Parasympathetic Nervous System

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Parasympathetic Nervous System

Characteristic Features of ANS:


1) Wide distribution throughout the body.

2) Speed and intensity at which ANS


regulates visceral functions, like;
a) Heart rate b) Sweating
b) Arterial pressure c) Urinary bladder emptying

3) Involuntary regulation
 by means of visceral reflexes.

4) In the peripheral NS, ANS is composed of:


a) nerves b) ganglia c) plexuses
ANS Subconscious Control:
 by means of visceral reflexes:

= Subconscious sensory signals from visceral organs;


 enter an autonomic ganglia
 to brainstem or hypothalamus,

= and still subconsciously;


 return the reflex response back to visceral organs
 to control their activities
Visceral Reflexes:
 are mostly mediated thru the CNS

A. Visceral Afferent Fibers:


from visceral structure are;
 the first link in the reflex arcs
of the ANS towards the CNS.

Except:
 the local axon reflexes
Parasympathetic Division of ANS:
(Cranio-Sacral Outflow)

Parasympathetic Visceral Sensory


System carries mainly:

a) Mechanoreceptor information

b) Chemosensory information
Parasympathetic Visceral Sensory System,
is transmitted by 4 Cranial Nerves:
1) Trigeminal (V)
 internal face and head
2) Facial (VII)
 tongue (taste)
3) Glossopharyngeal (IX)
 hard palate, upper oropharynx
4) Vagus ( X )
 carotid body, lower part of oropharynx, larynx,
trachea, esophagus, thoracic & abdominal organs.
Exception:
Spinal nerves S1 to S4
 which innervate the Pelvic viscera
Distribution PNS:
= PNS fibers in CN 111
 pupillary sphincter and ciliary muscle of eyes.
= Fibers from CN V11
 pass to lacrimal, nasal, and
submandibular glands.
= Fibers from CN 1X
 to parotid gland .
= Vagus (CN X)
 contains 75 % of all PNS nerve fibers
 pass to entire thoracic and abdominal regions
PNS (Cranio-Sacral Outflow):

= Preganglionic fibers originate from CNS at:


a) Midbrain
b) Medulla oblongata
c) Spinal cord level S2 to S4

A. Midbrain or Tectal Outflow:


 consist of fibers from Edinger- Westphal
nucleus of CN 111 (Occulomotor)

 to the ciliary ganglion at orbit.


Vagus Nerve (CN X)
= At intestinal wall,
 Vagus fibers terminate around ganglion
cells in Mesenteric and Submucosal plexuses.

 carry more afferent fibers from viscera,


(no pain fibers)

 to medulla with cell bodies found at


the Nodose Ganglion.
Neurotransmitters at PNS:
A. Acetylcholine:
= Synthesized and then stored in vesicles in high
concentration until its release.

= Released into tissues by the same


cholinergic nerve endings;

= Persists in tissue for only few seconds


 to quickly performs its nerve signal
transmitter function
 after which Ach is degraded into acetate and Choline.
= Acetylcholinesterase:
 catalyze the degradation of Ach, in the
same manner as in the NMJ of SKM.
= Choline is transported back into terminal nerve ending,
 to be recycled.
aa
Muscarinic and Nicotinic Ach Receptors:
= 2 Types of Ach Receptors:
1) Muscarinic Receptors
2) Nicotinic receptors

Nicotinic Receptors are found in:


1) Autonomic ganglia

2) Non-autonomic nerve endings,


 like at the NMJ of SKMs.
Autonomic Reflexes:
 regulate many visceral functions of the body.

A. Cardiovascular Autonomic Reflexes:


 to control arterial BP and HR
1) Baroreceptor reflex;
 by the Stretch Baroreceptors

B. Gastrointestinal Autonomic Reflexes:


1) Swallowing reflex
2) Defecation reflex

C. Reflex Emptying of Urinary Bladder


aa
Cholinergic Agents:

= Also known as:


> Cholinergic agonists
or
> Parasympathomimetics
Pharmacologic Blockade of Muscarinic
Cholinergic Receptors (mAchRs) by:

