2011

Wish you

Autonomic Nervous

System - “Autonomic

Pharmacology”

Department of Pharmacology

NEIGRIHMS, Shillong

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 neurobiology

to predict effects of drugs –

The autonomic nervous system

maintains the internal environment of

the body – clled HOMEOSTASIS

Role of ANS in homeostasis

links to target organs -

(Cardivascular System , smooth

muscle of GI and glands)

+

Drug A decreases

activity of

organ Y

Autonomic Pharmacology is Practical

Nerves to organ Y

release neurotransmitter

X,

and X increases

the activity of organ Y

Mimic or Block transmitters

Drug A blocks

receptors for

neurotransmitte

r X

+

Atropine blocks muscarinic

receptors

and decreases intestinal motility

Atropine blocks

muscarinic

cholinergic

receptors

that respond to

ACh

Parasympathetic

nerves

release ACh

and increase

intestinal motility

Understanding actions of drugs that

influence the autonomic nervous

system allows prediction of their

effects!

Autonomic Drugs are very

much Clinically Relevant

Autonomic drugs are used for the

treatment of Angina

Autonomic drugs are used for the

treatment of Heart Failure

Autonomic drugs are used for the

treatment of High Blood

Pressure

• Autonomic drugs also used for

treatment of

- Anaphylactic shock

- Septic shock

- Benign prostatic hypertrophy

- Alzheimer’s disease

- Asthma

Objectives

• Review the anatomy of the autonomic

nervous system

• Know the neurotransmitters at autonomic

synapses

• Understand the mechanism of

neurotransmission in the autonomic

nervous system

• Be able to describe the distribution of

adrenergic and cholinergic receptors

• Describe general mechanisms by which

drugs interact with the autonomic nervous

system

Autonomic Pharmacology

I. Anatomy of Peripheral Nervous

System

Organization of The Nervous

System

Central Nervous System

“Brain and spinal cord”

Peripheral Nervous System

Autonomic Nervous System Somatic Nervous System

Afferent Division Efferent Division

Sympathetic

“thoracolumbar”

Parasympathetic

“craniosacral”

Differences Between

Somatic and ANS

Controls

skeletal

muscle

Controls

smooth &

cardiac

muscle &

glands

Peripheral Nervous System

Somatic

Nervous

System

Autonomic

Nervous

System

One

Neuron

Efferent

Limb

Two

Neuron

Efferent

LimbPostganglionic

Preganglionic

Skeletal

Muscle

Peripheral Nervous System

Somatic Nervous

System

Autonomic Nervous

System

Parasympathetic

Nervous System

Sympathetic

Nervous System

Selective

Activation

Diffuse

Activation

Glands, Smooth Muscle

& Cardiac Muscle

AUTONOMIC NERVOUS

SYSTEM

• SYMPATHETIC

• Fight or Flight

• PARASYMPATHETIC

• Rest and Digest

Parasympathetic Nervous System (Craniosacral Outflow)

Genitalia

Bladder

Large Intestines

Kidney

Bile Ducts

Gallbladder

Small Intestines

Stomach

Bronchi/Bronchial

Glands

SA & AV Node

Sphincter Muscle of Iris

Ciliary Muscle

Lacrimal Gland

Submaxillary &

Sublingual

Glands

Parotid Gland

Radial Muscle of Iris

Ciliary Muscle

SA & AV Nodes

His-Purkinje System

Myocardium

Bronchi/Bronchial

Glands

Stomach

Kidneys

Intestines

Bladder//Genitalia

Sublingual/Submaxillary

& Parotid Gland

Pilomotor Muscles

Sweat Glands

Blood Vessels

Sympathetic Nervous System

(Thoracolumbar Outflow)

Paravertebral Ganglia

Prevertebral Ganglia

Epinephrine

(+) Fatty Acid Release (-) Intestinal Motility

(+) Glycogenolysis

(+) ACTH & TSH

(+) Mental Alertness

(+) Muscle Contraction & Efficiency

(+) Dilates Airways

(+) Cardiac Output

ADRENAL

MEDULLA

Chromaffin Cells

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

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

Enteric Nervous System

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 direct proof of

humoral transmission – vagusstoff

and acceleranstoff

• Many Neurohumoral transmitters re

identified: Acetylcholine,

noradrenalin, Dopamine, 5-HT, GABA,

Purines, Peptides etc.

