Anticholinergic (Parasympatholytic)
Agents
AHPH 544
Pharmacology Aspects
of Clinical Physiology
Robert L. Joyner, Jr.,
Ph.D., RRT
Associate Professor of
Health Sciences
Salisbury University
Anticholinergic
Drugs
n
Given
by inhaled aerosol can block cholinergic induced bronchoconstriction.
Agent and
Clinical Use
n Agents in Use
n
Ipratropium
bromide (Atrovent)*
n
Atropine
sulfate
n
Glycopyrolate
(Robinul)
n
Oxytropium
Bromide
n Investigational agents
n
Tiotropium
n
Flutropium
n Indications for use
n
Maintenance
treatment of bronchoconstriction in COPD
n
Symptomatic
relief of allergic and non-allergic perennial rhinitis (nasal spray)
Mode of
Action
n Parasympathetic nerves
(vagus) enter the lung at the hila and travel along the airways.
n Parasympathetic post
ganglionic fibers terminate on or near airway epithelium, submucosal glands,
smooth muscle and mast cells.
n Parasympathetic
innervation and muscarinic receptors are concentrated in the larger airways.
n Normal
airways.
n
Basal
level of bronchomotor tone is caused by parasympathetic activity.
n
Basal
tone can be abolished by anticholinergic agents (e.g. atropine), indicating action is mediated by Ach.
n
Administration
of parasympathomimetic (cholinergic) agents (e.g. methacholine) can intensify
the level of bronchial tone to the point of constriction and stimulate
submucosal glands to produce mucus.
n Anticholinergic agents
(e.g. atropine, ipratropium) are antimuscarinic (i.e. they block the action of
Ach at parasympathetic postganglionic effector cell receptors) therefore
anticholinergic agents block cholinergic induced bronchoconstriction.
n The effect seen will
depend on the degree of tone present that can be blocked.
n This effect is minimal
in healthy persons, because only basal levels of tone exist.
Anticholinergic
Mechanism
COPD and
Vagally-Mediated Reflex Bronchoconstriction
n In
COPD.
n
Sensory
c-fiber nerves respond to a variety of stimuli (e.g. irritant aerosols, cold
air, increased flows).
n
When
activated – c-fibers produce an afferent nerve impulse to CNS that results in a
reflex cholinergic efferent impulse to cause constriction of ASM and release of
secretions from mucous glands as well as cough.
n
Since
atropine and its derivatives are competitive inhibitors of Ach at the
neuroeffector junction, such antagonists should block parasympathetic reflex
bronchoconstriction.
Vagally Mediated
Reflex Bronchoconstriction
Muscarinic
Receptor Subtypes
n
Anticholinergic
agents cause bronchodilation by blocking muscarinic receptor subtype M3
on ASM, preventing Ach from activating receptor and thereby preventing or
reversing bronchoconstriction.
Muscarinic
Receptor Subtypes
n
Muscarinic
M1 receptors on postganglionic neurons facilitate cholinergic nerve
transmission, leading to the release of Ach. Ach stimulates M3
receptor subtypes of ASM, causing contraction and exocytosis of secretions from
mucous glands.
Muscarinic
Receptor Subtypes
n
M2
receptors inhibit release of Ach from post ganglionic neurons. Occupation of M3
receptors by a drug prevents stimulation of the receptor by Ach and thereby
preventing stimulation induced bronchoconstriction and mucous release.
Anticholinergic
Mechanism of Bronchodilation
n Stimulation of the M3
receptor subtype activates Gs protein, that
in turn activates phospholipase C (PLC).
n PLC causes a breakdown
of phosphoinositides into inositol triphosphate (IP3) and diacyl glycerol (DAG).
n This leads to an
increase in cytoplasmic [Ca++] and smooth muscle contraction and
glandular secretion.
n Competitive blockade
of M3 receptors prevents this sequence.
n Blockade of M1
receptors prevents transmission of nervous impulse to neuroeffector site.
n Currently available
anticholinergic agents are all non-selective muscarinic receptor antagonists.
Anticholinergic
Mechanism of Bronchodilation
Clinical
Pharmacology
n Atropine
/ Scopolamine.
n
Tertiary
ammonium compounds.
n
Easily absorbed into blood stream.
n
Distributes throughout the body.
n
Crosses blood-brain barrier causing CNS
changes.
n Atrovent
/ Glycopyrolate.
n
Quaternary atropine derivative.
n
Poorly absorbed.
n
Does not enter CNS.
n
Minimal
systemic side effects if given by inhalation.
n
Wide therapeutic margins.
Chemical
Structures of Anticholinergics
Cholinergic
VS.
Anticholinergic Effects
Tertiary
VS.
Quaternary Anticholinergic Effects
Pharmacokinetics
of Ipratropium
n
Differs
from b - agonists.
n
Onset
in minutes but peak effect takes hours (b - agonists peak in 20
– 30 minutes).
n
In
asthma; duration of effect is equivalent to
b - agonists.
n
In
COPD; duration of effect is 1 to 2 hours longer.
Strengths,
Dosages and Duration of Action
Pharmacologic
Effects of Anticholinergics (Tertiary Ammonium Compounds)
n
Atropine / Scopolamine.
n
Respiratory tract.
n
Decreases mucociliary clearance.
n
Blocks hypersensitivity.
n
Relaxes smooth airway muscle.
n
CNS.
n
Crosses
BBB.
n
Restlessness.
n
Irritability.
n
Drowsiness.
n
Fatigue.
n
Mild excitement.
n
Increased
doses cause disorientation, hallucinations, coma.
n
Eye Effects.
n
Distribution
through blood stream can effect vision.
n
Block
contraction of iris (blurring).
n
Increases intraocular pressure in glaucoma.
n
Cardiac.
n
Increases
HR.
n
GI.
n
Decreases
GI motility (lomotic).
Pharmacologic
Effects of Anticholinergics (Quartnary Ammonium Compounds)
n Ipratropium
/ Glycopyrolate.
n
Respiratory Tract.
n
No
effect on mucociliary clearance.
n
Bronchodilation.
n
Decrease
in nasal mucosa.
n
CNS.
n
Does not cross CNS.
n
Eye Effects.
n
Must
use with caution in patient with glaucoma.
n
Cardiac and GI effects.
n
Does not get absorbed.
Side Effects
of Ipratropium
Specific
Anticholinergic Agents
n
Atrovent
is approved for use in patients diagnosed with COPD.
n
Combivent
– combination is superior to b2 or anticholinergic
alone.
Clinical
Application of Anticholinergic Agents
n
Superior to b2 agonists in COPD.
n
Likely due to disease pathology and location
of M3 receptors.
n
Use
in Asthma.
n
Nocturnal Asthma.
n
Psychogenic asthma.
n
Alternative to aminophylline.
n
Kid and ER admissions.
Comparison
of Effects
Combination
of b2 and Anticholinergics (Combivent)
n
Complementary sites of action (i.e. large vs.
small airways).
n
Mechanism of action separate.
n
Pharmacokinetics.
n
b2 – quick
acting and relatively short duration.
n
Anticholinergic
– slow and long duration.
n
Sequence of administration.
End