Atropine:
= does not block all excitatory neurotransmissions,
because Neurokinin A and substance P

 are also stored and released by the


excitatory motor neurons,

 both contribute to post-junctional excitation


via NK1 and NK2 receptors.
Properties & Subtypes of Muscarinic Receptors:
= Muscarinic Receptors:
 M1 (ganglionic)
 M2 (effector cells)

= Cloning of cDNAs encode 5 distinct Muscarinic receptors;


 identified as: M1 to M5 Muscarinic Receptors

= All known Muscarinic Receptors are


 G-protein-coupled receptors
 couple to various cellular effectors.
Stimulation of M1, M3, and M5 Receptors:
= Causes hydrolysis of Polyphosphoinositides
 and mobilization of intracellular Ca++ in.

= As a result of activation
 of Gq-PLC pathway,
 seen in several Ca++ -mediated responses.
Stimulation of M2 and M4 Receptors:

 inhibit adenylyl cyclase, and

 regulate specific ion channels

 via coupling to pertussis


toxin–sensitive Gi and Go

 decreased cAMP
A small dose IV of Acetylcholine:
 transient fall in BP;
= due to generalized vasodilation
= mediated by vascular endothelial NO,
 causes reflex tachycardia

A larger dose IV of Acetylcholine:


 direct effect to heart eliciting:
1) Bradycardia, or
2) AV nodal conduction block
= If Receptor is occupied by an Agonist (Ach):
> Ach activates the Gq–PLC–IP3 pathway,
 leading to Ca++ ion-calmodulin–dependent
activation of endothelial NO synthase,(eNOS)
> Production of NO;
 an endothelium-derived relaxing factor
 which diffuses to adjacent VSMCs
 to cause vascular relaxation

= In Endothelial Damaged:
> ACh acts on M3 Receptors on VSMCs
 causing vasoconstriction.
Baroreceptor or Chemoreceptor Reflexes:
 or direct stimulation of the Vagus nerve, (CN X)

= can elicit parasympathetic coronary vasodilation


 mediated by Ach,

 with consequent production of,


NO by the endothelium.

 Causing Vasodilatation
CVS Pharmacologic Effects of Ach:
 the physiological basis for the therapeutic uses of,
Muscarinic Receptor Agonists and Antagonists.

Acetylcholine has 4 Primary Effects on CVS:


1) Vasodilation
2) Decrease HR (negative chronotropic effect)
3) Decrease in conduction velocity in the AV node
(negative dromotropic effect)
4) Decrease the force of cardiac contraction
(negative inotropic effect)
ACh is rarely given systemically,

 but its cardiac actions are important

 because of the cardiac effects of:


1) Cardiac glycosides
2) Anti-arrhythmic agents

 that can cause changes in parasympathetic


(vagal) stimulation of the heart.
= PNS Afferent stimulation of the viscera during
surgical interventions can;

 cause reflex increase in vagal stimulation


of the heart,

 Reflex cardiac inhibition

 Reflex Bradycardia
Cardiac Function of Acetylcholine:
A. Is direct and indirect;
 thro’ inhibition of adrenergic stimulation to the heart.

= Normally cardiac impulses are initiated by;


 the spontaneous depolarization of the
pacemaker cells (SA node).

B. In the atria, Acetylcholine:


1) Causes hyperpolarization, increased duration of AP.

2) Inhibits cAMP formation and NE release


 decrease atrial contractility.
B. In the atria, Acetylcholine:

1) Causes hyperpolarization,

increased duration of APs.

2) Inhibits cAMP formation


and NE release
 decrease atrial contractility.
C. Acetylcholine Effect in the AV Node:
 AV node has Ca++ ion channel-dependent APs.

a) Slows conduction.
b) Increases refractory period.
 by inhibiting the L-type of Ca++ channels.

c) Decreased AV conduction
 responsible for complete heart block
 in large doses of systemic Cholinergic agonists.
It is important to note that:
 Cholinergic (Vagal) innervation to the:

a) His-Purkinje system
and
b) Ventricular myocardium
 is sparse.
Increasing Parasympathetic (vagal) Tone,
 as produced by Digitalis glycosides:

 Increases the refractory period of AV node.

 reduces the frequency by which aberrant


atrial impulses are transmitted to ventricles,

 decreases the ventricular rate during


atrial flutter or atrial fibrillation.
In the Respiratory Tract:
 PNS plays a major role in the
Broncho-motor Tone.

