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Autonomic Pharmacology:
Cholinergic Drugs
Prepared and presented by:
Marc Imhotep Cray, M.D.
Imhotep Virtual Medical School
BMSCK Teacher
eNotes:
ANS- Autonomic Nervous
System Pharmacology
(Cholinergic drugs section)
Tutorial Worth Visiting:
Cholinergic ANS
Clinical:
e-Medicine Article
Myasthenia Gravis
2
Reference Resource
Principles of Pharmacology: The
Pathophysiologic Basis of Drug Therapy Cairo
CW, Simon JB, Golan DE. (Eds.); LLW 2012
3
Cholinergic Biosynthesis
Acetylcoline is formed
from two precursors:
 choline: which is
derived from dietary
and intraneuronal
sources
 acetyl coenzyme: which
is made from glucose in
mitochondria of neurons
 Acetylcholine is synthesized
from choline and acetyl-CoA
by the enzyme choline
acetyl transferase (ChAT)
to form acetylcholine, which is
immediately stored in small
vesicular compartments
closely attached to
cytoplasmic side of
presynaptic membranes
 ChAT is a selective marker for
cholinergic neurons
4
Cholinergic Biosynthesis
1) Synthesis of acetylcholine (ACh) from
acetyl CoA and choline
2) Storage of ACh in synaptic vesicles
3) Release of ACh ( fusion of synaptic vesicle
with presysnaptic membrane and release
of ACh into the synapse)
4) Action of ACh by binding to and activating
receptors (nicotinic in autonomic ganglia
and neuromuscular junction and,
muscarinic in many sites)
5) Inactivation by enzymatic breakdown of
ACh by acetylcholinesterase (AChE)
located in the synapse.
ACh is degraded in the synaptic cleft by
acetylcholinesterase to choline and
acetate
5
Cholinergic Agents-Direct Acting
and Indirect Acting
 Choline Esters
 Acetylcholine
 Bethanechol
(Urecholine)
 Carbachol
 Methacholine
(Provocholine)
 Alkaloids
 Muscarine
 Pilocarpine (Pilocar)
 There are three main types
of cholinesterase:
 Short-acting: edrophonium
 medium-acting: neostigmine
(2-4h), pyridostigmine (3-
6h) physostigmine
 irreversible:
organophosphates, dyflos,
ecothiopate
Agents-Direct Acting Indirect Acting
6
Spectrum of Action of Choline
Esters
Location of cholinergic synapses mainly
determine the spectrum of action of
acetylcholine and choline esters
Cholinergic Synaptic Sites
 autonomic effector sites:
innervated by post-ganglionic
parasympathetic fibers
 some CNS synapses
 autonomic ganglia and the
adrenal medulla
 skeletal muscle motor
endplates (motor nerves)
7
Spectrum of Action of Choline
Esters(2)
Cholinergic influences are prominent in many organ systems:
Choline Ester
Sensitivity
to ACHE
Cardio-
vascular
Gastrointe
stinal
Urinary
Bladder
Eye
(Topical)
Atropine
Sensitive
Activity at
Nicotinic
Sites
Acetylcholine
Methacholine
Carbachol No
Bethanechol No ? ? No
8
Spectrum of Action of Choline
Esters(3)
Cholinergic Receptors:
 Cholinergic refers to responses in various systems to
the natural transmitter molecule Acetylcholine (ACh)

If one looks at a set of responses where ACh is the
normal transmitter, observation has shown that those
same responses are differently sensitive to the extrinisic
molecules Nicotine and Muscarine
 Nicotine comes from tobacco,
 Muscarine comes from certain mushrooms
9
Spectrum of Action of Choline
Esters(4)
Based on the different sensitivities shown above,
Cholinergic receptors are subclassified into two categories,
Nicotinic and Muscarinic, named for the extrinsic
compounds that stimulate only that category
10
Spectrum of Action of Choline
Esters(5)
Nicotinic Receptors
 Stimulated by ACh and nicotine, not
stimulated by muscarine
 Found at all ganglionic synapses
 Also found at neuromuscular junctions
 Blocked by hexamethonium
11
Spectrum of Action of Choline
Esters(6) Nicotinic Receptors
 The physiological
responses to stimulation
and block are complex
since both sympathetic
and parasympathetic
systems are affected
 The final response of any
one organ system depends
on which system has a
stronger tonic influence
 Example: Under normal
circumstances, the heart
receives more
parasympathetic influence
than sympathetic

Ganglionic blockade would
lower parasympathetic
influence more than
sympathetic, and thus heart
rate would increase
12
Spectrum of Action of Choline
Esters(6) Muscarinic Receptors
 Stimulated by ACh and muscarine, not
stimulated by nicotine
 Found at target organs when ACh is released
by post-ganglionic neurons (all of
parasympathetic, and some sympathetic)
 Stimulated selectively by Muscarine and
Bethanechol etc.
 Blocked by Atropine
13
Spectrum of Action of Choline
Esters(7) Muscarinic Receptors
Stimulation causes:
 Increased sweating
 Decreased heart rate
 Decreased blood pressure due to decreased cardiac
output
 Bronchoconstriction and increased bronchosecretion
 Contraction of the pupils, and contraction of ciliary body
for near vision
 Tearing and salivation
 Increased motility and secretions of the GI system
 Urination and defecation
 Engorgement of genitalia
14
Cholinergic Receptors: Subtypes,
Tissues, Responses and Molecular
Mechanisms
Muscarinic Receptor Coupling Mechanisms
 Five types of cholinergic receptors have been
identified by molecular cloning methods.
