Pharmacology and Action of Local Anesthetics Flashcards
how does nerve conduction happen?
- electrical gradient across cell membrane from Na+ ions outside, K+ inside = voltage gradient
- inside of cell: 70mV. nociceptor activation at nerve terminal causes voltage to rise in side the cell (become less negative)
- voltage gated Na+ channels open locally: Na+ flows down concentration gradient into cell and now inside of cell becomes positive
if Na+ channels can’t open up, then they can’t have transmission: this is how anesthetics work!
where does polarization and depolarization in myelinated nerves occur?
only happens in breaks in the myelin sheath: nodes of Ranvier. in between these nodes, the intracellular charge changes rapidly due to ion flow, so change in voltage happens much quicker
do anesthetics have a high affinity for the active or resting state?
active/inactive state! if there is no impulse traveling to muscles/nerves then local anesthetics don’t work bc don’t have affinity for receptor in that state
ropivicaine and lidocaine are what type of drug?
amides
how do all local anesthetics act by? (MOA?)
blocking Na+ influx thru VG Na+ channels on the cell membrane
- have to do this on inside of channel so have to cross membrane
- mix of ionized and unionized: local pH has an effect on intracellular availability of the drug!
how does pH affect local anesthetics?
- low pH (acidic) environment: less drug able to cross membrane, but increase in H+ will increase amt available for Na+ channel blockade
- also leads to trapping of local anesthetic in cell and make it unable to diffuse out = increased risk of cellular toxicity!!
how do you choose your local anesthetic?
expected duration of action, site of administration, patient characteristics
what is the maximum recommended dose of bupivacaine in a 5kg dog?
2mg/kg = 10mg in this 5kg dog
if using 0.5% bupivacaine, = total volume of 2mL
local anesthetics should/should not be mixed
should not be mixed (ie do not give lidocaine + bupivacaine) bc there is not
what is the exception of local anesthetics that can be mixed?
use of equal doses of 0.5% bupivacaine and liposomal encapsulated bupivacaine administered together: this results in a more dense early blockade, while keeping duration
ex of local anesthetics
lidocaine, mepivacaine, bupivacaine, ropivacaine, liposomal bupivacaine
how can you extend the duration of action of local anesthetics?
addition of a vasoconstrictor like epinephrine
contraindicated when blocking distal extremities bc of risk of ischemic necrosis
lidocaine parameters (routes/onset/duration)
PNB: 5-10 min, 60-120 duration
epidural: 5-15, 60-120 duration
spinal: 5-15, 30-90 duration
what is PNB?
peripheral nerve block
what are common additives to local anesthetics?
epinephrine, dexmedetomidine, buprenorphine
why do you add epinephrine in with local anesthetics?
- provides local vasoconstriction
- decreases rate of LA removal from area and increases the duration of action
when should epinephrine not be added to LA?
when intense vasoconstriction could cause local tissue ischemia: like distal fingers, nose, toes
why do you add dexmedetomidine in with LA?
- alpha 2 agonist: provides some local vasoconstriction, slows removal of LA
- have some intrinsic LA properties: expect 50-100% increase in duration of local anesthetics
why do you add buprenorphine in with LA?
- when added to bupivicaine, can increase duration of dental nerve blocks 3-4X!
- doesn’t happen in other nerve locations, so limited to maxillary/facial and mandibular/mental nerve blocks
what anatomic locations are buprenorphine additives LA used for?
only in the face: effect doesn’t happen in other nerve locations, so limited to maxillary/facial and mandibular/mental
when are steroids/NSAIDS added to LA?
steroids: improvement of chronic pain, no benefit for acute pain
NSAID: extend duration of local nerve blockade, esp meloxicam
what is LAST?
local anesthetic systemic toxicity
why is prevention of LAST important?
- LA toxicity has spectrum of adverse effects on nervous and CV systems
- not a lot of info known about risk factors and prevention
- need to know nature of local anesthetic toxicity as well as basic principles when administering LA
when is LA systemic toxicity seen? what is this toxic dose?
- CNS toxicity from LA generally seen prior to CV depression
- dose necessary for CVS toxicity is 2-4x dose that will demonstrate CNS toxicity
exception: amide LA bupivacaine: dose that produces CNS toxicity and dose that produces CVS toxicity are almost near equal; so may see CVS before CNS signs
what are signs of early CNS toxicity in the awake human?
auditory changes, circumoral numbness, metallic taste, agitation
rapidly progress to sedation, toxicity, muscle tremors, clonic-tonic seizures, and coma
what causes the CNS excitation in systemic toxicity from LA?
initial blockade of inhibitory pathways as well as stimulation of release of glutamate: stimulatory NT
further increase of dose in LA leads to inhibition of both inhibitory and excitatory neurons: causes excitatory phase to be followed by generalized CNS depression: coma and death
how does LA CVS toxicity manifest?
hypotension and dysrhythmias
hypotension: from myocardial depression, relaxation of sm mm, interruption of Sym outflow
hypotension is dose dependent and generally noted prior to complete CV collapse
when using LA, what system will show signs of a toxic dose first?
