Transcript nervous system

Overview

The body has two major control/regulatory
systems which coordinate the regulation
and integration of bodily functions: the
nervous system & the endocrine system

The nervous system exerts its function by
the rapid transmission of electrical
impulses over nerve fibres that terminate
at the effector cells, which specifically
respond to the release of neuromediator
substances
Nervous system
Peripheral nervous
system
Central nervous
system
Efferent
division
Afferent
division
Autonomic
system
Somatic
system
Enteric
Parasympathatic
Sympathatic
Anatomy of the ANS

The ANS carries nerve impulses from
the CNS to the effector organs by
way of two types of efferent
neurons:
 The
preganglionic neurons (cell bodies
are located within the CNS
 The
postganglionic neurons (cell bodies
originating in the ganglion)
Brainstem or
spinal cord
Preganglionic
neuron
Ganglionic transmitter
Postganglionic
neuron
Neuroeffector transmitter
Effector organ
Anatomy of the ANS (Cont’d)

The ANS lends itself to division on
anatomic grounds into three major
divisions:
I.
Sympathetic (thoracolumbar) division
II.
Parasympathetic
division
III.
Enteric nervous system (ENS) division
(craniosacral)
Neurotransmitter chemistry of the
autonomic nervous system

Communication between nerve cells- and
between nerve cells and effector organsoccurs through the release of specific
chemical signal, called neurotransmitters,
from the nerve terminals

The ANS can be divided into two groups based
on the primary neurotransmitter released:
a.
Cholinergic: if transmission is mediated by
acetylcholine
b.
Adrenergic: if transmission is mediated by
norepinephrine or epinephrine
Overview

Drugs affecting the ANS are divided into two
groups according to the type of neuron
involved in the mechanism of action:
a)
b)

The cholinergic drugs: they act on receptors
that are activated by acetylcholine (Ach)
The adrenergic drugs: they act on receptors
that are activated by norepinephrine or
epinephrine
Cholinergic and adrenergic drugs both act by
either stimulating or blocking receptors of the
ANS
Cholinoceptor-activating &
Cholinesterase-inhibiting drugs
Neurotransmission at cholinergic neurons
Na+
Muscarinic
Receptor
ACh
Choline
Acetyltransferase
Acetylcholinesterase
Acetyl CoA
+
Choline
Action Potential
Na+
Acetylcholine
H+
ACH
Nicotinic
Choline Acetate
Receptor
Choline
Presynaptic neuron
Postsynaptic target
Cholinergic Receptors
(Cholinoceptors)

Cholinoceptor denotes receptors
that respond to acetylcholine

Two
families/subtypes
of
cholinoceptors were named after the
alkaloids originally used in their
identification: muscarinic (M) and
nicotinic (N) receptors
I. Muscarinic (M) receptors

These receptors, in addition to binding
acetylcholine, also recognize muscarine,
but show a weak affinity for nicotine

These receptors have been found in
organs innervated by parasympathetic
nerves as well as on some tissues that are
not innervated by these nerves, eg,
endothelial, and on those tissues
innervated by postganglionic sympathetic
cholinergic nerves
I. Muscarinic (M) receptors

Five
subclasses
of
muscarinic
receptors: M1, M2, M3, M4, and M5 have
been identified

Muscarinic receptors are
coupled
receptors
transmembrane domains)

These receptors have different signal
transduction mrchanisms based on the
G-protein to which they are coupled
G-protein
(seven
I. Muscarinic (M) receptors

M1/M3/M5 activations stimulate IP3
and DAG. These receptors are
primarily responsible for activating
Ca+2-dependent responses, such as
secretion by glands and the contraction
of smooth muscle

M2/M4 ativation inhibits adenylyl
cyclase leading to decreased cAMP
II. Nicotinic (N) receptors

These receptors, in addition to binding ACh,
also recognize nicotine, but show a week
affinity for muscarine

