Transcript Lecture 3 - ectuDirec Cholinomimetics (2012).pptx

Autonomic Nervous System
Prof. Alhaider 1434 H
Revision of Physiology and Anatomy
What is the peripheral Nervous System?
What is the differences between autonomic and
somatic?
Why is Acetylcholine an important
neurotransmitter?
Why ACH is not in clinical practice?
By the end of this lecture the student should know
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
Classification of nervous system.
Describe the various steps in cholinergic transmission.
Mention the different types, locations and actions of
cholinergic receptors.
Describe the effects of acetylcholine on major organs
Classify cholinomimetic drugs.
Describe the kinetics, actions and uses of direct acting
cholinomimetic drugs.
Nervous system
Peripheral nervous
system
Central nervous
system
Efferent Division
Afferent Division
Autonomic nervous
system
Somatic
system
Enteric nervous system
Parasympathetic nervous system
Sympathetic nervous system
 Why
Acetylcholine is very important
neurotransmitter?
 See the Next Figure
 Biosynthesis
and pathway of Acetylcholine
 (Cholinergic Transmission)
Cholinergic transmission
CHOLINOMIMETIC AGENTS
Nerve
Heart
glands and
endothelium
“Reversible”
Alkaloids
Muscarinic
Direct-acting
drugs
Receptors
Ach
Indirect acting
Drugs
Nicotinic
“Irreversible”
Choline esters
Neuromuscular
Ganglionic
Subtypes and characteristics of Cholinergic
Receptors
Receptor type
Other Name
Location
Structural
features
Postrecptor
mechanism
M1
M1a
Nerves
7 transmembrane
segments,G protein
linked
IP3,DAG cascade
M2
M2a,cardiac M2
Heart, nerves, smooth
muscle
7 transmembrane
segment,Gproteinlinked
Inhibition of cAMP
production, activation
of K channels
M3
M2b glandular M2
Glands,smooth
muscle,endothelium
7 transmembrane
segment ,G-protein
linked
IP3,DAG
casaded→↑cytosolic
calcium released
m4
? CNS
7membrane segment
Gprotein linked
Inhibition of cAMP
producation
m51
? CNS
7membrane segment
Gprotein linked
IP3 ,DAG,cascade
NM
Muscle type,end plate
receptor
Skeletal muscle
neuromuscular
junction
Pentamer(αβδγ)2
Na+,K+depolarizing ion
channel
NN
Neuronal type ,
ganglion receptor
Postganglionic cell
body,dendrites
αandβsubunitss only
as α2β2α3β3
Na+,K+depolarizing ion
channel
Receptor
M1
(Neural)
Excitatory
M2
(Cardiac)
Inhibitory
Locations
Pharmacological actions
CNS
CNS excitation
Autonomic ganglia Gastric acid secretion
gastric parietal cells Activation of phospholipase C 
IP3 &DAG   Ca
Heart
Cardiac inhibition
Presynaptic cholinergic Presynaptic inhibition
fibers
• Inhibition of adenyl cyclase
( cAMP)
• Opening of K channels
M3
Glandular
Excitatory
Exocrine glands
Smooth muscles
Vascular endothelium
• Secretion of glands
• Smooth muscle contraction
• Vasodilatation (via NO)
• Activation of phospholipase C 
IP3 & DAG.
Nicotinic receptors
Central cholinoceptor
Muscarinic receptors
Peripheral cholinoceptor
Ion channel linked receptors
G protein linked receptors
Autonomic ganglia (sympathetic &
parasympathetic) stimulation ( Nn )
On all peripheral organs that
receive postganglionic
parasympathetic fibers
Adrenal medulla (Nn)
release of catecholamines
(Adrenaline & Noradrenaline)
Heart (M2) inhibition
exocrine glands (M3) contraction
Skeletal muscle (Neuromuscular
junction)
(Nm) Contraction
Almost excitatory
Smooth muscles (GIT, urinary
tract, bronchial muscles)
(M3) contraction
Excitatory or inhibitory
Nicotinic receptors
Type I receptors : ion channel linked receptors
1. Autonomic ganglia (Nn).
2. Adrenal medulla (Nn).
3. CNS (Nn)
3.Neuromuscular junction (Nm)
Summary
 Based
on the receptor type,
Acetylcholine has two main effects:


