Neuroscience MD817

Cholinergics I
(Direct acting)
Katzung: Chapter 7
Olivier Thibault, Ph.D.
April 10
th
, 2013
10:00-11:00
1
Objectives
Use pharmacological principles to differentiate the
subtypes of cholinergic receptor subtypes, their associated
2nd messengers, their location and their primary regulating
activities in a given physiologic system

Describe the clinical use of different ACh agonists and how
their susceptibility to cholinesterases dictates their duration
of action

Differentiate between a direct acting and indirect
acting cholinergic drug


Log (Dose)
M
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R
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B
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Log (Dose)
N
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Sir Henry Dale, Acetylcholine Otto Loewi, Vagustoff
Both shared the Nobel prize 1936, physiology / medicine
5
2
Signal transduction through Nicotinic receptors



Ligand-gated ion channel ---FAST
Na
+
and Ca
2+
enter = depolarization
Pentameric receptor ( 5 subunits)

NMJ: ( 1)
2
or ( 1)
2

subunits have the ACh binding site
2 ACh molecules are necessary for activation



Alpha subunits: 1- 10
1 in skeletal muscles
7-10 are Ca
2+
-permeant
2-10 in CNS

2-5

CNS: ( 4)
2
( 4)
3
or ( 7)
5

Autonomic ganglia: (
5
3)
2
( 4)
3
(only use and subunits)
http://www.zptech.net/science.html
P
r
e

P
o
s
t

G-protein linked receptors (7 transmembrane domains). 2nd messengers: IP3, DAG, cAMP

There are 5 different isoforms M1-M5 that are present in different cell types:
M1 are neural (in the CNS) and in enteric nervous system and ganglia.
M2 are cardiac in atria, AV and SA nodes, also found in smooth muscles,
(some in the brain as presynaptic).
M3 are glandular exocrine glands, smooth muscles, endothelial cells, parietal
cells.

M1, M3 and M5 isoforms are linked to Gq. The Gq- subunit activates phospholipase C which
in turn, forms IP3 and DAG from membrane constituents. Result: increased secretion and
smooth muscle contraction - DEPOLARIZATION
M2 and M4 isoforms have a high affinity for G
i.
This leads to inhibition of adenylyl cyclase,
result: decreased cAMP which decreases force and rate of myocardial contraction -
HYPERPOLARIZATION
Signal transduction through Muscarinic receptors
3
Are synapses of the cholinergic system
excitatory?
Is it a good idea to promote
cholinergic functions?
How specific can we get (i.e., nicotinic
vs. muscarinic)?
What about CNS permeability (BBB
crossed?)


Therapeutic value?
Glaucoma

Xerostomia

Myasthenia Gravis

Alzheimers disease

Antidote to atropine poisoning

Antidote to mycetism

Post-operative atonia (GI)

Asthma
4
Sympathetic Innervation of
Adrenal Medulla
Sympathetic Parasympathetic
Preganglionic
Neurons
Acetylcholine Acetylcholine Acetylcholine
Acetylcholine
Adrenal Medulla
Release of Epinephrine
Adrenergic Receptor
Nicotinic Receptor
Ganglia
Postganlionic
Nicotinic Receptor
Nicotinic Receptor
Nicotinic
Receptor
Norepinephrine Acetylcholine
Adrenergic Receptor Muscarinic receptor
No Ganglia
EFFECTOR ORGANS; heart, lungs, eyes, glands
Striated Muscles
Cholinomimetics
Defined as substances that
mimic the effects of
parasympathetic nerve
discharge

Cholinergic agonists due to
their ability to activate
cholinergic receptors

Can be classified into two
categories

Direct acting
Bind to, and directly activate
muscarinic or nicotinic
receptors

Indirect acting
Produce their primary
effects by inhibiting
acetylcholinesterase thus
increasing synaptic levels of
ACh
N M
M N
M N
M N
M N
M
N
M
CHOLINERGIC
AGONISTS
I. DIRECT
ACTING
II. INDIRECT
ACTING
N M
M N
M N
M N
M N
M
N
M

Acetylcholine
Bethanechol
Methacholine
Carbachol

Pilocarpine
Muscarine
Nicotine
Cevimeline
REVERSIBLE


Edrophonium
Neostigmine
Physostigmine
Pyridostigmine

ne
IRREVERSIBLE


Nerve gases,
Organophosphates
Ecothiophate
Isoflurophate
II INDIRE DIRECT
RSIBLE
Cholinergic Agonists:
5
Direct-Acting Cholinergic Agonists:
Chemical Structures
Esters
Includes acetylcholine,
methacholine, carbachol
and bethanechol
All are permanently
charged quaternary
amines : relatively
insoluble in lipids
Alkaloids
Includes muscarine,
pilocarpine and nicotine
all are tertiary amines
except muscarine
(quaternary amine)

carbachol bethanechol


nicotine
acetylcholine
pilocarpine
muscarine
methacholine
Direct-Acting Cholinergic Agonists
Esters
Poorly absorbed and poorly
distributed into CNS due to
hydrophilicity (charged)

All are hydrolyzed in GI tract
following oral administration but
do not cross membrane well :
diminished effectiveness. Best to
use SC.

