3. • Excitability of a tissue depends on its
membrane potential
– Excitable tissues have more negative RMP
( - 70 to - 90 mV)
– Non-excitable tissues have less negative RMP
( - 40 mV)
excitable Non-excitable
Red cell
GIT
neuron
muscle
4. Factors contributing to RMP
• One of the main factors is K+ efflux
• (Nernst Equilibrium Potential: -94mV)
• Contribution of Na influx is little
• (Nernst Equilibrium Potential: +61mV)
• Na/K pump causes more negativity inside the
membrane
•
Negatively charged protein remaining inside due to
impermeability contributes to the negativity
• Net result: -70 mV inside
5. Ionic channels
• Leaky channels (K-Na leak channel)
– More permeable to K
– Allows free flow of ions
K+
Na+
6. Na/K pump
• Active transport system for Na-K exchange using
energy
• It is an electrogenic pump since 3 Na efflux coupled
with 2 K influx
• Net effect of causing negative charge inside the
membrane
3 Na+
2 K+
ATP ADP
8. Physiological basis of AP
• When the threshold level is reached
– Voltage-gated Na channels open up
– Since Na conc outside is more than the inside
– Na influx will occur
– Positive ion coming inside increases the positivity of the membrane potential and
causes depolarisation
– When it reaches +35, Na channels closes
– Then Voltage-gated K channels open up
– K efflux occurs
– Positive ion leaving the inside causes more negativity inside the membrane
– Repolarisation occurs
• Na/K pump restores Na and K conc slowly
– By pumping 3 Na ions outward and 2 K ions inward
9. • At rest: the activation gate is closed
• At threshold level: activation gate opens
– Na influx will occur
– Na permeability increases to 500 fold
• when reaching +35, inactivation gate closes
– Na influx stops
• Inactivation gate will not reopen until resting
membrane potential is reached
outside
inside
outside
inside
-70 Threshold level +35
Na+ Na+
outside
inside
Na+m gate
h gate
10. – At rest: K channel is closed
– At +35
• K channel open up slowly
• This slow activation causes K efflux
– After reaching the resting still slow K channels may
remain open: causing further hyperpolarisation
outside
inside
outside
inside
-70 At +35
K+ K+
n gate
11. Propagation of AP
• When one area is depolarised
• A potential difference exists between that site
and the adjacent membrane
• A local current flow is initiated
• Local circuit is completed by extra cellular fluid
12. Propagation of AP
• This local current flow will cause opening of
voltage-gated Na channel in the adjacent
membrane
• Na influx will occur
• Membrane is deloparised
13. Propagation of AP
• Then the previous area become repolarised
• This process continue to work
• Resulting in propagation of AP
18. AP propagation along myelinated
nerves
• Na channels are conc around nodes
• Therefore depolarisation mainly occurs at
nodes
19. AP propagation along myelinated
nerves
• Local current will flow one node to another
• Thus propagation of A.P. is faster. Conduction
through myelinated fibres also faster.
• Known as Saltatory Conduction
25. Synapse
• A gap between two neurons
• More commonly chemical
• Rarely they could be electrical (with gap junctions)
• Although an axon conducts bothways, conduction
through synapse is oneway
26. Presynaptic terminal (terminal knob,
boutons, end-feet or synaptic knobs)
Terminal has synaptic vesicles and mitochondria
Mitochondria (ATP) are present inside the presynaptic
terminal
Vesicles containing neurotransmitter (Ach)
27. Presynaptic terminal (terminal knob,
boutons, end-feet or synaptic knobs)
Presynaptic membrane contain voltage-gated Ca2+ channels
The quantity of neurotransmitter released is proportional to
the number of Ca2+ entering the terminal
Ca2+ ions binds to the protein molecules on the inner surface
of the synaptic membrane called release sites
Neurotransmitter binds to these sites and exocytosis occur
29. Synthesis of Ach
• Synthesised from choline and acetyl-coenzyme A (acetyl-coA) in the
terminal axoplasm of motor neurons
• Acetyl-coA is synthesised from pyruvate in the mitochondria in the axon
terminals
• Approximately 50% of the choline is extracted from extracellular fluid by a
sodium dependent active transport system
• Other 50% is from acetylcholine breakdown at the neuromuscular junction.
• Majority of the choline originates from the diet with hepatic synthesis only
accounting for a small proportion
30. • Postsynaptic membrane contain nicotinic
acetylcholine receptor
Ach
Na+
• This receptor contains several
sub units (2 alpha, beta, delta &
epsilon)
• Ach binds to alpha subunit
• Na+ channel opens up
• Na+ influx occurs
• End Plate Potential (EPP)
•This is a graded potential
•Once this reaches the threshold
level
•AP is generated at the
postsynaptic membrane
31. Ach vesicle docking
• With the help of Ca entering the presynaptic terminal
• Docking of Ach vesicles occur
• Docking:
– Vesicles move toward & interact with membrane of
presynaptic terminal
• There are many proteins necessary for this purpose
• These are called SNARE proteins
• eg. Syntaxin, synaptobrevin etc
32. NMJ blocking
• Useful in general anaesthesia to facilitate inserting tubes
• Muscle paralysis is useful in performing surgery
• Commonly used to paralyze patients requiring intubation
whether in an emergency as a life-saving intervention or for a
scheduled surgery and procedure
• To assist with mechanical ventilation in patients who have
reduced lung compliance
• Indications for intubation during an emergency
– failure to maintain or protect the airway
– failure to adequately ventilate or oxygenate
– anticipation of a decline in clinical status
33. Earliest known NMJ blocker - Curare
• Curare has long been used in South America as
an extremely potent arrow poison
• Darts were tipped with curare and then
accurately fired through blowguns made of
bamboo
• Death for birds would take one to two minutes,
small mammals up to ten minutes, and large
mammals up to 20 minutes
• NMJ blocker used in patients is tubocurarine
• Atracurium is now used
34. Non-depolarising blocking agents
– eg.
