2. Nervous system
• Central nervous system (CNS)
• Peripheral nervous system
1. autonomic nervous system, which includes the enteric nervous
system
2. somatic efferent nerves, innervating skeletal muscle
3. somatic and visceral afferent nerves
3. Somatic Autonomic
Organ supplied Skeletal muscle All other organs
Distal most synapse Within CNS Outside CNS
Peripheral plexus Absent Present
Efferent transmitter Acetylcholine Ach, NA
Nerve fibres Myelinated Pre ganglionic-
myelinated
Post gang- non-
myelinated
Effect of nerve
section on
organsupplied
Paralysis and
atrophy
No atrophy
4. ANATOMY OF THE AUTONOMIC NERVOUS
SYSTEM
(1) The sympathetic or thoracolumbar outflow
(2) The parasympathetic or craniosacral outflow
5. Sympathetic Parasympathetic
Origin Thoraco-lumbar(T1-L3) Craniosacral (3,7,9,10;S2-4)
Distribution wide Head, neck and trunk
Ganglia Away from organs On or close to the organ
Post gangl fibre long short
Transmitter NA (major) Ach( minor) Ach
Stability of
transmitter
NA stable, diffuses for wide
action
Ach-rapidly destroyed locally
Important
function
Tackling stress and
emergency
“fight or flight” responses
Assimilation of food,
conservation of energy
”rest and digest” responses
6. ENTERIC NERVOUS SYSTEM (ENS)
neurons lying in the intramural plexuses of the gastrointestinal
tract
inputs from sympathetic and parasympathetic systems
can act on its own to control the motor and secretory functions
of the intestine.
12. 2. Transmitter release
AP Release of transmitter stored in prejunctional nerve endings
within synaptic vesicles
Fusion of synaptic and vesicular membranes
Ca 2+ entry exocytosis of all contents
13. RELEASE MODULATED BY
1. Transmitter itself
2. Other agents through receptors located on pre junctional
membrane
NA release (-) by NA (α2),dopamine, adenosine, prostaglandins
Ach release at autonomic sites (-) α2 and muscarinic agonists
14. 3.Transmitter action on post junctional
membrane
Transmitter combines with receptor on post jnl membrane EPSP or
IPSP
EPSP permeability to all cationsNa+ or Ca 2+ influx depolarization
followed by K+ efflux
IPSP permeability to smaller ions, I .e Cl
Cl- influx hyperpolarization
21. Cotransmission
• On stimulation most peripheral and central neurons have been shown
to release more than one active substance
• Purines (ATP, adenosine)
• Peptides ( VIP, NPY, substance P)
• NO, prostaglandins
VIPAch
ATP Ach, NA
Vasc adrenergic nerves NPY
23. Cholinergic Transmission
• All preganglionic nerve endings
• All parasympathetic postganglionic nerves
• Few sympathetic postganglionic nerves
• To the neuromuscular junction
24. Synthesis ,storage and release of ACh
• Transport of Choline into the vesicle
• Synthesis of Acetyl choline from Acetyl CoA & Choline
• Transport of Acetyl choline into the vesicle
25.
26. Botulinum toxin
• Clostridium botulinum
• long-lasting loss of cholinergic transmission
• (BOTOX) or its haemagglutinin complex (DYSPORT)
• blepharospasm, spastic cerebral palsy, strabismus.
27. CHOLINERGIC TRANSMISSION
• Choline transported into the neuron by a Na-choline cotransporter .
the rate-limiting step in acetylcholine synthesis.
• blocked by hemicholiniums.
• Ach is syn in the cytoplasm from acetyl-CoA & choline by choline
acetyltransferase (ChAT).
• transported from the cytoplasm into the vesicles by a vesicle-
associated transporter (VAT)
• This antiporter can be blocked vesamicol.
28. • Vesicles interaction of so-called SNARE proteins on the
vesicle (esp synaptobrevin) & on the inside of the terminal
cell membrane (esp syntaxin and SNAP-25).