 The five muscarinic receptor subtypes, M1 - M5,
are associated with specific anatomical sites
 For example:
 M1 -ganglia; secretory glands
 M2 - myocardium, smooth muscle
 M3 , M4 :smooth muscle, secretory glands
15
Cholinergic Receptors: Subtypes,
Tissues, Responses and Molecular
Mechanisms
Nicotinic Muscle Receptor
Antagonists Tissue Responses
Molecular
Aspects
Tubocurarine
alpha-bungarotoxin
Neuromuscular
Junction
Membrane
Depolarization
leading to muscle
contraction
Nicotinic (muscle)
receptor's cation
ion channel
opening
16
Cholinergic Receptors: Subtypes,
Tissues, Responses and Molecular
Mechanisms(2)
Nicotinic Neuronal Receptor
Antagonists Tissue Responses
Molecular
Aspects
Mecamylamine
(Inversine)
Autonomic
Ganglia
Depolarization:
postsynaptic cell
activation
Nicotinic
(muscle)
receptor's cation
ion channel
openingAdrenal Medulla
Catecholamine
secretion
CNS unknown
17
Cholinergic Receptors: Subtypes,
Tissues, Responses and Molecular
Mechanisms(3)
Muscarinic Type M1
Antagonist Tissue Responses
Molecular
Aspects
Atropine
Pirenzepine
(more
selective)
Autonomic
Ganglia
Depolarization
(late EPSP)
Stimulation of
Phospholipase C
(PLC): activation of
inositol-1,4,5
triphosphate (IP3 )
and diacylglycerol
(DAG) leading to
increased
cytosolic Ca2+
CNS Unknown
18
Cholinergic Receptors: Subtypes,
Tissues, Responses and Molecular
Mechanisms(4)
Muscarinic Type M2
Tissue (Heart) Responses Molecular Aspects
SA node
decreased phase 4
depolarization;
hyperpolarization
K+ channel activation
through ß-gamma Gi
subunits;
Gi -mediated inhibition of
adenylyl cyclase which
decreases intracellular
Ca2+ levels.
(Gi can inhibit directly
Ca2+ channel opening)
Atrium
decreased contractility;
decreased AP duration
AV node
decreased conduction
velocity
Ventricle decreased contractility
19
Signal Transduction: Comparison
of Muscarinic and Nicotinic Receptors
Nicotinic Receptors
 Ligand-gated ion channels
 Agonist effects blocked by tubocurarine
 Receptor activation results in:
 rapid increases of Na+ and Ca2+ conductance
 deplorization
 excitation
 Subtypes based on differing subunit
composition: See Muscle and Neuronal Classification
Discussed in previous slides
20
Signal Transduction: Comparison
of Muscarinic and Nicotinic Receptors
Muscarinic Receptors
 G-protein coupled receptor system
 Slower responses
 Agonist effects blocked by atropine
 At least five receptor subtypes have
been described by molecular cloning
21
Muscarinic Receptors:
Second Messenger Systems
 Activation of IP3, DAG cascade
 DAG may activate smooth muscle Ca2+ channels
 IP3 releases Ca2+ from endoplasmic and
sarcoplasmic reticulum
 Increase in cGMP
 Increase in intracellular K+ by cGMP-K+ channel
binding
 inhibition of adenylyl cyclase activity (heart)
22
Muscarinic Receptors: Second
Messenger Systems(2)
23
Direct vs. Indirect-Acting
Cholinomimetics
 A direct-acting cholinomimetic drug
produces its pharmacological effect by receptor
activation
 An indirect-acting drug inhibits
acetylcholinesterase, thereby increasing
endogenous acetylcholine levels, resulting in
increased cholinergic response.
24
Pharmacological Effects of
Cholinomimetics
1)Vasodilation
 This effect is mediated by muscarinic
receptor activation and is especially
prominent in the salivary gland and
intestines
25
Pharmacological Effects of
Cholinomimetics (2)
Vasodilation cont.
 The vascular response
is due to endothelial
cell nitric oxide (NO)
release following
agonist interactions
with endothelial
muscarinic receptor
 Increased NO
activates guanylate
cyclase which
increases cyclic GMP
concentrations
26
Pharmacological Effects of
Cholinomimetics (3)
Vasodilation cont.
 Subsequent activation of a Ca2+ ion pump reduces
intracellular Ca2+
 Reduction in intracellular Ca2+ causes vascular
smooth muscle relaxation
 Ca2+ complexes with calmodulin activating light-
chain myosin kinase
 Increased cGMP promotes dephosphorylation of myosin
light-chains.
 Smooth-muscle myosin must be phosphorylated in order
to interact with actin and cause muscle contraction.
27
Nitric Oxide (NO) and Vasodilitation
From: http://www.nature.com/nature/journal/v396/n6708/fig_tab/396213a0_F1.html
28
Pharmacological Effects of
Cholinomimetics(4)
2)Negative chronotropic effect
(Decrease in heart rate)
 Decreases phase 4 (diastolic
depolarization)
 As a result, it takes longer for the
membrane potential to reach threshold.
