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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