with COPD may have significant airway dilation
due to a higher degree of parasympathetic activity (beyond
normal resting level) due to vagally-mediated reflex
bronchoconstriction
Vagally Mediated Reflex Bronchoconstriction
a. A portion of the bronchoconstriction seen in COPD may be due to a
mechanism of vagally mediated reflex innervation of airway smooth
muscle
b. Sensory C-fiber nerves respond to a variety of stimuli, such as
irritant aerosols, cold air, cigarette smoke, noxious fumes, and
mediators of inflammation such as histamine
c. When C-fiber nerves are activated, they produce an afferent nerve
impulse to the CNS, which results in a reflex cholinergic efferent
impulse
i. Constriction of airway smooth muscle
ii. Mucous gland secretion
III.
iii. Cough
Muscarinic Receptor Subtypes
a. Anticholinergic agents are nonselective muscarinic receptor
antagonists
Receptor
M1
Location
Postganglionic neuron
M2
M3
Postganglionic neuron
Airway smooth muscle
Submucosal glands
Effect
Facilitate cholinergic nerve transmission
causing the release of ACH
Inhibits further ACH release
Causes contraction of smooth muscle
Increased secretion
Adverse Effects
Side Effects Seen with Anticholinergic Aerosol (Ipratropium)
MDI and SVN (common)
MDI (occasional)
SVN
Dry mouth
Cough
Nervousness
Irritation
Dizziness
Headache
Palpitation
Rash
Pharyngitis
Dyspnea
Flu-like symptoms
Bronchitis
Upper respiratory infections
Nausea
Occasional bronchoconstriction
Eye pain
Urinary retention (<3%)
Side effects were reported in a small percentage (<1% to 5%)
Precautions: Use with caution in patients with narrow-angle glaucoma, prostatic
hypertrophy, bladder neck obstruction, constipation, bowel obstruction, or tachycardia
The eye must be protected from drug exposure:
MDI – holding chamber
SVN – mouthpiece and reservoir tube to expiratory side
Clinical Application
Comparison of Effects for Anticholinergic and β adrenergic Bronchodilators
Parameter
Onset
Time to peak effect
Duration
Tremor
Fall in PaO2
Tolerance
Site of action
I.
II.
III.
IV.
Anticholinergic
Slightly slower
Slower
Longer
None
None
None
Larger, central airways
β Agonist
Faster
Faster
Shorter
Yes
Yes
Yes
Central and peripheral
airways
Use in Chronic Obstructive Pulmonary Disease
a. Anticholinergic agents were found to be more potent
bronchodilators than β-adrenergic agents in bronchitis-emphysema
Use in Asthma
a. Anticholinergic agents not proven superior to β-adrenergic agents
b. They offer an additional avenue of management
c. They are especially useful for
i. Nocturnal asthma
ii. Psychogenic asthma (vagally mediated)
iii. Patients on beta blockers (angina, HTN, glaucoma)
iv. Patients with notable side effects from theophylline
v. Acute, severe episodes of asthma not responding well to βadrenergic agents
Combination Therapy: β-adrenergic and Anticholinergic Agents in
COPD
a. Theoretically useful
i. Complementary sites of action
ii. Mechanism of action separate and complimentary
iii. Pharmacokinetics somewhat complementary (onset, peak,
duration)
iv. Possible additive effects – results conflicting
v. Combivent Study: 462 patients at 24 centers
Agent
Mean increase in FEV1
Combivent
31-33%
Atrovent
24-25%
Albuterol
24-27%
Sequence of Administration
a. Frequently debated
i. Anticholinergic bronchodilator acts in the central, larger
airways
1. some argue it should be given before the β-adrenergic
ii. β-adrenergic often given first
1. have more rapid onset and beta-2 receptors are
distributed in the large and small airways
b. Combivent® and DuoNeb® make it a moot point