 Mediated by M2 muscarinic receptors
29
Pharmacological Effects of
Cholinomimetics(5)
3) Decreased SA nodal and AV nodal
conduction velocity
 Excessive vagal tone may induce bradyarrhythmias
including partial or total heart block (impulses
cannot pass through AV node to drive ventricular
rate
 in this case, the idioventricular or intrinsic ventricular
rate must maintain adequate cardiac output
 Transmission through the AV node is especially
dependent on Ca2+ currents.
 ACh decreases calcium currents in the atrioventricular
node
30
Pharmacological Effects of
Cholinomimetics(6)
4) Negative inotropism (decreased myocardial
contractility)
 more prominent in atrial than ventricular tissue
 due to a decrease in Ca2+ inward current
 in ventricle, adrenergic tone dominates;
 at higher levels of sympathetic tone, a reduction in
contractility due to muscarinic stimulation is noted
 Muscarinic stimulation reduces response to
norepinephrine by opposing increases in cAMP in
addition to reducing norepinephrine release from
adrenergic terminals
31
Clinical Uses
Gastrointestinal & Genitourinary
 Bethanechol (Urecholine)
 GI smooth muscle stimulant
 postoperative abdominal distention
 paralytic ileus
 esophageal reflux; promotes increased esophageal
motility (other drugs are more effective, e.g.
dopamine antagonist (metoclopramide) or serotonin
agonists (cisapride)
32
Clinical Uses(2)
Urinary bladder stimulant
 post-operative; post-partum urinary retention
 alternative to pilocarpine to treat diminished
salivation secondary e.g. to radiation
 Carbachol not used due to more prominent
nicotinic receptor activation
Diagnostic tool
 Methacholine used for diagnostic purposes
 testing for bronchial hyperreactivity and asthma
33
Clinical Uses(3)
Opthalmological Uses
 Acetylcholine and Carbachol may be used for
intraocular use as a miotic in surgery
 Carbachol may be used in treatment of glaucoma
 Pilocarpine is used in management of glaucoma
and has become the standard initial drug for
treating the open-angle form.
 Sequential administration of atropine (mydriatic)
and pilocarpine (miotic) is used to break iris-
lens adhesions
34
Adverse Effects: Muscarinic
Agonists
Adverse Effects: Muscarinic Agonists
 salivation
 diaphoresis
 colic
 GI hyperactivity
 headache
 loss of accommodation
35
Major contraindication to the use
of muscarinic agonists
 Asthma: Choline esters (muscarinic agonists) can
produce bronchoconstriction
 In the predisposed patient, an asthmatic attack may
be induced
 Hyperthyroidism: Choline esters (muscarinic agonists)
can induce atrial fibrillation in hyperthyroid patients
 Peptic ulcer: Choline esters (muscarinic agonists), by
increasing gastric acid secretion, may exacerbate ulcer
symptoms.
 Coronary vascular disease: Choline esters
(muscarinic agonists), as a result of their hypotensive
effects, can further compromise coronary blood flow
36
Indirect-acting Cholinomimetic
Drugs
 Acetylcholinesterase Inhibitors
 There are three classes of anticholinesterase
agents
1. Reversible, Short-Acting Anticholinesterases
2. Carbamylating Agents: Intermediate-
Duration Acetylcholinesterase Inhibitors
3. Phosphorylating Agents: Long-Duration
Acetylcholinesterase Inhibitors
37
Reversible, Short-Acting
Anticholinesterases
1) edrophonium (Tensilon) and
2) tacrine (Cognex) , associate with choline
binding domain
 The short duration of edrophonium (Tensilon)
action is due to its binding reversibility and
rapid renal clearance
 Tacrine (Cognex), being more lipophillic, has
a longer duration
38
Carbamylating Agents: Intermediate-
Duration Acetylcholinesterase
Inhibitors
 Physostigmine
 Neostigmine are
acetylcholinesterase inhibitors
that form a moderately stable
carbamyl-enzyme derivative
 The carbamyl-ester linkage is
hydrolyzed by esterase, but
much more slowly compared to
acetylcholine
 As a result, enzyme
inhibition by these drugs
last about 3 - 4 h (t ½ =
15 - 30 min).
 Neostigmine possesses
a quaternary nitrogen
and thus has a
permanent positive
charge
 By contrast,
physostigmine is a
tertiary amine
39
Phosphorylating Agents: Long-Duration
Acetylcholinesterase Inhibitors
 Organophosphate acetylcholinesterase
inhibitors, such as diisopropyl
fluorophosphate (DFP) form stable
phosphorylated serine derivatives
 For DFP enzyme effectively does not
regenerate following inhibition
40
Phosphorylating Agents: Long-Duration
Acetylcholinesterase Inhibitors(2)
 Furthermore, in the case of DFP, the loss,
termed "aging", of an isopropyl group, further
stabilizes phosphylated enzyme
 The application of terms "reversible" and
"irreversible" depends on the duration of
enzyme inhibition rather than strictly based on
mechanism
41
Organophosphate poisoning
Parathion
 Parathion, a low volatility and
aqueous-stable,
organophosphate is used as an
agriculural insecticide.
