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Nervous system

Peripheral Nervous System

CNSPNS

Peripheral nervous system

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

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

Anger, Alert, Aggressive Flushing of Face

Bronchodilatation

Mydriasis

In. Cardiac outputInc. Muscle tone

Lipolysis-Energy

Liver GlucogenolysisMore energy prod

Large B vessels dilate to speed up blood flow

Parasympathetic system• ACh is a first neurotransmitter discovered• It is synthesized from two common chemicals Acetyl Co enzyme A and Choline.

• Cholinomimetics, mimic the action of Ach c/s parasympathomimetics”

• External Ach is no therapeutic value due to its ultra short acting.

• Hypothalamus is major controlling centre • It is metabolized by Acetylcholine esterase.

Parasympathetic

Ach release

• Hemicholinium: It acts by blocking choline uptake.

• Vesamicol: It acts by inhibiting active transport of ACh into synaptic vesicle by interfering with VAT

• Botulinum toxin : It acts by inhibiting release of ACh from synaptic vesicle.

• Black widow spider: It acts by inducing massive release and causes depletion of ACh.

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) facilitator 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 NLocation 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 neuro effector junction of all smooth muscle

and glands.• M receptors are linked to G-protein (metabotrophic)• Responses are slower and longer lived• Serpantain receptor(7phosphtidil )

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 3

2

Mechanism -M1,3,5

Mechanism –M2,4

M1 (Neuronal and gastric)

M2 (Cardiac) M3(Glandular) M4 M5

Distribution

Ganglia, Gastric (parietal) , CNS (cortex, hippocampus)

Myocardium, presynaptic CNS

GlandsGIT smooth muscle Bladder BronchusCNS

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

• 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 up to 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

• Bronchial smooth muscle mucous gland contain M3 receptors

Bronchoconstriction Inc. bronchial secretions

Gastric parietal cells M1- Acid secretionGIT smooth muscle, gastric gland – M3

• Sphincters – Relaxation• Glands – secretions

Pancreas – Acini cells M3 secretion of pancreatic juice.

Detrusor muscle (M3)- ContractionRelaxation 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 (M action)

• Uses:- i) To reverse post operative atony of baldderii) To treat GIT atony, inc motility, tone iii) 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) poison

• 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

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 crisisWorsen - Cholinergic crisis

R Myasthenia gravis

Tab. Neostigmine 15mg – 6hrlyOr

Tab. Pyridostigmine 60mg – 8hrlyTab. Prednisolone 20mg 1tab 8hrlyTab. Atropine 0.5mg ODPlasmapheresis-removal antibodiesGlucocorticoids (Prednosolone 10mg /OD)Immunosuppresants (Azathioprine 2.5mg/kg/OD)Thymectomy-Produce antibodies

Glaucoma

• Glaucoma is an increased intraocular

pressure. (>21mm/Hg)

• If persistent it leads to optic nerve damage

result in blindness.

• Glaucoma is caused

• drainage

• aqueous humor production

LENS

90%

10%

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 patency 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 angleIn 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 glaucoma

Pilocarpine nitrate 4% eye drops with physostigmine salicylate1%

Install 2drops every 10min initially then

longer intervals 2Hrs

+ Inj. Manitol 20% 100ml slow IV +

Acetazolamide 500mg orally 1tab 2 a day

Advantage of β Blockers

• No cahnge in pupil size• No myopia• No head ache/brow pain due to persistent

spasmof iris• No fluctuations in iot (occurs with pilocarpine)• Convenient twice/once daily

Open angle B-blockers

Alpha-Blcokrs

PG Latanoprost

CAIAcetazolami

de

OrganophosphatesINSECTICIDES• Echothiophate• Isoflurophate• Parathion, Malathion

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

Mechanism of ActionPhosphorylating the activeSite

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

AtropineReverses muscarinic but not nicotinic

AchE reactivating drugsPralidoxime (Pyrindine 2-Aldoxime Methylcholride 2-PAM):

HON=CH

H20

N=CH

Oxime

Oxime Phosphonate complex

General supportiveRemoval of clothes, washing of contaminated skin,

gastric lavage , artificial respiration,

If convulsions Diazeepam

Pradlidoxime 1-2g Slow IV infusion over 15-30min to reactive and regeneration of AChE

2 mg IV repeated every 10 mins till signs of full atropinization

i.e. dilatation of pupils, tachycardia

R Organo Phosphorus poison

Diacetylmonoxime cross BBB

Thank Q

N MCholine + Acetate

PyuPDH

Ac Co A

Ach by exocytosis

cyto

plasm

Hemicholine -

AChE

PDH: Pyruvate dehyrogenase AChE: Acetylcholine esterase

PNS• Consists of bundles of sensory and motor

neurons• It relaying information between the central

nervous system and muscles or sensory organs.

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