Local Anesthetic Pharmacology Flashcards
3 ways that local anesthetics work are
Autonomic blockade
Somatic sensory blockade
Somatic motor blockade
Local ane sites of administration are?
- infiltrated around nerve
- applied to skin and mucous membranes
- Injected into subarachnoid and pleural space
- Injected into blood vessels..(Exsanguinated)
Membrane ion conc
Extracellular…sodium high/K low
Intracellular …potassium high/sodium low.
Ion Channels guarded by a gating mechanism- opens or closes depending on changing physiologic conditions
How is The Velocity an impulse travels proportional to the diameter of fibre
Directly proportional to fiber diameter.
the larger the diameter, the higher the conduction velocity
3 types of fibre are
A, B and C fibers
Explain A fibres
A fibers (myelinated) 1 to 22 microns Subdivided into: α β γ δ in order of decreasing size. alpha fibers are the fastest
Explain B fibres
B fibers (myelinated) 1 to 3 micrometers
Explain C fibres
C fibers (unmyelinated fibers) 0.1 to 2.5 micrometers slowest
PNS fibres comprise of ?
A-alpha fibers: motor & proprioception .
A-beta fibers: motor, touch, pressure
A- gamma fibers: motor/muscle tone (muscle spindle)
A-delta fibers: pain, temperature,touch
B-fibers: PREganglionic autonomic
C- fibers: dull pain, temperature, touch, POSTganglionic autonomic– NO MYELIN
the lower the size,the slower the conduction,the easiest to block
Characteristics of the fibers include
Fast and Slow pathways
Myelinated A-delta fibers (slowest of the A fibers)
Unmyelinated C fibers (much slower)
XXX Large fibers have the highest conduction velocity and the lowest threshold for excitability
How is the sensitivity of a PN to local Anesthesia related to size
The sensitivity of a peripheral nerve to LA is inversely related to size. That is why you see autonomic blockade first, sensory second and motor last
Fyi
In a laboratory…larger fibers A delta and gamma are actually more sensitive to local anesthetics than the C fibers which are unmyelinated and small
Factors that affect blockade in different nerve s
anatomic issues (larger nerves found deeper in nerve bundles – harder for the LA to reach) variable activity in different nerves (pain fibers fire at higher frequency)….i.e. frequency dependent blockade variable ion channel mechanisms
Motor nerves have larger spaces between their nodes
Autonomic more on the outside…
C fibres are on outside …so easier to block
A alpha needs more to get to it.
Faster or more firing may also increase rate of block
Frequency dependent blockade
Outer…mantle..
Check temp in comparative extremities. Like the toes…if one is colder..pls reposition or pull back catheter…remember autonomic blocked first.
How location affects the spread of local anesthetic
Outer surface of a peripheral nerve is known as the mantle (usually more proximal structures)
Inner surface known as core (these fibers usually serve more distal structures)
THE SEQUENCE OF ONSET AND RECOVERY FROM A LOCAL ANESTHETIC BLOCK IN A MIXED PERIPHERAL NERVE RELIES HEAVILY ON WHERE IT IS LOCATED
This factor is much more important than the inherent sensitivity of the nerve fiber to local anesthetics
What is the Clinical sequence of anesthesia:
1st- sympathetic block (vasodilatation, warm skin)
2nd – Loss pain and temperature sensation
3rd – Loss of proprioception
4th - Loss of touch and pressure
5th – Motor blockade
Mode of action nerve blockade
Voltage gated sodium channels in the inactivated-closed state serve as receptors for local anesthetic molecules
Local anesthetics bind at specific sites on the internal H gate of the channel & physically obstruct the external openings of the channels.
Local anesthetics prevent passage of sodium ions through these channels by binding and stabilizing them in the inactivated-closed conformational state
This blocks impulse conduction during the depolarization phase of the action potential.
prevent from reaching threshold.
can be compared to Inverse agonist.
myelination
Myelinated Nerve Fiber:
A Schwann-cell wraps itself around the axon several times, enveloping the axon in a myelin sheath…lipid insulating barrier
Unmyelinated Nerve Fiber:
A single Schwann cell surrounds several axons
Effects of Myelination on a nerve fibre
Decreasing resistance … increasing capacitance Difficult to assess at the myelin… Works at the node. Block 3 nodes to block a nerve Nerve fiber bigger….spaces get far apart.
Compare conduction btwn myelinated fibre and unmyelinated fibre
propagation of impulse is similar.
Unmyelinated fibers: impulses travel along the length of the fiber in a continuous fashion
Myelinated fibers, conduction is “saltatory”so fast (50X) that it appears as if impulses leap from one node of Ranvier (no myelin) to the next
How Does Frequency of cycling affect the rate of blockade
LA s easily access nerve cell Na channels in the “activated-open” state
LA’s easily bind to the receptor in the “inactivated-closed” state
The more frequently the nerve is in this state, (i.e. cycled through an action potential) the more rapidly blockade occurs
since Resting nerve is less sensitive to block than a repetitively stimulated nerve.What will determine the accessibility for block
Lipid solubility determines (i.e. it has to diffuse through the axonal membrane instead of through the Na channel to reach its target)
The higher the lipid solubility,the faster the block
How does the distance between nodes of ranvier and the size of a fibre affect the sensitivity of a fibre to a block.How can this be mitigated
Distance between Nodes of Ranvier in myelinated fibers contributes to differential nerve block
The internodal distance increases with fiber diameter
An impulse can make it through two blocked nodes but not a third
Blockade of three nodes (1cm) eliminates conduction along a myelinated nerve fiber (A fibers)
Explain differential block
Bupivacaine was the first local anesthetic shown to produce a beneficial differential block: Sensory block with incomplete motor block
Pain conducting fibers (A delta, C fibers) blocked
A alpha, beta, & gamma fibers not completely blocked
Patients feel pressure but not pain with surgical stimulation
Name the 2 main classifications of LA
and how the structure is arranged
Local anesthetics are classified chemically as aminoamides or aminoesters
The typical molecule consists of a lipophilic head (an aromatic ring), an intermediate chain containing either an amide (NH) or an ester (COO-)
and a hydrophilic tail (a tertiary amine).
BINDS better if it has a charge.
Analyze the difference in metabolism between Aminoamides and Aminoesters
Ester linkage: readily hydrolyzed by non-specific esterases in the plasma and tissues (mostly liver)
Faster hydrolysis
Cocaine exception…decreases norepi reuptake,,more Norepi in the SA node,hence tarchycardia
Cocaine decreases bleeding 2/2 to being great vasoconstrictor…monitor cardiac numbers for MI
Amide linkage: metabolized in the liver…slower …higher risk of toxicity
What is the variability in potency and DOA between Lipid soluble anesthetics and water soluble anesthetics per molecular structure.
Highly Lipid soluble anesthetics are more potent and have a longer duration of action than water soluble anesthetics.
Factors that affect toxicity and potentcy in the molecular structure.
Increase in the length of the intermediate chain (increase number of carbon atoms) increases potency and toxicity and alters metabolism rate and DOA
Potency and toxicity also increased with the length of the terminal groups located on the tertiary amine (tail) and aromatic ring
Enantiomers of a chiral drug may vary in terms of the pharmacokinetics, pharmacodynamics, and toxicity.
Ex. Bupivacaine (racemic) VS L-Bupivacaine(levo enantiomer)
FYI for block guide(CM)
Minimum Blocking Concentration
Nerve fiber diameter influence
Motor nerve higher Cm than sensory
Tissue pH,,acidic(infected tissue not good)
Onset level becomes very high
Frequency of nerve stimulation…faster block
Potency of particular LA…more potent..need less molecules