 Parathion is converted to
paraoxon by mixed function
oxidases. Both the parent
compound and its metabolite are
effective acetylcholinesterase
inhibitors (P=S to P=O)
 Parathion probably is
the most common
cause of accidental
organophosphate
poisoning and death
 The phosphothioate
structure is present in
other common
insecticides: dimpylate,
fenthion, and
chlorpyrifos
42
Tx of Organophosphate
poisoning-Pralidoxine
 Pralidoxine is a
cholinesterase activator
 It is used as an antidote to
organophosphates poisoning
 Unfortunately, pralidoxine
does not cross the blood brain
barrier to treat central effects
of organophosphate poisoning
 It has to be given very
early after poisoning as
within a few hours the
phosphorylated enzyme
undergoes a change
(aging) that renders it
no longer susceptible to
reactivation
43
Clinical applications of
anticholinesterases
 They are also used in cases of overdose with either
the muscarinic antagonist, atropine, or muscle
relaxants (nicotinic antagonists)
 Pralidoxine is a cholinesterase activator
organophosphates poisoning
44
Opthalmological Uses of
Anticholinesterase Drugs
 When applied to conjunctiva, acetylcholinesterase
inhibitors produce:
 constriction of the pupillary sphincter muscle
(miosis)
 contraction of the ciliary muscle (paralysis of
accommodation or loss of far vision)
 Loss of accommodation disappears first, while miotic
effect is longer lasting
 During miosis, elevated intraocular pressure (glaucoma)
declines due to enhanced flow of aqueous humor
 In glaucoma, elevation of intraocular pressure can
cause damage to optic disc and blindness
45
Gastrointestinal and Urinary
Bladder
 Neostigmine is anticholinesterase agent
of choice for treatment of paralytic ileus
or urinary bladder atony
 Direct acting cholinomimetic drugs are
also useful
46
Myasthenia Gravis
See e-Medicine Article
Myasthenia Gravis
 Myasthenia Gravis appears to be caused
by binding of anti-nicotinic receptor
antibodies to nicotinic cholinergic
receptor
 Binding studies using snake alpha-
neurotoxins determined a 70% to 90%
reduction of nicotinic receptors per
motor endplate in myasthenic patients
47
Myasthenia Gravis(2)
Receptor number is reduced by:
 increased receptor turnover (rapid
endocytosis)
 blockade of the receptor binding domain
 antibody damage of postsynaptic muscle
membrane
48
Myasthenia Gravis(3)
 Anticholinesterase, edrophonium
(Tensilon), is useful in differential diagnosis
for myasthenia gravis.
 In this use, edrophonium (Tensilon) with
its rapid onset (30 s) and short duration
(5 min) may cause an increase in muscle
strength.
49
Myasthenia Gravis(4)
 This change is due to transient increase in
acetylcholine concentration at the end plate
 Edrophonium (Tensilon) may also be used to
differentiate between muscle weakness due to
excessive acetylcholine (cholinergic crisis) and
inadequate drug dosing
50
Antimuscarinic Effects on Organ
Systems
Central Nervous System
Effects of Antimuscarinic Agents
 In normal doses, atropine produces little CNS effect
 In toxic doses, CNS excitation results in restlessness,
hallucinations, and disorientation
 At very high doses, atropine can lead to CNS
depression which causes circulatory and respiratory
collapse
 By contrast, scopolamine at normal therapeutic doses
causes CNS depression, including drowsiness, fatigue
and amnesia
51
Antimuscarinic Effects on Organ
Systems
Central Nervous System
Effects of Antimuscarinic Agents
cont.
 Scopolamine also may produce
euphoria, a basis for some abuse
potential
 Scopolamine may exhibit more CNS
activity than atropine because
scopolamine crosses the blood brain
barrier more readily
 Scopolamine (transdermal) is
effective in preventing motion
sickness
 Antimuscarinics are used
clinically as preanesthetic
medication to reduce vagal
effects secondary to
visceral manipulation
during surgery
 Antimuscarinics with L-
DOPA are used in
Parkinson's disease
 Extrapyramidal effects
induced by some
antipsychotic drugs may be
treated with antimuscarinic
agents
52
Antimuscarinic Effects on Organ
Systems
Autonomic Ganglia and Autonomic Nerve Terminals
 Primary cholinergic receptor class at autonomic ganglia is
nicotinic; however, muscarinic M1-cholinergic receptors are
also present
 Muscarinic M1-ganglionic cholinergic receptor activation
produce a slow EPSP that may have a modulatory role
 Muscarinic receptors are also located at adrenergic and
cholinergic presynaptic sites where their activation reduces
transmitter release
 Blockade of these presynaptic receptors increase
transmitter release
53
Opthalmological
 Muscarinic receptor antagonists block
parasympathetic responses of ciliary muscle
and iris sphincter muscle, resulting in
paralysis of accommodation (cycloplegia) and
mydriasis (pupillary dilation)
 Mydriasis results in photophobia, whereas
cycloplegia fixes lens for far vision only (near
objects appear blurred)
Antimuscarinic Effects on Organ
Systems
54
Opthalmological cont.
 Systemic atropine at usual doses does not produce
significant ophthalmic effect
 By contrast, systemic scopolamine results in both
mydriasis and cycloplegia
 Note that sympathomimetic-induced mydriasis occurs
without loss of accommodation
 Atropine-like drugs can increase intraocular pressure,
sometimes dangerously, in patients with narrow-angle
glaucoma
 Increases in intraocular pressure is not typical in
wide-angle glaucoma
Antimuscarinic Effects on Organ
Systems
55
Antimuscarinic Effects on Organ
Systems
Cardiovascular
System
Antagonist Tissue (Heart) Responses
Molecular
Aspects
The dominant
effect of atropine
or other
antimuscarinic drug
administration is an
increase in heart
rate.
