Nervous system

Peripheral Nervous System

CNSPNS

PNS

• Consists of bundles of sensory and motor neurons

• It relaying information between the central nervous system and muscles or sensory organs.

ANS• Auto: Self; Nomos:Governing

involuntary and maintain homeostasis

• Each autonomic fibres made up of two neurons

• It innervates the heart, smooth muscles and endocrine glands

• ANS controls visceral functions such as circulation, digestion, excretion etc.,

Somatic nervous system

• Voluntary control

• Somatic fibres made up of single motor neuron, connect CNS to skeletal muscle

• It innervates skeletal muscle

• Controls skeletal muscle tone

E

ANS• Afferent (Sensory) Sensory organs to CNS• Efferent (Motor) CNS to effector cells.• Motor responses are auto regulatory in nature.

Regulates unconscious body functions such as:

– All exocrine and some endocrine secretions – heart rate – Blood pressure– Some metabolic functions

Divisions:-

–Sympathetic–Parasympathetic

Arise from

Length of pre / postganglionic fibres

Ganglion

Branching of axons

NT released by preganglionic axons

NT released by post ganglionic axons

Sympathetic Para sympathetic

Arise from thoracolumbar division T1 –L2

craniosacral division III,VII,IX,X, S2-S4 of spinal

Length of postganglionic fibres

long postganglionic fibres short postganglionic fibres

Ganglion Away from effector organ Near or on effector organ

Pre ganglion fibres Myelinated Myelinated

Post ganglion fibres NonMyelinated Myelinated – Ciliary muscleNon myelinated to other

Neurotransmitter released by preganglionic axons

cholinergic Cholinergic

Neurotransmitter released by post ganglionic axons

adrenergic cholinergic

Branching of axons highly branchedInfluences many organs

few branches Localized effect

Anger, Alert,

Aggressive

Flushing of Face

Bronchodilatation

Mydriasis

In. Cardiac output

Inc. Muscle tone

Lipolysis-Energy

Liver GlucogenolysisMore energy prod

Large B vessels dilate to speed up blood flow

Parasympathetic system

• ACh is a first neurotransmitter to be discovered

• It a main NT at the neuromuscular junction

• It is synthesized from two common chemicals

Acetyl Co enzyme A and Choline.

• It is metabolized by Acetylcholine esterase.

• Cholinomimetics, mimic the action of Ach

c/s parasympathomimetics” • All parasympathetic fibres release Ach.

• External Ach is no therapeutic value due to its ultra

short acting.

• Hypothalamus is major controlling centre

N MCholine + Acetate

PyuPDH

Ac Co A

Ach by exocytosis

cyto

plas

m

Hemicholine -

AChE

PDH: Pyruvate dehyrogenase AChE: Acetylcholine esterase

Metabolism:- In synaptic cleft, Ach is rapidly hydrolyzed by acetyl cholinesterase (AChE) enzyme

Two type of cholinesterases.

True And Pseudo cholinesterase

True cholinesterase: • Found in cholinergic neurons, ganglia, RBCs and NMJ.• Highly specific for Ach, other acetylesters (methacholine

and bethanechol)

Pseudo cholinesterase/ butyrylcholinesterase / Plasma choline esterase :

• Synthesized in liver• found in plasma and intestine .• Actions are non specific • It hydrolyzed Ach, benzoylcholine and

butyrylcholine esters• Genetically variation• atypicalcholine esterase slowly hydrolyzesis• Typical choline (Fast acetylates)

N receptors

• The cholinergic receptors are divided into Nicotinic and Muscarinic.

• Nicotinic receptors located – NMJ and Autonomic ganglia– brain (located presynaptically) facilitatory role in

release of other NT like DA and Glutamate.

• N receptor subtypes are muscle type (NM), neuronal type (NN) and central nicotinic receptors.

Nicotinic receptors

NM NN Central N

Location Skeletal NMJ post synaptic

All autonamic ganglia and adrenal medulla

Sensory nerve terminals presynaptically

Function Contraction of Sk. muscle

NE & E from adrenal medulla

Facilitate release of Dopamine, glutamate

Mechanism Ligand gated channel

Ligand gated channel

• N receptors are inotropic receptors• Quaternary structure indicate five sub

units (two alpha, beta, delta and gamma)• Ach binding sites between α and γ

subunit, and α and δ subunit

Mechanism of action

• Ach interacts with nicotinic Ach receptor, it opens Na+ channel and Na+ ions flow into the membrane

• Causes a depolarization, and result in EPP.

