Autonomic nervous system

Nervous system

Peripheral nervous systemCentral nervous system

ParasympatheticSympathetic

Spinal cordBrainAutonomicSomatic

Autonomic Nervous systemSyn:Involuntery N.S., Vegetative or Visceral

nervous system.

-- It innervates : + Plain or involuntery or

Smooth muscles

Exocrine glands

Visceral organs

Respiration,circulation,digestion,body

temprature,metabolism, sweating, secretion

of glands are regulated in a part and entirely

by A.N.S and its control connections

Division of autonomicnervous system

Cranial

(Brain) Parasympathetic

Thoraco-lumber

Sympathetic

Sacral region

S.C.

Divisions of the autonomic nervous system:

1- The parasympathetic division (Craniosacral):

a- Cranial outflow originates from III, VII, IX & Xcranial nerves i.e. oculomotor, facial,glossopharyngeal and vagus nerves .

b- Sacral outflow originates at 2, 3 & 4 sacralsegments of the spinal cord to supply the lowerintestine, bladder and genitalia.

Divisions of the autonomic nervous system:

• The parasympathetic fibers have a longpreganglionic fiber, the ganglia being close to orembedded in the effector organ and a shortpostganglionic fiber.

• The system is concerned with restoration ofenergy, it slows the heart, lowers the bloodpressure, increases motility and secretion in theGIT and empties the bladder and rectum.

Divisions of the autonomic nervous system:2- Sympathetic division (Thoracolumbar):

• It comes from all the thoracic and upper three lumbar

segments of the spinal cord. The nerves have a short

preganglionic fiber and long post-ganglionic ones. Ganglia

is usually located near the spinal cord in the form of a chain

(sympathetic chain). Sympathetic system makes

adjustments for body reactions to stress (fright, fight & flight)

e.g. acceleration of the heart rate, rise of blood pressure,

dilatation of the pupil and bronchioles.

• Most of the tissues and organs are innervated by both

divisions of the autonomic nervous system. In general,

activities of the two divisions produce opposite effects.

Neurotransmitters

1- Ach

❑ Synthesis:

Choline acetylase Enz

➢ Acetate + Choline Ach

➢ Ach is stored in vesicles.

❑ Metabolism:

➢ The duration of action of Ach is very short due to rapid hydrolysis into Acetate

and Choline by Cholinesterase enzyme.

Cholinesterase Enz

➢ Ach Acetate + Choline

9

Types of choline-esterases

_____________________________________________

true choline-eterase Pseudocholine-

esterase

________________________________________________________

1.Specificity specific non specific

2. Site Brain, neurons,ganglia plasma,liver

t Tissues,myoneural pancreas

junction, RBCs

3. Onset o action Rapidly slowly

4. Regenration in 3 monthes in 3 weeks

2- Catecholamines:

❑ Synthesis:

▪ Tyrosine ➔ Dopa ➔ Dopamine ➔ Noradrenaline ➔ Adrenaline

▪ Catecholamines are stored in chromaffin granules.

❑ Metabolism:

1- Catechol-o-methyltransferase (COMT) converts epinephrine into metanephrine

and norepinephrine into normetanephrine.

2- Monoamine oxidase (MAO) converts metanephrine and normetanephrine into

vanilyl mandelic acid (VMA) which excreted with urine.

NOTES:

▪ Neurotransmitter of parasympathetic: Ach

▪ Neurotransmitter of sympathetic: Adrenaline, Noradrenaline and Dopamine

11

AUTONOMIC RECEPTORSI. Cholinergic receptors:

1- Nicotinic receptors (Central cholinergic receptors )

• Sites of occurrence: These receptors present in the autonomic ganglia, suprarenal medulla and skeletal neuromuscular junction.

a. (NM) receptors : present in the skeletal muscles and are blocked by d- Tubocurarine

b. (NN) receptors: present in the autonomic ganglia are blocked with Hexamethonium.

Types of muscarinic receptors

• M1 neural) in the CNS, ganglia, parietal cells of the stomach responsible for the gastric secretion. Blocked by Pirenzepine (Gastrozepin ) & Telenzepine

• M2:(cardiac) in the heart

• M3:(glandular) in smooth muscles and exocrine glands

• M4 and M5: in certain areas of the brain.

II. Adrenergic receptors

They are classified according to their type and location into:

1. receptors which are classified into:

1- postsynaptic receptors

2- Presynaptic receptors

2.-adrenergic receptors which are classified into:

– 1 Receptors in the heart.

– 2 Receptors: mainly found in the blood vessels of the skeletal muscles, the bronchi and the uterus.

– 3 Receptors: present in adipose tissue.