This effect is
mediated by M2-
receptor blockade
thereby blunting
cardiac vagal tone.
atropine
SA node
decreased phase 4
depolarization;
hyperpolarization
K+ channel
activation
(hyperpolarizing)
through ß-gamma
Gi subunits*;
Gi -mediated
inhibition of
adenylyl cyclase*
(negative
inotropism)
(Gi can inhibit
directly Ca2+
channel opening)
Atrium
decreased
contractility;
decreased AP
duration
AV node
decreased
conduction velocity
Ventricle
decreased
contractility
Muscarinic Type M2
THE END
56

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ANS Pharmacology-Cholinergic Agents

  • 1. Autonomic Pharmacology: Cholinergic Drugs Prepared and presented by: Marc Imhotep Cray, M.D. Imhotep Virtual Medical School BMSCK Teacher eNotes: ANS- Autonomic Nervous System Pharmacology (Cholinergic drugs section) Tutorial Worth Visiting: Cholinergic ANS Clinical: e-Medicine Article Myasthenia Gravis
  • 2. 2 Reference Resource Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Cairo CW, Simon JB, Golan DE. (Eds.); LLW 2012
  • 3. 3 Cholinergic Biosynthesis Acetylcoline is formed from two precursors:  choline: which is derived from dietary and intraneuronal sources  acetyl coenzyme: which is made from glucose in mitochondria of neurons  Acetylcholine is synthesized from choline and acetyl-CoA by the enzyme choline acetyl transferase (ChAT) to form acetylcholine, which is immediately stored in small vesicular compartments closely attached to cytoplasmic side of presynaptic membranes  ChAT is a selective marker for cholinergic neurons
  • 4. 4 Cholinergic Biosynthesis 1) Synthesis of acetylcholine (ACh) from acetyl CoA and choline 2) Storage of ACh in synaptic vesicles 3) Release of ACh ( fusion of synaptic vesicle with presysnaptic membrane and release of ACh into the synapse) 4) Action of ACh by binding to and activating receptors (nicotinic in autonomic ganglia and neuromuscular junction and, muscarinic in many sites) 5) Inactivation by enzymatic breakdown of ACh by acetylcholinesterase (AChE) located in the synapse. ACh is degraded in the synaptic cleft by acetylcholinesterase to choline and acetate
  • 5. 5 Cholinergic Agents-Direct Acting and Indirect Acting  Choline Esters  Acetylcholine  Bethanechol (Urecholine)  Carbachol  Methacholine (Provocholine)  Alkaloids  Muscarine  Pilocarpine (Pilocar)  There are three main types of cholinesterase:  Short-acting: edrophonium  medium-acting: neostigmine (2-4h), pyridostigmine (3- 6h) physostigmine  irreversible: organophosphates, dyflos, ecothiopate Agents-Direct Acting Indirect Acting
  • 6. 6 Spectrum of Action of Choline Esters Location of cholinergic synapses mainly determine the spectrum of action of acetylcholine and choline esters Cholinergic Synaptic Sites  autonomic effector sites: innervated by post-ganglionic parasympathetic fibers  some CNS synapses  autonomic ganglia and the adrenal medulla  skeletal muscle motor endplates (motor nerves)
  • 7. 7 Spectrum of Action of Choline Esters(2) Cholinergic influences are prominent in many organ systems: Choline Ester Sensitivity to ACHE Cardio- vascular Gastrointe stinal Urinary Bladder Eye (Topical) Atropine Sensitive Activity at Nicotinic Sites Acetylcholine Methacholine Carbachol No Bethanechol No ? ? No
  • 8. 8 Spectrum of Action of Choline Esters(3) Cholinergic Receptors:  Cholinergic refers to responses in various systems to the natural transmitter molecule Acetylcholine (ACh)  If one looks at a set of responses where ACh is the normal transmitter, observation has shown that those same responses are differently sensitive to the extrinisic molecules Nicotine and Muscarine  Nicotine comes from tobacco,  Muscarine comes from certain mushrooms
  • 9. 9 Spectrum of Action of Choline Esters(4) Based on the different sensitivities shown above, Cholinergic receptors are subclassified into two categories, Nicotinic and Muscarinic, named for the extrinsic compounds that stimulate only that category
  • 10. 10 Spectrum of Action of Choline Esters(5) Nicotinic Receptors  Stimulated by ACh and nicotine, not stimulated by muscarine  Found at all ganglionic synapses  Also found at neuromuscular junctions  Blocked by hexamethonium
  • 11. 11 Spectrum of Action of Choline Esters(6) Nicotinic Receptors  The physiological responses to stimulation and block are complex since both sympathetic and parasympathetic systems are affected  The final response of any one organ system depends on which system has a stronger tonic influence  Example: Under normal circumstances, the heart receives more parasympathetic influence than sympathetic  Ganglionic blockade would lower parasympathetic influence more than sympathetic, and thus heart rate would increase
  • 12. 12 Spectrum of Action of Choline Esters(6) Muscarinic Receptors  Stimulated by ACh and muscarine, not stimulated by nicotine  Found at target organs when ACh is released by post-ganglionic neurons (all of parasympathetic, and some sympathetic)  Stimulated selectively by Muscarine and Bethanechol etc.  Blocked by Atropine
