Acetylcholine Neurotransmitter

Neurohumoral transmission in autonomic nervous system
(This slideShare detailed about neurotransmitters - Acetyl
choline).
Synthesis, storage, release, binding, receptors, metabolism and reuptake of acetylcholine.
Step in neurohumoral transmission.
Classification of cholinergic and anticholinergic agents

1. Acetylcholine (Ach)

Presented by A. Gowtham Sashtha 1st M.pharm
Department of pharmacology
K.M College of pharmacy.

2. It is located from the neurons and muscles at the neuromuscular
junction

Also involved in direct neurotransmission in autonamic ganglia.

a chemical message released by nerve cells to send signals to
other cells, such as neurons, muscle cells and gland cells.

Binding with muscarinic and nicotinic receptors
Biosynthesis: choline acetyltransferase enzyme
Metabolism: acetylcholinesterase enzyme

3. Egg: 1 large hard-boiled egg contains 27% of the DV(Daily Value)
Beef liver: 3 ounces (85 grams) contain 65% of the DV
Milk: 1 cup (240 mL) contains 8% of the DV.

Broccoli, boiled: 1/2 cup (78 grams) contains 6% of the DV.

4. @ Synthesis
@ Storage
@ Release
@ Binding
@ Receptors
@ Metabolism
@ Reuptake

>

6. SYNTHESIS

Choline acetyltransferase
Na+
+ ACCOA ¡acetyicoonayme A}

presynaptic vesicle

1. Glucose enters the nerve terminal by passive

transport (facilitated diffusion).

2. Glycolysis occurs in the neuronal cytop!

asm, and

pyru-vate (pyruvic acid) molecules are generated.

3. Pyruvate is transported into the mitochondria, and an

acetyl group derived from pyruvic acid col

mbines with

coenzyme-A present in the mitochondria to form

ace-tylcoenzyme-A, which is transported
cytoplasm.

4, Choline, the precursor for Ach, is active
into the neuronal terminal from the syna
Na+ (sodium) and choline transporters.

back into the

y transported
tic cleft via

5. FINALLY - Acetyl CoA + Choline = Acetylcl

oline

7. LEASE

1. Ach is then transported into vesicles and stored
there.

Presyna 2, It is then released into the synaptic cleft by
exocytosis process

3. Its concentration is very high (about 100 mmol/l),

and from which release occurs by exocytosi triggered
by Ca2+ entry into the nerve terminal

Posts:

8. EPTORS

Release acetylcholine bind with
post synaptic membrane receptors

9. muscarinic Nicotinic
receptor(metabotr: eceptor(ionotropic)

. Neurotransmitter binds
Neurotransmitter |< protein-coupled

receptor

Inside cell

Ka
Q à
G protei lonsZo o opens, ions
activated flow across
Activated G protein subunit membrane for

moves to adjacent ion channel, a longer period
which imposes a brief delay of time

10. BIYPES

Muscarinic receptors are divided into five main subtypes M1, M2, M3, M4, and M5.

M1: CNS
= Gastric parietal cells(Gastric acid secretion)
3 Peripheral neuron

Agonist : Oxotremorine
Antagonist : Pirenzepine, Telenzepine

M2 : Heart Decrease the heart rate)
Vagus stimulators

Agonist : Methacholine
Antagonist : Methoctramine,Tripitramine

11. M3 3 Glandular/smooth muscle.
stimulation of glandular secretion
=> Contraction of visual smooth muscle

Agonist : Bethanechol
Antagonist : Solifenacin,Darifenacin.

M4&M5 : confined to CNS (behaviour changes)

12. Nicotinic receptor are derived into two types Nn, Nm

Nn : Autonomic ganglia,CNS, adrenal medulla and nuero muscular
junction

Agonist: Nicotine
Antagonist : Tubocurarine,

Nm: = Neuromuscular junction

Agonist : Nicotine
Antagonist : Hexamethonium, Trimethaphan

M1,M3,M5 -----------=>Stimulato:
M2,M4 => Inhibi

13. 1.Acetylcholine metabolism in cholinergic nerve
terminals.

2.acetylcholine is rapidly metabolized by
acetylcholinesterase and converted into choline
and acetate

14. MECHANISM OF
ACETYLCHOLINESTERASE

15. of action (Theory)

rs The active region of AChE forms a gorge which contains
an anionic site (near glutamate4) and an esteratic site formed by serine
and histidine.

t= Hydrolysis of ACh involves electrostatic attraction of positively
charged N+ of ACh to the anionic sit.