19

Autonomic Drugs

I. Cholinergic

Drugs

II. Adrenergic

Drugs

A) Peripheral

Cholinergic Drugs

B) Central

Cholinergic Drugs

1- Parasympathomimetics 1- Sympathomimetics

2- Parasympatholytics 2- Sympatholytics

I- Cholinergic Drugs

Cholinergic Agonists

20

▪ Cholinergic drugs are drugs which act on the

cholinergic receptors.

▪ They are classified into 2 main classes:

A) Peripheral Cholinergic Drugs:

They acts on the peripheral cholinergic receptors

(Muscarinic R).

B) Central Cholinergic Drugs:

They acts on the central cholinergic receptors (Nicotinic

R).

A) Peripheral Cholinergic Drugs

21

These are drugs which act on the peripheral cholinergic receptors (Muscarinic R)

which found on Cardiac M., Smooth Ms. & Exocrine glands.

Peripheral Cholinergic Drugs may be:

1- Muscarinic stimulants OR Parasympathomimetics.

2- Muscarinic blockers OR Parasympatholytics.

1- Parasympathomimetics (Cholinomimetics)

• These are drugs which stimulate the muscarinic receptors

➔ i.e stimulate the parasympathetic division.

MOA: Parasympathomimetics acts by 2 mechanisms:

1- Direct receptor activation: by stimulation of the muscarinic receptors.

2- Indirect receptor activation: by inactivation of cholinesterase enzyme leading

to accumulation of Ach.

Parasympathomimetics includes:

22

(1) Choline

esters

(2) Choline

alkaloids

(3) Anticholinesterases

▪ ACh

▪ Methacholine

▪ Carbachol

▪ Bethanechol

▪ Pilocarpine

Reversible

(Short acting)

Irreversible

(Long acting)

▪Physostigmine

(Eserine)

▪Neostigmine

▪Organophosphates

(Diazenon, Parathion,

Malathion, Asuntol)

(1) Choline esters

24

a- Ach:

It is the neurotransmitter of the cholinergic

nerves.

➢Ach acts on the Muscarinic and Nicotinic

receptors SO it has 2 types of action:

1- Muscarinic action.

2- Nicotinic action.

25

Muscarinic Action Nicotinic Action

▪ It is the action of Ach on the

Muscarinic receptors which present

on Cardiac M, smooth Ms and

Exocrine glands.

▪ It is the action of Ach on the Nicotinic

receptors which present on skeletal M,

Autonomic ganglia and adrenal medulla.

▪ The action of Ach on these

receptors is similar to that produced

by Muscarine which produces

stimulation in small or large dose.

▪ The action of Ach on these receptors is

similar to that produced by Nicotine which

produce stimulation in small dose and

inhibition in large dose

▪ This action can be blocked by

atropine.

▪ This action can be blocked on skeletal M

by gallamine & tubocurarine.

Muscarinic action:

26

❑ Eye:

➢ Ach binds to the muscarinic receptors in the circular muscle of the iris

(constrictor pupillae) producing pupillary constriction (miosis).

➢ In addition, it opens the angle of Schlem SO improves the drainage of aqueous

humor and reduces the intra-ocular pressure (IOP).

➢ It also increases the lacrimal secretions.

Muscarinic action:

27

❑ Respiratory System:

➢ Ach binds to the muscarinic receptors in the smooth muscle of the bronchioles

producing constriction of bronchioles (bronchial asthma).

o It also increases the bronchial secretions.

❑GIT:

➢ Ach binds to the muscarinic receptors in the smooth muscle of stomach and

intestine so increases the contractions of stomach (may lead to vomiting) and

increases the motility of the intestinal muscle (may lead to spasms or

diarrhea).

o It also increases the salivary, gastric and intestinal secretions.

❑CVS:

Heart:

Ach binds to the muscarinic receptors in:

• SA node: so decreases the heart rate (bradycardia).

• AV node: so decreases conduction (block).

• Atria & Ventricles: so decreases the contractility

Blood vessels:

Ach binds to the muscarinic receptors in the smooth muscle of blood vessels so

induces vasodilatation.

Blood pressure:

Ach lowers blood pressure due to:

1- Bradycardia. 2- Vasodilatation.

28

29

❑Urinary System:o Ach increases the contraction of smooth muscle of urinary bladder and relaxes the

sphincter.

❑ Skin: Ach increases sweating

Uses:

• Ach is not used clinically because:

o When given orally, it is rapidly hydrolyzed in the digestive tract

o When given by injections, it is rapidly metabolized by cholinesterase enzyme.

b- Methacholine:

It is a synthetic drug, destructed slowly by cholinesterase enzyme.

