INTRO TO ANS and Parasympathomimetic drugs

Pharmacology.

1. AUTONOMIC
NERVOUS SYSTEM

2. SECOND MESSENGER SYSTEM
ADENYL CYCLASE, IONIC CHANNELS
PHOSPHOTIDYL INOSITOL SYSTEM
NEUROMODULATORS
AMINES -DOPAMINE, 5HT
PEPTIDES -VIP,ENKEPHALINS, EDRF
OTHERS -ADENOSINE, ATP, PG

3. AUTOS :SELF
NOMOS :GOVERNING
ANATOMICAL DIVISIONS
PARASYMPATHETIC
SYMPATHETIC
INNERVATES
SMOOTH MUSCLE , HEART,
BLOOD VESSELS, EXOCRINE GLANDS

4. FUNCTIONSOF ANS
CONTROLS :
CIRCULATION, OXYGEN SUPPLY,
DIGESTION, METABOLISM
MAINTAINS HOMEOSTASIS
SYMPATHETIC : FIGHT OR FLIGHT
PARASYMPATHETIC : REST OR DIGEST
OPPOSING INFLUENCE OF 2 SYSTEMS

5. TRANSMISSION OF IMPULSE IN ANS
CHEMICAL TRANSMISSION
NEURO TRANSMITTERS
1.Acetylcholine
2.Norepinephrine ( Adrenaline )

6. SECOND MESSENGER SYSTEM
1.ADENYL CYCLASE, IONIC CHANNELS
2.PHOSPHOTIDYL INOSITOL SYSTEM
NEUROMODULATORS
1.AMINES -DOPAMINE, 5HT
2.PEPTIDES -VIP,ENKEPHALINS, EDRF
3.OTHERS -ADENOSINE, ATP, PG

7. Neurotransmitter Schematic of ANS

9. Peripheral Nervous System
Somatic
1.Skeletal muscle
2.Within CNS
3.Myelinated
4.Ach only
5.Paralysis & atrophy
6.Voluntry
Autonomic
1.All other organs
2.Outside CNS
3.Pre -gng-myelinated,
Post –gng -nonmye.
4.PSNS-Ach & SNS-NAd
5.Activity maintained, no
atrophy
6.Involuntry

10. Cholinergic transmission
(motor portion of the NS)
ANS
Largely autonomous
( independent )
Concerned with
visceral functions
like
cardiac output
blood flow
Somatic
Under control
Concerned with
consciously
controlled functions
like
posture
movement

11. STEPS INVOLVED IN NEUROHUMORAL
TRANSMISSION
Impulse conduction
Transmitter release
Postsynaptic action of transmitter
Postjunctional response
Transmitter inactivation
Cotransmission

13. Cotransmission

14. NEUROTRANSMITTERS
SYNTHESIS
PRECURSOR, ENZYMES
STORAGE
RELEASE
TRANSPORT TO SYNAPSE
EFFECTOR CELL
TERMINATION OF ACTION
METABOLISM
REUPTAKE

16. Synthesis
1. Mitochondria
Formation of adenyl acetate
2. Axoplasmacetyl kinase
Co A AcetylCoA
Choline Acetylcholine
CoA
(-) Ch.acetyl transferase
Hemicholinium

17. Storage
vesicle
Ach Ach
blocked by
vesimicol
1000 -50000
molecules

18. Release
vesicle synaptic cleft
Ach Ach
(-)
Botu.toxin, alphaBungaro Toxin,excess Mg
++

19. Degradation
Ach Acetic acid + Choline
Acetylcholinesterases ( AchE )
(-)
Anticholinesterases ( Anti ChE )
Ach at synaptic cleft

20. Receptor Classification

21. Response to ‘R’ stimulation
MR
1.Excitatory / inhibitory
2.↑ cGMP or ↑↓cAMP
3.G-protein coupled ‘R’s
4.May / may not involve ion
channels
5.Slow response
6.Agonists always stimulate
‘R’s
NR
1.Always excitatory
2.Conformational change in
protein
3.Ligand gated ‘R’s
4.Channel opening → Na+ influx
/ K+ efflux
5.Rapid response
6.Small dose (+) of R Large dose
(-) of R (Depolerising
blockade)

22. Muscarinic receptors
Sir Henry Dale
Alkaloid muscarine mimicked –
parasympathetic nerve discharge
Mediated by the ‘R’s at the effector cells & not
ganglia
Effect of Ach-referred to as
parasympathomimetic effects mediated by
muscarinic receptors

23. M
1
ANS GANGLIA ( EPSP )
GASTRIC GLANDS ( acid secretion )
IP3 / DAG / ↑ cAMPGq
Antagonist : Pirenzipine
M
2
HEART DEPRESSANT
K
+
CHANNEL OPENING -↓CAMP
M
3VISCERAL Smooth Muscle ( CONTRACTION )
VASCULAR S.M.–‘NO’ RELEASE-VASODILATATION
IP3 / DAG -↑ Ca
++
-Gq
↓ NT RELEASE( PRESYNAPTIC )

