Autonomic Nervous System - “Autonomic Pharmacology”

Department of PharmacologyNEIGRIHMS, 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 – called HOMEOSTASIS

Role of ANS in homeostasis links to target organs -

(Cardivascular System, smooth muscle of GI and glands)

+

Drug A decreases activity of

organ O

Autonomic Pharmacology is Practical

Nerves to organ O release neurotransmitter N,

and N increasesthe activity of organ O

Mimic or Block transmitters

Drug A blocks receptors for

neurotransmitter N

+

Atropine blocks muscarinic receptors

and decreases intestinal motility

Atropine blocks muscarinic cholinergic receptors

that respond to ACh

Understanding actions of drugs that influence the autonomic nervous system allows prediction of their

effects!Parasympathetic

nervesrelease ACh

and increase intestinal motility

For a definite clinical outcome!

Sympathetic nervesrelease

Noradrenalineand increase

Blood Pressure

Propranolol blocks β-adrenergic

receptorsthat respond to NA

Propranolol blocks β-adrenergic receptors

and decreases Blood Pressure

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 – Recall

Organization ofNervous System - Recall

Central Nervous System

“Brain and spinal cord”

Peripheral Nervous System

Autonomic Nervous System Somatic Nervous System

Afferent Division Efferent Division

Sympathetic

“thoracolumbar”

Parasympathetic

“craniosacral”

Controls skeletal muscle

Controls

cardiac muscle &

glands

Peripheral Nervous System

SomaticNervousSystem

AutonomicNervous System

One NeuronEfferent

Limb

Two NeuronEfferent

LimbPostganglionic

Preganglionic

smooth &

Recall Differences - Somatic Vs ANS

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

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 brain

medulla

Organization of ANS – Efferent fibres

• Motor limb – Sympathetic and Parasympathetic

• Most organs receive both innervations

• Functionally antagonistic of each other

• Overall – depends on the tone at particular moment • EXCEPTIONS:– Most Blood vessels, sweat

glands and hair follicles – Sympathetic

– Gastric and pancreatic glands, cilliary muscles - Parasympathetic

AUTONOMIC NERVOUS SYSTEM

• SYMPATHETIC– Fight or Flight

• PARASYMPATHETIC– Rest and Digest

Next slide – Distriibution:

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 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

Impulse conduction across synapse

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 Neurons 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.

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 Muscles4. CNS: Cortex Basal ganglia, spinal chord and othersParasympathetic Stimulation – Acetylcholine (Ach) release at neuroeffector junction

- biological effectsSympathetic stimulation – Noradrenaline (NA) at neuroeffector junction - biological

effects

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 Choline 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 AChEsTrue AChE Pseudo AChE

Distribution All cholinergic sites, RBCs, gray matter

Plasma, liver, Intestine and white matter

Action on: Acetycholine Methacholine

Very FastSlower

SlowNot hydrolyzed

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

Acetylcholine (cholinergic receptors) – Muscarinic Receptors

1. Selectively stimulated by Muscarine and blocked by Atropine – all are G-protein coupled receptors

2. Primarily located in heart, eye, smooth muscles and glands of GIT3. Subsidiary M receptors are also present in ganglia for modulation4. Autoreceptors (M type) are present in prejunctional cholinergic Nerve

endings – also in adrenergic nerve terminals leading to vasodilatation when Ach is injected

5. Blood vessels: All blood vessels have muscarninc receptors although no cholinergic innervations

Amanita muscaria

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

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

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 Smooth Muscles

Nicotinic (N) Receptors

Nicotinic receptors: nicotinic actions of ACh are those that can be reproduced by the injection of Nicotine (Nicotiana tabacum)

Can be blocked by tubocurarine and hexamethonium

• ligand-gated ion channels– activation results in a rapid increase in cellular

permeability to Na+ and Ca++ resulting - depolarization and initiation of action potential

Nicotinic (NM and NN) Receptor - comparison

NM (Muscle type)1. Location: Skeletal Muscle

end plates 2. Function: Stimulate skeletal

muscle (contraction)3. MOA: Postsynaptic and

Excitatory (increases Na+ and K+ permeability)

