cholinergic transmission , acetycholine action and its receptor antagonist , succinycholine , neuro muscular blockade

1. DR . TUSHAR S DHAWALE
ASSO. PROFESSOR
DEP. OF PHARMACOLOGY
PRATIBHA MEDICAL COLLEGE
TRICHUR
“Cholinergic
transmission and drugs
“
25/02/15

2. Acetycholine
It is also the preganglionic neurotransmitter for
both the sympathetic and parasympathetic
nervous system.
Acetylcholine (ACh) is the postganglionic
neurotransmitter in the parasympathetic nervous
system
.

3. Cholinergic fibre means
All such fibre that release the acetycholine as
the neuro transmitter
1 all the somatic motor neuron to the skeletal
muscle
2 all preganglionic sympathetic and
parasympathetic fibre
3All the parasympathetic fibre to the neuro-
effectors junction
4 post ganglionic sympathetic fibre to sweat
gland

4. Para sympathetic nervous
system

5. Distribution of parasympathetic
nervous system

6. Comparison of the pre and post
ganglionic fibre

7. Acetycholine synthesis

8. Muscarinic receptor
Features M1 M2 M3
Location Autonomic and enteric
ganglia
Paracrine cell gastric gland
CNS
SA node , AV node ,
presynaptic terminal
Exocrine gland ,
smooth muscle ,
vascular endothelium
Function Gastric acid
Cns excitation
Gi motility
Dercrase rate of impulse
generation
Velocity of conduction
Bradycardia
contractility
Increase in exocrine
secretion , smooth
muscle contraction
Mechanism ip3 , DAG ,
increase in ca 2+ conc.
Inhibition of adenyl cyclase
, decrease CAMP opening
of k+ channel
Same as the M1
receptor
Agonist Oxotremorine Methacholine Bethacholine
Antagonist Pirenzepine
Telenzepine
Triptramine Tolterodine
Darifenacin

9. Eyes: contraction of ciliary muscle and smooth muscle of the
iris sphincter (miosis)
Heart : Bradycardia (possibly preceded by tachycardia),
decrease force of conytraction
Blood vessel : vasodilation ( EDRF)
Lung : bronchoconstriction and increase secretion
Pancreas : increased pancreatic juice
Urinary bladder : voiding of urine ( detrusor and spincter)
Sweat gland : increased sweating
Acetylcholine – muscarinic
action

10. Acetycholine : nicotinic action
Neuro-muscular Junction: nicotinic Nm receptor
Stimulation lead to muscle contraction
Sympathetic And P. Sympathetic Ganglia: Nn
receptor
Release of NE and Ach
Adrenal Medulla : Nn receptor
Release of adrenaline

11. Location of nicotinic receptor
In sympathetic and parasympathetic ganglia
 in the adrenal medulla
 in the neuromuscular junction of the skeletal
muscle
 in the central nervous system.

12. Cholimimetic drugs
Directly acting ( acetylcholine is prototype)
Synthetic Natural alkaloid Miscellaneous
Methacholine Muscarine Tremorine
Bethanchol Nicotine Oxy tremorine
Carbachol Pilocarpine Cevimeline
Arecoline

13. Directly acting cholimimetic drug
(synthetic )
Synthetic cholinester
Bethanchol
Long acting drug
Resistant to true and pseudo cholinesterase
Indication
Atony of bladder Urinary retention
Git atony
Xerostomia

14. Bethanchol
Side effect
Cns stimulation, Miosis
Spasm of accomodation for distant vision
Abdominal cramps
Flushing, Salivation
Contraindication
*Hyperthyroidism ,Asthma
Peptic ulcer ,My . Infarction
Preparation : urotonin , bethacol 25 mg tab.

