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Autonomic Nervous System - PPT 1

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AUTONOMIC NERVOUS

SYSTEM

BY:

PROF. DR. SHAH MURAD


Introduction

2
Nervous System

Peripheral NS Central NS

Efferent Division Afferent Division

Autonomic Somatic

Sympathetic Parasympathetic
Feedback loop of the
autonomic nervous system.

4
Anatomy

5
ANATOMY

1) SYMPATHETIC
(THORACOLUMBAR) DIVISION.

2) PARASYMPATHETIC
(CRANIOSACRAL) DIVISION.
EFFERENT NEURONS

 PREGANGLIONIC NEURONS

 POSTGANGLIONIC NEURON

 
7
Brain stem or spinal cord
pregnanglionic neuron

ganglia

postganglionic neuron

effector organ
How neurons regulate other cells.
The basic steps in the process by which neurons elicit
responses from other cells are

(1) axonal conduction, (2) transmitter (T) release, and (3)


binding of transmitter to its receptor on the postsynaptic cell.

9
The basic anatomy of the parasympathetic and sympathetic nervous systems and the
somatic motor system. 10
Transmitters employed at specific junctions of the peripheral nervous system
11
Steps of Synaptic Transmission

13
Steps in synaptic transmission.
Step 1, Synthesis of transmitter (T) from precursor molecules (Q, R, S
Step 2, Storage of transmitter in vesicles.
Step 3, Release of transmitter:
Step 4, Action at receptor:
Step 5, Termination of transmission:

14
AUTONOMIC
NEUROTRANSMITTERS

15
NEUROTRANSMITTERS
 Epinephrine
 Nor epinephrine
 Acetylcholine
 Dopamine

Each of these binds to specific family of receptors.

16
SITES OF RELEASE OF Ach
&
NOR EPINEPHRINE

17
Sites where Ach is released

 All preganglionic efferent fibers

 All parasympathetic postganglionic fibers

 Few sympathetic postganglionic fibers

 Somatic, Motor fibers

18
Sites where Nor epinephrine is
released

 Postganglionic sympathetic fibers

19
AUTONOMIC RECEPTORS

20
AUTONOMIC RECEPTORS
CHOLINERGIC RECEPTORS ----- 2 Types
– Muscarinic receptors
– Nicotinic receptors

ADRENERGIC RECEPTORS------- 2 Types


Alpha -1
(i) alpha adrenoceptor

Alpha -2

Beta -1
(ii) beta adrenoceptor
21
Subtypes of Cholinergic and
Adrenergic Receptors
 Cholinergic receptor
– Nicotinic n
– Nicotinic m
– Muscarinic
 Adrenergic receptor
– Alpha1 and alpha2
– Beta1 and beta2
– Dopamine

22
23
24
25
26
27
FUNCTIONS OF AUTONOMIC
RECEPTORS

28
Functions of Cholinergic
Receptor Subtypes
 Nicotinic n (neuronal)
– Promotes ganglia transmission
– Promotes release of epinephrine
 Nicotinic m (muscle)
– Contraction of skeletal muscle
 Muscarinic
– Activates parasympathetic nervous system

29
Functions of Adrenergic
Receptor Subtypes
 Alpha1
– Vasoconstriction
– Ejaculation
– Contraction of bladder neck and prostate
 Alpha2
– Located in presynaptic junction
– Minimal clinical significance

30
 36 years old male patient came in medical OPD at tehseel
headquarter hospital renalakhurd, district okara, Punjab,
Pakistan. He told his doctor about his history of having
hypertension, urinary retention. He also told when asked by
doctor that he has problem in sexual intercourse with his
wife. Doctor asked more about his sexual problem. He shied
but replied that he do not ejaculate during intercourse, every
time. Doctor guessed that he has problem of delayed
ejaculation.
Which neurotransmitter may be involved in this clinical
scenario:
(a) Dopamine
(b) Norepinephrine /Epinephrine
(c) Acetylcholine
(d) Nicotine
(e) Histamine 31
Functions of Adrenergic
Receptor Subtypes (cont.)
 Beta1

 Heart

– Increases
 heart rate
 force of contraction
 velocity of conduction in AV node
 Kidney

