ans & cholinergics 1- drdhriti

7/31/2019 ANS & Cholinergics 1- Drdhriti

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Autonomic Nervous System -

Autonomic Pharmacology

Department of Pharmacology

NEIGRIHMS, Shillong


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Goal

To Learn about the drugs affecting the

autonomic nervous system

Be prepared to link mechanism of drug action

with knowledge mainly of cardiovascular anatomy,physiology and neurobiologyto predict effects of drugs


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The autonomic nervous system

maintains the internal environment

of the body called HOMEOSTASISRole of ANS in homeostasis

links to target organs -

(Cardivascular System, smoothmuscle of GI and glands)


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+

Drug A decreases

activity of

organ O

Autonomic Pharmacology is Practical

Nerves to organ

release neurotransmitter ,

and N increases

the activity of organ

Mimic or Blocktransmitters

Drug A blocks

receptors for

neurotransmitter


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+

Understanding actions of drugs that

influence the autonomic nervous

system allows prediction of theireffects!


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For a definite clinical outcome!


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Autonomic drugs are usedfor the

treatment ofAngina


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Autonomic drugs are used

for thetreatment ofHeart

Failure


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Autonomic drugs are used for t

treatment ofHigh Blood

Pressure


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Objectives

Review the anatomy of the autonomic nervous system

Know the neurotransmitters at autonomic synapses

Understand the mechanism of neurotransmission in theautonomic nervous system

Be able to describe the distribution of adrenergic andcholinergic receptors

Describe general mechanisms by which drugs interact withthe autonomic nervous system


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Autonomic Pharmacology

I. Anatomy of Peripheral Nervous System

Recall


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Controlsskeletal

muscle

Controls

cardiac

muscle &

glands

Peripheral Nervous System

SomaticNervousSystem

AutonomicNervous

System

One

NeuronEfferent

Limb

Two

NeuronEfferent

LimbPostganglionic

Preganglionic

smooth &


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Recall Differences - Somatic Vs ANS


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ANS - Organization

Autonomic afferents:

Mixed and nonmyelinated Nerves

Cell bodies are located in the dorsal root ganglion

of Spinal Nerves and the sensory ganglia of

Cranial Nerves

Mainly mediate visceral pain

Also reflexes from CVS, visceral and respiratory


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Organization of ANS

Central Connections

No Exclusive autonomic area in CNS

Intermixing and integration of somatic and ANS occurs

Hypothalamus is the organ to regulate

Sympathetic Lateral and Posterior sympathetic

Parasympathetic Anterior and Medial

Many autonomic centres are located in mid brainmedulla


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Organization of ANS Efferent fibres

Motor limb

Sympatheticand Parasympathetic

Most organs receive bothinnervations

Functionally antagonistic of

each other Overall depends on the tone

at particular moment EXCEPTIONS:

Most Blood vessels, sweatglands and hair folliclesSympathetic

Gastric and pancreatic glands,cilliary muscles -Parasympathetic


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AUTONOMIC NERVOUS SYSTEM

SYMPATHETIC

Fight or Flight

PARASYMPATHETIC

Rest and Digest

Next slide

Distriibution:


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Parasympathetic Nervous System (Craniosacral Outflow)

Genitalia

Bladder

Large Intestines

Kidney

Bile DuctsGallbladder

Small Intestines

Stomach

Bronchi/BronchialGlands

SA & AV Node

Sphincter Muscle of Iris

Ciliary Muscle

Lacrimal Gland

Submaxillary &Sublingual

Glands

Parotid Gland


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Radial Muscle of IrisCiliary Muscle

SA & AV NodesHis-Purkinje System

Myocardium

Bronchi/Bronchial

Glands

Stomach

Kidneys

Intestines

Bladder//Genitalia

Sublingual/Submaxillary& Parotid Gland

Pilomotor MusclesSweat Glands

Blood Vessels

Sympathetic Nervous System(Thoracolumbar Outflow)