The acetylated enzymnreacts with water to produce acetic acid
and cholin.

The esteratic site is freed in a fraction of a millisecond.

isthe carbamylated enzyme reacts slowly and the phosphorylated
enzyme (irreversible inhibitors) reacts extremely slowly.

16. Remaining acetylcholine
reuptake at a powerful
hydrolytic enzyme of
acetylcholinesterase (AChE).

“ Hemicholinium also known

as hemicholine, is a drug
which blocks the reuptake of
choline by the high-affinity
choline transporter

17. BRAIN
@ ADRENAL MEDULLA AREA
O GLANDs

@ ORGANS

@ MUSCLES

18. caudate
nucleus

cerebral
cortex

nucleus of
meynert

amygdala

hippocampus

thalamus

brainstem
nuclei

DISTRIBUTION IN BRAIN

overall importance of acetylcholine (ACh)
and its actions for nurses or mental health
providers:

With Alzheimer’s disease, acetylcholine
evels are reduced.

For proper functioning, there must be a
balance between two neurotransmitters,
Dopamine (DA) and ACh.

The reason for mentioning DA is because
BOTH of these neurotransmitters contribute
o the lack of movement and control
(physically and behaviorally),

19. IN OTHER AREA

Autonomic Somatiledical
2 Tube

Sympathetic Parasympathetic

Nicotinic

receptor
Nw

Nicotinic
receptor
Ne

No Ganglia

Ach ®

Nicotinic

Nicotinic
receptor
Na

, mv Fa)
a — cane
oe oe =

Organ Organ

Muscle

20. ransmission of Acetylcholine

Excitatory Ar
transmitter ©) Impulse conduction

Inhibitory
transmitter Release of
transmitter

Depolarization (EPSP)

js Excitation
Hyperpolarization (IPSP)

Inhibition

21. ohumoral Transmission

nduction
permeability and its active extrusion from the
neurone. Stimulationor arrival of an electrical impulse causes
sudden increase in Na+ conductance R depolzation
K+ ions then move out in the direction of their
concentration gradient and repolarization is achieved.tion

Il. Transmitter release:

Nerve impulse promotes fusion of
vesicular and axonal membranes through Ca2 entry which
fluidizes membranes. All contents of
the vesicle (transmitter, enzymes and otherproteins) are extruded
(exocytosis) in junctional cleft.

22. 111. Transmitter action on postjunctional membran :
1)(EPSP) excitatory postsynaptic potential :
Nat or Ca2+ influx (through fast or slow channels)causes depolarization

2)(IPSP) inhibitory postsynaptic potential :
Cl” ions move in (axonal Cl” concentration is lower than its extracellular
concentration) hyperpolarize the membrane .

23. Drug Acting on Neurohumoral Transmission

24. >BOTU OXIN produced by the bacterium clostridium botulinum.

it's prevent the release of the acetylcholine esterase enzymes.

Botulinum toxin used to botulism disease (toxicity of muscarinic and nicotinic
receptors)

ADR:
Respiratory problems,dysphagia, seizure,flu like a syndrome, Muscle
weakness.

THERAPEUTIC USES:
cervical dystonia,tremor, bruxism,stroke,brain injury,spinal cord
injury,cosmetic use hyperkinetic facial lines

25. hyperkinetic facial lines and treatment

26. CLASSIFICATION OF CHOLINERGIC DRUGS

(Cholinomimetic, Parasympathomimetic)

Cholinergic agonists Anticholinesterases

Irreversible

Reversible

Carbachol

| Bethanechol Physostigmine | Tacrine || Carbaryl* Dyflos (DFP)
(Eserine) (Sevin) Echothiophate
Neostigmine Propoxur* Malathion*
——— Pyridostigmine (Baygon) Diazinon*
* Insecticides Edrophonium (TIK-20)
£ Nerve gases Rivastigmine Tabun £
for chemical Donepezil Sarin £

£
warfare Galantamine Soman

27. ON CHOLINERGIC AGENTS
1)pilocarpi

>pilocarpine mimics the effect of the chemical
acetylcholine which produced by nerve cells
>This drug is used to treatment of Glaucoma disease
ADR
Dizziness, vomiting, flushing, diarrhoea,runny nose, sweating.