Vary in susceptibility to
hydrolysis by cholinesterase in
body (bethanechol and
carbachol are least sensitive)

Vary in affinity for muscarinic vs.
nicotinic receptors
methacholine and bethanechol
have virtually no activity at the
nicotinic receptor
Alkaloids
Well absorbed from most sites of
administration (except muscarine
which has limited GI absorption,
a 4
0
amine)

Excreted chiefly by the kidneys

Nicotine poisoning


Insecticide
and
or
usea,
6
Acetylcholine; endogenous transmitter has no therapeutic values
not specific (nicotinic and muscarinic receptors are activated)
readily hydrolyzed by AChE (esterases) [~ 5-20 s effect after large IV bolus]
would activate non-discriminately parasympathetic and sympathetic

Bethanecol; relatively selective for muscarinic receptors involved in GI and
bladder control
specific (Parasympathomimetic), with less activity at Nicotine receptor
not readily hydrolyzed by AChE
promotes GI / bladder motility in atony or in neurogenic bladder
or paralytic ileus
does not cross BBB
side effects: sweating, urinary urgency, diarrhea, decreased BP and HR, nausea,
abdominal pain, bronchoconstriction and spasms (asthma patients: be careful),
increased salivation (sialogogue) and lacrimation
CHOLINOMIMETICS I (Direct acting)
Cholinomimetics increase ACh in 5 different areas of the PNS ------ Specificity?
and
or
HR, nausea,
Methacholine;
Bit more specific for muscarinic receptors
less hydrolyzed by AChE
Used as methacholine challenge test (MCT; bronchoprovocation test for asthma) in
patients with normal spirometric readings but complain of chest tightness and difficulty
breathing


Carbachol;
relatively selective for nicotinic receptors, but still has significant activity at
muscarinic receptors
Not hydrolyzed by AChE
promotes miosis of iris (constrict sphincter); prior to occular surgery (miostat )
Topical application (glaucoma)
CHOLINOMIMETICS I (Direct acting)
7
Pilocarpine; - used to treat in glaucoma (emergency) and xerostomia
specific (muscarinic receptor agonist)-comes from a shrub (Pilocarpus jaborandi)
not hydrolyzed by AChE
causes miosis of iris (constrict sphincter); decreases intra-ocular pressure, and causes
blurred vision (constrict ciliary muscle forcing near-vision)
crosses BBB

Cevimeline; useful in treatment of xerostomia as in the case of Sjogrens disease;
antineoplastic agents; neck radiation; aging.
specific muscarinic receptor agonist at M1 and M3
cheaper than pilocarpine (3tid instead of 4)

Xerostomia symptoms:
dry, painful tongue
dry throat
dry eyes
sand sensation in eyes
burning feeling in eyes
dry mouth
mucus in and around the eyes
dry nose
difficulty speaking without drinking water
difficulty chewing and swallowing food
difficulty sleeping due to dryness of the mouth and throat
Venus Williams withdraws from U.S. Open after
revealing she has incurable immune system disease

8
Summary of Cholinergic Effects
Eye
Sphincter muscle of iris = contraction
(miosis)
Ciliary muscle = contraction for near
vision
Heart
SA node = decrease in rate (negative
chronotropy)

Atria = decrease in contractile
strength (negative inotropy)

AV node = Decrease in conduction
velocity (negative dromotropy);
increase in refractory period
Blood vessels
Arteries = dilation (via NO production)
Veins = dilation (via NO production)
Lung
Bronchial smooth muscle = contraction
(bronchoconstriction)
Bronchial glands = stimulation (mucous)
GI tract
Motility = increased
Sphincters = relaxation
Secretion = stimulation
Urinary bladder
Detrusor muscle = contraction
Trigone and sphincter = relaxation
Glands
Sweat, salivary, lacrimal,
nasopharyngeal = secretion
S
L
U
D
Gi-
E
9
Direct-Acting Cholinergic Agonists:
Indications for Use
While many cholinergic agonists have been studied, only ~5
are used clinically:
Carbachol
Pilocarpine
Bethanechol
Methacholine
Cevimeline

Major therapeutic uses:
Glaucoma (carbachol, pilocarpine)
Postoperative GI atony (bethanechol)
Neurogenic bladder (bethanechol)
Dry mouth (cevimeline)
Bronchoprovocation challenge (methacholine)

Administered topically in the eye or given orally, but can be
given IV or SC
Bethanechol rather selective for GI and urinary tract with
minimal CV effects when administered orally. New evidence
points to bethanechol working to reduce afferent signals sending
info to brain on bladder status.