Paravertebral Ganglia

Prevertebral Ganglia


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Epinephrine

(+) Fatty Acid Release (-) Intestinal Motility

(+) Glycogenolysis

(+) ACTH & TSH

(+) Mental Alertness

(+) Muscle Contraction & Efficiency

(+) Dilates Airways

(+) Cardiac Output

ADRENAL

MEDULLA

Chromaffin Cells


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Sympathetic Parasympathetic

Origin Dorso-lumber (T1 to L2 or 3) Craniosacral (S2-4)

Distribution Wide Head, neck and trunk

Ganglia Away from Organ supplied On or close to the organ

Postganglionic fibers Long Short

Pre and post fiber ratio 1:20 to 1:100 1:1 or 1: 2

Transmitter Noradrenalin Acetylcholine

Duration Long and wider action Ach rapid destroy

Function Tackling stress and emergency Assimilation of food and

conservation of energy


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Enteric Nervous System

Considered 3rd Division of ANS

Auerbach`s plexus or myenteric plexus

Meissner`s plexus or submucous plexus

Stimulation of these neurones causes release of Ach, NE,VIP, ATP, Substance P, 5-HT etc.

May be excitatory or inhibitory in Nature


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Enteric Nervous System


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Neurohumoral

Transmission

Neurohumoral transmission

means the transmission of

message across synapse and

neuroeffector junctions by

release of humoral (chemical)

messages

Initially junctional

transmission was thought to

be Electrical

But, Dale (1914) and Otto

Loewi (1921) provided directproof of humoral transmission

vagusstoffand

acceleranstoff

Many Neurohumoral

transmitters identified:Acet lcholine noradrenalin


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Neurohumoral

Transmission - Steps

1. Impulse Conduction

Tetrodotoxin andsaxitoxin

2. Transmitter Release

3. Transmitter release onpostjunctional membrane

EPSP and IPSP

4. Postjunctional activity

5. Termination of transmitter

action

NET, SERT, DT


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Impulse conduction across synapse


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Ach

Ach

Ach

Ach NE

AchEPI/NE

Ach Ach

Somatic

Sympathetic

Sympathetic

Sympathetic

Para-

sympathetic

Postganglionic Fiber:

Adrenergic

Adrenal Gland

MotorFiber

SweatGlands

Smooth Muscle

Cardiac Cells

Gland Cells

Smooth MuscleCardiac Cells

Gland Cells

Skeletal

Muscle

Ganglion

Ganglion

Ganglion


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Cholinergic and Adrenergic System

Accordingly:

Cholinergic Drugs,i.e., they act by releasing

acetylcholine

But also utilize nitric oxide (NO) or peptides fortransmission

Noradrenergic(commonly called "adrenergic")

Drugs- act by releasing norepinephrine (NA)


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Cotransmission

Peripheral and central Neurons release more than one activesubstance when stimulated

In ANS, besides Ach and NA neurones elaborate Purines(ATP, adenosines), Peptides (VIP) or NPY, substance P, NO,enkephalins etc.

ACH and VIP, ATP with both Ach and NA

Stored in same neurones, but distinct vesicles ATP and NA insame vesicle

NANC gut, vas deferens, urinary tract, salivary glands andcertain blood vessels.


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Sites of Cholinergic Transmission

Acetylcholine (Ach) is major neurohumoral transmitter at

autonomic, somatic and central nervous system:

1. All preganglionic sites (Both Parasympathetic and

sympathetic)

2. All Postganglionic Parasympathetic sites and sympathetic to

sweat gland and some blood vessels

3. Skeletal Muscles

4. CNS: Cortex Basal ganglia, spinal chord and others

Parasympathetic Stimulation Acetylcholine (Ach) release at neuroeffector junction

- biological effects

Sympathetic stimulation Noradrenaline (NA) at neuroeffector junction - biological

effects


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CholinergicTransmission: Cholinergic neurons contain largenumbers of small membrane-boundvesicles (containing ACh) concentratednear the synaptic portion of the cellmembrane ACh is synthesized in the cytoplasmfrom acetyl-CoA and cholineby the

catalytic action of Cholineacetyltransferase (ChAT)

