Neurophysiology and Local Anesthetics Quiz

Basics of the Nervous System 2

• Learning Objectives: Describe the distribution of ions across cell membranes, the origin of membrane potential, the relationship between equilibrium potential and membrane potential, the relationship between membrane potential and ion concentrations, the role of the Na+/K+ ATPase, action potential generation and propagation along nerves, and how local anaesthetics work.

Excitable Cells

• Excitable cells use electrical energy to function
• Muscle cells (skeletal, cardiac, and smooth)
• Immune cells migrate
• Nerve cells transmit signals over distances

Membrane Potential (Vm)

• Ions have different concentrations inside and outside cells
• Cell membranes have differing permeabilities for different ions
• Membrane potential is due to separation of electrical charges across the membrane

Variations in Vm

• All cells have a resting membrane potential (Vm)
• Resting potential varies between cell types
• In some cells, resting potential is static
• In other cells, resting potential changes with homeostasis and signal transduction
• Action potentials are a specific type of change in Vm

Na+/K+ ATPase

• Actively transports Na+ and K+ in different directions across the membrane
• Requires metabolic energy (ATP)
• Maintains concentration gradients of Na+ and K+ across the membrane

Ion Distribution

• Ions are present in different concentrations inside and outside neurons
• Neurons have different permeabilities for different ions
• Key ion concentrations are shown in a table, including extracellular and intracellular concentrations (mM) and relative permeability

The Resting Membrane Potential

• Electrical neutrality is maintained across the cell membrane
• Positive charges balance negative charges, differing intracellularly and extracellularly
• The resting membrane potential is due to the high membrane permeability to K+
• K+ leak channels are always open, and the action of the Na+/K+ ATPase maintains K+ cycling

The Electrochemical Equilibrium

• Equilibrium potential (E) is the voltage at which the electrical force on an ion is equal and opposite to the chemical force
• Each ion has an equilibrium potential (Eion)
• For a membrane solely permeable to K+, the membrane potential equals the equilibrium potential for K+ (Vm = Ek)

The Nernst Equation

• Mathematical expression for calculating equilibrium potential
• Includes variables like the gas constant (R), temperature (T), Faraday's constant (F), and ion concentrations

Applying the Nernst Equation

• The nernst equation predicts equilibrium potentials for various ions (Na+, K+, Cl-).
• Vm is a simplification because it is actually governed by multiple ion concentrations.

The Goldman Equation

• More realistic model of membrane potential, accounting for the permeability of multiple ions
• Takes into account the permeabilities of Na+, K+, and Cl- ions

Resting Vm and Polarization

• The resting membrane potential of cells is typically negative (-50 to -90 mV).
• Depolarization occurs when Vm becomes less negative.
• Hyperpolarization occurs when Vm becomes more negative.

Clinical Case

• Discusses a case of hypokalemia (low potassium in the blood), explaining the effect it has on neuronal function.
• Low potassium leads to cell hyperpolarization and reduces neuronal excitability, causing symptoms like weakness and fatigue, confusion, and arrhythmias.

Neuronal Signaling - Action Potentials

• Neuronal signaling is binary, occurring whether or not a threshold is reached.
• Action potentials are a very short-lived depolarization of the plasma membrane.
• Electrical propagation occurs along axons.
• Chemical transmission occurs at synapses and terminals using neurotransmitters.
• These relay processes can be blocked pharmacologically.

Action Potentials (APs)

• Initial change in membrane potential (depolarization) is needed for an action potential.
• Reaching a threshold depolarization triggers an action potential.
• APs are binary (all-or-nothing), short-lived (~1-2 ms) processes.
• Hyperpolarization follows repolarization, creating a refractory period.

Ion Movements vs Permeability

• The actual number of ions moving during an AP is small relative to the total ion numbers.
• The change in membrane permeability, rather than ion concentrations, underlies APs.
• Reversal of the AP (repolarisation) is not dependent on "pumping out" excess Na+.