Neurohumoral

Transmission - Steps

1. Impulse Conduction

• Tetrodotoxin and

saxitoxin

2. Transmitter Release

3. Transmitter release on

postjunctional

membrane

• EPSP and IPSP

4. Postjunctional activity

5. Termination of

transmitter action

• NET, SERT, DT

What is a synapse?

A synapse is a junction between two neurones across

which electrical signals pass. The human body contains up

to 500 trillion synapses.

presynaptic

cell

postsynaptic

cell

Release of

neurotransmittersWhen a nerve impulse arrives at the end of one neurone it triggers the

release of neurotransmitter molecules from synaptic vesicles.

synaptic

vesicle

neurotransmitter

molecules

Continuing the impulse

The neurotransmitters diffuse across the synaptic cleft and

bind with receptors on the next neurone, triggering another

impulse.

nerve

impulse

receptor

synaptic

cleft

Ach

Ach

Ach

Ach NE

AchEPI/NE

Ach Ach

Somatic

Sympathetic

Sympathetic

Sympathetic

Para-

sympathetic

Postganglionic Fiber:

Adrenergic

Adrenal Gland

Motor Fiber

Sweat

Glands

Smooth Muscle

Cardiac Cells

Gland Cells

Smooth Muscle

Cardiac Cells

Gland Cells

Skeletal

Muscle

Ganglion

Ganglion

Ganglion

Cholinergic and

Adrenergic System

• Accordingly:

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

releasing acetylcholine

• But also utilize nitric oxide (NO) or

peptides for transmission

• Noradrenergic (commonly called

"adrenergic") Drugs - act by

releasing norepinephrine (NA)

Cotransmission

• Peripheral and central Neurones release more than

one active substance 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 in same vesicle

• NANC – gut, vas deferens, urinary tract, salivary

glands and certain blood vessels.

Cholinergic System and

Drugs

Cholinergic

Transmission

• Acetylcholine (Ach) is major

neurohumoral transmitter at autonomic,

somatic and central nervous system:

• The important sites of Acetylcholine as

Neurohumoral transmitters are:

1. All Postganglionic and few postganglionic

sympathetic to sweat glands and some blood

vessels – Muscarinic

2. All preganglionic (Para and sympathetic) i.e.

ganglia and Adrenal medulla - Nicotinic (NN)

3. Skeletal Muscle – Nicotinic (NM)

4. Central Nervous System (cortex, basal ganglia

and spinal chord) – Muscarinic and Nicotinic

Cholinergic Transmission:

• Cholinergic neurons contain large

numbers of small membrane-bound

vesicles (containing ACh) concentrated

near the synaptic portion of the cell

membrane

• ACh is synthesized in the cytoplasm

from acetyl-CoA and choline by the

catalytic action of acetyltransferase

(ChAT)

• Acetyl-CoA is synthesized in

mitochondria, which are present in large

numbers in the nerve ending

• Choline is transported from the

extracellular fluid into the neuron terminal

by a sodium-dependent membrane carrier

(carrier A). This carrier can be blocked by

a group of drugs called hemicholiniums

The action of the choline

transporter is the rate-limiting

step in ACh synthesis

Cholinergic Transmission:

• Synthesized, ACh is transported from the

cytoplasm into the vesicles by an antiporter

that removes protons (carrier B). This

transporter can be blocked by vesamicol

• Release is dependent on extracellular Ca2+

and occurs when an action potential reaches

the terminal and triggers sufficient influx of

Ca2+ ions

• The increased Ca2+ concentration

"destabilizes" the storage vesicles by

interacting with special proteins associated

with the vesicular membrane (VAMPs)