= Diverse stimuli cause reflex increase


in PNS activity that contributes to:
a) Bronchoconstriction
b) Increased tracheobronchial secretion.
c) Stimulation of the chemoreceptors of
the carotid and aortic bodies.
 effects mediated by M3 receptors.
In the Urinary Tract:

PNS Sacral Innervation Causes:

a) Contraction of detrusor muscle


(M2 and M3 receptors)

b) Increase voiding pressure.

c) Increase Ureteral peristalsis.


In the GI Tract:
= Stimulation of Vagal input to GIT:
a) increases tone
b) increase amplitude of contractions
c) increase secretory activity of the
stomach and intestine

= M3 Muscarinic Receptors
 mediate cholinergic control of GI motility.
• Features of the PNS, Cont’d :

> Each PNS pre-ganglionic nerve fiber


transmits impulses to only one
post-ganglionic nerve fiber.

> PNS generally, has a slowing-down


effect that balances effect of the SNS.

> PNS releases Ach at the effectors


(gland or muscle)  therefore
postganglionic parasympathetic
fibers are cholinergic.
.
aa
GIT Autonomic Reflexes:

As Feces Fills the Rectum;


= Sensory impulses initiated
by stretching of rectal wall.
= Sent to Sacral portion of spinal cord,
= A reflex signal is transmitted back thru
the sacral parasympathetic to distal colon,
 results in strong peristaltic contractions,
 that cause defecation.
Muscarinic Receptor Agonists
 divided into 2 groups:

A. Choline Esters:
a) Acetylcholine

b) Synthetic Esters that are of clinical applications


1) Methacholine (acetyl-methylcholine)
 the methyl analog of Ach.
2) Carbachol
3) Bethanechol

B. Naturally occurring Cholinomimetic Alkaloids:


a) Pilocarpine
b) Muscarine
c) Arecoline
Clinical Applications of
Synthetic Choline Derivatives:

1. Methacholine (acetyl-methylcholine)
 differs from Ach by its:

a) Greater duration of action;


 due to the added methyl group,

 which increases its resistance to


hydrolysis by Cholinesterases.

b) Greater selectivity of action;


 due to predominance of muscarinic,
with only minor nicotinic actions.
(manifested in CVS)
Synthetic Choline Derivatives:
2. Bethanechol (URECHOLINE)
 primarily affects the urinary and GI tracts.

A. In the Urinary Tract, Bethanechol;


 is used to treat urinary retention and
inadequate emptying of the bladder.

 In the Absence of Organic Obstructions like in:


a) Postoperative urinary retention.
b) Diabetic autonomic neuropathy.
c) Certain cases of chronic hypotonic, myogenic,
or neurogenic bladder.
 So that catheterization can be avoided.
b) In the GI tract, Bethanechol:

1) stimulates peristalsis

2) increases motility

3) increases resting lower esophageal


sphincter pressure.
Major Natural Alkaloid Muscarinic Agonists:
 have the same principal sites of action as the choline esters.

1. Muscarine:
= acts exclusively at muscarinic receptor sites
= has toxicological significance.

2. Arecoline:
 the same principal sites of action as choline esters.

3. Pilocarpine:
Major Natural Alkaloid Muscarinic Agonists:

3. Pilocarpine:
 has a dominant muscarinic action,
a partial rather than a full agonist.

 Sweat glands are particularly sensitive to Pilocarpine

 clinical use of Pilocarpine is restricted as a


sialagogue and miotic agent.
P/K of Natural Alkaloid Muscarinic Agonists:
 are predicted by their structures:

a) Muscarine and Choline esters:


= are quaternary amines;
 thus are poorly absorbed orally.

= limited capacity to cross the BBB,


 but can still have CNS effects.

= resist hydrolysis, but the choline esters are short-acting,


 due to rapid renal elimination.
b) Pilocarpine and Arecoline:
 are tertiary amines.

= are readily absorbed, can cross BBB.

= Pilocarpine clearance;
 is decreased in patients with renal impairment,
 natural alkaloids are eliminated by the kidneys.