24. M
4
BASAL FORE BRAIN
STRIATUM
(-) Ca ++ channel-G i
M
5
SUBSTANTIA NIGRA
IP3 / DAG -↑ Ca
++
-G q
Ach & muscarine (+) all subtypes
ATROPINE blocks all subtypes

25. Nicotinic Receptors
Activated by nicotine, blocked by tubocurarine
Two subtypes
N N& N M receptors
NM
Skeletal muscle end plates
Mediate skeletal muscle contraction
NN
Ganglion cells, adrenalmedullary cells, spinal cord
Constitute the primary pathway of transmission in
ganglia

26. Cholinimimetics
Direct Indirect
Cholinergic agonists Anticholinesterases
Esters: Acetylcholine Carbachol,
MethacholineBethanechol
Alkaloids: Muscarine, Pilocarpine
Nicotine

30. Pharmcological actions
MR
1. Smooth muscle
2. Cardiac muscle
3. Glands( gastric & exocrine )
NR
1. Ganglia
2. NMJ

31. Eye
Sphinctor pupillae : miosis
USE :glaucoma
Ciliary muscle
eye fixed for near vision
ADR : Spasm of
accommodation

32. GIT
Motility ↑ ↑ ↑ sed
Sphinctersrelaxed
defecation
use : in paralytic ileus
Acid Secretion↑ ↑ ↑sed
ADR : peptic ulcer

33. Urinary bladder
Detrusorcontraction
Trigone & sphincterrelaxation
Use:in urinary retention
ADR:micturition
Bronchii
Bronchial muscle : Contraction
Bronchial glands: ↑ secretion
ADR :Pptn. of Asthma

34. Blood vessels
Arteriesdilatation
Veins dilatation
Heart
S.A. node (-)chronotropy
Atria (-)inotropy
AV node (-)dromotropy
Ventricle (-)no marked effect
USE :PSVT

35. CNS
NR & MR
Excitation followed depression
USE:antimuscarinic poisoning
Autonomic ganglia
CVS: sympathetic excess
GIT & UT: cholinergic excess
NMJ
Skeletal muscle contraction
USE: in myasthenia gravis

36. Adverse Effects
1.Miosis & spasm of accommodation
2.Diarrhea
3.Urinary urgency
4.Excessive salivation & sweating
5.Bronchospasm
6.Nausea

37. 1.Not destroyed by ChE
M, P, B, C
2.CVS ADR Least With
B , less with C & P
3.GIT & UB
Equipotent : C, B, M & P
Less : Mch & Ach
4.Anta. by Atropine: least with C
5.No nicotinic activity: M, P & B

38. Pilocarpine
P. jaborandi, P. microphyllus
Use :acute & narrow angle glaucoma
1.Gel 4% ODat bed time
2.Oculosert:7days
elipticallyshaped, reservoir for P. enclosed within
copolymer layer
3.Drops:0.5 to 4% 4 –8 hr
Advantage :
No stinging sensation, no myopia,
improved control of iop

39. Anticholinesterases

40. Anticholinesterases
Inhibit ChEs→protect Ach from hydrolysis
→ Potentiate Ach action
Location of the enzyme
Cholinergic neurones : dendrites, axon, etc.
Other tissues:vicinity of cholinergic synapses
Motor end plate : localised at the surface and
infoldingsof post junctional membranes

41. Mechanism of action
AChE is the primary target of these drugs
Butyrylcholinesterase is also inhibited
Ach binds to active site of the Enz. –hydrolyzed
All the AChEs inhibit AChE & ↑ conc of Ach in
the synaptic cleft
Molecular details of interaction vary
according to the chemical subgroup

42. Classification
Reversible Irreversible
Carbamates Carbamates OrganoPO
4
Eye Insecticides Eye
Physostigmine Carbaryl (baygon) Echothiopate
Myasthenia Insecticides
Neostigmine Tik-20
Pyridostigmine Parathion
Edrophonium Malathion
Alzheimer Nerve gas
Rivastigmine Sarin
Donepezil Soman
Tacrine Tabun

43. EDROPHONIUM CARBAMATES ORG.PO4
+ Ach -
N R
- +
Anionic site Esteratic site
Ach E
Role of drugs that bind with the Enzyme ?