– Renin release

32
A 25 years old female patient came in cardiac OPD,
complaining chest pain. She was hypertensive. Her
plasma renin level was increased. ECG revealed
increased heart rate, force of cardiac contraction,
and increased velocity of conduction in AV node.
Which receptor type may be involved when
stimulated, in this case.
(a) Muscrinic cholinergic
(b) Nicotinic cholinergic
(c) Beta-1 adrenergic
(d) Beta-2 adrenergic
(e) All of above receptor types
33
Functions of Adrenergic Receptor
Subtypes (cont.)
 Beta2
– Bronchial dilation
– Relaxation of uterine muscle
– Vasodilation
– Glycogenolysis
 Dopamine
– Dilates renal blood vessels

34
Effect of
Organ Sympathetic Parasympathetic
Action Receptor Action Receptor

Eye
Iris
-------- -------
Radial muscle Contracts α1
-------- ---------
Circular muscle Contracts M3
Ciliary muscle Relaxes β contract M3

Heart
SA node Accelerate β1 Decelerates M2
----------
Ectopic pacemaker Accelerate β1
Contractility Increases β1 Decreases M2 35
Vascular Sympathetic Parasympath
Smooth Muscle etic

Skin, ……
Splanchnic Contract
α -----

vessels
Skeletal Muscle Relaxes β2 --------- --------
vessels

Contract α --------- --------

Relaxes M3 --------- …….

36
Bronchial smooth Relaxes β2 contracts M3
muscles
G.I.T

Walls Relaxes α 2, β2 Contracts M3

Sphincters Contracts α1 Relaxes M3


-------- -------
Secretion Increases M3

Myenteric plexus Activates M1

Genitourinary
System
Bladder wall Relaxes β2 Contracts M3

Sphincter Contracts α1 Relaxes M3


37
------- -------
Relaxes β2
Uterus, pregnant
------- --------
Contracts α
Penis, Seminal Ejaculation Erection M3
Vesicles
α
Skin
Pilomotor Contract
smooth muscles
α ------- -------

Sweat glands
Thermoregualtory
Increases M

Apocrine (stress) Increases


α -------- --------

38
Metabolic Sympathetic Parasympat
hetic
Functions
-------- --------
Liver Gluconeo β2 / α
genesis

-------- --------
Liver Glycogeno β2 / α
lysis

-------- --------
Fat cells Lipolysis α 2/
β1/β3

-------- --------
Kidney Renin β1
release
39
FUNCTION OF
PARASYMPATHETIC
&
SYMPATHETIC
NEVOUS SYSTEM

40
Parasympathetic Nervous
System (PNS)
 Rest & Digest situations.
The regulatory functions of PNS affect these sites
 Heart rate
 Gastric secretions
 Bladder and bowel
 Vision
 Bronchial smooth muscle

41
Sympathetic Nervous System
Main functions of the SNS
 Regulation of cardiovascular system
 Regulation of body temperature
 Implementation of “fight or flight” reaction

 FIGHT OR FLIGHT RESPONSE


 Stressful Situations ----

trauma, fear , hypoglycemia.

42
Opposing effects of parasympathetic and
sympathetic nerves.

43
ORGANS RECEIVING ONLY SYMPATHETIC
INNERVATION

 Adrenal Medulla
 Kidney
 Pilomotor muscles
 Sweat glands
 Vessels
 Metabolic processes

44
THREE MECHANISMS BY WHICH BINDING OF
NEUROTRANSMITTER LEADS TO A CELLULAR RESPONSE
AND EFFECT:

RECEPTORS COUPLED TO A ION CHANNEL


  Cholinergic nicotinic receptors
  GABA receptors

Ions

Change in membrane potential or ionic


Concentration in cell.
Ions
45
 RECEPTORS COUPLED TO ADENYLYL CYCLASE
  Beta- adrenoceptors
  Alpha-2 adrenoceptors

Adenylyl

ATP cyclase cAMP

 PROTEIN PHOSPHORYLATION



 INTRACELLULAR EFFECT 46

RECEPTORS COUPLED TO DIACYLGLYCEROL (DAG) & INOSITOL
TRIPHOSPHATE

Alpha-1 adrenoceptor
Cholinergic muscarinic receptor

DAG IP3

Protein phosphorylation & increase in intracellular Ca

47
Intracellular effect
CHOLINERGIC AGONIST

CLASSIFICATION
48
Cholinergic agonists
Direct Acting
a. Alkaloids
muscarine, nicotine, pilocarpine
b. Choline Esters
ACh, methacholine, carbachol, bethanechol

