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112 Cards in this Set
- Front
- Back
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LA produce clinical effects by interfering w/_____ activity of the _____ system
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Electrical activity
Nervous system |
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LA ________ propagation of nerve impulses in peripheral nerves and spinal cord
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Inhibit propagation
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LA act _____ on sensory nerve endings when applied ______
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Act directly
Applied topically |
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LA inhibit synaptic transmission in the spinal cord via _____ or _____ block
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Via Epidural or Intrathecal (Spinal) Block
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Peripheral nerves are mixed, meaning they contain ____ and ____ fibers that are either _____ or not.
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Contain afferent and efferent fibers that are MYELINATED or non-myelinated
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An Axon is...
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the functional unit of a peripheral nerve
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An axon is an extension of a....
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...centrally located neruon
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What are the two components of an axon?
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Cell membrane (axolemma)
Intracellular contents (axoplasm) |
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An impulse travels along an axon by ______ flowing beetween what two things?
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Currents flowing between:
Active (depolarized) membrane and Adjacent (resting) membrane |
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What are the 3 layers of s periph nerve from outside in?
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1. Epineurium--encases perineurium
2. Perineurium 3. Endoneurium |
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What is the epineurium layer of a periph nerve composed of?
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Composed of dense connective tissue.
Functionally holds fascicles together as periph nerve |
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What is the perineurium? What is its purpose?
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Flattened overlapping cells of connective tissue
Binds a group of fasicles together |
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What is the endoneurium layer of a periph nerve composed of? Purpose?
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Composed of connective tissue and longitudinally arranged collagen
Surrounds and embeds axons in fascicles |
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Individual myelinated nerve fibers are encased in a ____ ___
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myelin sheath
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Myelinated nerve fibers extend from what to what?
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Extend discontinuously from roots of spinal cord to near the region of entry at target organ
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Each segment of myelin is formed by what?
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1 schwann cell
Wraps around axon, forming insulated cylinder for up to several hundred bilayer membranes |
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Schwann cells provide ____ and ____
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Support and insulation
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In UNmyelinated nerves, 1 Schwann cell covers __-__ axons
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5-10 axons
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What kind of mammalian nerves are myelinated?
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All mammalian nerves >1ug in diameter
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Nodes of Ranvier seperate what?
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Seperate myelinated regions along nerve
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What is the purpose of the nodes of ranvier?
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They concentrate structural elements for neuronal excitation
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Nodes of Ranvier are covered by interdigitations from what 2 things?
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Nonmyelinating Schwann cells
Negatively charged glycoproteins |
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Nodes have limited ______ _____ for drugs to _____
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Diffusion barriers for drugs to penetrate
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What MAY be the primary site where LA exert their action?
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Nodes of Ranvier
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Nodes of Ranvier contain a large # of ____ channels that can generate an intense AP
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Na+ channels
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Depolarization in one segment of nerve results in what?
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Depolarization of the adjacent segment!
D/T difference in electrical potential (I think this is saltatory conduction?) |
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Once nerve stimulation occurs, transmission of impulse is...
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Self-propogating and self-sustaining
ALL or NOTHING |
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Is conduction fast or slow in an UNmyelinated nerve? Why or why not?
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SLOW
D/t resistive and capacitative current loss Requires achievement of threshold potential at immediately adjacent membrane |
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Is impulse conduction rapid or slow in a myelinated nerve? Why or why not?
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RAPID
Travels further before fading below threshold impulse |
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In a myelinated nerve, impulse propagation proceeds by...
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leaping from node of Ranvier to node of Ranvier
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Saltatory conduction significantly facilitates...
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...conduction speed along axon
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Does nerve size matter?
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Size ALWAYS matters, duh ;)
a THIN axon will be blocked before a THICK one. |
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A solid LA block is deemed to be how many successful nodes?
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3
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Membranes are composed of a lot of stuff. Name some.
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Phospholipids
Other lipids Cholesterol Proteins Carbohydrates |
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Carbs are usually conjugated to other compounds as ____ and ____
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proteins and lipids
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What makes up > 1/3rd of the dry mass of nonmyelinated nerves?
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Proteins
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Where are most proteins located?
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At the membrane surface and affect membrane's ionic conductance or permeability
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Most ion channels are ____ w/complex ____ attached to _____ facing regions
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Glycoproteins
Carbs Extracellular |
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Nerve membranes are mainly...
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lipid bilayers encasing proteins
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Fluidity describes the rotational tumbling and flexing of...
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phospholipid fatty acyl groups
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Nerve lipids are somewhat ordered and behave as what?