• It cause excitatory on skeletal muscle.Response is fast and short lived.

Muscarinic • Parasympathetic neuroeffector junction of all smooth muscle

and glands.• M receptors are linked to G-protein (metabotrophic)• Responses are slower and longer lived• More sterospecific and structure specific then ‘N’

Types of M receptors

• 5 types of “M” receptors

• M1,M3,M5 (Odd) are excitatory effect through IP3,DAG.

• M2,M4 are inhibitory effect cAMP and opening of K+ channels.

• M1,M2,M3 are well characterized.

M1 (Neuronal and gastric)

M2 (Cardiac) M3(Glandular) M4 M5

Distribution

Ganglia, gastric parietal cells, CNS (cortex, hippocampus)

Myocardium, smooth muscle, presynaptic PNS,CNS

Exocrine glands, visceral smooth muscle, vascular endothelium

Neostriatum Substantia nigra

Function

Gastric acid secretion, GI motility, CNS excitation

SA node rate of impulse generationAV node velocity and decrease atrial and ventricular contraction

Exocrine secretions. Smooth muscle contraction (expect urinary, Blood vessels

- -

Mech G protein (Gq), IP3,DAG,depolarization

Gi cAmp, opening of K+ channels

G protein (Gq), IP3,DAG,depolarization

Gi cAmp, opening of K+ channels

G (Gq), IP3,DAG,depolariz

Agonist

Oxotremorine Methacholine Bethanechol - -

Anta gonist

Pirenzepine, Telenzepine

Methoctramine,Tripitramine

4-DAMP, Hexa hydrosiladifenidol

• Ach is more effective with “M” receptors. • “N” receptor activation require larger

doses.

• At high dose it acts on “N” receptors cause release of NE & Epinephrine from adrenal medulla.

M N

Ach- contraction circular muscle of iris- Miosis . (M3)

Contraction of ciliary muscle (M3)

- suspensory ligaments loose- eye accommodated for near vision

MiosisAccommodated for near visionInc. drainage Lacrimal gland (M3) inc. secretion

LENS

Ciliary muscle

Circular muscle

Radial muscle

• Parasympathetic supply only upto

SA node, atria and AV node.• Ventricular myocardium has M receptors

but no innervation.• SA node M2 receptors activation:

– heart rate (-ve chronotrophic)– contractile strength(-ve inotrophic)

• AV node M2 activation:

conduction velocity and

refractory period

RP RP

• Bronchial smooth muscle

mucous gland contain

M3 receptors

Bronchoconstriction

Inc. bronchial secretions

Gastric parietal cells M1- Acid secretion

GIT smooth muscle, sphincters and gastric gland – M3

• GIT smooth muscle- tone, motility • Sphincters – Relaxation• Glands – secretions

Pancreas – Acini cells M3 secretion of pancreatic juice.

Detrusor muscle (M3)- Contraction

Relaxation of sphincter .

Emptying of urinary bladder.

Vascular bed of erectile tissue is dilated,

venous sphincters closed.

Erection of penis.

• Arteries have no parasympathetic, but M receptors.

• Release EDRF, cause vasodilatation.• Exogenous Ach cause fall in BP, it evoke

baroreceptor reflex, result sympathetic discharge at heart.

• Bardycardia initial, after followed by tachycardia.

CENTRAL NERVOUS SYSTEMBrain

PARASYMPATHETIC

Spinalcord

Stimulates salivation VII

Constricts bronchi X

Slows heartbeat X

Stimulates activity

Contracts bladder

Stimulates erectionof sex organs S

Stimulates gallbladder

Gallbladder

Contracts pupil III

Parasympathomimetics

Directly acting Indirectly acting 1. Ach2. Synthetic choline esters Reversible Irreversible

Methacholine CarbamatesCarbachol 1. Natural alkaloids 1.