  • 13. 13 Spectrum of Action of Choline Esters(7) Muscarinic Receptors Stimulation causes:  Increased sweating  Decreased heart rate  Decreased blood pressure due to decreased cardiac output  Bronchoconstriction and increased bronchosecretion  Contraction of the pupils, and contraction of ciliary body for near vision  Tearing and salivation  Increased motility and secretions of the GI system  Urination and defecation  Engorgement of genitalia
  • 14. 14 Cholinergic Receptors: Subtypes, Tissues, Responses and Molecular Mechanisms Muscarinic Receptor Coupling Mechanisms  Five types of cholinergic receptors have been identified by molecular cloning methods.  The five muscarinic receptor subtypes, M1 - M5, are associated with specific anatomical sites  For example:  M1 -ganglia; secretory glands  M2 - myocardium, smooth muscle  M3 , M4 :smooth muscle, secretory glands
  • 15. 15 Cholinergic Receptors: Subtypes, Tissues, Responses and Molecular Mechanisms Nicotinic Muscle Receptor Antagonists Tissue Responses Molecular Aspects Tubocurarine alpha-bungarotoxin Neuromuscular Junction Membrane Depolarization leading to muscle contraction Nicotinic (muscle) receptor's cation ion channel opening
  • 16. 16 Cholinergic Receptors: Subtypes, Tissues, Responses and Molecular Mechanisms(2) Nicotinic Neuronal Receptor Antagonists Tissue Responses Molecular Aspects Mecamylamine (Inversine) Autonomic Ganglia Depolarization: postsynaptic cell activation Nicotinic (muscle) receptor's cation ion channel openingAdrenal Medulla Catecholamine secretion CNS unknown
  • 17. 17 Cholinergic Receptors: Subtypes, Tissues, Responses and Molecular Mechanisms(3) Muscarinic Type M1 Antagonist Tissue Responses Molecular Aspects Atropine Pirenzepine (more selective) Autonomic Ganglia Depolarization (late EPSP) Stimulation of Phospholipase C (PLC): activation of inositol-1,4,5 triphosphate (IP3 ) and diacylglycerol (DAG) leading to increased cytosolic Ca2+ CNS Unknown
  • 18. 18 Cholinergic Receptors: Subtypes, Tissues, Responses and Molecular Mechanisms(4) Muscarinic Type M2 Tissue (Heart) Responses Molecular Aspects SA node decreased phase 4 depolarization; hyperpolarization K+ channel activation through ß-gamma Gi subunits; Gi -mediated inhibition of adenylyl cyclase which decreases intracellular Ca2+ levels. (Gi can inhibit directly Ca2+ channel opening) Atrium decreased contractility; decreased AP duration AV node decreased conduction velocity Ventricle decreased contractility
  • 19. 19 Signal Transduction: Comparison of Muscarinic and Nicotinic Receptors Nicotinic Receptors  Ligand-gated ion channels  Agonist effects blocked by tubocurarine  Receptor activation results in:  rapid increases of Na+ and Ca2+ conductance  deplorization  excitation  Subtypes based on differing subunit composition: See Muscle and Neuronal Classification Discussed in previous slides
  • 20. 20 Signal Transduction: Comparison of Muscarinic and Nicotinic Receptors Muscarinic Receptors  G-protein coupled receptor system  Slower responses  Agonist effects blocked by atropine  At least five receptor subtypes have been described by molecular cloning
  • 21. 21 Muscarinic Receptors: Second Messenger Systems  Activation of IP3, DAG cascade  DAG may activate smooth muscle Ca2+ channels  IP3 releases Ca2+ from endoplasmic and sarcoplasmic reticulum  Increase in cGMP  Increase in intracellular K+ by cGMP-K+ channel binding  inhibition of adenylyl cyclase activity (heart)
  • 23. 23 Direct vs. Indirect-Acting Cholinomimetics  A direct-acting cholinomimetic drug produces its pharmacological effect by receptor activation  An indirect-acting drug inhibits acetylcholinesterase, thereby increasing endogenous acetylcholine levels, resulting in increased cholinergic response.
  • 24. 24 Pharmacological Effects of Cholinomimetics 1)Vasodilation  This effect is mediated by muscarinic receptor activation and is especially prominent in the salivary gland and intestines
  • 25. 25 Pharmacological Effects of Cholinomimetics (2) Vasodilation cont.  The vascular response is due to endothelial cell nitric oxide (NO) release following agonist interactions with endothelial muscarinic receptor  Increased NO activates guanylate cyclase which increases cyclic GMP concentrations
  • 26. 26 Pharmacological Effects of Cholinomimetics (3) Vasodilation cont.  Subsequent activation of a Ca2+ ion pump reduces intracellular Ca2+  Reduction in intracellular Ca2+ causes vascular smooth muscle relaxation  Ca2+ complexes with calmodulin activating light- chain myosin kinase  Increased cGMP promotes dephosphorylation of myosin light-chains.  Smooth-muscle myosin must be phosphorylated in order to interact with actin and cause muscle contraction.