= excretion of tertiary amines


 can be accelerated by acidification of urine.
Therapeutic Uses Muscarinic Receptor Agonists:

1) For the treatment of:


a) Urinary bladder disorders
b) Xerostomia

2) In ophthalmology:
a) as miotic agents
b) for the treatment of Glaucoma.

Acetylcholine (Miochol-e):
 for topical application as 1% solution by instillation.
 to induce mydriasis during:
a) Ophthalmic examinations
b) Ophthalmic Surgery
Synthetic Choline Derivatives:
 influence the naturally mediated release
of the neurotransmitters.
a) Adenosine
b) Dopamine (DA)
c) Glutamate- aminobutyric acid (GABA)
d) Prostaglandins
e) Enkephalins

= Receptors for these agents exert their modulatory effects partly,


 by altering the function of pre-junctional ion channels.
Stimulus Rate affect the Degree of SNS & PNS Effects:
= ANS = Only a low frequency stimulation;
 is required for full activation of ANS effectors.

> Only one nerve impulse every few seconds


 is enough to maintain normal ANS effect.

> Full activation occurs when nerve fibers


 discharge 10 to 20 X per second.

= Skeletal Nervous System;


 full activation requires 50 to 500 or more
impulses per second.
aa
Anticholinesterase Agents

Mechanism of Action of AChE Inhibitors:

= Three distinct Domains on AChE:


 constitute binding sites for inhibitory ligands,

 the basis for specificity differences between


AChE and Butyrylcholinesterase.

= Reversible inhibitors, such as:

Edrophonium and Tacrine,


 bind to the choline sub-site.
= Edrophonium:
> has a brief duration of action;
a) due to its quaternary structure;
 that facilitates renal elimination and its
b) reversible binding to AChE active center.

= Donepezil:
 binds with higher affinity to AchE active center.

= Propidium and the snake peptidic toxin Fasciculin:


 bind to the peripheral anionic site on AChE.
Destruction of Cholinergic Transmitter:

= The Anti-ChE agents;


 are chemically diverse group of compounds,
 their primary action is inhibition of AChE,
 with consequent accumulation of endogenous Ach.

= At the NMJ:
 accumulation of Ach;
 produces depolarization of end plates,
 causing flaccid paralysis.
= At postganglionic muscarinic effector sites;
 the response is either:
1) excessive stimulation,
 results in contraction and secretion,

2) or, an inhibitory response


 mediated by hyperpolarization.

= At ganglia;
 depolarization and enhanced transmission.
Drugs Acting at NMJ and Autonomic Ganglia:
Structure of Nicotinic Receptor:

= the prototype for other pentameric ligand-gated channels like:


a) GABA
b) 5-Ht
NEURALMUSCULAR JUNCTION (NMJ)
Neuromuscular Blocking Agents:
 Curare is the classical neuromuscular blocker.

= 2 Classes of the recent NMJ Blocking Agents:

1) Depolarizing:
 Succinylcholine (ANECTINE, QUELICIN)
the only NMJ blocking agent used clinically so far.

2) Competitive/non-depolarizing:
 Curare: localized paralysis
= Site of action of D-tubocurarine, and
other competitive blocking agents;
 the motor end plate, (post-junctional membrane).

= Competitive antagonists
 bind with Nicotinic ACh receptor at the end plate,
 competitively block the binding of Ach, so that
 so that the muscle cell becomes insensitive to the
motor-nerve impulses.

= But, end-plate region and the rest of SKM fiber membrane,


 retain their sensitivities to K+ depolarization
and direct electrical stimulation.
Steps involved like:

= ACh release during the nerve AP,

= development of miniature end-plate potentials (MEPPs),

= summation to form a post-junctional EPP

= triggers the muscle AP to effect muscle contraction.


= The fundamental event elicited by,
ACh or other agonists;

 is an "all or none" opening of individual


receptor channels,
 with an average pulse open-channel conductance
of 20-30 picosiemens (pS), with a duration of ~1ms

= Duration of channel opening:


 is dependent more on nature of agonist,
 than the magnitude of open-channel conductance.
= Increasing concentration of competitive antagonist:
(Tubocurarine)

 progressive decrease in amplitude of EPP.

 as amplitude of potential falls to below 70%,


is now insufficient to initiate propagated muscle AP.

 provide a safety factor in NM transmission.


