Autonomic Nervous System.ppt 1

AUTONOMIC NERVOUS AUTONOMIC NERVOUS SYSTEMSYSTEM

BY:

PROF. DR. SHAH MURAD

shahmurad655@yahoo.com

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Introduction

Nervous System

Peripheral NS Central NS

Efferent Division Afferent Division

Autonomic Somatic

Sympathetic Parasympathetic

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Feedback loop of the Feedback loop of the autonomic nervous system.autonomic nervous system.

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Anatomy

ANATOMYANATOMY

1)    SYMPATHETIC (THORACOLUMBAR) DIVISION. 2 ) PARASYMPATHETIC (CRANIOSACRAL) DIVISION.

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EFFERENT NEURONSEFFERENT NEURONS

PREGANGLIONIC NEURONS

POSTGANGLIONIC NEURON

pregnanglionic neuron

ganglia

postganglionic neuron

effector organ

effector organ

1)    SYMPATHETIC (THORACOLUMBAR) DIVISION. 2) PARASYMPATHETIC ( CRANIOSACRAL) DIVISION. 

Brain stem or spinal cord

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How neurons regulate other cells.How neurons regulate other cells. The basic steps in theThe basic steps in the process by which neurons elicit process by which neurons elicit

responses from other cells are responses from other cells are

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

binding of transmitter to its receptor on the postsynaptic cell. binding of transmitter to its receptor on the postsynaptic cell.

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The basic anatomy of the parasympathetic and sympathetic nervous systems and the somatic motor system.

11Transmitters employed at specific junctions of the peripheral nervous system

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Steps of Synaptic Transmission

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

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AUTONOMIC

NEUROTRANSMITTERS

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NEUROTRANSMITTERSNEUROTRANSMITTERS

Epinephrine Nor epinephrine Acetylcholine Dopamine

Each of these binds to specific family of receptors.

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SITES OF RELEASE OF Ach

&

NOR EPINEPHRINE

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Sites where Ach is releasedSites where Ach is released

All preganglionic efferent fibers

All parasympathetic postganglionic fibers

Few sympathetic postganglionic fibers

Somatic, Motor fibers

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Sites where Nor epinephrine is Sites where Nor epinephrine is releasedreleased

Postganglionic sympathetic fibers

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AUTONOMIC RECEPTORS

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AUTONOMIC RECEPTORSAUTONOMIC RECEPTORSCHOLINERGIC RECEPTORS ----- 2 Types

– Muscarinic receptors– Nicotinic receptors

ADRENERGIC RECEPTORS------- 2 Types Alpha -1 (i) alpha adrenoceptor

Alpha -2 Beta -1 (ii) beta adrenoceptor Beta-2

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Subtypes of Cholinergic and Subtypes of Cholinergic and Adrenergic ReceptorsAdrenergic Receptors

Cholinergic receptor– Nicotinic n– Nicotinic m– Muscarinic

Adrenergic receptor– Alpha1 and alpha2

– Beta1 and beta2

– Dopamine

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FUNCTIONS OF AUTONOMIC RECEPTORS

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Functions of Cholinergic Functions of Cholinergic Receptor SubtypesReceptor Subtypes

Nicotinic n (neuronal)– Promotes ganglia transmission– Promotes release of epinephrine

Nicotinic m (muscle) – Contraction of skeletal muscle

Muscarinic– Activates parasympathetic nervous system

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Functions of Adrenergic Functions of Adrenergic Receptor SubtypesReceptor Subtypes

Alpha1 – Vasoconstriction– Ejaculation– Contraction of bladder neck and prostate

Alpha2

– Located in presynaptic junction– Minimal clinical significance

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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

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Functions of Adrenergic Functions of Adrenergic Receptor Subtypes (cont.)Receptor Subtypes (cont.)

Beta1

Heart

– Increases heart rate

force of contraction

velocity of conduction in AV node

Kidney

– Renin release

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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

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Functions of Adrenergic Receptor Functions of Adrenergic Receptor Subtypes (cont.)Subtypes (cont.)