Fusion of the vesicular membranes with the

terminal membrane results in exocytotic

expulsion of ACh into the synaptic cleft

• The ACh vesicle release process is blocked

by botulinum toxin through the enzymatic

removal of two amino acids from one or more

of the fusion proteins. Black widow spider

Cholinergic Transmission:

• After release - ACh molecules may bind to

and activate an ACh receptor

(cholinoceptor)

• Eventually (and usually very rapidly), all of

the ACh released will diffuse within range of

an acetylcholinesterase (AChE) molecule

• AChE very efficiently splits ACh into

choline and acetate, neither of which has

significant transmitter effect, and thereby

terminates the action of the transmitter.

• Most cholinergic synapses are richly

supplied with AChE; the half-life of ACh in

the synapse is therefore very short. AChE

is also found in other tissues, eg, red blood

cells.

• Another cholinesterase with a lower

specificity for ACh, butyrylcholinesterase

[pseudo cholinesterase], is found in blood

plasma, liver, glial, and many other tissues

Differences between 2

AChEs

True AChE Pseudo AChE

Distribution All cholinergic

sites, RBCs, gray

matter

Plasma, liver,

Intestine and

white matter

Action on

ACh

Very Fast Slow

Inhibition More sensitive to

Physostigmine

More sensitive to

Organophosphates

Function Termination of

Ach action

Hydrolysis of

Ingested Esters

Cholinergic receptors - 2

types

• Muscarinic (M) and Nicotinic (N)

Muscarinic

(M) - GPCR

•Nicotinic (N) –

ligand gated

Sites of Cholinergic

transmission

Site Types Selective

agonist

Selective

antagonist

1. All Postganglionic

Parasympathetic

2. Postganglionic

sympathetic to sweat

gland & BV

Muscarinic Muscarine Atropine

Ganglia (Both Para and

sympathetic and also

Adrenal Medulla

NN DMPP Hexamethoniu

m

Skeletal Muscle NM PTMA Curare

CNS Muscarinic Muscarine

Oxotremor

ine

Atropine

Cholinergic receptors

– Muscarinic (M) and Nicotinic (N)

• Nicotinic receptors:

• nicotinic actions of ACh are those

that can be reproduced by the

injection of Nicotine

• and also can be blocked by

tubocurarine and hexamethonium

• ligand-gated ion channels

• activation results in a rapid increase

in cellular permeability to Na+ and

Ca++

• results in depolarization and initiation

of action potential

Nicotinic (NM and NN)

Receptor Locations

NM (Muscle type) and NN (Ganglion type)

• NM (Muscle type): at neuromuscular junctions of skeletal

muscle:

• Postsynaptic and Excitatory (increases Na+ and K+ permeability)

• Stimulate skeletal muscle (contraction)

• Agonists: ACh, carbachol (CCh), suxamethonium

• Selective stimulation by phenyl trimethyl ammonium (PTMA)

• Antagonists: tubocurarine, hexamethonium

• NN type: In autonomic ganglia of all type (ganglion

type) – Sympathetic, Parasympathetic and also Adrenal

Medulla

• Depolarization and postganglionic impulse – stimulate all

autonomic ganglia

• Excitatory – Na+, K+ and Ca+ channel opening

• Agonists: ACh, CCh, nicotine

• Selectively stimulated by phenyl piperazinium (DMPP)

• Antagonists: mecamylamine, trimetaphan

Muscarinic (M)

Receptors

Amanita muscaria

Acetylcholine (cholinergic

receptors)