In-direct Acting
Reversible
Edrophonium, neostigmine, physostigmine, demecarium
Irreversible
Ecothiophate, isoflurophate, Soman, parathion, malathion
Reactivator of acetylcholinesterase ---
Pralidoxime 49
Structural classification
Indirect acting drugs
1. Simple alcohols:
 Edrophonium

2. Carbamic acid esters of alcohols:


Neostigmine
3. Organophosphates:
Isoflurophate

50
51
24 years old ,married, beautiful female patient came in medical OPD
of Ghurki teaching hospital. 3rd year MBBS students were waiting for
their senior teacher to attend clinical class at OPD. When they got
medical history from married, beautiful lady. She told that she
remains hypertensive, remains hungry even after excessive food
intake, her body hairs raise when she listen any bad news at TV, and
she has problems of frequent micturation and increased sweating.
Medical students are discussing on ANS. Which group’s statement is
true:
f) Her problems are due to her crucial husband
g) She is in depression
h) She has no problem at all
i) Her complains related with kidney, adrenal medulla,
vessels, pilomotor muscles, sweat glands and metabolic
processes are due to sympathetic ANS stimulation
j) All her problems are related with histamine release 52
MOA
 DIRECTLY ACTING CHOLINERGIC
AGONIST DRUGS ACT DIRECTLY
through RECEPTORS (affinity + intrinsic
activity of concerned receptors)

53
Mechanism of action
of
Indirect acting
Cholinergic agonist

54
Mechanism of Action
ACETATE

ACETYLCHOLINE ACETYLCHOLINESTERASE
Ach

ACETYLCHOLINESTERASE CHOLINE
INHIBITORS

1.Choline + Acetylated Enzyme

H20
2. Acetylated Enzyme Acetate + Enzyme
55
Cholinergic Neurotransmitter

56
CHOLINERGIC
NEUROTRANSMITTER
 ACETYLCHOLINE

SITES WHERE Ach IS RELEASED AS TRANSMITTER:

The Preganglionic fibers to adrenal medulla.

The postganglionic fibers of parasympathetic


division.

The autonomic ganglia (both sympathetic


and parasympathetic)
57
Drug structure and receptor
selectivity

•The structure of Acetylcholine allows this transmitter to interact


with both receptor subtypes.
•In contrast, because of their unique configurations,
Nicotine and Muscarine are selective for the cholinergic receptor
subtypes whose structure complements their own. 58
Cholinergic Receptors

59
Cholinergic receptors with locations and effects on
effector tissues
Receptor Typical location MOA

M1 CNS neurons, Formation of IP3 & DAG,


Sympathetic postganglionic intracellualr Calcium
neurons,
M2 Myocardium, smooth muscles Opening of potassium channels,
inhibition of adenyl cyclase.
M3 Exocrine glands, vessels Formation of IP3 & DAG,
(smooth muscles & intracellualr Calcium
endothelium)
Nn Post ganglionic neurons, Opening of Na, K channels,
depolarization
Nm Skeletal muscle Opening of Na, K channels,
neuromuscular endplates depolarization

60
Synthesis & Transmission
of
Acetylcholine

61
Life cycle of Acetylcholine

62
Actions of cholinergic agonist
on
various systems

63
ACTIONS OF CHOLINERGIC AGONIST
CVS:
The action of Ach on heart mimic the effects of VAGAL stimulation.
  The normal vagal activity regulates the heart by
 release of Ach at SA node.

  Vasodilatation
 Decrease in heart rate ( -ve chronotropic effect).
 Decrease in force of contraction ( -ve Inotropic
 effect).
 Decrease in rate of conduction in SA & AV
 nodes ( -ve dromotropic effect).
64
G.I.T:

 Increase salivary secretions

 Stimulates intestinal secretions

 Stimulates intestinal motility.

65
RESPIRATORY SYSTEM:

 Stimulates bronchiolar secretions

66
G.U SYSTEM:

 Increase tone of detrusor muscle

 Relaxes sphincter and trigone.

67
EYE:

 Contraction of sphincter pupillae


 muscle--- pupil constricts
 (Miosis).

