DRUGS AFFECTING THE SODIUM CHANNEL BOTH BLOCKER AND OPENERS, STRUCTURE OF SODIUM CHANNEL AND ITS LOCATION. SODIUM CHANNEL GATTING MECHANISM BY WITCH THEY ACTING. TYPES OF SODIUM CHANNEL AND ITS FUCTIONS. THEIR THERAPEUTIC APPLICATION WITH EXAMPLES OF DRUGS.

1. Presented byPresented by
mohan lalmohan lal
M. PharmM. Pharm
mohanlalchoudhary1992@gmail.commohanlalchoudhary1992@gmail.com
Sodium Channels AndSodium Channels And
Their ModulatorsTheir Modulators

2. Overview
What are Ion channels?
Localization
Molecular Structure of Channel
Gating mechanism
Types of Na+ channel
Sodium Channel Function
Sodium channel modulation
Therapeutic application
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3. What are ion channels?
Integral membrane proteins
Responsible for generating
and regulating the electrical
signals through the tissues.
Designed to form water-
filled pores that span the
membrane
Exist in three states resting,
open and closed
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4. Localization
Present in many tissues like:
Peripheral nervous system
Brain
Heart
Endocrine cells
Smooth and skeletal muscles
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5.  Consist of a large α-subunit associated with other proteins,
such as -subunits.β
 An -subunit forms the core of the channel and is functional onα
its own.
 ß-subunit displays altered voltage dependence and cellular
localization.
 -subunit has four repeat domains, labelled I through IV, eachα
containing six membrane-spanning regions, labelled S1 through
S6.
 The highly conserved S4 region acts as channel's voltage sensor.
 The voltage sensitivity of this channel due to positive amino
acids located at every third position.
 When stimulated by a change in transmembrane voltage, this
region moves toward the extracellular side of the cell
membrane, allowing the channel to become permeable to ions.
Structure of Na+
channel
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6. Structure of sodium channelsStructure of sodium channels
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Representation of the “typical” voltage-activated sodium channel

7. Structure of α sub-unit
 The ions are conducted through a pore, which can be
broken into two regions.
The more external (i.e., more extracellular) portion of the pore is
formed by the "P-loops" (the region between S5 and S6) of the four
domains. This region is the most narrow part of the pore and is
responsible for its ion selectivity.
The inner portion (i.e., more cytoplasmic) of the pore is formed by
the combined S5 and S6 regions of the four domains.
 The region linking domains III and IV is also important for
channel function. This region plugs the channel after
prolonged activation, inactivating it.
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8. Structure of β sub-unit
Two types of β subunits are observed.
β 1- abundantly present in muscles, heart,
and brain. It is bound non covalently.
β 2 forms a single intracellular carboxyl
terminal domain and a large glycosylated
extracellular amino terminal domain. Bound
covalently and forms a heterotrimer.
Main function of these sub units is to
modulate the kinetics of inactivation
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9. Gating
Gating, a change between the non-
conducting and conducting state of a
channel
The S4 transmembrane serve as voltage
sensors.
Every third position within these segments
has a positively charged amino acid
(arginine or lysine) residue.
The electrical field, which is negative
inside, exerts a force on these charged
amino acid residues to pull them towards
the intracellular side of the membrane15. 9

10. Impermeability to other ions
The pore of sodium channels contains a selectivity
filter made of negatively charged amino acid
residues, which attract the positive Na+
ion and
keep out negatively charged ions such as chloride.
The cations flow into a more constricted part of the
pore that is 0.3 by 0.5 nm wide, which is just large
enough to allow a single Na+
ion with a water
molecule associated to pass through.
The larger K+
ion cannot fit through this area.
Differently sized ions also cannot interact as well
with the negatively charged glutamic acid residues
that line the pore.
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11. States
Voltage gated sodium channels are present in
three states:
Resting: This is the closed state, which
prevails at the normal resting potential. During
this state, the activation gate is closed and
the inactivation gate is open.
Activated: This is the open state favoured by
brief depolarization. There is an abrupt
flipping open of the activation gate and slow
closure of inactivation gate.
Inactivated: Blocked state resulting from a
trap door-like occlusion of the channel by a
floppy part of the intracellular region of the
channel protein i.e. by the inactivation gate.
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12. 12

13. Types Of Na+ Channels
1. Voltage gated – Changes in membrane
polarity open the channel
2. Ligand gated (nicotinic acetylcholine
receptor) – Ligand binding alters
channel/receptor conformation and
opens the pore
3. Mechanically gated (stretch receptor) –
Physical torsion or deformation opens
the channel pore
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14. Sodium Channels - Function
Play a central role in the transmission of
action potentials along a nerve
Can be in different functional states
• A resting state when it can respond to a
depolarizing voltage changes
• Activated, when it allows flow of Na+ ions
through it
• Inactivated, when subjected to a
“suprathreshold” potential, the channel will
not open
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15. Na+ Channel Modulation
Phosphorylation
serine/threonine and tyrosine kinases & tyrosine
phosphatases.
Mutation
Altered amino acid sequence/structure
Pharmacology
block Na+ channel to reduce the conductance
e.g. Tetrodotoxin, Amioderone, Lidocaine,
Procainamide
Mexilitine ,Ketamine
Proteolysis- (cleavage)
Proteases may cleave specific residues or sequences
that inactivate a channel.

16. Conditions in which they are usedConditions in which they are used
Epilepsy or convulsions
Neuropathic pain
Neuoprotection in stroke and ischemia
Local anaesthesia
Cardiovascular like arrhythmias
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17. Pain
Neuropathic pain arises from increased no.
of sodium channels in sensory nerve fibres.
Hence increased spontaneous action
potential in peripheral nerves
Condition: neuropathic pain, diabetic
neuropathy, trigeminal neuralgia
Drugs used: carbamazepine, lidocaine,
mexilitine etc.
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18. Local anesthetics
Sodium channels open when membrane is
depolarized.
Modification of channels may be by
 blockage of the channels
modification of gating behaviour
Local anesthetics block nAch gated channels by
interacting with S6 transmembrane helical domain
LAs enter at the open state and stabilize the
inactivated state of the channels, by shifting the
equilibrium between resting and inactivated state
towards the latter.

19. Anticonvulsants
 Affects excitability by an action on vol. dependent Na
channels which carry inward current necessary for
generation of action pot.
 Higher the frequency of firing, greater the block
 Antiepileptics bind to depolarized state and reduces
the no. of functional channels for action pot.
generation
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20. Thus blockage of sodium channels in brain has a
major neuroprotective effect
Beneficial in ischemia, stroke etc.
Drugs used:
Phenytoin
Carbamazepine
Lamotrigine
Fosphenytoin etc.
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Continued….

21. Heart
Depolarization of the resting Na channel to
threshold voltage results in opening of the channel.
This lead to increased permeability of the Na
channel, activated state
Then the channel closes leading to inactivated state
and then again it reverts to resting state which can
be excited for next impulse.
Refractory period depends upon the time taken by
the channel to move from inactivated state to
resting state.
Class I antiarrhythmic drugs increases refractory
Period & decreases rhythm of heart.

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23. Side effects associatedSide effects associated
1. Cardiovascular: reduces systemic B.P. at high
doses, also decreases heart rate, sometimes
cardiac arrest
2. CNS: lidocaine affects myelinated and
unmyelinated axons, paralysis, tremors,
seizures and status epilepticus
3. Diuretics: potassium sparing diuretics block
Na channels with supplement of potassium.
Hence potentiating effect
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24. 
Thank you…..
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