– Muscarinic Receptors

• Selectively stimulated by Muscarine nd

blocked by Atropine

• G-protein coupled receptors

• Primarily located in heart, blood vessels,

eye, smooth muscles and glands of GIT

• Subsidiary M receptors are also present in

ganglia for modulation

• Autoreceptors (M type) are present in

prejunctional cholinergic Nerve endings

Muscarinic Receptors -

Subtypes

• M1, M2, M3, M4 and M5

• M1, M2 and M3 are major ones and present

in effector cell and prejunctional nerve

endings in CNS

• M4 and M5 are present in certain areas of

Brain and regulate other neurotransmitters

• All subtypes have little agonist selectivity

but selective antagonist selectivity

M1 M2 M3

Location Autonomic ganglia, Gastric

glands and CNS

Heart and CNS SMs of Viscera,

Eye, exocrine

glands and

endothelium

Functions EPSP & Histamine release &

acid secretion with CNS

learning and motor functions

Less impulse

generation, less

velocity of

conduction,

decreased

contractility,

less Ach release

Visceral SM

contraction,

Constriction of

pupil, contraction

of Cilliary muscle

and vasodilatation

Agonists Oxotremorine and MCN and

MCN-343A

Methacholine Bethanechol

Antagonists Pirenzepine Methoctramine

& Triptramine

Darifenacin

Muscarinic Receptor

Subtypes

Acetylcholine (cholinergic

receptors)

– Muscarinic Receptors

• Selectively stimulated by

Muscarine and blocked by

Atropine

M1 M2 M3

Ganglia Heart Glands and SM

Cholinergic Drugs or

Cholinomimetic or

Parasympathomimetics

Drugs producing actions similar

to Ach – by interacting with

Cholinergic receptors or by

increasing availability of Ach at

these sites.

Classifiction - Direct-

acting (receptor

agonists )

• Choline Esters

• Natural: Acetylcholine

• Synthetic: Methacholine,

Carbachol and Bethanechol.

• Alkaloids: pilocarpine,

muscarine, arecholine

• Synthetic: Oxotremorine

Cholinergic Drugs –

Indirect acting

• Cholinesterase inhibitors or reversible

anticholinesterases:

• 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 Esters Carbaryl and Propoxur (Baygon)

Question…

• What side effects might you

expect to see in a patient

taking a cholinergic drug?

• Hint… Cholinergic = “Colon-

Urgent”

Ach actions - Muscarinic

1. Heart: M2

• Hyperpolarization of SA node, reuction in impulse

generation and Bradycardia

• 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 Nitric oxide (NO) release

• Penile erection

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 Iris – miosis

• Contraction of Ciliary muscles – spasm of

accommodation, increased outflow and

reduction in IOP

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)

Pilocarpine

• Alkaloid from leaves of Pilocarpus

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

Pilocarpine – contd.

• Used as eye drops in treatment of narrow

angle and wide angle glaucoma to reduce

IOP

• Used to reverse mydriatic effect of

atropine

• To break adhesion between iris and

cornea/lens alternated with 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 )

Pilocarpine – Mechanism

in Eye

Causes opening up

of trabecular

pores and

increased

drainage

Muscarine

• Alkaloid from mushroom Amanita

muscaria

• Only muscarinic actions

• No clinical use

• Cause mushroom poisoning due to

ingestion of poisonous mushroom

= Early onset mushroom poisoning

= Late onset mushroom poisoning

(neurogenic)

Early Onset Mushroom

Poisoning

• Occurs ½ to 1 hour.

• Muscaria cause mild cholinergic symptoms like

nausea, vomiting, salivation, lacrimation,

headache, bronchospasm, diarrhoea

• ntidote is Atropine sulphate (0.5-I mg IM twice

daily)

• Inocybe or Clitocybe – severe cholinergic symptoms

like bradycardia, dyspnoea, hypotension,

weakness, cardiovascular collapse, convulsions

and coma

• Antidote is Atropine sulphate ( 2-3 mg IM hrly till

• improvement )

Volvariella volvacea

Late Onset Mushroom

Poisoning

• Occurs within 6-15 hours

• Amanita phylloides – irritability,

restlessness, nausea, vomiting, ataxia,

hallucination, delirium, sedation,

drowsiness and sleep.