15. Directly acting cholimimetics

16. Pilocarpine
Natural alkaloid
Tertiary amine in nature
Dominat m3 action
Mild nicotinic action
Indication
1 Open glaucoma 0.5-4 % solution
2 Xerostomia 5- 10 mg
3 stimuation of salivary secretion in post-op. Patient

17. Miscellaneous cholimimetic drug
Cevimiline
Indication
Xerostomia in chemotherapy patient
Sjogren syndrome
Tremorine & oxytremorine
To produce parkinsonism in animal

18. Indirectly acting cholimimetic
drugs
Mechanism
They prevent the degradation/ hydrolysis of the
acetylcholine and analogue
Further divided into
Reversible Irreversible
Cholimimetic cholimimetic

19. Indirectly acting cholimimetic
drug
Reversible Irreversible
Natural Quaternary
compound
Organophosphate Carbamate
Physiostigmi
ne
Edophronium Isoflurophate Propoxur
Neostigmine Ecothiophate
Pyridostigmin
e
Parathion
Demercarium Malathion
Rivastgmine Diazinon
ambernonium Paraxon

20. Pathology : myashtenia gravis
• Autoimmune disorder
• Incidence- 1 in 10000
• Auto antibodies against the ach receptor
Response failed to incite contraction

21. Myashtenia Gravis Sign & Symptoms

22. Tensilon test
A Diagnostic Test For Myasthenis Gravis
Drug Used- Edophronium chloride
Dose – Given 0.3 Mg
Ultra Short Duration Of Action
it differentiate between the cholinergic crisis and
the myashtenic crisis
Cause worsening of symptoms in cholinergic crisis

23. Myasthenia Gravis Treatment
Pyridostigmine – 60 mg tds
Neostigmine - 15-30 mg per day orally
0.5 -2.5 mg IM/SC
prolonged treatment with the AChE drug,
Myasthenia cholinergic
Crisis crisis
(Therapeutic (over treatment)
Failure )
Treatment of toxic effects
Atropine 0.5 mg /sc
* Tolerance developed to muscarinic S/E effects

24. Myasthenia gravis treatment

25. Algorithm for M. Gravis
treatment

26. Cholimimetic drugs
Irreversible Anticholinestarases
Organophoshates carbamate
Isoflurophate propxur
Ecothiophate
Parathion
Malathion

27. Irreversible AchE blocker
phosphorylate the esteric site of the
AChE by forming the coavalent bond
The AChe become inactive
Resistant to hydrolysis
Ectothipate have additional quaternary nitrogen
That bind with the anionic site of the enzyme
Hence slow hydrolysis can be still possible with
ecothiopate binding

28. After the phosphorylation of the enzyme
undergoes
Molecular arrangement
, become completely resistant to the hydolysis
Loss of one alkyl or alkoxy group .
Organophosphates having di- isopropyl group (
DFP)
Are more prone to ageing than parathion (
diethyl)
Irreversible AchE blocker

29. Organo phosphorus poisoning
Agent causing
• Malathion
• Parathion
• Ectothiopate
• Diazion
• Diflos ( DFP)
• Carbate derivatives
• Propoxur and carbaryl

30. organophosphorus poisoning
1)Accidental , occupational hazard
2)Suicide
Treatment option
Atropine ache reactivating drug
To counter the pralidoxime 2- PAM
Antimuscarinic drug

31. Organophosphate poisoning
initially
Atropine in dose of the 2 mg i.v is
administered
Every 15 min till the sign of the atropinisation
appear
pralidoxime in dose of the 1-2 g
Given via iv infusion of over 15-20 min
For reactivation of the enzyme

32. Ache Reactivator
Pralidoxime activate the enzyme by
Binding to the anionic site of the enzyme
the phosphorylated esteric site now attract the
Oxime group of PAM
The phosphate – oxime group seperate out
Leaving the enzyme in the active form
DAM ( diacetyl mono oxime )
Has an advantage since it cross the blood brain
barrier

33. Limitation of the oxime therapy
Shortcoming
 No reactivation after the Ageing
 Not effective in carbamate group insecticide
 PAM and OBIDOXIME do not cross the blood
brain