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Fluid components w/in membrane interior
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Why does greater fluid motion occur in the center of a membrane?
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Phospholipid tails are the most fluid and have the least orientation near the center of the hydrocarbon region
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What is interdigitated among phospholipids in the membrane?
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Cholesterol
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What are 2 things cholesterol does?
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1. Influences behavior favoring parallel order of fatty acid chains of phospholipids
2. Reduces rotation of fatty acyl chains |
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Why do we care about all this membrane lipid bilayer crap?
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Because dynamics of lipids can affect...
-membrane partitioning -permeability of LA -LA access and orientation to target proteins w/in membrane |
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cell membranes are 'Capacitors' what does this mean?
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They are electrical insulators beetween 2 conducting ionic solutions which store electrical energy
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The insulating portion of membrane corresponds to...
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The hydrocarbon tails of phospholipids that fill core of the bilayer membrane
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Charged and polar ends of the lipids are at the membrane ______
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surface
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What is the 1st passive electrical property of nerves?
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Capacitance
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Capacitance is a function of what 2 things?
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1. Width of membrane
2. Dielectric constant of material in membrane interior |
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What is the 2nd passive electrical property of nerves?
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Resting membrane ionic permeability
Varies from nerve to nerve and between regions of the same nerve |
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Nerve impulses result from ____ ____ and selective ionic ______ changes in nerve membrane
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Ionic gradients (gradients are like batteries)
Selective ionic permeability changes in the nerve membrane (perm changes are like switches that permit current to flow) |
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What is the RMP of a NEURAL membrane?
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-70mV
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At resting (R) state, Na+ channels are _______
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closed
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Generation of an A.P is primarly d/t activation of _____-gated ____ channels...
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voltage-gated Na channels...therefore nerve stimulation occurs
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What membrane potential causes firing threshold?
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-55mV
Conformational changes occur in proteins of Na channels causing firing threshold |
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Peak AP gradient at the membrane is how many mV? What is the total mV change?
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+40mV
Average AP: -70mV to +40mV= 110mV change |
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What happens in the resting (R) state of a Na Channel?
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Membrane polarizes to its resting potential
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What happens in the open (O) state of a Na channel?
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Nerve is stimulated and membrane potential is reversed until threshold potential is reached
Conformational change in proteins that compromise channel |
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What happens in the inactive (I) state of a Na channel?
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Return of Na channel to impermeable state
Prevents initiation of AP and lasts until restoration of RMP |
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What is the irreversible method of conduction block?
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Severing the nerve or directly apply phenol or alcohol
(Used with end-stage CA pt's) |
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How do LAs reversibly produce a conduction block?
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Alter ion gradients across membrane
Disrupts impulse generation and propagation by blocking mem permeability to Na+, therefore interfering w/processes that generate an AP |
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What is the "locus of activity" of LAs?
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The Na+ channel of nerve membrane
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LA block is a ___________ block. Comparable to what?
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NONDEPOLARIZING block. Comparable to curare action at the NMJ.
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When Na+ enterance is denied, the axon remains in what state?
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Polarized resting "R" state
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LA must first ______ cell membrane before it can produce its effects. This is faciliated by what?
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Penetrate cell membrane
Facilitated if drug is uncharged or UN-ionized state |
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What is the modulated receptor hypothesis?
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States that affinity for specific protein receptor w/in Na+ channel changes as a fucntion of the conformational state of pore protein molecules blah blah blah...
Binding affinity INC in O and I states (bec prevents it from returning to resting state) Binding affinity DEC in R state |
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What hypothesis says that it is easier to block RAPIDLY firing nerves than slow nerves?
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Modulated Receptor Hypothesis
Why we see sensory blocks before motor blocks (sensation= rapidly firing nerves) |
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What is the guarded receptor hypothesis?
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Assumes binding affinity for protein rec is universal throughout all phases of Na channel kinetcis but access to binding sites altered
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Both the modulated rec hypotehsis and the Guarded rec hypothesis support what?
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Frequencty-dependent block
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What does freq-dependent block mean?
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Rapidly firing nerves are easier to block
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A use-dependent block is d/t what?
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Repeated stimulation
More channels to become drug-bound adn non-conducting |
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Cmin=
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lowest conc. of drug needed for blocking impulse propagation
comparable to MAC for inhaled anesthetics |
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Small diameter axons are grouped togetehr by non-myelinating Schwann cells into structures called ____ ____
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Remak bundles
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Are C fibers in Remak bundles hard or easy to block?
