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Questions and Answers
Why is the plasma membrane more permeable to K+ compared to other ions?
Why is the plasma membrane more permeable to K+ compared to other ions?
What would be the main effect of a drug that blocked resting K+ permeability on nerve cell membrane potential?
What would be the main effect of a drug that blocked resting K+ permeability on nerve cell membrane potential?
How does hyperkalaemia affect nerve and muscle cell excitability?
How does hyperkalaemia affect nerve and muscle cell excitability?
At what pH should local anesthetics ideally be formulated for optimal efficacy?
At what pH should local anesthetics ideally be formulated for optimal efficacy?
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What is the significance of pKa in the context of local anesthetics?
What is the significance of pKa in the context of local anesthetics?
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What physiological change results from hypokalemia in this clinical case?
What physiological change results from hypokalemia in this clinical case?
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What is the membrane potential (Vm) in relation to potassium ion concentrations in this case?
What is the membrane potential (Vm) in relation to potassium ion concentrations in this case?
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How does the frequency of action potentials relate to signal strength in neurons?
How does the frequency of action potentials relate to signal strength in neurons?
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What causes confusion and muddled states in patients with hypokalemia?
What causes confusion and muddled states in patients with hypokalemia?
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What results from the loss of K+ in the stomach and intestines?
What results from the loss of K+ in the stomach and intestines?
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What is the significance of the initial depolarization in action potential generation?
What is the significance of the initial depolarization in action potential generation?
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Why do muscle contractions decrease in patients with hypokalemia?
Why do muscle contractions decrease in patients with hypokalemia?
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What does the term 'binary signalling' in neuron communication imply?
What does the term 'binary signalling' in neuron communication imply?
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What physiological pH is typically associated with a greater proportion of ionized local anesthetics?
What physiological pH is typically associated with a greater proportion of ionized local anesthetics?
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How does the pKa of a local anesthetic affect its ionization at a given pH?
How does the pKa of a local anesthetic affect its ionization at a given pH?
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Which local anesthetic has the highest pKa among the examples provided?
Which local anesthetic has the highest pKa among the examples provided?
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At a physiological pH of 7.4, which local anesthetic is predominantly un-ionized?
At a physiological pH of 7.4, which local anesthetic is predominantly un-ionized?
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Which of the following statements is correct regarding the metabolism of local anesthetics?
Which of the following statements is correct regarding the metabolism of local anesthetics?
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Why do C fibers transmit pain signals more readily compared to A fibers when using local anesthetics?
Why do C fibers transmit pain signals more readily compared to A fibers when using local anesthetics?
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What role does the Henderson-Hasselbalch equation play in understanding local anesthetics?
What role does the Henderson-Hasselbalch equation play in understanding local anesthetics?
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Which local anesthetic is likely to have the fastest onset of action based on its degree of ionization at physiological pH?
Which local anesthetic is likely to have the fastest onset of action based on its degree of ionization at physiological pH?
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What is the typical pKa range for local anesthetics?
What is the typical pKa range for local anesthetics?
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Which local anesthetic can penetrate the nerve membrane more effectively due to its pKa?
Which local anesthetic can penetrate the nerve membrane more effectively due to its pKa?
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What is the likely consequence of a local anesthetic being predominantly ionized at physiological pH?
What is the likely consequence of a local anesthetic being predominantly ionized at physiological pH?
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Which statement best describes the effect of drug ionization on local anesthetic action?
Which statement best describes the effect of drug ionization on local anesthetic action?
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Regarding local anesthetics, why are myelinated fibers harder to penetrate?
Regarding local anesthetics, why are myelinated fibers harder to penetrate?
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Study Notes
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.
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Description
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.