44. MECHANISM
very fast
1. Ach + E Acetylated E Free E
milli sec
slow
2. Carbamate + E carbamylated E Free E
4-8 h
3. Org. PO4 + E Unstable Phosphorylated E
min to hrs
Extremely slow
stable phosphorylated E Free E
> 100 h

45. Pharmacological actions
&
ADR Profile
Similar to that of but not
identicaldirectly acting agents

46. Pharmacological actions
CVS
Muscarinic action :bradycardia & hypotension
Ganglionic stimulation:increase in heart rate & BP
Skeletal muscles
ACh is not destroyed, rebinds to the same
receptor
Diffuses to act on neighboring receptors
Causes twitching and fasciculations
Higher doses cause persistent depolarization
of end plates -Weakness & paralysis

47. Lipid soluble agents
Marked
Muscarinic, ganglionic & CNSeffects
Good
CNS entry
Oral absorption
Corneal penetration
Physostigmine & Organophosphates
except echothiophate

48. Lipid insoluble agents
Quaternary ammonium carbamates
Marked (++)
Gnglionic & Ske.muscle effects
Less
Muscarinic effects
Poor
Oral absorption ; CNS entry ;
Penetration of cornea
Neostigmine: stimulates N
Mdirectly

49. Edrophonium
consists of quaternary alcohols
Binds electrostatically & by hydrogen
bonds to the active site
Prevents access of Ach
Enzyme –inhibitor complex does not
involve a covalent bond
Short lived –2 to 10 mins

50. Carbamate esters
Neostigmine
Undergo hydrolysis similar to Ach
The covalent bond of the carbomylated
enzyme is resistant to hydrolysis
This step is prolonged –30 mins to 6
hours

51. Organophosphates
Undergo binding & hydrolysis by the enzyme
Resulting in a phosphorylated active site
Forms stable covalent phosphorous –Enz. Bond
Hydrolyzes in water at a slow rate
Phosphorylated Enz. complex undergoes aging
The rate of aging varies with the
organophosphate compound
Pralidoxime –splits the phosphorous –enzyme
bond before aging

52. USES
Application as toxic agents
1.Agricultural insecticides
2.Potential chemical warfare –nerve gases
Application as therapeutic agents
1.Glaucoma
2.Alzheimer’s disease
3.Myasthenia gravis
4.Belladona Poisoning
5.Cobra bite
6.Post operative decurerization

53. 1.Glaucoma
Disease characterized by raised intraocular
pressure
2 types –open angle and angle closure
Open angle or chronic simple glaucoma
Genetically predisposed degenerative disease
Affects the patency of the trabecular
meshwork
The intraocular tension rises progressively

54. Treatment of open angle glaucoma
Topical βblockers( First choice drugs )
Blocks the βR present in the ciliary epithelium
Timolol ,Betaxolol, Levobunolol
Miotics
They increase the tone of the ciliary muscle &
sphincter pupillae
Improve the alignment of the trabaculae
Outflow is facilitated –fall in i.o.t
Pilocarpine –prefered miotic
Physostigmine –to supplement pilocarpine

55. αadrenergic agonists
Constrict ciliary vessels and reduce
aqueous secretion –α1
Reduce aqueous secretion –α2 located on
ciliary epithelium
Dipivefrine
Prodrug of Adr, penetrates the cornea
Hydrolysed by esterases into Adr
Longer & more consistent action

56. Carbonic anhydrase inhibitors
Acetazolamide
Oral treatment reduces aqueous formation
Used to supplement βblockers
Prostaglandins
Act by increasing uveoscleral out flow
Increase the permeability of the tissues in
ciliary muscle
Latanoprost

57. Treatment of Angle closure glaucoma
Occurs in individuals with a narrow iridocorneal
angle
Shallow anterior chamber
Attack is precipitated by mydriasis
Nearly always a medical emergency
Drugs are useful in control of acute attacks
Long term –surgical
Peripheral iridectomy

58. 2. Myasthenia gravis
Neuromuscular disease characterized by
weakness & fatigability
Autoimmune disorder
Antibodies are directed to nicotinic ‘R’s
Reduction in the number of nicotinic ‘R’s
Structural damage to the neuromuscular
junction

59. Neostigmine & Pyridostigmine–improves
muscle contraction
Prednisolone –inhibits production of
antibodies & increase synthesis of
nicotinic receptors
Azathioprine –inhibits antibody synthesis
Plasmapheresis –to remove the
antibodies

60. 3. Postoperative decurarization–
neostigmine & atropine
4. Cobra bite –curare like neurotoxin
Neostigmine & atropineare used to
reverse respiratory paralysis
5. Postoperative paralytic ileus–neostigmine
6. Belladona poisoning–physostigmine
7. Alzeimer’s disease –tacrine, donepezil
rivastigmine

61. Anticholinesterase poisoning
Easily available agricultural & household insecticide
Accidental, suicidal & homicidal poisoning common
Muscarinic,central & nicotinic effects –
depolarizing neuromuscular blockade
Treatment
Decontamination –removal of clothes & washing
MaintainABC
Convulsions –diazepam
Specific antidotes –atropine & ChE reactivators

62. Atropine –2mg IV repeated every 10 mins
till pupils dilate
Maintenance doses may be required for 1
to 2 weeks
Cholinesterase reactivators
Pralidoxime
Attaches to the anionic site of the enzyme
which remains unoccupied
Ineffective in carbamate AChEs poisoning
–anionic site is not free