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Hard to block
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Cmin varies depending on what 3 things?
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1. pH (local)
2. temperature 3. Ca++ conc. of bathing solution |
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Once injected into tissue, Cmin varies depending on what 3 things?
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1. Drug movement away from site of action (inc CO-->inc uptake away from site)
2. Dilution 3. Systemic absorption and degredation (length of nerve fiber and ease at whcih LA can reach nerve membrane) |
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With a differential block, what is the order in which things are blocked?
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Loss of autonomic function first
Perception of superficial pain Touch Temperature Motor function Proprioception (last) |
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Peripheral nerves contain axons varying in what 4 categoreis?
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1. Function
2. Diameter 3. Myelination 4. Conduction velocity |
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Speed of conduction in compound action potential is proporitonal to what 2 things?
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Nerve diameter
Extent of myelination |
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Largest myelinated fibers (A) conduct at ____m/sec. Slower conduction velocity of (C) fibers at __-___m/sec
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A fibers: 120m/sec
C fibers: 1-2m/sec |
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A fibers...
Diameter: fast or slow? Heavily myelinated or unmyelinated? Conduction velocity: fast or slow? Responsible for what 2 responses? |
A fibers:
LARGEST diameter HEAVILY myelinated FASTEST conduction Responsible for motor function and proprioception |
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B fibers...
Conduction velocity? Myelination? Where are they located? |
B fibers:
Slwoer conduction velocity than A Less myelinated than A In pre-ganglionic autonomic nerves |
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C fibers...
Diameter? Conduction? Myelinated? Responsible for what? |
SMALLEST diameter
SLOWEST conduction UNmyelinated Responsible for pain and temp impulses |
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What fibers are more sensitive to block?
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C fibers, then B, then A
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___ fibers are ______
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C fibers are unmyelinated
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What is differntial blockade influenced by?
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Rate of diffusion across myelin sheath
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Clinical resistance to blockade in A-fibers may be d/t what?
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A slower osnet resulting from >diffusion barrier
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Diffusion of LA is influenced by what 3 thigns?
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1. pKa
2. Concentration of LA 3. pH of surrounding tissue and nerve fiber |
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What is Conduction Safety referring to?
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The voltage change needed for propagation of AP along nerve
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conduction safety is the ratio between...
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AP and critical membrane potential
Provides a margin of safety for transmission. Is greater in small, slow fibers than large, fast ones |
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What was the first LA to be discovered?
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Cocaine
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Who produced the 1st spinal block and described the 1st spinal headache?
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August Bier
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What came first, the ester or the amide?
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Ester
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Both Amide and Esters have three characteristic segments:
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1. Intermediate carbon group
2. Unsaturated (aromatic) ring system 3. Teritary amine |
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What are the two main ways amides are diff from esters?
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Metabolism is different
Esters cause allergies |
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What causes LA to be lipophilic?
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Its aromatic ring
Lipid-solubility correlates with potency |
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What provides hydrophilic characteristics of LAs?
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Its Tertiary or Quaternary amine
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Ester or Amide linkage binds ____ ____ to ____ ___
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Aromatic ring to carbon group
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Increased lipid solubility correlates with...
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INC protein binding
INC potency LONGER Doa INC risk of CV toxitiy |
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Amides are metabolized...
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in the liver
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Ester LAs are metabolized...
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by plasma cholinesterases
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All clinically used LA are ____ ____!!!
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WEAK BASES!!!
(proton acceptors) |
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pKa=
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pH at whcih ionized (quaternary) and UNionized (tertiary) portions are present in equal amounts
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What does the Henderson-Hasselbach Equation describe?
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How a given substance will dissolve at a given pH
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Basic LAs are:
highly ______ at ____ pH highly _____ at ____ pH |
Highly IONIZED at LOW pH
Highly UNIONIZED at HIGH pH |
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Ex:
Lido: pKa 7.9 Tetracaine: pKa 8.6 Which drug will h ave a faster onset? Why? |
Lido will have faster onset because less is ionized (about 65%, compared to Tetracaine that is 95% ionized)
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LAs work on the _______ side of the _____ channel
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INTRACELLULAR side of the Na+ channel
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What is the dominantly active form of an LA?
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The charged form
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As pKa approaches pH, more LA is found in _____ form
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Basic
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The more protein bound...
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the longer the DOA
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Most LAs have a TERTIARY amine, except what 2 drugs?
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Prilocaine uses a secondary amine (in EMLA cream)
Benzocaine uses a primary amine (Hurricaine spray) |