➔ So produce a prolonged duration of action than Ach.

Actions:

1- Muscarinic: ……………………

➔ It has a selective action on Cardiac M.

Uses:

Used for Tachycardia.

c- Carbachol:

30

It is a synthetic drug, destructed slowly by cholinesterase

enzyme.

➔ So produce a prolonged duration of action than Ach.

Actions:

1- Muscarinic:……………………

It has a selective action on smooth muscle of GIT and urinary

bladder.

2- Nicotinic.

Uses:

➢ Paralytic ileus

➢ Non-obstructive urinary retention like that resulting from

general anesthetics.

d- Bethanechol:

31

It is a synthetic drug, hydrolyzed slowly by cholinesterase

enzyme.

➔ So produce a long duration of action than Ach.

Actions:

1- Muscarinic:……………………

It has a selective action on smooth M of GIT and urinary

bladder.

Uses:

➢ Paralytic ileus.

➢ Non-obstructive urinary retention like that resulting from

general anesthetics.

(2) Choline alkaloids

CHOLINOMIMETIC ALKALOIDS

Pilocarpine:

➢ It is a naturally occurring alkaloid obtained from jaborandi leaves.

➢ It is readily absorbed from the GIT.

➢ Not inactivated by cholinesterase enzyme.

➔ So produce a prolonged duration of action than Ach.

Action:

Muscarinic………………………

It has a selective action on eye pupil & gland secretions.

Uses:

1- In the form of eye drops for Glaucoma (miosis reduces IOP).

2- It is a powerful diaphoretic, so used to remove edema.

3- It is a powerful sialagogue, so used in dryness of mouth following use of

atropine.

32

(3) Anticholinesterases:

These are drugs which inhibit the cholinesterase enzyme so prolong the

muscarinic and nicotinic actions of Ach.

Classes of anticholinesterases:

1- Reversible (Short acting):

➢ Physostigmine (Eserine)

➢ Neostigmine

2- Irreversible (Long acting):

➢ Organophosphates (Diazenon, Parathion, Malathion, Asuntol)

33

34

1- Reversible

(Short acting)

2- Irreversible

(Long acting)

Binding to

cholinesterase enz

Loose Firm

Duration of action Short Long

Examples • Physostigmine (Eserine)

• Neostigmine

Organophosphates (Diazenon,

Parathion, Malathion, Asuntol)

MOA

They react with

cholinesterase enzyme

forming carbamylated

enzyme which hydrolysed

slowly, so Ach released,

accumulate and prolong its

action.

They react with cholinesterase

enzyme forming

phosphorylated enzyme which

not hydrolysed, so Ach

released, accumulate and

prolong its action.

35

1- Reversible anticholinesterases (Short acting):Physostigmine Neostigmine

Source Natural alkaloid obtained from the

seeds of Calabar beans.

Synthetic

Oral route Complete absorption from GIT Incomplete

Distribution Pass through BBB Cannot pass

Actions

1- Muscarinic: ……………..

Mainly eye

2- Nicotinic:

Muscle twitches.

3- CNS stimulation.

1- Muscarinic: ……………….

Mainly GIT, Urinary tract

2- Nicotinic:

.aMuscle twitches.

.bDirect skeletal M stimulation

a + b = Powerful M stimulation

Uses

1- In the form of eye drops for

Glaucoma (miosis reduces IOP).

2- Atropine poisoning:

It antagonizes the actions of

Atropine.

1- Paralytic ileus

2- Post operative urine retention.

3- Myasthenia gravis (given with

atropine to block the muscarinic

action)

2- Irreversible anticholinesterases (Long acting):

Ex: Organophosphates (Diazenon, Parathion, Malathion, Asuntol)

• They are highly soluble in lipids, so:

➔ Absorbed from all sites, even the intact skin.

➔ Distributed to all tissues, even CNS (pass through BBB).

Actions: 1- Muscarinic. 2- Nicotinic.

Uses: Used as insecticide.

Toxicity of organophosphates:

Symptoms:

1- Muscarinic symptoms:

▪ Lacrimation, salivation, sweating.

▪ Miosis, bronchial asthma, vomiting, diarrhea, colic, urination.

2- Nicotinic symptoms: Skeletal muscle twitches followed by paralysis.

36

Treatment:

1- Atropine:

➢ Given to block the muscarinic receptors, so antagonize the action of ACh on the

muscarinic receptors in cardiac M, smooth m and exocrine glands.

➢ Given IV or IM (2 mg) every 5-10 min till:

➔ Dilatation of eye pupil. ➔ Dryness of mouth.