  • 27. 27 Nitric Oxide (NO) and Vasodilitation From: http://www.nature.com/nature/journal/v396/n6708/fig_tab/396213a0_F1.html
  • 28. 28 Pharmacological Effects of Cholinomimetics(4) 2)Negative chronotropic effect (Decrease in heart rate)  Decreases phase 4 (diastolic depolarization)  As a result, it takes longer for the membrane potential to reach threshold.  Mediated by M2 muscarinic receptors
  • 29. 29 Pharmacological Effects of Cholinomimetics(5) 3) Decreased SA nodal and AV nodal conduction velocity  Excessive vagal tone may induce bradyarrhythmias including partial or total heart block (impulses cannot pass through AV node to drive ventricular rate  in this case, the idioventricular or intrinsic ventricular rate must maintain adequate cardiac output  Transmission through the AV node is especially dependent on Ca2+ currents.  ACh decreases calcium currents in the atrioventricular node
  • 30. 30 Pharmacological Effects of Cholinomimetics(6) 4) Negative inotropism (decreased myocardial contractility)  more prominent in atrial than ventricular tissue  due to a decrease in Ca2+ inward current  in ventricle, adrenergic tone dominates;  at higher levels of sympathetic tone, a reduction in contractility due to muscarinic stimulation is noted  Muscarinic stimulation reduces response to norepinephrine by opposing increases in cAMP in addition to reducing norepinephrine release from adrenergic terminals
  • 31. 31 Clinical Uses Gastrointestinal & Genitourinary  Bethanechol (Urecholine)  GI smooth muscle stimulant  postoperative abdominal distention  paralytic ileus  esophageal reflux; promotes increased esophageal motility (other drugs are more effective, e.g. dopamine antagonist (metoclopramide) or serotonin agonists (cisapride)
  • 32. 32 Clinical Uses(2) Urinary bladder stimulant  post-operative; post-partum urinary retention  alternative to pilocarpine to treat diminished salivation secondary e.g. to radiation  Carbachol not used due to more prominent nicotinic receptor activation Diagnostic tool  Methacholine used for diagnostic purposes  testing for bronchial hyperreactivity and asthma
  • 33. 33 Clinical Uses(3) Opthalmological Uses  Acetylcholine and Carbachol may be used for intraocular use as a miotic in surgery  Carbachol may be used in treatment of glaucoma  Pilocarpine is used in management of glaucoma and has become the standard initial drug for treating the open-angle form.  Sequential administration of atropine (mydriatic) and pilocarpine (miotic) is used to break iris- lens adhesions
  • 34. 34 Adverse Effects: Muscarinic Agonists Adverse Effects: Muscarinic Agonists  salivation  diaphoresis  colic  GI hyperactivity  headache  loss of accommodation
  • 35. 35 Major contraindication to the use of muscarinic agonists  Asthma: Choline esters (muscarinic agonists) can produce bronchoconstriction  In the predisposed patient, an asthmatic attack may be induced  Hyperthyroidism: Choline esters (muscarinic agonists) can induce atrial fibrillation in hyperthyroid patients  Peptic ulcer: Choline esters (muscarinic agonists), by increasing gastric acid secretion, may exacerbate ulcer symptoms.  Coronary vascular disease: Choline esters (muscarinic agonists), as a result of their hypotensive effects, can further compromise coronary blood flow
  • 36. 36 Indirect-acting Cholinomimetic Drugs  Acetylcholinesterase Inhibitors  There are three classes of anticholinesterase agents 1. Reversible, Short-Acting Anticholinesterases 2. Carbamylating Agents: Intermediate- Duration Acetylcholinesterase Inhibitors 3. Phosphorylating Agents: Long-Duration Acetylcholinesterase Inhibitors
  • 37. 37 Reversible, Short-Acting Anticholinesterases 1) edrophonium (Tensilon) and 2) tacrine (Cognex) , associate with choline binding domain  The short duration of edrophonium (Tensilon) action is due to its binding reversibility and rapid renal clearance  Tacrine (Cognex), being more lipophillic, has a longer duration
  • 38. 38 Carbamylating Agents: Intermediate- Duration Acetylcholinesterase Inhibitors  Physostigmine  Neostigmine are acetylcholinesterase inhibitors that form a moderately stable carbamyl-enzyme derivative  The carbamyl-ester linkage is hydrolyzed by esterase, but much more slowly compared to acetylcholine  As a result, enzyme inhibition by these drugs last about 3 - 4 h (t ½ = 15 - 30 min).  Neostigmine possesses a quaternary nitrogen and thus has a permanent positive charge  By contrast, physostigmine is a tertiary amine
  • 39. 39 Phosphorylating Agents: Long-Duration Acetylcholinesterase Inhibitors  Organophosphate acetylcholinesterase inhibitors, such as diisopropyl fluorophosphate (DFP) form stable phosphorylated serine derivatives  For DFP enzyme effectively does not regenerate following inhibition
  • 40. 40 Phosphorylating Agents: Long-Duration Acetylcholinesterase Inhibitors(2)  Furthermore, in the case of DFP, the loss, termed "aging", of an isopropyl group, further stabilizes phosphylated enzyme  The application of terms "reversible" and "irreversible" depends on the duration of enzyme inhibition rather than strictly based on mechanism
  • 41. 41 Organophosphate poisoning Parathion  Parathion, a low volatility and aqueous-stable, organophosphate is used as an agriculural insecticide.  Parathion is converted to paraoxon by mixed function oxidases. Both the parent compound and its metabolite are effective acetylcholinesterase inhibitors (P=S to P=O)  Parathion probably is the most common cause of accidental organophosphate poisoning and death  The phosphothioate structure is present in other common insecticides: dimpylate, fenthion, and chlorpyrifos