= Tubocurarine reduces the frequency of
channel-opening events;

 but does not affect the conductance, nor


duration of opening for a single channel.

= At higher concentration, Curare and other


competitive antagonists;
 non-competitively block the channel
directly with agonists,

 dependent on membrane potential.


= Concentration of unbound Ach;
 at synapse released from nerve,
 diminishes more rapidly than the decay of EPP.

= In the presence of Anti-cholinesterase Drugs,


 EPP is prolonged up to 25-30 ms.

 rebinding of transmitter to neighboring receptors


before hydrolysis by AChE or diffusion from synapse.
= Succinylcholine, (depolarizing agents)
 act by a different mechanism.

 depolarize membrane by opening channels


in the same manner as ACh

 But, persist longer at the NMJ due to their


resistance to AChE.

Thus depolarization is longer-lasting,


 results to a brief period of repetitive excitation
 that elicit transient and repetitive muscle
excitation (fasciculations).
= The initial depolarization;
 is followed by blockade of NM transmission
 and flaccid paralysis (phase I block).

= Block occurs because, after an initial opening,


peri-junctional Na+ ion channels close, and
 will not reopen until the end plate is repolarized.

= Neural release of ACh result in binding to Ach receptors


 on an already depolarized end plate.

= Closed peri-junctional channels keep the depolarization


signal from affecting downstream channels, and
 effectively shield the rest of muscle from activity
at the motor end plate.
• Alzheimer's Disease:
• = Pathology;
•  a deficiency of intact cholinergic neurons,
• particularly those extending from subcortical areas, such as the nucleus basalis of Meynert,
•  observed in patients with progressive dementia of the Alzheimer type.

• = Rationale of current modes of therapy:


•  to enhance the concentrations of cholinergic neurotransmitters in the CNS.

• = Three cholinesterase inhibitors, had gained FDA approval,


•  for their required affinity and hydrophobicity to cross the blood-brain barrier,
•  and exhibit a prolonged duration of action.
• = Given along with Memantine,
•  that mimic, an excitatory amino acid transmitter.

• = These agents are not disease modifying nor have


• well-documented actions on the pathology
• of Alzheimer's disease.
aa
• aa = Three cholinesterase inhibitors, had gained FDA approval,
•  for their required affinity and hydrophobicity
• to cross the blood-brain barrier,
•  and exhibit a prolonged duration of action.
• = Given along with Memantine,
•  that mimic, an excitatory amino acid transmitter.

• = These agents are not disease modifying nor have


• well-documented actions on the pathology
• of Alzheimer's disease.
• = The evidences indicate that these Drugs;
•  slow the decline in cognitive function and
• behavioral manifestation, for only a limited
• intervals of time.
•  Associated symptoms, such as Depression,
• may be delayed.
• Tacrine (tetrahydroaminoacridine)
= for use in mild to moderate Alzheimer's disease.
= but a high incidence of enhanced alanine aminotransferase
and hepatotoxicity had limited the use of this drug.
= The other side effects were typical of AChE inhibitors.

• Donepezil then had approval for clinical use.


= Improved cognition and global clinical function
seen in the 21–81-week intervals.
= In long-term studies, Donepezil delayed symptomatic
progression of the disease for periods up to 55 weeks.
= Side effects are due to excessive cholinergic stimulation,
 with nausea, diarrhea, and vomiting.
= is well tolerated in single daily doses of 5-mg doses at night;
if this dose is well tolerated, it can be increased to 10 mg daily.
Rivastigmine:
 a long-acting carbamoylating inhibitor,
is approved for use in the U.S. and Europe.

= its efficacy, tolerability, and side effects;


 are similar to those of Donepezil.

Galantamine:
 An AChE inhibitor recently approved by the FDA.

= has a side-effect profile similar to those o


Donepezil and Rivastigmine.
Current clinical research efforts on AD:

 are directed to synergistic actions of;


= arresting inflammatory processes or neurodegeneration,

= and combining cholinesterase inhibition


with selective cholinergic receptor modulation
THANK YOU

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