34. Organophosphate therapeutic indication
Ectothiopate
It is quaternary ammonium compound
Hence does not cross blood brain barrier
Water soluble
0.05-0.25 % solution are used
Topically as miotic and glaucoma
Longer acting 1-2 weeks
Carbaryl
Carbamate derivative
Used topically for the control of the head lice

35. Antimuscarinic drugs
Natural
alkaloids
Semisynthetic
derivatives
Synthetic derivatives
Atropine Homatropine Eucatropine Oxybutinin
Atropine methionitrate Cyclopentolate Telenzepine
Scopolami
ne
Hyoscine Tropicamide Pirenzepine
Ipratropium Dicylomine trihexyphenidyl
Tiotropium Flavoxate propantheline
Glycopyrrolate Clidinium
Tolterodine Valethamate

36. Atropine mechanism of action
Competitive antagonist of the acetylcholine at the
M1 to M5 receptor
Antagonism is reversible
Proposed mechanism blockade of the inhibition of
release of the ip3 m1 and m3
M2 receptor mediated action causing inhibition of
The adenyl cyclase
Antagonism is more pronounce for the
Exogeneolsly administed choline ester

37. Atropine effect
Central nervous system
Central excitation
Restlessness, irritabilty , disorientation ,
Hallucination and delirum
Scopolamine
Low dose
Drem like state, amnesia, drowsiness
Depression of emetic centre
High dose hallucination
Excitment , agitation
Large dose
Stimulation followed by depression

38. Effect of atropine
Salivary gland : dry mouth, difficult swallowing
Gastric: reduces volume secretion & total acidity
Others:
Reduces secretion in nose, mouth, pharynx, bronchi
(viscid)
formation of mucus plug
Decrease sweating

39. Effect of atropine
GI:Reduces tone & motility (antispasmodic)
Biliary tract : weak anti spasmodic
Urinary tract: reduce tone of fundus of bladder &
enhance tone of trigonal sphincter -- uri
retention
Bronchi: relaxes musc of bronchi & bronchioles
Eye: mydriasis (sphincter of iris & ciliary musc) –
paralysis of accomodation or cyclopegia

40. effect of atropine on cvs
 Initially decreases HR – partial agonist of Ach
or stimulation of vagal nuclei
 Followed by tachycardia (↑ by 30-40 bpm) –
blocking of M2 ® in SA node
 Toxic doses: dilatation of cutaneous blood
vessels – atropine flush & hypotension)

41. Atropine p/k
Distribution
Widely distributed
Scopolamine has wide distribution and distributed into
The brain parenchyma as well
Metabolism
By phase 2 reaction in the liver ( conjugation )
Species variation – like rabbit due to inherent active enzyme
the atropine esterase that degrade the atropine rapidly
Excretion via renal route
t1/2 is 3 hrs
Except in eye it is around 72 hrs

42. Atropine p/k
atropine pk properties
Tertiary amine like atropine and hyoscine and scopolamine
Absorbed well from gut and mucous membrane
Drug like scopolamine absorbed from skin also
Quaternary compound like
Poor lipid solubilty and
Poor penetration into the brain

43. ACUTE BELLADONA
POISONING
 Peripheral Muscarinic Blockade
 Dryness Of Mouth, Difficult Swallowing, Thirst
 Tachycardia , Palpitations
 Hyperpyrexia (Inhibition Of Sweating)
 Mydriasis, Blurred Vision, Photophobia
 Difficult Micturation, Retention
 Central Actions
 Excitement, Restlessness
 Motor Incoordination
 Slurring Of Speech, Memory Disturbance
 Confusion, Hallucination, Mania, Delirium
 Coma,

44. Belladona poisoning
management
 Ingestion: gastic lavage
 Physostigmine 1-4mg (children 0.5-1mg) IV (pref.
in CNS symp)
 Neostigmine 2-5mg s.c.
 Repeated at intervals of 1-2hrs
 Other symptomatic mgmt (dark room, tepid
sponging, oxygen, artificial vent, catheterization)