  • 42. 42 Tx of Organophosphate poisoning-Pralidoxine  Pralidoxine is a cholinesterase activator  It is used as an antidote to organophosphates poisoning  Unfortunately, pralidoxine does not cross the blood brain barrier to treat central effects of organophosphate poisoning  It has to be given very early after poisoning as within a few hours the phosphorylated enzyme undergoes a change (aging) that renders it no longer susceptible to reactivation
  • 43. 43 Clinical applications of anticholinesterases  They are also used in cases of overdose with either the muscarinic antagonist, atropine, or muscle relaxants (nicotinic antagonists)  Pralidoxine is a cholinesterase activator organophosphates poisoning
  • 44. 44 Opthalmological Uses of Anticholinesterase Drugs  When applied to conjunctiva, acetylcholinesterase inhibitors produce:  constriction of the pupillary sphincter muscle (miosis)  contraction of the ciliary muscle (paralysis of accommodation or loss of far vision)  Loss of accommodation disappears first, while miotic effect is longer lasting  During miosis, elevated intraocular pressure (glaucoma) declines due to enhanced flow of aqueous humor  In glaucoma, elevation of intraocular pressure can cause damage to optic disc and blindness
  • 45. 45 Gastrointestinal and Urinary Bladder  Neostigmine is anticholinesterase agent of choice for treatment of paralytic ileus or urinary bladder atony  Direct acting cholinomimetic drugs are also useful
  • 46. 46 Myasthenia Gravis See e-Medicine Article Myasthenia Gravis  Myasthenia Gravis appears to be caused by binding of anti-nicotinic receptor antibodies to nicotinic cholinergic receptor  Binding studies using snake alpha- neurotoxins determined a 70% to 90% reduction of nicotinic receptors per motor endplate in myasthenic patients
  • 47. 47 Myasthenia Gravis(2) Receptor number is reduced by:  increased receptor turnover (rapid endocytosis)  blockade of the receptor binding domain  antibody damage of postsynaptic muscle membrane
  • 48. 48 Myasthenia Gravis(3)  Anticholinesterase, edrophonium (Tensilon), is useful in differential diagnosis for myasthenia gravis.  In this use, edrophonium (Tensilon) with its rapid onset (30 s) and short duration (5 min) may cause an increase in muscle strength.
  • 49. 49 Myasthenia Gravis(4)  This change is due to transient increase in acetylcholine concentration at the end plate  Edrophonium (Tensilon) may also be used to differentiate between muscle weakness due to excessive acetylcholine (cholinergic crisis) and inadequate drug dosing
  • 50. 50 Antimuscarinic Effects on Organ Systems Central Nervous System Effects of Antimuscarinic Agents  In normal doses, atropine produces little CNS effect  In toxic doses, CNS excitation results in restlessness, hallucinations, and disorientation  At very high doses, atropine can lead to CNS depression which causes circulatory and respiratory collapse  By contrast, scopolamine at normal therapeutic doses causes CNS depression, including drowsiness, fatigue and amnesia
  • 51. 51 Antimuscarinic Effects on Organ Systems Central Nervous System Effects of Antimuscarinic Agents cont.  Scopolamine also may produce euphoria, a basis for some abuse potential  Scopolamine may exhibit more CNS activity than atropine because scopolamine crosses the blood brain barrier more readily  Scopolamine (transdermal) is effective in preventing motion sickness  Antimuscarinics are used clinically as preanesthetic medication to reduce vagal effects secondary to visceral manipulation during surgery  Antimuscarinics with L- DOPA are used in Parkinson's disease  Extrapyramidal effects induced by some antipsychotic drugs may be treated with antimuscarinic agents
  • 52. 52 Antimuscarinic Effects on Organ Systems Autonomic Ganglia and Autonomic Nerve Terminals  Primary cholinergic receptor class at autonomic ganglia is nicotinic; however, muscarinic M1-cholinergic receptors are also present  Muscarinic M1-ganglionic cholinergic receptor activation produce a slow EPSP that may have a modulatory role  Muscarinic receptors are also located at adrenergic and cholinergic presynaptic sites where their activation reduces transmitter release  Blockade of these presynaptic receptors increase transmitter release
  • 53. 53 Opthalmological  Muscarinic receptor antagonists block parasympathetic responses of ciliary muscle and iris sphincter muscle, resulting in paralysis of accommodation (cycloplegia) and mydriasis (pupillary dilation)  Mydriasis results in photophobia, whereas cycloplegia fixes lens for far vision only (near objects appear blurred) Antimuscarinic Effects on Organ Systems
  • 54. 54 Opthalmological cont.  Systemic atropine at usual doses does not produce significant ophthalmic effect  By contrast, systemic scopolamine results in both mydriasis and cycloplegia  Note that sympathomimetic-induced mydriasis occurs without loss of accommodation  Atropine-like drugs can increase intraocular pressure, sometimes dangerously, in patients with narrow-angle glaucoma  Increases in intraocular pressure is not typical in wide-angle glaucoma Antimuscarinic Effects on Organ Systems
  • 55. 55 Antimuscarinic Effects on Organ Systems Cardiovascular System Antagonist Tissue (Heart) Responses Molecular Aspects The dominant effect of atropine or other antimuscarinic drug administration is an increase in heart rate. This effect is mediated by M2- receptor blockade thereby blunting cardiac vagal tone. atropine SA node decreased phase 4 depolarization; hyperpolarization K+ channel activation (hyperpolarizing) through ß-gamma Gi subunits*; Gi -mediated inhibition of adenylyl cyclase* (negative inotropism) (Gi can inhibit directly Ca2+ channel opening) Atrium decreased contractility; decreased AP duration AV node decreased conduction velocity Ventricle decreased contractility Muscarinic Type M2