OrganophosphatesBethanechol

3. Natural alkaloids 2. Quaternary

4.Miscellaneous 2. Carbamates

Acridine Tacrine

• Edrophonium• Neostigmine• Pyridostigmine• Ambenonium• Demecarium• Rivastigmine • Popoxour

• Carbaryl• Tremorine• Oxotremorine

• Muscarine• Nicotine• Pilocarpine• Arecoline

• Physostigmine • Ecothophate• Isoflurophate• Paraoxon• Parathion• Malathion• Diazon

• Methacholine:- Seldom used therapeutically Use to supra ventricular tachycardia but now not

using better drugs available. Muscarinic Mycocardium (3Ms)

• Bethanechol:- (Urocholine) resistant to True/Pseudocholinestrase , t½ long

• Uses:- i) To reverse post operative atony of baldderii) To treat GIT atonyiii) to treat salivary gland malfunctioniv) intra cerebroventricular inj beneficial effect in

Alzheimer's disease

Carbachol:– Totally resistances to true/Pseudo chE– N and M action – Avoided therapeutic use bcoz of Large nicotinic action

Precautions : for all cholinesters– Never give IV

• Sudden rise cardiac collapse

CI:– Bronchial asthma– Peptic ulcers– MI– Hyperthyrodism

Pilocarpine (natural)

• Obtained from the leaves of Pilocrapus microphyllus.

• Tertiary amine cross BBB• Prominent Muscarinic action.• Increases all the secretions .• Have complex effect on CVS, small doses

decreases BP but larger doses have opposite action. (Ganglionic stimulation NN stimulation)

• Penetrates cornea• Promptly causes miosis• Ciliary muscle contracts and IOP reduces. • Uses:

0.5 - 4% eye drops for open angle glaucoma. To counteract mydriatics after refraction testing. To prevent or break adhesions of iris with lens

• A/E: stinging sensations, painful spasms of accomodation.

• Muscarine :source Amantia muscaria

Not used therapeutically

• Arecoiline: Found in Beetel nuts Areca catechu

Muscrinic as well as nicotinic action

Not used therapeutically

Side effects:- result of over stimulation of the parasympathetic system .

• Cardiovascular:– Bradycardia, hypotension, conduction

abnormalities (AV block and cardiac arrest)• CNS:

– Headache, dizziness, convulsions• Gastrointestinal:

– Abdominal cramps, increased secretions, nausea, vomiting

• Respiratory:– Increased bronchial secretions,

bronchospasms

Other:

– Lacrimation, sweating, salivation, loss of binocular accommodation, miosis

Physostigmine

Physostigma venenosum

Physostigmine and NeostigminePhysostigmine Neostigmine

Source Natural alkaloid Synthetic

Chemistry Tertiary amine Quaternary amine

CNS action Present Absent

Oral absorption Good Poor

Applied to eye Cross cornea No

Action on cholino receptors Absent Present

Prominent effect on Autonomic effectors Skeletal muscles (Post operative decurization)Post operative paralytic ileus / urinary retention (1mg SC)

Use Glaucoma Myasthenia gravis

Belladona (Atropine) poision

• Physostigimine specific antidote for atropine

• It cross BBB dec central action and peripheral action

• Poison :- 0.5- 1mg IM dose. • 2mg IV/IM initially and additional dose if

required

Rivastigmine & Tacrine• Lipophilic • Cross BBB• Cerebroselective ChE • Used for Alzheimer’s Disease

Glaucoma

• Glaucoma is an increased intraocular

pressure.

• If persistent it leads to optic nerve damage

result in blindness.

• Glaucoma is caused by impaired drainage

or inc. aqueous humor.

• Out flow of aqueous humor: Produced by ciliary epithelium Posterior chamber

Flow to anterior chamber by passing betn lens and iris

Out through pupil

Leaves anterior chamber by flowing through trabecu-lar- mesh work

Drainage through canal of Schlemm

Episcleral venous plexus

Systemic circulation

LENS

90%

10%

3 Types of glaucoma1.Primary (after trauma)2.secondary (followed by cataract operation)3.congenital.(By birth)

-Primary / secondary glaucoma Physostigmine in combination with pilocarpine used.

-Congenital glaucoma hardly respond to drug therapy, except surgery.

Primary glaucoma is subdivided to 2 types1. Narrow angle 2. Open angle

• Narrow angle (Closed angle, Acute congestive)• Iris physically blocking canal of Schlemm.• It is medical emergency, drugs may control

acute attack but long term surgical (partial iridectomy)

• Wide angle (Open angle, Chronic simple):-

• Angle is remain wide but trabecular meshwork losses potency due to degeneration.

• So outflow of aqueous humor is impeded.

• surgery is not useful.

Cholinomimetics decrease the IOP in both types.

