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 actionwith 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

neurotransmitter X

+

Atropine blocks muscarinic receptors

and decreases intestinal motility

Atropine blocks muscarinic cholinergic receptors

that respond to ACh

Parasympathetic nerves

release AChand 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

SomaticNervousSystem

AutonomicNervous System

One NeuronEfferent

Limb

Two NeuronEfferent

LimbPostganglionic

Preganglionic

SkeletalMuscle

Peripheral Nervous System

Somatic NervousSystem

Autonomic NervousSystem

ParasympatheticNervous System

SympatheticNervous System

SelectiveActivation

DiffuseActivation

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 DuctsGallbladder

Small Intestines

Stomach

Bronchi/Bronchial Glands

SA & AV Node

Sphincter Muscle of IrisCiliary Muscle

Lacrimal Gland

Submaxillary &Sublingual

Glands

Parotid Gland

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

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 - Steps1. Impulse Conduction

• Tetrodotoxin and saxitoxin

2. Transmitter Release3. Transmitter release on

postjunctional membrane• EPSP and IPSP

4. Postjunctional activity5. 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 impulseThe 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

Po

stg

ang

lio

ni c

F

iber

: C

ho

l in

erg

i c

Adrenal Gland

Motor Fiber

Sweat Glands

Smooth MuscleCardiac Cells

Gland Cells

Smooth MuscleCardiac Cells

Gland Cells

Skeletal Muscle

Pr e

gan

gli

on

ic F

iber

: C

ho

lin

erg

ic

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 Hexamethonium

Skeletal Muscle NM PTMA Curare

CNS Muscarinic MuscarineOxotremorine

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 LocationsNM (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 BP2. 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 Glaucoma2. To antagonise mydriatic effect of atropine3. To break adhesions between iris and cornea

alternating with mydriatic drops4. Belladonna poisoning, TCAs & Phenothiazine

poisoning5. 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/parenteral0.1-1% eye drop

0.5-2.5 mg IM/SC15-30 mg orally

Duration of action

4-6 Hrs 3-4 Hrs

Therapeutic Uses – cholinergic drugs1. 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