Post on 07-May-2015
description
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