N receptors are transmembrane polypeptide
whose subunits form cation-selective ion
channels

N receptors are located on plasma
membranes of postganglionic cells in all
autonomic ganglia, of muscles innervated by
somatic motor fibers (i.e. Neuromuscular
junction), and of some CNS neurons
II. Nicotinic (N) receptors

When the nicotnic AchR is stimulated, the
channel opens and allows Na+ to rush into the
cell

This triggers depolarization of the cell and
elicits a neruronal action potential (in
postganglionic nerve) or nuscle contraction (in
skeletal muscles)

N receptors located at the neuromuscular
junction are sometimes designated NM and the
ganglionic (neuronal) receptors are designated
NN
Subtypes and Characteristics of
Cholinoceptors
Receptor
Other Names
Type
Location
G protein
Post-receptor Mechanism
M1
Nerves
Gq
IP3, DAG cascade
M2
Heart, nerves,
smooth muscle
Gi
Inhibition of cAMP
production, activation of K+
channels
M3
Glands, smooth
muscle, endothelium
Gq
IP3, DAG cascade
M4
CNS
Gi
Inhibition of cAMP
production
M5
CNS
Gq
IP3, DAG cascade
None
Na+, K+ depolarizing ion
channel
None
Na+, K+ depolarizing ion
channel
NM
NN
Cardiac M2
Muscle type,
Skeletal muscle
end plate
neuromuscular
receptor
junction
Neuronal type,
CNS postganglionic
ganglion
cell body, dendrites
receptor
Sites of actions of cholinergic agonists in the autonomic and somatic nervous systems
Sympathatic innervation
of adrenal medulla
Sympathatic
Parasympathatic
Somatic
Ganglionic
transmittion
NN receptor
Adrenal
medulla
NN receptor
NN receptor
Neuroeffector
transmittion
Acetylcholine
Norepinephrine
Effector organ
Effector organ
α or β Adrenergic receptor
M receptor
Neuromuscular junction
NM receptor
Cholinergic drugs

Nonselective cholinoceptor stimulants in
sufficient dosage can produce very diffuse and
marked alterations in organ system function

Selectivity of action is based on several
factors:
1)
Receptor selectivity: muscarinic vs. nicotinic
2)
Pharmacokinetic selectivity: using appropriate
routes of administration so that desired effects
can often be achieved while while minimizing
systemic effects
Cholinomimetic agents

Cholinomimetic drugs can elicit some
or all of the effects that acetylcholine
(ACh) produces

Include agents that act directly
(cholinoceptor agonists/stimulants) or
indirectly
acting
mechanisms
(cholinesterase inhibitors)
Neurotransmission at cholinergic neurons
Na+
Muscarinic
Receptor
ACh
Choline
Acetyltransferase
Acetylcholinesterase
Acetyl CoA
+
Choline
Action Potential
Na+
Acetylcholine
H+
ACH
Nicotinic
Choline Acetate
Receptor
Choline
Presynaptic neuron
Postsynaptic target
Direct acting cholinergic
stimulants
Direct acting cholinergic stimulants

Cholinergic receptor agonists mimic
the effects of ACh by binding
directly to cholinoceptors

They differ in their spectrum of
action (muscarnic vs. nicotinic
stimulation)
and
in
their
pharmacokinetics
Cholinomimetic agents

The directly acting cholinomimetics can be
subdivided into:
I.
Parasympathomimetic drugs: agents that
exert their effects primarily through
stimulation of muscarinic receptors at
parasympathetic neuro-effector junctions
II.
Agents that stimulate nicotinic receptors
in autonomic ganglia and at the
neuromuscular junction
Direct acting cholinergic stimulants

These agents can be divided into two
groups:
 Choline
esters
(acetylcholine,
metacholine,
carbachol,
&
bethanechol)
 Naturally
occurring cholinomimetic
alkaloids
(muscarine,
nicotine,
pilocarpine, & lobeline)
Direct acting cholinergic stimulants
Pharmacokinetics
I.
Choline esters