Acetyl-CoA is synthesized inmitochondria, which are present in largenumbers in the nerve endingCholine is transported from theextracellular fluid into the neuron terminal

by a sodium-dependent membrane carrier(carrier A). This carrier can be blocked bya group of drugs called hemicholiniums

The action of the cholinetransporter is the rate-limitingstep in ACh synthesis


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Cholinergic Transmission:

Synthesized, ACh is transported from the

cytoplasm into the vesicles by an antiporterthat removes protons (carrier B). Thistransporter can be blocked by vesamicol Release is dependent on extracellular Ca2+and occurs when an action potential reachesthe terminal and triggers sufficient influx ofCa2+ ions The increased Ca2+ concentration"destabilizes"the storage vesicles byinteracting with special proteins associatedwith the vesicular membrane (VAMPs)Fusion of the vesicular membranes with theterminal membrane results in exocytotic

expulsion of ACh into the synaptic cleft The ACh vesicle release process is blockedby botulinum toxinthrough the enzymaticremoval of two amino acids from one or moreof the fusion proteins. Black widow spider??


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Cholinergic Transmission:

After release - ACh molecules may bind to

and activate an ACh receptor(cholinoceptor) Eventually (and usually very rapidly), all ofthe ACh released will diffuse within range ofanacetylcholinesterase (AChE)molecule AChE very efficiently splits ACh intocholineandacetate, neither of which hassignificant transmitter effect, and therebyterminates the action of the transmitter. Most cholinergic synapses are richlysupplied with AChE; the half-life of ACh inthe synapse is therefore very short. AChEis also found in other tissues, eg, red blood

cells. Another cholinesterase with a lowerspecificity for ACh, butyrylcholinesterase[pseudo cholinesterase], is found in bloodplasma, liver, glial, and many other tissues


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Differences between 2 AChEs

True AChE Pseudo AChE

Distribution All cholinergic

sites, RBCs,

gray matter

Plasma, liver,

Intestine and

white matter

Action on:

Acetycholine

Methacholine

Very Fast

Slower

Slow

Not hydrolyzed

Inhibition More sensitiveto

Physostigmine

More sensitive toOrganophosphates

Function Termination of

Ach action

Hydrolysis of

Ingested Esters


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Cholinergic receptors - 2 types

Muscarinic (M) and Nicotinic (N):


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Acetylcholine (cholinergic receptors)

Muscarinic Receptors

1. Selectively stimulated by Muscarineand blocked by Atropineall are G-

protein coupled receptors2. Primarily located in heart, eye, smooth muscles and glands of GIT

3. Subsidiary M receptors are also present in ganglia for modulation

4. Autoreceptors (M type) are present in prejunctional cholinergic Nerveendings also in adrenergic nerve terminals leading to vasodilatation

when Ach is injected5. Blood vessels: All blood vessels have muscarninc receptors although no

cholinergic innervations


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Muscarinic Receptors - Subtypes

Pharmacologically - M1, M2, M3, M4 and M5

M4 and M5 are present in certain areas of Brain and regulate

other neurotransmitters

M1, M3 and M5 fall in one class, while M2 and M4 in another

class

However till today, M1, M2 and M3 are major ones and

present in effector cell and prejunctional nerve endings in CNS

All subtypes have little agonist selectivity but selective

antagonist selectivity

Most organs usually have more than one subtype but one

subtype predominates in a tissue


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Muscarinic Receptors - Location

M1:Ganglion Cells and Central Neurons (cortex,

hippocampus, corpus striatum)

Physiological Role: Mediation of Gastric acid secretion and

relaxation of LES

Learning, memory and motor functions

M2: Cardiac Muscarinic receptors

Mediate vagal bradycardia

Also auto receptors in cholinergic nerve endings M3:Visceral smooth muscles, glands and vascular

endothelium. Also Iris and Ciliary muscles


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Location Autonomic ganglia,

Gastric glands and CNS

Heart and CNS SMs of Viscera,

Eye, exocrine

glands and

endothelium

Functions EPSP & Histaminerelease & acid

secretion with CNS

learning and motor

functions

Less impulsegeneration, less

velocity of

conduction,

decreased

contractility,

less Achrelease

Visceral SMcontraction,

Constriction of

pupil,

contraction of

Cilliary muscle

andvasodilatation

Agonists Oxotremorine and MCN

and MCN-343A

Methacholine Bethanechol

Antagonis

ts

Pirenzepine Methoctramine

& Triptramine

Darifenacin

Muscarinic Receptor

Subtypes


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Acetylcholine (cholinergic receptors)