 Contraction of ciliary muscle-----------

 ---- accommodation of lens for


68
 26 years old patient came in hospital for his
treatment. He complained about increased
salivation, GIT cramps, diarrhea, increased sweating
, frequent urination. Whatever the diagnosis of the
problem is ,can you just guess that:
b) All symptoms are due to muscrinic receptors
stimulation
c) All symptoms are due to sympathetic stimulation
d) All symptoms are due to his anxiety
e) All symptoms are due to dopaminergic inhibition
f) All symptoms are due to his abdominal pain

69
Therapeutic Uses
of
Cholinergic agonist
70
THERAPEUTIC USES OF CHOLINERGIC AGONIST

ACETYLCHOLINE:
 No therapeutic use

BETHENECOL :
 to stimulate atonic bladder
 post partum or post operative non obstructive
urinary retention

PILOCARPINE:
 Emergency lowering of I.O.P in glaucoma

71
PHYSOSTIGMINE
 Rx of atony of bladder.
 Rx of Glaucoma—to decrease I.O.P by miosis.
 Antidote for anticholinergic overdosage (Atropine
Poisoning)

AMBENONIUM:
Rx of myasthenia gravis
D.O.A: 4-8 hours

72
PYRIDOSTIGMINE:
 Chronic Rx of Myasthenia gravis
D.O.A: 3-6 hours

EDROPHONIUM
 Diagnosis of Myasthenia gravis.
 To reverse the neuromuscular blockage produced by
non depolarizing skeletal muscle relaxants.

D.O.A: 5-15 minutes.

NEOSTIGMINE
 Antidote for Tubocurarine & other NMS blockers.
 Symptomatic Rx of Myasthenia gravis
D.O.A: 0.5 TO 2 hour
73
Organophosphates
Ecothiophate
 Rx of Glaucoma

 D.O.A: 100 hours

74
Cholinergic Crises
 Excessive
cholinergic (muscarinic) stimulation
 Neuromuscular blockage.

Occurs because:
 Irreversible anticholinesterases

(organophosphate insecticides or nerve gases)


binds the enzyme acetylcholinesterase and inactivates
it.
75
Management of Cholinergic
Crises
 Decontamination
 Activated charcoal
 Gastric Lavage.
 Atropine (to counter the muscarinic effects)
 Pralidoxime (Cholinesterase reactivator):
to relieve neuromuscular blockage.
 Diazepam: to control seizures
 Mechanical Ventilation- resp paralysis
76
 31 years old male patient was brought at HUJRA SHAH
MUKEEM HOSPITAL, tehseel Debalpur. He had
headache, excessive salivation, diarrhea, frequent urination.
History revealed that he took powder kept in cupboard, to
check, weather it is table salt or something else. Which
statement is true to keep symptoms of the patient:
a) Powder might be table salt, he took
b) Powder was histamine, which was incidentally kept in
house
c) Powder was basically old grinded sugar, which was
contaminated
d) Powder was not the etiology of these symptoms, it was
something else
e) Powder was insecticide 77
Cholinergic agonist
as
Anti dotes

78
Use of cholinergic agonist as
Antidote
Antidote
Neuromuscular blockage/ Neostigmine
Skeletal muscle paralysis Pyridostigmine
caused by non depolarizing Edrophonium
muscle relaxants

Anticholinergic poisoning Physostigmine


(Atropine or TCA)
79
 29 years old patient was used to take antidepressant,
TOFRANIL tablets (imipramine 25 mg) 1 X 8 hly since
long time. One day he took 10 TOFRANIL tablets at once
due to some disputed problem with his father. He was
brought in casualty with symptoms like lethargy,
drowsiness, headache, lower abdominal pain, and difficulty
in urination. What should be the appropriate treatment:

a) Antidote for anticholinergic drug poisoning, like


physostigmine is the best treatment
b) Gastric levage and atropine must be given by IV route
immediately
c) Adrenaline s/c is sufficient treatment to relieve the
symptoms
d) Psychological counseling is the best advise for the patient
e) IV glucose may be given as infusion to relieve drowsiness,
PONSTON for headache and lower abdominal pain and
LASIX may be given to start urination 80
Antidote for cholinergic drug
overdosage

Atropine

81
CHOLINERGIC ANTAGONISTS

82
CHOLINERGIC ANTAGONIST
(PARASYMPATHOLYTICS)
ANTIMUSCARINIC AGENTS……..

Atropine
Ipratropium
Scopolamine/ Hyoscine
Pirenzipine.
GANGLIONINC BLOCKERS……...
Mecamylamine
Nicotine
Trimethaphan