Beta2 – Bronchial dilation– Relaxation of uterine muscle– Vasodilation– Glycogenolysis

Dopamine– Dilates renal blood vessels

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OrganEffect of

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

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Vascular Smooth Muscle

Sympathetic   

Parasympathetic

Skin, Splanchnic vessels

Contract α -----

……

Skeletal Muscle vessels

Relaxes β2 --------- --------

  Contract α ---------

--------

  Relaxes M3 --------- …….

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Bronchial smooth muscles

Relaxes β2 contracts M3

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

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 Uterus, pregnant

Relaxes β2------- -------

Contracts α------- --------

Penis, Seminal Vesicles

Ejaculation α Erection M3

Skin       

Pilomotor smooth muscles

Contract α ------- -------

Sweat glandsThermoregualtory

Increases

M

Apocrine (stress) Increases

α -------- --------

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Metabolic Functions

Sympathetic   

Parasympathetic

Liver Gluconeogenesis

β2 / α-------- --------

Liver Glycogenolysis

β2 / α-------- --------

Fat cells Lipolysis α 2/ β1/β3

-------- --------

Kidney Renin release

β1-------- --------

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FUNCTION OF

PARASYMPATHETIC

&

SYMPATHETIC

NEVOUS SYSTEM

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Parasympathetic Nervous Parasympathetic Nervous System (PNS)System (PNS)

Rest & Digest situations.The regulatory functions of PNS affect these sites Heart rate Gastric secretions Bladder and bowel Vision Bronchial smooth muscle

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Sympathetic Nervous SystemSympathetic Nervous System

Main functions of the SNS Regulation of cardiovascular system Regulation of body temperature Implementation of “fight or flight” reaction

FIGHT OR FLIGHT RESPONSEStressful Situations ----

trauma, fear , hypoglycemia.

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Opposing effects of parasympathetic and Opposing effects of parasympathetic and sympathetic nerves.sympathetic nerves.

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ORGANS RECEIVING ONLY SYMPATHETIC ORGANS RECEIVING ONLY SYMPATHETIC INNERVATIONINNERVATION

Adrenal Medulla Kidney Pilomotor muscles Sweat glands Vessels Metabolic processes

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THREE MECHANISMS BY WHICH BINDING OF THREE MECHANISMS BY WHICH BINDING OF NEUROTRANSMITTER LEADS TO A CELLULAR RESPONSE NEUROTRANSMITTER LEADS TO A CELLULAR RESPONSE

AND EFFECT:AND EFFECT:

   RECEPTORS COUPLED TO A ION CHANNEL       Cholinergic nicotinic receptors       GABA receptors Ions

Change in membrane potential or ionic Concentration in cell. Ions

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RECEPTORS COUPLED TO ADENYLYL CYCLASE       Beta- adrenoceptors     Alpha-2 adrenoceptors

Adenylyl

ATP cyclase cAMP 

PROTEIN PHOSPHORYLATION     INTRACELLULAR EFFECT  

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RECEPTORS COUPLED TO DIACYLGLYCEROL (DAG) & INOSITOL RECEPTORS COUPLED TO DIACYLGLYCEROL (DAG) & INOSITOL TRIPHOSPHATETRIPHOSPHATE

DAG IP3

Protein phosphorylation & increase in intracellular Ca

Intracellular effect

Alpha-1 adrenoceptor

Cholinergic muscarinic receptor

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CHOLINERGIC AGONIST

CLASSIFICATION

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Cholinergic agonistsCholinergic agonistsDirect 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

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Structural classification Structural classification Indirect acting drugsIndirect acting drugs

1. Simple alcohols:Edrophonium

2. Carbamic acid esters of alcohols: Neostigmine

3. Organophosphates:

Isoflurophate

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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:

a) Her problems are due to her crucial husbandb) She is in depressionc) She has no problem at alld) Her complains related with kidney, adrenal medulla,

vessels, pilomotor muscles, sweat glands and metabolic processes are due to sympathetic ANS stimulation

e) All her problems are related with histamine release

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MOAMOA

DIRECTLY ACTING CHOLINERGIC AGONIST DRUGS ACT DIRECTLY through RECEPTORS (affinity + intrinsic activity of concerned receptors)