• Maintain blood pressure, respiration

• Inj. Diazepam 5 mg IM

• Atropine contraindicated as it may cause

convulsions and death

• Gastric lavage and activated charcoal

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)

AChEs - MOA

• Acetylcholinesterase (AchE) is

an enzyme, which hydrolyses

Acetylcholine

• The active site of AChE is made

up of two subsites – anionic and

esteratic

• The anionic site 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 esteratic subsite

• The AChE itself gets acetylated

at serine site

• 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

presynaptic membrane

Hydrolysis of ACh

NO

CCH3

O

+

-

+ NO

CCH3

O

+

-

+

OH-

NO

CCH3

O

+

-

OH

NOH CH3

O

+HO

+

Anti-ChEs (MOA) –

contd.

• Anticholinesterases also react with the enzyme ChEs in

similar fashion like Acetylcholine

• Carbamates – carbamylates the active site of the enzyme

• Phosphates – Phosphorylates the enzyme

• Carbamylated (reversible inhibitors) reacts with water

slowly and the esteratic site is freed and ready for action

– 30 minutes (less than synthesis of fresh enzyme)

• But, Phosphorylated (irreversible) reacts extremely

slowly or not at all – takes more time than synthesis of

fresh enzyme

• Sometimes phosphorylated enzyme losses one alkyl group

and become resistant to hydrolysis – aging

• Edrophonium and tacrine reacts only at anionic site while

Organophosphates reacts only at esteratic site

Cholinesterase inhibitors –

contd.

Anticholinesterases –

Individual Drugs

• 2 (two) important clinically used

drugs –

• Physostigmine – lipid soluble,

ganglion acting and less action in

skeletal muscle

• Also organophosphates

• Neostigmine – lipid insoluble,

skeletal muscle acting

Physostigmine

• Alkaloid from dried ripe seed (Calabar bean) of African

plant Physostigma venenosum

• 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 nerve endings and causes ACh

accumulation

• Muscarinic action on eye causing miosis and spasm of

accommodation on local application

• Antagonises mydriasis and cycloplegia produced by

atropine and anticholinergic drugs

• Salivation, lacrimation, sweating and increased

tracheobronchial secretions.

• Increased heart rate & causes hypotension

Physostigmine - uses

1. Used as miotic drops to decrease IOP in

Glaucoma

2. To antagonise mydriatic effect of atropine

3. To break adhesions between iris and

cornea alternating with mydriatic drops

4. Belladonna poisoning, TCAs &

Phenothiazine poisoning

5. Alzheimer’s disease- pre-senile or senile

dementia.

6. Atropine is antidote in physostigmine

poisoning.

7. ADRs – CNS stimulation followed by

depression.

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

neuromuscular junction (motor end plate) of

skeletal muscle

• Antagonises (reverses) skeletal muscle relaxation

(paralysis) caused by tubocurarine and other

competitive neuromuscular blockers

• Stimulates autonomic ganglia in small doses

• Large doses block ganglionic transmission

• No CNS effects

Neostigmine – Uses and

ADRs

• Used in the treatment of Myasthenia

Gravis to increase muscle 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 to weakness

• Atropine is the antidote in acute

neostigmine poisoning

Physostigmine and

Neostigmine - Summary

Physostigmine Neostigmine

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 gravis

Dose 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

Therapeutic Uses –

cholinergic drugs

1. Myasthenia gravis: Edrophonium to

diagnose and Neostigmine,

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

Alzheimer’s disease: Rivastigmine,

Gallantamine, Donepezil.

5. Physostigmine in Belladonna poisoning

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

Myasthenic crisis

• Acute weakness and respiratory

paralysis

• Tracheobronchial intubation and

mechnical ventilation

• Methylprednisolone IV with

withdrawal of AChE

• Gradual reintroduction of AChE

• Thymectomy

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 Poisoning)

• Poisoning may be –

Occupational, accidental,

Suicidal

• Symptoms:

• Fall in BP, bradycardia or tachycardia,

cardiac arrhythmia and vascular

collapse

• Irrittion of Eye, lacrimation, salivation,

colic, involuntary defection,

breathlessness, blurring of vision

• Muscular fasciculations and weakness

• Death due to respiratory paralysis –

peripheral and central

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

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 the phosphorylated 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

Khublei Shibun/Thank you