Autonomic Nervous System.ppt 1

AUTONOMIC NERVOUS SYSTEM

BY: PROF. DR. SHAH MURAD

Introduction 2

Nervous System

Peripheral NS

Efferent Division

Autonomic

Sympathetic

Central NS

Afferent Division

Somatic

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 10 somatic motor system.

11 Transmitters employed at specific junctions of the peripheral nervous system

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 31 (e) Histamine

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

Organ

Effect of Sympathetic Action

Receptor

Parasympathetic Action

Receptor

Eye Iris

α1

--------

-------

--------

---------

Contracts

M3

Relaxes

β

contract

M3

SA node

Accelerate

β1

Decelerates

M2

Ectopic pacemaker

Accelerate

β1

----------

Contractility

Increases

β1

Decreases

Radial muscle

Contracts

Circular muscle Ciliary muscle

Heart

M2

35

Vascular Smooth Muscle Skin, Splanchnic vessels Skeletal Muscle vessels

Parasympath etic

Sympathetic

Contract Relaxes

Contract

Relaxes

α

-----

……

β2

---------

--------

α

---------

--------

---------

…….

M3

36

Bronchial smooth muscles G.I.T

Relaxes

β2

contracts

M3

Walls

Relaxes

α 2, β2

Contracts

M3

Sphincters

Contracts

α1

Relaxes

M3

Secretion

--------

-------

Increases

M3

Activates

M1

Myenteric plexus Genitourinary System Bladder wall

Relaxes

β2

Contracts

M3

Sphincter

Contracts

α1

Relaxes

M3 37

β2

-------

-------

Contracts

α

-------

--------

Ejaculation

α

Erection

M3

Contract

α

Relaxes Uterus, pregnant

Penis, Seminal Vesicles

Skin Pilomotor smooth muscles

Sweat glands Thermoregualtory Apocrine (stress)

Increases Increases

-------

-------

--------

--------

M

α

38

Metabolic Functions

Sympathetic

Parasympat hetic

Liver

Gluconeo genesis

β2 / α

--------

--------

Liver

Glycogeno lysis

β2 / α

--------

--------

Fat cells

Lipolysis

α 2/ β1/β3

--------

--------

Kidney

Renin release

β1

--------

--------

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

Intracellular effect

47

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) g) h) i)

j)

Her problems are due to her crucial husband She is in depression She has no problem at all Her complains related with kidney, adrenal medulla, vessels, pilomotor muscles, sweat glands and metabolic processes are due to sympathetic ANS stimulation 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 CHOLINE

ACETYLCHOLINESTERASE 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, Sympathetic postganglionic neurons,

Formation of IP3 & DAG, intracellualr Calcium

M2

Myocardium, smooth muscles

Opening of potassium channels, inhibition of adenyl cyclase.

M3

Exocrine glands, vessels (smooth muscles & endothelium)

Formation of IP3 & DAG, intracellualr Calcium

Nn

Post ganglionic neurons,

Opening of Na, K channels, depolarization

Nm

Skeletal muscle neuromuscular endplates

Opening of Na, K channels, 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/ Skeletal muscle paralysis caused by non depolarizing muscle relaxants

Neostigmine Pyridostigmine Edrophonium

Anticholinergic poisoning (Atropine or TCA)

Physostigmine 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 80 LASIX may be given to start urination

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 ACTION

NOTES

Nicotine

Autonomic ganglia, CNS

No clinical uses

Lobeline

Autonomic ganglia, NMJ

Stimulation then block Stimulation Stimulation Depolarization block

Muscle 85 relaxant

AGONISTS

Suxamethonium

ANTAGONIST

Main site

Type of response Hexamethonium Autonomic Transmission ganglia block

Notes

Trimethaphan

Autonomic Transmission ganglia block

Tubocurarine

Autonomic Transmission ganglia block

B.Pressure lowering in surgery (rare) Now rarely used

Pancuronium Atracurium Vecuronium

Autonomic Transmission ganglia block

no clinical use

Widely used as muscle relaxant86 in anesthesia

Muscarinic Antagonist

87

Muscarinic Antagonist Compound Atropine

Hyoscine

Clinical Uses Adjunct

for anesthesia. Anticholinestera se poisining. Bradycardia. Antispasmodic. Motion sickness

Adverse effects Urinary

retention. Dry mouth Blurred vision. Hyperthermia. Constipation Sedation(CNS depressant) 88

Compound

Clinical Uses

Adverse effects

Ipratropium

Asthma, Bronchitis

Rare

Tropicamide

Ophthalmic use to produce mydriasis & cycloplegia

Increase I.O.P

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 90 I.O.P

 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 NMJ

depolarized Na

PHASE-II

Membrane repolarizes but receptor is desensitize to effect of Ach

Nicotinic receptor NMJ

repolarized 95

Neuromuscular blocking drugs Drug

Onset

Duration

S.E

Tubocurarine Slow (> 5 min)

Long (1-2h)

Gallamine

Long

Hypotension (histamine release) Bronchoconstriction Tachycardia

Pancuronium Intermediate (2-3 min)

Long

Slight Tachycardia

Vecuronium

Intermed (30-40 min)

Few side effects

Slow

Intermediate

96

Drug

Onset

Duration

S.E

Atracurium

Intermediate

Intermediate (< 30 min)

Transient hypotension

Mivacurium

Fast (-2 min)

Short (-15 min) Transient hypotension

97

Drug

Onset

Duration

Suxamethonium

Fast

Short (-10 min)

S.E

Bradycardia Cardiac

Dysrhythmias ( Plasma K+) Post operative muscle pain

98