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Mechanism of action of

Indirect acting Cholinergic agonist

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Mechanism of ActionMechanism of Action

ACETATE

ACETYLCHOLINE ACETYLCHOLINESTERASE

Ach

CHOLINE

1.Choline + Acetylated Enzyme

H202. Acetylated Enzyme Acetate + Enzyme

ACETYLCHOLINESTERASE INHIBITORS

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Cholinergic Neurotransmitter

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CHOLINERGIC NEUROTRANSMITTER ACETYLCHOLINEACETYLCHOLINE

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)

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Drug structure and receptor Drug structure and receptor selectivityselectivity

•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.

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Cholinergic Receptors

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Cholinergic receptors with locations and effects on Cholinergic receptors with locations and effects on effector tissueseffector 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

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Synthesis & Transmission of

Acetylcholine

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Life cycle of AcetylcholineLife cycle of Acetylcholine

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Actions of cholinergic agonist on

various systems

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ACTIONS OF CHOLINERGIC AGONISTACTIONS 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).

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G.I.T:

      Increase salivary secretions

      Stimulates intestinal secretions

      Stimulates intestinal motility.

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RESPIRATORY SYSTEM: Stimulates bronchiolar secretions

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G.U SYSTEM:

  Increase tone of detrusor muscle

  Relaxes sphincter and trigone.

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EYE:

 Contraction of sphincter pupillae muscle--- pupil constricts (Miosis).

  Contraction of ciliary muscle----------- ---- accommodation of lens for

Near vision

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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:

a) All symptoms are due to muscrinic receptors stimulation

b) All symptoms are due to sympathetic stimulation

c) All symptoms are due to his anxiety

d) All symptoms are due to dopaminergic inhibition

e) All symptoms are due to his abdominal pain

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Therapeutic Uses

of

Cholinergic agonist

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THERAPEUTIC USES OF CHOLINERGIC AGONISTTHERAPEUTIC 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

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PHYSOSTIGMINE

Rx of atony of bladder.Rx of atony of bladder.

Rx of Glaucoma—to decrease I.O.P by miosis.Rx of Glaucoma—to decrease I.O.P by miosis.

AntidoteAntidote for anticholinergic overdosage (Atropine for anticholinergic overdosage (Atropine

Poisoning)Poisoning)

AMBENONIUM:AMBENONIUM:

Rx of Rx of myasthenia gravismyasthenia gravis

D.O.AD.O.A: 4-8 hours: 4-8 hours

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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.

NEOSTIGMINENEOSTIGMINE AntidoteAntidote for Tubocurarine & other NMS blockers.for Tubocurarine & other NMS blockers.

Symptomatic Rx of Symptomatic Rx of Myasthenia gravis Myasthenia gravis

D.O.A:D.O.A: 0.5 TO 2 hour0.5 TO 2 hour

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Organophosphates Organophosphates

Ecothiophate Rx of Glaucoma

D.O.A: 100 hours

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Cholinergic CrisesCholinergic Crises

Excessive cholinergic (muscarinic) stimulation Neuromuscular blockage.

Occurs because: Irreversible anticholinesterases

(organophosphate insecticides or nerve gases)

binds the enzyme acetylcholinesterase and inactivates it.

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Management of Cholinergic Management of Cholinergic CrisesCrises

DecontaminationActivated charcoalGastric Lavage.Atropine (to counter the muscarinic effects)Pralidoxime (Cholinesterase reactivator): to relieve neuromuscular blockage.Diazepam: to control seizuresMechanical Ventilation- resp paralysis

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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

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Cholinergic agonist

as

Anti dotes

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Use of cholinergic agonist as Use of cholinergic agonist as AntidoteAntidote

AntidoteNeuromuscular blockage/ Skeletal muscle paralysis caused by non depolarizing muscle relaxants

