Pharmacology and Action of Local Anesthetics

Question 1

how does nerve conduction happen?

Answer 1

• 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!

Question 2

where does polarization and depolarization in myelinated nerves occur?

Answer 2

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

Question 3

do anesthetics have a high affinity for the active or resting state?

Answer 3

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

Question 4

ropivicaine and lidocaine are what type of drug?

Answer 4

amides

Question 5

how do all local anesthetics act by? (MOA?)

Answer 5

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!

Question 6

how does pH affect local anesthetics?

Answer 6

• 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!!

Question 7

how do you choose your local anesthetic?

Answer 7

expected duration of action, site of administration, patient characteristics

Question 8

what is the maximum recommended dose of bupivacaine in a 5kg dog?

Answer 8

2mg/kg = 10mg in this 5kg dog
if using 0.5% bupivacaine, = total volume of 2mL

Question 9

local anesthetics should/should not be mixed

Answer 9

should not be mixed (ie do not give lidocaine + bupivacaine) bc there is not

Question 10

what is the exception of local anesthetics that can be mixed?

Answer 10

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

Question 11

ex of local anesthetics

Answer 11

lidocaine, mepivacaine, bupivacaine, ropivacaine, liposomal bupivacaine

Question 12

how can you extend the duration of action of local anesthetics?

Answer 12

addition of a vasoconstrictor like epinephrine
contraindicated when blocking distal extremities bc of risk of ischemic necrosis

Question 13

lidocaine parameters (routes/onset/duration)

Answer 13

PNB: 5-10 min, 60-120 duration
epidural: 5-15, 60-120 duration
spinal: 5-15, 30-90 duration

Question 14

what is PNB?

Answer 14

peripheral nerve block

Question 15

what are common additives to local anesthetics?

Answer 15

epinephrine, dexmedetomidine, buprenorphine

Question 16

why do you add epinephrine in with local anesthetics?

Answer 16

• provides local vasoconstriction
• decreases rate of LA removal from area and increases the duration of action

Question 17

when should epinephrine not be added to LA?

Answer 17

when intense vasoconstriction could cause local tissue ischemia: like distal fingers, nose, toes

Question 18

why do you add dexmedetomidine in with LA?

Answer 18

• 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

Question 19

why do you add buprenorphine in with LA?

Answer 19

• 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

Question 20

what anatomic locations are buprenorphine additives LA used for?

Answer 20

only in the face: effect doesn’t happen in other nerve locations, so limited to maxillary/facial and mandibular/mental

Question 21

when are steroids/NSAIDS added to LA?

Answer 21

steroids: improvement of chronic pain, no benefit for acute pain
NSAID: extend duration of local nerve blockade, esp meloxicam

Question 22

what is LAST?

Answer 22

local anesthetic systemic toxicity

Question 23

why is prevention of LAST important?

Answer 23

• 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

Question 24

when is LA systemic toxicity seen? what is this toxic dose?

Answer 24

• 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

Question 25

what are signs of early CNS toxicity in the awake human?

Answer 25

auditory changes, circumoral numbness, metallic taste, agitation rapidly progress to sedation, toxicity, muscle tremors, clonic-tonic seizures, and coma

Question 26

what causes the CNS excitation in systemic toxicity from LA?

Answer 26

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

Question 27

how does LA CVS toxicity manifest?

Answer 27

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

Question 28

when using LA, what system will show signs of a toxic dose first?

Answer 28

CNS toxicity will show first; dose for CVS toxicity is 2-4x the one that will show CNS signs

Question 29

what species have the lowest tolerance to LA?

Answer 29

sheep, then rabbits, monkeys, cats, dog, mice equine and bovine have toxicity at doses in between cats and dogs

Question 30

what local anesthetics last the longest?

Answer 30

longest to shortest: - liposomal bupivacaine - bupivacaine - ropivacaine - mepivacaine - lidocaine procaine/chloroprocaine (human)

Question 31

T/F: the toxic dose of a longer lasting LA like bupivacaine is 4x less than a shorter acting LA like lidocaine

Answer 31

true

Question 32

what LA are better to use if you are concerned for seizures in a patient?

Answer 32

steroisomer LAs: ropivacaine, levobupivavaine: propensity for seizure activity is reduced by 1.5-2.5x than compared to racemic formulas: lidocaine, bupivacaine

Question 33

T/F: larger doses and plasma concentrations of lidocaine and ropivacaine (racemic) are tolerated than that of bupivacaine and levobupivacaine. (stereoisomer)

Answer 33

true: this makes lidocaine and ropivacaine better suited for larger volumes and CRI

Question 34

what LAs are better suited for larger volumes and CRI?

Answer 34

lidocaine and ropivacaine (racemic mixtures). also, minimal signs of CV toxicity have been noted after CNS toxicity occurs

Question 35

what is the primary risk factor for LAST?

Answer 35

dose of local anesthetic!! drug concentration x volume administered reduction of drug dose will decrease risk of LAST

Question 36

how can you decrease the dose of a LA, thus reducing the risk for LAST?

Answer 36

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

Question 37

T/F: systemic absorption is necessary for LAST

Answer 37

true

Question 38

systemic absorption is necessary for LAST. what other factors are required for LAST to occur?

Answer 38

reduction in local blood flow and recognition that more absorption will occur in areas of increased flow

Question 39

what is often added to local anesthetics? why?

Answer 39

epinephrine or other alpha 2s: for vasoconstriction and decrease systemic absorption of the LA

Question 40

T/F: vasoconstrictors should not be added to LAs for proximal nerve blocks at increased risk of necrosis

Answer 40

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!

Question 41

what can predispose a patient to LAST?

Answer 41

decrease in renal, hepatic, cardiac or pulmonary function

Question 42

why will a decrease in renal/hepatic/cardiac/pulmonary function predispose a patient to LAST?

Answer 42

- 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

Question 43

what do you do when a pt needs LAs but has some sort of organ dysfunction?

Answer 43

decrease dose for continuous infusions when hepatic dysfx, decrease dose for single shot and continuous infusions with renal dysfx

Question 44

how does CKD or hypertension affect LAs in the body? (these are very high CO states)

Answer 44

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

Question 45

how can patient age affect systemic LA concentration?

Answer 45

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

Question 46

how does general anesthesia affect outcomes for LAST?

Answer 46

- 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

Question 47

how does hypercapnia and acidosis affect LAs?

Answer 47

decreases the plasma protein binding of LAs, which increases the proportion available to diffuse into the cells.

Question 48

how do you prevent LAST?

Answer 48

- 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

Question 49

how do you treat LAST?

Answer 49

- 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