• Curare
• Atracurium
• Rocuronium
• Vencuronium
– Competitive
– Act by competing with Ach for the Ach receptors
– Binds to Ach receptors and blocks
– Prevent Ach from attaching to its receptors
– No depolarisation
– Late onset, prolonged action
– 70–80% of receptors should be occupied to produce an effect
– To produce complete block, at least 92% of receptors must be occupied
– Ach can compete & the effect overcomes by an excess Ach
– Anticholinesterases can reverse the action
35. Depolarising blocking agents
– eg. Succinylcholine
– non-competitive, chemically act like Ach
– Bind to motor end plate and once depolarises
– Persistent depolarisation leads to a block
• Due to inactivation of Na channels
– Ach cannot compete with depolarising blockers
– There are two phases in the depolarising block
– Phase I block and Phase II block
– Phase I block (depolarisation block)
• After a depolarizing agent binds to the motor end plate receptor, the
agent remains bound and thus the end plate cannot repolarize
• During this depolarizing phase the transient muscle fasciculation
occur
• Absence of fade to tetanic stimulation
• Prolonged exposure to succinylcholine leads to desensitisation block.
– This occurs when ACh receptors are insensitive to the channel-opening effects of
agonists, including ACh itself.
36. Depolarising blocking agents
– Phase II block
• This occurs after repeated boluses or a prolonged infusion of
succinylcholine
• After adequate depolarization has occurred, phase II sets in and the
muscles are no longer receptive to acetylcholine released by the
motor neurons
• After the initial depolarization, the membrane potential gradually
returns towards the resting state, even though the neuromuscular
junction is still exposed to the drug. Neurotransmission remains
blocked throughout.
• It is at this point that the depolarizing agent has fully
achieved paralysis
• Fade after tetanic stimulation
– Succinylcholine has quick action start within 1 min and last for 12 min
– Hydrolysed by plasma cholinesterase (also called pseudocholinesterase)
produced in the liver
– Prolonged blockade is seen in liver disease or pregnancy
– Inhibition of plasma cholinesterase occurs with OP compounds
– Side effect: hyperkalaemia
– Bind to nicotinic and muscarinic Ach, causes bradycardia
– Contraindicated in burns
39. Na+
Depolarized
Na+
PHASE I
Membrane depolarizes
resulting in an initial
discharge which
produces transient
fasciculations followed
by flaccid paralysis
- - - -
+ + + ++ + + +
- - - - - - - -+ + + + + + + +
- - - -- - - -
Depolarizing Neuromuscular blocking drugs
40. Repolarized
PHASE II
Membrane repolarizes
but the receptor is
desensitized to effect
of acetylcholine
+ + + +- - - -+ + + +- - - -
- - - -+ + + +
- - - -+ + + +
Depolarizing Neuromuscular blocking drugs
41. Anticholinesterases
• AchE inhibitors
– Inhibit AchE so that Ach accumulates and causes
depolarising block
• Reversible
– Competitive inhibitors of AChE
– Block can be overcome by curare
• physostigmine, neostigmine, edrophonium
• Irreversible
– Binds to AChE irreversibly
• , insecticides, nerve gases
42. Reversal of NMJ blockers
• Recovery from the effects of non-depolarising relaxants can
occur spontaneously by elimination of the agent either
unchanged or after metabolism
• However, this process may be slow, of variable time and cannot
be reliably predicted
• Pharmacological antagonism or reversal of NMJ block is
therefore indicated in clinical practice
• Anticholinesterases (eg. Neostigimine) reverse the action of
non-depolarising blockers
• Another drug (eg. sugammadex) which bind to non-depolarising
blocker and reverses its action is used
• There is no antagonist for succinylcholine but its action is short
lasting
43. NMJ disorders
• Myasthenia gravis
– Antibodies to Ach receptors
– Post synaptic disorder
• Lambert Eaton Syndrome (myasthenic syndrome)
– Presynaptic disorder (antibodies against Ca channels)
• Botulism
– Presynaptic disorder
– Binds to the presynatic region and prevent release of Ach
44. Botulinum toxin
• Most potent neurotoxin known
• Produced by bacterium Clostridium botulinum
• Causes severe diarrhoeal disease called botulism
• Action:
– enters into the presynaptic terminal
– cleaves proteins (syntaxin, synaptobrevin) necessary for Ach vesicle
release with Ca2+
• Chemical extract is useful for reducing muscle spasms, muscle
spasticity and even removing wrinkles (in plastic surgery)
45.
46. Organophosphates
• Phosphates used as insecticides
• Action
– AchE inhibitors
– Therefore there is an excess Ach
accumulation
– Depolarising type of postsynaptic
block
• Used as a suicidal poison
• Causes muscle paralysis and death
• Nerve gas (sarin)
47. Snake venom
• Common Krait (bungarus
caeruleus)
– Produces neurotoxin known as
bungarotoxin
– Very potent
• Causes muscle paralysis and death
if not treated
• Cobra
– venom contain neurotoxin
48. Myasthenia gravis
• Serious neuromuscular disease
• Antibodies form against acetylcholine nicotinic
postsynaptic receptors at the NMJ
• Characteristic pattern of progressively reduced
muscle strength with repeated use of the muscle and
recovery of muscle strength following a period of rest
• Present with ptosis, fatiguability, speech difficulty,
respiratory difficulty
• Treated with cholinesterase inhibitors