Neostigmine

Pyridostigmine

Edrophonium

Anticholinergic poisoning (Atropine or TCA)

Physostigmine

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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

immediatelyc) Adrenaline s/c is sufficient treatment to relieve the

symptomsd) Psychological counseling is the best advise for the patiente) 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

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Antidote for cholinergic drugAntidote for cholinergic drugoverdosageoverdosage

Atropine

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CHOLINERGIC ANTAGONISTS

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CHOLINERGIC ANTAGONISTCHOLINERGIC ANTAGONIST(PARASYMPATHOLYTICS)(PARASYMPATHOLYTICS)

ANTIMUSCARINIC AGENTS……..

Atropine IpratropiumScopolamine/ Hyoscine Pirenzipine.GANGLIONINC BLOCKERS……...MecamylamineNicotineTrimethaphan

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

Succinylcholine Atracurium

Doxacurium

Vecuronium

Mivacurium

Rocuronium

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NICOTINIC RECEPTOR AGONIST & ANTAGONISTNICOTINIC RECEPTOR AGONIST & ANTAGONIST

DRUGS MAIN SITE TYPE OF ACTION

NOTES

AGONISTS

Nicotine Autonomic ganglia, CNS

Stimulation then block

Stimulation

No clinical uses

Lobeline Autonomic ganglia,

Stimulation

Suxamethonium NMJ Depolarization block

Muscle relaxant

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ANTAGONIST Main site Type of response

Notes

Hexamethonium Autonomic ganglia

Transmission block

no clinical use

Trimethaphan Autonomic ganglia

Transmission block

B.Pressure lowering in surgery (rare)

Tubocurarine Autonomic ganglia

Transmission block

Now rarely used

Pancuronium

Atracurium

Vecuronium

Autonomic ganglia

Transmission block

Widely used as muscle relaxant in anesthesia

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Muscarinic Antagonist

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Muscarinic AntagonistMuscarinic Antagonist

Compound Clinical Uses Adverse effects

Atropine Adjunct for anesthesia.Anticholinesterase poisining.Bradycardia.Antispasmodic.

Urinary

retention.Dry mouthBlurred vision.Hyperthermia.Constipation

Hyoscine Motion sickness Sedation(CNS

depressant)

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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.

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Effects of muscarinic antagonistsEffects 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

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G.I.T: Decrease motility, inhibition of gastric acid secretion

(Pirenzipine). smooth muscles: relaxation of bronchial, biliary,

and urinary tact

smooth musclesCNS: excitatory effect on CNS (block muscarinic

receptors in brain).

At low doses ------- mild restlessness

At higher doses ---- agitation, disorientation.

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Clinical Uses of Muscarinic antagonistClinical 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

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Neuromuscular Blockers

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NON-DEPOLARIZINGNON-DEPOLARIZING (COMPETITIVE) (COMPETITIVE) BLOCKERSBLOCKERS

TUBOCURARINETUBOCURARINE

M.O.A:

Ion channel

Nicotinic receptorNMJ

TAch

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PHASE-IMuscle depolarizes resulting in an initial discharge which

produces transient fasiculation followed by flaccid paralysis

Nicotinic receptorNMJ

NaPHASE-IIMembrane repolarizes but receptor is desensitize to effect of Ach

Nicotinic receptorNMJ

depolarized

repolarized

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Neuromuscular blocking drugsNeuromuscular blocking drugs

Drug Onset Duration S.E

Tubocurarine Slow

(> 5 min)

Long (1-2h) Hypotension

(histamine release)

Bronchoconstriction

Gallamine Slow Long Tachycardia

Pancuronium Intermediate

(2-3 min)

Long Slight Tachycardia

Vecuronium Intermediate Intermed

(30-40 min)

Few side effects

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Drug Onset Duration S.E

Atracurium Intermediate Intermediate

(< 30 min)

Transient hypotension

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

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Drug Onset Duration S.E

Suxamethonium Fast Short (-10 min) BradycardiaCardiac

Dysrhythmias

( Plasma K+)Post operative muscle pain