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describe the structure of local anesthetics
there is a lipophilic group and a hydrophilic amine base that are joined together by EITHER an ester or an amide
Where do LAs bind?
to the inner pore of the VG Na+ channels
explain the affinity for the LA to the Na channel
Las have a higher affinity for the open (activated) and inactivated state than the closed (resting) state
Explain pKa, pH, and the LAs
an LA with a pKa closest to physiological pH → higher concentration of uncharged LA base passes through cell membrane → more rapid onset
What is the clinical correlate of the physicochemical characteristics of the LAs?
infected tissue has a low pH, thus LAs are less effective bc there is a lower concentration of uncharged base
Explain the use-dependent block of LAs
the blockade is more marked at higher frequencies of depolarization
(works better/more on firing axons than resting ones)
explain the state-dependent block
open (activated and inactivated) channel states have a higher affinity for the LA than the closed resting state
explain the voltage-dependent block
voltage changes cause changes in the conformation of the inner pore
higher frequency of stimulation and more positive membrane-potential cause a greater degree of anesthetic block
explain the time-dependent block
recovery from a drug-induced block is 10-1000x slower than recovery of channels from normal inactivation
explain the relationship between potency and lipid solubility
greater lipid solubility → greater affinity for the nerve cell membrane → greater fraction of drug gets in neuron → lower dose needed to get effect → more potent
overview:
more soluble = more potent
less soluble = less potent
a more potent LA has ______ and _____
slower onset and longer duration of action
what is the most potent LA?
tetracaine
describe the flow of the LA
uncharged form of LA passes through lipid bilayer to cytoplasm
in the cytoplasm equilibrium between charged and uncharged is re-established
the charged LA binds to the inner pore
sensitivity to blockade is determined by _____ and ____, along with other various factors
axonal diameter and degree of myelination
nerve fibers with a ____ diameter require lower concentration of drug
small diameter
____ fibers need exposure of at least ___ nodes of Ranvier to the LA for successful block
myelinated fibers; 3
explain the relationship between myelination of fibers and resistance/susceptibility to LAs
myelinated = more susceptible, less resistant
unmyelinated = less susceptible, more resistant
What is a bier block?
IV regional anesthesia (requires a torniquet to keep LA at site and not in systemic circulation)
the rate of distribution is proportionate to _____
vascularity at injection site
Explain the relationship between epinephrine and LAs
epinephrine is a vasoconstrictor so it decreases blood flow to the area which decreases the rate of absorption → higher concentration of LA at site of action and allows metabolism to keep pace with absorption (decreases toxicity)
What is the fastest and slowest route of admin?
intravenous = fastest
subcutaneous = slowest
explain the metabolism of ester-linked LAs
PABA
explain the metabolism of the amide-linked LAs
CYPs
Explain the first pass effect of LAs
highly perfused lungs metabolize or sequester significant amounts of circulating LA before it reaches the arterial circulation
What does LAST stand for?
local anesthetic systemic toxicity
LAST can be ____
fatal
What is the treatment for the systemic toxicities of the local anesthetics?
lipid rescue (because the LAs are lipophilic)
lipid sink or lipid shuttle
With _____ and ____ there is a high incidence of transient neurologic symptoms
lidocaine (most) and also mepivacaine
____ and ____ are associated with methemoglobinemia
prilocaine (toxic metabolite o-toluidine)
aerosol benzocaine (bronchoscopy or endoscopy)
Why is methemoglobinemia a concern?
this is when the hemoglobin is in a state where it doesn’t carry oxygen which can lead to cyanosis and even death
avoid ____ in teething infants and children’s mouth sores
benzocaine
What are the LAs commonly used in labor and delivery?
tetracaine, bupivacaine, ropivacaine, and lidocaine
“these bitches (the mothers <3) really like (the LAs)”
______ is associated with hypersensitivity reactions
ester metabolite PABA
What are the ester linked LAs?
Procaine, chloroprocaine, tetracaine, benzocaine, and cocaine
Which LA is used for spinal anesthesia? is it an ester or amide?
tetracaine; ester
Which LA is an intrinsic vasoconstrictor?
cocaine
Which LA has a very low pKa (3.5) and is highly lipophilic
benzocaine
What LA should be associated with hepatic metabolism to xylidide active metabolites?
lidocaine
What LA is associated with dental anesthesia?
mepivacaine
When you see o-toluidine you think ____ and _____
prilocaine (drug)
methemoglobinemia (adverse effect)
What is the most cardiotoxic of the LAs?
bupivacaine
What are the long-acting amide LAs?
bupivacaine and ropivacaine