45. ADVERSE EFFECTS
 Dryness of mouth, difficult swallowing
 tachycardia
 Fever
 Constipation
 Blurring of vision, ppts glaucoma (elderly)
 Retention of urine (elderly)
 Local allergy: dermatitis, conjunctivitis, swelling of
eyelids

46. Effect of the atropine
effect of the atropine on the eye
 Passive mydriasis
 Paralysis of accomodation ( cycloplegia )
 Photophobia
 Drynesss of eyes ( sandy eye )

47. Atropine therapeutic application in
the eye
 Testing of the refractive errors
 For othalmoscopic examination
 To break adhesions along with the miotics
Most preffered combination is
Homatropine and pilocarpine

48. Uses of atropine and analogue
Drug indication
Atropine Malathion poisoning
Scopolamine Motion sickness
Benzotropine parkinson’s disease
Trihexyphenidyl Parkinson’s disease
Biperiden Parkinson’s disease
Tropicamide Measurement of refractory
error
Cyclopentolate Ophthalmic examination

49. Uses of atropine and analogue
Drugn Indication
Homatropine To break adhesion iris and
anterior surface of lens
Oxybutyrin In eneures, involuntary
bladder
Glycopyrrolate To reduce the secretion
Pirenzepine and
telenzepine
In control of gastric acid
secretion

50. Skeletal muscle relaxant
Peripheral acting skeletal muscle relaxant
This act peripherally at neuro-muscular
junction .
Act on nicotinic Nm receptor
Divided into –
non depolarising muscle relaxant
( d- tubocurarine is prototype)
depolarising muscle relaxant
( succinycholine )

51. non depolarising muscle
blocker
Long acting – tubocurarine
Mid acting - pancurorium
pipecurorium
atracurirum
cisacurirum
rocurirum
Short acting - mivacurium
rapacurium

52. Non depolaring muscle blocker
Affinity for the Nm receptor
Prevent binding of the ach to this receptor
failure to open the sodium channel
Failure to produce end plate potential
Failure to elicit contraction
Skeletal muscle relaxation occcur
Produce surmountable antagonism

53. p/k property of the non depolarising
mjuscle relaxant
Quaternary ammonium compound
Remain ionised at the physiological ph
Volume of distribution
Smaller volume of distribution
Confined to extracellular fluid
Don to cross bb ( exc. Atracurium )

54. Reversal of neuro- muscular
blockade
1)Neostigmine / pyridostigmine
availability of ach
2)Sugammadex
It is ý – clycodextrin compund
form water soluble complex with the steroidal
n-m blocker
favour movement of steroidal n-m blocker from
n-m junction in plasma , excreted via urine .

55. Succinylcholine
Action on the ganglia
Agonist action the nn receptor
Cause histamine release
Vagal ganglia – bradycardia
sympethetic gangia- tachycardia and
hypertension
Also act on the muscarinic receptor to reduce
b.p
Hence ther net no effect on the blood pressure is
seen

56. Succinycholine
Mechanism of action
Succinycholine
at the nmj it act on the nm receptor lead to
opening of the na channel
Cause depolarisation
Produce repetitive excitation and relaxation
Produce muscle fasciculation . When
acetylcholine bind with it it can not elicit any
response hence an flaccid paralysis ensure

57. Succinylcholine
Pharmacodynamics
Single iv dose
Fasciculation over chest and abdomen
Complete relaxation with in the 1-2 min
Sequence of paralysis
Cheek and abdomenn –
Neck – limb – face- trunk –respiratory paralysis

58. Succinylcholine
Pharmacokinetic
Brief duration of the action
5-10 min
Dose 0.75-1.5 mg/ kg iv
Cause : rapid hydolysis by the plasma pseudo
cholinesterase
Move from motor end plate into the extracellular
fluid

59. Dibucaine No.
dibucaine and local anaesthetic
Reduce activity of the true cholinesterase by 80%
and pseudo cholinesterase by 20 % hence the
dibucaine no. Of less than 80 indicate activity of
the atypical enzyme