Poorly absorbed and poorly distributed into
the CNS because they are hydrophilic and
susceptible to esterase hydrolysis in the GIT

Methacholine is more resistant to hydrolysis,
and the carbamic acid esters carbachol and
bethanechol are still more resistant to
hydrolysis by cholinesterase and have
correspondingly longer durations of action
Direct acting cholinergic stimulants
Pharmacokinetics
Natural cholinomimetic alkaloids
 Tertiary amines (pilocarpine, nicotine,
lobeline) is well absorbed from most sites
of administration, and it can cross the
BBB
II.

Quaternary amine (Muscarine) is less
completely absorbed from the GIT than
the tertiary amines but is toxic when
ingested and it even enters the brain
Muscarinic agonists:
Parasympathomimetics

Cholinergic receptor agonists (also
called acetylcholine-like agonists)
mimic the effects of ACh by binding
directly to cholinoceptors

They show relatively few selectivity
for M2/M4 vs. M1/M3/M5
Pharmacology of acetylcholine-like agonists
Susceptibility to
Cholinesterase
Acetylcholine chloride
++++
Carbachol
Negligible
Choline Ester
Muscarinic
Action
+++
++
Nicotinic Action
+++
+++
Methacholine
+
+++
None
Bethanechol
Negligible
+++
None
Muscarine
Pilocarpine
Negligible
Negligible
+++
+++
None
None
Direct acting cholinergic stimulants
Organ system effect
a.

Cardiovascular system
ACh has four primary effects on the cardiovascular system:
a)
Vasodilation*
b)
Decrease in heart rate (negative chronotropic
effect)**
c)
Decrease in the conduction velocity in the
atrioventricular (AV) node (negative dromotropic
effect)**
d)
Decrease in the force of cardiac contraction
(negative inotropic effect)**
* activation of endothelial M3
** activation of M2 receptors
Direct acting cholinergic stimulants
Organ system effect
Eye
 Muscarinic agonists cause contraction of
the smooth muscle of the:
1) Iris sphincter*: resulting in miosis
2) Ciliary
muscle*:
resulting
in
accommodation of the eye for near vision
b.
* activation of M3 receptor
Direct acting cholinergic stimulants
Organ system effect
c.
Other Organ Systems

Respiratory system*: bronchoconstriction
increase tracheobronchial secretion

GIT***: stimulation of salivation and acid
secretion, increased intestinal tone and peristaltic
activity, and relaxation of most sphincters

Genitourinary tract: stimulation of the detrusor
muscle* and relax the trigone and sphincter
muscles of the bladder**, thus promoting urination
* M3 activation ** M2 activation ***M2 and M3 activation
&
Direct acting cholinergic stimulants
Organ system effect
Other Organ Systems
 Miscellaneous Secretory Glands*: stimulation
secretion by thermoregulatory sweat, lacrimal,
and nasopharyngeal glands
c.

CNS: Muscarinic agonists are able to produce
marked CNS owing to activation of M1receptors in the brain areas involved in
cognition
* M3 activation
Clinical uses of the direct acting
cholinomimetics
a)
Glaucoma:
b)
Bladder and bowel atony after surgery:
Bethanechol
c)
Xerostomia associated with Sjögren's
syndrome and that caused by radiation
damage of the salivary glands: pilocarpine &
cevimeline
cholinomimetics
reduce
intraocular pressure by causing contraction of
the ciliary body so as to facilitate outflow of
aqueous humor (e.g pilocarpine and
carbachol)
Toxicity

Potentially severe adverse effects can result
from systemic administration of cholinomimetic
drugs and the comsumption mushrooms of the
genus Inocybe (Muscarine)

Overdosage is characterized chiefly by
exaggeration
of
the
various
parasympathomimetic effects: NVD, urinary
urgency, salivation, sweating, hypotension with
reflex tachycardia, cutaneous vasodilation, and
bronchial constriction
Toxicity