1) Cholinergic (cholinomimetics) actions
2) Nicotinic Actions
Nicotinic Actions
Skeletal muscles:
 Low

conc. muscle contraction
High conc.  persistent depolarization &
paralysis.
Ganglia: stimulation of sympathetic &
parasympathetic ganglia.
Adrenal medulla release of catecholamines (A &
NA).
Features of Good Directly
Acting Cholinergic Drugs
 Since
Ach is not specific and easily
destroyed by Cholinesterase, thus it
is very essential to obtain
Cholinergic Drugs that have low
nicotinic activity, high muscarenic
selectivity but with low susceptibility
to cholinesterase. (See Figure)
 Which drug that has such features?
ACh
Pilocarpine
Complete
Carbachol
Complete
Absorption
NOT
Metabolism
Hydrolyzed
NOT
by
hydrolyzed by
cholinesterase cholinesterase
NOT
hydrolyzed by
cholinesterase
NOT
hydrolyzed by
cholinesterase
Duration
Very short
Longer (++)
Longer (++)
Administ.
I.V.
Longer (++)
oral,
eye drops
Complete
Bethanechol
Oral,
eye drops
Oral, S.C.
(Pharmacological Actions of Cholinomimetic Agents
Note: They are continuation of the physiological effects of
ACH.
A)
Directly Acting Drugs
1)
Effect on Eye (M3) (contraction of circular muscle leadi
to miosis and contraction of ciliary muscle leading to
accommodation for near vision). Both effects are
utilized in the Rx of Glaucoma to decrease intraocular
pressure.
1)
Effects on CVS: here remember the repolarizing
action mediated by stimulation of M2 receptor.
i) AV and SA nodes: decrease rate of depolarization
and conduction in the nodes leading to bradycardia
at low doses.
What will happen if high concentration of Ach were given?
Muscarinic actions
Organs
Cholinergic actions
Eye
Contraction of circular muscle of iris (miosis)(M3)
Contraction of ciliary muscles for near vision (M3)
bradycardia ( heart rate ) (M2)
Release of NO (EDRF)
Heart
endothelium
Lung
Constriction of bronchial smooth muscles
Increase bronchial secretion M3
GIT
Increased peristalsis
Increased secretion
Contraction of sphincter M3
Urinary
bladder
Contraction of muscles
Relaxation of sphincter M3
Exocrine
glands
Increase of sweat, saliva, lacrimal, bronchial,
intestinal secretions M3
ii)
Atrail muscle: decrease conductivity and
contractility.
iii) Ventricles: no effect Why?
iv) Blood vessels (vasodilation How?).
Here remember EFFECTS that are mediated by stimulation of M1 and
M3 .
I)
II)

Lung: Bronchoconstriction
GIT: increase the tone and motility leading to diarrhea and
cramps.
III) Bladder (destrusor (contraction) vs sphincher (Relaxation)
What are the clinical significant of such effects?
4) Effects on Glands (Exocrine) (M3)

5) Effects on CNS
5) Effects on Neuromuscular Junction (Nicotinic
Receptors)
Very important and related to the clinical uses.
What are the the naturally occuring alkaloids (e.g:
Pilocarpine and Oxotremorine and Muscarine) ?
What is mushrooms poisoning?
ACh
Pilocarpine
Complete
Carbachol
Complete
Absorption
NOT
Metabolism
Hydrolyzed
NOT
by
hydrolyzed by
cholinesterase cholinesterase
NOT
hydrolyzed by
cholinesterase
NOT
hydrolyzed by
cholinesterase
Duration
Very short
Longer (++)
Longer (++)
Administ.
I.V.
Longer (++)
oral,
eye drops
Complete
Bethanechol
Oral,
eye drops
Oral, S.C.
ACh
Pilocarpine
Carbachol
Receptors
Muscarinic
Nicotinic
Muscarinic
Muscarinic
Nicotinic
Muscarini
c
+++
+++
Selectivity
NOT
More on eye,
secretion
Nicotinic
+++
NO
Uses
NO
Xerostomia
Glaucoma
+++
Eye, GIT
Urinary
bladder
+++
Glaucoma
Urinary
retention
Paralytic
ileus
Bethanechol
Muscarinic
+++
GIT, Urinary
bladder
NO
Urinary
retention
Paralytic ileus
New Drugs
Cevimeline
Direct acting cholinomimetics
A muscarinic agonist, with particular effect on
M3 receptors
It is given orally.
Increased salivation.
Used for treatment of dry mouth symptom
associated with Sjogren's syndrome.