Muscarinic Receptors

Selectively stimulated by Muscarine and

blocked by Atropine


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Nicotinic (N) Receptors

Nicotinic receptors: nicotinic actions of ACh arethose that can be reproduced by the injection ofNicotine (Nicotiana tabacum)

Can be blocked by tubocurarine andhexamethonium

ligand-gated ion channels

activation results in a rapid increase in cellularpermeability to Na+ and Ca++ resulting -depolarization and initiation of action potential

Ni ti i (N d N ) R t


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Nicotinic (NM and NN) Receptor -

comparison

NM (Muscle type)

1. Location: Skeletal Muscleend plates

2. Function:Stimulate skeletal

muscle (contraction)3. MOA: Postsynaptic and

Excitatory (increases Na+ andK+ permeability)

4. Agonists:ACh, carbachol(CCh), suxamethonium

Selective stimulation by phenyltrimethyl ammonium (PTMA)

5. Antagonists: tubocurarine,hexamethonium

NN (Ganglion type)

1. Location: In autonomic ganglia ofall type (ganglion type) Sympathetic, Parasympathetic andalso Adrenal Medulla

2. Function: Depolarization andpostganglionic impulse stimulateall autonomic ganglia

3. MOA: Excitatory Na+, K+ andCa+ channel opening

4. Agonists: ACh, CCh, nicotine

Selectively stimulated by

phenyl piperazinium (DMPP)

5. Antagonists: mecamylamine,trimetaphan


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Sites of Cholinergic transmission

and types of Receptors

All Postganglionic

Parasympathetic

Postganglionic sympathetic to

sweat gland & BV

Muscarini

c

Muscarine Atropine

Ganglia (Both Para and

sympathetic and also

Adrenal Medulla

NN DMPP Hexamethoniu

m

Skeletal Muscle NM PTMA Curare

CNS Muscarini

c

Muscarine

Oxotremorin

e

Atropine


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Ganglia Concept - summary


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Cholinergic Drugs or Cholinomimetic

or ParasympathomimeticsDrugs producing actions similar to Achby interacting with Cholinergic receptors

or by increasing availability of Ach at thesesites.

l f (


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Classifiction - Direct-acting (receptor

agonists )

Choline Esters

Natural: Acetylcholine

Synthetic: Methacholine, Carbachol and

Bethanechol

Alkaloids:Pilocarpine, Muscarine, Arecholine

Synthetic: Oxotremorine


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Cholinergic Drugs Indirect acting

Cholinesterase inhibitors or reversibleanticholinesterases:

Natural:Physostigmine

Synthetic:neostigmine, pyridostigmine, distigmine,

rivastigmine, donepezil, gallantamine, edrophonium,ambenonium, demecarium

Irreversible anticholinesterases:

Organophosphorous Compounds (OPC) Diisopropyl

fluorophosphate (DFP), Ecothiophate, Parathion,malathion, diazinon (insecticides and pesticides)

Tabun, sarin, soman (nerve gases in war)

Carbamate EstersCarbaryl and Propoxur (Baygon)


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Question

What side effects might you expect to

see in a patient taking a cholinergic drug?

Hint Cholinergic = Colon-Urgent


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Ach actions - Muscarinic

1. Heart: M2

Hyperpolarization of SA node, reduction in impulse generation andBradycardia

RP in SAN and PF increased but atrial muscles fibers abbreviated

Slowing of AV conduction and His-purkinje fibres partial or

complete block

Atrial fibrillation and flutter nonuniform vagal innervations

Decrease in ventricular contractility

2. Blood Vessels: M3

Cholinergic innervations is limited skin of face and neck

But, M3 present in all type blood vessel Vasodilatation by Nitricoxide (NO) release

Penile erection


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Muscarinic action contd.