Pilocarpine can cross the BBB and affect
cognitive function especially among the elderly

Cholinomimetics elicit miosis and spasm of
accommodation, both of which disturb vision

Treatment consists of the parenteral
administration of atropine in doses sufficient to
cross the BBB and measures to support the
respiratory and CV systems and to counteract
pulmonary edema
Nicotinic drugs

Drugs that modulate nicotinic receptors have
very limited application because of the
localization of these receptor subtypes

Pharmacological stimulation of ganglionic
neuronal receptors (NN) has limited utility
because this receptor affect both branches of
the ANS

The tissue and organ effect depend on the
autonomic innervation of the organ involved
Nicotinic drugs

Excessive stimulation of NM receptors can
cause depolarization block: loss of
electrical excitability due to inactivation of
voltage-gated sodium channels

If repeated doses of the agonist is used,
the nicotinic cholinergic receptors can
quickly become desensitized leading to
fasciulations and paralysis
Nicotinic drugs

In the brain, the α4β2 oligomer is the most
abundant nicotinic receptor in the brain

Activation of α4β2 nicotinic receptors is
associated with greater release of
dopamine in the mesolimbic system: mild
alerting action and the addictive property
of nicotine absorbed from tobacco

Sustained desensitization may contribute
to the benefits of nicotine replacement
therapy in smoking cessation regimens
Nicotinic drugs

Direct acting nicotine agonists have no
therapeutic applications exept in smoking
sessation (nicotine and varenicline) and
producing skeletal muscle paralysis
(succinylcholine)
Nicotin replacement therapy

To help patients stop smoking

Available in the form of gum,
transdermal patch, nasal spray, or
inhaler

Sustained desensitization of α4β2
receptors in the CNS and reduces
the desire to smoke and the
pleasurable feelings of smoking
Varenicline (Chantix®)

Is a partial agonist at α4β2 nicotinic
receptors

Varenicline prevents the stimulant effect of
nicotine at presynaptic α4β2 receptors that
causes release of dopamine

ADRs:
nausea,
insomnia,
and
exacerbation of psychiatric illnesses,
including anxiety and depression
Indirect acting
cholinomimetics
Indirect acting cholinomimetics

Acetylcholinesterase (AChE) is an enzyme
that specifically cleaves ACh to acetate
and choline and, thus, terminates its action

Inhibitors of AChE indirectly provide a
cholinergic action by prolonging the
lifetime of acetylcholine in synapses where
acetylcholine is released physiologically
(i.e. they have both muscarinic and
nicotinic effets)
Indirect acting cholinomimetics

There are three chemical groups of
cholinesterase inhibitors:
(1)
Simple
alcohols
bearing
a
quaternary ammonium group, eg,
edrophonium
(2)
Carbamates (eg, neostigmine)
(3)
Organophosphates (eg, echothiophate)
Therapeutic Uses and Durations of Action of Cholinesterase Inhibitors
Uses
Approximate Duration of Action
Alcohols
Edrophonium
Myasthenia gravis,
ileus, arrhythmias
Carbamates and related agents
Neostigmine
Myasthenia gravis,
ileus
Pyridostigmine
Myasthenia gravis
Physostigmine
Glaucoma
Ambenonium
Myasthenia gravis
Demecarium
Glaucoma
Organophosphates
Echothiophate
Glaucoma
5–15 minutes
0.5–2 hours
3–6 hours
0.5–2 hours
4–8 hours
4–6 hours
100 hours
Indirect acting cholinomimetics

The anti-ChE agents potentially
produce all the following effects:
can
1)
Stimulation
of
muscarinic
receptor
responses at autonomic effector organs
2)
Stimulation, followed by depression or
paralysis, of all autonomic ganglia and
skeletal muscle (nicotinic actions)
3)
Stimulation, with occasional subsequent
depression, of cholinergic receptor sites in
the CNS
Indirect acting cholinomimetics
Organ system effect
a.
Central nervous system (CNS)