• Release from the vesicles AP triggers sufficient influx of
Ca ions via N-type Ca channels
• Ca interacts with the VAMP synaptotagmin & triggers fusion
results in exocytotic expulsion –
• The release process is blocked - botulinum toxin
• Massive release is & depletion – Black widow spider toxin
29. • Ach binds to : postsynaptic/ presynaptic receptors
• Action rapidly terminated, because
acetylcholinesterase cleaves Ach to choline & acetate in
the synaptic cleft
Ach esterase Butyrylcholine esterase
Distrib All cholinergic sites
RBC, Gray matter
Plasma. Liver, int,white
matter
Hydrolysis
Ach
Methacholine
Benzoylcholine
Butyrylcholine
Very fast
Slower than Ach
Not Hydrolysed
Not Hydrolysed
Slow
Not Hydrolysed
Hydrolysed
Hydrolysed
Inhibition Physostigmine OP
Function Term of Ach action Hydrolysis of ingested esters
39. M4
Location CNS(forebrain)
Molecular mechanism Similar to M2
Functional response Inhibit transmitter release
Facilitate dopamine release
Location Substantia nigra
Molecular
mechanism
Similar to M1 & 3
Functional
response
Cerebral vasodilatation
Facilitates DA release :Drug seeking behaviour
M5
40. ACTIONS (Ach)
MUSCARINIC
HEART
• Hyperpolarises SA node -↓ diastolic depolarisation :↓ HR
• AV node - ↓ conduction & RP ↑: ↑PR interval
• Atria - ↓contraction & RP ↓ Non uniform vagal innervation : AF
• Ventricle- ↓ contraction but not marked
41. SMOOTH MUSCLE
• ↑contraction ( M3)
• Tone & peristalisis in GIT ↑, Sphincters relax Abd cramps &
evacuation of bowel
• Ureter peristalsis↑, Detrusor contracts, Bladder trigone &
sphincter relax: Voiding
• Bronchospasm
42. BLOOD VESSELS
• All blood vessels dilated
• Fall in BP & flushing
• EDRF
• Erection – releasing NO & dilating cavernosal vessels : M3
43. GLANDS
• Secretion from all glands↑
• Salivation , Sweating, lacrimation, Gastric & Tracheobronchial
secretion
• Secretion of milk & bile not affected
EYE
• Contraction of circular muscle of iris MIOSIS M3
• Contraction of ciliary muscle Spasm of accomod, ↑outflow
facility ,↓ IOP
44.
45. NICOTINIC
1. AUTONOMIC GANGLIA
• Symp + Para symp stim( only at high doses)
• If higher dose of Ach given after atropine ↑ BP & HR
2. SKELETAL MUSCLES
• Contraction of fibre
3. CNS
• IV – no effect
• Direct inj into brain – complex pattern of stimulation followed by
depression
51. USES
1. EYE -
Penetrates cornea – Miosis, Ciliary muscle contraction, ↓IOP lasting
4 – 8 hrs
• 3rd line drug - POAG
• S/E : Initial stinging sensation,
• Painful spasm of accomodation
• To counteract Mydriatics
• Prev adhesions by altering with mydriatics
2. As SIALOGOGUE
52. MUSCARINE
• Obt from poisonous mushrooms
• Amanita muscaria & Inocybe
• only muscarinic actions
• No therapeutic indications
• Quarternary alkaloid BBB penetration
53. MUSHROOM POISONING
• 3 types of mushroom poisoning
MUSCARINE TYPE
• Inocybe
• Symp appear within an hour of eating
• Reversed by ATROPINE
HALLUCINOGENIC TYPE
PHALLOIDIN TYPE
54. HALLUCINOGENIC TYPE
• Muscimol & other Isoxazole compds A muscaria
• Compds activate amino acid receptors & block muscarinic receptors in
brain – HALLUCINOGENIC
• Manifestation – central
• No specific Rx. Atropine is CI
• Another hallucinogenic – Psilocybe mexicana
• Active principle : PSILOCYBINE - Tryptaminergic
55. PHALLOIDIN TYPE
• PEPTIDE TOXINS
• Found in A phalloides, Galerina
• (-) RNA & protein syn
• Symp start after many hrs & due to damage: GI mucosa , Liver & Kidney
• Rx : Supportive measures
• Thioctic acid : Antidotal effect
56. ARECOLINE
• Betel nut
• Predominant M + slight N
• Prominent CNS effect
• Enhancer of cognitive dementia
61. MECHANISM OF ACTION
The active site contains:
• Aromatic anionic site ( Tryptophan)
• Esteratic site ( Serine, Glutamate, Histidine)
• Carbamylates carbamylate
• OP Phosphorylate
62. A E
The carbamylated enz reacts slowly
The phosphorylated enz reacts extremely slowly
1. Hydrolysis of Ach involves electrostatic attraction
of N⁺ of Ach to aromatic site
2. Nucleophilic attack by serine OH
3. Acetylated enz reacts with water rapidly acetic
acid & choline
63. Carbamates
• Binds to both sites
OP
• Binds to esteratic site
EDROPHONIUM
TACRINE
• Hydrostatic bond
E
A
A
E
E
A
64. PHARMACOLOGICAL ACTIONS
LIPID SOLUBLE – ( Physostigmine & OP)
• Marked Muscarinic & CNS effects