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

– Selective stimulation by phenyl trimethyl ammonium (PTMA)

5. Antagonists: tubocurarine, hexamethonium

NN (Ganglion type)1. Location: In autonomic ganglia of

all type (ganglion type) – Sympathetic, Parasympathetic and also Adrenal Medulla

2. Function: Depolarization and postganglionic impulse – stimulate all autonomic ganglia

3. MOA: Excitatory – Na+, K+ and Ca+ channel opening

4. Agonists: ACh, CCh, nicotine– Selectively stimulated by

phenyl piperazinium (DMPP)5. Antagonists: mecamylamine,

trimetaphan

Sites of Cholinergic transmission and types of Receptors

Site Types Selective agonist

Selective antagonist

All Postganglionic Parasympathetic

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

Ganglia Concept - summary

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.

Classification - 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 - Muscarinic1. Heart: M2

– Hyperpolarization of SA node, reduction in impulse generation and Bradycardia

– 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 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 glands5. Eye: M3

– Contraction of circular fibres of Iris – miosis– Contraction of Ciliary muscles – spasm of accommodation,

increased outflow and reduction in IOP

Ach actions - Nicotinic1. 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 urinary

obstruction, neurogenic bladder and GERD (10-40 mg oral)

Pilocarpine• Alkaloid from leaves of Pilocarpus

microphyllus• Prominent muscarinic actions• Profuse salivation, lacrimation,

sweating• Dilates blood vessels, causes

hypotension• On Eyes:

– it produces miosis by contraction of circular muscles of iris

– Contraction of cilliary muscles• spasm of accommodation -

fixed for near vision• Increased outflow of AH

• 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 )

Muscarine

• Alkaloid from mushroom Amanita muscaria• Only muscarinic actions• No clinical use• Mushroom poisoning due to ingestion of poisonous

mushroom = Early onset mushroom poisoning (Muscarine type) = Late onset mushroom poisoning (neurogenic)

Early Onset Mushroom Poisoning

• Occurs ½ to 1 hour • Symptoms are characteristic of Muscarinic actions• Inocybe or Clitocybe – severe cholinergic symptoms like

vomiting, salivation, lacrimation, headache, bronchospasm, diarrhoea bradycardia, dyspnoea, hypotension, weakness, cardiovascular collapse, convulsions and coma

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

Hallucinogenic type: due to Muscimol or ibotenic acid present in A. muscria. Blocks muscarinic receptors in brain and activate mio acid receptors. No specific treatment – Atropine is contraindicated.

Volvariella volvacea

Late Onset Mushroom Poisoning

• Occurs within 6-15 hours• Amanita phylloides – due to peptide toxins – Inhibit RNA and

protein synthesis• Irritability, restlessness, nausea, vomiting, bloody diarrhoea

ataxia, hallucination, delirium, sedation, drowsiness and sleep – Kidney, 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

Cholineste

rase

Inhibitors

“ANTICHOLINESTERASE

S”

Cholinesterase inhibitors - Classification

• 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)

Overall …

• Most reversible Anti-ChEs are Carbamic acid compounds – Physostigmine, Neostigmine, pyridostigmine and Edrophonium Physostigmine is tertiary amine (has tertiary amino N radical) – lipid

soluble Neostigmine – Quarternary amine (has tertiary amino N radical) - lipid

insoluble Exception: Tacrine – Acridine derivative

• Most Irreversible Anti-ChEs contain Phosphoric acid – ORGANOPHOSPHATES – highly lipid soluble• A few Irreversible Anti-ChEs are lipid soluble Carbamates - Carbaryl

and Propoxur

AChEs - MOA

• Acetylcholinesterase is the primary target• Normally Acetylcholine - binds to the enzyme's active site and is

hydrolyzed, yielding free choline and the acetylated enzyme• The active site has two subsites – anionic and esteratic• The anionic site serves to bind a molecule of ACh to the enzyme• Once the ACh is bound at anioic site, the hydrolytic reaction occurs at

a second region of the active site - esteratic subsite• AChE itself gets acetylated by acetylation of serine site • Acetylated enzyme reacts with water to form Acetic acid and choline

(Bond splits)

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

Anti-ChEs (MOA) – contd.