In low concentrations, the lipid-soluble
cholinesterase inhibitors cause diffuse
activation on the electroencephalogram
and a subjective alerting response

In higher concentrations, they cause
generalized convulsions, which may be
followed by coma and respiratory arrest
Indirect acting cholinomimetics
Organ system effect
b.
Eye, Respiratory Tract, GIT, & Urinary
Tract

The effects of the cholinesterase
inhibitors are qualitatively quite similar
to the effects of the direct-acting
cholinomimetics
Indirect acting cholinomimetics
Organ system effect
Neuromuscular junction
 Low (therapeutic) concentrations moderately
prolong and intensify the actions of
physiologically released acetylcholine. This
increases the strength of contraction
d.

At higher concentration, with marked inhibition
of
acetylcholinesterase,
depolarizing
neuromuscular blockade occurs and that may
be followed by a phase of nondepolarizing
blockade (i.e. nicotinic receptors can quickly
become desensitized)
Clinical uses of the indirect acting
cholinomimetics
a.
Glaucoma: physostigmine, demecarium,
echothiophate, isoflurophate
b.
Gastrointestinal and Urinary Tracts:
Neostigmine is most commonly used
anticholinesterase
agents
in
the
treatment of adynamic ileus and atony of
the urinary bladder, both of which may
result from surgery
Clinical uses of the indirect acting
cholinomimetics
C.
Myasthenia gravis

Anticholinesterase agents help to alleviate the
weakness by elevating and prolonging the
concentration of ACh in the synaptic cleft,
producing a greater activation of the remaining
nicotinic receptors

Anticholinesterase agents play a key role in
the diagnosis and therapy of myasthenia
gravis, because they increase muscle strength
Clinical uses of the indirect acting
cholinomimetics
Myasthenia gravis
 Carbamates (Pyridostigmine, neostigmine
, and ambenonium): anticholinesterase
agents used in the long-term therapy for
myasthenia gravis
C.

Edrophonium (IV) is used for the diagnosis
of myasthenia gravis and in differentiating
myasthenic crisis from cholinergic crises
(adequecy of treatment)
Clinical uses of the indirect acting
cholinomimetics
d.
Antimuscarinic Drug Intoxication

To treat overdoses of drugs with
antimuscarinic actions, such as atropine

Physostigmine (cholinesterase inhibitor)
has been used for this application because
it enters the CNS and reverses the central
as well as the peripheral signs of
muscarinic blockade
Clinical uses of the indirect acting
cholinomimetics
Alzheimer’s Disease
 Tacrine,
donepezil,
rivastigmine,
&
galantamine are approved for the palliative
treatment of Alzheimer’s disease
e.

These agents can cross the BBB to produce a
reversible inhibition of AChE in the CNS

They produce modest but significant
improvement in the cognitive function of
patients with mild to moderate Alzheimer’s
disease, but they do not delay progression of
the disease
Toxicity

Major cause of toxicity is accidental
intoxication from the use pesticide use in
agriculture and in the home

With increasing inhibition of AChE and
accumulation of ACh, the first signs are
muscarinic stimulation, followed by nicotinic
receptor stimulation and then desensitization
of nicotinic receptors

CNS symptoms include agitation, dizziness,
and mental confusion (compounds of
extremely high lipid solubility)
Toxicity

Excessive inhibition can ultimately lead to a
cholinergic crisis that includes:
1. GIT distress: NVD & excessive salivation
2. Respiratory
distress:
bronchospasm
&
increased bronchial secretions
3. CV distress: bradycardia
4. Visual disturbance: miosis, blurred vision
5. Sweating
6. Loss of skeletal motor function: progressing
through incoordination, muscle cramps,
weakness, fasciculation, and paralysis