3. Smooth Muscles: M3 Abdominal cramps, diarrhoea due to increased peristalsis and

relaxed sphincters

Voiding of Bladder

Bronchial SM contraction dyspnoea, attack of asthma etc.

4. Glands: M3 Increased secretions: sweating, salivation, lacrimation,

tracheobronchial tree and gastric glands

5. Eye: M3 Contraction of circular fibres of Irismiosis

Contraction of Ciliary muscles spasm of accommodation,increased outflow and reduction in IOP


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Ach actions - Nicotinic

1. Autonomic ganglia: Both Sympathetic and parasympathetic ganglia are stimulated

After atropine injection Ach causes tachycardia and rise in BP

2. Skeletal muscle IV injection no effect

Application causes contraction of skeletal muscle

3. CNS: Does not penetrate BBB

Local injection in CNS complex actions

(Acetylcholine is not used therapeutically)

Bethanecol Uses: Postoperative and postpartum urinaryobstruction, neurogenic bladder and GERD (10-40 mg oral)


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Pilocarpine

Alkaloid from leaves ofPilocarpus microphyllus Prominent muscarinic actions

Profuse salivation, lacrimation, sweating

Dilates blood vessels, causes hypotension

On Eyes it produces miosis and spasm of accommodation Lowers intraocular pressure (IOP) in Glaucoma when applied

as eye drops

Too toxic for systemic use


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Pilocarpine contd.

Used as eye drops in treatment of narrow angle and wideangle glaucoma to reduce IOP

Used to reverse mydriatic effect of atropine

To break adhesion between iris and cornea/lens alternatedwith mydriatic

Pilocarpine nitrate eye drops ( 1 to 4% )

CNS toxicity after systemic use Atropine used as antidote in acute pilocarpine poisoning ( 1-2

mg IV 8hrly )


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Pilocarpine Mechanism in Eye

Causes opening up

of trabecular

pores and

increased

drainage


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Muscarine

Alkaloid from mushroomAmanita muscaria

Only muscarinic actions

No clinical use

Mushroom poisoning due to ingestion of poisonousmushroom

= Early onset mushroom poisoning (Muscarine type)

= Late onset mushroom poisoning (neurogenic)


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Early Onset Mushroom Poisoning

Occurs to 1 hour

Symptoms are characteristic of Muscarinic actions

Inocybe or Clitocybe severe cholinergic symptoms likevomiting, salivation, lacrimation, headache, bronchospasm,

diarrhoea bradycardia, dyspnoea, hypotension, weakness,cardiovascular collapse, convulsions and coma

Antidote is Atropine sulphate ( 2-3 mg IM every hrly tillimprovement)

Hallucinogenic type: due to Muscimol or ibotenic acid presentin A. muscria. Blocks muscarinic receptors in brain andactivate mio acid receptors. No specific treatmentAtropineis contraindicated.

Volvariella volvacea

L t O t M h


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Late Onset Mushroom

Poisoning

Occurs within 6-15 hours

Amanita phylloides due to peptide toxins Inhibit RNA andprotein synthesis

Irritability, restlessness, nausea, vomiting, bloody diarrhoeaataxia, hallucination, delirium, sedation, drowsiness and sleepKidney, liver and GIT mucosal damage

Maintain blood pressure, respiration

Inj. Diazepam 5 mg IM Atropine contraindicated as it may cause convulsions and

death

Gastric lavage and activated charcoal


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Cholinesterase inhibitors:

Reversible anticholinesterases (Carbamates): Natural:Physostigmine

Synthetic: Neostigmine, pyridostigmine, distigmine,rivastigmine, donepezil, gallantamine, edrophonium,ambenonium, demecarium

Irreversible anticholinesterases: Organophosphorous Compounds (OPC) Diisopropyl

fluorophosphate (DFP), Ecothiophate, Parathion,

malathion, diazinon (insecticides and pesticides) Tabun, sarin, soman (nerve gases in war)

Carbamate: Carbaryl and Propoxur (Baygon)