83
 NEUROMUSCULAR BLOCKERS..
 1. Non - Depolarizing 2. Depolarizing
 Tubocurarine

Succinylcholine
 Atracurium

 Doxacurium

 Vecuronium

 Mivacurium

 Rocuronium 84
NICOTINIC RECEPTOR AGONIST & ANTAGONIST

DRUGS MAIN SITE TYPE OF NOTES


ACTION
AGONISTS

Nicotine Autonomic Stimulation No clinical


ganglia, CNS then block uses
Stimulation
Lobeline Autonomic Stimulation
ganglia,
Suxamethonium NMJ Depolarization Muscle
85
block relaxant
ANTAGONIST Main siteType of Notes
response
Hexamethonium Autonomic Transmission no clinical
ganglia block use
Trimethaphan Autonomic Transmission B.Pressure
ganglia block lowering in
surgery
(rare)
Tubocurarine Autonomic Transmission Now rarely
ganglia block used

Pancuronium Autonomic Transmission Widely used


Atracurium ganglia block as muscle
Vecuronium relaxant86 in
anesthesia
Muscarinic Antagonist

87
Muscarinic Antagonist
Compound Clinical Uses Adverse effects

Atropine Adjunct for Urinary


anesthesia. retention.
Anticholinestera Dry mouth
se poisining. Blurred vision.
Bradycardia.
Hyperthermia.
Antispasmodic.
Constipation
Hyoscine Motion sickness Sedation(CNS
depressant) 88
Compound Clinical Uses Adverse effects

Ipratropium Asthma, Rare


Bronchitis

Tropicamide Ophthalmic use to Increase I.O.P


produce mydriasis
& cycloplegia

Pirenzipine Peptic Ulcer Selective for M1


receptors, fewer
side effects.
89
Effects of muscarinic antagonists
 Inhibition of secretion: Salivary, lacrimal,
Bronchial & sweat glands

 Heart rate: Tachycardia (Modest)


 Eye: Mydriasis, pupil unresponsive to light, paralysis of


accomodation (cycloplegia), impaird near vision,
increased
I.O.P 90
 G.I.T: Decrease motility, inhibition of gastric
acid secretion
(Pirenzipine).
 smooth muscles: relaxation of bronchial, biliary,
and urinary tact
smooth muscles
 CNS: excitatory effect on CNS (block muscarinic

receptors in brain).
At low doses ------- mild restlessness
At higher doses ---- agitation,
disorientation.
91
Clinical Uses of Muscarinic antagonist
 CVS: Rx of sinus bradycardia ------ Atropine.
 Opthalmic: to dilate the pupil e.g tropicamide.
 Neurological:Prevention of motion sickness e.g
hyoscine
 Parkinson's: e.g Bentropine, Benhexol.
 Respiratory: Asthma---- Ipratropium
 Anesthetic Premedication: Atropine
 Gastrointestinal:
 Hyoscine ------- Antispasmodic action
 Pirenzipine ----- Treatment of peptic ulcer disease

 92
Neuromuscular
Blockers
93
NON-DEPOLARIZING (COMPETITIVE) BLOCKERS
TUBOCURARINE

 M.O.A:
Ach
T
Nicotinic receptor
NMJ

 Ion channel
94
PHASE-I
Muscle depolarizes resulting in an initial discharge which
produces transient fasiculation followed by flaccid
paralysis

Nicotinic receptor
depolarized
NMJ

Na
PHASE-II
Membrane repolarizes but receptor is desensitize to effect of Ach

Nicotinic receptor repolarized


NMJ 95
Neuromuscular blocking drugs
Drug Onset Duration S.E

Tubocurarine Slow Long (1-2h) Hypotension


(> 5 min) (histamine release)
Bronchoconstriction
Gallamine Slow Long Tachycardia

Pancuronium Intermediate Long Slight Tachycardia


(2-3 min)
Vecuronium Intermediate Intermed Few side effects
(30-40 min) 96
Drug Onset Duration S.E

Atracurium Intermediate Intermediate Transient


(< 30 min) hypotension

Mivacurium Fast (-2 min) Short (-15 min) Transient


hypotension

97
Drug Onset Duration S.E

Suxamethonium Fast Short (-10 min) Bradycardia


Cardiac

Dysrhythmias
( Plasma K+)
Post operative
muscle pain

98

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