• Stimulate ganglia but action on skeletal mus ↓
LIPID INSOLUBLE – ( Neostigmine & Quarternary)
• Effect on Skeletal mus & stimulate ganglia
• Muscarinic effects ↓
• Dont penetrate CNS & have no central effects
65. GANGLIA
• Local hydrolysis less imp in ganglia
• Inactivation occurs
• Partly by diffusion
• Hydrolysis in plasma
• Anti CHE stimulate ganglia: muscarinic receptors
• High doses Persistent depolarisation Blockade
66. SKELETAL MUSCLE
• Ach released not degraded – Rebinds to same R activates pre
junctional fibresrepititive firing Twitching & Fasciculations
• Force of contraction in partially curarised & myasthenic muscles ↑
• High doses Persistent depolarisation in end plate Blockade of
NM transmission weakness & paralysis
67. CVS
• Effects complex
• M : ↓HR & BP
• Ganglia : ↑HR & BP
OTHER EFFECTS
• Stimulation of smooth mus & glands of GIT
68. PHYSOSTIGMINE NEOSTIGMINE
Natural Alkaloid from
Physostigma
Venenosum
Synthetic
Tertiary amine Quarternary ammonium
Oral abs Good
CNS action +
Penetrates cornea
Oral abs Poor
CNS action (-)
(-)
No DIRECT action on NM +
Prom effect on
autonomic effectors
Skeletal muscle
IMP USE : MIOTIC MYASTHENIA GRAVIS
69. PYRIDOSTIGMINE
• -- Neostigmine
• LESS Potent
• Longer acting
EDROPHONIUM
• Brief dur( 10- 30 min)
• Diagnostic agent in Myasthenia
• Post operative Decurarization
70. RIVASTIGMINE
• Lipophilic
• Relative cerebroselective
• Alzheimers disease
GALANTAMINE
• Natural Alkaloid
• Weak agonistic action on N
• Used in Alzheimers
71. TACRINE
• Lipophilic acridine compd
• Crosses BBB
• Longer duration of action
• ↑Brain Ach- partial improvement in AD
DONEPEZIL
• Centrally acting
• Cognitive & behavioural improvement in AD
72. ECHOTHIOPHATE
• OP + Quarternary structure
• Water soluble, Local irritant ↓
• Long acting
DYFLOS
• Very potent, Long acting
• Used as miotic
• Not used now - Irritant
73. USES
• AS MIOTIC
A) GLAUCOMA
• ↑ tone of ciliary mus ( attached to scleral spur) &
• ↑ tone of Sphincter pupillae pull on & improve
alignment of trabeculae outflow facility is ↑
74. Cont…….
• Pilocarpine : Rapid & short lasting ,
↓vision in dim light, spasm of accomod , Brow pain.
Sys SE : N, D, Sweating & Bronchospasm
• Physostigmine (0.1 %)
• Aphakic glaucoma
B ) TO REVERSE EFFECT OF MYDRIATICS
C ) TO PREVENT FORMATION OF ADHESIONS
75. MYASTHENIA GRAVIS
Anticholinesterases
• Edrophonium, neostigmine, and pyridostigmine
Immunosuppression
• Immediate – IV Ig or plasmapheresis
• Intermediate (1-3 months) – glucocorticoids, cyclosporine.
• Many months (6-12) – azathioprine, cyclosporine.
Thymectomy
76.
77. POST OP PARALYTIC ILEUS / URINARY RETENTION
• Neostigmine(0.5-1mg) s/c
POST OP DECURARIZATION
• Neostigmine(0.5-2 mg) iv preceded by atropine/
glycopyrrolate
COBRA BITE
• Neostigmine + Atropine prev Resp Paralysis
78. Cont……
BELLADONA POISONING
• Physostigmine(0.5-2 mg iv )
ANTI CHOLINERGIC OVERDOSAGE
• TCAD, Phenothiazine, Anti Histamine – Physostigmine.
ALZHEIMERS DISEASE
• Tacrine , Donepezil , Rivastigmine, Galantamine
79. ANTI CHOLINE ESTERASE POISONING
• Local M effects Systemic effects M, N & Central
• Irritation of eye, lacrimation, salivation, sweating , copious
Tracheo-bronchial secretion, miosis, blurring of vision,
breathlessness, colic, invol defecation & urination
81. TREATMENT
• Termination of further exposure to poison – fresh air,
wash the skin & mucous membrane with soap & water,
gastric lavage
• Maintain patent airway, PPV if its failing
• Supportive measures – Maintain BP, Hydration , control
of convculsions with judicious use of diazepam
82. SPECIFIC ANTIDOTES
1. ATROPINE
• Highly effective in counteracting M symp, but higher
doses req to antagonise central effects
• Doesnt reverse peripheral muscle paralysis
• 2 mg IV repeated every 10 min till dryness of mouth
• Maintenance dose may be req for 1- 2 weeks
83. CHOLINE ESTERASE REACTIVATORS
• OXIMES – Restore NM transmission
• Phosphorylated enz reacts very slowly with water
• PRALIDOXIME
• Quarternary N : Attaches to Anionic site – which
remains unoccupied in OP poisoning
85. • Its oxime end reacts with Phosphorous atom attached to
anionic site: Oxime Phosphonate diffuses away leaving
reactivated Ach E
• Not effective in Carbamate poisoning
• Given within 24 hrs B4 aging sets in
• OBIDOXIME ( more potent )