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AChEs - MOA

Acetylcholinesterase (AchE) isan enzyme, which hydrolyses

The active site of AChE is made

up of

The serves to bind a

molecule of ACh to the enzyme

Once the ACh is bound, the

hydrolytic reaction occurs at a

second region of the active site

called the

Acetylated enzyme reacts with

water to produce acetic acid and

choline

Choline is then immediately

taken up again by the high affinity

choline uptake system on the


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Hydrolysis of ACh

N

O

C

CH3

O

+

-

+ NO

CCH

3

O

+

-

+

OH-

NO

CCH3

O

+

-

OH

NOH CH3

O

+

HO

+


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Anti-ChEs (MOA) contd.

Anticholinesterases also react with the enzyme ChEs in similar fashion likeAcetylcholine

Carbamates carbamylates the active site of the enzyme

Phosphates Phosphorylates the enzyme

Carbamylated (reversible inhibitors) reacts with water slowly and the esteratic siteis freed and ready for action 30 minutes (less than synthesis of fresh enzyme)

But, Phosphorylated (irreversible) reacts extremely slowly or not at all takesmore time than synthesis of fresh enzyme Sometimes phosphorylated enzyme losses one alkyl group and become resistant to

hydrolysisaging

Edrophonium and tacrine reacts only at anionic site while Organophosphatesreacts only at esteratic site


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Cholinesterase inhibitors contd.


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Anticholinesterases Individual Drugs

2 (two) important clinically used drugs

Physostigminelipid soluble, ganglion acting and

less action in skeletal muscle

Also organophosphates

Neostigminelipid insoluble,skeletal muscle

acting


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Physostigmine

Alkaloid from dried ripe seed (Calabar bean) of African plant Physostigmavenenosum

Tertiary amine, lipid soluble, well absorbed orally and crosses BBB

Hydrolyzed in liver and plasma by esterases.

Long lasting action (4-8 hours)

Reversible anticholinesterase drug

It indirectly prevents destruction of acetylcholine released from cholinergic nerveendings and causes ACh accumulation

Muscarinic action on eye causing miosis and spasm of accommodation on localapplication

Antagonises mydriasis and cycloplegia produced by atropine and anticholinergicdrugs

Salivation, lacrimation, sweating and increased tracheobronchial secretions.

Increased heart rate & causes hypotension


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Physostigmine - uses

1. Used as miotic drops to decrease IOP in Glaucoma2. To antagonise mydriatic effect of atropine

3. To break adhesions between iris and cornea alternating withmydriatic drops

4. Belladonna poisoning, TCAs & Phenothiazine poisoning5. Alzheimers disease- pre-senile or senile dementia.

6. Atropine is antidote in physostigmine poisoning.

7. ADRs CNS stimulation followed by depression.


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Neostigmine

Synthetic reversible anticholinesterase drug. Quaternary ammonium compound and lipid soluble.

Cannot cross BBB

Hydrolysed by esterases in liver & plasma

Short duration of action (3-5 hours)

Direct action on nicotinic (NM) receptors present in neuromuscularjunction (motor end plate) of skeletal muscle

Antagonises (reverses) skeletal muscle relaxation (paralysis) caused bytubocurarine and other competitive neuromuscular blockers

Stimulates autonomic ganglia in small doses

Large doses block ganglionic transmission

No CNS effects


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Neostigmine Uses and ADRs

Used in the treatment of Myasthenia Gravis to increasemuscle strength

Post-operative reversal of neuromuscular blockade

Post-operative complications gastric atony paralytic ileus,

urinary bladder atony Cobra snake bite

Produces twitchings & fasciculations of muscles leading toweakness

Atropine is the antidote in acute neostigmine poisoning

Ph ti i d N ti i


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Physostigmine and Neostigmine -

Summary

Source Natural Synthetic

Chemistry Tertiary amine Quaternary ammonium

compound

Oral absorption Good Poor

CNS action Present Absent

Eye Penetrates cornea Poor penetration

Effect Ganglia Muscle

Uses Miotic Mysthenia gravisDose 0.5-1 mg

oral/parenteral

0.1-1% eye drop

0.5-2.5 mg IM/SC

15-30 mg orally

Duration of

action

4-6 Hrs 3-4 Hrs


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Therapeutic Uses cholinergic drugs

1. Myasthenia gravis: Edrophonium to diagnose andNeostigmine, Pyridostigmine & Distigmine to treat

2. To stimulate bladder & bowel after surgery:

Bethanechol, Carbachol, Distigmine.

