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	Date	Event
Belladonna alkaloids	Thousands of Years	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.
Datura species of plants	India – 17^th century Great Britain – 1802 United States – c1850	Fumes from burning the Datura species of plants were inhaled as a treatment for respiratory disorders
Aerosols of Datura	19^th century	Aerosols of liquid with Datura were noted and the respiratory route for delivery of medications began to be appreciated.
Atropine	1833	The alkaloid daturine was identified as Atropine by Geiger and Hesse
Anticholinergic (parasympatholytic) agents	19^th century	Many physicians in Great Britain and America considered the use of inhaled parasympatholytic agents as “quackery”
Anticholinergic (parasympatholytic) agents	19^th and early 20^th century	Physician disagreement 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	Brand Name	Adult Dosage	Time Course
Ipratropium bromide	Atrovent	MDI: 18 mcg/puff 2 puffs qid SVN: 0.02% sol. 500 mcg tid, qid	Onset: 15 min. Peak: 1-2 hr Duration: 4-6 hr
Ipratropium bromide and albuterol	Combivent	MDI: ipratropium 18 mcg/puff and albuterol 90 mcg/puff 2 puffs qid	Onset: 15 min. Peak: 1-2 hr Duration: 4-6 hr
Ipratropium bromide and albuterol	DuoNeb	SVN: ipratropium 0.5 mg and albuterol 3.0 mg Unit dose qid	Onset: 15 min. Peak: 1-2 hr Duration: 4-6 hr
Oxitropium bromide*	Oxivent	MDI: 100 mcg/puff 2 puffs bid, tid	Onset: 15 min. Peak: 1-2 hr Duration: 8 hr
Tiotropium bromide	Spiriva	DPI: 18 mcg/inhalation 1 inhalation daily	Onset: 30 min. Peak: 3 hr Duration: 24 hr

*Available outside the United States

Clinical Pharmacology

I. Tertiary Ammonium Compounds

a. Agents

i. Atropine sulfate

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

II. 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	Anticholinergic Effect
Decreased heart rate	Increased heart rate
Miosis (contraction of iris, eye)	Mitosis (pupil dilatation)
Salivation	Drying of the upper airway
Lacrimation	Inhibition of tear formation
Urination	Urinary retention
Defecation	Antidiarrheal or constipation
Secretion of mucus	Mucociliary slowing
Bronchoconstriction	Inhibition of constriction

Table 7-3

Pharmacologic Effects of Tertiary versus Quaternary Anticholinergic Agents Given by Inhalation

Organ System	Tertiary	Quaternary
Respiratory Tract	Bronchodilation Decreased mucociliary clearance Blocks hypersecretion	Bronchodilation Little or no change in mucociliary clearance Blocks nasal hypersecretion
Central Nervous System	Altered CNS function	No effect
Eye	Mydriasis Cycloplegia Increased intraocular pressure	Usually no effect*
Cardiac	Minor slowing of heart rate (smaller doses) Increased heart rate (larger doses)	No effect
Gastrointestinal	Dry mouth, dysphagia, dysphonia	Dry mouth
Genitourinary	Urinary retention	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. 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

II. 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. Cough

III. Muscarinic Receptor Subtypes

a. Anticholinergic agents are nonselective muscarinic receptor antagonists

Receptor	Location	Effect
M1	Postganglionic neuron	Facilitate cholinergic nerve transmission causing the release of ACH
M2	Postganglionic neuron	Inhibits further ACH release
M3	Airway smooth muscle Submucosal glands	Causes contraction of smooth muscle Increased secretion

Adverse Effects

Side Effects Seen with Anticholinergic Aerosol (Ipratropium)

MDI and SVN (common)	Dry mouth Cough
MDI (occasional)	Nervousness Irritation Dizziness Headache Palpitation Rash
SVN	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	Anticholinergic	β Agonist
Onset	Slightly slower	Faster
Time to peak effect	Slower	Faster
Duration	Longer	Shorter
Tremor	None	Yes
Fall in PaO2	None	Yes
Tolerance	None	Yes
Site of action	Larger, central airways	Central and peripheral airways

I. Use in Chronic Obstructive Pulmonary Disease

a. Anticholinergic agents were found to be more potent bronchodilators than β-adrenergic agents in bronchitis-emphysema

II. 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 β-adrenergic agents

III. 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%

IV. 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