2)Neostigmine(Reversible Carbamate)
> Neostigmine increases acetylcholine in the synaptic cleft
This drug is used to treatment of myasthenia gravis
ADR
Abdominal cramps, increase in saliva/mucus, sweating, decrease in pupil size

28. arbamate)
of the Neostigmine but long duration of action
is used to treatment of chronic condition of myasthenia gravis.

ADR:
same reaction of Neostigmine

4)Tacrine (Acridine)

Tacrine is a centrally acting acetylcholinesterase inhibitor and indirect
cholinergic agonist. It was the first centrally acting cholinesterase inhibitor
approved for the treatment of Alzheimer's disease,

ADR:
Nausea , vomiting , diarrhoea, dyspepsia, Anorexia and ataxia

29. CHOLINOMIMETIC ALKALOIDS

ent muscarinic actions and also stimulate ganglia—mainly through
ganglionic rinc receptors.

Applied to the eye, it penetrates cornea and promptly causes miosis ciliary muscle
contraction and fall in intraoculartension lasting 4-8 hours(GLAUCOMA DISEASE)

GLAUCOMA DISEASE :

Comea

Dilator Constrctor Iris.
muscle | muscle Pathway for

jueous humour

Canal of
Schlemm

Ciiary
body

Suspensory
ligaments

30. OPEN ANGLE GLAUCOMA. CLOSER ANGLE GLAUCOMA

31. ON CHOLINERGIC AGONIST

Pharm Cal action:

A. Muscarinic actions

1. Heart
ACh hyperpolarizes the SA nodal cells and decreases their rate of diastolic depolari-

zation. As a result, rate of impulse generation is reduced—bradycardia or even cardiac
arrest may occur.
2. Blood vessels

All blood vessels are dilated, though only few (skin of face, neck, salivary glands)

receive cholinergic innervation
ACh can diffuse to the vascular smooth muscle and cause vasoconstriction via M3

receptors located on their plasma membrane.

3. Smooth muscle
Smooth muscle in most organs is contracted (mainly through M3 recep-tors).

Tone and peristalsis in the gastrointestinal tract is increased and sphincters relax.

32. increased via M3 and some M2 receptors: sweating, salivation,
ed tracheobronchial and gastric secretion. The effect on pancreatic
ds is not marked. Secretion of milk and bile is not affected.

5. Eye
Contraction of circular muscle of iris R miosis.Contraction of ciliary muscle R spasm

of accomodation, increased outflow facility, reduction n intraocular tension (especially in
glaucomatus patients).

B. Nicotinic actions

1. Autonomic ganglia

Both sympathetic and parasympathetic ganglia are stimulated.High dose of ACh
given after atropine causes tachycardia and rise in BP

2. Skeletal muscles
ACh to muscle endplate causes contraction of the fibre. Intraarterial injection of
high dos can cause twitching and fasciculation.

33. 7

C.CNS Action :
ACh injected i.v. does not penetrate blood-brain barrier and no central effects are

seen. However, direct injection into the brain produces arousal response followed by
depression.

THERAPEUTIC USES :

Choline esters are rarely, if ever, clinically used. ACh is not used because of
evanescent. Methacholine was occasionally used to terminate paroxysmal supraventricular
tachycardia but is obsolete now.

Bethanechol has been used in urinary retention,neurogenic bladder to promote
urination.

34. N CHOLINERGIC ANTAGONIST

Classification of antimuscarinic d

comme

Atropine Methonitrate

Hyo: + Homatropine Mydriatics Vasicoselective
(Scopolamine) _|+ Hyoscine buiybromide |FCycopenoiate | |» Oxyeutnin
à TRS HE Tropicamide + Tolterodine
en EI + Flavoxate
+ Darifenacin
Antisecretory- antispasmodics * Solifenacin
+ Trospium
Quaternary Comps. Tertiary amines —
+ Propantheline + Dicyclomine |Antiparkinsonian |
+ Oxyphenonium + Valethamate + Trihexyphenidyl
+ Clidinium + Pirenzepine (Benzhexol)
+ Glycopyrrolate + Procyclidine
+ Biperiden
+ Benztropin

35. N CHOLINERGIC RECEPTORS

ural Alkaloids)

1)Atrop

> ne it works by blocking the action of acetylcholine

This drug is used to reduced said vation and bronchial secretion and increase in
pupil size.