3. To lower IOP in chronic simple glaucoma: Pilocarpine, Physostigmine

4. To improve cognitive function in Alzheimers disease:Rivastigmine, Gallantamine, Donepezil.

5. Physostigmine in Belladonna poisoning


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Myasthenia gravis

Autoimmune disorder affecting 1 in 10,000 population Causes: Development of antibodies directed to Nicotinic receptors in

muscle end plate reduction in number by 1/3rd of NM receptors

Structural damage to NM junction

Symptoms: Weakness and easy fatigability

Treatment:

Neostigmine 15 to 30 mg orally every 6 hrly

Adjusted according to the response*

Pyridostigmine less frequency of dosing

Other drugs: Corticosteroids (prednisolone 30-60 mg /day)

Azathioprin and cyclosporin also Plasmapheresis


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Myasthenic crisis

Acute weakness and respiratory paralysis

Tracheobronchial intubation and mechnical

ventilation

Methylprednisolone IV with withdrawal of AChE Gradual reintroduction of AChE

Thymectomy


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Snake venom Poisoning

Asian Cobra Bite

Symptoms are similar to Myasthenia gravis

Atropine sulfate 0.6 mg IV slowly to

counteract Muscarinic action Edrophonium chloride (Tensilon) - 10 mg IV

over 2 minutes reversal of occulomotor and

respiratory paralysis

AChE Poisoning (Organophopsphorous


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AChE Poisoning (Organophopsphorous

Poisoning)

Poisoning may be

Occupational, accidental,Suicidal

Symptoms:

Fall in BP, bradycardia or tachycardia, cardiac arrhythmiaand vascular collapse

Irrittion of Eye, lacrimation, salivation, colic, involuntarydefection, breathlessness, blurring of vision

Muscular fasciculations and weakness

Death due to respiratory paralysis peripheral and central

l f


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Principles of Treatment

Remove soiled clothes Wash soiled skin and eyes

Prone Positioning and clear mouth and throat

Intubation of airway Gastric lavage

Atropine: All cases of AChE poisoning, 2mg IV every`10 minutes continue till atropinization occurs

Cholinesterase reactivators: Oximes


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Cholinesterase Reactivators - Oximes

Pralidoxime (2-PAM), Obidoxime Diacetyl monoxime (DAM) Oximes have generic formula R-CH=N-OH

Provides reactive group OH to the enzymes to reactivate thephosphorylated enzymes

PAM: Quaternary Nitrogen of PAM gets attaches to Anionic site of the

enzyme and reacts with Phosphorous atom at esteratic site

Forms Oxime-phosphonate complex making esteratic site free

Not effective in Carbamate poisoning

Dose: 1-2 gm IV slowly


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Khublei Shibun/Thank you


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SkeletalMuscle


Somatic NervousSystem

Autonomic NervousSystem

Parasympathetic

Nervous System

Sympathetic

Nervous System

SelectiveActivation

DiffuseActivation

Glands, Smooth Muscle& Cardiac Muscle

Ch li i T i i


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Cholinergic Transmission

Acetylcholine (Ach) is major neurohumoraltransmitter at autonomic, somatic andcentral nervous system:

The important sites of Acetylcholine as Neurohumoral

transmitters are:1. All Postganglionic and few postganglionic sympathetic to sweat

glands and some blood vesselsMuscarinic

2. All preganglionic (Para and sympathetic) i.e. ganglia and Adrenalmedulla - Nicotinic (NN)

3. Skeletal MuscleNicotinic (NM)

4. Central Nervous System (cortex, basal ganglia and spinal chord)Muscarinic and Nicotinic


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