If You Want to Know More …

Please follow the coming Slides!

HN

Hydrolysis of acetylcholine by AChE

Trp 86

Esteratic site

ON

CH3

CH3

CH3

O

OH

Ser 203

Phe 338

Anionic site

CO

OGlu 327

N

HN

His 440

O

O

HN

Hydrolysis of acetylcholine by AChE

Trp 86

Esteratic site

Ser 203

Phe 338

Anionic siteHO

N

CH3

CH3

CH3

CO

OGlu 327

N

HN

His 440

O

O

HN

Hydrolysis of acetylcholine by AChE

Trp 86

Esteratic site

Ser 203

Phe 338

Anionic siteHO

N

CH3

CH3

CH3

choline

CO

OGlu 327

N

HN

His 440

O

O

HN

Hydrolysis of acetylcholine by AChE

Trp 86

Esteratic site

Ser 203

Phe 338

Anionic site

CO

OGlu 327

N

HN

His 440 HO H

OH

HN

Hydrolysis of acetylcholine by AChE

Trp 86

Esteratic site

Ser 203

Phe 338

Anionic siteOH

Oacetate

CO

OGlu 327

N

HN

His 440

Action Potential

Na+

Ca 2+

Acetylcholinesterase

Pharmacologic manipulation of AChE: No inhibition

Presynaptic neuronPostsynaptic target

Muscarinic

Receptor

ACH

ACH

CholineAcetate

ACHACH

ACH

ACHACH

ACH

ACHACH

ACH

Action Potential

Na+

Ca 2+

Acetylcholinesterase

Pharmacologic manipulation of AChE: Inhibition by drugs

Presynaptic neuronPostsynaptic target

Muscarinic

Receptor

ACH

ACH

ACHACH

ACH

ACHACH

ACH

ACHACH

ACH

ACHACH

ACH

ACH

ACH

ACH

Anti-ChEs – Pharmacological Actions

• Qualitatively similar to directly acting cholinergics, but quantitatively different – two important clinically used drugs:– Lipid soluble agents (physostigmine) – more muscarinic and CNS effects

(stimulate ganglia) – less skeletal muscle effect– Lipid insoluble ones like Neostigimine – more skeletal muscle effect, stimulate

ganglia but less muscarinic effect

• Ganglia: Stimulates ganglia through muscarinic receptors, but high doses may cause persistent depolarization of Nicotinic receptors and block transmission

• CVS: Complex action – muscarinic-bradycardia, ganglionic-tachycardia etc.• Skeletal Muscle: Repetitive firing – twitching and fasciculation

– High doses – persistent depolarization and NM blockade

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 - uses1. 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

Atropine is antidote in physostigmine poisoningADRs – 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 drugs

1. Myasthenia gravis: • Edrophonium to diagnose• 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– Dose requirement may fluctuate time to time – adjustment required– Pyridostigmine – less frequency of dosing– Other drugs: Corticosteroids (prednisolone 30-60 mg /day)

• Azathioprin and cyclosporin also Plasmapheresis– Plasmapheresis

Myasthenia Gravis - Images

Myasthenic crisis• Acute weakness and respiratory paralysis

– Tracheobronchial intubation and mechanical ventilation– Methylprednisolone IV with withdrawal of AChE– Gradual reintroduction of AChE– Thymectomy

• Edrophonium is used for diagnosis of Myasthenic crisis (disease itself) and cholinergic crisis (overdose of Anti-ChE)– Improvement of symptoms – myasthenic crisis– Worsening – Cholinergic crisis

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 has a quaternary Nitrogen – gets attached to Anionic site of the enzyme - unoccupied in Organophosphorous poisoning

– and reacts with Phosphorous atom at esteratic site– Forms Oxime-phosphonate complex making esteratic site free– Not effective in Carbamate poisoning– Available as 500 mg/20 ml infusion or 1 gm/vial for infusion– Injected slow IV - 1-2gm

Khublei Shibun / Thank you