Pharmacological Tools to Study APs

• Tetrodotoxin (TTX) blocks voltage-gated Na+ channels (VGSCs)
• Tetraethylammonium (TEA) blocks voltage-gated K+ channels
• Quabain inhibits Na+/K+ ATPase.

APs - Refractory Periods

• Refractory periods are the time after an action potential when another action potential cannot be initiated.
• Refractory periods are caused. by the inactivation of voltage-gated Na+ channels in the plasma membrane of the neuron.

Information Flow Through APs

• Action potentials encode information via their frequency, not their amplitude.
• Upper frequency is limited by the refractory period.

Frequency vs Amplitude

• The strength of a neural signal is determined by the frequency of action potentials.
• The amplitude of the individual action potentials does not vary.

APs - Refractory Periods

• Refractory period is caused by the inactivation of voltage-gated sodium channels.

Propagation of AP Along an Axon

• Depolarisation at one segment triggers depolarisation in the next.
• Na+ channels in the previous depolarising segment are inactivated during the refractory period, so the AP does not travel backward.

Speed of Conductance

• Factors influencing speed:
  • Temperature
  • Axon diameter
  • Myelination (saltatory conduction)

Myelination

• Myelin sheath insulates axons permitting faster and efficient signal propagation.
• Myelination is provided by glial cells (oligodendrocytes in the CNS and Schwann cells in the PNS)
• Saltatory conduction occurs faster along axons due to myelin sheath surrounding the axon membrane, allowing movement of action potentials to the node of Ranvier, instead of continually across the plasma membrane.

Nerve Fiber Classification

• Nerve fibers are classified by diameter and myelination for different types of signals
• Table of nerve fiber type, diameter, conduction velocity and myelin

Neuronal Transmission and Pain

• Pain transmission involves neuronal transmission.
• Neuronal transmission can be targeted/modified for pain management
• Alterations in neuronal transmission can cause pain

Gated Ion Channels

• Normal neuronal firing is due to the rapid depolarization caused by the opening of voltage-gated cation channels.
• Ion channels can be voltage-gated, ligand-gated, or tension-gated.

Voltage-gated Ion Channels (VGICs)

• VGICs are similar across different ion species (Na+, K+, Ca2+).
• VGIC structure and central pore allow for ion passage based on electrochemical gradients.
• Auxiliary subunits are seen in VGICs

VGIC Structure - Examples

• Illustrates different VGIC structures, their components and functions.

VGSC and Pain Transmission

• VGSCs are key for action potentials and pain signaling.
• Pain signals are transduced by sensory terminals and amplified into action potentials at this stage for relay to the spinal cord.
• Varying types of VGSCs can differentiate sensitivity to different types of pain

Local Anaesthetics (LAs)

• LAs inhibit voltage-gated sodium channels.
• LAs are weak bases that readily cross the plasma membrane in their un-ionized form, then ionize inside the cell, binding to VGSC proteins
• LAs are metabolised into inactive compounds.

LAs: Examples and Metabolism

• Lists examples of local anaesthetics and their chemical structures.
• Shows how esters and amides are metabolised and differences between their metabolic routes

LAs are Weak Bases

• LAs exist in both ionized and un-ionized forms.
• pKa of the LA determines the proportion of the ionized and un-ionized molecules at a particular pH.
• LAs are more readily absorbed as an un-ionized form, and become absorbed more effectively when the pH is higher (more basic)

Self-Test Questions

• A series of self-test questions are included on the various concepts learned.
• Provide answers to the given self-test questions.

Local Anesthetics Practical

• Introduces a practical to explore how local anaesthetics work in a study design.
• Explains the aims & objectives of the practical.

Preparation

• Lists necessary items and procedures for the practical.

Test your understanding of neurophysiology concepts including potassium ion permeability, the effects of hypokalemia, and the principles of local anesthetics. This quiz covers the physiological implications of ion concentrations and membrane potentials in nerve and muscle excitability. Dive into the nuances of action potentials and binar signalling.