60. Succinycholine
Adverse effect
 Muscle soreness
 Malignat hyperthermia
 Masseter muscle rigidity
 Hyperkalemia
 Rise in iop
 Prolonged apnoea
 Incresed intragastric pressure
 Malignat hypertension

61. Succinylcholine
Adverse effect
Hyperkalemia
Efflux of k+ occur during the depolarisation
blockade
Target group –
Burn , spinal injury , uremia
Precipitation of arrythmia ,
Even cardiac arrest

62. Succinylcholine
Malignat hyperthermia
Autosomal dominant condition
calcium channel rynodine calcium channel
On administration of the SCh
Persistent release of the ca2+ from the
sarcoplasmic reticulum
Cause persistent muscle contraction
Incresed heat production
Increased suseptibility following admininstration of
the halothane along with the succinycholine

63. Depolarising v/s non depolarising muscle
blocker

64. Monitoring of neuro-muscular
blockade

65. Therapeutic use of n-m blockers
For brief procedure like
 Endotracheal intubation
 Laryngoscopy
 Bronchoscopy
 Combined with diazepam to prevent the
injury due excess convulsion
 In spastic condition like tetanus , status
epilepticus

66. Difference between the competitive and
depolarisinng muscle blocker
parameter D tubocurarine Succinylcholine
Blockade type Competitive blockade Depolarising blockade
Type of relaxation Flaccid paralysis Fasciculation followed by
paralysis
Neostigmine addition + antagonism Potentiation
Effect of other
neuromuscular blocking
drug
Decreased effect Increases effect
Histamine release ++ release negligible
Serum k+ level No change Hyperkalemia
Pharmocogenetic
variation
nil pesudocholinesterase
Cardiac M2 receptor No effect stimulate (bradycardia )

67. Nicotine
Alkaloid in nature
Stimulate cns
Low dose depolarise N-M junction
High dose paralysis
Stimulation of sympathetic and Para sympathetic
ganglia
Adverse effect
• High incidence of hypertension
• Chronic bronchitis
• Tobacco ambylopia
• Lung cancer

68. Clinical use of nicotine
Nicotine transdermal patch
As an aid to quit smoking

69. Ganglionic blocker
Block the transmission from the pre to post ganglionic
neuron
Block both the sympathetic as well as parasympathetic
ganglia
Inhibition of release of ach and ne
Persistent depolarising blocker
Nicotine , carbachol
Non – depolarising blocker
Trimethapan, hexamethonium, mecamyline
Therapeutic use
Hy. tension in dissecting aneurysm
Hypertensive emergency

70. Thank .... U

71. Nervi erigentes
Terminal ganglia
Vagus nerve lie within
Short post ganglionic fibre
Non mylinated except the ciliary
parasympaathetic post ganglionic fibre r
mylianated

72. Location Of Ach Receptor
Nicotinic receptor
1. Neuromuscular junction
2. All the autonomic ganglia
3. In the brain
Muscarinic receptor
Parasympathetic neuro-effector junction
1. M1 – sympathetic ganglia , gastric parietal cell ,
cerebral cortex(+)
2. M2 – myocardium , smooth muscle (-), presynaptic
nerve terminal
3. M3- glandular and visceral smooth muscle (+)

73. Degradation acetycholine
Acetyl choline is hydrolysed by the acetycholine
esterase
True acetycholineesterase
Cholinergic synaptic cleft
Methacholine
Succinyl choline , butyryl choline
Neuronal membrane
Rbc and placenta

74. Degradation acetycholine
Plasma cholinesterse / pseudo cholineesterase
from in Liver
Location : plasma and Intestine
Hydrolyses benzocholine and butyrylcholine
esters
Genetic variation found

75. Succinycholine
This case have denervated muscle and Nm
receptor show denervated supersensitivity
nasuea and vomitting occur due to rise in intra
gastric pressure