ADR
dizziness,blurred vision,abdominal pain.

2)Scopolamine
A muscarinic receptor antagonist (MRA) is a type of anticholinergic agent that
blocks the activity of the muscarinic acetylcholine effect.
Drug is used to treatment of motion sickness
ADR
constipation,dry mouth, decreased sweating, dizziness

36. 2)curare :
=Curare is analkaloid family of or;

Hates muscle relaxant that Blocks the nicotinic acetylcholine receptor
nAChR),

This drug is used to primary skeletal muscle relaxant.

anic compounds, example of a

ADR:
muscle weakness
paralysis of the diaphragm
hypoxia(deficiency in the amount of oxygen reaching the tissues)

37. Neurotransmitter

Atropine, scopolamine
(block muscarinic receptors)

Curare
(blocks nicotinic
receptors)

Inside cell

G protein

38. logical action :

Atropine has an overall CNS stimulant action.
Hyoscine produces central effects (depressant)
High doses cause cortical excitation, restlessness, disorientation,

hallucinations and delirium followed by respiratory depression and
coma

Heart:

Atropine substitutes which do not cross blood- brain barrier

The most prominent effect of atropine is tachycardia.
Glands :

Atropine markedly decreases sweat, salivary, tracheobronchial
and lacrimal secretion (M3 blockade). Skin and eyes become dry,
talking and swallowing may be difficult.

39. Smooth muscles :

All visceral smooth muscles that receive parasympathetic
motor innervation are relaxed by atropine (M3 blockade)

Atropine causes bronchodilatation and reduces airway
resistance.

Atropine has relaxant action on ureter and urinary bladder.

Local Anaesthetic :
Atropine has a mild anaesthetic action on the cornea.

40. derivatives : (pharmacology action)

Hyoscine butyl bromide :
20-40 mg oral, less potent and longer acting than atropine used for esophageal

and gastrointestinal spastic conditions

Atropine methonitrate
2.5-10 mg oral,; for abdominal colics and hyperacidity.

Ipratropium bromide :
oral inhalation is used to prevent wheezing, shortness of breath, coughing, and
chest tightness in people with chronic obstructive pulmonary disease

Tiotropium bromide :
A newer drug of ipratropium bromide which binds very tightly to bronchial M1/
M3 muscarinic receptors producing long lasting bronchodilatation

41. Oxybutynin

This newer antimuscarinic has high affinity for receptors in urinary
bladder and salivary glands alongwith additional smooth muscle relaxant
and also act as local anaesthetic properties.

Flavoxate
it has properties similar to oxybutynin and is indicated in urinary

frequency.

42. IFESTATIONS

A cholinergic crisis develops as a result of overstimulation of nicotinic and
muscarinic receptors at the neuromuscular junctions.

=> Excessive accumulation of acetylcholine (ACh) at the neuromuscular
junctions causes symptoms of both muscarinic and nicotinic toxicity.
This is usually inhibition of acetylcholinesterase (AChE), for example
(Botulinum toxin)

43. cramps

= increased salivation

=> increased lacrimation

muscular weakness

> paralysis

muscular fasciculation

=>diarrhea and blurry vision

also included alzheimer and Huntington's disease.

44. Y

Alzheimer's disease :
alzheimer disease is characterized by deficiency of cholinergic

neurons

Huntington's disease :

huntington disease is characterized by prominent loss of
neurons in the CNS area.

>No cure exists, but drugs, physiotherapy and talk therapy can help
manage some symptoms.

45. DISEASE — DRUGS RECEPTOR TARGET

Alzheimer's Galantamine, M1,M2,M3,M4,M5(Agonist
Rivastigmine,

schizophrenia Chlorpromazine, M1,M2,M3,M4(Agonist)
Clozapine,
Olanzapine

parkinsonism Levodopa,carbidopa fj M1,M2,M3,M4(Antagonist)

Type 2 diabetes. Bethanechol M3(Agonist)
Carbachol

Obesity Orlistat. M3(Antagonist)

46. DISEASE DRUGS RECEPTOR TARGET

DMPP(Dimethyl Nn(Agonist)
Phenylpiperazinium
Nicotine
Muscle disease
Phenyltrimethlyl Nm(Agonist)

ammonium, Nicotin