2- Cholinestrase reactivators (Oximes):

➢ They are effective only in early stages (within 12 h).

➢ Oximes react with the phosphorylated enzyme to free the active unit.

➢ Example of oximes: Pralidoxime (PAM).

3- Anticonvulsants as Diazepam (IV).

4- Other measures:

➔ Stomach wash (gastric lavage) ➔ Skin wash

37

Contraindications of parasympathomimetics

1- Bronchial asthma

2- Peptic Ulcer

3- Angina Pectoris → (Hypotension → reduction of coronary

blood flow).

38

2- Parasympatholytics

Antimuscarinic• These are drugs which prevent the access of Ach to the muscarinic receptors, so

inhibit the muscarinic actions of Ach.

MOA:

They act by blocking the muscarinic receptors on cardiac M, smooth Ms and

exocrine glands.

Parasympatholytics include:

(1) Natural alkaloids

• Atropine, Hyoscine

(2) Atropine substitutes

39

(1) Natural alkaloids

a- Atropine: It is an alkaloid obtained from Atropa bella-dona.

Actions:

❑ Eye:

➢ Atropine blocks the muscarinic receptors in the circular muscle of the iris

(constrictor pupillae) producing pupillary dilatation (myderiasis).

➢ Duration of action of atropine on the eye ; 7-10 days

➢ In addition, it increases the intra-ocular pressure (IOP).

➢ It also reduces the lacrimal secretions.

❑ Respiratory:

➢ It relaxes the smooth M of bronchi (bronchodilatation).

➢ Reduce bronchial secretion.

40

❑ GIT:

➢ It relaxes the smooth M of stomach (anti-emetic) and intestine (antispasmodic,

spasmolytic) and constrict sphincters.

➢ Reduce salivary secretion (dry mouth).

➢ Reduce GI secretions (antisecretory) leading to constipation.

❑ CVS: It increase the heart rate (Tachycardia).

❑ Urinary:

➢ It relaxes the smooth M and constrict the sphincter of urinary bladder leading to

urine retention.

❑ Sweat glands: Reduce sweating.

41

Uses:

1- Used locally on the eye for eye examination (Cyclopentolate andTropicamide as eye drops are better derivatives ).

2- Bronchial asthma (Ipratropium by inhalation is a betterderivative)

3- Pre-anesthetic medication before volatile anesthesia.

➔ Reduce respiratory tract secretions, so avoid suffocation.

4- Vomiting, Spasmodic colic, diarrhea.

5- Used as antidote in case of toxicity by organophosphates &digitalis.

6-Hyperhidrosis (excessive sweating)

42

2. Action On The Central Nervous System:

• Stimulant Actions:

• Stimulation of the respiratory center causingrespiratory stimulation

• High doses stimulate the Cerebral cortex leading torestlessness, hallucinations and delirium. This centralexcitation is followed by depression

• Depressant Actions:

• Decreased tremors and rigidity, so used in parkinsonism

• Inhibits vomiting centers : Antiemetic action

3. Cardiovascular system:• Heart: Small doses produce bradycardia due to blockade of M1

receptors on the inhibitory prejunctional neurons thus increaseacetylcholine release.

• Large doses produce tachycardia due to blocking of the M2

receptors

Atropine poisoning (Adverse Effects)

after frequent application, but it rarely produces death

because it has a wide safety margin.

symptoms of poisoning include mouth dryness, dilation of

the eye pupil, tachycardia, constipation, urine retention,

flushing , hyperthermia and muscular in coordination.

• Treatment of atropine poisoning:

– Administration of Physostigmine slowly I.V. to antagonize both

central and peripheral effects of atropine.

– Neostigmine can be used to antagonize peripheral actions only.

– Respiratory stimulant, CNS stimulant and cold fomentation.

•Synthetic Atropine substitutesThere are five chief classes of synthetic atropinesubstitutes:1-Mydriatic Atropine substitutes They have shorterduration of action. Homatropine•Eucatropine2- Antisecretory – Antispasmodic Atropine substitutes

- Propantheline - Hyoscine butylbromideThey are used for treatment of spasms of the GIT, bileduct and urinary tract•Pirenzepine & telenzepine: these drugs are selective M1

receptor antagonists, used in the treatment of peptic ulcer( decrease HCl)

3. Antiparkinsonism – atropine substitutes

- Trihexphenidyl - Biperiden

4. Atropine substitutes used in bronchial asthma

• Ipratropium

• It has more selective bronchodilators effectwith a lesser action on sputum viscosity, itcan be used in combination with 2 agonists

• Ipratropium has no significant CNS effects .

THANK YOU