In closed angle:- Pulling the Iris, opening of angle

In open angle : contraction of longitudinal Ciliary muscle inc. drainage

Group Mech Dose

Directly acting Cholinomimetics Pilocarpine

Ciliary muscle contraction, opening of trabecular meshwork, Inc drainage

0.5 - 4% topical 3times a day or ocular inserts

Reversible Anti AChE PhysostigmineDemecuronium

Same 0.25 - 5% topical 2 a day0.25 - 5% topical 2 a week

IrreversibleEcothiophateOnly one drug used clinically

Same 0.05 - 0.25% once in 2weeks0.03% topically

Beta blockers (DOC for Open)

TimololBetaxololLevobunololCarteolol

Dec. aqueous humor by blocking β2 present in ciliary epithelium

0.25% - 0.5% topical 2 a day0.25% - 0.5% topical 2 a day0.25% - 0.5% topical 1 a day1% solution topically

Non seletive α agonistEpinephrineDipivefrine

α1 Bloodα 2 Aqueous secretion 0.5 - 2% topically

0.1%opically 2 or 3 a day

Seletive α2 agonistApraclonidineBrimonidine

Dec formation by α2 agonistPotent ocular hypotensive ≠ BBB no systemic side effects

0.5 -1% topically0.5 -1% topicallyRestricted use for acute IOP

Group Mech Dose

Carbonic anhydrase inhibitors AcetazolamideDorzolamide

Reduce aqueous humor by dec. formation of HCO3 ions in ciliary epithelium

250 – 500mg 3 a day orally 2% soln. 3 a day

Hypertonic solutions ©Manitol (20%)Glycerol (10%)

Reduce IOP intaocular dehydration by osmatic action

IV Infusion

Prostaglandins (O)Latanopost

Facilitate outflow via uveoscleral

Acute glauco

ma

Pilocarpine nitrate 4% eye drops

with physostigmi

ne salicylate1

% Install 2drops every 10min

initially then longer

intervals 2Hrs

Inj. Manit

ol 20% 100ml slow

IV

Acetazolam

ide 500m

g orally 1tab 2 a day

Myasthenia gravis

• Autoimmuno disorder• Occurs 1 in 10,000• It is associated with production of IgG

antibody that binds to Ach receptors at post junctional motor end plate

• Fast moving muscles are affected first

Symptoms–Ptosis–Diplopia–Slurring of speech –Difficulty in swallowing

DiagnosisEdrophonium test: 1-2mg IV

Very shorting anti ChE (5min)

Improve –Myasthenia crisis

Worsen - Cholinergic crisis

R Myasthenia gravis

Tab. Neostigmine 15mg – 6hrly

Or

Tab. Pyridostigmine 60mg – 8hrly

Tab. Prednisolone 20mg 1tab 8hrly

Tab. Atropine 0.5mg OD(to dec M action)

Plasmapheresis-removal antibodies

Thymectomy-Produce antibodies

OrganophosphatesINSECTICIDES• Echothiophate• Isoflurophate• Parathion, Malathion

CHEMICAL WEAPONSChemical warfare agents-nerve gases• Tabun• Serin • Soman

Mechanism of ActionPhosphorylating the activeSite of serine.

Covalent modification

Duration: days

Irreversible action

By the loss of one of the

alkyl group the

phosporylated enzyme may

become resistant to

hydrolysis thus causing

irreversibility.

Uses of AChE

Ecothiophate • Quaternary compound• Water soluble• Don’t cross BBB• Used as miotic and management of

glaucoma (Ophthalmic solution 0.05- 0.25%)• Potent and longer acting • No local irritation

Isofluorophosphate : • oil in character cause local irritation

Effects • Cardiovascular:

Bradycardia, hypotension

• Gastrointestinal: Nausea, vomiting, diarrhea

• Urinary tract:Incontinence, urinary urgency

• Glands: Salivation, lacrimation, sweating

• Eye: Miosis, blurred vision

• Respiratory bronchoconstriction, bronchial secretion

Toxicity of AChE Inhibitors

2. Skeletal Muscle: Fasciculations, weakness, paralysis

3. CNS: Ataxia, confusion, convulsions, coma, paralysis

4. Death:

Respiratory depression due to bronchoconstriction, increased

secretions, paralysis of diaphragm and intercostals muscles

and central respiratory depression

Treatment of AChE Poisoning

Atropine

Reverses muscarinic but not nicotinic

AchE reactivating drugs

Pralidoxime (Pyrindine 2-Aldoxime Methylcholride 2-PAM):

HON=CH

H20

N=CH

Oxime

Oxime Phosphonate complex

R Organo Phosphorus poison

Diacetylmonoxime cross BBB

Thank Q