CNS toxicity will show first; dose for CVS toxicity is 2-4x the one that will show CNS signs
what species have the lowest tolerance to LA?
sheep, then rabbits, monkeys, cats, dog, mice
equine and bovine have toxicity at doses in between cats and dogs
what local anesthetics last the longest?
longest to shortest:
- liposomal bupivacaine
- bupivacaine
- ropivacaine
- mepivacaine
- lidocaine
procaine/chloroprocaine (human)
T/F: the toxic dose of a longer lasting LA like bupivacaine is 4x less than a shorter acting LA like lidocaine
true
what LA are better to use if you are concerned for seizures in a patient?
steroisomer LAs: ropivacaine, levobupivavaine: propensity for seizure activity is reduced by 1.5-2.5x than compared to racemic formulas: lidocaine, bupivacaine
T/F: larger doses and plasma concentrations of lidocaine and ropivacaine (racemic) are tolerated than that of bupivacaine and levobupivacaine. (stereoisomer)
true: this makes lidocaine and ropivacaine better suited for larger volumes and CRI
what LAs are better suited for larger volumes and CRI?
lidocaine and ropivacaine (racemic mixtures). also, minimal signs of CV toxicity have been noted after CNS toxicity occurs
what is the primary risk factor for LAST?
dose of local anesthetic!! drug concentration x volume administered
reduction of drug dose will decrease risk of LAST
how can you decrease the dose of a LA, thus reducing the risk for LAST?
electrolocation or US guided local analgesia: where close proximity of needle to nerve allows for lower total volumes of local anesthetic. where a large volume of LA is necessary, a reduction in concentration may be necessary: ex dilutions of ropivacaine or bupivacaine to 0.1% are effective when placed in close proximity to the nerves
T/F: systemic absorption is necessary for LAST
true
systemic absorption is necessary for LAST. what other factors are required for LAST to occur?
reduction in local blood flow and recognition that more absorption will occur in areas of increased flow
what is often added to local anesthetics? why?
epinephrine or other alpha 2s: for vasoconstriction and decrease systemic absorption of the LA
T/F: vasoconstrictors should not be added to LAs for proximal nerve blocks at increased risk of necrosis
FALSE: they should not be added for distal or peripheral nerve blocks! intense vasoconstriction may cause local or distal necrosis of the tissue due to decreased blood supply!
what can predispose a patient to LAST?
decrease in renal, hepatic, cardiac or pulmonary function
why will a decrease in renal/hepatic/cardiac/pulmonary function predispose a patient to LAST?
- first pass clearance thru lungs: clearance of LA
- liver/kidneys: decrease systemic concentration of LAs
- hepatic dysfunction will decrease extraction of LAs from blood
- decrease in plasma proteins made by liver (AAG) will increase free fraction of highly bound protein LAs like bupivacaine and ropivacaine and increase likelihood of LAST
- reduced renal clearance: increases plasma concentration of LAs + metabolites
what do you do when a pt needs LAs but has some sort of organ dysfunction?
decrease dose for continuous infusions when hepatic dysfx, decrease dose for single shot and continuous infusions with renal dysfx
how does CKD or hypertension affect LAs in the body? (these are very high CO states)
may increase absorption of LAs from peripheral sites and dose reduction is warranted
highly protein bound LAs are less affected by these states bc their clearance by liver is not flow limited
how can patient age affect systemic LA concentration?
pediatric patients have a lower CO and lower plasma protein concentrations: opposing factors that may override each other
geriatric patients are more likely to have decreased muscle mass and increased body fat, resulting in a larger volume of distribution and prolonged clearance of the more lipophilic LAs
how does general anesthesia affect outcomes for LAST?
- cited as risk factor, but not seen in pediatric studies
- in majority of studies it actually reduces incidence of LAST
- consequences noted will affect pharmacokinetics and possibility of LAST
^ hypercapnia increases cerebral blood flow, increasing amount of LA that is delivered to CNS
^ increase in PaCO2 causes more CO2 to diffuse out of cells: decreasing pH
how does hypercapnia and acidosis affect LAs?
decreases the plasma protein binding of LAs, which increases the proportion available to diffuse into the cells.
how do you prevent LAST?
- dose of LA minimized and adjusted for species
- if large volumes needed, administer incrementally to avoid chance of entire dose being given IV
- aspiration before each injection to indicate placement
- pt with hepatic dysfunction: dose reduced for continuous block by 10-20%
- pediatric and geriatric patients need dose reduction
- electrolocation and ultrasound guidance used to reduce dose of LA necessary
how do you treat LAST?
- supportive care
- seizures: give benzos
- hypotensive: drugs that give CV support
- should have a catheter!! difficult to get drugs in if seizing and dont have catheter
