autonomic pharmacology and cholinergics - drdhriti
DESCRIPTION
A power point presentation on "Autonomic Pharmacology and Cholinergics" suitable for UG MBBS level studentsTRANSCRIPT
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