PDA III Exam 2 - Local Anesthetics - HM

what are local anesthetics

drugs applied locally to block transmission of nerve impulses

what is the intent of local anesthetics

to produce loss of sensation in a limited area

are local anesthetics reversible

yes and recovery is complete

do local anesthetics all have the same MOA

yes

PPA nociceptor

job of responding to pain stimuli (has different forms)

what is the g-protein coupled receptor for

acidic compounds

what are ion channels for

mechanical injuries and heat

what do local anesthetics inhibit

the function of Na+ channels

affinity of resting conformation

low to none

affinity of intermediate (between resting and active) conformation

high affinity; stops channel from opening

affinity of activated conformation

high affinity; binding results in blocking of the pore and decreased Na+ entry

affinity of inactivated conformation

highest affinity; binding results in stabilization of refractory conformation and prolonging of absolute refractory period

what do the different affinities for different conformations mean

the neuron cannot fire the pain stimulus APs and leads to a decrease in the frequency of APs

what type of neurons do local anesthetics favor

ones that are firing high frequency APs

how can the amine group of a local anesthetic exist

in either the protonated, charged form, or the deprotonated or base form

when do you have more amine groups in the charged form

at physiological pH because local anesthetics are weak bases

only the uncharged form of the amine group can do what

travel through the membrane, but need to moderate hydrophobicity for it to work

structure-activity relationship

either have an ester or an amide structure

what will the ester and amide structures always try to do

always try to reach an equilibrium between the protonated and unprotonated forms

what will increasing the partition coefficient of a local anesthetic do

increase its potency and protein binding, which in turn decreases the duration of action due to the binding which hold them at the site of action for a long period of time

what limits an anesthetic

its ability to diffuse away and get removed from the site of action by circulation

what does the rate of onset depend on

rate of diffusion which depends on ability to penetrate site (lipophilicity)

what can increase the rate of onset

increase in proportion of unionized form

local anesthetics are weak bases with a pKa of 8-10, so diffusion would be what

favored by alkaline conditions

infected tissues tend to what

have a lower pH which favors the charged form (makes local anesthetics less effective in infected tissues)

when bicarbonate is added to the anesthetic, what happens

raises the concentration of the un-ionized form and shorten onset block

loss of effect of anesthetics is due to what

the diffusion away from site of action and distribution away from site of action by the blood

local anesthetics may be given along with two other drugs, what are these drugs and why

epinephrine or phenylephrine; they vasoconstrict the area and reduce the ability of the blood to take up the local anesthetic, this increases the duration of action

local anesthetics tend to either vasodilate or have no effect on blood vessels, what are the two exceptions

cocaine and prilocaine

what are some long-acting local anesthetics

-bupivacine (amide)

-etidocaine (amide)

-tetracaine (ester)

what are some intermediate-acting local anesthetics

-lidocaine (amide)

-mepivicaine (amide)

-prilocaine (amide)

what are some short-acting local anesthetics

-cocaine (ester)

-procaine (ester)

-chloroprocaine (ester)

what are the esters metabolism

hydrolyzed by plasma esterases

the faster an ester is hydrolyzed...

the less systemic toxicity

metabolites of procaine are what

PABA-like and can cause allergic reactions

what are the amides metabolism

metabolized by liver enzymes

is it common to be allergic to amides

no, if there is a reaction check the preservatives first

systemic toxicity

absorption into the systemic circulation leads to toxicities

what can limit absorption

vasocontstrictor

which is less toxic, esters or amides

esters because they are hydrolyzed faster (amides require passage through the liver)

what happens if local anesthetics are highly protein bound

can limit free concentration in the plasma

what can happen to the CNS when systemic of local anesthetics happens

stimulation including tremors, nervousness, and seizures

why is systemic absorption of local anesthetics dangerous to the CNS

excitation is usually followed by coma and respiratory depression

what effect do local anesthetics have on the cardiovascular system

decrease the excitability and FOC of the heart and causes vasodilation

what treatments are there for local anesthetics in the systemic system

-maintaining breathing via ventilation and maintaining blood pressure with pressor agents

-may admin diazepam or thiopental to stop the seizures

what are some clinical uses of local anesthetics given systemically

-infiltration anesthesia (ID and SQ injections)

-IV regional anesthesia (rarely used because of toxicity risk; used with tourniquet-occluded limb)

-peripheral nerve blockade (injected near nerve bundle)

-central neural blockade (epidural or spinal)

-topical anesthesia

benzocaine

-very water insoluble

-presents very little chance of systemic absorption

-opens sores and wounds

eutectic mixture of local anesthetics (EMLA)

-lidocaine and prilocaine

-applied to skin and covered with dressing

-produces anesthesia in 30-60 minutes and then lasts ~1-2 hours